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Sample records for dose-adjusted epoch-rituximab da-epoch-r

  1. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy

    DEFF Research Database (Denmark)

    Sabers, A

    2012-01-01

    Sabers A. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2011.01627.x. © 2011 John Wiley & Sons A/S. Background -  Treatment with lamotrigine (LTG) during pregnancy is associated with a pronounced risk of seizure deterior......Sabers A. Algorithm for lamotrigine dose adjustment before, during, and after pregnancy. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2011.01627.x. © 2011 John Wiley & Sons A/S. Background -  Treatment with lamotrigine (LTG) during pregnancy is associated with a pronounced risk of seizure...

  2. Dose Adjustment- An Important Issue in Critical Care

    Directory of Open Access Journals (Sweden)

    Dr. M. C. Joshi

    2006-01-01

    Full Text Available There is at times marked variability in drug responsiveness especially in critically ill patients admitted in the Intensive care units. In order to obtain therapeutic effectiveness with in pharmacokinetic parameters related to therapeutic dose, it is always desirable to monitor and to maintain drug dose adjustment in such a way especially in presence of organ failure like renal failure, hepatic failure or any other clinical situation necessitating Therapeutic Drug Monitoring (TDM so that one can use safe and effective drug therapy with least toxicity due to inaccurate and invalid drug doses.

  3. Dose adjustment of carboplatin in patients on hemodialysis.

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    Guddati, Achuta K; Joy, Parijat S; Marak, Creticus P

    2014-03-01

    Carboplatin is one of the most prescribed cytotoxic drug, which is extensively used in the treatment regimens of several malignancies. The therapeutic efficiency of carboplatin has been found to correlate the area under curve (AUC). The Calvert formula has been extensively used to determine the dose of carboplatin for a fixed AUC and glomerular filtration rate (GFR). This formula has also been used in patients with end-stage renal disease on hemodialysis by assuming that the GFR is zero. This is applicable to patients who receive hemodialysis within 12-18 h after carboplatin infusion. After the first 24 h, a majority of the carboplatin is bound to proteins is not easily dialyzable and hence continues to remain in the blood stream despite repeated sessions of hemodialysis. We derive a correction factor to calculate the resultant AUC in such patients. The analysis done by using this correction factor shows that the AUC can increase by eightfold in patients who received the adjusted dose but whose hemodialysis was delayed beyond 24 h after infusion. The correction factor proposed here can also be used to calculate the dose adjustment required a priori in patients who may receive delayed hemodialysis. It is also useful to predict the AUC and estimate the resultant toxicity in such patients.

  4. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources.

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    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-09-09

    : Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX(®), UpToDate(®), Medscape(®) and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss' kappa coefficient was 0.265 for nephrotoxicity (p sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

  5. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

    Directory of Open Access Journals (Sweden)

    Millena Drumond Bicalho

    2015-09-01

    Full Text Available : Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319 and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401, indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

  6. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

    Science.gov (United States)

    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-01-01

    Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality. PMID:26371029

  7. Dose-adjusted Chemotherapy for Untreated c-MYC-positive Lymphoma

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    In this trial, adult patients with newly diagnosed Burkitt lymphoma or c-MYC-positive DLBCL will be separated into low-risk and high-risk groups; those in the low-risk group will be treated with at least three cycles of dose-adjusted EPOCH-R

  8. Dose Adjustment for Normal Eating: A Role for the Expert Patient?

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    Harold David McIntyre

    2014-04-01

    Full Text Available The Dose Adjustment for Normal Eating (DAFNE programme of intensive insulin therapy for type 1 diabetes provides a structured educational intervention to improve glycemic control, reduce hypoglycemia and improve quality of life. Enhancement of self-management skills is a key element of DAFNE and patients acquire detailed skills in insulin dose adjustment. Following DAFNE training, patients report improved confidence in their ability to manage their own insulin dosing, but generally still seek and require the assistance of health professionals when making substantial changes to their insulin regimens. Some DAFNE trained patients may be able to assist their peers in aspects of diabetes management within a group environment, but widespread introduction of the expert patient/peer educator role in the self-management of type 1 diabetes, in particular related to insulin dose management, would require formal and detailed evaluation, preferably in randomized controlled clinical trials, before being introduced into routine clinical practice.

  9. [Pharmacokinetic principles and drug-dosing adjustments during continuous renal replacement therapies (CRRT)].

    Science.gov (United States)

    Morabito, S; Guzzo, I; Vitaliano, E; Muzi, L; Solazzo, A; Pistolesi, V; Pierucci, A

    2006-01-01

    In the critically ill, acute renal failure (ARF) and "Multiple Organ Dysfunction Syndrome" (MODS) can be associated with significant modifications of many pharmacokinetic parameters, such as protein binding, volume of distribution and total body clearance. The start of renal replacement therapy (RRT) represents an additional variable to take in consideration for drug-dosing adjustments. Drugs significantly eliminated by the kidney are likely to be removed during RRT and a supplemental dose or further dosing adjustments are required if extracorporeal clearance is more than 25-30% of total body clearance. The impact of RRT on plasma drug concentrations can be substantially different in relation to the type of treatment (diffusive, convective or both), membrane characteristics (low-flux or high-flux), filter surface area and prescribed dialysis dose. The molecular weight cut-offs of high-flux membrane are much higher than the molecular weight of most drugs. Therefore, molecular size will not be a limitation for the removal of the unbound fraction of the drugs most commonly used in the critically ill undergoing continuous renal replacement therapy (CRRT). However, diffusive clearance could be significantly lower than convective clearance for drugs in the middle molecular weight range. In any case, the extracorporeal clearances report-ed with the use of high-volume CRRT (>50-60 L/2 h) are often surprisingly elevated and can lead to drug underdosing in clinical conditions where adequate antibiotic treatment is essential.

  10. Drug Dose Adjustment in Dialysis Patients Admitted in Clinics Other Than Internal Medicine.

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    Solak, Yalcin; Biyik, Zeynep; Gaipov, Abduzhappar; Kayrak, Mehmet; Ciray, Hilal; Cizmecioglu, Ahmet; Tonbul, Halil Zeki; Turk, Suleyman

    2016-01-01

    Many drugs that are administered during hospitalization are metabolized or excreted through kidneys, consequently require dosage adjustment. We aimed to investigate inappropriate prescription of drugs requiring renal dose adjustment (RDA) in various surgical and medical inpatient clinics. We retrospectively determined dialysis patients hospitalized between January 2007 and December 2010. Inpatient clinics, including cardiology, pulmonary medicine, neurology, infectious diseases (medical clinics) and cardiovascular surgery, orthopedics, general surgery, obstetrics and gynecology, and neurosurgery (surgical clinics), were screened via electronic database. Total and RDA medications were determined. RDA drugs correctly adjusted to creatinine clearance were labeled as RDA-A (appropriate), otherwise as RDA-I (inappropriate). Renal doses of RDA medications were based on the "American College of Physicians Drug Prescribing in Renal Failure, fifth Edition." Two hundred seventeen hospitalization records of 172 dialysis patients (92 men and 80 women) were included in the analysis. Mean age of patients was 59.4 ± 14.6 years, and the mean hospitalization duration was 8.5 ± 7.8 days. In total, 247 (84.3%, percentage in drugs requiring dose adjustment) and 175 (46.2%) drugs have been inadequately dosed in surgical and medical clinics, respectively. The percentage of patients to whom at least 1 RDA-I drug was ordered was 92% and 91.4% for surgical and medical clinics, respectively (P > 0.05). Nephrology consultation numbers were 8 (7.1%) in surgical and 32 (30.4%) in medical clinics. The most common RDA-I drugs were aspirin and famotidine. A significant portion of RDA drugs was ordered inappropriately both in surgical and medical clinics. Nephrology consultation rate was very low. Measures to increase physician awareness are required to improve results.

  11. Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

    Science.gov (United States)

    2016-08-24

    Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

  12. Effectiveness of pharmacist dosing adjustment for critically ill patients receiving continuous renal replacement therapy: a comparative study.

    Science.gov (United States)

    Jiang, Sai-Ping; Zhu, Zheng-Yi; Wu, Xiao-Liang; Lu, Xiao-Yang; Zhang, Xing-Guo; Wu, Bao-Hua

    2014-01-01

    The impact of continuous renal replacement therapy (CRRT) on drug removal is complicated; pharmacist dosing adjustment for these patients may be advantageous. This study aims to describe the development and implementation of pharmacist dosing adjustment for critically ill patients receiving CRRT and to examine the effectiveness of pharmacist interventions. A comparative study was conducted in an intensive care unit (ICU) of a university-affiliated hospital. Patients receiving CRRT in the intervention group received specialized pharmacy dosing service from pharmacists, whereas patients in the no-intervention group received routine medical care without pharmacist involvement. The two phases were compared to evaluate the outcome of pharmacist dosing adjustment. The pharmacist carried out 233 dosing adjustment recommendations for patients receiving CRRT, and 212 (90.98%) of the recommendations were well accepted by the physicians. Changes in CRRT-related variables (n=144, 61.81%) were the most common risk factors for dosing errors, whereas antibiotics (n=168, 72.10%) were the medications most commonly associated with dosing errors. Pharmacist dosing adjustment resulted in a US$2,345.98 ICU cost savings per critically ill patient receiving CRRT. Suspected adverse drug events in the intervention group were significantly lower than those in the preintervention group (35 in 27 patients versus [vs] 18 in eleven patients, Pdosing adjustment, which was 8.93 days vs 7.68 days (P=0.26) and 30.10% vs 27.36% (P=0.39), respectively. Pharmacist dosing adjustment for patients receiving CRRT was well accepted by physicians, and was related with lower adverse drug event rates and ICU cost savings. These results may support the development of strategies to include a pharmacist in the multidisciplinary ICU team.

  13. Effectiveness of pharmacist dosing adjustment for critically ill patients receiving continuous renal replacement therapy: a comparative study

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    Jiang SP

    2014-06-01

    Full Text Available Sai-Ping Jiang,1 Zheng-Yi Zhu,2 Xiao-Liang Wu,3 Xiao-Yang Lu,1 Xing-Guo Zhang,1 Bao-Hua Wu1 1Department of Pharmacy, the First Affiliated Hospital, 2Department of Pharmacy, Children’s Hospital, College of Medicine, Zhejiang University, Hangzhou, 3Intensive Care Unit, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China Background: The impact of continuous renal replacement therapy (CRRT on drug removal is complicated; pharmacist dosing adjustment for these patients may be advantageous. This study aims to describe the development and implementation of pharmacist dosing adjustment for critically ill patients receiving CRRT and to examine the effectiveness of pharmacist interventions. Methods: A comparative study was conducted in an intensive care unit (ICU of a university-affiliated hospital. Patients receiving CRRT in the intervention group received specialized pharmacy dosing service from pharmacists, whereas patients in the no-intervention group received routine medical care without pharmacist involvement. The two phases were compared to evaluate the outcome of pharmacist dosing adjustment. Results: The pharmacist carried out 233 dosing adjustment recommendations for patients receiving CRRT, and 212 (90.98% of the recommendations were well accepted by the physicians. Changes in CRRT-related variables (n=144, 61.81% were the most common risk factors for dosing errors, whereas antibiotics (n=168, 72.10% were the medications most commonly associated with dosing errors. Pharmacist dosing adjustment resulted in a US$2,345.98 ICU cost savings per critically ill patient receiving CRRT. Suspected adverse drug events in the intervention group were significantly lower than those in the preintervention group (35 in 27 patients versus [vs] 18 in eleven patients, P<0.001. However, there was no significant difference between length of ICU stay and mortality after pharmacist dosing adjustment, which

  14. Pharmacokinetics and drug dosing adjustments during continuous venovenous hemofiltration or hemodiafiltration in critically ill patients.

    Science.gov (United States)

    Bugge, J F

    2001-09-01

    Continuous renal replacement therapy (CRRT) in critically ill patients with renal failure may significantly increase drug clearance, requiring drug dosing adjustments. Drugs significantly eliminated by the kidney often undergo substantial removal during CRRT, and a supplemental dose corresponding to the amount of drug removed by CRRT should be administered. Clearance by CRRT can either be measured or estimated. The high-flux membranes used in CRRT make no filtration barrier to most drugs, and the filtrate concentration can be estimated by the unbound fraction of the drug in plasma. When adding dialysis to filtration, this approach overestimates drug clearance, and a correcting factor should be used. A method for estimating drug clearance as a function of creatinine clearance is also suggested, but it has the same limitations in overestimating drug clearance when dialysis is combined with filtration. For non-toxic drugs, doses can safely be increased 30% above actual estimates to ensure adequate dosing. For drugs with a narrow therapeutical margin, monitoring plasma concentrations are mandatory. When appropriate, the use of a readily available reference for drug dosing is recommended.

  15. Impact of pharmacist antimicrobial dosing adjustments in septic patients on continuous renal replacement therapy in an intensive care unit.

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    Jiang, Sai-Ping; Zhu, Zheng-Yi; Ma, Kui-Fen; Zheng, Xia; Lu, Xiao-Yang

    2013-12-01

    Correct dosing of antimicrobial drugs in septic patients receiving continuous renal replacement therapy (CRRT) is complex. This study aimed to evaluate the effects of dosing adjustments performed by pharmacists on the length of intensive care unit (ICU) stay, ICU cost, and antimicrobial adverse drug events (ADEs). A single-center, 2-phase (pre-/post-intervention) study was performed in an ICU of a university-affiliated hospital. Septic patients receiving CRRT in the post-intervention phase received a specialized antimicrobial dosing service from critical care pharmacists, whereas patients in the pre-intervention phase received routine medical care without involving pharmacists. The 2 phases were compared to evaluate the outcomes of pharmacist interventions. Pharmacists made 183 antimicrobial dosing adjustment recommendations for septic patients receiving CRRT. Changes in CRRT-related variables (116, 63.4%) were the most common risk factors for dosing errors, and β-lactams (101, 55.2%) were the antimicrobials most commonly associated with dosing errors. Dosing adjustments were related to a reduced length of ICU stay from 10.7 ± 11.1 days to 7.7 ± 8.3 days (p = 0.037) in the intervention group, and to cost savings of $3525 (13,463 ± 12,045 vs. 9938 ± 8811, p = 0.038) per septic patient receiving CRRT in the ICU. Suspected antimicrobial adverse drug events in the intervention group were significantly fewer than in the pre-intervention group (19 events vs. 8 events, p = 0.048). The involvement of pharmacists in antimicrobial dosing adjustments in septic patients receiving CRRT is associated with a reduced length of ICU stay, lower ICU costs, and fewer ADEs. Hospitals may consider employing clinical pharmacists in ICUs.

  16. NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation

    DEFF Research Database (Denmark)

    Barraclough, Katherine A; Isbel, Nicole M; Lee, Katie J

    2012-01-01

    , median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) μg·h/L/mg versus 15 (9, 24) μg·h/L/mg; P =0.0007]. Using multivariable logistic regression......, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele...... imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly...

  17. Dose Adjustment Strategy of Cyclosporine A in Renal Transplant Patients: Evaluation of Anthropometric Parameters for Dose Adjustment and C0 vs. C2 Monitoring in Japan, 2001-2010

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    Kokuhu, Takatoshi; Fukushima, Keizo; Ushigome, Hidetaka; Yoshimura, Norio; Sugioka, Nobuyuki

    2013-01-01

    The optimal use and monitoring of cyclosporine A (CyA) have remained unclear and the current strategy of CyA treatment requires frequent dose adjustment following an empirical initial dosage adjusted for total body weight (TBW). The primary aim of this study was to evaluate age and anthropometric parameters as predictors for dose adjustment of CyA; and the secondary aim was to compare the usefulness of the concentration at predose (C0) and 2-hour postdose (C2) monitoring. An open-label, non-randomized, retrospective study was performed in 81 renal transplant patients in Japan during 2001-2010. The relationships between the area under the blood concentration-time curve (AUC0-9) of CyA and its C0 or C2 level were assessed with a linear regression analysis model. In addition to age, 7 anthropometric parameters were tested as predictors for AUC0-9 of CyA: TBW, height (HT), body mass index (BMI), body surface area (BSA), ideal body weight (IBW), lean body weight (LBW), and fat free mass (FFM). Correlations between AUC0-9 of CyA and these parameters were also analyzed with a linear regression model. The rank order of the correlation coefficient was C0 > C2 (C0; r=0.6273, C2; r=0.5562). The linear regression analyses between AUC0-9 of CyA and candidate parameters indicated their potential usefulness from the following rank order: IBW > FFM > HT > BSA > LBW > TBW > BMI > Age. In conclusion, after oral administration, C2 monitoring has a large variation and could be at high risk for overdosing. Therefore, after oral dosing of CyA, it was not considered to be a useful approach for single monitoring, but should rather be used with C0 monitoring. The regression analyses between AUC0-9 of CyA and anthropometric parameters indicated that IBW was potentially the superior predictor for dose adjustment of CyA in an empiric strategy using TBW (IBW; r=0.5181, TBW; r=0.3192); however, this finding seems to lack the pharmacokinetic rationale and thus warrants further basic and clinical

  18. Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease.

    Science.gov (United States)

    Hassan, Yahaya; Al-Ramahi, Rowa' J; Aziz, Noorizan Abd; Ghazali, Rozina

    2009-10-01

    Appropriate drug selection and dosing for patients with chronic kidney disease (CKD) is important to avoid unwanted drug effects and ensure optimal patient outcomes. To assess the rate of inappropriate dosing in patients with CKD in a nephrology unit and to evaluate the impact on dose adjustment, adverse drug events (ADEs), and drug cost of having a pharmacist accompany a team of physicians on their rounds. This was a comparative study with a preintervention and postintervention design. The preintervention phase served as the control; it was prospective and observational only and was conducted from the beginning of February to the end of May 2007. The second phase (intervention phase) was conducted from the beginning of March to the end of June 2008. Two random samples of 300 patients with an estimated creatinine clearance less than or equal to 50 mL/min were included. During the intervention phase, a clinical pharmacist made rounds with the nephrology unit team and gave dosing adjustment recommendations when needed. A collection of reliable and up-to-date drug information references that are commonly used globally were used during the intervention. In the preintervention group, drug dosage adjustment or avoidance, based on renal function, was necessary in 607 of 2814 (21.6%) prescriptions. Of these, 322 (53.0%) did not comply with guidelines. In the intervention group, adjustment was necessary for 640 of 2981 (21.5%) prescriptions. The pharmacist made 388 recommendations related to dosing adjustment, 212 (54.6%) of which were accepted by physicians. Clinicians' noncompliance with dosing guidelines decreased to 176 (27.5%) (p < 0.001). In the preintervention group, 64 (21.3%) patients had a suspected ADE, with a total of 73 events. In the intervention group, this number was significantly lower with 49 events in 48 (16.0%) patients (p < 0.05). The intervention resulted in drug cost savings of $2250 US. A renal drug dosing service for patients hospitalized with CKD

  19. Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy.

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    Chiesa, Robert; Cappelli, Barbara; Crocchiolo, Roberto; Frugnoli, Ilaria; Biral, Erika; Noè, Anna; Evangelio, Costanza; Fossati, Marco; Roccia, Tito; Biffi, Alessandra; Finizio, Valentina; Aiuti, Alessandro; Broglia, Monica; Bartoli, Antonella; Ciceri, Fabio; Roncarolo, Maria Grazia; Marktel, Sarah

    2010-05-01

    beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease. Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  20. Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience

    Science.gov (United States)

    Hirano, Ryuichi; Sakamoto, Yuichi; Kitazawa, Junichi; Yamamoto, Shoji; Tachibana, Naoki

    2016-01-01

    Background Vancomycin (VCM) requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP) on attaining target VCM trough concentrations and pharmacokinetics (PK)/pharmacodynamics (PD) parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Materials and methods The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation) and from April 2012 to December 2014 (postimplementation), 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51). In 65 patients (pre, n=15; post, n=50), 24-hour area under the concentration–time curve (AUC 0–24 h)/minimum inhibitory concentration (MIC) ratios were calculated. Results Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33). The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL) was significantly higher during postimplementation (84%, 43/51) than during preimplementation (39%, 11/28) (P400) was significantly higher during postimplementation (84%, 42/50) than during preimplementation (53%, 8/15; P=0.013). There were no significant differences in nephrotoxicity or mortality rate. Conclusion Our ASP increased the percentage of patients that attained optimal VCM trough concentrations and PK/PD parameters, which contributed to the appropriate use of VCM in patients with MRSA infections. PMID:27789965

  1. Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience

    Directory of Open Access Journals (Sweden)

    Hirano R

    2016-10-01

    Full Text Available Ryuichi Hirano,1 Yuichi Sakamoto,2 Junichi Kitazawa,2 Shoji Yamamoto,1 Naoki Tachibana2 1Department of Pharmacy, 2Laboratory Medicine and Blood Transfusion, Aomori Prefectural Central Hospital, Aomori-shi, Japan Background: Vancomycin (VCM requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP on attaining target VCM trough concentrations and pharmacokinetics (PK/pharmacodynamics (PD parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA infections. Materials and methods: The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation and from April 2012 to December 2014 (postimplementation, 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51. In 65 patients (pre, n=15; post, n=50, 24-hour area under the ­concentration–time curve (AUC 0–24 h/minimum inhibitory concentration (MIC ratios were calculated. Results: Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33. The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL was significantly higher during postimplementation (84%, 43/51 than during preimplementation (39%, 11/28 (P<0.01. The percentage of patients who attained target PK/PD parameters (AUC 0–24 h/MIC >400 was significantly higher during postimplementation (84%, 42/50 than during preimplementation (53%, 8/15; P=0.013. There were

  2. Dose Adjustment of the Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) during Concurrent Rifampicin-Containing Tuberculosis Therapy: One Size does not Fit All

    Science.gov (United States)

    Kwara, Awewura; Ramachandran, Geetha; Swaminathan, Soumya

    2009-01-01

    Importance of the field HIV/TB coinfection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy (HAART) during TB treatment is associated with substantial survival benefit but drug-drug interactions complicate NNRTI dosing. Areas covered in this review We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. Pub Med database was searched from 1966 to July 2009, using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed. What the reader will gain A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies controlled for genetic factors and there was limited data on children. Take home message There was insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug-gene interactions. PMID:19968575

  3. Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

    Science.gov (United States)

    Treluyer, Jean-Marc; Illamola, Silvia M.; Pressiat, Claire; Lui, Gabrielle; Valade, Elodie; Mandelbrot, Laurent; Lechedanec, Jerome; Delmas, Sandrine; Blanche, Stéphane; Warszawski, Josiane; Urien, Saik; Tubiana, Roland; Hirt, Déborah

    2015-01-01

    The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy. PMID:26149996

  4. The Diabeo Software Enabling Individualized Insulin Dose Adjustments Combined With Telemedicine Support Improves HbA1c in Poorly Controlled Type 1 Diabetic Patients

    Science.gov (United States)

    Charpentier, Guillaume; Benhamou, Pierre-Yves; Dardari, Dured; Clergeot, Annie; Franc, Sylvia; Schaepelynck-Belicar, Pauline; Catargi, Bogdan; Melki, Vincent; Chaillous, Lucy; Farret, Anne; Bosson, Jean-Luc; Penfornis, Alfred

    2011-01-01

    OBJECTIVE To demonstrate that Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support significantly improves HbA1c in poorly controlled type 1 diabetic patients. RESEARCH DESIGN AND METHODS In a six-month open-label parallel-group, multicenter study, adult patients (n = 180) with type 1 diabetes (>1 year), on a basal-bolus insulin regimen (>6 months), with HbA1c ≥8%, were randomized to usual quarterly follow-up (G1), home use of a smartphone recommending insulin doses with quarterly visits (G2), or use of the smartphone with short teleconsultations every 2 weeks but no visit until point end (G3). RESULTS Six-month mean HbA1c in G3 (8.41 ± 1.04%) was lower than in G1 (9.10 ± 1.16%; P = 0.0019). G2 displayed intermediate results (8.63 ± 1.07%). The Diabeo system gave a 0.91% (0.60; 1.21) improvement in HbA1c over controls and a 0.67% (0.35; 0.99) reduction when used without teleconsultation. There was no difference in the frequency of hypoglycemic episodes or in medical time spent for hospital or telephone consultations. However, patients in G1 and G2 spent nearly 5 h more than G3 patients attending hospital visits. CONCLUSIONS The Diabeo system gives a substantial improvement to metabolic control in chronic, poorly controlled type 1 diabetic patients without requiring more medical time and at a lower overall cost for the patient than usual care. PMID:21266648

  5. Impact of β-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

    Science.gov (United States)

    Economou, Caleb J P; Wong, Gloria; McWhinney, Brett; Ungerer, Jacobus P J; Lipman, Jeffrey; Roberts, Jason A

    2017-05-01

    The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of β-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). β-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered β-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of β-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of β-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. β-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive β-lactam concentrations. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  6. Characteristics and Determinants of Partial Remission in Children with Type 1 Diabetes Using the Insulin-Dose-Adjusted A1C Definition

    Directory of Open Access Journals (Sweden)

    Aurore Pecheur

    2014-01-01

    Full Text Available To evaluate the characteristics and determinants of partial remission (PR in Belgian children with type 1 diabetes (T1D, we analyzed records of 242 children from our center. Clinical and biological features were collected at diagnosis and during follow-up. PR was defined using the insulin-dose-adjusted A1C definition. PR occurred in 56.2% of patients and lasted 9.2 months (0.5 to 56.6. 25.6% of patients entered T1D with DKA, which correlated with lower PR incidence (17.6% versus 82.3% when no DKA. In our population, lower A1C levels at diagnosis were associated with higher PR incidence and in young children (0–4 years initial A1C levels negatively correlated with longer PR. Early A1C levels were predictive of PR duration since 34% of patients had long PRs (>1 year when A1C levels were ≤6% after 3 months whereas incidence of long PR decreased with higher A1Cs. C-peptide levels were higher in patients entering PR and remained higher until 3 years after diagnosis. Initial antibody titers did not influence PR except for anti-IA2 titers that correlated with A1C levels after 2 years. Presence of 2 versus 1 anti-islet antibodies correlated with shorter PR. PR duration did not influence occurrence of severe hypoglycemia or diabetes-related complications but was associated with lower A1C levels after 18 months. We show that, at diagnosis of T1D, parameters associated with β-cell mass reserve (A1C, C-peptide, and DKA correlate with the occurrence of PR, which affects post-PR A1C levels. Further research is needed to determine the long-term significance of PR.

  7. Recurrent Hospitalization Among Patients With Atrial Fibrillation Undergoing Intracoronary Stenting Treated With 2 Treatment Strategies of Rivaroxaban or a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy

    Science.gov (United States)

    Pinto, Duane S.; Chi, Gerald; Arbetter, Douglas; Yee, Megan; Mehran, Roxana; Bode, Christoph; Halperin, Jonathan; Verheugt, Freek W.A.; Wildgoose, Peter; Burton, Paul; van Eickels, Martin; Korjian, Serge; Daaboul, Yazan; Jain, Purva; Lip, Gregory Y.H.; Cohen, Marc; Peterson, Eric D.; Fox, Keith A.A.

    2017-01-01

    Background: Patients with atrial fibrillation who undergo intracoronary stenting traditionally are treated with a vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT), yet this treatment leads to high risks of bleeding. We hypothesized that a regimen of rivaroxaban plus a P2Y12 inhibitor monotherapy or rivaroxaban plus DAPT could reduce bleeding and thereby have a favorable impact on all-cause mortality and the need for rehospitalization. Methods: Stented subjects with nonvalvular atrial fibrillation (n=2124) were randomized 1:1:1 to administration of reduced-dose rivaroxaban 15 mg daily plus a P2Y12 inhibitor for 12 months (group 1); rivaroxaban 2.5 mg twice daily with stratification to a prespecified duration of DAPT of 1, 6, or 12 months (group 2); or the reference arm of dose-adjusted VKA daily with a similar DAPT stratification (group 3). The present post hoc analysis assessed the end point of all-cause mortality or recurrent hospitalization for an adverse event, which was further classified as the result of bleeding, a cardiovascular cause, or another cause blinded to treatment assignment. Results: The risk of all-cause mortality or recurrent hospitalization was 34.9% in group 1 (hazard ratio=0.79; 95% confidence interval, 0.66–0.94; P=0.008 versus group 3; number needed to treat=15), 31.9% in group 2 (hazard ratio=0.75; 95% confidence interval, 0.62–0.90; P=0.002 versus group 3; number needed to treat=10), and 41.9% in group 3 (VKA+DAPT). Both all-cause death plus hospitalization potentially resulting from bleeding (group 1=8.6% [P=0.032 versus group 3], group 2=8.0% [P=0.012 versus group 3], and group 3=12.4%) and all-cause death plus rehospitalization potentially resulting from a cardiovascular cause (group 1=21.4% [P=0.001 versus group 3], group 2=21.7% [P=0.011 versus group 3], and group 3=29.3%) were reduced in the rivaroxaban arms compared with the VKA arm, but other forms of rehospitalization were not. Conclusions: Among patients with

  8. Simulation of the impact of rifampicin on darunavir/ritonavir PK and dose adjustment strategies in HIV-infected patients: a population PK approach

    Directory of Open Access Journals (Sweden)

    Laura Dickinson

    2014-11-01

    Full Text Available Introduction: Treatment of HIV/TB co-infection is challenging due to high drug–drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF. The PK interaction between darunavir/ritonavir (DRV/RTV and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV/RTV PK and generate alternative dosing strategies to aid future clinical trial design. Materials and Methods: A previously developed model describing DRV/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV/RTV 800/100 mg (n=32 or 900/100 mg once daily (qd; n=19 (1. The PK interaction between DRV/RTV and RIF was assumed to mimic that observed in HIV-infected, TB negative patients receiving lopinavir (LPV/RTV (n=21 (2. Simulations of DRV/RTV 800/100 mg qd (n=1000 were performed (-RIF. The model was adapted to increase the typical value of apparent oral clearance (CL/F by 71% and 36% and decrease relative bioavailability (F by 20% and 45% for DRV and RTV, respectively (2; 1000 simulations were generated (+RIF. Dose adjustments of DRV/RTV 1200/200 mg qd, 800/100 mg and 1200/150 mg twice daily (bid were simulated to overcome the interaction. DRV trough (Ctrough for each dosing scenario was compared to the reference (-RIF by GMR (90% CI. Results: DRV and RTV were described by a 1 and 2-compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL/F, best described the relationship between the drugs. Compared to the reference (-RIF, simulated DRV Ctrough was 70%, 46% and 20% lower for 800/100 mg qd, 1200/200 mg qd and 800/100 mg bid all +RIF, respectively. Ctrough was 38% higher with 1200/150 mg bid +RIF (Table 1. Conclusions: Modelling and simulation was used to investigate the theoretical impact of RIF on DRV/RTV PK. Based on simulations, 800/100 mg and 1200/150 mg both bid could largely overcome the impact of the

  9. Chemotherapy dose adjustment for obese patients undergoing hematopoietic stem cell transplantation: a survey on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

    Science.gov (United States)

    Shem-Tov, Noga; Labopin, Myriam; Moukhtari, Leila; Ciceri, Fabio; Esteve, Jordi; Giebel, Sebastian; Gorin, Norbert-Claude; Schmid, Christopher; Shimoni, Avichai; Nagler, Arnon; Mohty, Mohamad

    2015-01-01

    Appropriate chemotherapy dosing for obese patients with malignant diseases is a significant challenge because limiting chemotherapy doses in these patients may negatively influence outcome. There is a paucity of information addressing high-dose chemotherapy in obese patients undergoing hematopoietic stem cell transplantation (HSCT). The Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) designed an electronic survey to assess current practice of dose adjustment of chemotherapy in obese patients undergoing HSCT. A total of 56 EBMT centers from 27 countries responded to the online survey. Overall, 45 centers declared that they routinely adjust chemotherapy doses for obese patients (80.5%), and only 11 (19.5%) declared they do not adjust dose. Among the former group, most used body mass index as the parameter for defining obesity (28 centers, 62%). The method for determining the weight for chemotherapy calculation was actual body weight (ABW) in 16 centers, ideal body weight (IBW) in 10 centers, IBW plus 25% of the difference between IBW and ABW in 16 centers, and other methods for the rest. Among centers that used dose adjustment, 44% also capped the dose at 2 m(2) for a chemotherapy dose based on body surface area (BSA), whereas 56% did not cap. Interestingly, most of the centers (9 of 11) that did not adjust dose for weight also did not cap the BSA at 2 m(2). This EBMT survey revealed large diversity among transplant centers regarding dose-adjustment practice for high-dose conditioning chemotherapy. Our next step is to analyze outcomes of transplantation according to dose-adjustment practice and, subsequently, to formulate a methodology for future prospective studies. ©AlphaMed Press.

  10. Effects of exogenous human insulin dose adjustment on body mass index in adult patients with type 1 diabetes mellitus at Kalafong Hospital, Pretoria, South Africa, 2009 - 2014.

    Science.gov (United States)

    Sehloho, Tohlang Solomon A; Van Zyl, Danie G

    2017-05-24

    To maintain fasting blood glucose levels within near to the normal range in type 1 diabetes mellitus (DM), frequent insulin dose adjustments may be required with short-, intermediate- and long-acting insulin formulations. Patients on human insulin generally experience weight gain over time, regardless of the level of glycaemic control achieved. To determine the effects of human insulin, adjusted quarterly to achieve glycaemic control, on body mass index (BMI), and establish dose regimens that achieve optimal glycaemic control without increasing BMI in patients with type 1 DM at the Kalafong Diabetes Clinic in Pretoria, South Africa. The sample size (N=211, 48.8% male) was obtained by non-probability convenience sampling of all available records of patients with type 1 DM aged ≥18 years at baseline at the clinic. The longitudinal relationships of covariates with time-varying BMI, as well as with time-varying glycated haemoglobin (HbA1c) levels, were explored using multilevel mixed-effects linear regression modelling. The majority of the patients (84.8%) received the twice-daily biphasic human insulin regimen and the remainder received the basal neutral protamine Hagedorn (NPH) plus prandial regular human insulin regimen. The multivariable multilevel mixed-effects linear regression model indicated that time-varying BMI was significantly positively related to time-varying twice-daily biphasic insulin dosage (β (standard error) 0.464 (0.190), p=0.015), baseline HbA1c (0.092 (0.026), p<0.001) and baseline BMI (0.976 (0.016), p<0.001). There were significant inverse associations with the number of years spent in the study (-0.108 (0.052), p=0.038), time-varying HbA1c (-0.154 (0.031), p<0.001) and male sex (-0.783 (0.163), p<0.001). There were non-significant negative longitudinal associations of age (-0.005 (0.006), p=0.427) and current smoking status (-0.231 (0.218), p=0.290) with BMI outcomes. There was no evidence that optimal quarterly-prescribed daily dosage

  11. Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation.

    Science.gov (United States)

    Menting, Stef P; Dekker, Paul M; Limpens, Jacqueline; Hooft, Lotty; Spuls, Phyllis I

    2016-01-01

    There is a range of methotrexate dosing regimens for psoriasis. This review summarizes the evidence for test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and use of folic acid. A literature search for randomized controlled trials and guidelines was performed. Twenty-three randomized controlled trials (29 treatment groups) and 10 guidelines were included. Two treatment groups used a test-dose, 5 guidelines recommend it. The methotrexate start-dose in randomized controlled trials varied from 5 to 25 mg/week, most commonly being either 7.5 mg or 15 mg. Guidelines vary from 5 to 15 mg/week. Methotrexate was administered as a single dose or in a Weinstein schedule in 15 and 11 treatment-groups, respectively; both recommended equally in guidelines. A fixed dose (n = 18), predefined dose (n = 3), or dose adjusted on clinical improvement (n = 8) was used, the last also being recommended in guidelines. Ten treatment groups used folic acid; in 2 it was allowed, in 14 not mentioned, and in 3 no folic acid was used. Most guidelines recommend the use of folic acid. Authors' suggestions for methotrexate dosing are given.

  12. Phenytoin dose adjustment in epileptic patients.

    Science.gov (United States)

    Mawer, G E; Mullen, P W; Rodgers, M; Robins, A J; Lucas, S B

    1974-04-01

    1 A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 μg/ml). A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient. 2 Fifteen patients were each given an oral test dose of 600 mg phenytoin sodium and the serum concentration of phenytoin was measured at intervals over 48 h; the concentration rose during the first 4 h and decayed between 12-48 h as an almost linear function of time. 3 The serum concentration/time curves were fitted by an interative computer program based on the Michaelis-Menten equation. The mean saturated rate of elimination of phenytoin was 435 mg/day and the serum concentration (K(m)) corresponding with 50% saturation was 3.8 μg/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 μg/ml was 345-400 mg/day. 4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 μg/ml it is then appropriate to adjust dose by small steps of about 25 mg.

  13. A longitudinal qualitative study examining the factors impacting on the ability of persons with T1DM to assimilate the Dose Adjustment for Normal Eating (DAFNE principles into daily living and how these factors change over time

    Directory of Open Access Journals (Sweden)

    White Florence

    2011-08-01

    Full Text Available Abstract Background The literature reveals that structured education programmes, such as DAFNE, result in many positive outcomes for people with Type 1 diabetes including a decrease in HbA1c levels and reductions in hypoglycaemia. While there is evidence that some of these outcomes are maintained we do not know at present what factors are most important over time. The study aim was to identify the key factors impacting on persons with Type 1 diabetes ability to assimilate the Dose Adjustment For Normal Eating (DAFNE DAFNE principles into their daily lives and how these factors change over time. Methods This is a longitudinal descriptive qualitative study. Interviews were undertaken with 40 participants who had attended DAFNE in one of 5 study sites across the Island of Ireland, at 6 weeks, 6 and 12 months after completion of the programme. The interviews lasted from 30 to 60 minutes and were transcribed verbatim. Data were analysed in three ways, a within time analysis, a cross sectional analysis for each participant and a thematic analysis which focused on examining changes over time Results Four themes that influenced participants' ability to assimilate DAFNE into their daily lives over time were identified. These were: embedded knowledge, continued responsive support, enduring motivation and being empowered. Support at the 6 month period was found to be crucial to continued motivation. Conclusions Understanding the factors that influence people's ability to assimilate DAFNE principles over time into their daily lives can help health professionals give focused responsive support that helps people with diabetes become more empowered. Understanding that continued support matters, particularly around 6 months, is important as health professionals can influence good management by providing appropriate support and enhancing motivation. Trial registration ISRCTN79759174

  14. A longitudinal qualitative study examining the factors impacting on the ability of persons with T1DM to assimilate the Dose Adjustment For Normal Eating (DAFNE) principles into daily living and how these factors change over time

    LENUS (Irish Health Repository)

    Casey, Dympna

    2011-08-30

    Abstract Background The literature reveals that structured education programmes, such as DAFNE, result in many positive outcomes for people with Type 1 diabetes including a decrease in HbA1c levels and reductions in hypoglycaemia. While there is evidence that some of these outcomes are maintained we do not know at present what factors are most important over time. The study aim was to identify the key factors impacting on persons with Type 1 diabetes ability to assimilate the Dose Adjustment For Normal Eating (DAFNE) DAFNE principles into their daily lives and how these factors change over time. Methods This is a longitudinal descriptive qualitative study. Interviews were undertaken with 40 participants who had attended DAFNE in one of 5 study sites across the Island of Ireland, at 6 weeks, 6 and 12 months after completion of the programme. The interviews lasted from 30 to 60 minutes and were transcribed verbatim. Data were analysed in three ways, a within time analysis, a cross sectional analysis for each participant and a thematic analysis which focused on examining changes over time Results Four themes that influenced participants\\' ability to assimilate DAFNE into their daily lives over time were identified. These were: embedded knowledge, continued responsive support, enduring motivation and being empowered. Support at the 6 month period was found to be crucial to continued motivation. Conclusions Understanding the factors that influence people\\'s ability to assimilate DAFNE principles over time into their daily lives can help health professionals give focused responsive support that helps people with diabetes become more empowered. Understanding that continued support matters, particularly around 6 months, is important as health professionals can influence good management by providing appropriate support and enhancing motivation. Trial registration ISRCTN79759174

  15. Perspective research of preliminarily diagnosed angioimmunoblastic T-cell lymphoma with dose-adjusted EPOCH regimen%剂量调整的EPOCH方案治疗初治血管免疫母T细胞淋巴瘤的前瞻性研究

    Institute of Scientific and Technical Information of China (English)

    仲凯励; 苏航; 肖秀斌; 刘静; 鲁云; 陈喜林; 达永; 路春蕾; 张伟京

    2014-01-01

    Objective:The effect and side effect of the dose-adjusted EPOCH regimen were evaluated perspectively for the pre-liminarily diagnosed angioimmunoblastic T-cell lymphoma. Methods: Nine cases of untreated angioimmunoblastic T-cell lymphoma were diagnosed and enrolled in our department from September 2008 to September 2012. All patients received dose-adjusted EPOCH regimen as first-line chemotherapy. Results: The median age of 9 patients was 54 years. The male-to-female ratio was 2∶1. About 88.9%of all patients were at Ann Arbor stageⅢ/Ⅳ, and 77.8%presented with B symptoms. Anemia was found in 66.7%of 9 patients, and lactate dehydrogenase elevated in 55.6%of patients. After an average of 4.7 cycles of chemotherapy of dose-adjusted EPOCH regi-men, the complete remission rate was 22.2%, and the total response rate was 66.7%. With a median follow-up of 20 months, the 4-year progression-free survival rate was 11.1%, and the overall survival rate was 33.3%. The median survival time was 19 months. The most common adverse events of EPOCH chemotherapy were hematologic toxicity. Grades 3-4 neutropenia and thrombocytopenia were re-ported in 77.8%and 33.3%of patients. Febrile neutropenia was observed in 44.4%of patients. Non-treatment-related mortality was al-so noted. Conclusion: The results of our research showed no clear benefit of treating preliminarily diagnosed angioimmunoblastic T-cell lymphoma with dose-adjusted EPOCH regimen. The main adverse events were hematologic toxicity and could be tolerated.%目的:前瞻性研究剂量调整的EPOCH方案对初治血管免疫母T细胞淋巴瘤(AITL)患者的疗效及不良反应。方法:选择2008年9月至2012年9月中国军事医学科学院附属307医院确诊的初治AITL患者9例。全组患者均接受剂量调整的EPOCH方案一线化疗。结果:全组患者发病中位年龄54岁,男∶女为2∶1,88.9%为Ann-Arbor stageⅢ~Ⅳ期,77.8%合并B症状。初诊时伴有贫血的患者占66.7%

  16. Dose adjustment of carboplatin in patients on peritoneal dialysis.

    Science.gov (United States)

    Guddati, Achuta K; Joy, Parijat S; Marak, Creticus P

    2014-05-01

    The Calvert equation has been extensively used to determine the dosage of carboplatin. However, in patients on dialysis, it predicts the same dosage regardless of the frequency of dialysis. Clearance of carboplatin during hemodialysis has been studied to a lesser extent, but there have been very few studies which have investigated the clearance of carboplatin in patients on peritoneal dialysis. A mathematical formula is proposed here to predict the dose of carboplatin for a given AUC in patients on peritoneal dialysis. This formula takes into account the frequency of dialysis sessions and the time delay between carboplatin infusion and the initiation of dialysis. The formula predicts an approximately similar dosage of carboplatin as that of the Calvert formula in patients undergoing peritoneal dialysis four times per day if dialysis is initiated 12 h after infusion. The formula may help in guiding the adjustment of carboplatin dose in patients who receive a lesser number of dialysis sessions per day and in those patients whose dialysis is initiated at different times (0-24 h) after carboplatin infusion. It is suggested that usage of this formula will result in a better dosage of carboplatin to suit specific dialysis frequencies in specific patients and eventually may result in a better efficacy and toxicity profile.

  17. Dose adjustment and supportive care before and during treatment.

    Science.gov (United States)

    Brunello, Antonella; Loaldi, Elena; Balducci, Lodovico

    2009-10-01

    Though elderly patients represent a majority of cancer patients, their treatment of is still inadequate, mainly due to the lack of data deriving from randomized clinical trials. Factors limiting the use of standard chemotherapy regimens in elderly cancer patients are the fear of toxicity and unexpected side effects. The assessment of comorbidity and the multidimensional geriatric assessment are of major importance in the decision plan. All supportive measures must be adopted in order to successfully treat vulnerable and unfit elderly patients with cancer, and in particular, the use of growth factors when chemotherapy is given with curative intent; rule out anemia and possible causes of anemia, and correct them whenever possible; choose cytotoxics according to expected adverse events and possible interference with concomitant medications. Particular attention must be paid to treatment of pain in the elderly with cancer. Caregivers must be involved in the treatment plan, and phone contacts with the patient and caregivers are needed to verify physical conditions and compliance to prescriptions.

  18. Emerging Strategies in Treating Double Hit Lymphomas.

    Science.gov (United States)

    Nabhan, Chadi; Mato, Anthony R

    2017-06-21

    Double hit lymphomas (DHLs) are a new category in the World Health Organization newest classification for lymphoid malignancies. DHL encompasses various histologies of lymphomas where the MYC oncogene and either BCL2 or BCL6 oncogenes are present concomitantly. Several observational studies and retrospective series have demonstrated that patients with DHL carry a poor prognosis and respond less and for a shorter duration to standard R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone). These studies have also proposed that dose intensification (with Burkitt-like regimens such as DA-EPOCH-R [dose-adjusted rituximab, etoposide, vincristine, Adriamycin, cyclophosphamide, and prednisone]) might offer patients with DHL better outcomes and improved prognosis. In this timely review, we discuss incidence of DHL, testing implications of MYC translocation, current treatment strategies, and future directions. Understanding this entity and its therapeutic consequences is essential to improve patients' outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The prognostic analysis of dose adjustment for beta blockers in the acute exacerbation of chronic congestive heart failure in the elderly%老年慢性充血性心力衰竭急性加重期患者美托洛尔剂量调整的临床研究

    Institute of Scientific and Technical Information of China (English)

    陈春泉; 王敏; 李庆丰; 翁小雁; 陈积党

    2015-01-01

    Objective To evaluate the effects and the prognosis of beta receptor blocker (metoprolol)dose adjustment of senile patients with chronic congestive heart failure (CHF)of acute exacerbation,and to provide reference for clinical treatment.Methods 76 cases with chronic CHF in acute exacerbation who treated with beta blockers and other reasonable treatment were randomly divided into half dose group (40 cases)and full stop group (36 cases).After adjusted for 3 months,the clinical symptoms were observed,noninvasive hemodynamic machine was used to detect cardiac index (CI),left cardiac work (LCW),cardiac output (CO)and changes of other indicators. Immunoradiometric analysis was used to detect plasma type B natriuretic peptide (BNP).Results 72h after treatment,in the half dose group,the progression of the disease in 13 cases,improved in 27 cases,in the full stop group,progression in 20 cases,improvement in 16 cases,the difference was statistically significant (χ2 =4.09,P <0.05).Before the adjustment of metoprolol,the index of the two groups had statistically significant difference(χ2 =4.52,P <0.05 ).Compared with pretreatment,the changes of NYHA classification,Co,CI,LCW of the half dose group were not obvious,and he change of NYHA of the full stop group was obvious,,III /IV the progression of the disease the number of cases increased in 5 cases and 3 cases,Co,Ci,LCW were reduced by about 25%,35% and 30%.After the adjustment of metoprolol,BNP of the half dose group was (321.8 ±97.6 )mg/L,which was significantly lower than (422.3 ±139.4)mg/L of the full stop group,the difference was statistically significant (t =3.94,P <0.05 ).Conclusion In the patients with beta blockers combined with other reasonable treatment, CHF patients with acute exacerbation of the beta blockers than the discontinuation of the prognosis,and the safety is high.%目的:评价美托洛尔剂量调整对老年人慢性充血性心力衰竭急性加重期的临床疗效和对预后的影响,为

  20. Dose adjustment guidelines for medications in patients with renal impairment: how consistent are drug information sources?

    Science.gov (United States)

    Khanal, A; Castelino, R L; Peterson, G M; Jose, M D

    2014-01-01

    It is known that patients with renal disease are often administered inappropriate dosages of drugs. A lack of quantitative data in the available drug information sources and inconsistency in dosing information may augment the problem of dosing error. To determine the concordance among five drug information sources regarding the dosing recommendations provided for drugs considered problematic in patients with renal impairment and to determine the consistency among the sources regarding the definition of renal impairment and categorisation of chronic kidney disease. Five standard drug information sources were reviewed for 61 drugs recommended to be used with caution in renal impairment. Information on recommendations for dosage adjustment in renal impairment was extracted and analysed. Further, the definition and classification of renal impairment were recorded. The recommendation for each drug was coded into six different categories and the intersource reliability was calculated. Only slight agreement was observed among the sources (Fleiss Kappa: 0.3). Qualitative data were not well defined, and there was a lack of consistency in quantitative values. Some drugs marked as contraindicated in one source were not mentioned as such in others. Also, drugs considered as not requiring dosage adjustment in one source had explicit recommendations in other sources. The definition and classification of renal impairment differed among the five information sources. There should be an evidence-based approach to drug dosage adjustment in order to bring uniformity to the recommendations. Regular updating of the content of the drug information sources is also important. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  1. Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations.

    Science.gov (United States)

    Vlavonou, Raphaël; Perreault, Marc M; Barrière, Olivier; Shink, Eric; Tremblay, Pierre-Olivier; Larouche, Richard; Pichette, Vincent; Tanguay, Mario

    2014-05-01

    The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.

  2. Development of a dose-adjustable α-particle irradiation facility for radiobiological studies

    Institute of Scientific and Technical Information of China (English)

    HU Bu-Rong; WU Jie-Feng; HAN Wei; WANG Xu-Fei; WU Li-Jun; YU Zeng-Liang

    2005-01-01

    Bystander effects induced by low-dose or low dose-rate radiation have put a great challenge to the traditional model for radiation protection. In order to get a better assessment of the adverse effects of radiation, especially the low-dose radiation risk in environment, a radioactive irradiation facility, by which the dose and dose-rate to the biological targets can be controlled by rotating the sample bracket and changing the space between the radioactive source and the targets, was developed. The energy of our α-radioactive source (241Am) is measured averagely 3.5MeV at the position of the irradiated sample. The dose rate was measured by using a silicon surface barrier detector and a CR39 particle track detector. A dose rate ranging from 0.045 cGy/s to 1.07 cGy/s can be obtained by changing the space length from the radioactive source to the sample dish.

  3. Pharmacokinetics and antimicrobial dosing adjustment in critically ill patients during continuous renal replacement therapy.

    Science.gov (United States)

    Kuang, D; Verbine, A; Ronco, C

    2007-05-01

    Appropriate antimicrobial therapy poses one of the greatest challenges during the management of a septic patient in the intensive care unit (ICU). Acute renal failure (ARF) is a common complication of sepsis and often occurs as a component of multiple organ dysfunction syndrome. Continuous renal replacement therapy (CRRT) is increasingly used as an effective extracorporeal blood purification therapy in this critically ill patient population. Available data demonstrate that sepsis, ARF and different modalities of CRRT may have profound effects on the pharmacokinetics and pharmacodynamics of various antimicrobial agents used in the ICU. Guidelines for antimicrobial prescription which will fit the individual patient undergoing a particular method of treatment are still unavailable. Understanding the principles of drug removal by CRRT and pharmacokinetics of various agents can help to modify the drug dosage and dosing intervals for individualized therapy. Meanwhile, monitoring the drug serum concentration is still mandatory whenever clinically feasible.

  4. Effectiveness of pharmacist dosing adjustment for critically ill patients receiving continuous renal replacement therapy: a comparative study

    OpenAIRE

    Jiang SP; Zhu ZY; Wu XL; Lu XY; Zhang XG; Wu BH

    2014-01-01

    Sai-Ping Jiang,1 Zheng-Yi Zhu,2 Xiao-Liang Wu,3 Xiao-Yang Lu,1 Xing-Guo Zhang,1 Bao-Hua Wu1 1Department of Pharmacy, the First Affiliated Hospital, 2Department of Pharmacy, Children’s Hospital, College of Medicine, Zhejiang University, Hangzhou, 3Intensive Care Unit, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China Background: The impact of continuous renal replacement therapy (CRRT) on drug removal is complicated...

  5. Bivalirudin dosing adjustments for reduced renal function with or without hemodialysis in the management of heparin-induced thrombocytopenia.

    Science.gov (United States)

    Tsu, Laura V; Dager, William E

    2011-10-01

    While not approved by the Food and Drug Administration for treatment of heparin-induced thrombocytopenia (HIT), except in patients undergoing percutaneous interventions, the direct thrombin inhibitor bivalirudin is a treatment option that is gaining use. An initial dose of bivalirudin 0.15-0.2 mg/kg/h, adjusted to an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the baseline value, has been suggested. Initial dosing in patients with renal dysfunction, including those on hemodialysis, is unclear. To evaluate initial bivalirudin dosing requirements in patients with and without renal dysfunction, including patients on different forms of dialysis. A retrospective analysis of 135 patients treated with bivalirudin for HIT between June 2004 and October 2009 was conducted at a tertiary care medical center. The patients were divided into groups, based on renal function. Patients receiving dialysis were divided into 3 subgroups based on the mode of hemodialysis: intermittent hemodialysis (IHD, n = 24), sustained low-efficiency daily diafiltration (SLEDD, n = 12), or continuous renal replacement therapy (CRRT, n = 5). Patients not receiving dialysis were separated into 3 subgroups based on calculated creatinine clearance (CrCl): CrCl >60 mL/min (n = 52), CrCl 30-60 mL/min (n = 26), and CrCl 60 mL/min), patients with differing degrees of renal dysfunction (CrCl 30-60 and doses of bivalirudin to achieve aPTT goal (0.13 vs 0.08 vs 0.05 mg/kg/h, respectively; p CRRT) also required dose reductions (0.07, 0.09, and 0.07 mg/kg/h) compared with patients with normal renal function, but higher dosing requirements than patients not receiving dialysis with CrCl dose of bivalirudin to reach a therapeutic aPTT goal. Slightly higher doses may be observed in patients receiving hemodialysis.

  6. Dose adjustment and application of intravenous anaesthetics in obese patients%肥胖患者静脉麻醉药应用及剂量调整

    Institute of Scientific and Technical Information of China (English)

    磨凯; 徐世元; 刘中杰; 李凤仙; 梁启波; 张庆国

    2013-01-01

    背景 肥胖患者麻醉药药代与药效动力学较体重正常人群个体差异更大,其心输出量与身体肌肉、脂肪等组织构成比的变化影响众多麻醉药物分布、消除规律,按总体重给药易致药物过量,按理想体重给药则可能剂量不足. 目的 阐述常用静脉麻醉药在肥胖患者中的药代与药效动力学特性,有助于此类患者合理用药,减少并发症. 内容 综述肥胖患者常用静脉麻醉药按总体重、理想体重、体表面积和瘦体重用药研究现状. 趋势 为避免肥胖患者肌松药术后残余作用所致并发症,非去极化肌松药按理想体重给药较合适,而大多数静脉麻醉药(包括阿片类药物)则适于按瘦体重给药.%Background Obese patients have greater inter-individual variations than the standard-size patients in the anesthetic pharmacokinetics and pharmacodynamics.In obese population,changes in cardiac output and alterations in body composition affect the distribution of numerous anaesthetics,therefore,administration of drugs based on total body weight could result in overdose,conversely,administration of drugs based on ideal body weight could result in an inadequate dose.Objective This review focuses on the pharmacokinetics and pharmacodynamics properties of intravenous anesthetic in obese patients in order to provide recommendation for rational application of intravenous anesthetic in obese patients and reduce complications.Content Discussing dosing scalars based on total body weight,ideal body weight,body surface area and lean body weight as well as its recent advances in clinical application of intravenous anaesthetics in the obese.Trend To avoid postoperative residual curarization,the ideal body weight might be appropriate for dosing scalar of the non-depolarizing neuromuscular blocking agents,whereas,lean body weight is the optimal dosing scalar for the majority of anaesthetic agents including opioids and anaesthetic-induction agents for obese patients.

  7. 基于肾功能状况调整顺铂剂量的研究进展%Progress of Cisplatin Dose Adjustment Based on the Renal Function

    Institute of Scientific and Technical Information of China (English)

    朱妍蒨; 于锋; 葛卫红

    2011-01-01

    To investigate the effect of edaravone on chronic cerebral ischemia and expression of MDA and SOD in rats. Methods: A chronic cerebral ischemic model was established by ligation of bilateral carotid arteries in rats. Edaravone was peritoneally injected at 3 mg·kg-1 3 weeks after operation. The neural function impairment was evaluated by the stroke index and neurological symptom score. The positive expression of MDA and SOD in different portion was observed through visible spectrophotometry. Results: The neurological disfunction in edaravone group was significantly lighter than that in control group or cerebrolysin vial group 4 weeks after cerebral ischemia. The level of MDA was significantly lower, the activity of SOD was significantly higher than those in the other two groups 4 weeks after operation, respectively (P<0.01). The positive expression was highest during 4~12 weeks. The most obvious expression of MDA was in frontal lobe and the secondary in hippocampus; the most obvious expression of SOD was in hippocampus and the secondary in frontal lobe. Conclusion: Edaravone can protect neural tissue against ischemic injury in rats. The mechanisms include up-regulation of SOD, elimination of free radical and inhibition of lipid peroxidation.%顺铂化疗对肾功能的损害已有共识.目前,国外根据肌酐清除率调整顺铂剂量,而国内对顺铂化疗剂量的选择与调整缺乏规范与标准,无法为肿瘤患者提供优质的个体化治疗.通过查阅国内外文献,全面介绍肿瘤患者肾功能的评估指标,总结化疗药物剂量调整原则及方式,综述国外顺铂剂量选择与调整的现状.

  8. Validity of a clinical decision rule-based alert system for drug dose adjustment in patients with renal failure intended to improve pharmacists' analysis of medication orders in hospitals.

    Science.gov (United States)

    Boussadi, A; Caruba, T; Karras, A; Berdot, S; Degoulet, P; Durieux, P; Sabatier, B

    2013-10-01

    The main objective of this study was to assess the diagnostic performances of an alert system integrated into the CPOE/EMR system for renally cleared drug dosing control. The generated alerts were compared with the daily routine practice of pharmacists as part of the analysis of medication orders. The pharmacists performed their analysis of medication orders as usual and were not aware of the alert system interventions that were not displayed for the purpose of the study neither to the physician nor to the pharmacist but kept with associate recommendations in a log file. A senior pharmacist analyzed the results of medication order analysis with and without the alert system. The unit of analysis was the drug prescription line. The primary study endpoints were the detection of drug dose prescription errors and inter-rater reliability (Kappa coefficient) between the alert system and the pharmacists in the detection of drug dose error. The alert system fired alerts in 8.41% (421/5006) of cases: 5.65% (283/5006) "exceeds max daily dose" alerts and 2.76% (138/5006) "under-dose" alerts. The alert system and the pharmacists showed a relatively poor concordance: 0.106 (CI 95% [0.068-0.144]). According to the senior pharmacist review, the alert system fired more appropriate alerts than pharmacists, and made fewer errors than pharmacists in analyzing drug dose prescriptions: 143 for the alert system and 261 for the pharmacists. Unlike the alert system, most diagnostic errors made by the pharmacists were 'false negatives'. The pharmacists were not able to analyze a significant number (2097; 25.42%) of drug prescription lines because understaffing. This study strongly suggests that an alert system would be complementary to the pharmacists' activity and contribute to drug prescription safety. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Effects of basal rate verification on CSⅡ dose adjustments in brittle diabetes%基础率验证在脆性糖尿病持续皮下胰岛素输注剂量调整中的作用

    Institute of Scientific and Technical Information of China (English)

    孙蔚; 陆志强; 花霞; 高鑫

    2013-01-01

    基础率验证是找寻并验证基础血糖代谢所需持续皮下胰岛素输注(CSⅡ)基础率的过程.本研究5例脆性糖尿病患者采用赖脯胰岛素CSⅡ治疗,CSⅡ剂量调整至血糖平稳,行基础率验证.结果显示,CSⅡ治疗后血糖整体水平和稳定性得到改善.基础率验证前后,CSⅡ总量无明显差异,基础率由总量的50%减至30%(P<0.05),餐时大剂量增至70%(P<0.05);午餐与晚餐时段基础率减少一半(P<0.05);午餐与晚餐大剂量增至1.5倍(P<0.05),需加用方波控制餐后血糖.结果提示,CSⅡ能平稳控制脆性糖尿病血糖,不依赖基础率验证.然而实施验证能更好地确定适合基础血糖代谢的基础率,进而有助于确定与饮食相关的餐时大剂量.%Basal rate verification is the process to find and verify the basal rate of continuous subcutaneous insulin infusion (CSⅡ) required for basal glucose metabolism.In the present study,five cases of brittle diabetes were treated by CSⅡ with Insulin Lispro.After doses were adjusted to reach steady blood glucose levels,basal rate verifying tests were carried out.The results showed that the overall level and stability of blood glucose were improved markedly after CSⅡ.Before and after the verification of the basal rate,there was no significant difference in CSⅡ total doses.Basal rates decreased from 50% of total to 30% (P<0.05),and boluses increased to 70% (P<0.05).The basal rates during lunch and supper time were reduced by half (P<0.05),the boluses of lunch and supper were increased 1.5 times (P<0.05),and square waves were needed to control postprandial blood glucose.These results suggest that the CSⅡ could smoothly control blood glucose level in brittle diabetes without basal rate verification.However,the implementation of the verification could better determine the basal rates for basal glucose metabolism,and thus help to identify diet-related boluses.

  10. Cutaneous presentation of Double Hit Lymphoma

    Directory of Open Access Journals (Sweden)

    Yousef Khelfa MD, FACP

    2016-04-01

    Full Text Available Diffuse large B-cell lymphoma (DLBCL is the most common type of non-Hodgkin lymphoma (NHL, representing approximately 25% of diagnosed NHL. DLBCL is heterogeneous disease both clinically and genetically. The 3 most common chromosomal translocations in DLBCL involve the oncogenes BCL2, BCL6, and MYC. Double hit (DH DLBCL is an aggressive form in which MYC rearrangement is associated with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass, often with B symptoms. Extranodal disease is often present. Though there is a paucity of prospective trials in this subtype, double hit lymphoma (DHL has been linked to very poor outcomes when patients are treated with standard R-CHOP. There is, therefore, a lack of consensus regarding the standard treatment for DHL. Several retrospective analyses have been conducted to help guide treatment of this disease. These suggest that DA EPOCH-R may be the most promising regimen and that achievement of complete resolution predicts better long-term outcomes.

  11. Drug-induced renal injury

    African Journals Online (AJOL)

    Drugs can cause acute renal failure by causing pre-renal, intrinsic or post-renal toxicity. Pre-renal ... incidence of drug dose adjustment in renal impairment in the SAMJ. ... Fever, haemolytic anaemia, thrombocytopenia, renal impairment and.

  12. [Therapeutic drug monitoring of antimicrobials

    NARCIS (Netherlands)

    Mouton, J.W.; Aarnoutse, R.E.

    2014-01-01

    The importance of dose adjustments of antimicrobials based on measured concentrations in an individual ('therapeutic drug monitoring', TDM) is increasingly recognized. There are several reasons for this. First, there is a better understanding of the relationships between doses administered,

  13. Bioavailability of IgG Administered by the Subcutaneous Route

    OpenAIRE

    Berger, Melvin; Jolles, Stephen; Orange, Jordan S.; Sleasman, John W

    2013-01-01

    Purpose US licensing studies of subcutaneous IgG (SCIG) calculate dose adjustments necessary to achieve area under the curve (AUC) of serum IgG vs. time on SCIG that is non-inferior to that on intravenous IgG (IVIG), within the FDA-set limit of ±20 %. The results are interpreted as showing that different SCIGs differ in bioavailability. We used three approaches to determine if the bioavailabilities were actually different. Methods Dose adjustments and AUCs from published licensing studies wer...

  14. Outliers on the dose-response curve: how to minimize this problem using therapeutic drug monitoring, an underutilized tool in psychiatry.

    Science.gov (United States)

    Preskorn, Sheldon H

    2010-05-01

    This column continues the discussion of outliers on the dose-response curve begun in earlier columns. It focuses on therapeutic drug monitoring (TDM) as an underutilized tool in psychiatry to minimize this problem. The scientific rationale for dose adjustment based on TDM is presented and its efficiency is contrasted with dose adjustment based on clinical assessment of response. In current practice, the use of TDM with psychiatric drugs is generally restricted to drugs with narrow therapeutic windows or drugs imported into psychiatry from neurology where TDM is more commonly used. Examples of each of these types of drugs are cited.

  15. Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard

    2016-01-01

    BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on do...

  16. 75 FR 73104 - Clinical Development Programs for Sedation Products; Request for Assistance

    Science.gov (United States)

    2010-11-29

    ... sedation products in adult and pediatric age groups. FDA is inviting any interested party, or parties, to... example, pediatric and geriatric age groups often require dose adjustment because of varying metabolic..., Midazolam, Propofol, Ketamine, and Dexmedetomidine are commonly used sedation products. Of these, Midazolam...

  17. Immunoassay analysis of Kanamycin in serum using the Tobramycin kit

    NARCIS (Netherlands)

    Dijkstra, J A; Voerman, A J; Greijdanus, B; Touw, D J; Alffenaar, J W C

    2016-01-01

    Kanamycin is one of the aminoglycosides used in the treatment of multidrug resistant tuberculosis. Blood concentrations of kanamycin are predictive for the treatment efficacy and the occurrence of side effects and dose adjustments can be needed to optimize therapy. However, an immunoassay method for

  18. Immunoassay Analysis of Kanamycin in Serum Using the Tobramycin Kit

    NARCIS (Netherlands)

    Dijkstra, J.A.; Voerman, A. J.; Greijdanus, B.; Touw, D. J.; Alffenaar, J. W. C.

    2016-01-01

    Kanamycin is one of the aminoglycosides used in the treatment of multidrug-resistant tuberculosis. Blood concentrations of kanamycin are predictive for the treatment efficacy and the occurrence of side effects, and dose adjustments can be needed to optimize therapy. However, an immunoassay method fo

  19. Out-of-office hours nurse-driven acute telephone counselling service in a large diabetes outpatient clinic

    DEFF Research Database (Denmark)

    Due-Christensen, Mette; Kaldan, Gudrun; Almdal, Thomas P

    2015-01-01

    attending the clinic (p...%) of patients called less than five times. However, 8% called 16 times or more accounting for 52% of all calls. A retrospective audit identified them as physically and/or psychologically fragile patients. CONCLUSION: Hyperglycaemia was the most frequent reason for calling, and insulin dose adjustment the most...

  20. Hepatoprotective activity of Eclipta alba against carbon tetrachloride-induced hepatotoxicity in albino rats

    Directory of Open Access Journals (Sweden)

    Ravindra S. Beedimani

    2015-06-01

    Conclusion: The results of the study confirmed the hepatoprotective activity of aqueous extracts of E. alba at doses of 250 mg/kg and 500 mg/kg against CCl4 induced hepatotoxicity in rats. However, the dose adjustments may be necessary to optimize the similar hepatoprotective efficacy in clinical settings. [Int J Basic Clin Pharmacol 2015; 4(3.000: 404-409

  1. Partiële acenocoumarol- en fenprocoumonresistentie door enzympolymorfisme

    NARCIS (Netherlands)

    Wilms, E B; Veldkamp, R F; van Meegen, E; Touw, D J

    2006-01-01

    A 78-year-old man was treated with coumarin derivatives following myocardial infarction. The international normalised ratio was not increased by using standard loading doses and dose adjustments for acenocoumarol and phenprocoumon. The desired level of anticoagulation was achieved with a high dosage

  2. Correlation of serum lithium levels and thyroid function tests in subjects of bipolar affective disorder: a prospective hospital-based study

    Directory of Open Access Journals (Sweden)

    M. S. Manjuprasad

    2015-02-01

    Conclusions: As already known, Lithium is a drug of narrow therapeutic index and females are more prone for thyroid function abnormalities. Appropriate monitoring of serum lithium levels will aid in necessary dose adjustment and ensure proper utilization of drug. [Int J Basic Clin Pharmacol 2015; 4(1.000: 51-54

  3. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study

    DEFF Research Database (Denmark)

    Gattermann, Norbert; Finelli, Carlo; Porta, Matteo Della;

    2010-01-01

    patients were chelation-naïve or previously chelated; changes were dependent on dose adjustments and ongoing iron intake. Sustained reductions in labile plasma iron were observed. Discontinuation rate (48.7%) and adverse event profile were consistent with previously reported deferasirox data in MDS...

  4. ORIGINAL ARTICLES Prevalence of drug-drug interactions of ...

    African Journals Online (AJOL)

    2008-02-02

    Feb 2, 2008 ... in the private health care sector in South Africa. N L Katende-Kyenda ... them by dose adjustments and patient education, so that they are not life .... risk of drug interactions and statin-induced hepatotoxicity and myopathy.1 ...

  5. Population pharmacokinetic analysis of ceftobiprole for treatment of complicated skin and skin structure infections.

    Science.gov (United States)

    Kimko, Holly; Murthy, Bindu; Xu, Xu; Nandy, Partha; Strauss, Richard; Noel, Gary J

    2009-03-01

    Population pharmacokinetic analysis demonstrated that renal function, as assessed by creatinine clearance (CL(CR)), was the patient characteristic that had a clinically relevant impact on ceftobiprole pharmacodynamics. Dosing adjustments based on CL(CR) for subjects with renal impairment should provide ceftobiprole exposure similar to that in patients with normal renal function.

  6. Micro-costing study of rituximab subcutaneous injection versus intravenous infusion in dutch setting

    NARCIS (Netherlands)

    Mihajlović, J.; Bax, P.; Van Breugel, E.; Blommestein, H.M.; Hoogendoorn, M.; Hospes, W.; Postma, M.J.

    2015-01-01

    Background: Rituximab for subcutaneous (SC) administration has recently been approved for use in common forms of diffuse large B-cell lymphoma (DLBCL). This form of rituximab is supplied in ready-to-use vials that do not require individual dose adjustment. It is expected that SC-injection will

  7. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial

    DEFF Research Database (Denmark)

    Bousser, M.G.; Bouthier, J.; Buller, H.R.;

    2008-01-01

    BACKGROUND: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this random...

  8. Drug-drug interactions with tyrosine-kinase inhibitors

    NARCIS (Netherlands)

    Croes, Sander; de Vries, Frank

    2014-01-01

    In their Review, Roelof van Leeuwen and colleagues1 recommend various dose adjustments during concomitant use of tyrosine-kinase inhibitors and drugs that inhibit or induce cytochrome P450 3A4 (CYP3A4).1 Most information is taken from the US Food and Drug Administration (FDA)'s drug label or the Eur

  9. Lenalidomide is effective and safe for the treatment of patients with relapsed multiple myeloma and very severe renal impairment.

    Science.gov (United States)

    João, Cristina; Freitas, José; Gomes, Fernando; Geraldes, Catarina; Coelho, Inês; Neves, Manuel; Lúcio, Paulo; Esteves, Susana; Esteves, Graça V

    2016-05-01

    Patients with multiple myeloma (MM) and severe renal impairment (SRI) have shorter survival than MM patients without renal failure. Although lenalidomide is a highly active drug, this immunomodulatory agent is frequently neglected in this context due to its predominant renal clearance and, consequently, an increased risk of toxicity. This risk might be overcome with the proper lenalidomide dose adjustment to renal function. This study evaluates the outcomes of 23 relapsed MM patients with SRI (baseline creatinine clearance (CrCl) lenalidomide-dexamethasone (LenDex), including 56 % (13 patients) under hemodialysis. The median CrCl at start of LenDex was 19 mL/min; an overall response rate (partial response or better) of 56 % was obtained, with a median follow-up from start of LenDex of 52 months (8-79). The median time until maximal response was 4 months, and in 58 % (7/12), the response was longer than 2 years. Nine percent had renal improvement, but all the 13 patients on hemodialysis remained under treatment. LenDex was interrupted in three cases because of adverse events (infections and cutaneous events); 78 % of the patients were on thromboprophylaxis with aspirin. It is important to notice that, after initial dose adjustment of therapy, there should be a continuous process of dose adjustment, taking into account variations in renal function. Furthermore, lenalidomide dose adjustment should be made according to the individual tolerance, even with stable renal function. LenDex dose adjustment, according to these principles, does not negatively impact response and improves treatment tolerance. It has a clear potential to treat this group of patients and to induce long duration of responses [event-free survival (EFS) 20.5 m and overall survival (OS) 42.6 m].

  10. The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant Recipients

    DEFF Research Database (Denmark)

    Madsen, Mads Juul; Bergmann, Troels K; Brøsen, Kim

    2017-01-01

    INTRODUCTION: Tacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations......>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients. METHODS: Seventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase......>A, POR*28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus (CMV) within the first year was identified (p transplantation were on target...

  11. The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant Recipients

    DEFF Research Database (Denmark)

    Juul Madsen, Mads; Bergmann, Troels K; Brøsen, Kim

    2017-01-01

    . Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A5*3, PPARA c.209-1003G......>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients. METHODS: Seventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase...... chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients' medical charts. RESULTS: It was confirmed that CYP3A5*1 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations...

  12. Composite Lymphoma: Opposite Ends of Spectrum Meet

    Science.gov (United States)

    Khan, Uqba; Hadid, Tarik; Ibrar, Warda; Sano, Dahlia; Al-Katib, Ayad

    2017-01-01

    An 18-year-old African-American female presented with an episode of syncope. Initial investigations revealed large lung mass with invasion into right atrium along with lesions in kidneys and liver. Patient also developed superior vena cava syndrome due to lung mass. Biopsy of lung mass revealed diagnosis of composite lymphoma with involvement by primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma. Patient was started on dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) with complete response to treatment. This case represents an extremely rare type of aggressive lymphoma and can guide clinicians in managing such cases since there are no standard guidelines for treatment. To the best of our knowledge, this is the first reported case of composite lymphoma of PMBCL and classical Hodgkin lymphoma successfully treated with dose-adjusted EPOCH-R regimen.

  13. Fungal infections today: size of the problem and focus on the initial cost of therapy with echinocandin

    Directory of Open Access Journals (Sweden)

    Mario Venditti

    2010-06-01

    Full Text Available Three candins had been approved for the treatment of invasive candidiasis (IC: caspofungin, micafungin, and anidulafungin. Different drugs are associated with different needs for dose adjustment which might affect the total cost. A Spanish economic analysis estimated the budget impact of caspofungin, micafungin and anidulafungin in the treatment of 100 patients with invasive candidiasis from the perspective of the Spanish hospital pharmacy setting. It has demonstrated that patients treated with anidulafungin did not required dose adjustment unlike caspofungin and micafungin, and the use of anidulafungin in the treatment of adult non-neutropenic patients with invasive candidiasis is a cost saving treatment option, from the pharmacy department perspective in Spain. The aim of this study was to estimate the initial costs of therapy with caspofungin, micafungin, and anidulafungin in the perspective of the Italian hospital setting.

  14. New oral anticoagulants in non-valvular atrial fibrillation.

    Science.gov (United States)

    Francia, Pietro; Adduci, Carmen; Santini, Daria; Musumeci, Beatrice; Tocci, Giuliano

    2013-06-01

    Atrial fibrillation (AF) is associated with an increased risk of embolic stroke. Dose-adjusted vitamin K antagonists (VKAs) to a target international normalized ratio (INR) range of 2.0-3.0 reduce the risk of ischemic stroke and are currently recommended in all patients with AF at moderate-high risk for stroke or systemic embolism. However, VKAs have several drawbacks, including unpredictable anticoagulant response, food and drug interactions, need for regular laboratory monitoring and dose adjustment. These limitations prompted the introduction of new oral anticoagulants (NOA) that target thrombin and factor Xa, key-enzymes in the coagulation pathway. NOA have predictable pharmacodynamics, allowing fixed dosing without the need of laboratory monitoring, and have few drug and food interactions. The present review focuses on pharmacological properties, safety, and appropriate clinical use of dabigatran, rivaroxaban and apixaban.

  15. Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients.

    Science.gov (United States)

    Tierce, J C; Porterfield-Baxa, J; Petrilla, A A; Kilburg, A; Ferguson, R M

    2005-12-01

    Mycophenolate mofetil (MMF), a mycophenolic acid prodrug, is a highly effective adjunct immunosuppressive agent in transplant therapy. Although MMF is generally well tolerated, optimal therapy may be limited by adverse effects, in particular gastrointestinal (GI) toxicity, which has been reported to occur in up to 45% of MMF-treated patients. MMF dose changes resulting from these adverse events may lead to sub-therapeutic dosing and impaired clinical outcomes. This retrospective study analyzed clinical records from 772 renal transplant patients from 10 US transplant centers who were initiated on MMF. The analysis revealed that 49.7% (n = 382) of patients experienced at least one GI complication within the first 6 months post-transplant, with 66.8% (n = 255) of these having multiple GI complications. Of the patients with GI complications, 39.0% experienced MMF dose adjustments or discontinuation of MMF therapy. Patients with GI complications who experienced MMF dose adjustments/discontinuation had a significantly increased incidence of acute rejections compared with patients without GI complications (30.2% vs. 19.4%; p = 0.005). Mean treatment costs were higher in patients with GI complications than in those with no GI complications, particularly in those who experienced MMF dose adjustments/discontinuation (p = 0.0001). The mean incremental cost for patients experiencing GI complications was US$3700 per patient during the 6 months post-transplant (p MMF dose adjustments/discontinuations are associated with a significant negative impact on transplant outcomes and markedly increase short-term treatment costs.

  16. Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs.

    Science.gov (United States)

    Moltó, José; Rajoli, Rajith; Back, David; Valle, Marta; Miranda, Cristina; Owen, Andrew; Clotet, Bonaventura; Siccardi, Marco

    2017-03-01

    Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model. In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated. Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses. PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients.

  17. Effective dose of dexmedetomidine to induce adequate sedation in elderly patients under spinal anesthesia

    OpenAIRE

    2015-01-01

    Background During sedation with dexmedetomidine, a dose adjustment may be needed based on the invasiveness of the procedure, the patient's general condition, and their age. We aim here to determine the effective dose (ED) of dexmedetomidine to induce an adequate depth of sedation in elderly patients undergoing spinal anesthesia. Methods In this study, 47 patients aged 65 years or older, American Society of Anesthesiologists physical status I or II, undergoing spinal anesthesia were included. ...

  18. Evaluation of Certain Pharmaceutical Quality Attributes of Lisinopril Split Tablets

    OpenAIRE

    Khairi M.S. Fahelelbom; Moawia M. M. Al-Tabakha; Nermin A. M. Eissa; Jeevani Javadi

    2016-01-01

    Tablet splitting is an accepted practice for the administration of drugs for a variety of reasons, including dose adjustment, ease of swallowing and cost savings. The purpose of this study was to evaluate the physical properties of lisinopril tablets as a result of splitting the tablets either by hand or with a splitting device. The impact of the splitting technique of lisinopril (Zestril® tablets, 20 mg) on certain physical parameters such as weight variation, friability, disintegration, dis...

  19. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Nielsen, Stine N; Frandsen, Thomas L;

    2014-01-01

    The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug...... intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens...

  20. Dose escalation improves therapeutic outcome: post hoc analysis of data from a 12-week, multicentre, double-blind, parallel-group trial of trospium chloride in patients with urinary urge incontinence

    Directory of Open Access Journals (Sweden)

    Bödeker Rolf-Hasso

    2010-09-01

    Full Text Available Abstract Background Flexible dosing of anticholinergics used for overactive bladder (OAB treatment is a useful strategy in clinical practice for achieving a maximum effective and maximum tolerated level of therapeutic benefit. In this post hoc analysis we evaluated the efficacy and tolerability of trospium chloride treatment for urinary urge incontinence (UUI with focus on flexible dosing. Methods The data came from a 12-week, randomised, double-blind, phase IIIb study in which 1658 patients with urinary frequency plus urge incontinence received trospium chloride 15 mg TID (n = 828 or 2.5 mg oxybutynin hydrochloride TID (n = 830. After four weeks, daily doses were doubled and not readjusted in 29.2% (242/828 of patients in the trospium group, and in 23.3% (193/830 in the oxybuytnin group, until the end of treatment. We assessed the absolute reduction in weekly UUI episodes and the change in intensity of dry mouth, recorded in patients' micturition diaries. Adverse events were also evaluated. Statistics were descriptive. Results Dose escalation of either trospium or oxybutynin increased reduction in UUI episodes in the population studied. At study end, there were no relevant differences between the "dose adjustment" subgroups and the respective "no dose adjustment" subgroups (trospium: P = 0.249; oxybutynin: P = 0.349. After dose escalation, worsening of dry mouth was higher in both dose adjusted subgroups compared to the respective "no dose adjustment" subgroups (P P Conclusions Flexible dosing of trospium was proven to be as effective, but better tolerated as the officially approved adjusted dose of oxybutynin. Trial registration (parent study The study was registered with the German Federal Institute for Drugs and Medical Devices (BfArM, Berlin, Germany, registration number 4022383, as required at the time point of planning this study.

  1. Warfarin dose requirement and cytochrome P450 2C9 and Vitamin K epoxide reductase complex subunit 1-1639 genetic polymorphisms in Thai patients

    Directory of Open Access Journals (Sweden)

    Burassakorn Subsuphan

    2016-01-01

    Conclusions: Using stepwise multiple linear regression, VKORC1-1639 AA, age, and weight could explain about 45.3% of the variation of warfarin maintenance dose. Multivariate analysis of the equation indicated a significant negative correlation between warfarin dose and VKORC1-1639 AA and age, but a significant positive correlation between warfarin dose and weight. This suggested that VKORC1 genotyping may be more important in warfarin dose adjustment and should be a priority for genotype measurement.

  2. Post-operative analgesia for major abdominal surgery and its effectiveness in a tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Aliya Ahmed

    2013-01-01

    Conclusion: Epidural, PCIA and opioid infusions are used for pain relief after major abdominal surgeries at our hospital. Although there is limited drug availability, regular assessments and appropriate dose adjustments by acute pain management service (APMS and use of multimodal analgesia led to a high level of patient satisfaction. We recommend that feedback to the primary anesthesiologists by APMS is of utmost importance to enable improvement in practice.

  3. Drug dosage recommendations in patients with chronic liver disease Recomendaciones para la dosificación de medicamentos en pacientes con insuficiencia hepática crónica

    OpenAIRE

    Leonor Periáñez-Párraga; Iciar Martínez-López; Pere Ventayol-Bosch; Francesc Puigventós-Latorre; Olga Delgado-Sánchez

    2012-01-01

    Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were al...

  4. Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes

    DEFF Research Database (Denmark)

    Kaas, Anne; Andersen, Marie Louise Max; Fredheim, Siri

    2012-01-01

    Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose-adjusted haemoglobin A1c (IDAA1C), gluc......), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes....

  5. Renal function in atrial fibrillation patients switched from warfarin to a direct oral anticoagulant.

    Science.gov (United States)

    Minhas, Anum S; Jiang, Qingmei; Gu, Xiaokui; Haymart, Brian; Kline-Rogers, Eva; Almany, Steve; Kozlowski, Jay; Krol, Gregory D; Kaatz, Scott; Froehlich, James B; Barnes, Geoffrey D

    2016-11-01

    All available direct oral anticoagulants (DOACs) are at least partially eliminated by the kidneys. These agents are increasingly being used as alternatives to warfarin for stroke prevention in patients with atrial fibrillation. The aim of this study was to identify changes in renal function and associated DOAC dosing implications in a multicenter cohort of atrial fibrillation patients switched from warfarin to DOAC treatment. We included all patients in the Michigan Anticoagulation Quality Improvement Initiative cohort who switched from warfarin to a DOAC with atrial fibrillation as their anticoagulant indication between 2009 and 2014, and who had at least two creatinine values. Compliance with FDA-recommended dosing based on renal function was assessed. Of the 189 patients switched from warfarin to a DOAC, 34 (18.0 %) had a baseline creatinine clearance renal function. Of these 23 patients, 6 (26.1 %) should have impacted the DOAC dosing, but only 1 patient actually received an appropriate dose adjustment. Additionally, 15 (7.9 %) of patients on DOACs had a dose change performed, but only one patient demonstrated a change in renal function to justify the dose adjustment. Most atrial fibrillation patients who switched from warfarin to a DOAC had stable renal function. However, the majority of patients who had a change in renal function did not receive the indicated dose change. As the use of DOACs expands, monitoring of renal function and appropriate dose adjustments are critical.

  6. Renal Drug Dosage Adjustment According to Estimated Creatinine Clearance in Hospitalized Patients With Heart Failure.

    Science.gov (United States)

    Altunbas, Gokhan; Yazc, Mehmet; Solak, Yalcin; Gul, Enes E; Kayrak, Mehmet; Kaya, Zeynettin; Akilli, Hakan; Aribas, Alpay; Gaipov, Abduzhappar; Yazc, Raziye; Ozdemir, Kurtulus

    2016-01-01

    It is of clinical importance to determine creatinine clearance and adjust doses of prescribed drugs accordingly in patients with heart failure to prevent untoward effects. There is a scarcity of studies in the literature investigating this issue particularly in patients with heart failure, in whom many have impaired kidney function. The purpose of this study was to determine the degree of awareness of medication prescription as to creatinine clearance in patients hospitalized with heart failure. Patients hospitalized with a diagnosis of heart failure were retrospectively evaluated. Among screened charts, patients with left ventricular ejection fraction renal dose adjustment were determined and evaluated for appropriate dosing according to eGFR. A total of 388 patients with concomitant heart failure and renal dysfunction were included in the study. The total number of prescribed medications was 2808 and 48.3% (1357 medications) required renal dose adjustment. Of the 1357 medications, 12.6% (171 medications) were found to be inappropriately prescribed according to eGFR. The most common inappropriately prescribed medications were famotidine, metformin, perindopril, and ramipril. A significant portion of medications used in heart failure requires dose adjustment. Our results showed that in a typical cohort of patients with heart failure, many drugs are prescribed at inappropriately high doses according to creatinine clearance. Awareness should be increased among physicians caring for patients with heart failure to prevent adverse events related to medications.

  7. Diabetes mellitus and kidney disease in the elderly.

    Science.gov (United States)

    Iglesias, Pedro; Heras, Manuel; Díez, Juan J

    2014-05-21

    Management of diabetic elderly patients with chronic kidney disease involves specific characteristics that affect both metabolic control and therapeutic measures. Blood glucose control targets should be individualised based on life expectancy, renal function, hypoglycaemia risk and comorbidity. Metformin may be used alone or in combination with other oral anti-diabetic drugs but must be discontinued when the glomerular filtration rate is less than 30 mL/min. Gliclazide and glipizide are sulfonylureas that do not require dose adjustment in chronic kidney disease but they should be avoided in cases of advanced kidney disease because of the risk of hypoglycaemia. Repaglinide is the only meglitinide recommended in these patients. Alpha-glucosidase inhibitors must be avoided in patients with a glomerular filtration rate of less than 25 mL/min or those undergoing dialysis. Pioglitazone does not require dose adjustment but it has potentially adverse effects in this population. Dipeptidyl peptidase-4 inhibitors are effective and well tolerated. Of the latter, linagliptin does not require dose adjustment. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are not recommended in elderly patients with advanced kidney disease. Lastly, insulin therapy, particularly using the new insulin analogues, allows adequate management of hyperglycaemia in these patients, with different therapeutic regimens that must be individualised in order to avoid hypoglycaemia.

  8. An open-label conversion study of pramipexole to ropinirole prolonged release in Parkinson's disease.

    Science.gov (United States)

    Lyons, Kelly E; Pahwa, Rajesh

    2009-10-30

    Ropinirole prolonged release (PR) is a once daily oral dopamine agonist approved for the treatment of Parkinson's disease (PD). The goal of this 4 week, open-label study was to determine the most effective conversion ratio with the fewest adverse effects (AEs) when switching from pramipexole to ropinirole PR. Sixty patients with PD taking pramipexole were converted overnight to ropinirole PR at ratios of 1:3, 1:4, or 1:5 such that 20 consecutive subjects were enrolled in each group. Ropinirole PR dose adjustments were allowed to maintain efficacy or to reduce AEs. An overnight switch from pramipexole to ropinirole PR was found to be well tolerated and AEs were typical for a dopamine agonist. The most common AEs were worsening of PD symptoms, dizziness, somnolence, and nausea, the majority of which resolved after dose adjustments. Thirteen subjects discontinued ropinirole PR before 4 weeks. These subjects were taking a significantly greater dose of pramipexole, the majority greater than 4 mg/day, and tended to have longer disease durations. A conversion ratio of 1 mg of pramipexole to 4 mg of ropinirole PR resulted in the fewest discontinuations of ropinirole PR, the fewest dose adjustments and the largest percentage of subjects that preferred ropinirole PR.

  9. The effect of veno-venous ECMO on the pharmacokinetics of Ritonavir, Darunavir, Tenofovir and Lamivudine.

    Science.gov (United States)

    Ghazi Suliman, Mohamed A; Ogungbenro, Kayode; Kosmidis, Christos; Ashworth, Alan; Barker, Julian; Szabo-Barnes, Anita; Davies, Andrew; Feddy, Lee; Fedor, Igor; Hayes, Tim; Stirling, Sarah; Malagon, Ignacio

    2017-08-01

    To our knowledge, there is no published data on the pharmacokinetic (PK) profile of antiretroviral (ART) drugs on patients undergoing extracorporeal membrane oxygenation (ECMO) therapy. We present PK analyses of Ritonavir, Darunavir, Lamivudine and Tenofovir in a patient with HIV who required veno-venous ECMO (VV ECMO). Plasma concentrations for Ritonavir, Darunavir, Tenofovir and Lamivudine were obtained while the patient was on ECMO following pre-emptive dose adjustments. Published population PK models were used to simulate plasma concentration profiles for the drugs. The population prediction and the observed plasma concentrations were then overlaid with the expected drug profiles using the individual Bayesian post-hoc parameter estimates. Following dose adjustments, the PK profiles of Ritonavir, Darunavir and Tenofovir fell within the expected range and appeared similar to the population prediction, although slightly different for Ritonavir. The observed data for Lamivudine and its PK profile were completely different from the data available in the literature. To our knowledge, this is the first study reporting the PK profile of ART drugs during ECMO therapy. Based on our results, dose adjustment of ART drugs while on VV ECMO may be advisable. Further study of the PK profile of Lamivudine is required. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients

    Directory of Open Access Journals (Sweden)

    Suno M

    2015-05-01

    Full Text Available Manabu Suno,1,* Yuriko Endo,1,* Hiroyuki Nishie,2 Makoto Kajizono,3 Toshiaki Sendo,3 Junji Matsuoka4 1Department of Oncology Pharmaceutical Care and Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 3Department of Pharmacy, Okayama University Hospital, 4Faculty of Health Sciences, Okayama University Medical School, Okayama, Japan *These authors contributed equally to this work Background: An appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose-adjusted plasma fentanyl concentrations in cancer patients.Methods: Blood was collected from 21 Japanese cancer patients treated with a 24-hour transdermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS, and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations.Results: Eight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal–Wallis test and post hoc Mann–Whitney U-test, P<0.01. The factors that

  11. The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies

    Directory of Open Access Journals (Sweden)

    Davies M

    2016-06-01

    Full Text Available Melanie Davies,1,2 Sudesna Chatterjee,1,2 Kamlesh Khunti1,2 1Diabetes Research Centre, University of Leicester, 2Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK Abstract: Worldwide, an estimated 200 million people have chronic kidney disease (CKD, the most common causes of which include hypertension, arteriosclerosis, and diabetes. Importantly, ~40% of patients with diabetes develop CKD, yet evidence from major multicenter randomized controlled trials shows that intensive blood glucose control through pharmacological intervention can reduce the incidence and progression of CKD. Standard therapies for the treatment of type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2–5 and without dose adjustment; there are contraindications and dose adjustments required for the remaining standard therapies. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment. Notably, reductions in albuminuria, a marker of CKD, are observed with many of the drug classes. Dipeptidyl peptidase-IV inhibitors can be used in all stages of renal impairment, with appropriate dose reduction, with the exception of linagliptin, which can be used without dose adjustment. No dose adjustment is required for liraglutide, albiglutide, and dulaglutide in CKD stages 2 and 3, although all glucagon-like peptide-1 receptor agonists are currently contraindicated in stages 4 and 5 CKD. At stage 3 CKD or greater, the sodium

  12. Adjusting eptifibatide doses for renal impairment: a model of dosing agreement among various methods of estimating creatinine clearance.

    Science.gov (United States)

    Healy, Martha F; Speroni, Karen Gabel; Eugenio, Kenneth R; Murphy, Patricia M

    2012-04-01

    Because of the renal elimination and increased risk for bleeding events at supratherapeutic doses of eptifibatide, the manufacturer recommends dosing adjustment in patients with renal dysfunction. Methods commonly used to estimate renal dysfunction in hospital settings may be inconsistent with those studied and recommended by the manufacturer. To compare hypothetical renal dosing adjustments of eptifibatide using both the recommended method and several other commonly used formulas for estimating kidney function. Sex, age, weight, height, serum creatinine, and estimated glomerular filtration rate (eGFR) were obtained retrospectively from the records of patients who received eptifibatide during a 12-month period. Renal dosing decisions were determined for each patient based on creatinine clearance (CrCl) estimates via the Cockcroft-Gault formula (CG) with actual body weight (ABW), ideal body weight (IBW) or adjusted weight (ADJW), and eGFR from the Modification of Diet in Renal Disease formula. Percent agreement and Cohen κ were calculated comparing dosing decisions for each formula to the standard CG-ABW. In this analysis of 179 patients, percent agreement as compared to CG-ABW varied (CG-IBW: 90.50%, CG-ADJW: 95.53%, and eGFR: 93.30%). All κ coefficients were categorized as good. In the 20% of patients receiving an adjusted dose by any of the methods, 68.6% could have received a dose different from that determined using the CG-ABW formula. In the patients with renal impairment (CrCl <50 mL/min) in this study, two thirds would have received an unnecessary 50% dose adjustment discordant from the manufacturer's recommendation. Because failure to adjust eptifibatide doses in patients with renal impairment has led to increased bleeding events, practitioners may be inclined to err on the side of caution. However, studies have shown that suboptimal doses of eptifibatide lead to suboptimal outcomes. Therefore, correct dosing of eptifibatide is important to both patient

  13. Prevention of venous thromboembolism and safe use of heparin in Spanish hospitals.

    Science.gov (United States)

    Saturno, Pedro J; Gama, Zenewton A S; Fonseca, Yadira A

    2011-04-01

    To assess compliance with basic and actionable indicators in relation to prevention of venous thromboembolism (VTE) and safe use of heparin. We built, pilot tested and measured a set of evidence-based structure (existence of guidelines) and process (risk assessment for VTE, and dose adjustment to patient weight and renal function when prescribing heparin) indicators in a nation-wide random sample of 22 hospitals. Compliance with process indicators is estimated at national level and by groups of hospitals (stratified by size). At hospital level, compliance is assessed with Lot Quality Acceptance Sampling, for 85% compliance standard (α ≤ 0.05), 55% threshold (β ≤ 0.10). Contents of existing guidelines are analyzed, and their influence on performance is assessed using logistic regression. Acute care hospitals in Spain. None Problem identification through indicators assessment. Less than half of hospitals have guidelines and their contents are very variable and incomplete. No hospital complies with the standard for VTE prevention and only one for heparin dose adjustment. Nationally, VTE risk assessment is performed in 5.8% of patients (95% CI: 5.6-6.0), and heparin dose is explicitly adjusted in 17.5% (95% CI: 16.8-18.2). Performance is relatively higher in large hospitals and it is associated with the existence of guidelines for VTE prevention (OR: 8.3; 95% CI: 2.1-32.1). We have identified some actionable contributing factors to safety problems using evidence-based structure and process indicators. Explicit process design and key clinical interventions (risk assessment for VTE and heparin dose adjustment) should be addressed to improve the current situation.

  14. Successful salvage treatment of native valve Enterococcus faecalis infective endocarditis with telavancin: two case reports.

    Science.gov (United States)

    Thompson, Mickala M; Hassoun, Ali

    2017-07-01

    Infective endocarditis (IE) one-year mortality rates approach 40%. Here, we report two native valve Enterococcus faecalis IE cases in patients successfully treated with telavancin. An 88-year-old with mitral valve endocarditis and a penicillin allergy, initially treated with intravenous vancomycin, was switched to telavancin. A 69-year-old, who previously received amoxicillin and intravenous vancomycin for presumed enterococcal bacteraemia, was diagnosed with dual valve endocarditis for which he received telavancin. Both received six weeks of telavancin. Neither had telavancin-related adverse events, evidence of infection at six months, nor required telavancin dosing adjustments. Documented use of novel treatments for serious enterococcal infections is needed.

  15. Deoxyspergualin in relapsing and refractory Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Flossmann, O; Baslund, B; Bruchfeld, A

    2008-01-01

    at entry and prednisolone doses adjusted according to clinical status. Deoxyspergualin, 0.5 mg/kg per day, was self-administered by subcutaneous injection in six cycles of 21 days with a 7-day washout between cycles. Cycles were stopped early for white blood count less than 4000 cells/mm(3). The primary......-threatening (> or = grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leucopaenias. CONCLUSIONS: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener's granulomatosis. Adverse events were common but rarely led...

  16. Drug Dosing in Patients with Renal Insufficiency in a Hospital Setting using Electronic Prescribing and Automated Reporting of Estimated Glomerular Filtration Rate

    DEFF Research Database (Denmark)

    Nielsen, Anita L.; Henriksen, Daniel Pilsgaard; Marinakis, Christianna;

    2014-01-01

    . We conclude that despite implementation of electronic prescribing and automated reporting of eGFR, patients with renal insufficiency may still be exposed to inappropriate drug use, with potential increased risk of adverse effects. Initiatives to reduce medication errors such as the use of electronic......GFR in the range of 10-49 ml/min/1.73m(2) were included. We identified 436 episodes with administration of renal risk drugs (prescribed to 183 patients): 410 drugs required dose adjustment according to the eGFR and 26 should be avoided. In total, the use or dosing of 66 (15%) of the 436 renal risk drugs...

  17. [How I treat...Recommendations for controlling and optimizing a pharmacological therapy].

    Science.gov (United States)

    Scheen, A J

    2014-11-01

    Any pharmacological treatment should ideally be effective and safe. The supervision of an ongoing therapy should control that individualized goals are reached while tolerance and safety are present. In case of not reaching the predefined objectives, the causes of failure should first be screened (for instance, exclusion of poor patient compliance), and the treatment should be then optimized: dose adjustment, add-on of another drug (if possible synergistic combination) and/or shift to a more effective pharmacological therapy. In some cases, therapeutic monitoring may be useful or even mandatory in order to better adjust drug dosing and thus guarantee both efficacy and safety.

  18. Drug utilization review of ciprofloxacin in the outpatient department of Boru Meda Hospital, South Wollo Zone, Amhara Region, Ethiopia

    Directory of Open Access Journals (Sweden)

    Tessema Tsehay Biru

    2014-02-01

    Conclusions: Due From the retrospective Drug Use Evaluation (DUE study, it was identified that there was inappropriate ciprofloxacin use in the outpatient department of Boru Meda hospital even though the drug’s use regarding indications was a better performance and dosing practices were almost appropriate as per the criteria used for the study (assuming that there were no dose adjustments. There was a great problem concerning the duration of ciprofloxacin drug therapy. Ciprofloxacin use along with potentially interacting drugs and against contraindications was also another problem indicated in the study. [Int J Basic Clin Pharmacol 2014; 3(1.000: 171-178

  19. CYP3A4/5 polymorphisms affect the blood level of cyclosporine and tacrolimus in Chinese renal transplant recipients.

    Science.gov (United States)

    Li, Dan-ying; Teng, Rui-chen; Zhu, Huai-jun; Fang, Yun

    2013-06-01

    Both cyclosporine and tacrolimus display a narrow therapeutic index as well as high interindividual pharmacokinetic variability. We approached the effect of the CYP3A4*18B and CYP3A5*3 polymorphisms and haplotypes on the whole blood cyclosporine or tacrolimus concentration in Chinese renal transplant patients during the first month after transplantation. A total of 83 recipients receiving tacrolimus or cyclosporine was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The whole blood concentration was measured by enzyme-multiplied immunoassay technique. Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the tacrolimus dose-adjusted trough concentration (C0/D). The tacrolimus C0/D was higher in carriers of haplotype GG compared with the non-carriers. The cyclosporine dose-adjusted 2-hour post-dose concentrations (C2/D), dose-adjusted C0 + C2 ((C0 + C2)/D) and C2/C0 during Days 15 - 21 displayed significant difference among the three genotypes. Statistical difference was observed between CYP3A4*1/*1 and CYP3A4*18B/*18B groups and between CYP3A4*1/*18B and CYP3A4*18B/*18B groups, but no difference was detected between CYP3A4*1/*1 and CYP3A4*1/*18B groups. No difference was found in C0/D among the three genotypes of CYP3A4*18B polymorphism, and neither CYP3A5*3 polymorphisms nor CYP3A haplotype-derived genotypes affected the cyclosporine dose-adjusted concentration. Genetic polymorphisms of CYP3A5*3 and CYP3A4*18B may be partly responsible in large interindividual variability of cyclosporine and tacrolimus blood levels in Chinese renal transplant patients during the first month after transplantation. A patient carried combined genotype of CYP3A4*1/*1-CYP3A5* 3/*3 might require lower tacrolimus doses to achieve target concentration levels. Genotyping of CYP3A4*18B and CYP3A5*3 before transplantation is of benefit in determining a suitable initial dose for each patient.

  20. Therapeutic Drug Monitoring in the Treatment of Active Tuberculosis

    Directory of Open Access Journals (Sweden)

    Aylin Babalik

    2011-01-01

    Full Text Available Therapeutic drug monitoring ensures optimal dosing while aiming to reduce toxicity. However, due to the high costs and complexity of testing, therapeutic drug monitoring is not routinely used in the treatment of individuals with active tuberculosis, despite the efficacy demonstrated in several randomized trials. This study reviewed data spanning five years regarding the frequency of finding low drug levels in patients with tuberculosis, the dosing adjustments that were required to achieve adequate levels and the factors associated with low drug levels.

  1. Nanomedicine: Recent developments and opportunities in Africa

    CSIR Research Space (South Africa)

    Swai, HS

    2012-10-01

    Full Text Available in faeces ? Cytochrome P450 enzymes (CYPs) metabolise drug so that only a fraction reaches systemic circulation unchanged ? At liver ? Pgp pumps drug into bile ? CYPs further metabolise unchanged drug distribution to tissues metabolism...?= 2-3 hours) Gabizon et al., Cancer Res. 1994 Nanodrug Doxil Free drug 10 0 5000 10000 15000 0 5 10 Hours [P ac lit ax el] , n g/ m l Abraxane ? nano formulated (dose-adjusted to 175 mg/m2) Taxol ? free drug (dose175 mg/m2) A...

  2. Targeting blood glucose management in school improves glycemic control in children with poorly controlled type 1 diabetes mellitus.

    Science.gov (United States)

    Nguyen, Thanh M; Mason, Kimberly J; Sanders, Cynthia G; Yazdani, Parvin; Heptulla, Rubina A

    2008-10-01

    We hypothesized that school nurse supervision of glucose and insulin-dose adjustment significantly improves the hemoglobinA(1c) (HbA(1c)) level in pediatric patients with poorly controlled type 1 diabetes mellitus (HbA(1c) > or = 9%). A total of 36 subjects were enrolled and 18 subjects were randomized to receive the 3-month intervention. Their average HbA(1c) was lowered by 1.6%, suggesting that this intervention helps this difficult group of patients.

  3. Clinical practice guidelines for translating pharmacogenomic knowledge to bedside. Focus on anticancer drugs.

    Directory of Open Access Journals (Sweden)

    José A G Agúndez

    2014-08-01

    Full Text Available The development of clinical practice recommendations or guidelines for the clinical use of pharmacogenomics data is an essential issue for improving drug therapy, particularly for drugs with high toxicity and/or narrow therapeutic index such as anticancer drugs. Although pharmacogenomic-based recommendations have been formulated for over 40 anticancer drugs, the number of clinical practice guidelines available is very low. The guidelines already published indicate that pharmacogenomic testing is useful for patient selection, but final dosing adjustment should be carried out on the basis of clinical or analytical parameters rather than on pharmacogenomic information.Patient selection may seem a modest objective, but it constitutes a crucial improvement with regard to the pre-pharmacogenomics situation and it saves patients’ lives. However we should not overstate the current power of pharmacogenomics. At present the pharmacogenomics of anticancer drugs is not sufficiently developed for dose adjustments based on pharmacogenomics only, and no current guidelines recommend such adjustments without considering clinical and/or analytical parameters.

  4. Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment.

    Science.gov (United States)

    Guedes, Erika Paniago; Hohl, Alexandre; de Melo, Thais Gomes; Lauand, Felipe

    2013-05-22

    Type 2 diabetes mellitus (T2DM) has a high prevalence and incidence around the world. The complex pathophysiology mechanism is among the barriers for diabetes treatment. Type 2 diabetes patients have dysfunction in incretin hormones (as glucagon-like peptide-1 or GLP-1, and glucose-dependent insulinotropic polypeptide or GIP). By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, it is possible to slow the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner. Linagliptin is a highly specific and potent inhibitor of DPP-4 that is currently indicated for the treatment of type 2 diabetes. Clinical studies with linagliptin demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients, while maintaining a placebo-like safety and tolerability profile. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination and the main implication of this characteristic is that no dose adjustment is necessary in patients with renal disease. Also, no dose adjustment is required in patients with hepatic insufficiency, as well in elderly or obese patients. This article will review the pharmacokinetic profile, efficacy data and safety aspects of linagliptin in type 2 diabetes patients.

  5. Review of the safety, efficacy, and pharmacokinetics of elvitegravir with an emphasis on resource-limited settings

    Directory of Open Access Journals (Sweden)

    Lee JSF

    2012-01-01

    Full Text Available Janice Soo Fern Lee1, Alexandra Calmy1,2, Isabelle Andrieux-Meyer1, Nathan Ford1,31Médecins Sans Frontières, 2HIV/AIDS Unit, Infectious Disease Service, Geneva University Hospital, Geneva, Switzerland; 3Centre for Infectious Disease Epidemiology and Research, University of Cape Town, South AfricaAbstract: Integrase inhibitors represent an important new class of antiretroviral drugs. Elvitegravir, the second available integrase inhibitor to be submitted for regulatory approval appears to be a promising once-daily agent when combined with other antiretroviral drugs. Elvitegravir has demonstrated good efficacy and safety, with minimal side effects and no specific requirements in terms of laboratory monitoring. In addition, elvitegravir is available as a fixed-dose combination. However, the drug requires boosting and this leads to a number of drug–drug interactions and necessary dose adjustment when dosing with certain drugs, including dose reduction in the presence of atazanavir, lopinavir, rifabutin, and ketoconazole, and dose increase for ethinyl estradiol when co-administered with boosted elvitegravir. The main advantage of elvitegravir lies in its potential to be administered as a once-daily, single pill. Limitations include dose adjustment requirements, a relatively low genetic barrier to resistance, high price, and lack of data for use in children. Clinical trials addressing specific challenges encountered in resources-limited settings should be encouraged.Keywords: elvitegravir, efficacy, safety, resistance, resource-limited settings

  6. Pancreatic enzyme replacement therapy in cystic fibrosis: dose, variability and coefficient of fat absorption.

    Science.gov (United States)

    Calvo-Lerma, Joaquim; Martínez-Barona, Sandra; Masip, Etna; Fornés, Victoria; Ribes-Koninckx, Carmen

    2017-07-27

    Pancreatic enzyme replacement therapy (PERT) remains a backbone in the nutritional treatment of cystic fibrosis. Currently, there is a lack of an evidence-based tool that allows dose adjustment. To date, no studies have found an association between PERT dose and fat absorption. Therefore, the aim of the study was to assess the influence of both the PERT dose and the variability in this dose on the coefficient of fat absorption (CFA). This is a retrospective longitudinal study of 16 pediatric patients (192 food records) with three consecutive visits to the hospital over a twelve-month period. Dietary fat intake and PERT were assessed via a four-day food record and fat content in stools was determined by means of a three-day stool sample collection. A beta regression model was built to explain the association between the CFA and the interaction between the PERT dose (lipase units [LU]/g dietary fat) and the variability in the PERT dose (standard deviation [SD]). The coefficient of fat absorption increased with the PERT dose when the variability in the dose was low. In contrast, even at the highest PERT dose values, the CFA decreased when the variability was high. The confidence interval suggested an association, although the analysis was not statistically significant. The variability in the PERT dose adjustment should be taken into consideration when performing studies on PERT efficiency. A clinical goal should be the maintenance of a constant PERT dose rather than trying to obtain an optimal value.

  7. Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

    Science.gov (United States)

    Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

    2014-01-01

    Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

  8. Population pharmacokinetic-pharmacodynamic modeling of biological agents: when modeling meets reality.

    Science.gov (United States)

    Mould, Diane R; Frame, Bill

    2010-09-01

    The pharmacokinetics (PK) and pharmacodynamics (PD) of many biological agents (biologics) have inherent complexities requiring specialized approaches to develop reliable, unbiased models. Three cases are covered: preponderance of zero values, nonresponder subpopulations, and adaptive dosing. Engineered biologics exhibit high affinity for target receptors. Biologics can saturate receptors, abolishing free receptor levels for protracted periods. Consequently, the distribution of observations can be heavy at, and near, the boundary. A 2-part model (ie, a truncated δ log-normal distribution) may be appropriate. Mixture models identify subpopulations based on bimodal or multimodal distributions of η values. With biologics, PD may be compromised because of lack of receptors, or the PD may be affected because of other events resulting in erratic excursions. Nonresponders exhibit a random walk-around placebo trajectory, resulting in high residual variability. The distributions of etas are often badly skewed or polymodal. An indescribable mixture model separates subjects who are nonresponders, providing diagnostic pharmacologic information on the drug. Many biologics use PD-based adaptive dosing. During model development, data used for model development include adaptive dosing. For simulation, adaptive dosing must be implemented. Failure to account for dose adjustments results in biased or inflated prediction intervals because subjects in the simulated data undergo inappropriate dose adjustments.

  9. A shape-modification strategy of electron-beam direct writing considering circuit performance in LSI interconnects

    Science.gov (United States)

    Midoh, Yoshihiro; Osaki, Atsushi; Nakamae, Koji

    2014-03-01

    As the feature size of LSI shrinks, the cost of mask manufacturing and turn-around-time continue to increase. Maskless lithography using electron beam direct writing (EBDW) technology attracts attention. On the other hands, with continuous scaling and the introduction of low-k dielectrics in Cu interconnect technology, reliability degradation caused by time-dependent dielectric breakdown (TDDB) and electromigration has become important issues. Therefore, EBDW in backend process is needed to ensure superior patterning quality and reliability using high-accuracy proximity effect correction (PEC). We have already proposed a dose-modification strategy of EBDW considering reliability for TDDB degradation. In this paper, furthermore, we propose a shape-modification strategy of EBDW considering circuit performance in LSI interconnects for improving EB drawing throughput. We use effectively patterns with rounded corner in order to reduce EB shots increased by PEC and avoid the local high current density at the corner of metal lines. We applied the proposed method to a microprocessor layout synthesized with the Nangate 45nm Open Cell Library. As a result, the drawn pattern by corner rounding and coarse dose adjustment achieved 2.5% higher throughput than that by no corner rounding and fine dose adjustment.

  10. Valganciclovir dosing using area under the curve calculations in pediatric solid organ transplant recipients.

    Science.gov (United States)

    Villeneuve, David; Brothers, Adam; Harvey, Eric; Kemna, Mariska; Law, Yuk; Nemeth, Thomas; Gantt, Soren

    2013-02-01

    Pediatric valganciclovir dosing recommendations have not been extensively validated for prevention or treatment for CMV infection. As such, we performed a pharmacokinetic study to compare different valganciclovir dosing regimens and the potential benefits of individualized dose adjustments in children following organ transplantation. Ganciclovir AUCs were calculated from four plasma drug levels in pediatric SOT recipients aged six months through three yr receiving valganciclovir suspension by mouth. Of the 28 ganciclovir AUC calculations performed, 11 (39%) were outside the therapeutic target range of 40-60 mcg h/L leading to a valganciclovir dose adjustment. Current manufacturer-recommended dosing based on BSA and CrCl was estimated to result in therapeutic AUCs in fewer patients than the simple weight-based formula used in our institution (4 vs. 13; p = 0.017). An AUC calculation using only the two- and five-h measurements was strongly correlated with the AUC using all four time measurements (R(2) = 0.846; p < 0.001). A simple weight-based dosing approach gives a higher probability for therapeutic AUCs compared to the manufacturer-recommended dosing in pediatric transplant patients aged six months through three yr with normal renal function. An AUC calculated using two sample times might allow for fewer blood draws in the future. © 2012 John Wiley & Sons A/S.

  11. Higher concentration insulins: an overview of clinical considerations.

    Science.gov (United States)

    Reid, Timothy S; Schafer, Fryn; Brusko, Cynthia

    2017-06-01

    Three higher concentration insulin products (insulin lispro 200 units/mL, insulin degludec 200 units/mL, and insulin glargine 300 units/mL) received US Food and Drug Administration (FDA) approval in 2015. Although human regular insulin 500 units/mL (U-500) was approved in 1997, a pen and dedicated U-500 syringe became available in 2016. These products offer more treatment options for the increasing numbers of patients requiring insulin to achieve and maintain glycemic targets. Higher concentration insulins have some unique safety and efficacy considerations. Important considerations when transitioning patients from the 100 unit/mL concentration (U-100) to the higher concentration include bioequivalence, pen dose increments, and pen appearance. Bioequivalent insulins have similar pharmacokinetic properties and no dose adjustments are expected when transitioning from the U-100 to the higher concentration. In contrast, higher concentration insulins with different pharmacokinetic and pharmacodynamic properties compared with the U-100 formulation may require dose adjustments. In order to provide safe and effective therapy to patients with higher daily insulin dose requirements, it is important for healthcare professionals to become very familiar with the characteristics of and differences between each of the higher concentration insulins. This paper highlights differences between the U-100 and higher concentration insulins and focuses on practical aspects of use.

  12. Direct oral anticoagulants in real practice: which doses for which patients. Limitations and bleeding risk compared to vitamin K antagonists

    Directory of Open Access Journals (Sweden)

    Giancarlo Landini

    2013-12-01

    Full Text Available The new oral direct anticoagulants (DOACs could represent a new frontier for management of thromboembolic diseases. However, the new drugs have limitations that need to be considered. Despite the fact that their efficacy and safety profile are at least not inferior to comparators, bleeding risk represents the most feared complication, as for all the antithrombotic drugs. Bleeding risk increases with conditions that interfere with pharmacokinetics, in addition to the risk strictly linked to patients or their co-morbidities. Since all DOACs are excreted from kidneys (even though at different percentages according to the different molecules, renal impairment represents one of the leading causes of DOACs accumulation and bleeding risk. Moderate renal failure is the main condition in which dose adjustment of DOACs could be required, while severe renal impairment represents an absolute contraindication for their use. Renal function must, therefore, be carefully monitored before prescription and during assumption. The older population is at higher bleeding risk, and dose adjustment of DOACs could be required. Although to a lesser degree than oral anticoagulant vitamin K antagonists, DOACs can have drug interactions, especially with P-glycoprotein and cytochrome P3A4 inducers or inhibitors, and these interactions must be taken into account in real practice to avoid accumulation or under dosage. The concomitant use of other drugs, especially antithrombotics, may expose the patients to bleeding risk by reducing the hemostatic properties.

  13. [Pharmacokinetics of antibiotics in continuous renal replacement therapies (CRRT)].

    Science.gov (United States)

    Morabito, Santo; Pistolesi, Valentina; Maggiore, Umberto; Fiaccadori, Enrico; Pierucci, Alessandro

    2012-01-01

    In the critically ill patient, acute kidney injury (AKI) is frequently associated with infective complications requiring appropriate antimicrobial treatment. AKI and multiple organ dysfunction syndrome can affect the pharmacokinetic parameters of many drugs. Furthermore, the start of renal replacement therapy (RRT) is an additional variable to be taken into consideration to avoid inappropriate antimicrobial therapy. Continuous renal replacement therapies (CRRT) are widely adopted in the intensive care unit (ICU) and antibiotics that are significantly eliminated by the kidney are likely to be removed during RRT. Generally, drug-dosing adjustments are required if the extracorporeal clearance accounts for more than 25-30% of the total body clearance. The molecular weight cutoffs of the more widely used membranes are much higher than the molecular weight of most drugs. Therefore, molecular size will not be a limitation for the removal of the unbound fraction of the antibiotics most commonly used in ICU patients. However, CRRTs are still not standardized and the impact of RRT on plasma drug concentrations can be substantially different depending on the CRRT modality (diffusive, convective or both), membrane characteristics and delivered dialysis dose. In any case, drug-dosing adjustments should be based on the knowledge of the pharmacokinetic and pharmacodynamic properties of the different classes of antimicrobials, taking into account that high extracorporeal clearances could lead to drug underexposure in clinical conditions where appropriate antibiotic treatment is essential.

  14. Would artificial neural networks implemented in clinical wards help nephrologists in predicting epoetin responsiveness?

    Directory of Open Access Journals (Sweden)

    Marone Claudio

    2006-09-01

    Full Text Available Abstract Background Due to its strong intra- and inter-individual variability, predicting the ideal erythropoietin dose is a difficult task. The aim of this study was to re-evaluate the impact of the main parameters known to influence the responsiveness to epoetin beta and to test the performance of artificial neural networks (ANNs in predicting the dose required to reach the haemoglobin target and the monthly dose adjustments. Methods We did a secondary analysis of the survey on Anaemia Management in dialysis patients in Switzerland; a prospective, non-randomized observational study, enrolling 340 patients of 26 centres and in order to have additional information about erythropoietin responsiveness, we included a further 92 patients from the Renal Services of the Ente Ospedaliero Cantonale, Bellinzona, Switzerland. The performance of ANNs in predicting the epoetin dose was compared with that of linear regressions and of nephrologists in charge of the patients. Results For a specificity of 50%, the sensitivity of ANNs compared with linear regressions in predicting the erythropoietin dose to reach the haemoglobin target was 78 vs. 44% (P P P Conclusion In predicting the erythropoietin dose required for an individual patient and the monthly dose adjustments ANNs are superior to nephrologists' opinion. Thus, ANN may be a useful and promising tool that could be implemented in clinical wards to help nephrologists in prescribing erythropoietin.

  15. Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications.

    Science.gov (United States)

    Hostetter, A; Stowe, Z N; Strader, J R; McLaughlin, E; Llewellyn, A

    2000-01-01

    The use of antidepressants during pregnancy has undergone considerable scrutiny with respect to safety issues, though limited data with respect to dose management and symptom resolution is available. Previous reports on tricyclic antidepressants (TCAs) have demonstrated the need to adjust maternal dose later in pregnancy to maintain therapeutic serum concentrations. However, there is no data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to maintain symptom resolution in women treated for major depression during pregnancy. The purpose of this study, then, was to assess the medication dosage requirements of SSRIs during this time. In this naturalistic study, pregnant women with a primary diagnosis of major depression were followed prospectively through pregnancy at monthly intervals with symptom assessment. Subjects were included in data analysis if they presented prior to 28 weeks gestation, were treated with SSRI monotherapy, received all psychiatric treatment during the pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and achieved euthymia after initial treatment intervention (CGI = 1 and Beck Depression Inventory (BDI) < 9) during pregnancy or failed to respond after eight weeks of treatment. Medication selection was based on personal treatment history or family treatment history (if any), and the published data on SSRIs in pregnancy. All medication dose adjustments were based on depressive symptoms as measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant women were included in final analysis. Two thirds of the subjects (n = 22) required an increase in their daily dose of medication to maintain euthymia. The dose increases occurred at 27.1 +/- 7.1 weeks gestation, with mean BDI scores of 16.4 +/- 9.6, compared to a mean treatment response BDI of 6.9 +/- 5.4. Subject's age, education, past personal and familial psychiatric history were not significantly associated with dose adjustment. These

  16. Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients.

    Science.gov (United States)

    Zhang, Yu; Li, Jia-li; Fu, Qian; Wang, Xue-ding; Liu, Long-shan; Wang, Chang-xi; Xie, Wen; Chen, Zhuo-jia; Shu, Wen-ying; Huang, Min

    2013-04-01

    Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation. A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4(*)1G, CYP3A5(*)3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation. The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 -94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the -94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026]. These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.

  17. Pirfenidone treatment in idiopathic pulmonary fibrosis

    DEFF Research Database (Denmark)

    Salih, Goran Nadir; Shaker, Saher Burhan; Madsen, Helle Dall

    2016-01-01

    BACKGROUND: Pirfenidone was approved by the European Medicines Agency and introduced in most European countries in 2011 for treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To describe the national Danish experiences of pirfenidone treatment for IPF during 30 months with respect......-resolution computed tomography (HRCT), histopathology, forced vital capacity (FVC) and 6-min walk test (6MWT). Longitudinal data on FVC, walk test, adherence to the treatment and vital status were also collected. RESULTS: Pirfenidone treatment was initiated in 113 patients. Mean age was 69.6±8.1 years (±SD), and 71......: Patients with IPF treated with pirfenidone experienced tolerable adverse events. Patients were maintained on treatment due to a careful follow-up and dose adjustment programme. The annual decline in physiological parameters and mortality rate was comparable to previous randomised controlled trials....

  18. Paediatric pharmacokinetics: key considerations

    Science.gov (United States)

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-01-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials. PMID:25855821

  19. Formulations for children: problems and solutions

    Science.gov (United States)

    Batchelor, Hannah K; Marriott, John F

    2015-01-01

    Paediatric formulation design is complex as there is a need to understand the developmental physiological changes that occur during childhood and their impact on the absorption of drugs. Paediatric dose adjustments are usually based on achieving pharmacokinetic or pharmacodynamic profiles equivalent to those achieved in adult populations. However, differences in the way in which children handle adult products or the use of bespoke paediatric formulations can result in unexpected pharmacokinetic drug profiles with altered clinical efficacy. Differences in drug formulations need to be understood by healthcare professionals involved in the prescribing, administration or dispensing of drugs to children such that appropriate advice is given to ensure that therapeutic outcomes are achieved. This issue is not confined to oral medicines but is applicable for all routes of administration encountered in paediatric therapy. PMID:25855822

  20. Pharmacokinetics of drugs in cachectic patients: a systematic review.

    Directory of Open Access Journals (Sweden)

    Katja Trobec

    Full Text Available Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

  1. Sofosbuvir for the treatment of chronic hepatitis C virus infection.

    Science.gov (United States)

    Temesgen, Z; Talwani, R; Rizza, S A

    2014-06-01

    Sofosbuvir is a nucleotide analogue selective inhibitor of the RNA-directed RNA polymerase (NS5B) enzyme of the hepatitis C virus (HCV) genome. It has shown potent antiviral activity across all HCV genotypes and in a variety of patient populations, including treatment-naive patients; treatment-experienced patients who had failed previous standard therapy; patients with decompensated liver disease, including cirrhosis; and HIV co-infected patients. It is administered as a single, once-daily 400-mg tablet, has no food restrictions, has low potential for drug interactions, and requires no dose adjustment in mild to moderate kidney or liver impairment. When sofosbuvir is combined with pegylated interferon and/or ribavirin, its clinical and laboratory safety profile is similar to that which is expected from pegylated interferon or ribavirin alone. Rates of treatment discontinuation and dose reduction with sofosbuvir-containing regimens were lower than those commonly observed with pegylated interferon and ribavirin.

  2. Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation

    DEFF Research Database (Denmark)

    Bergmann, Troels K; Barraclough, Katherine A; Lee, Katie J

    2012-01-01

    Prednisolone and prednisone are integral components of induction and maintenance immunosuppressive regimens in solid organ transplantation. The pharmacokinetics of these agents are extremely complex. Prednisolone is the active drug moiety while prednisone is both a pro-drug and inactive metabolite...... of prednisolone. Within the dosage range used in transplantation, prednisolone and prednisone exhibit concentration-dependent non-linear pharmacokinetics when parameters are measured with reference to total drug concentration. Dose dependency disappears when free (unbound) prednisolone is measured. Altered organ...... function, changing biochemistry and use of a number of concomitant medicines in transplantation appear to lead to pharmacokinetic differences in transplant recipients compared with other patient groups. Greater than threefold variability in dose-adjusted exposure to total prednisolone in transplant...

  3. A B-cell lymphoma case that is unclassifiable, and intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma of lacrimal gland

    Science.gov (United States)

    Yunoki, Tatsuya; Murakami, Jun; Imagawa, Yukihiro; Nakajima, Takahiko; Hayashi, Atsushi

    2017-01-01

    A 60-year-old woman presented with acute eyelid swelling and a subcutaneous hemorrhage in the right eye. Magnetic resonance imaging showed a spherical tumor of the lacrimal gland. The tumor was removed by the Kroenlein method. We diagnosed as a B-cell lymphoma that is unclassifiable, and intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (intermediate DLBCL/BL) based on its immunohistopathological examination and c-MYC/IgH rearrangement. We administered six cycles of dose-adjusted-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride, and rituximab) therapy, and remission of the lymphoma was obtained. This is the first case of an intermediate DLBCL/BL of a lacrimal gland. PMID:28203109

  4. [Treatment of head injury coma with prolonged pentobarbital anaesthesia (author's transl)].

    Science.gov (United States)

    Artru, F; Guerin, J M; Latarjet, J; Deleuze, R

    1981-04-11

    Forty-five patients in deep coma resulting from head injury were treated with pentobarbital in doses adjusted to maintain serum barbiturate levels between 15 and 25 mg/l and short burst suppression phases on EEG. Brain death occurred in 20%. The overall mortality rate was 60%, no death being attributable to treatment; 24% of the patients were able to resume active life. Patients with non-reactive pupils during the early phase of coma were compared with patients of similar ages and neurological symptoms non treated with pentobarbital. In treated patients the incidence of brain death was reduced by 50% and the mortality rate by 25% (p less than 0.05), without increase in deaths from intercurrent complications and in severe sequelae among survivors.

  5. Design of Electronic Medical Record User Interfaces: A Matrix-Based Method for Improving Usability

    Directory of Open Access Journals (Sweden)

    Kushtrim Kuqi

    2013-01-01

    Full Text Available This study examines a new approach of using the Design Structure Matrix (DSM modeling technique to improve the design of Electronic Medical Record (EMR user interfaces. The usability of an EMR medication dosage calculator used for placing orders in an academic hospital setting was investigated. The proposed method captures and analyzes the interactions between user interface elements of the EMR system and groups elements based on information exchange, spatial adjacency, and similarity to improve screen density and time-on-task. Medication dose adjustment task time was recorded for the existing and new designs using a cognitive simulation model that predicts user performance. We estimate that the design improvement could reduce time-on-task by saving an average of 21 hours of hospital physicians’ time over the course of a month. The study suggests that the application of DSM can improve the usability of an EMR user interface.

  6. PREVENTION OF THROMBOSES IN ANTIPHOSPHOLIPID SYNDROME

    Directory of Open Access Journals (Sweden)

    Lyubov Valeryevna Kondratyeva

    2009-01-01

    Patients with antiphospholipid (aPL antibodies and venous thromboses need long-term moderate-intensity warfarin therapy. Patients with ischemic strokes without other indications for the use of anticoagulants may be given either warfarin or ASA. In the latter case, there is no need for laboratory control or an individual dose adjustment. The primary prevention of thromboses in the presence of aPL is also performed with ASA. When pregnancy occurs, women with obstetric manifestations of APS may be given small-dose ASA in combination with heparins. To reduce the risk of hemorrhages, warfarin dosage adjustment is initiated with the minimum doses (<5 mg/day. Novel ASA formulations, such as ASA with the unabsorbed antacid magnesium hydroxide, have been developed to prevent gastrointestinal tract complications.

  7. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, L. B.; Porksen, S.; Andersen, M. L. M.;

    2011-01-01

    Background: The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients......-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes. Methods: The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association...... with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA(1c)), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA...

  8. Use of slaughterhouse waste and tannery-based organic compost for management of reniform nematode

    Directory of Open Access Journals (Sweden)

    Guilherme L. Asmus

    2014-07-01

    Full Text Available A greenhouse experiment was carried out with the objective of evaluating the effect of increasing soil amendments (1, 3, 9, 15 and 30%, v/v of organic compost produced from slaughterhouse waste and tannery residues on the reproduction of reniform nematodes and cotton development. The addition of organic composts to soil proportionately reduced the number of nematodes per gram of root and the reproduction factor. However, depending on the concentration of the compost, there was a reduction of height and dry mass of cotton shoots. We concluded that the organic compost produced with slaughterhouse and tannery waste has potential for controlling reniform nematodes, but requires dose adjustments or improvements in its composition to reduce the risk of phytotoxicity.

  9. Obesity in the intensive care unit: risks and complications.

    Science.gov (United States)

    Selim, Bernardo J; Ramar, Kannan; Surani, Salim

    2016-08-01

    The steady growing prevalence of critically ill obese patients is posing diagnostic and management challenges across medical and surgical intensive care units. The impact of obesity in the critically ill patients may vary by type of critical illness, obesity severity (obesity distribution) and obesity-associated co-morbidities. Based on pathophysiological changes associated with obesity, predominately in pulmonary reserve and cardiac function, critically ill obese patients may be at higher risk for acute cardiovascular, pulmonary and renal complications in comparison to non-obese patients. Obesity also represents a dilemma in the management of other critical care areas such as invasive mechanical ventilation, mechanical ventilation liberation, hemodynamic monitoring and pharmacokinetics dose adjustments. However, despite higher morbidity associated with obesity in the intensive care unit (ICU), a paradoxical lower ICU mortality ("obesity paradox") is demonstrated in comparison to non-obese ICU patients. This review article will focus on the unique pathophysiology, challenges in management, and outcomes associated with obesity in the ICU.

  10. HIV and HCV Medications in End-Stage Renal Disease.

    Science.gov (United States)

    Greenberg, Keiko I; Perazella, Mark A; Atta, Mohamed G

    2015-01-01

    Human immunodeficiency virus (HIV) infection and hepatitis C virus (HCV) infection affect populations worldwide. With the availability of over 35 Food and Drug Administration approved medications for treatment of HIV, the morbidity and mortality associated with HIV has greatly improved. On the other hand, treatment options for HCV have been limited until very recently. While the use of protease inhibitors (such as boceprevir and telaprevir) has become standard of care for treatment of hepatitis C in the general population, data for individuals with impaired kidney function, particularly those on dialysis, are extremely limited. Use of medications in dialysis patients can be challenging given the dose adjustments that must be made for renally cleared molecules, and potentially increased impact of adverse effects such as anemia. Recommendations for dosing of marketed therapies for HIV and HCV are reviewed.

  11. Executive summary. Management of influenza infection in solid-organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI).

    Science.gov (United States)

    López-Medrano, Francisco; Cordero, Elisa; Gavaldá, Joan; Cruzado, Josep M; Marcos, M Ángeles; Pérez-Romero, Pilar; Sabé, Nuria; Gómez-Bravo, Miguel Ángel; Delgado, Juan Francisco; Cabral, Evelyn; Carratalá, Jordi

    2013-10-01

    Solid organ transplant (SOT) recipients are at greater risk than the general population for complications and mortality from influenza infection. We have conducted a systematic review to assess the management and prevention of influenza infection in SOT recipients. Recommendations are provided about the procurement of organs from donors with influenza infection. We highlight the importance of the possibility of influenza infection in any SOT recipient presenting upper or lower respiratory symptoms, including pneumonia. The importance of early antiviral treatment of SOT recipients with suspected or confirmed influenza infection and the necessity of annual influenza vaccination are emphasized. The microbiological techniques for diagnosis of influenza infection are reviewed. Guidelines for the use of antiviral prophylaxis are provided. Recommendations for household contacts of SOT recipients with influenza infection and health care workers are also included. Antiviral dose adjustment guidelines are presented for cases of impaired renal function and for pediatric populations. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  12. Psychosis in Parkinson's disease: diagnosis and treatment.

    Science.gov (United States)

    Doraiswamy, M; Martin, W; Metz, A; Deveaugh-Geiss, J

    1995-09-01

    1. This article reviews the prevalence, diagnosis, pathophysiology and management of psychosis in Parkinson's disease. 2. Psychosis in Parkinson's disease has been associated with all antiparkinsonian medications. The most common symptoms are vivid disturbing dreams, visual hallucinations and paranoid delusions. 3. The emergence of psychosis reduces the patient's functional capacity and increases caregiver burden. It also poses a therapeutic dilemma because effective treatment of psychotic symptoms may result in worsening of motor symptoms and vice versa. 4. Increased physician awareness is essential for proper diagnosis and management. Withdrawal of anticholinergic medications and amantadine followed by levodopa dose adjustment is effective in many patients. 5. Atypical neuroleptics, in low doses, may be successful when other measures have failed. However, these agents are not approved for treating Parkinsonian psychosis and must be considered as investigational therapies.

  13. Antidotes for novel oral anticoagulants: current status and future potential.

    Science.gov (United States)

    Crowther, Mark; Crowther, Mark A

    2015-08-01

    The direct thrombin inhibitor dabigatran and the anti-Xa agents rivaroxaban, edoxaban, and apixaban are a new generation of oral anticoagulants. Their advantage over the vitamin K antagonists is the lack of the need for monitoring and dose adjustment. Their main disadvantage is currently the absence of a specific reversal agent. Dabigatran's, unlike the anti-Xa agents, absorption can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis. Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these drugs is the most suitable for emergency reversal. Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.

  14. Optimizing the Use of Aripiprazole Augmentation in the Treatment of Major Depressive Disorder: From Clinical Trials to Clinical Practice

    Science.gov (United States)

    Han, Changsu; Wang, Sheng-Min; Lee, Soo-Jung; Jun, Tae-Youn

    2015-01-01

    Major depressive disorder (MDD) is a recurrent, chronic, and devastating disorder leading to serious impairment in functional capacity as well as increasing public health care costs. In the previous decade, switching therapy and dose adjustment of ongoing antidepressants was the most frequently chosen subsequent treatment option for MDD. However, such recommendations were not based on firmly proven efficacy data from well-designed, placebo-controlled, randomized clinical trials (RCTs) but on practical grounds and clinical reasoning. Aripiprazole augmentation has been dramatically increasing in clinical practice owing to its unique action mechanisms as well as proven efficacy and safety from adequately powered and well-controlled RCTs. Despite the increased use of aripiprazole in depression, limited clinical information and knowledge interfere with proper and efficient use of aripiprazole augmentation for MDD. The objective of the present review was to enhance clinicians' current understanding of aripiprazole augmentation and how to optimize the use of this therapy in the treatment of MDD. PMID:26306301

  15. Metoprolol Dose Equivalence in Adult Men and Women Based on Gender Differences: Pharmacokinetic Modeling and Simulations

    Directory of Open Access Journals (Sweden)

    Andy R. Eugene

    2016-11-01

    Full Text Available Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

  16. Patient variation in veterinary medicine--part II--influence of physiological variables.

    Science.gov (United States)

    Modric, S; Martinez, M

    2011-06-01

    In veterinary medicine, the characterization of a drug's pharmacokinetic properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. In Part I of the series, we focused on the potential influence of disease processes, stress, pregnancy and lactation on drug pharmacokinetics. In this Part II of the series, we consider other covariates, such as gender, heritable traits, age, body composition, and circadian rhythms. The impact of these factors with respect to predicting the relationship between dose and drug exposure characteristics within an animal population is illustrated through the use of Monte Carlo simulations. Ultimately, an appreciation of these potential influences will improve the prediction of situations when dose adjustments may be appropriate. © 2010 Blackwell Publishing Ltd.

  17. Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score.

    Science.gov (United States)

    Henricks, Linda M; Lunenburg, Carin A T C; Meulendijks, Didier; Gelderblom, Hans; Cats, Annemieke; Swen, Jesse J; Schellens, Jan H M; Guchelaar, Henk-Jan

    2015-01-01

    The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.

  18. Insulinoma Causing Hypoglycemia in a Patient with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Wei-Yi Lei

    2007-05-01

    Full Text Available Insulinoma in a patient with pre-existing diabetes is extremely rare. A 74-year-old woman with type 2 diabetes mellitus who had been treated with a sulfonylurea for 6 years began experiencing frequent episodes of hypoglycemia. Endogenous hyperinsulinism was found 9 months after the sulfonylurea was discontinued, and transabdominal ultrasonography and magnetic resonance imaging identified a pancreatic tumor. Pathology examination of the resected tumor demonstrated an insulinoma. Postoperatively, the patient had no further episodes of hypoglycemia. Thereafter, she required insulin to control her hyperglycemia. Although hypoglycemic agents are the commonest cause of hypoglycemia in type 2 diabetes, insulinomas may occur in these patients. This possibility should be considered if the hypoglycemia persists despite dose adjustment or cessation of the drugs.

  19. Reducing error in anticoagulant dosing via multidisciplinary team rounding at point of care

    Directory of Open Access Journals (Sweden)

    Munish Sharma

    2017-04-01

    Full Text Available The incorporation of a clinical pharmacist in daily rounding can help identify and correct errors related to anticoagulation dosing. Inappropriate anticoagulant dosing increases the risk of developing significant bleeding diathesis. Conversely, inappropriate dosing may also fail to produce a therapeutic response. We retrospectively reviewed electronic medical records of 41 patients to confirm and analyze the errors related to various anticoagulants. A clinical pharmacist in an integrated rounding between the period of February 2016 and April 2016 collected this data. We concluded that integrated rounding improves patient safety by recognizing anticoagulant dosage error used for the purpose of prophylaxis or treatment. It also allows us to make dose adjustments based on renal function of the patient. We think that it is prudent for physicians to pay particular attention to creatinine clearance when dosing anticoagulants in order to achieve the intended dosing effect and reduce the risk of adverse drug events.

  20. Possible role of selective serotonin reuptake inhibitor sertraline on oxidative stress responses.

    Science.gov (United States)

    Battal, D; Yalin, S; Eker, E D; Aktas, A; Sahin, N O; Cebo, M; Berköz, M

    2014-01-01

    The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals and the most widely used that has been shown to have both antidepressant and antianxiety effects. In the present study the possible role of sertraline (acute and chronically doses) was evaluated on lipid peroxidation levels and antioxidant enzyme activities in plasma and brain tissues of (10, 40, 80 mg/kg) sertraline treated Wistar albino rats (n=48). Lipid peroxidation levels (MDA) of plasma and brain tissue increased in all acute and chronic sertraline treated rats (p sertraline administration enhances oxidative stress. Therefore, dose adjustment in depression patients seems significant as it may help prevention of further prognosis of the diseases.

  1. Epilepsy during pregnancy: focus on management strategies

    Science.gov (United States)

    Borgelt, Laura M; Hart, Felecia M; Bainbridge, Jacquelyn L

    2016-01-01

    In the US, more than one million women with epilepsy are of childbearing age and have over 20,000 babies each year. Patients with epilepsy who become pregnant are at risk of complications, including changes in seizure frequency, maternal morbidity and mortality, and congenital anomalies due to antiepileptic drug exposure. Appropriate management of epilepsy during pregnancy may involve frequent monitoring of antiepileptic drug serum concentrations, potential preconception switching of antiepileptic medications, making dose adjustments, minimizing peak drug concentration with more frequent dosing, and avoiding potentially teratogenic medications. Ideally, preconception planning will be done to minimize risks to both the mother and fetus during pregnancy. It is important to recognize benefits and risks of current and emerging therapies, especially with revised pregnancy labeling in prescription drug product information. This review will outline risks for epilepsy during pregnancy, review various recommendations from leading organizations, and provide an evidence-based approach for managing patients with epilepsy before, during, and after pregnancy. PMID:27703396

  2. The use of oral suspension and rationally prescribing alternatives may be supplemental to the implementation of clopidogrel new algorithm comprising CYP2C19 pharmacogenetics and drug interactions

    Directory of Open Access Journals (Sweden)

    Chen M

    2016-03-01

    Full Text Available Meng Chen, Quan Zhou Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaWe read with great interest the study by Saab et al,1 which shows that all patients who received combination therapy of clopidogrel and cytochrome P540 2C19 (CYP2C19 substrates require clopidogrel dose adjustment if they are not CYP2C19*1/*1 carriers and that therapeutic dose of 75 mg clopidogrel should be tailored in patients with different genotypes (eg, lowered to 6 mg or increased to 215 mg for the sake of efficacy and safety. We especially appreciate the new clinical pharmacogenetic algorithm they developed to optimize clopidogrel-based treatment. However, we found two points worthy of discussion and would like to share our perspectives in the following paragraphs.View original paper by Saab and colleagues. 

  3. A Multi-Criteria Framework with Voxel-Dependent Parameters for Radiotherapy Treatment Plan Optimization

    CERN Document Server

    Zarepisheh, Masoud; Li, Nan; Jia, Xun; Jiang, Steve B

    2012-01-01

    In a treatment plan optimization problem for radiotherapy, a clinically acceptable plan is usually generated by an optimization process with weighting factors or reference doses adjusted for organs. Recent discoveries indicate that adjusting parameters associated with each voxel may lead to better plan quality. However, it is still unclear regarding the mathematical reasons behind it. To answer questions related to this problem, we establish in this work a new mathematical framework equipped with two theorems. The new framework clarifies the different consequences of adjusting organ-dependent and voxel-dependent parameters for the treatment plan optimization of radiation therapy, as well as the different effects of adjusting weighting factors versus reference doses in the optimization process. The main discoveries are threefold: 1) While in the organ-based model the selection of the objective function has an impact on the quality of the optimized plans, this is no longer an issue for the voxel-based model sin...

  4. New oral anticoagulants: key messages for clinicians

    Directory of Open Access Journals (Sweden)

    Matteo Giorgi-Pierfranceschi

    2013-12-01

    Full Text Available New oral anticoagulants are an effective and safe alternative to vitamin K antagonists in many fields of clinical practice. The use of the direct inhibitors of activated Factor II (dabigatran and activated Factor X (apixaban and rivaroxaban, both in patients with non-valvular atrial fibrillation (NVAF and those with acute venous thromboembolism (VTE, is of great interest for internal medicine physicians. This paper aims to give practical guidance on management (starting therapy, follow up and bleeding complications of patients treated with dabigatran, rivaroxaban or apixaban for NVAF or acute VTE providing practical tables concerning the phases of therapy, management of complications, drug interaction and dose adjustment if renal impairment occurs.

  5. A neural network approach in diabetes management by insulin administration.

    Science.gov (United States)

    Gogou, G; Maglaveras, N; Ambrosiadou, B V; Goulis, D; Pappas, C

    2001-04-01

    Diabetes management by insulin administration is based on medical experts' experience, intuition, and expertise. As there is very little information in medical literature concerning practical aspects of this issue, medical experts adopt their own rules for insulin regimen specification and dose adjustment. This paper investigates the application of a neural network approach for the development of a prototype system for knowledge classification in this domain. The system will further facilitate decision making for diabetic patient management by insulin administration. In particular, a generating algorithm for learning arbitrary classification is employed. The factors participating in the decision making were among other diabetes type, patient age, current treatment, glucose profile, physical activity, food intake, and desirable blood glucose control. The resulting system was trained with 100 cases and tested on 100 patient cases. The system proved to be applicable to this particular problem, classifying correctly 92% of the testing cases.

  6. Optimized management of advanced hepatocellular carcinoma: Four long-lasting responses to sorafenib

    Institute of Scientific and Technical Information of China (English)

    Giovanni Abbadessa; Lorenza Rimassa; Tiziana Pressiani; Cynthia Carrillo-Infante; Emanuele Cucchi; Armando Santoro

    2011-01-01

    The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate. Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC. Nevertheless, in clinical practice, some patients are discontinuing this drug because of side effects, and misinterpretation of radiographic response may contribute to this. We highlight the importance of prolonged sorafenib adadministration, even at reduced dose, and of qualitative and careful radiographic evaluation. We observed two partial and two complete responses, one histologically confirmed, with progression-free survival ranging from 12 to 62 mo. Three of the responses were achieved following substantial dose reductions, and a gradual change in lesion density preceded or paralleled tumor shrinkage, as seen by computed tomography. This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib, and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.

  7. Hyperkalemic distal renal tubular acidosis caused by immunosuppressant treatment with tacrolimus in a liver transplant patient: case report.

    Science.gov (United States)

    Riveiro-Barciela, M; Campos-Varela, I; Tovar, J L; Vargas, V; Simón-Talero, M; Ventura-Cots, M; Crespo, M; Bilbao, I; Castells, L

    2011-12-01

    Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.

  8. Measurement and reversal of the direct oral anticoagulants.

    Science.gov (United States)

    Samuelson, Bethany T; Cuker, Adam

    2017-01-01

    Direct oral anticoagulants (DOACs) offer noninferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Unlike VKAs, DOACs do not require routine laboratory monitoring of anticoagulant effect and dose adjustment. In certain situations, however, laboratory assessment of anticoagulant effect may be desirable. Here we review the utility of currently available assays for assessment of DOAC effect and recommend an optimal assessment strategy for each drug, including calibrated dilute thrombin time or ecarin-based assays for dabigatran and calibrated anti-Xa activity assays for the factor Xa inhibitors. We also discuss reversal strategies, both specific and nonspecific, for each drug, including the preferential use of idarucizumab for the reversal of dabigatran and two agents, andexanet and ciraparantag, currently under development for the reversal of rivaroxaban, apixaban, and edoxaban. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Partial Remission Definition

    DEFF Research Database (Denmark)

    Andersen, Marie Louise Max; Hougaard, Philip; Pörksen, Sven

    2014-01-01

    of type 1 diabetes (T1D). Receiver operating characteristic curve (ROC) analysis was used to evaluate the predictive value of IDAA1c and age on partial C-peptide remission (stimulated C-peptide, SCP > 300 pmol/L). RESULTS: PR (IDAA1c ≤ 9) in the Danish and Hvidoere cohorts occurred in 62 vs. 61% (3 months......OBJECTIVE: To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c). SUBJECTS AND METHODS: The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset...

  10. New definition for the partial remission period in children and adolescents with type 1 diabetes

    DEFF Research Database (Denmark)

    Mortensen, Henrik B; Hougaard, Philip; Swift, Peter

    2009-01-01

    the definition of an insulin dose-adjusted A1C (IDAA1C) as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)]. A calculated IDAA1C peptide >300 pmol/l was used to define partial remission. The IDAA1C ..., for a definition of insulin dose remission and 66 ended, and for stimulated C-peptide (>300 pmol/l) 9 patients entered partial remission and 49 ended. IDAA1C at 6 months has good predictive power for stimulated C-peptide concentrations after both 6......OBJECTIVE To find a simple definition of partial remission in type 1 diabetes that reflects both residual beta-cell function and efficacy of insulin treatment. RESEARCH DESIGN AND METHODS A total of 275 patients aged

  11. Circulating microRNA levels predict residual beta cell function and glycaemic control in children with type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Samandari, Nasim; Mirza, Aashiq H; Nielsen, Lotte B

    2017-01-01

    from the Danish Remission Phase Cohort, and profiled for miRNAs. At the same time points, meal-stimulated C-peptide and HbA1c levels were measured and insulin-dose adjusted HbA1c (IDAA1c) calculated. miRNAs that at 3 months after diagnosis predicted residual beta cell function and glycaemic control......, hsa-miR-197-3p, hsa-miR-301a-3p and hsa-miR-375) at 3 months correlated with residual beta cell function 6-12 months after diagnosis. Stimulated C-peptide at 12 months was predicted by hsa-miR-197-3p at 3 months (p = 0.034). A doubling of this miRNA level corresponded to a sixfold higher stimulated C-peptide...

  12. Pirfenidone treatment in idiopathic pulmonary fibrosis: nationwide Danish results

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    Goran Nadir Salih

    2016-09-01

    Full Text Available Background: Pirfenidone was approved by the European Medicines Agency and introduced in most European countries in 2011 for treatment of idiopathic pulmonary fibrosis (IPF. Objective: To describe the national Danish experiences of pirfenidone treatment for IPF during 30 months with respect to target population, safety, adherence to the treatment and effect analysis in a well-characterised IPF population in a real-life setting. Methods: Retrospective data collection from medical records of all patients in Denmark with IPF from 2011 to 2014. Data included baseline demographics, high-resolution computed tomography (HRCT, histopathology, forced vital capacity (FVC and 6-min walk test (6MWT. Longitudinal data on FVC, walk test, adherence to the treatment and vital status were also collected. Results: Pirfenidone treatment was initiated in 113 patients. Mean age was 69.6±8.1 years (±SD, and 71% were male. Definite IPF diagnosis required thoracoscopic lung biopsy in 45 patients (39.8%. The remaining 68 cases had a definite (64 patients or possible usual interstitial pneumonia (four patients pattern on HRCT. Patients were followed for 0.1–33.8 months (median 9.4 months. Fifty-one patients (45.2% needed dose adjustment, 18 (16% patients discontinued therapy and 13 patients (11.5% died. The annual mean decline in FVC was 164 ml (SE 33.2. The decline in 6MWT was 18.2 m (SE 11.2. Nausea (44.2%, fatigue (38.9% and skin reactions (32.7% were frequent adverse events. Conclusion: Patients with IPF treated with pirfenidone experienced tolerable adverse events. Patients were maintained on treatment due to a careful follow-up and dose adjustment programme. The annual decline in physiological parameters and mortality rate was comparable to previous randomised controlled trials.

  13. Pirfenidone treatment in idiopathic pulmonary fibrosis: nationwide Danish results

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    Salih, Goran Nadir; Shaker, Saher Burhan; Madsen, Helle Dall; Bendstrup, Elisabeth

    2016-01-01

    Background Pirfenidone was approved by the European Medicines Agency and introduced in most European countries in 2011 for treatment of idiopathic pulmonary fibrosis (IPF). Objective To describe the national Danish experiences of pirfenidone treatment for IPF during 30 months with respect to target population, safety, adherence to the treatment and effect analysis in a well-characterised IPF population in a real-life setting. Methods Retrospective data collection from medical records of all patients in Denmark with IPF from 2011 to 2014. Data included baseline demographics, high-resolution computed tomography (HRCT), histopathology, forced vital capacity (FVC) and 6-min walk test (6MWT). Longitudinal data on FVC, walk test, adherence to the treatment and vital status were also collected. Results Pirfenidone treatment was initiated in 113 patients. Mean age was 69.6±8.1 years (±SD), and 71% were male. Definite IPF diagnosis required thoracoscopic lung biopsy in 45 patients (39.8%). The remaining 68 cases had a definite (64 patients) or possible usual interstitial pneumonia (four patients) pattern on HRCT. Patients were followed for 0.1–33.8 months (median 9.4 months). Fifty-one patients (45.2%) needed dose adjustment, 18 (16%) patients discontinued therapy and 13 patients (11.5%) died. The annual mean decline in FVC was 164 ml (SE 33.2). The decline in 6MWT was 18.2 m (SE 11.2). Nausea (44.2%), fatigue (38.9%) and skin reactions (32.7%) were frequent adverse events. Conclusion Patients with IPF treated with pirfenidone experienced tolerable adverse events. Patients were maintained on treatment due to a careful follow-up and dose adjustment programme. The annual decline in physiological parameters and mortality rate was comparable to previous randomised controlled trials. PMID:27616539

  14. Mineralocorticoid replacement during infancy for salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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    Larissa G. Gomes

    2013-01-01

    Full Text Available OBJECTIVE: The protocols for glucocorticoid replacement in children with salt wasting 21-hydroxylase deficiency are well established; however, the current recommendation for mineralocorticoid replacement is general and suggests individualized dose adjustments. This study aims to retrospectively review the 9-∝-fludrocortisone dose regimen in salt wasting 21-hydroxylase deficient children who have been adequately treated during infancy. METHODS: Twenty-three salt wasting 21-hydroxylase deficient patients with good anthropometric and hormonal control were followed in our center since diagnosis. The assessments of cortisone acetate and 9-∝-fludrocortisone doses, anthropometric parameters, and biochemical and hormonal levels were rigorously evaluated in pre-determined intervals from diagnosis to two years of age. RESULTS: The 9-∝-fludrocortisone doses decreased over time during the first and second years of life; the median fludrocortisone doses were 200 µg at 0-6 months, 150 µg at 7-18 months and 125 µg at 19-24 months. The cortisone acetate dose per square meter was stable during follow-up (median = 16.8 mg/m²/day. The serum sodium, potassium and plasma rennin activity levels during treatment were normal, except in the first month of life, when periodic 9-∝-fludrocortisone dose adjustments were made. CONCLUSIONS: The mineralocorticoid needs of salt wasting 21-hydroxylase deficient patients are greater during early infancy and progressively decrease during the first two years of life, which confirms that a partial aldosterone resistance exists during this time. Our study proposes a safety regiment for mineralocorticoid replacement during this critical developmental period.

  15. Interaction of antiretroviral medications with finasteride

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    D Ward

    2012-11-01

    Full Text Available Antiretroviral medications are known inhibitors and inducers of cytochrome p450 enzymes and can affect levels of non-HIV medications. Finasteride 1 mg (Propecia, which prevents the conversion of testosterone (T to dihydrotestosterone (DHT is commonly prescribed for prevention of hair loss. This medication is a substrate of p450 3A4. Its efficacy may therefore be affected by HIV medications which induce or inhibit this enzyme. Levels of DHT to prevent hair loss are not well established, but likely need to be<15–20 ng/dl, or a DHT/T ratio of<0.02. Observational analysis in a private practice, measuring DHT and T levels in patients on finasteride and various antiretrovirals 21 patients were identified. 7 patients were taking protease inhibitors and had DHT levels<12 ng/dL; DHT/T<0.20. Three of these patients decreased their finasteride dose to 1 mg every-other-day and still have DHT <10. 8 patients were taking potent p450 inducers (efavirenz or etravirine and had DHT levels between >20; DHT/T>0.025. Two of these patients increased the dose of finasteride to 2 mg/day and subsequently decreased DHT to 14 and 17. Two additional patients on efavirenz, however, had DHT levels of<15 without dose adjustment. Four patients taking nevirapine, a less potent inducer of p450 had DHT levels of<15, as did one patient on raltegravir, which does not affect CYP450. Antiretrovirals that affect CYP 3A4 may interact with finasteride. While it is unlikely that this interaction is dangerous, it may affect its efficacy of the finasteride. Evaluation of DHT/T levels, and/or dose adjustment of finasteride may be appropriate in men being treated for HIV.

  16. A MULTICENTER, LONGITUDINAL, INTERVENTIONAL, DOUBLE BLIND RANDOMIZED CLINICAL TRIAL IN HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS RESIDING IN REMOTE AREAS: LESSONS LEARNED FROM THE LATE CYTOMEGALOVIRUS PREVENTION TRIAL.

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    Kimball, Louise E; Stevens-Ayers, Terry; Green, Margaret L; Xie, Hu; Flowers, Mary E D; Jerome, Keith R; LeBlanc, Renee; Dahlgren, Christi; Nichols, W Garrett; Chemaly, Roy F; Papanicolaou, G; Boeckh, Michael

    2016-12-15

    The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment. A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC <1.0 × 10(9) cells/L). Blood samples for viral testing and safety monitoring were shipped to a central laboratory by overnight carrier. Real-time communication was established between the coordinating center and study sites, primary care physicians, and study participants to facilitate starting, stopping and dose adjustments of antiviral drugs and G-CSF. The time required to make these interventions was analyzed. Of the 4169 scheduled blood specimens, 3832 (92%) were received and analyzed; the majority (97%) arriving at the central site within 2 days. Among subjects with positive CMV DNAemia (N=46), over 50% received open label antiviral medication within one day. The median time to start G-CSF for neutropenia was <1 day after posting of laboratory results (range 0-6; N=38). Study drug dose adjustments for abnormal renal function were implemented 203 times; within one day for 48% of cases and within 2 days for 80% of cases. Complex randomized, double-blind, multicenter interventional trials with treatment decisions made at a central coordinating site can be conducted safely and effectively according to Good Clinical

  17. Bisphosphonate treatment recommendations for oncologists.

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    von Moos, Roger

    2005-01-01

    Renal safety is an important consideration for oncologists who are treating patients with bisphosphonates. In recent years, there has been increasing awareness about the development of bisphosphonate-induced nephrotoxicity. This has emerged mainly from increased clinical experience with zoledronic acid (Zometa); Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com). For this reason, the U.S. and European product labels for i.v. zoledronic acid were recently updated to include additional renal safety cautions, including dose adjustment in patients with mild-to-moderate renal impairment. However, renal toxicity is not a class effect. The product label for ibandronate (Bondronat), F. Hoffmann-La Roche Ltd., Basel, Switzerland, http://www.roche.com) has remained unchanged since the launch of the drug in the European Union in 2003. Ibandronate does not require mandatory monitoring of kidney function prior to each infusion. In addition, ibandronate can be used in patients with varying degrees of renal impairment. It also can be used without restrictions for nephrotoxic medications, and dose adjustment is only required in patients with severe renal impairment. Clinical implications of the renal safety of ibandronate include reducing the physician and nursing time needed for managing the adverse renal events associated with bisphosphonate therapy and dosing based on renal function. There also are no added renal safety risks and fewer inconvenient hospital visits with ibandronate therapy. In addition to i.v. ibandronate, an oral formulation of the drug is available. Oral ibandronate therapy is especially desirable because the medication is convenient (with a small, once-daily tablet that can be taken at home), reducing the health care costs associated with infusions. Clinical studies also indicate that 50 mg oral ibandronate has an efficacy similar to that of i.v. bisphosphonates and is associated with a low incidence of adverse

  18. Extensive expertise in endocrinology. Adrenal crisis.

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    Allolio, Bruno

    2015-03-01

    Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5-10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100  mg followed by 200  mg over 24  h as continuous infusion) and 0.9% saline (1000  ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis. © 2015 European Society of Endocrinology.

  19. Anticoagulation Quality and Complications of using Vitamin K Antagonists in the Cardiac Surgery Outpatient Clinic

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    Mário Augusto Cray da Costa

    Full Text Available ABSTRACT Introduction: In patients with mechanical prosthetic heart valves or atrial fibrillation requiring anticoagulation to prevent thromboembolic events, several factors influence adherence and anticoagulation complications. Objective: To evaluate the factors that interfere with the quality and complications of anticoagulation with vitamin K antagonists. Methods: A retrospective cohort study of 100 patients, in the period from 2011 to 2014, was performed. Anticoagulation conditions in the last year, regarding the presence of complications (embolisms/bleeding and inadequate treatment were assessed: achievement of less than 8 annual prothrombin times and International Normalized Ratio outside therapeutic target in more than 40% of prothrombin times. Results: There were 31 complications (22 minor bleeding without hospitalization and 9 major complications: 7 bleeding with hospitalization and two emboli; 70 were with International Normalized Ratio outside the target in more than 40% of the tests and 36 with insufficient number of prothrombin times. Socioeconomic factors, anticoagulant type and anticoagulation reason had no relationship with complications or with inadequate treatment. There were more complications in patients with longer duration of anticoagulation (P=0.001. Women had more International Normalized Ratio outside the target range (OR 2.61, CI:1.0-6.5; P=0.04. Patients with lower number of annual prothrombin times had longer times of anticoagulation (P=0.03, less annual consultations (P=0.02 and less dose adjustments (P=0.003. Patients with longer duration of anticoagulation have more complications (P=0.001. Conclusion: There was a high rate of major complications and International Normalized Ratio was outside the goal. Less annual prothrombin times was related to longer duration of anticoagulation, less annual consultations and less dose adjustments. More major complications occurred in patients with longer duration of

  20. Intensive Individualized Reinforcement Education Is Important for the Prevention of Hypoglycemia in Patients with Type 2 Diabetes

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    Yun-Mi Yong

    2015-04-01

    Full Text Available BackgroundWe investigated whether an intensive individualized reinforcement education program could influence the prevention of hypoglycemic events in patients with type 2 diabetes.MethodsFrom March 2013 to September 2013, patients aged 35 to 75 years with type 2 diabetes who had not previously participated in diabetes education, and treated with insulin or a sulfonylurea-containing regimen were included in the study. After structured group education, the patients assigned to the intensive individualized education group (IT were requested to visit for reinforcement. All subjects in the IT were encouraged to self-manage dose adjustments. Participants in both groups (control group [CG, group education only; n=22] and IT [n=24] attended follow-up visits at 2, 8, 12, and 24 weeks. At each visit, all patients were asked whether they had experienced hypoglycemia.ResultsThe total study population consisted of 20 men (43.5%; mean age and diabetic duration of 55.9±11.0 and 5.1±7.3 years, respectively. At 24 weeks, there were no significant differences in hemoglobin A1c values between the CG and IT. The total number of hypoglycemic events per patient was 5.26±6.5 in the CG and 2.58±2.3 times in the IT (P=0.004. Adherence to lifestyle modification including frequency of exercise, self-monitoring of blood glucose, or dietary habit was not significantly different between the groups. However, adherence to hypoglycemia management, especially the dose adjustment of medication, was significantly higher in the IT compared with the CG.ConclusionCompared with the structured group education, additional IT resulted in additional benefits in terms of avoidance of hypoglycemia and treating hypoglycemia in patients with type 2 diabetes.

  1. [Mechanisms of action, pharmacology and interactions of dolutegravir].

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    Ribera, Esteban; Podzamczer, Daniel

    2015-03-01

    Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI), whose potential and binding half-life in the integrase are far superior to those of raltegravir and elvitegravir, conferring it with unique characteristics in terms of its genetic barrier to resistance and activity against viruses with one or more mutations in the integrase. The pharmacokinetic properties of dolutegravir allow once-daily dosing (50 mg), with or without food, maintaining concentrations far above those effective against wild-type viruses. If integrase resistance mutations are present, the recommended dosing regimen is 50 mg/12 h. The distribution of dolutegravir in cerebrospinal fluid is good and effective concentrations are also reached in the male and female genital tracts. Dolutegravir is metabolized by UGT1A1 and, to a lesser extent, by CYP3A4, without being an inducer or inhibitor of the usual metabolic systems. It has a very low potential for drug interactions and can be administered in routine doses with most drugs. Dose adjustment is not required, even in patients with renal insufficiency or mild or moderate liver failure. Increasing the dose of dolutegravir (50 mg/12 h) is only recommended when administered with efavirenz, nevirapine, fosamprenavir/r, tipranavir/r, rifampicin, carbamazepine, phenytoin and phenobarbital. Coadministration of dolutegravir with etravirine is not recommended without a protease inhibitor or with Hypericum perforatum. Dolutegravir should be administered 2 h before or 6 h after antacids or products with polyvalent cations. Dolutegravir can reduce renal tubule secretion of substances excreted via OCT2, with a slight initial increase in creatinine, with no risk of renal toxicity. The drug can also increase metformin concentrations and consequently monitoring is recommended in case dose adjustment is required. In summary, dolutegravir has excellent pharmacokinetic and drug interaction profiles. Copyright © 2015 Elsevier España, S

  2. Unrecognized renal insufficiency and chemotherapy-associated adverse effects among breast cancer patients.

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    Lotan, Eyal; Leader, Avi; Lishner, Michael; Gottfried, Maya; Pereg, David

    2012-10-01

    Several studies have shown that more than half of cancer patients have unrecognized renal insufficiency (RI), which is a reduced glomerular filtration rate (GFR) with normal serum creatinine. The aim of this study was to determine whether unrecognized RI is associated with an increased risk for chemotherapy-associated adverse effects in breast cancer patients treated with combined doxorubicin and cyclophosphamide treatment. GFR was estimated for 95 breast cancer patients from January 2005 to August 2009 using the Cockcroft-Gault formula. Unrecognized RI was defined as GFR less than 75 ml/min/1.73 m and the patients were grouped according to their estimated GFR. Logistic regression models were used to assess the effect of GFR on clinical outcomes. In total, 49 (52%) patients experienced at least one of the following chemotherapy-associated adverse effects during the course of treatment: an episode of neutropenic fever with hospital admission, a delay in chemotherapy treatment for a medical reason, a need for dose adjustment because of toxicity of the chemotherapeutic drugs, and the need for use of granulocyte colony-stimulating factor. The incidence of these adverse effects occurred more frequently in patients with GFR less than 75 compared with patients with GFR at least 75 (64 vs. 42%, odds ratio 5.29, 95% confidence interval 2.10-13.33) and remained statistically significant after adjustment for age, BMI, and initial doses of chemotherapeutic drugs (odds ratio 3.56, 95% confidence interval 1.08-11.67). Neutropenic fever, dose delay, and dose adjustment as separate outcomes occurred more frequently in the GFR less than 75 group but lost statistical significance after adjustment. Our results demonstrate that unrecognized RI is associated with an increased risk for chemotherapy-associated adverse events in this patient population. Further prospective studies are required to determine whether a dose reduction in patients with unrecognized RI reduces adverse effects

  3. Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel.

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    van Hasselt, J G C; van Calsteren, K; Heyns, L; Han, S; Mhallem Gziri, M; Schellens, J H M; Beijnen, J H; Huitema, A D R; Amant, F

    2014-10-01

    Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments. A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients. The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Teneligliptin in Management of Diabetic Kidney Disease: A Review of Place in Therapy

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    Mishra, Preetesh; Swami, Onkar C.

    2017-01-01

    Diabetes is a global health emergency of this century. Diabetic nephropathy is the most common microvascular complication associated with Type 2 Diabetes Mellitus (T2DM). T2DM has been reported as a major etiological factor in almost 45% of patients undergoing dialysis due to kidney failure. Lifestyle modifications; cessation of smoking, optimum control of blood glucose, blood pressure and lipids are required to reduce the progression of Diabetic Kidney Disease (DKD). Presently, Dipeptidyl peptidase-4 (DPP-4) inhibitors are preferred in the management of T2DM due to their established efficacy; favorable tolerability including, low risk of hypoglycaemia; weight neutrality and convenient once-a-day dosage. Present evidence suggests that linagliptin and teneligliptin can be used safely without dose adjustments in patients with T2DM with renal impairment, including End Stage Renal Disease (ESRD). There is a limited data about teneligliptin particularly in T2DM patients with renal impairment. The objective of this review is to evaluate efficacy and safety of teneligliptin in T2DM patients with renal impairment, in order to assess the current place in therapy and future prospects of teneligliptin. Reported evidence suggests that teneligliptin has consistent pharmacokinetic in mild, moderate, severe or ESRD, without any need for dose adjustments. Limited data from small sample studies of teneligliptin in DKD patients reported significant improvements in glycaemic parameters. Additionally, there is an improvement in kidney parameters like glycated albumin, urinary albumin and eGFR. There is an evidence of reduction in biomarkers of kidney impairment like P-selectin (sP-selectin), Platelet-Derived Microparticles (PDMPs) and Plasminogen Activator Inhibitor 1 (PAI-1). Clinical significance of these will be known in near future. Thus, teneligliptin has an important place of therapy in the management of T2DM with renal impairment. PMID:28273997

  5. Comparison of Approaches for Stroke Prophylaxis in Patients with Non-Valvular Atrial Fibrillation: Network Meta-Analyses of Randomized Controlled Trials

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    Patel, Nirav; Hashim, Taimoor; Godara, Hemant; Ather, Sameer; Arora, Garima; Pasala, Tilak; Whitfield, Thomas T.; McGiffin, David C.; Ahmed, Mustafa I.; Lloyd, Steven G.; Limdi, Nita A.

    2016-01-01

    Background Multiple novel oral anticoagulants and left atrial appendage closure devices (WATCHMAN) have been tested against dose-adjusted vitamin K antagonists in randomized controlled trials for stroke prophylaxis in non-valvular atrial fibrillation. No direct comparisons of these strategies are available from randomized controlled trials. We conducted the current analyses by combining efficacy and safety characteristics of all FDA approved stroke prophylaxis treatment strategies for patients with non-valvular atrial fibrillation. Materials and Methods We searched SCOPUS from 1945 till October 2015 for randomized controlled trials comparing these strategies and reporting efficacy and safety outcomes. Six randomized controlled trials were identified and included in the final analyses and review. We followed PRISMA guidelines for network meta-analyses while reporting the current analyses. We collected data on ischemic stroke, major bleeding, and the composite primary safety endpoint as defined by various randomized controlled trials. Network meta-analyses were conducted using consistency and inconsistency models for efficacy and safety outcomes. Surface under the cumulative ranking curve were then utilized to cluster rank these treatments for safety and efficacy. Results Six randomized controlled trials with 59,627 patients comparing six treatment strategies were eligible for the analyses. All prophylaxis strategies had comparable rates of ischemic stroke. Apixaban was associated with the least number of primary safety endpoint events as compared with all other treatments. In the cluster analyses assessing safety and efficacy, apixaban, edoxaban and dabigatran ranked best followed by vitamin K antagonists and rivaroxaban, whereas the WATCHMAN left atrial appendage closure device ranked last. Conclusions Dose-adjusted vitamin K antagonists, novel oral anticoagulants, and the WATCHMAN left atrial appendage closure devices are equally efficacious for ischemic stroke

  6. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis.

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    Wilma Potze

    Full Text Available BACKGROUND: Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known. OBJECTIVES: We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis. PATIENTS/METHODS: Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs. RESULTS: Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001. The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma. CONCLUSIONS: The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis.

  7. Approaching low liver iron burden in chelated patients with non-transfusion-dependent thalassemia: the safety profile of deferasirox

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    Taher, Ali T; Porter, John B; Viprakasit, Vip; Kattamis, Antonis; Chuncharunee, Suporn; Sutcharitchan, Pranee; Siritanaratkul, Noppadol; Origa, Raffaella; Karakas, Zeynep; Habr, Dany; Zhu, Zewen; Cappellini, M Domenica

    2014-01-01

    Objective Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3. Methods THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10 mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6 months before reaching LIC<3 (Period 1), and the 6 months immediately before achieving LIC<3 (Period 2). Results Mean ± SD deferasirox treatment duration up to reaching LIC<3 was 476 ± 207 d, and deferasirox dose was 9.7 ± 3.0 mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LIC<3 compared with measurements near the previous LIC assessment. Conclusions The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation. PMID:24460655

  8. Factors Affecting Patients' Perception On, and Adherence To, Anticoagulant Therapy: Anticipating the Role of Direct Oral Anticoagulants.

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    Pandya, Ekta Y; Bajorek, Beata

    2017-04-01

    The role of the direct oral anticoagulants (DOACs) in practice has been given extensive consideration recently, albeit largely from the clinician's perspective. However, the effectiveness and safety of using anticoagulants is highly dependent on the patient's ability to manage and take these complex, high-risk medicines. This structured narrative review explores the published literature to identify the factors underpinning patients' non-adherence to anticoagulants in atrial fibrillation (AF), and subsequently contemplates to what extent the DOACs might overcome the known challenges with traditional warfarin therapy. This review comprised a two-tier search of various databases and search platforms (CINAHL, Cochrane, Current Contents Connect, EMBASE, MEDLINE Ovid, EBSCO, PubMed, Google, Google Scholar) to yield 47 articles reporting patients perspectives on, and patients adherence to, anticoagulant therapy. The findings from the literature were synthesised under five interacting dimensions of adherence: therapy-related factors, patient-related factors, condition-related factors, social-economic factors and health system factors. Factors negatively affecting patients' day-to-day lives (especially regular therapeutic drug monitoring, dose adjustments, dietary considerations) predominantly underpin a patient's reluctance to take warfarin therapy, leading to non-adherence. Other patient-related factors underpinning non-adherence include patients' perceptions and knowledge about the purpose of anticoagulation; understanding of the risks and benefits of therapy; socioeconomic status; and expectations of care from health professionals. In considering these findings, it is apparent that the DOACs may overcome some of the barriers to traditional warfarin therapy at least to an extent, particularly the need for regular monitoring, frequent dose adjustment and dietary considerations. However, their high cost, twice-daily dosing and gastrointestinal adverse effects may present

  9. Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Lyubov Chaykovska

    Full Text Available BACKGROUND: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD patients. Glucagon-like peptide-1 (GLP-1 may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4. METHODOLOGY/PRINCIPAL FINDINGS: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞ in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞ values; 41% and 28% (p = 0.0001 and p = 0.0324, respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h (p = 0.01. The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. CONCLUSIONS/SIGNIFICANCE: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP. Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

  10. Renal Drug Dosing. Effectiveness of Outpatient Pharmacist-Based vs. Prescriber-Based Clinical Decision Support Systems.

    Science.gov (United States)

    Vogel, Erin A; Billups, Sarah J; Herner, Sheryl J; Delate, Thomas

    2016-07-27

    The purpose of this study was to compare the effectiveness of an outpatient renal dose adjustment alert via a computerized provider order entry (CPOE) clinical decision support system (CDSS) versus a CDSS with alerts made to dispensing pharmacists. This was a retrospective analysis of patients with renal impairment and 30 medications that are contraindicated or require dose-adjustment in such patients. The primary outcome was the rate of renal dosing errors for study medications that were dispensed between August and December 2013, when a pharmacist-based CDSS was in place, versus August through December 2014, when a prescriber-based CDSS was in place. A dosing error was defined as a prescription for one of the study medications dispensed to a patient where the medication was contraindicated or improperly dosed based on the patient's renal function. The denominator was all prescriptions for the study medications dispensed during each respective study period. During the pharmacist- and prescriber-based CDSS study periods, 49,054 and 50,678 prescriptions, respectively, were dispensed for one of the included medications. Of these, 878 (1.8%) and 758 (1.5%) prescriptions were dispensed to patients with renal impairment in the respective study periods. Patients in each group were similar with respect to age, sex, and renal function stage. Overall, the five-month error rate was 0.38%. Error rates were similar between the two groups: 0.36% and 0.40% in the pharmacist- and prescriber-based CDSS, respectively (p=0.523). The medication with the highest error rate was dofetilide (0.51% overall) while the medications with the lowest error rate were dabigatran, fondaparinux, and spironolactone (0.00% overall). Prescriber- and pharmacist-based CDSS provided comparable, low rates of potential medication errors. Future studies should be undertaken to examine patient benefits of the prescriber-based CDSS.

  11. Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide.

    Science.gov (United States)

    Chen, Nianhang; Zhou, Simon; Palmisano, Maria

    2017-02-01

    Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration-time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3-4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug-drug interactions.

  12. Body mass index (BMI) but not body weight is associated with changes in the metabolism of risperidone; A pharmacokinetics-based hypothesis.

    Science.gov (United States)

    Paulzen, Michael; Haen, Ekkehard; Stegmann, Benedikt; Hiemke, Christoph; Gründer, Gerhard; Lammertz, Sarah E; Schoretsanitis, Georgios

    2016-11-01

    We sought to unravel the influence of body weight and body mass index (BMI), both consistently reported as pharmacokinetic relevant parameters, on metabolism of risperidone in a naturalistic sample. Conducting non parametrical tests we sought for correlations between plasma concentrations of RIS, 9-OH-RIS and AM and body weight and BMI in patients out of a therapeutic drug monitoring (TDM) database. Further, we stratified patients to three groups based upon BMI values and compared drug concentrations between groups. Although body weight failed to correlate with pharmacokinetic parameters, BMI was positively correlated with plasma concentrations of the active metabolite (9-OH-RIS) (rs=0.121, p=0.002) and active moiety (sum of RIS+9-OH-RIS) (rs=0.128, p=0.001) as well as dose adjusted plasma concentrations of the active moiety (rs=0.08, p=0.04). The comparison of pharmacokinetic parameters between different BMI groups yielded lower plasma concentrations of 9-OH-RIS in patients with low BMI (BMI ≥30kg/m(2)) when compared with the control group (30>BMI≥20kg/m(2)). By comparing low vs. high BMI patients, the latter group showed higher 9-OH-RIS plasma concentrations. Considerable alterations in metabolism of risperidone were detected when comparing obese and cachectic patients with the control group in alignment with the positive correlation between BMI values and plasma concentrations of the active metabolite and active moiety as well as dose adjusted plasma concentrations of the active moiety. We suggest changes in CYP2D6 or CYP3A4 activity or differences in P-glycoprotein function in obese patients with greater BMI as a plausible mechanism underlying these alterations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Effect of active infection on cytochrome P450-mediated metabolism of cyclosporine in renal transplant patients.

    Science.gov (United States)

    Hegazy, S K; Adam, A G; Hamdy, N A; Khalafallah, N M

    2015-06-01

    Infections downregulate cytochrome-P activities and thus may alter drug disposition, especially for drugs with a narrow therapeutic index. Cyclosporine (CyA), still used for the prevention of allograft rejection in renal transplant recipients in Egypt, seems to be affected by these infectious changes, based on random clinical observations. In the present study, the effects of bacterial and fungal infection on CyA metabolism were studied in renal transplant patients and subsequent nephrotoxicity was monitored. Twenty renal transplant patients, diagnosed with fungal or bacterial infection, were recruited from the renal transplantation outpatient clinic in Alexandria University Hospitals. No dose adjustment in CyA was performed at least 1 week before the onset of infection. Exclusion criteria were patients with acute or chronic unstable liver disease, elderly patients, and patients on concomitant drugs affecting CyA metabolism. CyA trough levels and serum creatinine (SCR) concentrations were measured by fluorescence polarization immunoassay and enzymatic assay, respectively, pre-infection, during infection and in many cases, post infection. CyA trough levels and SCR concentrations increased significantly during the infection (P < 0.001, P = 0.002) respectively. Of the patients, 87% experienced a concomitant rise in CyA trough level and SCR concentrations. No significant difference between pre-infection and post-infection levels of CyA trough and SCR was found. CyA trough and SCR levels increased during bacterial and fungal infections and returned to pre-infection levels once the infection was resolved. The data generated stress the importance of monitoring CyA levels during episodes of infection. Our recommendations concerning CyA dose adjustment differ according to severity and duration of infection. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Renal graft function and low-dose cyclosporine affect mycophenolic acid pharmacokinetics in kidney transplantation.

    Science.gov (United States)

    Cortinovis, Monica; Gotti, Eliana; Pradini, Silvia; Gaspari, Flavio; Perico, Norberto

    2011-09-15

    In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined. One hundred thirty-five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis. Dose-adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose-adjusted MPA AUC0-12 was higher (Prenal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12. In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency.

  15. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia: Clinical Facts and Fiction

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    Nielsen, Stine N.; Frandsen, Thomas L.; Nersting, Jacob

    2014-01-01

    The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients’ ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments

  16. [Analysis of adverse reactions induced by subcutaneous immunotherapy against dust mite allergy in 234 cases with allergic rhinitis and asthma].

    Science.gov (United States)

    Li, Meng-rong; Wang, Xiao-ning; Jiang, Han-dan; Wang, Qiong-yan; Li, Ying-chun; Lin, Jian; Jin, Ke; Zhang, Hai-lin; Li, Chang-chong

    2012-10-01

    To investigate the incidence of local reactions (LRs) and systemic reactions (SRs) of subcutaneous immunotherapy (SCIT) and to analyze the potential risk factors of such reactions in Chinese population. This is a retrospective study on 234 dust mite sensitized patients with allergic rhinitis and asthma who received allergen immunotherapy in our hospital from 2003 to 2010. Chart review was conducted to capture clinical data of reactions to immunotherapy. Parameters included signs and symptoms, the onset of reaction, and interventions in treating such reactions, particularly, the administration of epinephrine (EPI) and adjustment of vaccine dosage due to LRs and SRs. The 234 patients received a total of 7679 injections. Among them, 4973 LRs (64.8%) and 235 SRs (3.1%) were observed in 67 patients (28.6% of all patients). SRs included respiratory symptoms (205 events, 88.4%) and cutaneous symptoms (31.5%). Of the total of 235 SR events, 212 (90.2%) were presented as mild SRs and 23 (9.8%) were in severe SR category (grade III and grade IV, EAACI grading system). Overall, severe SRs accounted for 0.3% of total injections. Seventeen of the 23 SR events required epinephrine treatment (0.2% of total injections). Of the 67 patients, 61 completed the course of treatment after dose adjustment; 36 patients had their doses decreased prior to further advancing to target dose. Nineteen subjects tolerated splitting two injections at 30 minutes interval. Six patients advanced the dose based on protocol and another 6 had to stop immunotherapy. Most of the SRs (77.4%) occurred during the maintenance phase of immunotherapy. The levels of TIgE, SIgE D1 and SIgE D2 were found to be significantly higher in patients with SRs comparing to patients without SRs (P < 0.05). SRs more commonly occurred in patients with age less than 14 years than their older counterparts (95.5% vs. 85.6%, OR = 3.58, 95%CI = 1.040 - 12.322, P < 0.01). The incidence of SRs were significantly higher in asthma

  17. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

    Science.gov (United States)

    Jolliffe, David A; Hooper, Richard L; Greenberg, Lauren; Aloia, John F; Bergman, Peter; Dubnov-Raz, Gal; Esposito, Susanna; Ganmaa, Davaasambuu; Ginde, Adit A; Goodall, Emma C; Grant, Cameron C; Griffiths, Christopher J; Janssens, Wim; Laaksi, Ilkka; Manaseki-Holland, Semira; Mauger, David; Murdoch, David R; Neale, Rachel; Rees, Judy R; Simpson, Steve; Stelmach, Iwona; Kumar, Geeta Trilok; Urashima, Mitsuyoshi; Camargo, Carlos A

    2017-01-01

    Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not

  18. Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study.

    Science.gov (United States)

    Stroes, Erik; Guyton, John R; Lepor, Norman; Civeira, Fernando; Gaudet, Daniel; Watts, Gerald F; Baccara-Dinet, Marie T; Lecorps, Guillaume; Manvelian, Garen; Farnier, Michel

    2016-09-13

    The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events. Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879. © 2016 The Authors, Sanofi, and Regeneron Pharmaceuticals, Inc. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  19. Evaluation of the appropriate use of commonly prescribed fluoroquinolones and the risk of dysglycemia

    Directory of Open Access Journals (Sweden)

    Kabbara WK

    2015-04-01

    Full Text Available Wissam K Kabbara,1 Wijdan H Ramadan,1 Peggy Rahbany,2 Souhaila Al-Natour3 1Department of Pharmacy Practice, School of Pharmacy, Lebanese American University, Byblos, Lebanon; 2Children’s National Medical Center, Washington, DC, USA; 3Medex Pharmaceutical Company, Beirut, Lebanon Background: Fluoroquinolones are among the most widely prescribed antibiotics. However, concerns about increasing resistant microorganisms and the risk of dysglycemia associated with the use of these agents have emerged.Objective: The primary objective of the study was to evaluate the appropriate use of commonly prescribed fluoroquinolones, including appropriate indication, dose, dose adjustment in renal impairment, and duration of treatment. The secondary objective was to investigate the dysglycemic effect of fluoroquinolone use (hypoglycemia and/or hyperglycemia in diabetic and nondiabetic patients.Methods: A prospective observational study at a teaching hospital in Lebanon was conducted over a 6-month period. A total of 118 patients receiving broad-spectrum fluoroquinolones (levofloxacin, ciprofloxacin, and moxifloxacin were identified. Patients were mainly recruited from internal medicine floors and intensive care units.Results: The final percentage for the appropriate indication, dose, and duration of fluoroquinolone therapy was 93.2%, 74.6%, and 57.6%, respectively. A total of 57.1% of the patients did not receive the appropriate dose adjustment according to their level of renal impairment. In addition, dysglycemia occurred in both diabetic and nondiabetic patients. Dysglycemia was more frequently encountered with ciprofloxacin (50.0%, followed by levofloxacin (42.4% and moxifloxacin (7.6%. Hyperglycemia was more common than hypoglycemia in all groups. The highest incidence of hyperglycemia occurred with levofloxacin (70.0%, followed by ciprofloxacin (39.0% and moxifloxacin (33.3%. In contrast, hypoglycemia did not occur in the ciprofloxacin group, but it was

  20. HIV and chronic kidney disease.

    Science.gov (United States)

    Naicker, Saraladevi; Rahmanian, Sadaf; Kopp, Jeffrey B

    2015-01-01

    Chronic kidney disease (CKD) is a frequent complication of HIV infection, occurring in 3.5 - 48.5%, and occurs as a complication of HIV infection, other co-morbid disease and infections and as a consequence of therapy of HIV infection and its complications. The classic involvement of the kidney by HIV infection is HIV-associated nephropathy (HIVAN), occurring typically in young adults of African ancestry with advanced HIV disease in association with APOL1 high-risk variants. HIV-immune complex disease is the second most common diagnosis obtained from biopsies of patients with HIV-CKD. CKD is mediated by factors related to the virus, host genetic predisposition and environmental factors. The host response to HIV infection may influence disease phenotype through activation of cytokine pathways. With the introduction of antiretroviral therapy (ART), there has been a decline in the incidence of HIVAN, with an increasing prevalence of focal segmental glomerulosclerosis. Several studies have demonstrated the overall improvement in kidney function when initiating ART for HIV CKD. Progression to end stage kidney disease has been reported to be more likely when high grade proteinuria, severely reduced eGFR, hepatitis B and/C co-infection, diabetes mellitus, extensive glomerulosclerosis, and chronic interstitial fibrosis are present. Improved renal survival is associated with use of renin angiotensin system blockers and viral suppression. Many antiretroviral medications are partially or completely eliminated by the kidney and require dose adjustment in CKD. Certain drug classes, such as the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors, are metabolized by the liver and do not require dose adjustment. HIV-infected patients requiring either hemo- or peritoneal dialysis, who are stable on ART, are achieving survival rates comparable to those of dialysis patients without HIV infection. Kidney transplantation has been performed successfully in HIV

  1. Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma

    Science.gov (United States)

    Veal, Gareth J.; Errington, Julie; Rowbotham, Sophie E.; Illingworth, Nicola A.; Malik, Ghada; Cole, Michael; Daly, Ann K.; Pearson, Andrew D.J.; Boddy, Alan V.

    2012-01-01

    Purpose To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cisRA disposition in high-risk neuroblastoma patients. Experimental Design 13cisRA (160mg/m2 or 5.33mg/kg/day) was administered to 103 patients ≤21 years and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. 71 patients were recruited to a dose adjustment group, targeting a 13-cisRA Cmax of 2μM, with dose increases of 25-50% implemented for patients with Cmax values 2μM. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations >2μM in 18 patients (90%). 8/11 (73%) patients <12kg, receiving a dose of 5.33mg/kg, failed to achieve a Cmax ≥2μM. Significantly lower Cmax values were observed for patients treated with 5.33mg/kg versus 160mg/m2 (1.9±1.2 versus 3.1±2.0μM; mean±SD; P=0.023). Cmax was higher in patients who swallowed 13-cisRA capsules as compared to receiving the drug extracted from capsules (4.0±2.2 versus 2.6±1.8μM; P=0.0012). The target Cmax was achieved by 93% (25/27) versus 55% (42/76) of patients in these two groups respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters. Conclusions Dosing regimen and method of administration have a marked influence on 13-cisRA plasma concentrations. Body weight-based dosing should not be implemented for children <12kg and pharmacological data support higher doses for children unable to swallow 13-cisRA capsules. PMID:23087409

  2. Pharmacokinetic-pharmacodynamic correlation of imipenem in pediatric burn patients using a bioanalytical liquid chromatographic method

    Directory of Open Access Journals (Sweden)

    Silvia Regina Cavani Jorge Santos

    2015-06-01

    Full Text Available A bioanalytical method was developed and applied to quantify the free imipenem concentrations for pharmacokinetics and PK/PD correlation studies of the dose adjustments required to maintain antimicrobial effectiveness in pediatric burn patients. A reverse-phase Supelcosil LC18 column (250 x 4.6 mm 5 micra, binary mobile phase consisting of 0.01 M, pH 7.0 phosphate buffer and acetonitrile (99:1, v/v, flow rate of 0.8 mL/min, was applied. The method showed good absolute recovery (above 90%, good linearity (0.25-100.0 µg/mL, r2=0.999, good sensitivity (LLOQ: 0.25 µg/mL; LLOD: 0.12 µg/mL and acceptable stability. Inter/intraday precision values were 7.3/5.9%, and mean accuracy was 92.9%. A bioanalytical method was applied to quantify free drug concentrations in children with burns. Six pediatric burn patients (median 7.0 years old, 27.5 kg, normal renal function, and 33% total burn surface area were prospectively investigated; inhalation injuries were present in 4/6 (67% of the patients. Plasma monitoring and PK assessments were performed using a serial blood sample collection for each set, totaling 10 sets. The PK/PD target attained (40%T>MIC for each minimum inhibitory concentration (MIC: 0.5, 1.0, 2.0, 4.0 mg/L occurred at a percentage higher than 80% of the sets investigated and 100% after dose adjustment. In conclusion, the purification of plasma samples using an ultrafiltration technique followed by quantification of imipenem plasma measurements using the LC method is quite simple, useful, and requires small volumes for blood sampling. In addition, a small amount of plasma (0.25 mL is needed to guarantee drug effectiveness in pediatric burn patients. There is also a low risk of neurotoxicity, which is important because pharmacokinetics are unpredictable in these critical patients with severe hospital infection. Finally, the PK/PD target was attained for imipenem in the control of sepsis in pediatric patients with burns.

  3. Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity.

    Science.gov (United States)

    Murthy, Bindu; Schmitt-Hoffmann, Anne

    2008-01-01

    has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.

  4. Probability of target attainment for ceftobiprole as derived from a population pharmacokinetic analysis of 150 subjects.

    Science.gov (United States)

    Lodise, Thomas P; Pypstra, Rienk; Kahn, James B; Murthy, Bindu P; Kimko, Hui C; Bush, Karen; Noel, Gary J; Drusano, George L

    2007-07-01

    Ceftobiprole is a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) that is undergoing phase III trials for the treatment of complicated skin and skin structure infections and nosocomial pneumonia. The objectives were to describe the pharmacodynamic profiles of ceftobiprole given at 500 mg intravenously (i.v.) every 8 h (q8h) (2-h infusion) and 500 mg i.v. every 12 h (q12h) (1-h infusion) to determine the overall probability of target attainment (PTA) by weighting for the expected distributions of renal function in the populations of interests, to determine the PTA against representative pathogens encountered in clinical trials, and to determine the optimal renal dose adjustment for ceftobiprole at 500 mg i.v. q8h (2-h infusion). Data for a total of 150 subjects in phase I/II trials were analyzed by using the population pharmacokinetic modeling program BigNPOD (nonparametric optimal design). Monte Carlo simulation was performed with the ADAPT II program to estimate the PTA at which the free drug concentrations exceed the MIC for 30 to 60% of the dosing interval (30 to 60% fT > MIC). For ceftobiprole at 500 mg i.v. q12h, the probabilities of achieving 30% and 50% fT > MIC exceeded 90% for MICs ceftobiprole at 500 mg i.v. q8h, the probabilities of achieving 40 and 60% fT > MIC exceeded 90% for MICs ceftobiprole at both 500 mg i.v. q12h and 500 mg i.v. q8h, the probability of achieving a nearly bactericidal effect (50% fT > MIC) exceeded 90% for methicillin-susceptible S. aureus and MRSA. For gram-negative pathogens, the PTA for achieving a nearly maximal bactericidal effect (60% fT > MIC) for ceftobiprole at 500 mg i.v. q8h exceeded 90% for non-AmpC-producing gram-negative organisms. Ceftobiprole at 500 mg i.v. q12h, for patients who had a creatinine clearance rate of < or =50 ml/min, was identified as the most appropriate treatment regimen for patients who require renal dose adjustment for mild to moderate renal

  5. Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients.

    Science.gov (United States)

    Żochowska, Dorota; Wyzgał, Janusz; Pączek, Leszek

    2012-01-01

    Calcineurin inhibitor (cyclosporine, CsA) and mTOR inhibitors (sirolimus, SRL) - immunosuppressants used to prevent allograft rejection after renal transplantation - have a narrow therapeutic index and show considerable inter-individual pharmacokinetic differences. Differences in expression and activity of cytochrome P450 (CYP) 3A4 and 3A5 affect these pharmacokinetics; cytochrome activity differences are associated with CYP genetic polymorphisms. This study evaluated the effects of polymorphisms in CYP3A4 and CYP3A5 on immunosuppressive drug-dose adjusted trough blood concentrations. One hundred renal transplant recipients were genotyped for CYP3A4*1B and CYP3A5*3 using PCR-RFLP. Blood concentrations of CsA and SRL were determined by EMIT and HPLC/UV, respectively. The allelic frequencies of CYP3A4*1B and CYP3A5*3 in the study group were 2.5% and 96.5%, respectively. The mean cyclosporine dose in CYP3A4*1/*1B subjects was 455.04±128.68 mg/day vs. 261.68±64.72 mg/day in CYP3A4*1/*1 subjects (pcyclosporine dose-adjusted trough blood concentrations (ng/ml per mg/kg body weight) in CYP3A4*1/*1B subjects were lower than in the CYP3A4*1/*1 group (37.06±10.38 vs. 44.63±13.99; pcyclosporine dose in CYP3A5*1/*3 subjects was 400.65±164.97 mg/day vs. 263.52±64.39 mg/day in CYP3A5*3/*3 subjects (pcyclosporine pharmacokinetics after renal transplantation. Patients with at least 1 functional CYP3A5*1 or CYP3A4*1B allele require significantly higher doses of cyclosporine to reach target drug levels compared to patients with the CYP3A4*1 or CYP3A5*3 alleles.

  6. Supporting self-management after attending a structured education programme: a qualitative longitudinal investigation of type 1 diabetes patients’ experiences and views

    Directory of Open Access Journals (Sweden)

    Rankin David

    2012-08-01

    Full Text Available Abstract Background Structured education programmes for patients with diabetes and other chronic conditions are being widely adopted. However, follow-up studies suggest that course graduates may struggle to sustain the self-care practices taught on their courses over time. This study explored the support needs of patients with type 1 diabetes after attending a structured education programme promoting an empowerment approach and training in use of flexible intensive insulin therapy, a regimen now widely advocated and used to manage this condition. The objective was to inform future support offered to course graduates. Methods Repeat, in-depth interviews with 30 type 1 diabetes patients after attending Dose Adjustment for Normal Eating (DAFNE courses in the UK, and six and 12 months later. Data were analysed using an inductive, thematic approach. Results While the flexible intensive insulin treatment approach taught on DAFNE courses was seen as a logical and effective way of managing one’s diabetes, it was also considered more technically complex than other insulin regimens. To sustain effective disease self-management using flexible intensive insulin treatment over time, patients often expected, and needed, on-going input and support from health care professionals trained in the approach. This included: help determining insulin dose adjustments; reassurance; and, opportunities to trouble-shoot issues of concern. While some benefits were identified to receiving follow-up support in a group setting, most patients stated a preference or need for tailored and individualised support from appropriately-trained clinicians, accessible on an ‘as and when needed’ basis. Conclusions Our findings highlight potential limitations to group-based forms of follow-up support for sustaining diabetes self-management. To maintain the clinical benefits of structured education for patients with type 1 diabetes over time, course graduates may benefit from and

  7. Optimization of Cyclosporine Therapy with Predicted AUC in Renal Transplant Patients

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    increased and give misleading in dose adjustment. [Conclusions] Predicted AUC by C0/C2 equation is the best precise estimator of total CsA exposure in renal transplant patients. Rational basis for dose adjustments and reduce incidence of graft rejection. Pharmacodynamic level is still a problem in transplant patients. Which level of AUC should be taken for our patient to prolong the survival time must be the future work in our unit.

  8. Use of febuxostat in the management of gout in the United Kingdom

    Science.gov (United States)

    Waller, Arabella; Jordan, Kelsey M.

    2016-01-01

    Gout is the most common cause of inflammatory arthritis worldwide. Despite clinical cure being achievable and multiple evidence-based guidelines having been published, the incidence and prevalence continues to increase and the condition remains undertreated. Concerns regarding allopurinol have limited its use in those with renal impairment. Febuxostat, a novel xanthine oxidase inhibitor requiring no dose adjustment in mild−moderate renal impairment was launched in the United Kingdom (UK) in 2010. We review published data on the efficacy, safety and tolerability of febuxostat and provide an opinion on its place in the management of gout in the UK in the context of other published guidelines. One phase II trial, multiple phase III trials [febuxostat versus allopurinol controlled trial (FACT), APEX, CONFIRMS] and two open-label extension trials have demonstrated febuxostat given at the doses commonly used in UK practice (80 mg, 120 mg) to reduce serum urate more effectively than those receiving fixed-dose allopurinol. Overall adverse event rates were comparable across treatment groups aside from gout flare (more common in febuxostat-treated patients) and concerns regarding cardiovascular toxicity are being further evaluated in two large trials. If the outcomes of these are favourable, we would anticipate a marked increase in the use of febuxostat in the UK market. We would advocate the use of febuxostat to target a serum urate gouty flare with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or Cyclo-oxygenase-2 selective NSAID (COXIB) after febuxostat initiation. PMID:28255339

  9. Prospective evaluation of pregnant women with hypothyroidism: implications for treatment.

    Science.gov (United States)

    Neto, Leonardo Vieira; De Almeida, Carla Amaral; Da Costa, Sheila Mamede; Vaisman, Mário

    2007-03-01

    Pregnancy is characterized by a series of maternal hormonal and metabolic changes which can affect thyroid function and the course of thyroid dysfunction in different ways. Moreover, hypothyroidism is also associated with obstetric complications and morbidity to the fetus. The aim of the present study was to evaluate the influence of hypothyroidism during the course of pregnancy and the necessity of adjusting the dose of levothyroxine. We prospectively followed 16 patients with previous diagnosis of hypothyroidism. In ten patients (62.5%) it was necessary to raise the dose of levothyroxine, with a median increase of 20.7%. One pregnancy was complicated by premature amniorrhexis and two by pre-eclampsia. The screening for congenital hypothyroidism was negative in all newborns. We conclude that it is very important to offer screening to high-risk patients who wish to become pregnant. Dose adjustment based on serum levels of thyroid-stimulating hormone (TSH) is essential. In patients in whom TSH is not measured during the first weeks of pregnancy, a good approach could be to increase the dose of replacement therapy by 20-25% to avoid hypothyroidism.

  10. Transdermal testosterone replacement therapy in men

    Directory of Open Access Journals (Sweden)

    Ullah MI

    2014-01-01

    Full Text Available M Iftekhar Ullah,1 Daniel M Riche,1,2 Christian A Koch1,31Department of Medicine, University of Mississippi Medical Center, 2Department of Pharmacy Practice, The University of Mississippi, 3GV (Sonny Montgomery VA Medical Center, Jackson, MS, USAAbstract: Androgen deficiency syndrome in men is a frequently diagnosed condition associated with clinical symptoms including fatigue, decreased libido, erectile dysfunction, and metabolic syndrome. Serum testosterone concentrations decline steadily with age. The prevalence of androgen deficiency syndrome in men varies depending on the age group, known and unknown comorbidities, and the respective study group. Reported prevalence rates may be underestimated, as not every man with symptoms of androgen deficiency seeks treatment. Additionally, men reporting symptoms of androgen deficiency may not be correctly diagnosed due to the vagueness of the symptom quality. The treatment of androgen deficiency syndrome or male hypogonadism may sometimes be difficult due to various reasons. There is no consensus as to when to start treating a respective man or with regards to the best treatment option for an individual patient. There is also lack of familiarity with treatment options among general practitioners. The formulations currently available on the market are generally expensive and dose adjustment protocols for each differ. All these factors add to the complexity of testosterone replacement therapy. In this article we will discuss the general indications of transdermal testosterone replacement therapy, available formulations, dosage, application sites, and recommended titration schedule.Keywords: hypogonadism, transdermal, testosterone, sexual function, testosterone replacement therapy, estradiol

  11. Transdermal testosterone replacement therapy in men.

    Science.gov (United States)

    Ullah, M Iftekhar; Riche, Daniel M; Koch, Christian A

    2014-01-01

    Androgen deficiency syndrome in men is a frequently diagnosed condition associated with clinical symptoms including fatigue, decreased libido, erectile dysfunction, and metabolic syndrome. Serum testosterone concentrations decline steadily with age. The prevalence of androgen deficiency syndrome in men varies depending on the age group, known and unknown comorbidities, and the respective study group. Reported prevalence rates may be underestimated, as not every man with symptoms of androgen deficiency seeks treatment. Additionally, men reporting symptoms of androgen deficiency may not be correctly diagnosed due to the vagueness of the symptom quality. The treatment of androgen deficiency syndrome or male hypogonadism may sometimes be difficult due to various reasons. There is no consensus as to when to start treating a respective man or with regards to the best treatment option for an individual patient. There is also lack of familiarity with treatment options among general practitioners. The formulations currently available on the market are generally expensive and dose adjustment protocols for each differ. All these factors add to the complexity of testosterone replacement therapy. In this article we will discuss the general indications of transdermal testosterone replacement therapy, available formulations, dosage, application sites, and recommended titration schedule.

  12. Qualitative assessment of user experiences of a novel smart phone application designed to support flexible intensive insulin therapy in type 1 diabetes.

    Science.gov (United States)

    Knight, Brigid A; McIntyre, H David; Hickman, Ingrid J; Noud, Marina

    2016-09-15

    Modern flexible multiple daily injection (MDI) therapy requires people with diabetes to manage complex mathematical calculations to determine insulin doses on a day to day basis. Automated bolus calculators assist with these calculations, add additional functionality to protect against hypoglycaemia and enhance the record keeping process, however uptake and use depends on the devices meeting the needs of the user. We aimed to obtain user feedback on the usability of a mobile phone bolus calculator application in adults with T1DM to inform future development of mobile phone diabetes support applications. Adults with T1DM who had previously received education in flexible MDI therapy were invited to participate. Eligible respondents attended app education and one month later participated in a focus group to provide feedback on the features of the app in relation to usability for patient-based flexible MDI and future app development. Seven adults participated in the app training and follow up interview. App features that support dose adjustment to reduce hypoglycaemia risk and features that enable greater efficiency in dose calculation, record keeping and report generation were highly valued. Adults who are self managing flexible MDI found the Rapidcalc mobile phone app to be a useful self-management tool and additional features to further improve usability, such as connectivity with BG meter and food databases, shortcut options to economise data entry and web based storage of data, were identified. Further work is needed to ascertain specific features and benefit for those with lower health literacy.

  13. A Real-World, Multicenter Assessment of Drugs Requiring Weight-Based Calculations in Overweight, Adult Critically Ill Patients

    Directory of Open Access Journals (Sweden)

    Sandra L. Kane-Gill

    2013-01-01

    Full Text Available Prescribing appropriate doses of drugs requiring weight-based dosing is challenging in overweight patients due to a lack of data. With 68% of the US population considered overweight and these patients being at an increased risk for hospitalization, clinicians need guidance on dosing weight-based drugs. The purpose of this study was to identify “real-world” dose ranges of high-risk medications administered via continuous infusion requiring weight-based dosing and determine the reasons for dosing changes (ineffectiveness or adverse drug reactions. A prospective, multicenter, observational study was conducted in four intensive care units at three institutions. A total of 857 medication orders representing 11 different high-risk medications in 173 patients were reviewed. It was noted that dosing did not increase in proportion to weight classification. Overall, 14 adverse drug reactions occurred in nine patients with more in overweight patients (9 of 14. A total of 75% of orders were discontinued due to ineffectiveness in groups with higher body mass indexes. Ineffectiveness leads to dosing adjustments resulting in the opportunity for medication errors. Also, the frequent dosing changes further demonstrate our lack of knowledge of appropriate dosing for this population. Given the medications’ increased propensity to cause harm, institutions should aggressively monitor these medications in overweight patients.

  14. Effect of Rifampin on Thyroid Function Test in Patients on Levothyroxine Medication

    Science.gov (United States)

    Kim, Hye In; Kim, Tae Hyuk; Kim, Hosu; Kim, Young Nam; Jang, Hye Won; Chung, Jae Hoon; Moon, Seong Mi; Jhun, Byung Woo; Lee, Hyun; Koh, Won-Jung; Kim, Sun Wook

    2017-01-01

    Background Levothyroxine (LT4) and rifampin (RIF) are sometimes used together; however, no clinical studies have assessed the effects of these drugs on thyroid function or the need to adjust LT4 dose. Methods We retrospectively reviewed the records of 71 Korean patients who started RIF during LT4 treatment. Clinically relevant cases that required dose adjustment according to the American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) guidelines were identified, and risk factors of increased LT4 dose were analyzed. Results After administering RIF, median serum thyroid-stimulating hormone (TSH) level (2.58 mIU/L, interquartile range [IQR] 0.21–7.44) was significantly higher than that before RIF (0.25 mIU/L, IQR, 0.03–2.62; P hypothyroidism. Risk factor analysis showed that remaining thyroid gland (odds ratio [OR] 9.207, P = 0.002), the time interval between starting RIF and TSH measurement (OR 1.043, P = 0.019), and baseline LT4 dose per kg body weight (OR 0.364, P = 0.011) were clinically relevant variables. Conclusions In patients receiving LT4, serum thyroid function test should be performed after starting RIF treatment. For patients with no remnant thyroid gland and those receiving a lower LT4 dose, close observation is needed when starting RIF and TB medication. PMID:28081173

  15. Management of patients with type 2 diabetes and mild/moderate renal impairment: profile of linagliptin

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    Gallwitz B

    2015-05-01

    Full Text Available Baptist Gallwitz Department of Medicine IV, Eberhard-Karls University, Tübingen, Germany Abstract: Dipeptidyl-peptidase-IV (DPP-4 inhibitors are oral antidiabetic agents that can be administered as monotherapy in patients with contraindications to metformin or metformin intolerance, and in combination with other oral compounds and/or insulin. DPP-4 inhibitors act in a glucose-dependent manner and only increase insulin secretion and inhibit glucagon secretion under hyperglycemic conditions. Renal impairment is frequent in type 2 diabetes as a result of microvascular complications and diabetes treatment, and options in these patients are limited. Linagliptin is a DPP-4 inhibitor with a hepatobiliary route of elimination. In comparative studies, it was noninferior to metformin and sulfonylureas in lowering glycated hemoglobin (HbA1c and improving glycemic parameters. It can be used throughout all stages of renal impairment without dose adjustments. This review gives an overview of linagliptin in various stages of chronic kidney disease and has a focus on efficacy and safety parameters from clinical studies in patients with impaired renal function. These data are interpreted in the context of type 2 diabetes therapy in general. Keywords: type 2 diabetes, renal impairment, oral antidiabetic drugs, incretin based therapies, DPP-4 inhibitors, linagliptin

  16. Posaconazole: A Review of Drug Interactions with HIV Antiretroviral Agents

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    Mara Poulakos

    2014-03-01

    Full Text Available The purpose of this review is to examine the literature for reports of clinically significant interactions noted amongst HIV antiretroviral medications when coadministered with posaconazole. A literature search was conducted to identify studies addressing drug interactions between posaconazole and HIV antiretroviral medications. Two pharmacokinetic studies and three clinical trials involving the administration of posaconazole to HIV-infected patients were identified. The pharmacokinetic studies involved concomitant administration of either a protease inhibitor (PI or non-nucleoside reverse transcriptase inhibitor (NNRTI. Both studies showed alterations in systemic concentrations of either posaconazole or the HIV antiretroviral when administered together. Of the three clinical trials, all patients were on HIV antiretrovirals. However, their potential interaction with posaconazole was not explored. To date, there is no published literature regarding the interaction between maraviroc or elvitegravir and posaconazole. Dose adjustments for each are recommended when coadministered with strong CYP 3A4 inhibitors or inducers. Currently available literature points to the potential for clinically significant drug interactions when posaconazole is coadministered with HIV antiretrovirals, specifically NNRTIs and PIs. More studies are needed involving a wider range of HIV antiretrovirals to determine the significance of the interaction. Clinicians should be aware of this potentially significant interaction and avoid concomitant administration when possible. When available, consideration should be given to therapeutic drug monitoring of antiretroviral serum concentrations in select patients.

  17. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.

    Science.gov (United States)

    2015-11-01

    The 2015 American Geriatrics Society (AGS) Beers Criteria are presented. Like the 2012 AGS Beers Criteria, they include lists of potentially inappropriate medications to be avoided in older adults. New to the criteria are lists of select drugs that should be avoided or have their dose adjusted based on the individual's kidney function and select drug-drug interactions documented to be associated with harms in older adults. The specific aim was to have a 13-member interdisciplinary panel of experts in geriatric care and pharmacotherapy update the 2012 AGS Beers Criteria using a modified Delphi method to systematically review and grade the evidence and reach a consensus on each existing and new criterion. The process followed an evidence-based approach using Institute of Medicine standards. The 2015 AGS Beers Criteria are applicable to all older adults with the exclusion of those in palliative and hospice care. Careful application of the criteria by health professionals, consumers, payors, and health systems should lead to closer monitoring of drug use in older adults. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

  18. [The Choosing Wisely Initiative of the German Society of Internal Medicine : Recommendations of the German Society for Endocrinology and the German Society for Geriatrics].

    Science.gov (United States)

    Feldkamp, J; Schott, M; Gogol, M; Quinkler, M; Blüher, M; Diederich, S; Reincke, M

    2016-06-01

    A. After osteoporotic fractures in the elderly, as a rule specific antiosteoporotic therapy should be initiated. a. Osteoporosis as a disease of the elderly should be diagnosed and treated (recommendation of the German Society for Geriatrics). B. All patients with diabetes mellitus should complete a specific diabetes training program when antidiabetic drug medication is initiated. C. In Germany, all pregnant women should be advised to undertake iodine supplementation. D. Endocrine causes of hypertension should be ruled out in younger patients and in patients on multiple antihypertensive drugs. E. All unclear cases of hypercalcemia should be clarified. A. Testosterone substitution therapy should not be initiated on the basis of only one measurement of a reduced testosterone level without clinical signs and clarification of the underlying cause. B. Imaging procedures should only be used after the existence of hormonal disease has been confirmed. C. Sonographic screening for thyroid disease is not advised in the elderly. D. Long-term therapy with levothyroxine for nodular goiter should be avoided. E. In relevant stress situations hydrocortisone replacement therapy should not be continued without dose adjustment in patients with adrenal or pituitary insufficiency.

  19. HBV-Associated Cryoglobulinemic Vasculitis: Remission after Antiviral Therapy with Entecavir

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    Mauro Viganò

    2014-06-01

    Full Text Available Background/Aims: Cryoglobulinemic vasculitis remains an uncommon complication of hepatitis B virus infection. Methods: We report the case of a 40-years old female Chinese patient with chronic hepatitis B developing cryoglobulinemic vasculitis with multiple organ involvement (liver, kidney, and skin coupled with weakness, arthralgias, haemolytic anaemia, and autoimmune thyroiditis. She received entecavir mono-therapy at dose adjusted for estimated glomerular filtration rate. Results: Within five months of entecavir treatment, hepatitis B viraemia decreased below the limit of detection with normal serum amino-transferase levels, HBeAg clearance occurred, vasculitis regressed with disappearance of purpura and ascites; in addition, renal function normalized and nephritic syndrome remitted. After a five-year follow-up, the patient is asymptomatic with intact kidney function, proteinuria in the normal range, and normal liver biochemistry, despite the antiviral treatment was withdrawn and the patient remained HBsAg positive. Conclusions: This is the second case of hepatitis B virus-related cryoglobulinemic vasculitis successfully treated with entecavir suggesting that effective antiviral therapy may counteract both the hepatic and extra-hepatic manifestations of infection by hepatitis B virus.

  20. Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction.

    Science.gov (United States)

    Melandri, Giovanni; Vagnarelli, Fabio; Calabrese, Daniela; Semprini, Franco; Nanni, Samuele; Branzi, Angelo

    2009-01-01

    TNKase is a genetically engineered variant of the alteplase molecule. Three different mutations result in an increase of the plasma half-life, of the resistance to plasminogen-activator inhibitor 1 and of the thrombolytic potency against platelet-rich thrombi. Among available agents in clinical practice, TNKase is the most fibrin-specific molecule and can be delivered as a single bolus intravenous injection. Several large-scale clinical trials have enrolled more than 27,000 patients with acute myocardial infarction, making the use of this drug truly evidence-based. TNKase is equivalent to front-loaded alteplase in terms of mortality and is the only bolus thrombolytic drug for which this equivalence has been formally demonstrated. TNKase appears more potent than alteplase when symptoms duration lasts more than 4 hours. Also, TNKase significantly reduces the rate of major bleeds and the need for blood transfusions. The efficacy of TNKase may be further improved by enoxaparin substitution for unfractionated heparin, provided that enoxaparin dose adjustment is made for patients more than 75 years old. Hitherto, the small available randomized studies and international clinical registries suggest that pre-hospital TNKase is as effective as primary angioplasty, thus laying the foundations for a new fibrinolytic, TNKase-based strategy as the backbone of reperfusion in acute myocardial infarction.

  1. Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Jaekel, N; Lieder, K; Albrecht, S; Leismann, O; Hubert, K; Bug, G; Kröger, N; Platzbecker, U; Stadler, M; de Haas, K; Altamura, S; Muckenthaler, M U; Niederwieser, D; Al-Ali, H K

    2016-01-01

    Elevated serum ferritin contributes to treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The multicenter DE02 trial assessed the safety, efficacy and impact of deferasirox on iron homeostasis after allogeneic HSCT. Deferasirox was administered at a starting dose of 10 mg/kg per day to 76 recipients of allogeneic HSCT, with subsequent dose adjustments based on efficacy and safety. Deferasirox was initiated at a median of 168 days after HSCT, with 84% of patients still on immunosuppression. Baseline serum ferritin declined from 2045 to 957 ng/mL. Deferasirox induced a negative iron balance in 84% of patients. Hemoglobin increased in the first 3 months, and trough serum cyclosporine levels were stable. Median exposure was 330 days, with a median compliance rate of >80%. The most common investigator-reported drug-related adverse events (AEs) were increased blood creatinine (26.5%), nausea (9.0%) and abdominal discomfort (8.3%). Fifty-four (71.1%) patients experienced drug-related AEs, which occasionally resulted in discontinuation (gastrointestinal (n=6), skin (n=3), elevated transaminases (n=1) and creatinine (n=1)). The incidence of AEs appeared to be dose related, with 7.5 mg/kg per day being the best-tolerated dose. Low-dose deferasirox is an effective chelation therapy after allogeneic HSCT, with a manageable safety profile, even in patients receiving cyclosporine.

  2. Deferasirox nephrotoxicity-the knowns and unknowns.

    Science.gov (United States)

    Díaz-García, Juan Daniel; Gallegos-Villalobos, Angel; Gonzalez-Espinoza, Liliana; Sanchez-Niño, Maria D; Villarrubia, Jesus; Ortiz, Alberto

    2014-10-01

    In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

  3. Metabolic pathways and pharmacokinetics of natural medicines with low permeability.

    Science.gov (United States)

    Zeng, Mei; Yang, Lan; He, Dan; Li, Yao; Shi, Mingxin; Zhang, Jingqing

    2017-09-14

    Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.

  4. Burkitt lymphoma presenting as a mass in the thyroid gland: a clinicopathologic study of 7 cases and review of the literature.

    Science.gov (United States)

    Quesada, Andrés E; Liu, Huifei; Miranda, Roberto N; Golardi, Natalia; Billah, Shahreen; Medeiros, L Jeffrey; Jaso, Jesse Manuel

    2016-10-01

    Burkitt lymphoma presenting in the thyroid gland is rare, and only a few cases have been reported. We retrospectively reviewed 7 patients diagnosed with Burkitt lymphoma of the thyroid gland between 2000 and 2015. There were 4 men and 3 women with a median age of 41 years (range, 19-49 years). All patients presented with a rapidly growing neck mass associated with upper airway compression in 5 (71%) patients. Two patients presented with localized (stage I/II) and 5 patients with disseminated (stage III/IV) disease. All cases showed morphologic and immunophenotypic features of Burkitt lymphoma with MYC rearrangement in all 5 cases tested. One case showed evidence of concurrent Hashimoto thyroiditis. Six of 7 patients were treated primarily with rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone. One patient was treated primarily with dose-adjusted rituximab, etoposide, prednisolone, vincristine, and cyclophosphamide. At the end of the study period, 5 patients were alive: 4 in complete remission and 1 with persistent disease. Two patients died with persistent disease (median follow-up, 25 months; range, 12-361 months). We conclude that Burkitt lymphoma of the thyroid gland shows clinicopathologic features similar to sporadic Burkitt lymphoma at other anatomic sites, but patients present at an older median age. The clinical course is aggressive with a high frequency of disseminated disease at diagnosis; however, a subset of patients responds well to aggressive chemotherapy.

  5. Clinical Pharmacist Team-Based Care in a Safety Net Medical Home: Facilitators and Barriers to Chronic Care Management.

    Science.gov (United States)

    Price-Haywood, Eboni G; Amering, Sarah; Luo, Qingyang; Lefante, John J

    2017-04-01

    Collaborative care models incorporating pharmacists have been shown to improve quality of care for patients with hypertension and/or diabetes. Little is known about how to integrate such services outside of clinical trials. The authors implemented a 22-month observational study to evaluate pharmacy collaborative care for hypertension and diabetes in a safety net medical home that incorporated population risk stratification, clinical decision support, and medication dose adjustment protocols. Patients in the pharmacy group saw their primary care provider (PCP) more often and had higher baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) and A1c levels compared to patients who only received care from their PCPs. There were no significant differences in the proportion of patients achieving treatment goals (SBP patients who underwent collaborative care versus those who did not. Age, race, and number of PCP encounters were associated with BP and A1c trends. The median time to achieve disease control was longer in the pharmacy group. Although 70% of all patients with poorly controlled hypertension achieved treatment goals within 7 months, less than 50% of patients with poorly controlled diabetes achieved A1c culture, health information technology and related workflows, and pharmacy caseload optimization. Future studies should further examine implementation strategies that work best in specific settings to optimize the benefits of team-based care with clinical pharmacists.

  6. Incorporating an Exercise Detection, Grading, and Hormone Dosing Algorithm Into the Artificial Pancreas Using Accelerometry and Heart Rate.

    Science.gov (United States)

    Jacobs, Peter G; Resalat, Navid; El Youssef, Joseph; Reddy, Ravi; Branigan, Deborah; Preiser, Nicholas; Condon, John; Castle, Jessica

    2015-10-05

    In this article, we present several important contributions necessary for enabling an artificial endocrine pancreas (AP) system to better respond to exercise events. First, we show how exercise can be automatically detected using body-worn accelerometer and heart rate sensors. During a 22 hour overnight inpatient study, 13 subjects with type 1 diabetes wearing a Zephyr accelerometer and heart rate monitor underwent 45 minutes of mild aerobic treadmill exercise while controlling their glucose levels using sensor-augmented pump therapy. We used the accelerometer and heart rate as inputs into a validated regression model. Using this model, we were able to detect the exercise event with a sensitivity of 97.2% and a specificity of 99.5%. Second, from this same study, we show how patients' glucose declined during the exercise event and we present results from in silico modeling that demonstrate how including an exercise model in the glucoregulatory model improves the estimation of the drop in glucose during exercise. Last, we present an exercise dosing adjustment algorithm and describe parameter tuning and performance using an in silico glucoregulatory model during an exercise event.

  7. [Pharmacokinetics of carbapenems].

    Science.gov (United States)

    Suchánková, H; Rychlíčková, J; Urbánek, K

    2012-06-01

    Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

  8. Case anglysis for a patient with post-operative orbital cellulitis and endophthalmitis%1例白内障术后眼眶蜂窝织炎合并眼内炎患者的病例分析

    Institute of Scientific and Technical Information of China (English)

    韩芙蓉; 刘妍; 赵环宇; 李荔

    2015-01-01

    Objective:To analyze the common pathogenic bacteria of endophthalmitis and the selection of anti-infective drugs. Methods: According to the guidelines and patients' condition, the pharmaceutical care conducted by clinical pharmacist on a patient with post-operative orbital cellulitis and endophthalmitis was analyzed.Results:Clinical pharmacist can provide pharmaceutical care in the aspects of dose adjustment, blood concentration monitoring and adverse effects. Conclusion:Clinical pharmacist can take part in the clinical treatment so as to ensure the safet, effective, economic and suitable application of medications.%目的: 分析白内障术后眼内炎的常见致病菌以及抗感染药物的选择.方法:根据指南,结合患者病情,分析临床药师参与1例白内障术后眼内炎患者的药学监护点.结果:临床药师可以从药物剂量调整、血药浓度监测、不良反应监测等方面对患者进行药学监护.结论:临床药师参与临床治疗实践,有利于更好地保障患者用药的安全、有效、经济、适宜.

  9. Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

    Science.gov (United States)

    Lakshmi, Putcha; Singh, R. P.; Crady, V. A.; Derendorf, H.

    2011-01-01

    Space Motion sickness (SMS) is an age old problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is the most frequently used drug for the treatment of motion sickness (MS) which is currently available in transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability thus allowing precise and reduced dosing options in addition to offering rescue and treatment options. As such, an intranasal gel dosage formulation of scopolamine (INSCOP) was developed and Pharmacokinetics (PK) and bioavailability were determined under IND guidelines. The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostatic bedrest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 and 0.4 mg doses of INSCOP during AMB and ABR in a four-way crossover design. Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose. Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration versus time curve (AUC) during ABR after the 0.4 mg dose. This difference in AUC and Cls at the higher but not the lower dose during ABR may suggest that ABR may affect metabolism and/or clearance at higher doses of INSCOP. These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

  10. [Recommendations for antibiotic monitoring in ICU patients].

    Science.gov (United States)

    Alvarez, Francisco; Olaechea, Pedro; Grau, Santiago; Marín, Mónica; Domínguez, Alfonso; Martínez-Lanao, José; Soy, Dolors; Alos, Manuel; Victoria, María; Sádaba, Belén; Mediavilla, Africa; Fatela, Daniel

    2008-01-01

    Monitoring plasma concentrations of antimicrobial agents used to treat infection in critically ill patients is one of the recommended strategies for improving clinical outcome. Drug monitoring has a double aim: to limit adverse events and to increase the effectiveness of the drugs. In clinical practice, however, this approach is mainly limited to monitoring plasma concentrations of vancomycin and aminoglycosides, although future extension to other antimicrobial agents would be desirable. Application of this technique varies considerably between hospitals, and this makes interpretation and comparison of the results obtained difficult. For this reason, representatives of various scientific societies related to the pharmacokinetic area have developed a series of recommendations for monitoring plasma concentrations of antimicrobials using vancomycin and several aminoglycosides as the reference. The recommendations are based on 14 questions encompassing all steps of the process: indication for the test, blood sampling (timing of blood collection, blood volume, tubes), transport to the laboratory, techniques applied, normal values, dose adjustment, and reporting the results. The purpose of these guidelines is to develop a process of monitoring plasma antimicrobial concentrations that is as homogeneous as possible to facilitate the design of multicenter studies, as well as the interpretation and comparison of results.

  11. Regulatory requirements for marketing fixed dose combinations

    Directory of Open Access Journals (Sweden)

    B G Jayasheel

    2010-01-01

    Full Text Available The development of fixed-dose combinations (FDCs is becoming increasingly important from a public health perspective. FDCs have advantages when there is an identifiable patient population for whom treatment with a particular combination of actives in a fixed ratio is safe and effective and when all of the actives contribute to the overall therapeutic effect. Such combinations of drugs are particularly useful in the management of chronic diseases. In addition, there can be real clinical benefits in the form of increased efficacy and/or a reduced incidence of adverse effects. Additional advantages of FDCs are potentially lower costs of manufacturing compared to the costs of producing separate products administered concurrently, simpler logistics of distribution and reduced development of resistance in the case of antimicrobials. Above all, FDC therapy reduces pill burden and improves medication compliance. Although, FDCs seem to be ideal under certain pre-defined circumstances, if a dosing adjustment is warranted, there may not be an FDC available in the most appropriate strength for the patient and if an adverse drug reaction occurs from using an FDC, it may be difficult to identify the active ingredient responsible for causing the reaction. Appendix VI of Schedule Y (Drugs & Cosmetics Rules 1945, India states the requirements for marketing approval of various types of FDCs. The same is further elaborated in this article to provide a detailed guidance including the clinical trial requirements. However, the heterogeneity of the therapeutic field makes it difficult to develop a standard guidance document.

  12. The role of technology in avoiding bias in the design and execution of clinical trials

    Directory of Open Access Journals (Sweden)

    Goodale H

    2013-01-01

    Full Text Available Hazel Goodale, Damian McEntegartPerceptive Informatics Inc, Nottingham, United KingdomAbstract: There are many documented instances in which bias has had an adverse effect on the results of clinical trials. This has led to a number of design techniques being developed that can be implemented in clinical trials in order to reduce bias. Sources of bias referring to published case studies are reviewed and discussed. The potential uses of technology to alleviate bias are outlined, particularly the use of centralized interactive response systems to randomize patients and manage medication in such a way as to limit the risk of bias caused by knowledge of either a patient's current treatment or future treatment assignments. Potential sources of bias include selection bias, accidental bias, assessment bias, observer bias, and operational bias. These can arise through inadequate randomization and concealment methods during the trial. The blind may be broken by individual code breaks or through deduction in studies with frequent dose adjustments; there is scope for deduction in adaptive trials that might also introduce bias. Technology can reduce or eliminate the potential for bias in a variety of manners including central randomization and secure methods to protect the blinding and trial integrity. However, if the separation of randomization and dispensing, made possible by the use of technology, is not applied correctly then new unblinding scenarios can be introduced.Keywords: electronic systems, IVR, blinding, randomization

  13. [Comparison of the efficacy and tolerance of Kabi 2165 and standard heparin in the prevention of deep venous thrombosis in total hip prosthesis].

    Science.gov (United States)

    Barre, J; Pfister, G; Potron, G; Droulle, C; Baudrillard, J C; Barbier, P; Kher, A

    1987-01-01

    A series of 80 patients operated for total hip prosthesis under epidural anesthesia was randomly allocated to treatment with Kabi 2165 (n = 40): 2,500 U anti-Xa preoperatively and evening of operation and 2,500 U anti-Xa morning and evening daily up to the 9th or 10th day postoperatively, or standard heparin (n = 40): 3,750 U preoperatively and then 8 hourly, at a dose adjusted with thrombin time and cephalin + activator time, daily up to the 9th or 10th day. Phlebography was performed routinely on the 9th or 10th day. Venous thrombosis occurred in 7 patients (17.5%) in the Kabi 2165 group, including two high, potentially emboligenic, localizations (5%), and in 4 patients (10%) in the standard heparin group, including 2 potentially emboligenic clots (5%). The difference is not statistically significant (total number: p = 0.5; potentially emboligenic: p = 0.33). Pulmonary embolism did not occur. Overall tolerance, evaluated from hemoglobin and hematocrit values, intra- and post-operative bleeding and operation wound hematoma and at injection site was comparable in the two groups.

  14. [Approach and Registry of Anaphylaxis in Portugal].

    Science.gov (United States)

    Mota, Inês; Pereira, Ana Margarida; Pereira, Celso; Tomaz, Elza; Ferreira, Manuel Branco; Sabino, Filipa; Coelho, Anabela; Santos, Anabela; Martins, Henrique; Morais-Almeida, Mário

    2015-01-01

    Anaphylaxis has a growing incidence, especially in children. It represents a medical emergency and its successful therapy depends on early and proper intervention. Intramuscular epinephrine, with dose adjustment according to weight and age, is the drug of choice for anaphylaxis treatment. After resolution of the acute reaction, the patient should be kept under clinical surveillance for 6 to 24 hours, due to possible biphasic reactions. Prescription of an epinephrine auto injectable device should be considered in all patients with diagnosed or suspected anaphylaxis; additionally these patients should always be referred to an Immunoallergy consultation, to perform adequate investigation and management in order to reduce future risk. All anaphylaxis episodes must be recorded in The Portuguese Catalogue of Allergies and other Adverse Reactions (Catálogo Português de Alergias e outras Reações Adversas, CPARA), which represents a fundamental tool to share clinical information within the Health System. The present manuscript intends to disclose the most recent Portuguese guidelines for the diagnosis and treatment of anaphylaxis, making its clinical approach more effective and homogeneous, and to promote the use of The Portuguese Catalogue of Allergies and other Adverse Reactions as an essential tool to register and share information on anaphylaxis in Portugal.

  15. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis - review of the literature

    Directory of Open Access Journals (Sweden)

    Kofla G

    2011-04-01

    Full Text Available Abstract Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clinical use in various indications. They act as inhibitors of β-(1,3-glucan synthesis in the fungal cell wall and have a favorable pharmacological profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been observed against C. parapsilosis and C. guilliermondii. Data from clinical trials for invasive Candida infections/candidaemia suggest that the clinical outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clinical settings such as invasive Candida infections, Candida oesophagitis and candidaemia. Differences between the three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for intravenous use. All three agents have an excellent safety profile.

  16. Telemedicine for clinical management of diabetes - a process analysis of video consultations.

    Science.gov (United States)

    Fatehi, Farhad; Gray, Leonard C; Russell, Anthony W

    2013-10-01

    We analysed 56 video consultations provided in a 5-month period by two endocrinologists from the tele-endocrinology clinic of a tertiary teaching hospital in Brisbane. The patients were suffering from type 1 or type 2 diabetes, and 41% of them had at least one diabetic complication. Their mean age was 51 years and 45% were female. The consultations were provided to ten cities located 210-1800 km from Brisbane. A questionnaire was developed for analysing the video visits. It comprised 26 questions, arranged in six sections: (1) Patient characteristics, (2) Reason for referral, (3) Procedures and findings, (4) Recommendations, (5) Telehealth logistics, (6) Consultant's opinion. In 66% of consultations a nurse accompanied the patient. The specialist requested the nurse to perform a physical examination in 18% of these cases. No change in medications was made in 36% of the consultations. The most frequent recommendations were requesting laboratory tests (75%), insulin dose adjustments (39%) and referrals to an allied health professional (13%). Out of 56 consultations, the specialists indicated the need to perform a physical examination for 12 patients that was not possible remotely. However, they requested an in-person (face-to-face) visit for three patients. Nevertheless they believed that in 34% of the cases they could have made a better decision if the consultation had been in-person. Video consultation can substitute for a large proportion of in-person specialist consultations for people with diabetes who are referred to endocrinology specialists.

  17. A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

    Science.gov (United States)

    Agarwal, Suresh K; Kriel, Robert L; Cloyd, James C; Coles, Lisa D; Scherkenbach, Lisa A; Tobin, Michael H; Krach, Linda E

    2015-01-01

    Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.

  18. The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia.

    Science.gov (United States)

    Osser, David N; Roudsari, Mohsen Jalali; Manschreck, Theo

    2013-01-01

    This article is an update of the algorithm for schizophrenia from the Psychopharmacology Algorithm Project at the Harvard South Shore Program. A literature review was conducted focusing on new data since the last published version (1999-2001). The first-line treatment recommendation for new-onset schizophrenia is with amisulpride, aripiprazole, risperidone, or ziprasidone for four to six weeks. In some settings the trial could be shorter, considering that evidence of clear improvement with antipsychotics usually occurs within the first two weeks. If the trial of the first antipsychotic cannot be completed due to intolerance, try another until one of the four is tolerated and given an adequate trial. There should be evidence of bioavailability. If the response to this adequate trial is unsatisfactory, try a second monotherapy. If the response to this second adequate trial is also unsatisfactory, and if at least one of the first two trials was with risperidone, olanzapine, or a first-generation (typical) antipsychotic, then clozapine is recommended for the third trial. If neither trial was with any these three options, a third trial prior to clozapine should occur, using one of those three. If the response to monotherapy with clozapine (with dose adjusted by using plasma levels) is unsatisfactory, consider adding risperidone, lamotrigine, or ECT. Beyond that point, there is little solid evidence to support further psychopharmacological treatment choices, though we do review possible options.

  19. Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations.

    Science.gov (United States)

    Ichihara, Eiki; Hotta, Katsuyuki; Takigawa, Nagio; Kudo, Kenichiro; Kato, Yuka; Honda, Yoshihiro; Hayakawa, Hiromi; Minami, Daisuke; Sato, Akiko; Tabata, Masahiro; Tanimoto, Mitsune; Kiura, Katsuyuki

    2013-09-01

    Gefitinib is an essential drug for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations. The approved dosage is 250 mg/body/day without adjustment for physical size such as body surface area (BSA), and the impact of physical size on the efficacy of gefitinib has not been evaluated. Here, we sought to clarify this issue using a retrospective cohort. We reviewed the medical records of patients with consecutive advanced NSCLC harboring EGFR mutations who underwent gefitinib monotherapy at Okayama University Hospital. In total, 101 patients were included in this study, and the median BSA in this cohort was 1.5 m(2). The median progression-free survival (PFS) of the patients with higher BSA (≥1.5 m(2)) was significantly worse than that of those with lower BSA (BSA on PFS (hazards ratio, 2.34; 95% confidence interval, 1.78-2.89; p = 0.002). By contrast, no significant association between BSA and PFS was observed in those undergoing cytotoxic chemotherapy (4.0 vs. 5.1 months; p = 0.989, log-rank test), suggesting that BSA is a predictive, rather than a prognostic, marker for gefitinib therapy in EGFR-mutated NSCLC. In conclusion, BSA affected PFS in patients with EGFR-mutated NSCLC who underwent gefitinib monotherapy, suggesting the need for appraisal of BSA-based dose adjustment, even for this molecular target-based therapy.

  20. [Successful treatment with hyper-CVAD and highly active anti-retroviral therapy (HAART) for AIDS-related Burkitt lymphoma].

    Science.gov (United States)

    Suzuki, Kazuhito; Nakazato, Tomonori; Sanada, Yukinari; Mihara, Ai; Tachikawa, Natsuo; Kurai, Hanako; Yoshimura, Yukihiro; Hayashi, Hiroyuki; Yoshida, Sachiko; Kakimoto, Tsunayuki

    2010-03-01

    A 38-year-old man was admitted to our hospital because of continuous fever and right facial palsy. He was diagnosed as HIV positive. Abdominal CT scan showed a large mass in the ascending colon. Gallium scintigraphy demonstrated increased uptake in the ascending colon. Colonoscopy was performed and histological examination of the colon tumor revealed Burkitt's lymphoma (BL). He received highly active anti-retroviral therapy (HAART) and his facial palsy improved. Because CD4 count was significantly low at 31/microl, he was treated with dose-adjusted EPOCH (DA-EPOCH) combined with HAART. Although the tumor was decreased in size by DA-EPOCH, we changed to the combination of hyper-CVAD/MTX-Ara-C alternating therapy with HAART in order to increase dose intensity. Six cycles of hyper-CVAD/MTX-Ara-C were performed and complete remission was obtained. In the HAART era, the survival of patients with AIDS-related diffuse large cell lymphoma (DLCL) improved dramatically, whereas the survival of similarly treated patients with AIDS-related BL remained poor. Our case suggests that intensive chemotherapy with hyper-CVAD/MTX-Ara-C combined with HAART may be well tolerated and effective in AIDS-related BL.

  1. Clinical impact of the CYP3A5 6986A>G allelic variant on kidney transplantation outcomes.

    Science.gov (United States)

    Flahault, Adrien; Anglicheau, Dany; Loriot, Marie-Anne; Thervet, Eric; Pallet, Nicolas

    2017-01-01

    Meta-analyses and large cohort studies provide confusing results on the association of the CYP3A5 6986A>G allelic variant and adverse outcomes in kidney transplant recipients under tacrolimus-based immunosuppressive regimen. A residual effect of CYP3A5 recipient genotype is unexpected if kidney transplant recipients have similar exposure of tacrolimus. We have undertaken a population-based, observational study, to investigate all the consecutive patients who received a kidney transplant at the Necker hospital between 2005 and 2015, who were treated with tacrolimus and for whom the CYP3A5 genotype was available. We analyzed 577 patients followed for up to 5 years. We found a significant association of CYP3A5 genotypes with tacrolimus daily dose as well as with tacrolimus dose-adjusted concentrations. We however found no association of CYP3A5 genotypes with histology scores on biopsies, measured renal function, biopsy-proven acute rejection episodes and graft survival.

  2. [Evaluation and perioperative management of patients with diabetes mellitus. A challenge for the anesthesiologist].

    Science.gov (United States)

    Pontes, João Paulo Jordão; Mendes, Florentino Fernandes; Vasconcelos, Mateus Meira; Batista, Nubia Rodrigues

    2017-05-30

    Diabetes mellitus (DM) is characterized by alteration in carbohydrate metabolism, leading to hyperglycemia and increased perioperative morbidity and mortality. It evolves with diverse and progressive physiological changes, and the anesthetic management requires attention regarding this disease interference in multiple organ systems and their respective complications. Patient's history, physical examination, and complementary exams are important in the preoperative management, particularly glycosylated hemoglobin (HbA1c), which has a strong predictive value for complications associated with diabetes. The goal of surgical planning is to reduce the fasting time and maintain the patient's routine. Patients with Type 1 DM must receive insulin (even during the preoperative fast) to meet the basal physiological demands and avoid ketoacidosis. Whereas patients with Type 2 DM treated with multiple injectable and/or oral drugs are susceptible to develop a hyperglycemic hyperosmolar state (HHS). Therefore, the management of hypoglycemic agents and different types of insulin is fundamental, as well as determining the surgical schedule and, consequently, the number of lost meals for dose adjustment and drug suspension. Current evidence suggests the safe target to maintain glycemic control in surgical patients, but does not conclude whether it should be obtained with either moderate or severe glycemic control. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  3. Quantification of metformin and glyburide in blood for paediatric endocrinology

    Directory of Open Access Journals (Sweden)

    Radamés Alemón-Medina

    2014-10-01

    Full Text Available Background: The recent use of antidiabetic drugs such as metformin and glyburide for the treatment and control of childhood obesity, insulin resistance and type II diabetes mellitus in children and adolescents, has encouraged physicians to determine plasma levels of these drugs for the right dose adjustment. Objective: To implement and validate a UPLC-UV method to quantify metformin and glyburide in blood samples. Materials and methods: Only a 0.1 mL-volume blood sample was used. Both drugs are removed by precipitation with methanol. Quantitation was carried out with mobile phase of 4.6 mM potassium phosphate monobasic (KH2PO4 0.1 M pH = 6.5, sodium dodecyl sulphate (SDS and acetonitrile (63:7:30, at 0.8 mL/min through a VARIAN Pursuit® C8 150 x 3.9 mm column at 40°C, 236 nm. Results: The method allows the measurement of 20 to 600 nanograms of metformin and from 100 to 2 000 nanograms of glyburide per milliliter of blood. Both drugs are physicochemically stable in blood samples for up to 30 days at 4°C. Conclusion: Our method allows quantification of metformin and gly- buride in paediatric blood samples, to support the clinicians to monitor treatment compliance, bioavailability and pharmacokinetic profiles.

  4. Pharmacokinetics of sirolimus (rapamycin) in subjects with severe hepatic impairment.

    Science.gov (United States)

    Zimmerman, James J; Patat, Alain; Parks, Virginia; Moirand, Romain; Matschke, Kyle

    2008-03-01

    Nine subjects with severe hepatic impairment (Child-Pugh grade C) and 9 healthy matched control subjects were given a single 15-mg dose of sirolimus by oral solution. Increases (P < or = .002) in mean whole-blood sirolimus t(1/2) (168%), AUC(0-infinity) (210%), and MRT(oral) (261%), together with a decrease (P = .001) in CL/F (-67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. Sirolimus pharmacokinetic data in Child-Pugh grade A (n = 13, mild) and B (n = 5, moderate) subjects from a previous identically designed study were available for an inter-study comparison. Overall, mean t(1/2), weight-normalized AUC, and MRT(oral) increased steadily, whereas mean CL/F decreased steadily, with increasing degrees of hepatic impairment. CL/F showed large intersubject variabilities within subject types and extensive overlap among the subject types. The results of this study suggest that an initial sirolimus dose reduction of approximately 60% is appropriate in patients with acute severe hepatic impairment; this should be followed by further dose adjustment, based on therapeutic drug monitoring, until the trough concentrations have stabilized at sirolimus levels existing prior to the onset of acute liver failure.

  5. Renal replacement therapy in adult and pediatric intensive care : Recommendations by an expert panel from the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) French Group for Pediatric Intensive Care Emergencies (GFRUP) the French Dialysis Society (SFD).

    Science.gov (United States)

    Vinsonneau, Christophe; Allain-Launay, Emma; Blayau, Clarisse; Darmon, Michael; Ducheyron, Damien; Gaillot, Theophile; Honore, Patrick M; Javouhey, Etienne; Krummel, Thierry; Lahoche, Annie; Letacon, Serge; Legrand, Matthieu; Monchi, Mehran; Ridel, Christophe; Robert, René; Schortgen, Frederique; Souweine, Bertrand; Vaillant, Patrick; Velly, Lionel; Osman, David; Van Vong, Ly

    2015-12-01

    Acute renal failure (ARF) in critically ill patients is currently very frequent and requires renal replacement therapy (RRT) in many patients. During the last 15 years, several studies have considered important issues regarding the use of RRT in ARF, like the time to initiate the therapy, the dialysis dose, the types of catheter, the choice of technique, and anticoagulation. However, despite an abundant literature, conflicting results do not provide evidence on RRT implementation. We present herein recommendations for the use of RRT in adult and pediatric intensive care developed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system by an expert group of French Intensive Care Society (SRLF), with the participation of the French Society of Anesthesia and Intensive Care (SFAR), the French Group for Pediatric Intensive Care and Emergencies (GFRUP), and the French Dialysis Society (SFD). The recommendations cover 4 fields: criteria for RRT initiation, technical aspects (access routes, membranes, anticoagulation, reverse osmosis water), practical aspects (choice of the method, peritoneal dialysis, dialysis dose, adjustments), and safety (procedures and training, dialysis catheter management, extracorporeal circuit set-up). These recommendations have been designed on a practical point of view to provide guidance for intensivists in their daily practice.

  6. Multikinase inhibitors use in differentiated thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Jasim S

    2014-12-01

    Full Text Available Sina Jasim,1,* Levent Ozsari,2,* Mouhammed Amir Habra2 1Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA; 2Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA *These authors contributed equally in this work Abstract: Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required. Keywords: differentiated thyroid cancer, progression-free survival, adverse effects, targeted therapy, sorafenib, lenvatinib

  7. Potential beneficial effects of a gluten-free diet in newly diagnosed children with type 1 diabetes

    DEFF Research Database (Denmark)

    Svensson, Jannet; Sildorf, Stine Møller; Pipper, Christian B.

    2016-01-01

    Aim: Gluten-free diet has shown promising effects in preventing type 1 diabetes (T1D) in animals as well as beneficial effects on the immune system. Gluten-free diet at diabetes onset may alter the natural course and outcome of autoimmune diseases such as T1D. Methods: In a 12-month study, 15...... children newly diagnosed with T1D were instructed to follow a gluten-free diet. Questionnaires were used to evaluate adherence to the gluten-free diet. Partial remission (PR) was defined by insulin dose-adjusted A1c (IDAA1c) ≤9 or stimulated C-peptide (SCP) >300 pmol/L measured 90 min after a liquid mixed...... meal at the inclusion, six and 12 months after onset. The intervention group was compared with two previous cohorts. Linear mixed models were used to estimate differences between cohorts. Results: After 6 months, more children on a gluten-free diet tended to have SCP values above 300 pmol/L compared...

  8. A primer on concentrated insulins: what an internist should know.

    Science.gov (United States)

    Barnosky, Adrienne; Shah, Lisa; Meah, Farah; Emanuele, Nicholas; Emanuele, Mary Ann; Mazhari, Alaleh

    2016-05-01

    The common insulin concentration in most preparations of insulin is 100 units per mL or U-100. Human regular U-500 insulin was the first concentrated insulin introduced and it has been available in the United States since the 1950s. Humulin R is the only human regular U-500 available on the market. Human regular U-500 is five times more concentrated than U-100 and because of its pharmacodynamic properties, works as both a basal and a bolus insulin. Human regular U500 allows for delivery of a larger insulin dose with a smaller volume leading to better absorption compared to U-100 and has traditionally been used in patients with moderate to severe insulin resistance. More recently other forms of concentrated insulin have become available and the newer concentrated insulin preparations can be used in diabetic patients with or without insulin resistance. Our intent is to provide primary care physicians with a review of the pharmacology and current literature on concentrated insulins as well as recommendations for patient selection, dose initiation, and dose adjustment.

  9. Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses.

    Science.gov (United States)

    Lee, C D; Maxwell, L K

    2014-02-01

    In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light-breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light-breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three-compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 ± 0.30 mL/min/kg in miniature horses and 1.04 ± 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady-state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light-breed horses.

  10. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.

    Science.gov (United States)

    Smythe, Maureen A; Priziola, Jennifer; Dobesh, Paul P; Wirth, Diane; Cuker, Adam; Wittkowsky, Ann K

    2016-01-01

    Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. Despite the changing landscape of VTE treatment with the introduction of the new direct oral anticoagulants many uncertainties remain regarding the optimal use of traditional parenteral agents. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. This specific chapter addresses the practical management of heparins including low molecular weight heparins and fondaparinux. For each anticoagulant a list of the most common practice related questions were created. Each question was addressed using a brief focused literature review followed by a multidisciplinary consensus guidance recommendation. Issues addressed included initial anticoagulant dosing recommendations, recommended baseline laboratory monitoring, managing dose adjustments, evidence to support a relationship between laboratory tests and meaningful clinical outcomes, special patient populations including extremes of weight and renal impairment, duration of necessary parenteral therapy during the transition to oral therapy, candidates for outpatient treatment where appropriate and management of over-anticoagulation and adverse effects including bleeding and heparin induced thrombocytopenia. This article concludes with a concise table of clinical management questions and guidance recommendations to provide a quick reference for the practical management of heparin, low molecular weight heparin and fondaparinux.

  11. Epoetin zeta in the management of anemia associated with chronic kidney disease, differential pharmacology and clinical utility

    Directory of Open Access Journals (Sweden)

    Davis-Ajami ML

    2014-04-01

    Full Text Available Mary Lynn Davis-Ajami,1 Jun Wu,2 Katherine Downton,3 Emilie Ludeman,3 Virginia Noxon4 1Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, MD, USA; 2South Carolina College of Pharmacy, University of South Carolina, Greenville, SC, USA; 3Health Sciences and Human Services Library, University of Maryland, Baltimore, MD, USA; 4Department of Clinical Pharmacy and Outcomes Science, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA Abstract: Epoetin zeta was granted marketing authorization in October 2007 by the European Medicines Agency as a recombinant human erythropoietin erythropoiesis-stimulating agent to treat symptomatic anemia of renal origin in adult and pediatric patients on hemodialysis and adults on peritoneal dialysis, as well as for symptomatic renal anemia in adult patients with renal insufficiency not yet on dialysis. Currently, epoetin zeta can be administered either subcutaneously or intravenously to correct for hemoglobin concentrations ≤10 g/dL (6.2 mmol/L or with dose adjustment to maintain hemoglobin levels at desired levels not in excess of 12 g/dL (7.5 mmol/L. This review article focuses on epoetin zeta indications in chronic kidney disease, its use in managing anemia of renal origin, and discusses its pharmacology and clinical utility. Keywords: biosimilar, chronic kidney disease, epoetin alfa, erythropoiesis, renal anemia, Retacrit®

  12. Influence of IL-18 and IL-10 Polymorphisms on Tacrolimus Elimination in Chinese Lung Transplant Patients

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    Xiaoqing Zhang

    2017-01-01

    Full Text Available Aims. The influence of interleukin-10 (IL-10 and interleukin-18 (IL-18 polymorphisms on tacrolimus pharmacokinetics had been described in liver and kidney transplantation. The expression of cytokines varied in different kinds of transplantation. The influence of IL-10 and IL-18 genetic polymorphisms on the pharmacokinetic parameters of tacrolimus remains unclear in lung transplantation. Methods. 51 lung transplant patients at Shanghai Pulmonary Hospital were included. IL-18 polymorphisms (rs5744247 and rs1946518, IL-10 polymorphisms (rs1800896, rs1800872, and rs3021097, and CYP3A5 rs776746 were genotyped. Dose-adjusted trough blood concentrations (C/D ratio, mg/kg body weight in lung transplant patients during the first 4 postoperative weeks were calculated. Results. IL-18 rs5744247 allele C and rs1946518 allele A were associated with fast tacrolimus metabolism. Combined analysis showed that the numbers of low IL-18 mRNA expression alleles had positive correlation with tacrolimus C/D ratios in lung transplant recipients. The influence of IL-18 polymorphisms on tacrolimus C/D ratios was observed in CYP3A5 expresser recipients, but not in CYP3A5 nonexpresser recipients. No clinical significance of tacrolimus C/D ratios difference of IL-10 polymorphisms was found in our data. Conclusions. IL-18 polymorphisms may influence tacrolimus elimination in lung transplantation patients.

  13. Cultivation and Implementation of Community-Engaged Pharmacy Services in a Free Clinic to Enhance Care for the Medically Underserved

    Directory of Open Access Journals (Sweden)

    Emmeline Tran, Pharm.D. Candidate

    2013-01-01

    Full Text Available Partnerships between community free clinics and academic medical centers improve patient outcomes and enhance learning opportunities for students. A community-academic partnership between the Maliheh Free Clinic and the University of Utah College of Pharmacy was formed to fulfill a community need for pharmacy services, to promote interdisciplinary patient care, and to provide an experiential opportunity for students. The Maliheh Free Clinic based in Salt Lake City, Utah provides free primary health care to uninsured individuals who live 150% below federal poverty guidelines. Three pharmacy services were developed and implemented. These include: 1 clinic chart reviews which involve written recommendations following a comprehensive assessment of the patient’s chart examining his or her disease states and the appropriateness of his or her medications; 2 medication reconciliations and discussion of pharmacy-related recommendations with patients during Diabetes Day, an inclusive interdisciplinary patient appointment that addresses important aspects of diabetes care; and 3 an insulin dose adjustment service through a collaborative practice agreement with the clinic to monitor a patient’s blood glucose levels and adjust his or her medications accordingly on a weekly basis.

  14. Potential drug-drug interactions in intensive care units of a hospital in Southern Brazil

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    Gustavo Henrique Oliveira-Paula

    2014-12-01

    Full Text Available Drug-drug interactions are important causes of adverse reactions in health units. The high consumption of medicines in intensive care units predisposes patients to potential drug-drug interactions. This study aimed at examining the frequency and the characteristics of drug-drug interactions in intensive care units of Hospital Universitario of Universidade Estadual de Londrina. We analyzed the prescriptions of patients over 18 years, admitted from January to May 2010, who remained hospitalized for at least four days. The analysis of drug-drug interactions was carried out using the Micromedex Drug-Reax® system. The interactions were classified by severity, time required for the onset of adverse effects, mechanism of action and quality of scientific evidence. Moreover, the possible adverse events were analyzed, as well as the recommended strategies of management and monitoring. Altogether, 198 different potential drug-drug interactions were identified with the occurrence of 1242 episodes. Of these, 43% were characterized by moderate interactions, 35% major, 16% minor and 6% contraindicated. The therapeutic inefficacy was the most frequent possible adverse event (18% and the main recommended strategy of management was the dose adjustment (35.6%. The most frequent interactions were: fentanyl + midazolam (8.6%, phenytoin + ranitidine (5.5% and midazolam + ranitidine (4.8%. These results demonstrate the importance of drug-drug interactions as a significant adverse event in intensive care units and thus, preventive measures are required to minimize this problem.

  15. Pharmacokinetics of the Long‐Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function

    Science.gov (United States)

    Linnebjerg, Helle; Choi, Siak Leng; Lam, Eric Chen Quin; Mace, Kenneth F.; Hodgson, Teri S.; Sinha, Vikram P.

    2016-01-01

    Abstract The pharmacokinetics of LY2605541 (basal insulin peglispro), a novel long‐acting basal insulin analogue, was evaluated in 5 groups of subjects with varying degrees of renal function based on creatinine clearance: normal renal function (>80 mL/min), mild renal impairment (51–80 mL/min), moderate renal impairment (30–50 mL/min), severe renal impairment (renal disease (ESRD) requiring hemodialysis. Serial blood samples for pharmacokinetic analyses were collected up to 12 days following a single 0.33 U/kg subcutaneous dose of LY2605541. The apparent clearance (CL/F) and half‐life across groups were not affected by renal function. Cmax values were lower in subjects with increasing severity of renal impairment; however, the small decrease in Cmax did not affect the overall exposure. Regression analysis showed that LY2605541 clearance is independent of renal function (slope = 0.000863; P = .885). The mean fraction of LY2605541 eliminated by a single hemodialysis session was 13% in subjects with ESRD. LY2605541 was generally well tolerated in healthy subjects and those with renal impairment following a single 0.33 U/kg subcutaneous dose. Given these data, no dose adjustment of LY2605541 based on pharmacokinetics is recommended in renal impairment or in patients undergoing hemodialysis. PMID:27163501

  16. Novel stereoselective high-performance liquid chromatographic method for simultaneous determination of guaifenesin and ketorolac enantiomers in human plasma.

    Science.gov (United States)

    Maher, Hadir M; Al-Taweel, Shorog M; Alshehri, Mona M; Alzoman, Nourah Z

    2014-10-01

    A novel method was developed for the simultaneous determination of guaifenesin (GUA) and ketorolac tromethamine (KET) enantiomers in plasma samples. Since GUA probably increases the absorption of coadministered drugs (e.g., KET), it would be extremely important to monitor KET plasma levels for the purpose of dose adjustment with a subsequent decrease in the side effects. Enantiomeric resolution was achieved on a polysaccharide-based chiral stationary phase, amylose-2, as a chiral selector under the normal phase (NP) mode and using ornidazole (ORN) as internal standard. This innovative method has the advantage of the ease and reliability of sample preparation for plasma samples. Sample clean-up was based on simply using methanol for protein precipitation followed by direct extraction of drug residues using ethanol. Both GUA and KET enantiomers were separated using an isocratic mobile phase composed of hexane/isopropanol/trifluoroacetic acid, 85:15:0.05 v/v/v. Peak area ratios were linear over the range 0.05-20 µg/mL for the four enantiomers S (+) GUA, R (-) GUA, R (+) KET, and S (-) KET. The method was fully validated according to the International Conference on Harmonization (ICH) guidelines in terms of system suitability, specificity, accuracy, precision, robustness, and solution stability. Finally, this procedure was innovative to apply the rationale of developing a chiral high-performance liquid chromatography (HPLC) procedure for the simultaneous quantitative analysis of drug isomers in clinical samples. © 2014 Wiley Periodicals, Inc.

  17. New anticoagulants in the treatment of stroke:future promise

    Institute of Scientific and Technical Information of China (English)

    Emre Kumral; Tuba Cerraho(g)lu (S)irin

    2013-01-01

    Recent evidence is leading to the replacement of vitamin K antagonists,the efficacy of which in preventing stroke in patients with atrial fibrillation (AF) is well established,with better tolerated and more manageable new anticoagulant drugs,with a lower risk of intracranial bleeding,no clear interactions with food,fewer interactions with medications,and no need for frequent laboratory monitoring and dose adjustments.Among new anticoagulants,dabigatran etexilate is a direct,competitive inhibitor of thrombin.It was evaluated for patients with AF in the RE-LY trial,showing lower rates of stroke and systemic embolism at a dose of 150 mg twice daily with similar rates of major hemorrhage compared with warfarin; and non-inferiority compared with warfarin for the prevention of stroke and systemic embolism at a dose of 110 mg twice daily,with lower rates of major bleeding.Beside dabigatran,oral factor X a inhibitors are also emerging for the prevention of thromboembolic events in AF.Despite the obvious advantages of these new oral anticoagulants over vitamin K antagonists,further information is still needed on how to prioritize the patients deriving the greatest benefit from these novel agents on the basis of patient characteristics or drug pharmacokinetics.There is also a need for assessing their long-term efficacy and safety over decades in the real-world setting.

  18. Managing inadequate responses to frontline treatment of chronic myeloid leukemia: a case-based review.

    Science.gov (United States)

    Bixby, Dale L

    2013-05-01

    The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are the standard of care for treating patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). Compared with interferon-based treatment, the previous standard of care, imatinib is associated with significantly higher cytogenetic response rates and prolonged overall survival. Nilotinib and dasatinib, both newer and more potent TKIs, significantly improve cytogenetic and molecular response rates compared with imatinib. Despite significant advances in CML treatment enabled by the TKIs, a fraction of patients who receive frontline treatment with a TKI demonstrate inadequate response. The reasons for this vary, but in many cases, inadequate response can be attributed to non-adherence to the treatment regimen, intolerance to the drug, intrinsic or acquired resistance to the drug, or a combination of reasons. More often than not, strategies to improve response necessitate a change in treatment plan, either a dose adjustment or a switch to an alternate drug, particularly in the case of drug intolerance or drug resistance. Improved physician-patient communication and patient education are effective strategies to address issues relating to adherence and intolerance. Because inadequate response to TKI treatment correlates with poor long-term outcomes, it is imperative that patients who experience intolerance or who fail to achieve appropriate responses are carefully evaluated so that appropriate treatment modifications can be made to maximize the likelihood of positive long-term outcome.

  19. High Phenobarbital Clearance During Continuous Renal Replacement Therapy

    Science.gov (United States)

    Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

    2014-01-01

    Abstract Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring. A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure. Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus. The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed. Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring. PMID:25101986

  20. High phenobarbital clearance during continuous renal replacement therapy: a case report and pharmacokinetic analysis.

    Science.gov (United States)

    Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

    2014-08-01

    Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring.A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure.Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus.The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed.Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring.

  1. Plasmablastic Lymphoma: A Review of Current Knowledge and Future Directions

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    Ghaleb Elyamany

    2015-01-01

    Full Text Available Plasmablastic lymphoma (PBL is an aggressive subtype of non-Hodgkin’s lymphoma (NHL, which frequently arises in the oral cavity of human immunodeficiency virus (HIV infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM. PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine (CODOX-M/IVAC, or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH are possible options. Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.

  2. Retrospective Evaluation of Pharmacist Interventions on Use of Antimicrobials Using a Clinical Surveillance Software in a Small Community Hospital

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    Samuel R. Huber

    2016-10-01

    Full Text Available The Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America “Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship” recommend the use of computer-based surveillance programs for efficient and thorough identification of potential interventions as part of an antimicrobial stewardship program (ASP. This retrospective study examined the benefit of utilizing a clinical surveillance software program to help guide antimicrobial therapy in an inpatient setting, in a small community hospital, without a formal ASP. The electronic health record (EHR was used to retrieve documentations for the following types of antibiotic interventions: culture surveillance, duplicate therapy, duration of therapy and renal dose adjustments. The numbers of interventions made during the three-month periods before and after implementation of the clinical surveillance software were compared. Antibiotic related interventions aggregated to 144 and 270 in the pre- and post-implementation time frame, respectively (p < 0.0001. The total number of antibiotic interventions overall and interventions in three of the four sub-categories increased significantly from the pre-implementation to post-implementation period. Clinical surveillance software is a valuable tool to assist pharmacists in evaluating antimicrobial therapy.

  3. Clinical impact of laboratory error on therapeutic drug monitoring of once-daily tobramycin in cystic fibrosis: Case series

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    William A Prescott

    2014-01-01

    Full Text Available Once-daily dosing intravenous tobramycin is commonly used to treat cystic fibrosis pulmonary exacerbations. Clinicians often utilize historical therapeutic drug monitoring data to individualize the dose among patients who have been treated with tobramycin previously. This case series involves three patients with cystic fibrosis who had supra-therapeutic tobramycin levels despite use of a once-daily dosing that produced therapeutic drug levels during a previous hospital admission, raising questions about the validity of these levels. Investigation into several potential sources of error led to the discovery of an analyzer error in the laboratory. Once the laboratory’s tobramycin analyzer was recalibrated, the reported levels were comparable to historical levels. This case series emphasizes the clinical importance of critically analyzing reported levels, and specifically, the importance of utilizing past therapeutic drug monitoring data, if available, for all patients treated with intravenous tobramycin. If a patient was therapeutic on a similar dose of tobramycin during a previous admission, a dose adjustment may not be necessary, and clinicians should consider repeating levels while pursuing alternative explanations for the discrepant serum levels.

  4. Evaluation and management of shock States: hypovolemic, distributive, and cardiogenic shock.

    Science.gov (United States)

    Moranville, Michael P; Mieure, Katherine D; Santayana, Elena M

    2011-02-01

    Shock states have multiple etiologies, but all result in hypoperfusion to vital organs, which can lead to organ failure and death if not quickly and appropriately managed. Pharmacists should be familiar with cardiogenic, distributive, and hypovolemic shock and should be involved in providing safe and effective medical therapies. An accurate diagnosis is necessary to initiate appropriate lifesaving interventions and target therapeutic goals specific to the type of shock. Clinical signs and symptoms, as well as hemodynamic data, help with initial assessment and continued monitoring to provide adequate support for the patient. It is necessary to understand these hemodynamic parameters, medication mechanisms of action, and available mechanical support when developing a patient-specific treatment plan. Rapid therapeutic intervention has been proven to decrease morbidity and mortality and is crucial to providing the best patient outcomes. Pharmacists can provide their expertise in medication selection, titration, monitoring, and dose adjustment in these critically ill patients. This review will focus on parameters used to assess hemodynamic status, the major causes of shock, pathophysiologic factors that cause shock, and therapeutic interventions that should be employed to improve patient outcomes.

  5. Cyclophosphamide administration routine in autoimmune rheumatic diseases: a review.

    Science.gov (United States)

    Teles, Kaian Amorim; Medeiros-Souza, Patrícia; Lima, Francisco Aires Correa; Araújo, Bruno Gedeon de; Lima, Rodrigo Aires Correa

    2016-09-17

    Cyclophosphamide (CPM) is an alkylating agent widely used for the treatment of malignant neoplasia and which can be used in the treatment of multiple rheumatic diseases. Medication administration errors may lead to its reduced efficacy or increased drug toxicity. Many errors occur in the administration of injectable drugs. The present study aimed at structuring a routine for cyclophosphamide use, as well as creating a document with pharmacotherapeutic guidelines for the patient. The routine is schematized in three phases: pre-chemotherapy (pre-ChT), administration of cyclophosphamide, and post-chemotherapy (post-ChT), taking into account the drugs to be administered before and after cyclophosphamide in order to prevent adverse effects, including nausea and hemorrhagic cystitis. Adverse reactions can alter laboratory tests; thus, this routine included clinical management for changes in white blood cells, platelets, neutrophils, and sodium, including cyclophosphamide dose adjustment in the case of kidney disease. Cyclophosphamide is responsible for other rare-but serious-side effects, for instance, hepatotoxicity, severe hyponatremia and heart failure. Other adverse reactions include hair loss, amenorrhea and menopause. In this routine, we also entered guidelines to post-chemotherapy patients. The compatibility of injectable drugs with the vehicle used has been described, as well as stability and infusion times. The routine aimed at the rational use of cyclophosphamide, with prevention of adverse events and relapse episodes, factors that may burden the health care system.

  6. Long-Term Disease Control by Pomalidomide-/Dexamethasone-Based Therapy in a Patient with Advanced Multiple Myeloma: A Case Report and Review of the Literature

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    Sophia Danhof

    2015-04-01

    Full Text Available Background: Therapy for multiple myeloma (MM has substantially improved in the era of immunomodulatory drugs and bortezomib. However, the prognosis of patients with progressive disease despite treatment with these ‘novel agents' remains poor. Recently, pomalidomide was approved in this setting, but a median progression-free survival of Case Report: We present the case of a 68-year-old woman with refractory MM who received pomalidomide in combination with various drugs including anthracyclines, alkylators and proteasome inhibitors. Initially, major hematological toxicities and infectious complications including a hepatitis B virus reactivation were encountered. With careful dose adjustments and selection of combination partners, pomalidomide treatment was maintained for over 4 years and led to a sustained partial remission. In particular, the well-tolerated regimen of bortezomib, cyclophosphamide and dexamethasone together with pomalidomide was administered for >30 cycles. Conclusion: This case illustrates the value of an individualized approach to myeloma care given an increasing availability of ‘novel agents'. Tailored treatment using these drugs as a backbone is essential to achieve long-lasting responses and minimize side effects.

  7. The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

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    van Tilborg Theodora C

    2012-09-01

    Full Text Available Abstract Background Costs of in vitro fertilisation (IVF are high, which is partly due to the use of follicle stimulating hormone (FSH. FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT. The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT is more cost-effective than a standard dose regime. Methods/Design Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged  Discussion The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. Trial registration NTR2657

  8. The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients.

    Science.gov (United States)

    El-Najjar, Nahed; Jantsch, Jonathan; Gessner, André

    2017-08-28

    Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

  9. Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

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    Giovanni Sotgiu

    2015-03-01

    Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

  10. Insulin degludec, a long-acting once-daily basal analogue for type 1 and type 2 diabetes mellitus.

    Science.gov (United States)

    Berard, Lori; MacNeill, Gail

    2015-02-01

    Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes.

  11. Use of thiopurines in inflammatory bowel disease: Safety issues

    Institute of Scientific and Technical Information of China (English)

    Anastasia; Konidari; Wael; El; Matary

    2014-01-01

    Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Interindividual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.

  12. Translational research: precision medicine, personalized medicine, targeted therapies: marketing or science?

    Science.gov (United States)

    Marquet, Pierre; Longeray, Pierre-Henry; Barlesi, Fabrice; Ameye, Véronique; Augé, Pascale; Cazeneuve, Béatrice; Chatelut, Etienne; Diaz, Isabelle; Diviné, Marine; Froguel, Philippe; Goni, Sylvia; Gueyffier, François; Hoog-Labouret, Natalie; Mourah, Samia; Morin-Surroca, Michèle; Perche, Olivier; Perin-Dureau, Florent; Pigeon, Martine; Tisseau, Anne; Verstuyft, Céline

    2015-01-01

    Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound. The concept of targeted therapy, mostly used in cancer treatment, relies on the existence of a defined molecular target, involved or not in the pathological process, and/or on the existence of a biomarker able to identify the target population, which should logically be small as compared to the population presenting the disease considered. Targeted therapies and biomarkers represent important stakes for the pharmaceutical industry, in terms of market access, of return on investment and of image among the prescribers. At the same time, they probably represent only the first generation of products resulting from the combination of clinical, pathophysiological and molecular research, i.e. of translational research.

  13. Position statement for the use of omalizumab in the management of chronic spontaneous urticaria in Indian patients

    Directory of Open Access Journals (Sweden)

    Kiran Godse

    2016-01-01

    Full Text Available Chronic spontaneous urticaria (CSU affects 1% of the world population and also their quality of life, and 50% of these patients are refractory to H1-antihistamines. Omalizumab is a humanized monoclonal anti-IgE antibody that binds with free IgE antibodies and reduces the circulating levels of free IgE. This reduction in free IgE prevents mast-cell degranulation. The EAACI/GA2LEN/EDF/WAO guidelines recommend omalizumab as the third-line of therapy as an add-on to antihistamines. The recommended dose of omalizumab is 300 mg, 4 weekly in the management of CSU refractory to standard of care with H1-antihistamines in adults and adolescents ≥12 years of age. In some patients, a dose of 150 mg may be acceptable. Omalizumab has a good safety profile. However, due to the biologic nature of the drug, all patients administered omalizumab must be observed for 2 h after administration for anaphylactoid reactions. There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of omalizumab. While no particular dose adjustment is recommended, omalizumab should be administered with caution in these patients.

  14. Assessing Natural Product-Drug Interactions: An End-to-End Safety Framework.

    Science.gov (United States)

    Roe, Amy L; Paine, Mary F; Gurley, Bill J; Brouwer, Kenneth R; Jordan, Scott; Griffiths, James C

    2016-04-01

    The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach.

  15. Opioid rotation: the science and the limitations of the equianalgesic dose table.

    Science.gov (United States)

    Knotkova, Helena; Fine, Perry G; Portenoy, Russell K

    2009-09-01

    Opioid rotation refers to a switch from one opioid to another in an effort to improve the response to analgesic therapy or reduce adverse effects. It is a common method to address the problem of poor opioid responsiveness despite optimal dose titration. Guidelines for opioid rotation are empirical and begin with the selection of a safe and reasonably effective starting dose for the new opioid, followed by dose adjustment to optimize the balance between analgesia and side effects. The selection of a starting dose must be based on an estimate of the relative potency between the existing opioid and the new one. Potency, which is defined as the dose required to produce a given effect, differs widely among opioids, and among individuals under varying conditions. To effectively rotate from one opioid to another, the new opioid must be started at a dose that will cause neither toxicity nor abstinence, and will be sufficiently efficacious in that pain is no worse than before the change. The estimate of relative potency used in calculating this starting dose has been codified on "equianalgesic dose tables," which historically have been based on the best science available and have been used with little modification for more than 40 years. These tables, and the clinical protocols used to apply them to opioid rotation, may need revision, however, as the science underlying relative potency evolves. Review of these issues informs the use of opioid rotation in the clinical setting and defines key areas for future research.

  16. Review of the pharmacology and clinical studies of micafungin

    Directory of Open Access Journals (Sweden)

    Alison M Bormann

    2009-12-01

    Full Text Available Alison M Bormann1, Vicki A Morrison21Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, USA; 2Division of Hematology/Oncology and Infectious Disease, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN, USAAbstract: Micafungin, like other members of the echinocandin class, has a unique mechanism of action that inhibits the synthesis of 1,3-β-D glucans in the fungal cell wall. It has been approved for treatment of esophageal candidiasis, invasive candidiasis including candidemia, and for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Although efficacy and safety have also been demonstrated in pediatric populations, micafungin is approved for this indication in Europe and Japan, but not in the United States. It has demonstrated activity against Candida spp. including those that are azole-resistant as well as Aspergillus and a few other clinically important molds. It is administered intravenously as a once daily infusion and does not require dose adjustments for renal or moderate hepatic dysfunction. Its safety record, favorable tolerability profile, and few drug interactions make it an important agent for the treatment of invasive fungal infections.Keywords: micafungin, antifungal therapy, echinocandins, fungal infections, Candida, Aspergillus

  17. Statin intolerance: Now a solved problem

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    P Sikka

    2011-01-01

    Full Text Available Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are bound to discontinue statins due to their side effects. Hepatotoxicity, myotoxicity and peripheral neuropathy are important out of them. Discontinuation of statins leads to dylipidemia and its grave consequences. Hence, there should be enough strategies for statin intolerant patients, so that they can be saved from these consequences. These side effects can be avoided by the awareness of certain factors viz. potential drug interactions and dose adjustment according to patho-physiology of the patient. Baseline investigations for liver function and muscle toxicity should be done before initiating statin therapy. Here, we are discussing various options for statin intolerant hyperlipidemic patients such as lower and intermittent dosing of statins, alternate hypolipidemic drugs, red yeast rice, supplementation with coenzyme Q10 and vitamin D. A number of hypolipidemic drugs are in trial phases and hold promise for statin intolerant patients.

  18. Design, preparation and characterization of novel poly-lactic-co-glycolic acid-hyaluronic acid implants containing triptorelin acetate

    Directory of Open Access Journals (Sweden)

    Nersi Jafary Omid

    2014-01-01

    Full Text Available Hormones and their derivatives are widely used to treat different types of diseases such as prostate cancer which is treated by agonists of gonadotropin-releasing hormone. Triptoreline salts are the first therapeutics of this group launched into the market in the form of microparticles (microspheres. Implants, as one of attractive injectable dosage forms, have many advantages over multi-particulate systems. Some of these advantages are dose adjustability, drug absorption improvement, constant release profile, etc. In this research, a new composite of poly-lactic-co-glycolic acid and hyaluronic acid was designed and prepared in the form of implants containing triptorelin acetate for administration as an injection under the skin (subcutaneously in arm or thigh area. The manufactured implants characterized by Fourier transform infrared spectroscopy, thermas gravimetric analysis, X-ray diffraction and scanning electron microscopy to assess different aspects of structure and morphology. The drug release profile was assessed by high performance liquid chromatography. These characterizations confirmed that the newly designed drug delivery has a good stability during manufacturing process. The release pattern of the implant was also studied and revealed that the release of the model drug follows a zero-order and erosion mechanism. The compatibility between the components of the newly designed implants and the release profile of the delivery system make it a promising device for drug delivery.

  19. LINX(®) Reflux Management System in chronic gastroesophageal reflux: a novel effective technology for restoring the natural barrier to reflux.

    Science.gov (United States)

    Bonavina, Luigi; Saino, Greta; Lipham, John C; Demeester, Tom R

    2013-07-01

    Gastroesophageal reflux disease (GERD) results from incompetency of the lower esophageal sphincter that allows the contents of the stomach to reflux into the esophagus, the airways, and the mouth. The disease affects about 10% of the western population and has a profound negative impact on quality of life. The majority of patients are successfully treated with proton-pump inhibitors, but up to 40% have incomplete relief of symptoms even after dose adjustment. The laparoscopic Nissen fundoplication represents the surgical gold standard, but is largely underused because of the level of technical difficulty and the prevalence of side effects. These factors have contributed to the propensity of patients to continue with medical therapy despite inadequate symptom control and complications of the disease. As a consequence, a significant 'therapy gap' in the treatment of GERD remains evident in current clinical practice. The LINX(®) Reflux Management System (Torax Medical, St. Paul, MN, USA) is designed to provide a permanent solution to GERD by augmenting the sphincter barrier with a standardized, reproducible laparoscopic procedure that does not alter gastric anatomy and is easily reversible. Two single-group trials confirmed that a magnetic device designed to augment the lower esophageal sphincter can be safely and effectively implanted using a standard laparoscopic approach. The device decreased esophageal acid exposure, improved reflux symptoms and quality of life, and allowed cessation of proton-pump inhibitors in the majority of patients.

  20. Impact of epoetin alfa on left ventricular structure, function, and pressure volume relations as assessed by cardiac magnetic resonance: the heart failure preserved ejection fraction (HFPEF) anemia trial.

    Science.gov (United States)

    Green, Philip; Babu, Benson A; Teruya, Sergio; Helmke, Stephen; Prince, Martin; Maurer, Mathew S

    2013-01-01

    Anemia, a common comorbidity in older adults with heart failure and a preserved ejection fraction (HFPEF), is associated with worse outcomes. The authors quantified the effect of anemia treatment on left ventricular (LV) structure and function as measured by cardiac magnetic resonance (CMR) imaging. A prospective, randomized single-blind clinical trial (NCT NCT00286182) comparing the safety and efficacy of epoetin alfa vs placebo for 24 weeks in which a subgroup (n=22) had cardiac magnetic resonance imaging (MRI) at baseline and after 3 and 6 months to evaluate changes in cardiac structure and function. Pressure volume (PV) indices were derived from MRI measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVAiso), were calculated. Patients (75±10 years, 64% women) with HFPEF (EF=63%±15%) with an average hemoglobin of 10.3±1.1 gm/dL were treated with epoetin alfa using a dose-adjusted algorithm that increased hemoglobin compared with placebo (PHFPEF resulted in a significant increase in hemoglobin, without evident change in LV structure, function, or pressure volume relationships as measured quantitatively using CMR imaging.

  1. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: Xiaoxia.Yang@fda.hhs.gov; Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-07-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

  2. Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community-acquired bacterial pneumonia.

    Science.gov (United States)

    Van Wart, Scott A; Forrest, Alan; Khariton, Tatiana; Rubino, Christopher M; Bhavnani, Sujata M; Reynolds, Daniel K; Riccobene, Todd; Ambrose, Paul G

    2013-11-01

    Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2)  = 0.93) and individual post-hoc (r(2)  = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

  3. SEOM guidelines for the treatment of bone metastases from solid tumours.

    Science.gov (United States)

    Cassinello Espinosa, Javier; González Del Alba Baamonde, Aránzazu; Rivera Herrero, Fernando; Holgado Martín, Esther

    2012-07-01

    Bone metastases are a common and distressing effect of cancer, being a major cause of morbidity in many patients with advanced stage cancer, in particular in breast and prostate cancer. Patients with bone metastases can experience complications known as skeletal-related events (SREs) which may cause significant debilitation and have a negative impact on quality of life and functional independence. The current recommended systemic treatment for the prevention of SREs is based on the use of bisphosphonates: ibandronate, pamidronate and zoledronic acid- the most potent one- are approved in advanced breast cancer with bone metastases, whereas only zoledronic acid is indicated in advanced prostate cancer with bone metastases. The 2011 ASCO guidelines on breast cancer, recommend initiating bisphosphonate treatment only for patients with evidence of bone destruction due to bone metastases. Denosumab, a fully human antibody that specifically targets the RANK-L, has been demonstrated in two phase III studies to be superior to zoledronic acid in preventing or delaying SREs in breast and prostate cancer and non-inferior in other solid tumours and mieloma; it's convenient subcutaneous administration and the fact that does not require dose adjustment in cases of renal impairment, make this agent an attractive new therapeutic option in patients with bone metastases. Finally, in a phase III study against placebo, denosumab significantly increased the median metastasis-free survival in high risk non-metastatic prostate cancer, arising the potential role of these bone-modifying agents in preventing or delaying the development of bone metastases.

  4. Reduced raltegravir clearance in HIV-infected liver transplant recipients: an unexpected interaction with immunosuppressive therapy?

    Science.gov (United States)

    Cattaneo, Dario; Puoti, Massimo; Sollima, Salvatore; Moioli, Cristina; Foppa, Caterina Uberti; Baldelli, Sara; Clementi, Emilio; Gervasoni, Cristina

    2016-05-01

    Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to its optimal tolerability and its negligible interactions with immunosuppressive drugs. We aimed at providing data on the pharmacokinetics of raltegravir in LTx recipients, on which the available information is inconclusive. In this retrospective multicentre study we characterized the pharmacokinetics of raltegravir in a consecutive series of HIV-infected LTx recipients referred to our laboratory for therapeutic drug monitoring (TDM) and compared the obtained profiles with those collected from a control group of HIV-infected patients. Seventeen HIV-infected LTx patients were considered. LTx recipients had significantly higher raltegravir AUC0-12 compared with the control group of HIV-infected patients [14 314 (11 627-19 998) versus 8795 (5218-12 954) ng·h/mL; P < 0.01]. Two LTx patients experienced moderate increments in serum transaminases, nausea and vomiting that improved after raltegravir dose reduction. High raltegravir exposure and acceptable safety profile were observed in HIV-infected LTx recipients. Our results highlight that some patients may obtain an advantage from TDM-guided raltegravir dose adjustments with potential benefits in terms of drug tolerability. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Comparative analysis of the safety of triple therapy with telaprevir between HCV monoinfected and HIV coinfected patients

    Directory of Open Access Journals (Sweden)

    C. Sangrador Pelluz

    2014-01-01

    Full Text Available Purpose: To know the possible differences in the toxicity profile of triple therapy with telaprevir between monoinfected and coinfected patients. Method: A retrospective observational study (January 2012- November 2013 of patients with HCV genotype 1, both monoinfected and coinfected with HIV, who had completed 12 weeks of treatment with telaprevir. The necessary variables were collected to characterize patients and the treatment received. The classification was made according to the toxicity criteria of the Division of AIDS v.1.0. A descriptive and comparative statistical analysis using the SPSS v.15.0 software was performed. Results: 100 patients were included, 41% coinfected with HIV. Cirrhosis rate was observed at higher coinfected patients (97.6% vs 52.5%, p <0.001. Toxicity: increased incidence in coinfected hyperbilirubinemia (51.2% vs 27.1% p = 0.012. Toxicity grades: no differences in mild-moderate toxicity were observed between the two groups, while severe hyperbilirubinemia was higher in coinfected (26.8% vs 3.4% p = 0.001. Increased use of exogenous erythropoietin (39.9% vs 12.2% p = 0.003 was observed, and dose adjustment of ribavirin (64.4% vs 26.8% p <0.001 in monoinfected patients. Conclusions: The study shows a similar toxicity profile between the two groups except for hyperbilirubinemia appears greater in coinfected patients (possibly related to the use of atazanavir and less use of exogenous erythropoietin and dose reduction of ribavirin in them.

  6. Outcomes for newly diagnosed patients with acute myeloid leukemia dosed on actual or adjusted body weight.

    Science.gov (United States)

    Bray, Whitney M; Bivona, Cory; Rockey, Michelle; Henry, Dave; Grauer, Dennis; Abhyankar, Sunil; Aljitawi, Omar; Ganguly, Siddhartha; McGuirk, Joseph; Singh, Anurag; Lin, Tara L

    2015-10-01

    Data from solid tumor malignancies suggest that actual body weight (ABW) dosing improves overall outcomes. There is the potential to compromise efficacy when chemotherapy dosages are reduced, but the impact of dose adjustment on clinical response and toxicity in hematologic malignancies is unknown. The purpose of this study was to evaluate the outcomes of utilizing a percent of ABW for acute myeloid leukemia (AML) induction chemotherapy dosing. This retrospective, single-center study included 146 patients who received 7 + 3 induction (cytarabine and anthracycline) for treatment of AML. Study design evaluated the relationship between percentage of ABW dosing and complete response (CR) rates in patients newly diagnosed with AML. Percentage of ABW dosing did not influence CR rates in patients undergoing induction chemotherapy for AML (p = 0.83); nor did it influence rate of death at 30 days or relapse at 6 months (p = 0.94). When comparing patients dosed at 90-100 % of ABW compared to ABW, CR rates were not significantly different in patients classified as poor risk (p = 0.907). All favorable risk category patients obtained CR. Preemptive dose reductions for obesity did not influence CR rates for patients with AML undergoing induction chemotherapy and did not influence the composite endpoint of death at 30 days or disease relapse at 6 months.

  7. Monoclonal antibodies: pharmacokinetics as a basis for new dosage regimens?

    Science.gov (United States)

    Azanza, J-R; Sádaba, B; Gómez-Guiu, A

    2015-10-01

    Complete monoclonal IgG antibodies which are in use in clinical practice share some pharmacological properties resulting in high concentrations in plasma. This fact is reflected in their low volumes of distribution, which can also be correlated with a high molecular weight and water solubility. This feature allows a novel approach to be applied to the dosing schedule for this group of drugs with fixed doses being used instead of the initially developed weight- or body surface-adjusted dosing schedules. In addition, the development of a new formulation containing hyaluronidase allows a subcutaneous route of administration to be used, because hyaluronidase creates a space in the subcutaneous tissue that helps antibody absorption. This method requires higher doses, but has allowed testing the feasibility of administering a fixed dose, with no individual dose adjustments based on weight or body surface. Moreover, loading doses are not needed, because the first dose results, within 3 weeks, in minimum concentrations that are higher than effective concentrations.

  8. Treatment of community-acquired pneumonia.

    Science.gov (United States)

    Lee, Young R; Houngue, Coovi; Hall, Ronald G

    2015-01-01

    Community-acquired pneumonia is the sixth leading cause of death in the USA. Adherence to the 2007 Infectious Diseases Society of America/American Thoracic Society community-acquired pneumonia guidelines has been associated with improved clinical outcomes. However, choice between guideline-recommended treatments is at the discretion of the prescribing clinician. This review is intended to discuss the characteristics of these treatment options including dosing frequency, dose adjustment for renal/hepatic dysfunction, serious/common adverse events, drug interactions, lung penetration, pharmacokinetic-pharmacodynamic target and effect of obesity to help guide antimicrobial selection. An increasing portion of patients are receiving expanded empiric coverage for methicillin-resistant Staphylococcus aureus as recommended by the American Thoracic Society and Infectious Diseases Society of America for healthcare-associated pneumonia. However, this expanded coverage may not be achieving the desired improvements in clinical outcomes. We expect this increasingly diverse spectrum of patients with pneumonia to eventually result in the merger of these two guidelines to include all patients with pneumonia.

  9. Use of Sugammadex in Patients With Obesity: A Pooled Analysis.

    Science.gov (United States)

    Monk, Terri G; Rietbergen, Henk; Woo, Tiffany; Fennema, Hein

    A growing proportion of patients undergoing surgical procedures are obese, providing anesthesiologists with numerous challenges for patient management. The current pooled analysis evaluated recovery times following sugammadex reversal of neuromuscular blockade by body mass index (BMI) in general, and in particular, in patients with BMIs ≥30 kg/m (defined as obese) and sugammadex doses for reversal of moderate [reappearance of the second twitch of the train-of-four (TOF); sugammadex 2 mg/kg] or deep (1-2 post-tetanic counts or 15 minutes after rocuronium; sugammadex 4 mg/kg) rocuronium- or vecuronium-induced neuromuscular blockade. All doses of sugammadex were administered based on actual body weight. The recovery time from sugammadex administration to a TOF ratio ≥0.9 was the primary efficacy variable in all individual studies and in the pooled analysis. This analysis comprised a total of 1418 adult patients treated with sugammadex; 267 (18.8%) of these patients had a BMI ≥30 kg/m. The average time to recovery of the TOF ratio to 0.9 was 1.9 minutes for rocuronium-induced blockade and 3.0 minutes for vecuronium-induced blockade. No clinically relevant correlation was observed between BMI and recovery time. The recommended sugammadex doses based on actual body weight provide rapid recovery from neuromuscular blockade in both obese and non-obese patients; no dose adjustments are required in the obese patient.

  10. Quantification of Tricyclic Antidepressants in Serum Using Liquid Chromatography Electrospray Tandem Mass Spectrometry (HPLC-ESI-MS/MS).

    Science.gov (United States)

    Crutchfield, Christopher A; Breaud, Autumn R; Clarke, William A

    2016-01-01

    Tricyclic antidepressants (TCA) are used to treat major depressive disorder and other psychological conditions. The efficacy of these drugs is tied to a narrow therapeutic window. Inappropriately high drug concentrations can result in serious side effects such as hypotension, tachycardia, or coma. As a result, concentrations of tricyclic antidepressants are routinely monitored to ensure compliance and to prevent adverse side effects by dose adjustments. We describe a method for the determination of concentrations of amitriptyline, desipramine, imipramine, and nortriptyline in human serum using high-performance liquid chromatography coupled to a tandem mass spectrometer with electrospray ionization (HPLC-ESI-MS/MS). The method is rapid, requiring only 3.5 min per analysis. The method requires 100 μL of serum. Concentrations of each TCA were quantified by a calibration curve relating the peak area ratio of each TCA analyte to a deuterated internal standard (amitriptyline-D3, desipramine-D3, imipramine-D3, and nortriptyline-D3). The method was linear from ~70 ng/mL to ~1000 ng/mL for all TCAs, with imprecision ≤ 12%.

  11. Novel Pharmacotherapies for the Prevention of Stroke or Systemic Embolism in Adults with Non-valvular Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Christos Dresios

    2014-06-01

    Full Text Available Over the last decade, a paradigm shift is apparent in the eld of stroke prevention in atrial brillation (AF. For more than 6 decades, warfarin has represented the mainstay of anticoagulation therapy when used in AF patients. However, warfarin has important disadvantages, which limit its use in clinical practice. The recent emergence of novel oral anticoagulant drugs (NOACs that overcome many of limitations of warfarin has allowed the provision of e ective stroke prevention for many more patients with AF, as these drugs have a favorable e cacy–safety pro le but also certain pharmacokinetic and pharmacodynamic properties that render periodic anticoagulant monitoring and dose adjustments unnecessary. The NOACs fall into 2 broad categories, the oral direct thrombin inhibitors (dabigatran and the oral factor Xa inhibitors (rivaroxaban, apixaban.The scope of this manuscript is to review currently available data regarding NOACs and to address practical issues relating to the safe and e ective use of NOACs in clinical practice.

  12. Effect of prednisone on the pharmacokinetics of the integrase inhibitor dolutegravir.

    Science.gov (United States)

    Song, Ivy H; Borland, Julie; Chen, Shuguang; Savina, Paul; Peppercorn, Amanda F; Piscitelli, Stephen

    2013-09-01

    Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.).

  13. Dosage Optimization for Letrozole Treatment in Clomiphene-Resistant Patients with Polycystic Ovary Syndrome: A Prospective Interventional Study

    Directory of Open Access Journals (Sweden)

    Elham Rahmani

    2012-01-01

    Full Text Available Objective. Dose adjustment for induction of ovulation is one of the most important problem. Methods. In a prospective interventional study, 44 clomiphene-resistant infertile patients (113 cycles were selected from the Abolfazl Infertility Clinic of Bushehr University of Medical Sciences. Letrozole was given orally in a dose of 2.5 mg, 5 mg, and 7.5 mg, respectively. If the patient displayed no response, the dosage was increased. Results. In this patients ovulation occurred in 50 cycles (44.24%, clinical pregnancy rate according to number of cycles was 23.89% (27 of 113 cycles and according to the number of patients was 61.36% (27 of 44 patients. In the 2.5, 5, and 7.5 groups, follicles occurred in 22.9%, 42.1%, and 85.18% of cycles, and pregnancy rate was 14.58%, 28.94% and, 33.33%, respectively. Conclusions. It is better to administer Letrozole at a lower dosage to prevent complications and increase the dose based on sonographic results antral follicular count, anti-Müllerian hormone, LH/FSH, and estradiol.

  14. Sudden cardiac death in a dog during Holter recording-R on T phenomenon.

    Science.gov (United States)

    Gunasekaran, T; Sanders, R A

    2017-09-19

    A 6-year-old castrated male Golden Retriever was diagnosed with severe subaortic stenosis with severe left atrial enlargement and high heart rate due to atrial fibrillation. Treatment with digoxin and diltiazem to control ventricular response rate was initiated. Ambulatory electrocardiographic monitoring (Holter monitoring) was performed at the beginning of treatment and was repeated to evaluate the patient's response to drug therapy. Drug dose adjustments were made based on response to therapy as assessed by Holter monitoring. The dog experienced sudden death at home 19 days after beginning treatment while wearing the Holter monitor. Analysis of the Holter recording revealed marked increase in number and complexity of ventricular arrhythmias. A ventricular premature complex occurring on a T wave (R on T) was noted preceding the polymorphic ventricular tachycardia. This arrhythmia immediately degenerated into ventricular fibrillation followed by asystole. This case report describes the arrhythmia that preceded cardiac arrest and reviews the risk factors that could have potentiated the fatal arrhythmia in this dog. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Preliminary buprenorphine sublingual tablet pharmacokinetic data in plasma, oral fluid and sweat during treatment of opioid-dependent pregnant women

    Science.gov (United States)

    Concheiro, Marta; Jones, Hendreé E.; Johnson, Rolley E.; Choo, Robin; Huestis, Marilyn A.

    2011-01-01

    Background Buprenorphine is currently under investigation as a pharmacotherapy to treat pregnant women for opioid dependence. This research evaluates buprenorphine (BUP), norbuprenophine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) pharmacokinetics after high dose (14–20 mg) BUP sublingual tablet administration in three opioid-dependent pregnant women. Methods Oral fluid and sweat specimens were collected in addition to plasma specimens for 24 h during gestation weeks 28 or 29 and 34, and 2 months after delivery. Tmax was not affected by pregnancy; however, BUP and NBUP Cmax and AUC0–24h tended to be lower during pregnancy compared to postpartum levels. Results Statistically significant but weak positive correlations were found for BUP plasma and OF concentrations, and BUP/NBUP ratios in plasma and OF. Conclusion Statistically significant negative correlations were observed for times of specimen collection and BUP and NBUP OF/plasma ratios. BUP-Gluc and NBUP-Gluc were detected in only 5% of OF specimens. In sweat, BUP and NBUP were detected in only 4 of 25 (12 or 24 h) specimens in low concentrations (<2.4 ng/patch). These preliminary data describe BUP and metabolite pharmacokinetics in pregnant women and suggest that, like methadone, upward dose adjustments may be needed with advancing gestation. PMID:21860340

  16. Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid.

    Science.gov (United States)

    Lee, Soo-Yun; Huh, Wooseong; Jung, Jin Ah; Yoo, Hye Min; Ko, Jae-Wook; Kim, Jung-Ryul

    2015-01-01

    Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; C max, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and C max (95.7 [85.9-106.5] and 98.3 [91.6-105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary.

  17. Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.

    Science.gov (United States)

    Steinberg, Benjamin A; Holmes, Dajuanicia N; Piccini, Jonathan P; Ansell, Jack; Chang, Paul; Fonarow, Gregg C; Gersh, Bernard; Mahaffey, Kenneth W; Kowey, Peter R; Ezekowitz, Michael D; Singer, Daniel E; Thomas, Laine; Peterson, Eric D; Hylek, Elaine M

    2013-11-25

    Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown. We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, Pprivate insurance (33% versus 25%, Prisk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, PRisk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, Peducation was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, Prisk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted. Clinicaltrials.gov. Unique identifier: NCT01165710.

  18. Management of patients with hepatitis C infection and renal disease.

    Science.gov (United States)

    Bunchorntavakul, Chalermrat; Maneerattanaporn, Monthira; Chavalitdhamrong, Disaya

    2015-02-27

    Hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD) is associated with more rapid liver disease progression and reduced renal graft and patients' survival following kidney transplantation. Evaluations and management of HCV in patients with renal disease are challenging. The pharmacokinetics of interferons (IFN), ribavirin (RBV) and some direct acting antiviral (DAA), such as sofosbuvir, are altered in patients with ESRD. With dose adjustment and careful monitoring, treatment of HCV in patients with ESRD can be associated with sustained virological response (SVR) rates nearly comparable to that of patients with normal renal function. DAA-based regimens, especially the IFN-free and RBV-free regimens, are theoretically preferred for patients with ESRD and KT in order to increase SVR rates and to reduce treatment side effects. However, based on the data for pharmacokinetics, dosing safety and efficacy of DAA for patients with severe renal impairment are lacking. This review will be focused on the evaluations, available pharmacologic data, and management of HCV in patients with severe renal impairment, patients who underwent KT, and those who suffered from HCV-related renal disease, according to the available treatment options, including DAA.

  19. New oral anticoagulants and their implications for dental patients.

    Science.gov (United States)

    O'Connell, John Edward; Stassen, Leo F A

    2014-01-01

    Anticoagulation therapy is used in several conditions to prevent or treat thromboembolism. Over the last 40 years, warfarin has been the oral anticoagulant of choice and has been considered the mainstay of treatment. However, its use is limited by a narrow therapeutic index and complex pharmacodynamics, necessitating regular monitoring and dose adjustments. Recently, two new oral anticoagulants--dabigatran etexilate (a direct thrombin inhibitor) and rivaroxiban (a factor Xa inhibitor)--have been approved for use in North America and Europe. Unlike warfarin, dabigatran and rivaroxiban are relatively small molecules that work as anticoagulants by targeting specific single steps of the coagulation cascade. Their advantages, relative to warfarin, include: predictable pharmacokinetics; limited food and drug interactions; rapid onset of action; and, short half-life. They require no monitoring. However, they lack a specific reversal agent. The number of patients taking dabigatran and rivaroxaban is increasing. Therefore, it is inevitable that dentists will be required to perform invasive procedures on this cohort of patients. This paper outlines the various properties of the new oral anticoagulants and the most recent guidelines regarding the management of these dental patients taking these medications.

  20. An update on the management of anticoagulated patients programmed for dental extractions and surgery.

    Science.gov (United States)

    Jiménez, Yolanda; Poveda, Rafael; Gavaldá, Carmen; Margaix, María; Sarrión, Gracia

    2008-03-01

    Oral anticoagulants (OACs) antagonizing vitamin K - fundamentally sodium warfarin and acenocoumarol - are widely used for preventing arterial thromboembolism in patients with atrial fibrillation and/or heart valve prostheses, and for the treatment and prevention of deep venous thrombosis and pulmonary embolism. The handling of these drugs requires correct monitorization and dose adjustment to obtain the desired therapeutic effect while minimizing the adverse effects associated both with excessive anticoagulation (which leads to bleeding) and with insufficient antithrombotic action (which can produce thrombosis). This is particularly important when patients must be subjected to surgical procedures such as tooth extractions. In this context, a number of management recommendations are available. The present study offers an update on the recommendations for the management of anticoagulated patients programmed for tooth extractions. In recent years, most studies do not recommend reducing or interrupting anticoagulation, or replacing it with heparin, prior to tooth extraction - provided therapeutic international normalized ration (INR) levels are maintained, with emphasis on the application of local measures such as antifibrinolytic agents, for the control of hemostasia.

  1. Ceftobiprole medocaril in the treatment of hospital-acquired pneumonia.

    Science.gov (United States)

    Scheeren, Thomas W L

    2015-01-01

    Ceftobiprole medocaril is a fifth-generation cephalosporin approved in Europe as single-agent therapy for hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP). It is rapidly converted to the active metabolite ceftobiprole following intravenous administration. Ceftobiprole has a broad spectrum of activity, notably against methicillin-resistant Staphylococcus aureus, ampicillin-susceptible enterococci, penicillin-resistant pneumococci and Enterobacteriaceae not producing extended-spectrum β-lactamase. Ceftobiprole is primarily excreted renally by glomerular filtration, with minimal propensity for interaction with co-administered drugs. Normal dose is ceftobiprole 500 mg, administered by 2-h intravenous infusion every 8 h, with dose adjustment according to renal function. In a pivotal Phase III trial in patients with HAP, ceftobiprole monotherapy was as efficacious as ceftazidime/linezolid for clinical and microbiological cure and was noninferior to ceftazidime/linezolid in the subgroup of patients with HAP excluding VAP. Ceftobiprole and ceftazidime/linezolid were similarly well tolerated. Ceftobiprole is an efficacious and well-tolerated option for empirical treatment of patients with HAP (excluding VAP).

  2. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    Science.gov (United States)

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug.

  3. Linagliptin: a thorough characterization beyond its clinical efficacy

    Directory of Open Access Journals (Sweden)

    Maria Angela eSortino

    2013-02-01

    Full Text Available Linagliptin, one of the five dipeptidyl peptidase-4 inhibitors available, has recently entered the market both in US and in most European countries for the treatment of type 2 diabetes mellitus. It presents a xanthine-based structure, and is characterized by unique pharmacokinetics, with non-linear profile, long terminal half-life allowing prolonged exposure to the drug. It is eliminated predominately through the intestinal tract and only minimally into urine, so that it can be administered, without any dose adjustment, in conditions of renal impairment. Linagliptin is effective in modifying all parameters of hyperglycemia either in monotherapy, or as add-on therapy, together with metformin or a sulphonylurea. It exhibits also a good tolerability profile with the appearance of few side effects, absence (when used in monotherapy or low risk (when in combination with a sulphonylurea of hypoglycemia. More importantly it has a neutral weight gain effect. A comprehensive report of the literature on linagliptin is provided, paying attention in particular to pre-clinical studies, interactions with other drugs, safety and tolerability and results obtained in animal models that highlight properties of linagliptin suggestive of potential additional uses. Particularly promising appear in fact data demonstrating a positive effect of linagliptin on metabolic dysfunction and renal and/or cardiovascular damage together with the more recently reported effects of linagliptin on tissue repair and neuroprotection.

  4. Melperone but not bisoprolol or metoprolol is a clinically relevant inhibitor of CYP2D6: evidence from a therapeutic drug monitoring survey.

    Science.gov (United States)

    Hefner, Gudrun; Unterecker, Stefan; Shams, Mohamed E E; Wolf, Margarete; Falter, Tanja; Haen, Ekkehard; Hiemke, Christoph

    2015-11-01

    Cytochrome P450 enzymes (CYP) can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. The objective of the study was to analyze the in vivo inhibitory potential of the beta-blockers bisoprolol and metoprolol as well as the low-potency antipsychotic melperone on CYP2D6. By utilizing a large therapeutic drug monitoring database of 2874 samples, data from patients who had been treated with venlafaxine (VEN) either without (control group) or with a concomitant medication with bisoprolol, metoprolol or melperone were evaluated retrospectively to study the CYP2D6-catalyzed O-demethylation to O-desmethylvenlafaxine (ODVEN). Dose-adjusted serum levels (C/D) of VEN and ODVEN as well as the metabolic ratios (ODVEN/VEN) were computed for the four groups and compared using Kruskal-Wallis test. In total, 381 patients could be included for analysis. No significant difference was found in the median C/D (VEN), C/D (ODVEN) or C/D of the active moiety (VEN + ODVEN) in either the metoprolol (N = 103) or bisoprolol group (N = 101), compared to the control group (N = 108). In contrast, a significantly higher median C/D (VEN) (0.79 ng/ml/mg, range 0.13-5.73 ng/ml/mg) (P metoprolol has a clinically relevant inhibitory potential on CYP2D6.

  5. An unusual case of hypothermia associated with therapeutic doses of olanzapine: a case report

    Directory of Open Access Journals (Sweden)

    Ratnayake Shiroma L

    2011-05-01

    Full Text Available Abstract Introduction We report a case of a 42-year-old man who had symptomatic hypothermia as a result of taking olanzapine for paranoid schizophrenia. According to published data, only a few cases of hypothermia associated with olanzapine have been reported since its introduction into clinical use. Case presentation A 42-year-old Sri Lankan man with schizophrenia who was being treated with a therapeutic dose of olanzapine presented with reduced level of consciousness. He had a core temperature of 32°C and was bradycardic. At the time of admission, the electrocardiogram showed sinus bradycardia with J waves. He did not have any risk factors for developing hypothermia except the use of olanzapine. There was improvement in his clinical condition with reversal of electrocardiogram changes following gradual rewarming and the omission of olanzapine. Conclusion Hypothermia induced by antipsychotic medications is not uncommon, but olanzapine-induced hypothermia is rare and occurrence has been reported during initiation or increasing the dose. But here the patient developed hypothermia without dose adjustment.

  6. Comparative risk impact of edoxaban in the management of stroke and venous thromboembolism

    Directory of Open Access Journals (Sweden)

    Tellor KB

    2016-04-01

    Full Text Available Katie B Tellor, Joseph S Van Tuyl, Anastasia L Armbruster Department of Pharmacy Practice, St Louis College of Pharmacy, St Louis, MO, USA Abstract: Edoxaban, a factor Xa inhibitor, was approved by the United States Food and Drug Administration in 2015 for stroke prevention in nonvalvular atrial fibrillation and treatment of venous thromboembolism. It is the fourth target-specific oral anticoagulant to be approved. Edoxaban is noninferior for efficacy compared to warfarin for both approved indications. Edoxaban is superior to warfarin for the first major or clinically relevant nonmajor bleeding event in venous thromboembolism and major bleeding in nonvalvular atrial fibrillation. Edoxaban is dosed once daily for both indications and requires dose adjustment for renal function. In patients with nonvalvular atrial fibrillation, use is not recommended in patients with a creatinine clearance greater than 95 mL/min due to reduced efficacy. Edoxaban offers a new therapeutic alternative to the currently available options in the market. Keywords: anticoagulation, stroke, deep vein thrombosis, pulmonary embolism, atrial fibrillation, Savaysa™

  7. Movement disorders induced by deep brain stimulation.

    Science.gov (United States)

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-04-01

    Deep brain stimulation represents a major advance in the treatment of several types of movement disorders. However, during stimulation new movement disorders may emerge, thus limiting the positive effects of this therapy. These movement disorders may be induced by: 1) stimulation of the targeted nucleus, 2) stimulation of surrounding tracts and nuclei, and 3) as a result of dose adjustment of accompanying medications, such as reduction of dopaminergic drugs in patients with Parkinson's disease. Various dyskinesias, blepharospasm, and apraxia of eyelid opening have been described mainly with subthalamic nucleus stimulation, whereas hypokinesia and freezing of gait have been observed with stimulation of the globus pallidus internus. Other deep brain stimulation-related movement disorders include dyskinesias associated with stimulation of the globus pallidus externus and ataxic gait as a side effect of chronic bilateral stimulation of the ventral intermediate nucleus of thalamus. These movement disorders are generally reversible and usually resolved once the stimulation is reduced or turned off. This, however, typically leads to loss of benefit of the underlying movement disorder which can be re-gained by using different contacts, changing targets or stimulation parameters, and adjusting pharmacological therapy. New and innovative emerging technologies and stimulation techniques may help to prevent or overcome the various deep brain stimulation-induced movement disorders. In this review we aim to describe the clinical features, frequency, pathophysiology, and strategies for treatment of these iatrogenic movement disorders.

  8. Febuxostat in the management of hyperuricemia and chronic gout: a review

    Directory of Open Access Journals (Sweden)

    Miao Hu

    2008-09-01

    Full Text Available Miao Hu, Brian TomlinsonDivision of Clinical Pharmacology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, ChinaAbstract: Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insufficiency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout flares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the first major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and efficacy is required.Keywords: febuxostat, TEI-6720, TMX-67, gout, hyperuricemia, xanthine oxidase inhibitor

  9. In vivo genotoxicity assessment of sertraline by using alkaline comet assay and the cytokinesis-block micronucleus assay.

    Science.gov (United States)

    Battal, Dilek; Aktas, Ayca; Sungur, Mehmet Ali; Kadioglu, Ela; Eker, Ebru Derici; Sahin, Nefise Ozlen; Saygi, Sahan

    2013-11-01

    Sertraline, a leading antidepressant in the selective serotonin reuptake inhibitor (SSRI) group of medicine, is the most frequently prescribed drug. In this study, the alkaline comet assay and the cytokinesis-block micronucleus (CBMN) assay were used to investigate genotoxicity potential of sertraline in the peripheral blood lymphocytes (PBLs) of acute and chronic sertraline-treated Wistar albino rats. Male Wistar albino rats (n = 48) were administered low, medium and high doses of sertraline (10, 40, 80 mg/kg) for acute and chronic treatment by employing the gavage method to investigate genotoxicity of the administered drug. The data (tail length, tail intensity and tail moment) were analysed and indicated that there was no statistically significant difference between sertraline-treated groups and the negative control group with respect to DNA damage (p > 0.05). However, it was observed that acute sertraline administration had caused much more DNA damage in comparison with chronic treatment (p sertraline treatment. Based on the outcome of comet assay, detection of statistically insignificant DNA damage may be due to the fact that sertraline did not cause damage on DNA. Also, increase in frequency of MN in chronic sertraline treatment suggests that chronic sertraline administration might influence some mechanisms of cell division. Therefore, dose adjustment in depressed patients seems significant as it may help prevent further prognosis of the diseases.

  10. Gentamicin Exposure and Sensorineural Hearing Loss in Preterm Infants.

    Directory of Open Access Journals (Sweden)

    Aline Fuchs

    Full Text Available To evaluate the impact of gentamicin exposure on sensorineural hearing loss (SNHL in very low birth weight (VLBW infants.Exposure to gentamicin was determined in infants born between 1993 and 2010 at a gestational age < 32 weeks and/or with a birthweight < 1500 g, who presented with SNHL during the first 5 years of life. For each case, we selected two controls matched for gender, gestational age, birthweight, and year of birth.We identified 25 infants affected by SNHL, leading to an incidence of SNHL of 1.58% in our population of VLBW infants. The proportion of infants treated with gentamicin was 76% in the study group and 70% in controls (p = 0.78. The total cumulated dose of gentamicin administered did not differ between the study group (median 10.2 mg/kg, Q1-Q3 1.6-13.2 and the control group (median 7.9 mg/kg, Q1-Q3 0-12.8, p = 0.47. The median duration of gentamicin treatment was 3 days both in the study group and the control group (p = 0.58. Maximum predicted trough serum levels of gentamicin, cumulative area under the curve and gentamicin clearance were not different between cases and controls.The impact of gentamicin on SNHL can be minimized with treatments of short duration, monitoring of blood levels and dose adjustment.

  11. Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells.

    Science.gov (United States)

    Faria, Juliana; Barbosa, Joana; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2016-06-01

    Opioid therapy and abuse are increasing, justifying the need to study their toxicity and underlying mechanisms. Given opioid pharmacodynamics at the central nervous system, the analysis of toxic effects in neuronal models gains particular relevance. The aim of this study was to compare the toxicological effects of acute exposure to tramadol and tapentadol in the undifferentiated human SH-SY5Y neuroblastoma cell line. Upon exposure to tramadol and tapentadol concentrations up to 600μM, cell toxicity was assessed through evaluation of oxidative stress, mitochondrial and metabolic alterations, as well as cell viability and death mechanisms through necrosis or apoptosis, and related signalling. Tapentadol was observed to trigger much more prominent toxic effects than tramadol, ultimately leading to energy deficit and cell death. Cell death was shown to predominantly occur through necrosis, with no alterations in membrane potential or in cytochrome c release. Both drugs were shown to stimulate glucose uptake and to cause ATP depletion, due to changes in the expression of energy metabolism enzymes. The toxicity mechanisms in such a neuronal model are relevant to understand adverse reactions to these opioids and to contribute to dose adjustment in order to avoid neurological damage.

  12. Patient Selection and Activity Planning Guide for Selective Internal Radiotherapy With Yttrium-90 Resin Microspheres

    Energy Technology Data Exchange (ETDEWEB)

    Lau, Wan-Yee, E-mail: josephlau@surgery.cuhk.edu.hk [Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Kennedy, Andrew S. [Wake Radiology Oncology, Cary, NC (United States); Department of Biomedical Engineering, North Carolina State University, Raleigh, NC (United States); Kim, Yun Hwan [Department of Radiology, Anam Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Lai, Hee Kit [Nuclear Medicine and PET Centre, Mount Elizabeth Hospital, Singapore (Singapore); Lee, Rheun-Chuan [Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan (China); Leung, Thomas W.T. [Comprehensive Oncology Centre, Hong Kong Sanatorium and Hospital (Hong Kong); Liu, Ching-Sheng [Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China); Salem, Riad [Division of Interventional Radiology, Northwestern University, Chicago, IL (United States); Sangro, Bruno [Liver Unit, Clinica Universitaria de Navarra and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Pamplona (Spain); Shuter, Borys [Department of Diagnostic Imaging, National University Hospital, Singapore (Singapore); Wang, Shih-Chang [Parker-Hughes Professor of Diagnostic Radiology, University of Sydney, Sydney, NSW (Australia)

    2012-01-01

    Purpose: Selective internal radiotherapy (SIRT) with yttrium-90 ({sup 90}Y) resin microspheres can improve the clinical outcomes for selected patients with inoperable liver cancer. This technique involves intra-arterial delivery of {beta}-emitting microspheres into hepatocellular carcinomas or liver metastases while sparing uninvolved structures. Its unique mode of action, including both {sup 90}Y brachytherapy and embolization of neoplastic microvasculature, necessitates activity planning methods specific to SIRT. Methods and Materials: A panel of clinicians experienced in {sup 90}Y resin microsphere SIRT was convened to integrate clinical experience with the published data to propose an activity planning pathway for radioembolization. Results: Accurate planning is essential to minimize potentially fatal sequelae such as radiation-induced liver disease while delivering tumoricidal {sup 90}Y activity. Planning methods have included empiric dosing according to degree of tumor involvement, empiric dosing adjusted for the body surface area, and partition model calculations using Medical Internal Radiation Dose principles. It has been recommended that at least two of these methods be compared when calculating the microsphere activity for each patient. Conclusions: Many factors inform {sup 90}Y resin microsphere SIRT activity planning, including the therapeutic intent, tissue and vasculature imaging, tumor and uninvolved liver characteristics, previous therapies, and localization of the microsphere infusion. The influence of each of these factors has been discussed.

  13. Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients

    Science.gov (United States)

    Gupta, Ajay; Lin, Vivian; Guss, Carrie; Pratt, Raymond; Ikizler, T Alp; Besarab, Anatole

    2015-01-01

    Ferric pyrophosphate citrate (FPC) is a water-soluble iron salt administered via dialysate to supply iron directly to transferrin. The PRIME study tested whether treatment with FPC could reduce prescribed erythropoiesis-stimulating agent (ESA) use and maintain hemoglobin in hemodialysis patients. This 9-month, randomized, placebo-controlled, double-blind, multicenter clinical study included 103 patients undergoing hemodialysis 3–4 times weekly. The FPC group received dialysate containing 2 μmol/l of iron. The placebo group received standard dialysate. A blinded central anemia management group facilitated ESA dose adjustments. Intravenous iron was administered according to the approved indication when ferritin levels fell below 200 μg/l. The primary end point was the percentage change from baseline in prescribed ESA dose at end of treatment. Secondary end points included intravenous iron use and safety. At the end of treatment, there was a significant 35% reduction in prescribed ESA dose in FPC-treated patients compared with placebo. The FPC patients used 51% less intravenous iron than placebo. Adverse and serious adverse events were similar in both groups. Thus, FPC delivered via dialysate significantly reduces the prescribed ESA dose and the amount of intravenous iron needed to maintain hemoglobin in chronic hemodialysis patients. PMID:26154926

  14. Methadone dosage and its relationship to quality of life, satisfaction, psychopathology, cognitive performance and additional consumption of non-prescribed drugs.

    Science.gov (United States)

    Pedrero-Pérez, Eduardo J; MethaQoL, Grupo

    2016-06-14

    The effectiveness of methadone maintenance treatment is beyond any doubt, but there remains some incertitude about the appropriate and effective dosage and the objectives that should be achieved by this therapy. Some authors maintain that only doses higher than 50-60 mg/day ought to be considered effective, since only these block all the opioid receptors. But others propose the use of doses adjusted to the needs of the patient, based on their recovery process. Quality of life, satisfaction with treatment, psychopathological symptoms, cognitive performance and additional intake of illegal and unprescribed drugs were evaluated in a representative sample of all patients treated with opioid agonists in the Addiction Institute of Madrid (N = 1898, n = 450) and the Junta de Extremadura (N = 100, n = 65). The results revealed a negative relationship between dose and quality of life, psychopathological symptoms and cognitive performance. Satisfaction with treatment, based on doses negotiated together by doctor and patient, was very high, regardless of the dose. To establish hypothetical causal dependencies among the studied variables structural equation modelling was performed. The results reject the need for high dosage if not required by the patient, and highlight the benefits of other psychosocial interventions that lead to recovery, despite the chronification that could imply the use of high doses. Whereas high dosage programmes provide better indicators of social control, the patient's quality of life must be one of the main indicators of a successful treatment, as in any other health problem.

  15. [INSULIN GLARGINE 300 U/mL (TOUJEO®)].

    Science.gov (United States)

    Scheen, A J

    2016-02-01

    This article presents a new formulation of insulin glargine concentrated at 300 U/mL (Gla-300). It is commercialized under the trade name of Toujeo® in an optimized pre-filled SoloStar™ pen for the treatment of type 1 and type 2 diabetes in adults. Besides a threefold higher concentration compared to the classical insulin Lantus® (100 U/mL or Gla-100), both pharmacokinetic and pharmacodynamic profiles of Gla-300 are flatter and longer (more than 24 hours) and have a lesser intra-/inter-variability, which makes them more reproducible. Overall, Toujeo® offers the same hypoglycaemic efficacy and the same safety profile when compared with Lantus®. However, a lower risk of hypoglycaemia, especially at night, a slightly smaller weight gain and a better flexibility in the time of injection have been reported. The two insulin formulations are not bioequivalent and the daily insulin requirement is slightly higher with insulin Gla-300 than with insulin Gla-100. The shift from an already available basal insulin towards Toujeo® may require a dose adjustment and a reinforcement of blood glucose monitoring.

  16. SGLT-2 inhibition in patients with kidney disease.

    Science.gov (United States)

    Gilbert, R E

    2014-12-01

    Accustomed to managing diabetes with agents that mostly act by modulating the secretion and actions of insulin, with the advent of sodium-glucose linked transporter-2 (SGLT-2) inhibitors, physicians are now aware that the kidney also needs to be considered in the spectrum of action of anti-hyperglycaemic agents. Though familiar with the need for dose adjustment when prescribing many of our current anti-hyperglycaemic drugs in the setting of kidney dysfunction, with the SGLT-2 inhibitors pharmacodynamic as well as pharmacokinetic aspects also need to be considered. Finally, through their ability to reduce intraglomerular pressure, systemic blood pressure and plasma uric acid concentration, the SGLT-2 inhibitors offers the possibility of kidney protection. An hypothesis that will need to be tested with long term studies that address changes in the kidney beyond albuminuria, assessing the rate of decline in glomerular filtration rate and 'hard'kidneyrelated endpoints such as the need for renal replacement therapy (dialysis, transplantation) will be important in this setting.

  17. The Effect of Vinpocetine on Human Cytochrome P450 Isoenzymes by Using a Cocktail Method

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    Lingti Kong

    2016-01-01

    Full Text Available Vinpocetine is a derivative of the alkaloid vincamine, which had been prescribed for chronic cerebral vascular ischemia and acute ischemic stroke or used as a dietary supplement for its several different mechanisms of biological activities. However, information on the cytochrome P450 (CYP enzyme-mediated drug metabolism has not been previously studied. The present study was performed to investigate the effects of vinpocetine on CYPs activity, and cocktail method was used, respectively. To evaluate the effects of vinpocetine on the activity of human CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, human liver microsomes were utilized to incubate with the mixed CYPs probe substrates and the target components. The results indicate that vinpocetine exhibited weak inhibitory effect on the CYP2C9, where the IC50 value is 68.96 μM, whereas the IC50 values for CYP3A4, CYP2C19, CYP2D6, and CYP2E1 were all over range of 100 μM, which showed that vinpocetine had no apparent inhibitory effects on these CYPs. In conclusion, the results indicated that drugs metabolized by CYP2C9 coadministrated with vinpocetine may require attention or dose adjustment.

  18. Pramipexole safely replaces ergot dopamine agonists with either rapid or slow switching.

    Science.gov (United States)

    Takahashi, H; Nogawa, S; Tachibana, H; Kawamura, J; Abe, T; Ogino, Y; Kashihara, K; Hamada, T; Kowa, H

    2008-01-01

    This prospective, open-label, multicentre study examined the efficacy and safety of rapidly (overnight) or slowly (after 2 weeks of concomitant usage) switching patients with Parkinson's disease (PD) from conventional ergot dopamine agonists (DAs) to the non-ergot DA, pramipexole. Fifty-nine early-to-advanced PD patients with motor symptoms that were inadequately controlled by ergot DAs were enrolled. Patients were switched from ergot derivatives to pramipexole and evaluated every 2 weeks for 12 weeks by Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale (UPDRS) and a modified Epworth Sleepiness Scale (mESS). The UPDRS III subscores and total UPDRS scores significantly improved, independent of switching method. Adverse events, all of which were mild, occurred in 29.2% of patients. No sudden onset of excessive daytime sleepiness or significant worsening in mESS was seen. Switching patients with PD from ergot DA to pramipexole, using either a slow or rapid switching method, appeared to be well tolerated and effective, although further dose adjustment may be necessary in some patients after the switch.

  19. Role and clinical utility of pramipexole extended release in the treatment of early Parkinson's disease.

    Science.gov (United States)

    Hametner, Eva-Maria; Seppi, Klaus; Poewe, Werner

    2012-01-01

    The aim of this article is to provide a short review of the most relevant pharmacological and clinical data on pramipexole extended release (ER) as well as to address the clinical utility and potential advantages of a once-daily formulation especially in the treatment of early Parkinson's disease (PD). Pramipexole is widely established as a symptomatic treatment in early as well as advanced PD. The development of an ER formulation, with stable pramipexole plasma concentration over 24 hours, now offers a bioequivalent once-daily alternative. Double-blind randomized controlled trials in early and advanced PD, have established noninferiority of pramipexole ER compared with immediate release as well as superiority of both formulations over placebo. The overnight switch from the standard to the once-daily formulation was shown to be successful in >80% of patients without requiring any dose adjustments. Potential benefits of the prolonged-release design, which have not yet been formally demonstrated in the pivotal trial program, include improved compliance and a potential for better symptomatic control, particularly in patients with early disease that can be managed with monotherapy.

  20. Exposure-response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer.

    Science.gov (United States)

    Wang, J; Song, P; Schrieber, S; Liu, Q; Xu, Q; Blumenthal, G; Amiri Kordestani, L; Cortazar, P; Ibrahim, A; Justice, R; Wang, Y; Tang, S; Booth, B; Mehrotra, N; Rahman, A

    2014-05-01

    Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability.

  1. A rational approach to dose reduction in CT: individualized scan protocols

    Energy Technology Data Exchange (ETDEWEB)

    Wilting, J.E.; Zwartkruis, A.; Timmer, J. [Philips Medical Systems Nederland BV, Best (Netherlands); Leeuwen, M.S. van; Feldberg, M. [University Medical Center, Utrecht (Netherlands); Kamphuis, A.G.A. [Rode Kruis Ziekenhuis, Beverwijk (Netherlands)

    2001-12-01

    The aim of this study was to demonstrate that dose reduction and constant image quality can be achieved by adjusting X-ray dose to patient size. To establish the relation between patient size, image quality and dose we scanned 19 patients with reduced dose. Image noise was measured. Four radiologists scored image quality subjectively, whereby a higher score meant less image quality. A reference patient diameter was determined for which the dose was just sufficient. Then 22 patients were scanned with the X-ray dose adjusted to their size. Again, image noise was measured and subjective image quality was scored. The dose reduction compared with the standard protocol was calculated. In the first group the measured noise was correlated to the patient diameter ({rho}=0.78). This correlation is lost in the second group ({rho}=-0.13). The correlation between patient diameter and subjective image quality scores changes from {rho}=0.60 (group 1) to {rho}=-0.69 (group 2). Compared with the standard protocol, the dose was reduced (mean 28%, range 0-76%) in 19 of 22 patients (86%). Dose reduction and constant noise can be achieved when the X-ray dose is adjusted to the patient diameter. With constant image noise the subjective image quality increases with larger patients. (orig.)

  2. Impact of Variations in Kidney Function on Nonvitamin K Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Recent Acute Heart Failure.

    Science.gov (United States)

    Andreu-Cayuelas, José M; Pastor-Pérez, Francisco J; Puche, Carmen M; Mateo-Martínez, Alicia; García-Alberola, Arcadio; Flores-Blanco, Pedro J; Valdés, Mariano; Lip, Gregory Y H; Roldán, Vanessa; Manzano-Fernández, Sergio

    2016-02-01

    Renal impairment and fluctuations in renal function are common in patients recently hospitalized for acute heart failure and in those with atrial fibrillation. The aim of the present study was to evaluate the hypothetical need for dosage adjustment (based on fluctuations in kidney function) of dabigatran, rivaroxaban and apixaban during the first 6 months after hospital discharge in patients with concomitant atrial fibrillation and heart failure. An observational study was conducted in 162 patients with nonvalvular atrial fibrillation after hospitalization for acute decompensated heart failure who underwent creatinine determinations during follow-up. The hypothetical recommended dosage of dabigatran, rivaroxaban and apixaban according to renal function was determined at discharge. Variations in serum creatinine and creatinine clearance and consequent changes in the recommended dosage of these drugs were identified during 6 months of follow-up. Among the overall study population, 44% of patients would have needed dabigatran dosage adjustment during follow-up, 35% would have needed rivaroxaban adjustment, and 29% would have needed apixaban dosage adjustment. A higher proportion of patients with creatinine clearance renal impairment. Further studies are needed to clarify the clinical importance of these needs for drug dosing adjustment and the ideal renal function monitoring regime in heart failure and other subgroups of patients with atrial fibrillation. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  3. Epilepsy during pregnancy: focus on management strategies

    Directory of Open Access Journals (Sweden)

    Borgelt LM

    2016-09-01

    Full Text Available Laura M Borgelt,1 Felecia M Hart,2 Jacquelyn L Bainbridge2 1Departments of Clinical Pharmacy and Family Medicine, 2Departments of Clinical Pharmacy and Neurology, University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA Abstract: In the US, more than one million women with epilepsy are of childbearing age and have over 20,000 babies each year. Patients with epilepsy who become pregnant are at risk of complications, including changes in seizure frequency, maternal morbidity and mortality, and congenital anomalies due to antiepileptic drug exposure. Appropriate management of epilepsy during pregnancy may involve frequent monitoring of antiepileptic drug serum concentrations, potential preconception switching of antiepileptic medications, making dose adjustments, minimizing peak drug concentration with more frequent dosing, and avoiding potentially teratogenic medications. Ideally, preconception planning will be done to minimize risks to both the mother and fetus during pregnancy. It is important to recognize benefits and risks of current and emerging therapies, especially with revised pregnancy labeling in prescription drug product information. This review will outline risks for epilepsy during pregnancy, review various recommendations from leading organizations, and provide an evidence-based approach for managing patients with epilepsy before, during, and after pregnancy. Keywords: epilepsy, teratogens, anticonvulsants, medication therapy management

  4. An extended treatment protocol with pegylated interferon and ribavirin for hepatitis C recurrence after liver transplantation

    Science.gov (United States)

    Hashemi, Nikroo; Araya, Victor; Tufail, Kashif; Thummalakunta, Laxmi; Feyssa, Eyob; Azhar, Ashaur; Niazi, Mumtaz; Ortiz, Jorge

    2011-01-01

    AIM: To evaluate the efficacy and tolerability of an extended treatment protocol and to determine the predictors of sustained virological response (SVR) after liver transplantation (LT). METHODS: Between August 2005 and November 2008, patients with recurrent hepatitis C virus (HCV) after LT were selected for treatment if liver biopsy showed at least grade 2 inflammation and/or stage 2 fibrosis. All patients were to receive pegylated interferon (PEG)/regimens combining ribavirin (RBV) for an additional 48 wk after HCV undetectability. RESULTS: Extended protocol treatment was initiated in thirty patients. Overall, 73% had end of treatment response and 60% had SVR. Nineteen patients completed treatment per protocol, of them, sixteen (84%) had end of treatment response, and fourteen (74%) achieved SVR. Both early virological response and 24-week virological response were individually associated with SVR but this association was not significant on multivariate analysis. Eleven patients (37%) discontinued therapy due to adverse effects. Cytopenias were the most common and most severe adverse effect, and required frquent growth factor use, dose adjustments and treatment cessations. The risk of rejection was not increased. CONCLUSION: Recurrent HCV after LT can be safely treated with extended virological response-guided therpy using PEG/RBV, but requires close monitoring for treatment-related adverse effects, particularly cytopenias. PMID:21866251

  5. Evaluation of Certain Pharmaceutical Quality Attributes of Lisinopril Split Tablets

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    Khairi M. S. Fahelelbom

    2016-10-01

    Full Text Available Tablet splitting is an accepted practice for the administration of drugs for a variety of reasons, including dose adjustment, ease of swallowing and cost savings. The purpose of this study was to evaluate the physical properties of lisinopril tablets as a result of splitting the tablets either by hand or with a splitting device. The impact of the splitting technique of lisinopril (Zestril® tablets, 20 mg on certain physical parameters such as weight variation, friability, disintegration, dissolution and drug content were studied. Splitting the tablets either by hand or with a splitter resulted in a minute but statistically significant average weight loss of <0.25% of the tablet to the surrounding environment. The variability in the weight of the hand-split tablet halves was more pronounced (37 out of 40 tablet halves varied by more than 10% from the mean weight than when using the tablet splitter (3 out of 40 tablet halves. The dissolution and drug content of the hand-split tablets were therefore affected because of weight differences. However, the pharmacopoeia requirements for friability and disintegration time were met. Hand splitting of tablets can result in an inaccurate dose and may present clinical safety issues, especially for drugs with a narrow therapeutic window in which large fluctuations in drug concentrations are undesirable. It is recommended to use tablets with the exact desired dose, but if this is not an option, then a tablet splitter could be used.

  6. A Case of Severe Hydroxychloroquine-Induced Retinal Toxicity in a Patient with Recent Onset of Renal Impairment: A Review of the Literature on the Use of Hydroxychloroquine in Renal Impairment

    Directory of Open Access Journals (Sweden)

    Rajen Tailor

    2012-01-01

    Full Text Available We present a case of a 67-year-old female who presented with a twelve-month history of progressive blurred vision in both eyes. The patient was on hydroxychloroquine 200 mg twice a day for eight years for the treatment of scarring alopecia. Two years prior to presenting, the patient was found to have chronic kidney disease stage 3 secondary to hypertension. Examination revealed bilateral reduced visual acuities with attenuated arterioles and pigmentary changes on retinal assessment. Goldmann visual fields showed grossly constricted fields in both eyes. The patient was diagnosed with retinal toxicity secondary to hydroxychloroquine probably potentiated by renal impairment. Risk factors for retinal toxicity secondary to hydroxychloroquine can be broadly divided into dose-related and patient-related factors. Our patient developed severe retinal toxicity despite being on the recommended daily dose (400 mg per day. Although retinal toxicity at this dose has been documented, the development of renal impairment without dose adjustment or close monitoring of visual function is likely to have potentiated retinal toxicity. This case highlights the need to monitor renal function in patients on hydroxychloroquine. Should renal impairment develop, either the drug should be stopped or the dose reduced with close monitoring of visual function by an ophthalmologist.

  7. AIDS-associated diarrhea and wasting in northeast Brazil is associated with subtherapeutic plasma levels of antiretroviral medications and with both bovine and human subtypes of Cryptosporidium parvum

    Directory of Open Access Journals (Sweden)

    Richard K. Brantley

    2003-02-01

    Full Text Available Advanced HIV infection is frequently complicated by diarrhea, disruption of bowel structure and function, and malnutrition. Resulting malabsorption of or pharmacokinetic changes in antiretroviral agents might lead to subtherapeutic drug dosing and treatment failure in individual patients, and could require dose adjustment and/or dietary supplements during periods of diarrheal illness. We determined the plasma levels of antiretroviral medications in patients that had already been started on medication by their physicians in an urban infectious diseases hospital in northeast Brazil. We also obtained blood samples from patients hospitalized for diarrhea or AIDS-associated wasting, and we found reduced stavudine and didanosine levels in comparison with outpatients without diarrhea or wasting who had been treated at the same hospital clinic. There was a predominance of the protozoal pathogens Cryptosporidium and Isospora belli, typical opportunistic pathogens of AIDS-infected humans, in the stool samples of inpatients with diarrhea. We conclude that severe diarrhea and wasting in this population is associated with both protozoal pathogens and subtherapeutic levels of antiretroviral medications.

  8. Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

    Directory of Open Access Journals (Sweden)

    Junji Saruwatari

    2010-08-01

    Full Text Available Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs. However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed.

  9. Blood purification in the critically ill patient. Prescription tailored to the indication (including the pediatric patient).

    Science.gov (United States)

    Sanchez-Izquierdo Riera, J A; Montoiro Allué, R; Tomasa Irriguible, T; Palencia Herrejón, E; Cota Delgado, F; Pérez Calvo, C

    2016-10-01

    We maintain a dynamic position on extracorporeal blood purification therapies (EBPT). Continuous therapies are of choice in the hemodynamically unstable patient. We recommend their early introduction in the course of the disease, and starting with a dose of 30-35mL/kg/h. Above all, however, daily re-evaluation is required of the hemodynamic and metabolic situation and water balance of our patients in order to allow dynamic dose adjustment. Some data suggest that continuous EBPT can favorably influence the clinical course of our patients, even in the absence of acute kidney injury. The potential usefulness of hemofiltration at doses higher than the conventional doses (continuous ultrafiltration >50mL/kg/h or pulses of at least 4h a day to more than 100dosesmL/kg/h) for achieving blood purification has also been commented. We review the possible indications of this technique, together with the peculiarities of implementing these therapies in children. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  10. Early non-steady-state population pharmacokinetics of oral cyclosporine in renal transplant recipients.

    Science.gov (United States)

    Baek, Hyunjeong; Han, Seunghoon; Yim, Dong-Seok; Kim, Sung Joo; Lee, Soo-Youn; Jang, Hye Ryoun; Lee, Jung Eun; Kim, Dae Joong; Kim, Yoon-Goo; Oh, Ha Young; Huh, Wooseong

    2014-01-01

    This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time-concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period.

  11. Editor's Choice-Recent therapeutic trials on fluid removal and vasodilation in acute heart failure.

    Science.gov (United States)

    Ennezat, Pierre V; Stewart, Merrill; Samson, Rohan; Bouabdallaoui, Nadia; Maréchaux, Sylvestre; Banfi, Carlo; Bouvaist, Hélène; Le Jemtel, Thierry H

    2016-02-01

    Recent therapeutic trials regarding the management of acute heart failure (AHF) failed to demonstrate the efficacy of newer therapeutic modalities and agents. Low- versus high-dose and continuous administration of furosemide were shown not to matter. Ultrafiltration was not found to be more efficacious than sophisticated diuretic therapy including dose-adjusted intravenous furosemide and metolazone. Dopamine and nesiritide were not shown to be superior to current therapy. Tezosentan and tovalptan had no effect on mortality. The development of rolofylline was terminated due to adverse effect (seizures). Lastly, preliminary experience with serelaxin indicates a mortality improvement at six months that remains to be confirmed. The disappointing findings of these recent trials may reflect the lack of efficacy of newer therapeutic modalities and agents. Alternatively the disappointing findings of these recent trials may be in part due to methodological issues. The AHF syndrome is complex with many clinical phenotypes. Failure to match clinical phenotypes and therapeutic modalities is likely to be partly responsible for the disappointing findings of recent AHF trials. © The European Society of Cardiology 2014.

  12. Practical Approaches to the Use of Lenalidomide in Multiple Myeloma: A Canadian Consensus

    Directory of Open Access Journals (Sweden)

    Donna Reece

    2012-01-01

    Full Text Available In Canada, lenalidomide combined with dexamethasone (Len/Dex is approved for use in relapsed or refractory multiple myeloma (RRMM. Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs. The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1 lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2 dexamethasone administered at 20–40 mg/week, and (3 continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1 all patients treated with Len/Dex should receive thromboprophylaxis, (2 erythropoiesis-stimulating agents (ESAs should be used cautiously, and (3 females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13 have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered.

  13. Low dose spinal anesthesia for knee arthroscopy

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    Lakhin R.E.

    2015-06-01

    Full Text Available Objective: to evaluate the nature of unilateral spinal anesthesia using various modes of administration of low doses of hyperbaric bupivacaine. Materials and Methods. Prospectively, the randomized study included 56 patients undergoing knee arthroscopy. In the control group bupivacaine of 5mg was administered simultaneously, in the main group — fractionally by 2.5 mg. The development of thermal and pain blocks from different sides was investigated. The data were statistically processed. Results. In the control group, the positioning of the patient usually began after the entire dose of anesthetic had been administered. In the case of temperature paresthesia in the area of the sacral segments of the full anesthesia throughout underlying limb was not always achieved. In 6 cases of block was not sufficient. In the main group patient positioning was performed after the administration of 2.5 mg of anesthetic and evaluate temperature paresthesia and in 2 cases the total dose was increased to 7.5 mg. The successful development of sensory block at fractional administration was significantly higher than in the single-step introduction. Conclusion. Temperature paresthesia occurs within the first minute and is an early predictor of developing spinal anesthesia. The area of arising paresthesia shows preferential distribution of the anesthetic. In the application of low dose local anesthetic the desired upper level of anesthesia via the patient positioning and dose adjustment may be achieved.

  14. Polypharmacy and Renal Failure in Nursing Home Residents: Results of the Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes (IMREN) Study.

    Science.gov (United States)

    Dörks, Michael; Herget-Rosenthal, Stefan; Schmiemann, Guido; Hoffmann, Falk

    2016-01-01

    Polypharmacy has become an emerging public health issue in recent years, since use of multiple medications or polypharmacy is beneficial for many conditions, but may also have negative effects like adverse drug reactions. The risk further increases in patients with chronic renal failure, a comorbidity very frequent in nursing home residents. Since more than 50% of all drugs were renally excreted, dose adjustments in patients with renal failure are required. To assess polypharmacy in German nursing homes, in particular in residents with renal failure. Multi-center cross-sectional study in 21 nursing homes in Bremen and Lower Saxony/Germany. Baseline data were analysed using descriptive statistics. Multivariable logistic regression model and 95% confidence intervals were used to study the association of renal failure and polypharmacy. Of all 852 residents, the analysis comprised those 685 with at least one serum creatinine value so that the estimated creatinine clearance could be calculated. Of those, 436 (63.6%) had a severe or moderate renal failure, defined as estimated creatinine clearance Polypharmacy (5-9 drugs) was found in 365 (53.3%) and excessive polypharmacy (≥10 drugs) in 112 (16.4%) residents. Diuretics and psycholeptics were the most commonly used drug classes. Severe renal failure (estimated creatinine clearance polypharmacy (OR: 2.8, 95% CI 1.4-5.7). Both, polypharmacy and renal failure are common in German nursing home residents and an association of both could be found. Further studies are needed to assess the appropriateness of polypharmacy in these patients.

  15. Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy.

    Science.gov (United States)

    Kunka, Megan E; Cady, Elizabeth A; Woo, Heejung C; Thompson Bastin, Melissa L

    2015-01-01

    Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours), which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient's actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

  16. Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy

    Directory of Open Access Journals (Sweden)

    Megan E. Kunka

    2015-01-01

    Full Text Available Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours, which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient’s actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

  17. Personalised 3D Printed Medicines: Which Techniques and Polymers Are More Successful?

    Directory of Open Access Journals (Sweden)

    Andrea Alice Konta

    2017-09-01

    Full Text Available The interindividual variability is an increasingly global problem when treating patients from different backgrounds with diverse customs, metabolism, and necessities. Dose adjustment is frequently based on empirical methods, and therefore, the chance of undesirable side effects to occur is high. Three-dimensional (3D Printed medicines are revolutionsing the pharmaceutical market as potential tools to achieve personalised treatments adapted to the specific requirements of each patient, taking into account their age, weight, comorbidities, pharmacogenetic, and pharmacokinetic characteristics. Additive manufacturing or 3D printing consists of a wide range of techniques classified in many categories but only three of them are mostly used in the 3D printing of medicines: printing-based inkjet systems, nozzle-based deposition systems, and laser-based writing systems. There are several drawbacks when using each technique and also the type of polymers readily available do not always possess the optimal properties for every drug. The aim of this review is to give an overview about the current techniques employed in 3D printing medicines, highlighting their advantages, disadvantages, along with the polymer and drug requirements for a successful printing. The major application of these techniques will be also discussed.

  18. Stochastic Differential Equations in Artificial Pancreas Modelling

    DEFF Research Database (Denmark)

    Duun-Henriksen, Anne Katrine

    Type 1 diabetes accounts for approximately 5% of the total diabetes population. It is caused by the destruction of insulin producing β-cells in the pancreas. Various treatment strategies are available today, some of which include advanced technological devices such as an insulin pump and a contin......Type 1 diabetes accounts for approximately 5% of the total diabetes population. It is caused by the destruction of insulin producing β-cells in the pancreas. Various treatment strategies are available today, some of which include advanced technological devices such as an insulin pump...... and a continuous glucose monitor (CGM). Despite these technological advances in the treatment of type 1 diabetes, the disease still poses an enormous and constant challenge for the patients. To obtain tight glucose control the patients are required to assess how much they will eat prior to the meal. They have......, the control algorithm computes the optimal dose adjustment and sends instructions to the insulin pump. To develop control algorithms, mathematical models of the physiological dynamics are needed. They attempt to describe the significant dynamics of the system and hence they approximate the system behavior...

  19. Management of patients with hepatitis C infection and renaldisease

    Institute of Scientific and Technical Information of China (English)

    Chalermrat Bunchorntavakul; Monthira Maneerattanaporn; Disaya Chavalitdhamrong

    2015-01-01

    Hepatitis C virus (HCV) infection in patients with endstagerenal disease (ESRD) is associated with morerapid liver disease progression and reduced renal graftand patients' survival following kidney transplantation.Evaluations and management of HCV in patients withrenal disease are challenging. The pharmacokineticsof interferons (IFN), ribavirin (RBV) and some directacting antiviral (DAA), such as sofosbuvir, are altered inpatients with ESRD. With dose adjustment and carefulmonitoring, treatment of HCV in patients with ESRD canbe associated with sustained virological response (SVR)rates nearly comparable to that of patients with normalrenal function. DAA-based regimens, especially the IFNfreeand RBV-free regimens, are theoretically preferredfor patients with ESRD and KT in order to increase SVRrates and to reduce treatment side effects. However,based on the data for pharmacokinetics, dosing safetyand efficacy of DAA for patients with severe renalimpairment are lacking. This review will be focusedon the evaluations, available pharmacologic data, andmanagement of HCV in patients with severe renalimpairment, patients who underwent KT, and thosewho suffered from HCV-related renal disease, accordingto the available treatment options, including DAA.

  20. Drug dosage protocol for calcium oxalate stone.

    Science.gov (United States)

    Marickar, Y M Fazil; Salim, Abiya

    2009-12-01

    In earlier studies, we have confirmed that in most patients with calcium oxalate stone formation, a combination of allopurinol and pyridoxine is best suited for treatment and prevention of the stone forming process. The objective of this study is to identify the most effective directed medical treatment of urinary stones. The drug dose adjustment was based on clinical, radiological, biochemical, and microscopic parameters. 444 patients with proved calcium oxalate stone disease who were getting a combination of allopurinol and pyridoxine for a minimum period of 36 months were enrolled in this prospective study. The dosage schedule of these patients was recorded. Dosage adjustment was made depending upon the various clinical, biochemical, microscopic, and radiological changes during the study period. The dosage schedules were in six categories, namely very high dose chemotherapy (VHDC), i.e. allopurinol 600 mg/day and pyridoxine 240 mg/day, high-dose chemotherapy (HDC), i.e. allopurinol 300 mg/day and pyridoxine 120 mg/day, moderate dose prophylaxis (MDP), i.e. allopurinol 200 mg/day and pyridoxine 80 mg/day, low-dose prophylaxis (LDP), i.e. allopurinol 100 mg/day and pyridoxine 40 mg/day, and very low-dose prophylaxis (VLDP), i.e. allopurinol 50 mg/day and pyridoxine 20 mg/day and intermittent VLDP, wherein the VLDP was given on alternate months and still later at longer intervals. The temporary risk was assessed at each visit and dosage adjustment was made. The effect of the intervention was assessed during the next visit. All the patients involved in the study needed dose adjustment. The following schedules were initiated: VHDC (12) 3.5%, HDC (103) 23.2%, MDP (78) 17.57%, or LDP (251) 56.53%. Patients who defaulted for more than a month were excluded from the study. During each visit for follow up, all patients were advised change over of dose depending upon the clinical situation at the time of review. Patients on VHDC were advised reduction to lower doses

  1. Long-term results of two schedules of radioiodine treatment for toxic multinodular goitre

    Energy Technology Data Exchange (ETDEWEB)

    Huysmans, D.A.K.C. (Dept. of Nuclear Medicine, Univ. Hospital Nijmegen St. Radboud (Netherlands)); Hermus, A.R.M.M. (Dept. of Medicine, Div. of Endocrinology, Univ. Hospital Nijmegen St. Radboud (Netherlands)); Corstens, F.H.M. (Dept. of Nuclear Medicine, Univ. Hospital Nijmegen St. Radboud (Netherlands)); Kloppenborg, P.W.C. (Dept. of Medicine, Div. of Endocrinology, Univ. Hospital Nijmegen St. Radboud (Netherlands))

    1993-11-01

    The long-term effects of two schedules of radioiodine therapy in patients with toxic multinodular goitre were evaluated. Forty-five patients (group A) were treated with low doses and 58 patients (group B) with calculated doses adjusted for thyroid weight (1.85-3.70 MBq/g) and radioactive iodine uptake. Follow-up (mean[+-]SEM) was 4.3[+-]0.2 years and 5.2[+-]0.3 years, respectively (P0.1). At the end of follow-up, hyperthyroidism was succesfully reversed in 73% (group A) and 88% (group B). In each group, hypothyroidism was present in 7%. The total dose per gram of thyroid tissue was not significantly different in groups A and B (2.1[+-]0.2 vs 2.7[+-]0.2 MBq/g). However, for patients treated with calculated doses the number of [sup 131]I administrations was significantly lower (1.3[+-]0.1) than for patients treated with low doses (2.2[+-]0.2), and the percentage of patients who were adequately treated with a single dose was more than twice as high (66% in group B versus 27% in group A). Euthyroidism was reached within a significantly shorter time after treatment with calculated doses (media time 0.6 years in group BVS 1.5 years in group A; life table analysis). It is concluded that radioiodine is an effective treatment for toxic multinodular goitre with a low risk of post-treatment hypothyroidism and that calculated (higher) doses appear to be preferable to low doses. (orig.)

  2. A multinational investigation of time and traveling costs in attending anticoagulation clinics.

    Science.gov (United States)

    Jowett, Sue; Bryan, Stirling; Mahé, Isabelle; Brieger, David; Carlsson, Jonas; Kartman, Bernt; Nevinson, Mark

    2008-01-01

    Anticoagulation is used in patients with atrial fibrillation to reduce the risk of ischemic stroke. The therapy requires regular monitoring and, frequently, dose adjustment. This study aimed to determine the time and traveling costs that patients incur to themselves and society in attending anticoagulation clinics. A subset of patients from 105 primary and secondary care clinics allocated to the warfarin arm of SPORTIF III (patients from Australia, France, Portugal, Spain, Sweden, and the UK) completed a questionnaire. Patients indicated the type of transport used for clinic visits, and estimated traveling expenses. Patients were also asked to estimate total traveling and clinic attendance time, and to confirm whether they were currently employed and whether they had to give up time from work to attend the clinic. Time cost of companions was also taken into consideration. Cost per visit was calculated (euro, 2003 prices). Questionnaires for a total of 381 patients were analyzed, with the majority of patients from Sweden (n = 130) and the UK (n = 101). Mean cost to patients varied widely between countries, ranging from euro6.9 (France) to euro20.5 (Portugal) per visit. For most countries, time costs (value of lost working and leisure time) were the main driver of costs. Mean time cost to society ranged from euro5.6 (France) to euro31.7 (Portugal) per visit. Patients incur considerable costs when visiting anticoagulation clinics, and these costs vary by country. The results suggest the importance of taking a broad economic perspective when considering the cost-effectiveness of warfarin.

  3. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2 inhibitor for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Joshua J Neumiller

    2014-06-01

    Full Text Available Type 2 diabetes is increasing in prevalence worldwide, and hyperglycemia is often poorly controlled despite a number of therapeutic options. Unlike previously available agents, sodium-glucose co-transporter 2 (SGLT2 inhibitors offer an insulin-independent mechanism for improving blood glucose levels, since they promote urinary glucose excretion (UGE by inhibiting glucose reabsorption in the kidney. In addition to glucose control, SGLT2 inhibitors are associated with weight loss and blood pressure reductions, and do not increase the risk of hypoglycemia. Empagliflozin is a selective inhibitor of SGLT2, providing dose-dependent UGE increases in healthy volunteers, with up to 90 g of glucose excreted per day. It can be administered orally, and studies of people with renal or hepatic impairment indicated empagliflozin needed no dose adjustment based on pharmacokinetics. In Phase II trials in patients with type 2 diabetes, empagliflozin provided improvements in glycosylated hemoglobin (HbA1c and other measures of glycemic control when given as monotherapy or add-on to metformin, as well as reductions in weight and systolic blood pressure. As add-on to basal insulin, empagliflozin not only improved HbA1c levels but also reduced insulin doses. Across studies, empagliflozin was generally well tolerated with a similar rate of hypoglycemia to placebo; however, patients had a slightly increased frequency of genital infections, but not urinary tract infections, versus placebo. Phase III studies have also reported a good safety profile along with significant improvements in HbA1c, weight and blood pressure, with no increased risk of hypoglycemia versus placebo. Based on available data, it appears that empagliflozin may be a useful option in a range of patients; however, clinical decisions will be better informed by the results of ongoing studies, in particular, a large cardiovascular outcome study (EMPA-REG OUTCOME™.

  4. Stable renal transplant recipients can be safely converted from MMF to enteric-coated mycophenolate sodium tablets: Interim results of a multicenter Latin American study.

    Science.gov (United States)

    Abbud-Filho, M; Girón, F; Hernández, E; Juarez, F; Liendo, C; Novoa, P; Toledo, M

    2004-01-01

    Enteric-coated mycophenolate sodium (EC-MPS) is designed to reduce mycophenolate acid (MPA)-related upper gastrointestinal (GI) adverse events (AEs). A multicenter, open-label, Latin American study in stable renal transplant patients is ongoing to assess the safety of the conversion from mycophenolate mofetil (MMF) to EC-MPS. An interim analysis was performed when 93 patients had completed 3 months. Prior to conversion, they had received MMF at a dose of 2 g/d, with the exception of eight adult patients who were receiving an average daily dose of 1.25 g. All adult patients were converted to EC-MPS (1.44 g/d; 0.450 g/m(2) bid for children). After conversion, the reported total incidence of AEs was 40.9%, including 28% infections, 1.1% hematologic, 19.4% GI, including 10.8% upper-GI AE (all mild) and 5.4% diarrhea. No patient discontinued the study medication due to adverse events. Only six patients (6%) required a dose adjustment. There were no episodes of acute rejection, death, or graft loss. During the period of analysis, the conversion from MMF to EC-MPS was safe, the enteric-coated tablet formulation prevented release of MPA in the upper GI tract, and only one patient had to reduce the dose due to an upper GI AE, concomitant with diarrhea. EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF, but in a formulation that may provide GI tolerability benefits.

  5. Managing diabetic patients with moderate or severe renal impairment using DPP-4 inhibitors: focus on vildagliptin

    Directory of Open Access Journals (Sweden)

    Russo E

    2013-04-01

    Full Text Available Eleonora Russo, Giuseppe Penno, Stefano Del Prato Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Disease, Azienda Ospedaliero Universitaria di Pisa, and University of Pisa, Pisa, Italy Background: Dipeptidyl peptidase-4 (DPP-4 inhibitors are novel classified oral anti-diabetic drugs for the treatment of type 2 diabetes mellitus (T2DM that provide important reduction in glycated hemoglobin, with a low risk for hypoglycemia and no weight gain. In T2DM patients with reduced renal function, adequate glycemic control is essential to delay the progress of kidney dysfunction, but they are at a greater risk of experiencing hypoglycemic events, especially with longer-acting sulfonylureas and meglitinides. Objective: To evaluate vildagliptin as an option to achieve glycemic control in T2DM patients with moderate or severe chronic kidney disease (CKD. Methods: A comprehensive search in the literature was performed using the term "vildagliptin." Original articles and reviews exploring our topic were carefully selected. Results: Vildagliptin provides effective glycemic control in patients with T2DM and CKD. Dose reductions are required for vildagliptin and other DPP-4 inhibitors, except linagliptin, in T2DM patients with moderate-to-severe CKD. Dose of vildagliptin had to be reduced by half (to 50 mg/day both for moderate (estimated glomerular filtration rate [eGFR] ≥30 to ≤50 mL/min and severe CKD (eGFR < 30 mL/min. Available results support a favorable efficacy, safety, and tolerability profile for vildagliptin in T2DM with moderate or severe renal failure. Preliminary data may suggest additional benefits beyond improvement of glycemic control. Conclusion: Vildagliptin can be safely used in T2DM patients with varying degrees of renal impairment. Dose adjustments for renal impairment are required. Potential long-term renal benefit of vildagliptin needs to be further explored. Keywords: type 2 diabetes mellitus, renal

  6. Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.

    Science.gov (United States)

    Devineni, Damayanthi; Manitpisitkul, Prasarn; Vaccaro, Nicole; Bernard, Apexa; Skee, Donna; Mamidi, Rao N V S; Tian, Hong; Weiner, Sveta; Stieltjes, Hans; Sha, Sue; Rothenberg, Paul

    2015-01-01

    Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 μg) + ethinyl estradiol (30 μg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin'€™s PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.

  7. To evaluate the effects of dexmedetomidine on intraocular pressure and haemodynamic changes in response to laryngoscopy and tracheal intubation

    Directory of Open Access Journals (Sweden)

    Tanuja

    2014-01-01

    Full Text Available Background: The most important prerequisites for neurosurgeries are brain relaxation, need of stable haemodynamics with less fluctuation in intracranial pressure and speedy recovery from anaesthesia. Endotracheal intubation is the major stressful stimuli that can elicit a marked pressor response. Various drugs have been used to attenuate these reflexes. Dexmedetomidine, a highly selective alpha 2-adrenoceptor agonist, have neuroprotective, cardioprotective, and sedative effects so it is potentially useful during neuroanaesthesia. This is a prospective randomised control trial carried out to see whether administration of Dexmedetomidine prior to intubation can attenuate the various haemodynamic responses, intraocular pressure (IOP and the requirement of induction dose of propofol in control and study group. Materials and Methods: Fifty patients (ASA grade 1, 2 scheduled for intracranial tumour surgeries were divided into two groups (25 each. Group D received Dexmedetomidine 0.8 μg/kg i.v. over 10 mins and group C received 20 ml saline. Anaesthesia induced with Propofol, dose adjusted using bispectral index monitor. The groups were compared with IOP, Heart rate (HR, Mean arterial pressure (MAP, and dose of Propofol required for induction. Results : Groups were well matched for their demographic data and pre-operative. IOP in both the eyes decreases significantly after premedication and remained below baseline even after 10 th min of intubation in group D while in Group C; it increased significantly after intubation and remained above baseline. The difference between groups was also statistically significant. HR and MAP decreased significantly in patients of group D compared to group C (P < 0.05. Patients were more haemodynamicaly stable at all time points after premedication in group D (P < 0.05. Propofol requirements for induction was lesser in group D (P < 0.05. Bradycardia and hypotension incidences were higher in group D. Conclusion

  8. Review article: chronobiology: influence of circadian rhythms on the therapy of severe pain.

    Science.gov (United States)

    Junker, Uwe; Wirz, Stefan

    2010-06-01

    Modern pain therapy widely follows the WHO (World Health Organization) guidelines using a three-step 'ladder' for pain relief. This escalating step scheme includes the administration in the order nonopioids, mild opioids and strong opioids, and adjuvants at any step. Analgesics should be given 'by the clock' rather than 'on demand'. However, the chronobiological parameters circadian pain rhythm, circadian efficacy of analgesics, and individual circadian need for analgesics are to be considered. The results of a multitude of studies in chronobiology are not consistent. Therefore, further studies with standardized protocols are needed that allow to assign more consistent rhythms to diseases, pain causes, and analgesic efficacy of opioids. In many cases, each patient perceives pain and its intensity individually during the time of day. By administration of analgesics over a constant or continuous dosage time fluctuations in pain perception and the outcomes of many studies in chronobiology are ignored that prove the influence of biological rhythms on the pharmacokinetic and pharmacodynamic aspects of analgesics. As different types of pain show different rhythms (highest pain intensities arising at different times of the day) analgesics should be dosed flexibly. It is also very important that drug therapy can be adjusted individually to the pain rhythm of the patient as well as to the type and cause of pain. In severe pain, therapy should be particularly careful. A flexible dosage depending on pain intensity and rapid dose adjustment are essentials of a modern pain therapy. Therefore, opioids that are flexible to use are better suited to treat the individual pain of the patient than rigid modified release oral or transdermal systems.

  9. Cirrhosis has no impact on therapeutic responses of entecavir for chronic hepatitis B.

    Science.gov (United States)

    Wang, Pin-Chao; Wei, Tao-Yang; Tseng, Tai-Chung; Lin, Hans Hsienhong; Wang, Chia-Chi

    2017-08-01

    As the efficacy of a direct antiviral agent is reduced in cirrhotic chronic hepatitis C patients, prolonged duration of treatment or addition of ribavirin is recommended to improve the rates of sustained virological response. However, the impact of cirrhosis on the efficacy of antiviral treatment for chronic hepatitis B (CHB) remained unclear. This retrospective cohort study screened entecavir (ETV)-treated CHB patients in Taipei Tzu Chi Hospital from January 2007 till October 2014. The diagnosis of cirrhosis was made on the basis of clinical/imaging or histologic findings. The primary endpoints were hepatitis B e antigen (HBeAg) loss in HBeAg-positive patients and undetectable hepatitis B virus (HBV) DNA in the overall study population. Initial virological response is defined as undetectable HBV DNA at 1-year ETV treatment. A total of 381 (262 men; mean age: 49.6±12.9 years) CHB patients were recruited for the final analysis. Of these, 138 were cirrhotic. In 143 HBeAg-positive patients, there was no difference in the rates of 1- and 2-year HBeAg loss between cirrhotic and noncirrhotic patients (P=0.226 and 0.729, respectively). In the overall population, the rate of 1-year undetectable HBV DNA was higher in patients with cirrhosis than those without cirrhosis (76.1 vs. 64.2%, P=0.016). The rate of 2-year undetectable HBV DNA was not different between these two groups. Using multivariate logistic regression analysis, baseline HBV DNA levels (P=0.006) and HBeAg status (P=0.007), were associated with initial virological response, but not cirrhosis. Therapeutic responses of ETV are not decreased in cirrhotic CHB patients. Thus, cirrhotic CHB patients can be treated with ETV without the need for dose adjustment.

  10. Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists.

    Science.gov (United States)

    Sigurdson, Alice J; Bhatti, Parveen; Chang, Shih-Chen; Rajaraman, Preetha; Doody, Michele M; Bowen, Laura; Simon, Steven L; Weinstock, Robert M; Linet, Martha S; Rosenstein, Marvin; Stovall, Marilyn; Alexander, Bruce H; Preston, Dale L; Struewing, Jeffery P

    2009-11-01

    Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1,083 controls within the US radiologic technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR = 0.3; 95% CI 0.1-0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR = 1.2; 95% CI 0.9-1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the dose-response relationship between personal diagnostic X-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (p (interaction) = 0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic X-ray exposure (p (interaction) = 0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.

  11. Evaluation of ocular defects and its relevant factors in patients with beta thalassemia major in Sari Boo Ali Sina hospital, (2006-2008

    Directory of Open Access Journals (Sweden)

    hosein Karami

    2009-03-01

    Full Text Available Background: As There is not accurate information about ocular defects in Thalassemia Major (TM patients in Mazandaran province ,this study was designed to assess the prevalence of ophtalmopathies in thalassemic patients and also recognize its relevant factors in Sari Boo Ali Sina hospital. Sari. Materials and Methods: This descriptive Cross-sectional was Carried out on 60 TM patients in Thalassemia center at Sari Boo Ali Sina hospital. Subjects were selected by systematic sampling. After gathering demographic data , patients were evaluated about their illness and its complications from their medical records. Their visual acuity was assessed using Snell chart by an optometrist. Evaluation of retina was done by our ophthalmologist colleague. Visual evoked potential (VEP was assessed by TOENEES instrument made in Italy which had the ability to assess both VEP and P300 . Findings were analyzed by SPSS13 software and Chi square and Mann-whitney tests. Results: 60 patients underwen this study that 33 of them (55% were male. 4 of them (6.6% had problems in visual acuity . 3 of these became normal after refractive correction. 3 patients (5% had Inferior Posterior Cortical Cataract. 2 of them (3.3% had punctuate lens cortical opacity and one (1.7% had mild nuclear sclerosis. 4 patients( 6.7% had macular pigmentation and one (1.7% had left optic nerve head pit. No abnormal finding was detected in VEP, such as latency in voltage. Conclusion: Totally 20 patients had ocular complications. These defects can be a result of desferal toxicity or Iron toxicity and drug effects on binding to cupper and zinc and removing them from retinal cells or extramedulary hematopoesis. So based on the results, ophthalmologic evaluation of TM patients and tight desferal dose adjustment in these patients seems necessary.

  12. Diagnosis and Treatment on the Rejection of Liver Transplantation%肝移植术后排斥反应的诊治

    Institute of Scientific and Technical Information of China (English)

    周晓俊; 钱海鑫; 田力平; 胡浩; 秦磊; 陈易人

    2001-01-01

    目的 探讨肝移植术后排斥反应的预防和诊治。方法 对1例Wilson病及1例肝门部肝内胆管癌实施肝移植术后,采用“FK506+MMF+Pred”新三联方案预防免疫排斥。结果 术后移植肝功能迅速恢复,黄疸减退。1例术后22d出现不典型的轻度排斥反应,经调整FK506的剂量和使用甲基强的松龙冲击治疗后好转。另1例未见排斥反应。结论 判断排斥反应的存在、严重程度,及时采取正确的治疗措施是肝移植术后的首要问题之一。%Objective To investigate the problem about the prevention and diagnosis-treatment for the liver rejection after liver transplantation.Methods Orthotopic liver transplantation (OLT) was successfuly performed on 2 parents with liver diseases,one was with Wilson's disease and the other with Klatskin tumor.Immunosurppressive protocol was tacrolimus (FK506),mycophenolate mofetil (MMF) and prednisone.Results Both transplant livers' function recovered rapidly with an obvious regression of jaundice.Except that in case 1 the patient suffered from atypical mild rejection on the 22nd postoperative day.With the dose adjustment of tacrolimus and the use of Methylprednisolone,the incidence of acute rejection with decreased.Conclusion How to determine the existence and seriousness of the liver rejection and how to adopt a correct treatment promptly are of a primary importance after OLT.

  13. Clinical pharmacology of deferasirox.

    Science.gov (United States)

    Tanaka, Chiaki

    2014-08-01

    Iron accumulation is a consequence of regular red cell transfusions, and can occur as a result of ineffective erythropoiesis secondary to increased intestinal iron absorption, in patients with various anemias. Without appropriate treatment, iron overload can lead to increased morbidity and mortality. Deferasirox is an oral iron chelator effective for reduction of body iron in iron-overloaded patients with transfusion-dependent anemias and non-transfusion-dependent thalassemia, with a well-established safety profile. This review summarizes the clinical pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of deferasirox, and the claims supporting once-daily dosing for effective chelation. Sustained labile plasma iron suppression is observed with no rebound between doses, protecting organs from potential tissue damage. Increased iron excretion positively correlates with increased deferasirox exposure; to optimize iron removal transfusional iron intake, body iron burden and safety parameters should also be considered. Deferasirox dispersible tablets should be taken ≥30 min before food due to an effect of food on bioavailability. Dosing is consistent across pediatric and adult patients and there is no ethnic sensitivity. Dose adjustment is required for patients with hepatic impairment and may be considered upon coadministration with strong uridine diphosphate glucuronosyltransferase inducers or bile acid sequestrants (coadministration should be avoided where possible), and patients should be monitored upon coadministration with cytochrome P450 (CYP) 3A4/5, CYP2C8, or CYP1A2 substrates. Coadministration with hydroxyurea, a fetal hemoglobin modulator, does not appear to impact deferasirox pharmacokinetics. In summary, a substantial body of clinical and pharmacokinetic data are available for deferasirox to guide its optimal use in multiple patient populations and clinical circumstances.

  14. Preemptive warfarin dose reduction after initiation of sulfamethoxazole-trimethoprim or metronidazole.

    Science.gov (United States)

    Powers, Anna; Loesch, Erin B; Weiland, Anthony; Fioravanti, Nicole; Lucius, David

    2017-07-01

    To evaluate the utility of a preemptive warfarin dose reduction at the time of initiation of either sulfamethoxazole-trimethoprim or metronidazole, a retrospective chart review of patients who received an outpatient prescription for warfarin and either sulfamethoxazole-trimethoprim and/or metronidazole from July 1, 2011 to July 1, 2015 was conducted. Clinical outcomes compared Veterans who had a warfarin dose reduction and those who did not within 120 h (5 days) of antibiotic initiation. The primary outcome compared the pre-and post-antibiotic International Normalized Ratio (INR) of patients in the intervention group (warfarin dose reduction) with those in the control group (no intervention). Secondary outcomes assessed incidence of thromboembolic and major bleeding events within 30 days of antibiotic completion. Fifty patients were assessed. Forty-nine patients had at least one follow-up appointment; 126 follow-up visits were evaluated. There was a statistically significant difference for the change in therapeutic INR at the first follow-up appointment (p = 0.029) for those patients in the control group. On average, the patients in the intervention group required fewer follow-up visits (p = 0.019). There were no statistically significant differences for the overall rate of therapeutic INR values between groups, as well as no instances of a thromboembolic or major bleeding events during the follow-up period. Clinically significant differences were observed for patients who received a preemptive warfarin dose reduction upon initiation of sulfamethoxazole-trimethoprim or metronidazole. Patients in the intervention group required fewer follow-up appointments and were more likely maintain a therapeutic INR within the 30 days following the antibiotic course. Results of this study will be presented the at Pharmacy and Therapeutics committee in an effort to seek approval for policy development to initiate a local preemptive warfarin dose adjustment as a standard

  15. β受体阻滞剂在心力衰竭治疗中的药物应用%β-Blocker Drugs Used in Treatment of Heart Failure

    Institute of Scientific and Technical Information of China (English)

    冯利

    2015-01-01

    Objective To investigate the β-blocker drugs used in treatment of heart failure.Methods The mechanism of beta blockers in the treatment of heart failure and clinical application analysis.Results Currently in congestive heart failure (CHF) treatment, the application of the important role of β-blockers reduce myocardial apoptosis, blocking cardiac remodeling and inhibit the biological effects of oxidative stress reactions.Conclusion In order to ensure the safety and effectiveness of β- blocker therapy, the appropriate starting dose adjustment is critical and individual doses. The basic principle is to start smal dose.%目的:探讨β受体阻滞剂在心力衰竭治疗中的应用。方法对β受体阻滞剂在心力衰竭治疗中的作用机理及临床应用进行分析。结果目前在充血性心力衰竭(CHF)的治疗中,应用β受体阻滞剂的重要作用是减少心肌细胞凋亡,阻断心肌重塑及抑制氧化应激反应等生物学效应。结论为了保证β-受体阻滞剂治疗的安全性和有效性,适当的起始剂量和个体剂量的调整至关重要。基本原则是从小剂量开始。

  16. Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti-TNF-like weak inducer of apoptosis (anti-TWEAK) monoclonal antibody.

    Science.gov (United States)

    Galluppi, Gerald R; Wisniacki, Nicolas; Stebbins, Chris

    2016-07-01

    Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is implicated in the pathogenesis of lupus nephritis. This study evaluated the pharmacokinetics, using the population approach, and pharmacodynamics of BIIB023, an anti-TWEAK monoclonal antibody, in healthy Chinese, Japanese and Caucasian volunteers. In this single-dose, randomized, double-blind, phase 1 study of BIIB023 in healthy volunteers, BIIB023 was administered by intravenous infusion (3 or 20 mg kg(-1) ) on Day 1; follow-up occurred through Day 71. BIIB023 serum concentration was measured using a validated enzyme-linked immunosorbent assay; BIIB023 concentration-time data were subjected to noncompartmental analysis. Population pharmacokinetic analysis was performed using data from this study and a prior phase 1 study of BIIB023 in subjects with rheumatoid arthritis. Soluble TWEAK and BIIB023 complex were evaluated. There were no differences in BIIB023 pharmacokinetics requiring dose adjustment among the three ethnic groups or between healthy volunteers and arthritis patients. BIIB023 central compartment volume (3050 ml) and clearance (7.42 ml h(-1) ) were comparable to those observed for other monoclonal antibody drugs. BIIB023 serum exposure increased in a dose-dependent manner in all groups, but not in direct proportion to dose level; at concentrations below ~10 μg ml(-1) , nonlinear clearance was observed. Soluble TWEAK levels decreased to below the level of quantitation after BIIB023 treatment, with concomitant changes in BIIB023 complex levels. No clinically meaningful differences were observed in BIIB023 pharmacokinetic and pharmacodynamic properties in healthy Chinese, Japanese and Caucasian volunteers; pharmacodynamic measures suggested target engagement. TWEAK may be an attractive therapeutic target for lupus nephritis treatment. © 2016 The British Pharmacological Society.

  17. How to improve drug dosing for patients with renal impairment in primary care - a cluster-randomized controlled trial

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    Erler Antje

    2012-09-01

    Full Text Available Abstract Background Patients with chronic kidney disease (CKD are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care. Methods A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (≥70 years suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by more than 30%. Results Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%. Conclusions A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices. Trial registration Current Controlled Trials ISRCTN02900734

  18. Establishing population distribution of drug-metabolizing enzyme activities for the use of salivary caffeine as a dynamic liver function marker in a Singaporean Chinese population.

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    Chia, Hazel Yiting; Yau, Wai-Ping; Ho, Han Kiat

    2016-04-01

    The salivary paraxanthine/caffeine molar ratio has been proposed as a novel dynamic liver function test to guide dose adjustments of drugs hepatically cleared by CYP1A2. Its usability requires an established population norm as well as the factors influencing the ratio and actual concentrations. To address this knowledge gap, salivary caffeine and paraxanthine concentrations were measured at 4 h post caffeine dose in healthy Chinese individuals who had undergone 24 h of caffeine abstinence. The metabolic ratio was calculated and statistical analysis was performed. From the 52 participants (26 males; 30 regular caffeine consumers) recruited, the salivary paraxanthine/caffeine molar ratio was normally distributed with a mean and SD of 0.5 ± 0.2. No statistically significant factors (BMI, body weight, gender and regularity of caffeine intake) affecting the metabolic ratio were found. The caffeine concentration and total caffeine plus paraxanthine concentrations were lower in males than in females, and lower in regular caffeine consumers than in non-regular caffeine consumers. The 4 h salivary metabolic ratio (mean: 0.5) was generally not significantly different from the literature reported salivary, serum and plasma ratios measured at 4-9 h in healthy individuals (mean range 0.4-0.7) but was significantly higher than the literature reported 6 h plasma ratio and salivary ratios measured at 1-6 h in patients with liver disease or mild abnormal liver function tests (mean range 0.03-0.2). Overall, the population norm of the salivary metabolic ratio in a Singaporean Chinese population established in this study is distinct from individuals with liver disease or mild abnormal liver function tests and provides the benchmark for dosage adjustments of drugs metabolized by CYP1A2. Copyright © 2016 John Wiley & Sons, Ltd.

  19. The use of integrase inhibitors in treatment-experienced patients

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    Gatell Jose M

    2009-11-01

    Full Text Available Abstract Raltegravir, the first approved HIV-1 integrase inhibitor, is able to block the strand transfer step of the HIV proviral DNA integration process into the cellular host DNA. The selected dosage for the pivotal phase III studies (subsequently approved by the regulatory agencies was 400 mg bid by oral route with or without food. Raltegravir has a week effect (either inhibition or induction on the hepatic cytochrone P450 activity. There is not need of dose adjustments in renal insufficiency or in mild-to-moderate hepatic impairment. The emerging paradigm in the field of salvage therapy was to achieve a viral load below limit of detection in almost all patients. Pretty soon it became apparent that this was feasible in more than 70-90% of patients. Raltegravir proved to be pivotal for this new paradigm. Raltegravir vs placebo both with an optimized background therapy has been tested for salvage therapy in the 005 and in the BENCHMRK studies (018 and 019. In all three studies proved to be superior to the placebo at 24, 48 and 96 weeks. Tolerance was remarkably good and virological failure was often associated with selection of integrase gene resistance mutations following the Y143C/H/R, Q148H/K/R o less frequently the NI55H paths. Finally, in the two SWITCHMRK studies non-inferiority vs Lopinavir/r could not be demonstrated in virogically suppressed patients with an stable cART containing Lopinavir/r. Most likely explanation was the presence of archived resistance mutationts to background therapy leading to a functional monotherapy with raltegravir.

  20. Comparison of propofol based anaesthesia to conventional inhalational general anaesthesia for spine surgery

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    L D Mishra

    2011-01-01

    Full Text Available Background : Often conventional Inhalational agents are used for maintenance of anaesthesia in spine surgery. This study was undertaken to compare propofol with isoflurane anaesthesia with regard to haemodynamic stability, early emergence, postoperative nausea and vomiting (PONV and early assessment of neurological functions. Patients & Methods: Eighty ASA grade I &II adult patients were randomly allocated into two groups. Patients in study group received inj propofol for induction as well as for maintenance along with N 2O+O2 and the control group patients received inj thiopentone for induction and N 2 O+O 2 +isoflurane for maintenance. BIS monitoring was used for titrating the anaesthetic dose adjustments in all patients. All patients received fentanyl boluses for intraoperative analgesia and atracurium as muscle relaxant. Statistical data containing haemodynamic parameters, PONV, emergence time, dose of drug consumed & quality of surgical field were recorded and compared using student t′ test and Chi square test. Results: The haemodynamic stability was coparable in both the groups. The quality of surgical field were better in study group. Though there was no significant difference in the recovery profile (8.3% Vs 9.02% between both the groups, the postoperative nausea and vomiting was less in propofol group than isoflurane group (25%Vs60%. The anaesthesia cost was nearly double for propofol than isoflurane anaesthesia. Conclusion: Haemodynamic stability was comparable in both the groups. There was no significant difference in the recovery time between intravenous and inhalational group. Patients in propofol group were clear headed at awakening and were better oriented to place than inhalational group.

  1. A pharmacokinetic approach to model-guided design of infliximab schedules in ulcerative colitis patients

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    Alejandro Pérez-Pitarch

    2015-03-01

    Full Text Available Background: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn's disease and ulcerative colitis, is administered at predefined interdose-intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. Aims: To explore optimal dosing strategies of infliximab in treatment-naïve patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. Methods: A population of 2,000 treatment-naïve patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix inter-dose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. Results: Strategies 2-6 reached trough levels statistically higher than strategy 1 (p < 0.05. Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 % without reaching higher peak concentrations. Conclusions: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab-naive patients with ulcerative colitis.

  2. SU-E-J-04: A Data-Driven, Response-Based, Multi-Criteria Decision Support System for Personalized Lung Radiation Treatment Planning

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    Luo, Y; McShan, D; Schipper, M; Matuszak, M; Ten Haken, R [University of Michigan, Ann Arbor, MI (United States); Kong, F [Georgia Regents University, Augusta, GA (Georgia)

    2014-06-01

    Purpose: To develop a decision support tool to predict a patient's potential overall survival (OS) and radiation induced toxicity (RIT) based on clinical factors and responses during the course of radiotherapy, and suggest appropriate radiation dose adjustments to improve therapeutic effect. Methods: Important relationships between a patient's basic information and their clinical features before and during the radiation treatment are identified from historical clinical data by using statistical learning and data mining approaches. During each treatment period, a data analysis (DA) module predicts radiotherapy features such as time to local progression (TTLP), time to distant metastases (TTDM), radiation toxicity to different organs, etc., under possible future treatment plans based on patient specifics or responses. An information fusion (IF) module estimates intervals for a patient's OS and the probabilities of RIT from a treatment plan by integrating the outcomes of module DA. A decision making (DM) module calculates “satisfaction” with the predicted radiation outcome based on trade-offs between OS and RIT, and finds the best treatment plan for the next time period via multi-criteria optimization. Results: Using physical and biological data from 130 lung cancer patients as our test bed, we were able to train and implement the 3 modules of our decision support tool. Examples demonstrate how it can help predict a new patient's potential OS and RIT with different radiation dose plans along with how these combinations change with dose, thus presenting a range of satisfaction/utility for use in individualized decision support. Conclusion: Although the decision support tool is currently developed from a small patient sample size, it shows the potential for the improvement of each patient's satisfaction in personalized radiation therapy. The radiation treatment outcome prediction and decision making model needs to be evaluated with more

  3. Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy.

    Science.gov (United States)

    Nieuwlaat, Robby; Hubers, Lowiek M; Spyropoulos, Alex C; Eikelboom, John W; Connolly, Benjamin J; Van Spall, Harriette G C; Schulze, Karleen M; Cuddy, Spencer M; Stehouwer, Alexander C; Schulman, Sam; Connolly, Stuart J

    2012-12-01

    Excellent control of the international normalised ratio (INR) is associated with improved clinical outcomes in patients receiving warfarin, and can be achieved by anticoagulation clinics but is difficult in general practice. Anticoagulation clinics have often used validated commercial computer systems to manage the INR, but these are not usually available to general practitioners. It was the objective of this study to perform a randomised trial of a simple one-step warfarin dosing algorithm against a widely used computerised dosing system. During the period of introduction of a commercial computerised warfarin dosing system (DAWN AC) to an anticoagulation clinic, patients were randomised to have warfarin dose adjustment done according to recommendations of the existing warfarin dosing algorithm or to those of the computerised system. The study tested if the computerised system was non-inferior to the existing algorithm for the primary outcome of time in therapeutic INR range of 2.0-3.0 (TTR), with a one-sided non-inferiority margin of 4.5%. There were 541 patients randomised to commercial computerised system and 527 to the algorithm. Median follow-up was 159 days. A dose recommendation was provided and followed in 91% of occasions for the computerised system and in 90% for the algorithm (p=0.03). The mean TTR was 71.0% (standard deviation [SD] 23.2) for the computerised system and 71.9% (SD 22.9) for the algorithm (difference 0.9% [95% confidence interval: -1.4% to 4.1%]; p-value for non-inferiority=0.002; p-value for superiority=0.34). In conclusion, similar maintenance control of the INR was achieved with a simple one-step dosing algorithm and a commercial computerised management system.

  4. Dosage considerations for transcranial direct current stimulation in children: a computational modeling study.

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    Sudha Kilaru Kessler

    Full Text Available Transcranial direct current stimulation (tDCS is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1 differences in neurophysiology and disease, and 2 variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1 further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2 further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation.

  5. Teneligliptin: a review on cardio-renal safety

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    Dixit K. Patel

    2016-04-01

    Full Text Available Type 2 diabetes mellitus (T2DM is a well-known risk factor for cardiovascular disease and chronic kidney disease (CKD. Various drugs including DPP4 inhibitors with different pharmacologic profile are being used in patients with type 2 diabetes for improving glycaemic control. Cardiovascular (CV safety is one of the important aspects while selecting the glucose lowering therapies. In addition, DPP-4 inhibitors differ in their mode of excretion and degree of accumulation, which require dose/frequency modification in patients with impaired renal function. Therefore, understanding the cardio-renal safety profile of DPP4 inhibitors is of great importance. Teneligliptin is a DPP4 inhibitor, approved recently for the management of type 2 diabetes mellitus. The purpose of the present review is to integrate published literature and evaluate the cardio-renal safety of teneligliptin in type 2 diabetic patients. As per the available evidence, teneligliptin has apparently positive effects on CV safety markers like no QT prolongation at clinically relevant dose, small but significant improvement in left ventricular (LV function, improvement in adiponectin levels and improvement in endothelial dysfunction. These findings support the cardiovascular safety of teneligliptin in T2DM patients. Dual route of excretion makes teneligliptin suitable (no dose adjustment required for T2DM patients with renal failure. Available clinical evidence suggests that teneligliptin exerts cardiovascular safety in T2DM patients. This drug can be used in T2DM patients with CKD including end stage renal disease patients without any major safety concern. [Int J Basic Clin Pharmacol 2016; 5(2.000: 229-234

  6. Supporting the recommended paediatric dosing regimen for rufinamide in Lennox-Gastaut syndrome using clinical trial simulation.

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    Marchand, M; Fuseau, E; Critchley, D J

    2010-02-01

    Rufinamide was approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) as adjunctive therapy in patients aged 4 years and older. Rufinamide pharmacokinetics (PK) has been established on pooled data from several clinical studies in epilepsy, including one in LGS patients. Demographic covariates and drug-drug interactions with several antiepileptic drugs have been explored using population PK modelling. Two types of drug-drug interactions models were developed and compared. The PK analysis demonstrated that the coadministration of valproate decreases rufinamide clearance, requiring potential dose adjustment. To explore rufinamide exposure under different dosing regimens in LGS patients, clinical trial simulations were performed. The objective of the simulations was to select the doses giving an exposure shown to be safe and efficacious in larger populations. The concentrations simulated in a subgroup of patients with body weight less than 30 kg presented a larger inter-individual variability than in other patients. Additional simulations demonstrated that this increased variability was due partly to greater valproate concentrations in some of the children treated with rufinamide. Simulations of the rufinamide exposure under different maximum daily dose in presence and in absence of valproate co-administration were used to establish the dosing recommendation. The simulations support the proposal of a lower maximum daily rufinamide dose for patients under 30 kg receiving both drugs: the dose of 600 mg/day was proposed as a maximum daily dose in children also receiving valproate concomitantly, whereas in absence of valproate, the maximum daily dose is 1000 mg/day.

  7. Cost effectiveness of novel oral anticoagulants for stroke prevention in atrial fibrillation depending on the quality of warfarin anticoagulation control.

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    Janzic, Andrej; Kos, Mitja

    2015-04-01

    Vitamin K antagonists, such as warfarin, are standard treatments for stroke prophylaxis in patients with atrial fibrillation. Patient outcomes depend on quality of warfarin management, which includes regular monitoring and dose adjustments. Recently, novel oral anticoagulants (NOACs) that do not require regular monitoring offer an alternative to warfarin. The aim of this study was to evaluate whether cost effectiveness of NOACs for stroke prevention in atrial fibrillation depends on the quality of warfarin control. We developed a Markov decision model to simulate warfarin treatment outcomes in relation to the quality of anticoagulation control, expressed as percentage of time in the therapeutic range (TTR). Standard treatment with adjusted-dose warfarin and improved anticoagulation control by genotype-guided dosing were compared with dabigatran, rivaroxaban, apixaban and edoxaban. The analysis was performed from the Slovenian healthcare payer perspective using 2014 costs. In the base case, the incremental cost-effectiveness ratio for apixaban, dabigatran and edoxaban was below the threshold of €25,000 per quality-adjusted life-years compared with adjusted-dose warfarin with a TTR of 60%. The probability that warfarin was a cost-effective option was around 1%. This percentage rises as the quality of anticoagulation control improves. At a TTR of 70%, warfarin was the preferred treatment in half the iterations. The cost effectiveness of NOACs for stroke prevention in patients with nonvalvular atrial fibrillation who are at increased risk for stroke is highly sensitive to warfarin anticoagulation control. NOACs are more likely to be cost-effective options in settings with poor warfarin management than in settings with better anticoagulation control, where they may not represent good value for money.

  8. Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents.

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    Ruff, Christian T; Giugliano, Robert P; Antman, Elliott M

    2016-07-19

    Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well.

  9. Live attenuated measles and mumps viral strain-containing vaccines and hearing loss: Vaccine Adverse Event Reporting System (VAERS), United States, 1990--2003.

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    Asatryan, Armenak; Pool, Vitali; Chen, Robert T; Kohl, Katrin S; Davis, Robert L; Iskander, John K

    2008-02-26

    Hearing loss (HL) is a known complication of wild measles and mumps viral infections. As vaccines against measles and mumps contain live attenuated viral strains, it is biologically plausible that in some individuals HL could develop as a complication of vaccination against measles and/or mumps. Our objectives for this study were: to find and describe all cases of HL reported in the scientific literature and to the US Vaccine Adverse Events Reporting System (VAERS) for the period 1990--2003; and to determine reporting rate of HL after live attenuated measles and/or mumps viral strain-containing vaccines (MMCV) administration. We searched published reports for cases of HL identified after vaccination with MMCV. We also searched for reports of HL after MMCV administration submitted to VAERS from 1990 through 2003 and determined the dose-adjusted reporting rate of HL. Our main outcome measure was reported cases of HL after immunization with MMCV which were classified as idiopathic. We found 11 published case reports of HL following MMCV. The review of the VAERS reports identified 44 cases of likely idiopathic sensorineural HL after MMCV administration. The onset of HL in the majority of VAERS and published cases was consistent with the incubation periods of wild measles and mumps viruses. Based on the annual usage of measles-mumps-rubella (MMR) vaccine, we estimated the reporting rate of HL to be 1 case per 6-8 million doses. Thus, HL following MMCV has been reported in the literature and to the VAERS. Further studies are needed to better understand if there is a causal relationship between MMCV and HL.

  10. Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures

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    Kremer, Joel M; Lawrence, David A; Hamilton, Robert; McInnes, Iain B

    2016-01-01

    Objective To describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters. Design Prospective, open-label, long-term mechanism of action study. Setting University clinic. Methods MTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6–36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation. Results Cytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=−0.63, p=0.007). Conclusions MTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion. PMID:27335660

  11. Intensive or conventional insulin therapy in type 2 diabetic patients? A population-based study on metabolic control and quality of life (The JEVIN-trial).

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    Schiel, R; Müller, U A

    1999-01-01

    Long-term micro- and macrovascular complications cause major morbidity and mortality in patients with type 2 diabetes mellitus. Up to the present it is not clear whether intensified or conventional insulin treatment is more effective to keep blood glucose concentrations close to the normal range. In the present trial 90% (n = 117) of all insulin-treated type 2 diabetic patients aged 16 to 60 years and living in the city of Jena (100,247 inhabitants), Thuringia, Germany were examined. Fourty patients (34%) were on intensive insulin therapy (ICT, > or = 2 injections of normal- and > or = 1 injection of NPH-/mixed-insulin/day, > or = 1 insulin-dose adjustments/week, > or = 2 blood-glucose self-tests/day) and 77 patients (66%) were on conventional insulin therapy (CIT). Patients with ICT had more injections/d (4.3 +/- 0.7 vs CIT 2.4 +/- 0.7, p ICT had higher insulin doses (0.71 +/- 0.32 vs 0.47 +/- 0.2 IU/kg body wt/d, p education or socio-economic factors. Also, in respect of quality of life and treatment satisfaction, assessed with standardized questionnaires according to Bradley et al. and Lewis et al., there were no differences between the two groups. In conclusion, in type 2 diabetic patients, ICT seems to be indicated in a second step in "problem-patients" with bad metabolic control under CIT and/or individual's need for more flexibility. Perhaps, in these patients ICT leads to an improvement in the quality of metabolic control.

  12. Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

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    Alejandro Ortiz-Covarrubias

    Full Text Available Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182 vs linezolid (N = 171 in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%. Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%. Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120 and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%. Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

  13. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes

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    Kishimoto M

    2013-05-01

    Full Text Available Miyako KishimotoDepartment of Diabetes and Metabolic Medicine, Center Hospital, Tokyo, Japan; Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, JapanAbstract: Dipeptidyl peptidase-4 (DPP-4 inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use

  14. Balloon Coating with Rapamycin Using an On-site Coating Device

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    Schmehl, Joerg, E-mail: joerg.schmehl@med.uni-tuebingen.de [Department of Diagnostic and Interventional Radiology, University Hospital of Tuebingen (Germany); Ruhr, Juergen von der [Institute of Anatomy, University of Tuebingen (Germany); Dobratz, Markus; Kehlbach, Rainer [Department of Diagnostic and Interventional Radiology, University Hospital of Tuebingen (Germany); Braun, Isabelle [Translumina GmbH (Germany); Greiner, Tim-Oliver [Clinic of Thoracic and Cardiovascular Surgery, University Hospital of Tuebingen (Germany); Claussen, Claus D. [Department of Diagnostic and Interventional Radiology, University Hospital of Tuebingen (Germany); Behnisch, Boris [Translumina GmbH (Germany)

    2013-06-15

    Purpose. The efficacy of drug-eluting balloons has been demonstrated in clinical trials. The drug predominantly used is paclitaxel because of its lipophilic properties and the rapid onset of action. The aim of the investigation was to evaluate the feasibility and efficacy of an alternative balloon coating with rapamycin that can be applied on site.MethodsThe balloon coating (3.0/18 and 3.0/12 mm, Cathy No. 4, Translumina GmbH) with rapamycin was conducted with a coating machine (Translumina GmbH). Concentrations were 2, 2 Multiplication-Sign 2, 3, and 4 %. Measurements regarding the amount of substance released to the vessel wall were carried out on explanted porcine coronaries by means of ultraviolet and visible-light spectroscopy. Inflation time varied between 30 and 120 s. The biological effect of the coating was evaluated in a porcine peripheral overstretch and stent implantation model. Results. The amount of rapamycin on the balloon surface ranged from 558 {+-} 108 {mu}g for the 2 % solution to 1,441 {+-} 228 {mu}g in the 4 % solution. An amount of 95 {+-} 63-193 {+-} 113 {mu}g was released into the vessel wall. The quantitative measurements of the angiographic examinations 4 weeks after treatment revealed a reduction of diameter stenosis from 20.6 {+-} 17.4 % in the control group to 11.6 {+-} 5.5 % in the drug-eluting balloon group. Conclusion. A balloon coating with rapamycin omitting an excipient is possible with a dose-adjustable coating machine. However, the biological effects are moderate, which make further optimization of the coating process and evaluation of appropriate excipients necessary.

  15. Comparison of the effects of lipoic acid and glutathione against cisplatin-induced ototoxicity in auditory cells.

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    Koo, Doo Yeob; Lee, Se Hee; Lee, SungHo; Chang, Jiwon; Jung, Hak Hyun; Im, Gi Jung

    2016-12-01

    The aims of this study were to examine lipoic acid (LA)- or glutathione (GSH)-mediated protection against cytotoxicity following cisplatin exposure in HEI-OC1 auditory cells and measure the potential of LA and GSH to scavenge reactive oxygen species (ROS). This study also compares their protective effects and discusses the determination of a preventive or therapeutic dose. HEI-OC1 cells were pretreated with LA or GSH for 24 h and then exposed to 15 μM cisplatin for 48 h. The resulting cytotoxicity was measured using a cell counting kit-8, and intracellular ROS level was measured using flow cytometry. The protective or anti-ROS effects of LA and GSH were compared. Measurement of caspase 3, 8, 9 activity and Western blot analysis of PARP were performed. Pretreatment with LA at 300 μM and GSH at 3 mM protected HEI-OC1 cells against cisplatin-induced cytotoxicity and significantly reduced the cisplatin-induced increase in ROS. LA showed a significantly more effective protection against cisplatin-induced ototoxicity compared to that shown by GSH (85.4% vs. 73.1% cell viability). Both LA and GSH showed the maximal protective effect at different concentrations in normal or cisplatin-induced cytotoxic conditions. The preventive or therapeutic dose for harmful conditions is quite different for the two drugs and needs careful adjustments. This comparative study on the protective effects of LA and GSH against cisplatin-induced ototoxicity in an auditory cell line posed many challenges. Although LA and GSH showed a significant protective effect against cisplatin, the LA's effect was superior. The concentration at which the maximal protective effect of LA or GSH was noted was 3 times higher in cytotoxic conditions than in normal conditions, which suggests the need for drug dose adjustments based on the purpose (preventive or therapeutic). Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

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    Vanelli Maurizio

    2011-03-01

    Full Text Available Abstract Background The protein tyrosine phosphatase nonreceptor type 2 (PTPN22 has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c, glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab in children during the first year after diagnosis of type 1 diabetes. Methods The C1858T variant was genotyped in an international cohort of children (n = 257 patients with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset. Results A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03 for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002, which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03. Conclusions The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

  17. Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

    Science.gov (United States)

    Kraft, John C.; McConnachie, Lisa A.; Koehn, Josefin; Kinman, Loren; Collins, Carol; Shen, Danny D.; Collier, Ann C.; Ho, Rodney J.Y.

    2017-01-01

    Objective: The aim of the present study was to determine whether a combination of anti-HIV drugs – tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) – in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma. Design: Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay. Results: For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Conclusions: A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes. PMID:28099191

  18. Drug dosage recommendations in patients with chronic liver disease.

    Science.gov (United States)

    Periáñez-Párraga, Leonor; Martínez-López, Iciar; Ventayol-Bosch, Pere; Puigventós-Latorre, Francesc; Delgado-Sánchez, Olga

    2012-04-01

    Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology.

  19. Radiation Leukemogenesis: Applying Basic Science of Epidemiological Estimates of Low Dose Risks and Dose-Rate Effects

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    Hoel, D. G.

    1998-11-01

    The next stage of work has been to examine more closely the A-bomb leukemia data which provides the underpinnings of the risk estimation of CML in the above mentioned manuscript. The paper by Hoel and Li (Health Physics 75:241-50) shows how the linear-quadratic model has basic non-linearities at the low dose region for the leukemias including CML. Pierce et. al., (Radiation Research 123:275-84) have developed distributions for the uncertainty in the estimated exposures of the A-bomb cohort. Kellerer, et. al., (Radiation and Environmental Biophysics 36:73-83) has further considered possible errors in the estimated neutron values and with changing RBE values with dose and has hypothesized that the tumor response due to gamma may not be linear. We have incorporated his neutron model and have constricted new A-bomb doses based on his model adjustments. The Hoel and Li dose response analysis has also been applied using the Kellerer neutron dose adjustments for the leukemias. Finally, both Pierce's dose uncertainties and Kellerer neutron adjustments are combined as well as the varying RBE with dose as suggested by Rossi and Zaider and used for leukemia dose-response analysis. First the results of Hoel and Li showing a significantly improved fit of the linear-quadratic dose response by the inclusion of a threshold (i.e. low-dose nonlinearity) persisted. This work has been complete for both solid tumor as well as leukemia for both mortality as well as incidence data. The results are given in the manuscript described below which has been submitted to Health Physics.

  20. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

    Science.gov (United States)

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven

    2015-04-01

    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  1. Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing.

    Science.gov (United States)

    Damlaj, Moussab; Alkhateeb, Hassan B; Hefazi, Mehrdad; Partain, Daniel K; Hashmi, Shahrukh; Gastineau, Dennis A; Al-Kali, Aref; Wolf, Robert C; Gangat, Naseema; Litzow, Mark R; Hogan, William J; Patnaik, Mrinal M

    2016-08-01

    Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively (P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively (P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB (P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR.

  2. Monitoring Levothyroxine Dose during Pregnancy: A Prospective Study

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    Juhi Agarwal

    2011-01-01

    Full Text Available Problem statement: Thyroid dysfunction in pregnant women can influence the outcome for mother and fetus at all stages of pregnancy. As the fetus is entirely dependent on maternal thyroid hormones for its development until about 13 weeks of gestation, it is important to ensure adequate thyroxine substitution in pregnant women during the first trimester. Objective: The aim of this prospective study was to explore whether hypothyroidic pregnant women are adequately levothyroxine (L-T4 substituted in early pregnancy. Approach: During March 2008 to July 2009, 93 pregnant females with thyroid diseases were followed at the outpatient department of INMAS. At the first visit 86 patients were on L-T4 substitution for hypothyroidism. Seven other patients had hyperthyroidism. The patients were regularly followed every 4-8 weeks during pregnancy for dose adjustment. Before each visit serum Free Thyroxine (FT4 and TSH concentrations were determined. Results: Of the 86 patients on thyroxine substitution for hypothyroidism 56 (65.12% had serum TSH values within the reference range at their first TSH test. Thirty (34.9% had TSH values outside the reference range. In 5 patients TSH was 4 increase at the first evaluation during pregnancy was 17.46±30.8µg day1. In the 50 patients who needed to increase L-T4, 26% reached a definitive therapeutic dosage within 12th week of pregnancy, 24% within the 20th week and 50% within the 31st week. Conclusion/Recommendations: In 34.9% of pregnant women on L-T4 substitution for hypothyroidism, serum TSH values were abnormal when first tested and they had increased chances of fetal loss if not treated timely. Thyroid function in pregnant women on thyroxine substitution should be monitored as soon as pregnancy has been confirmed and carefully followed during pregnancy.

  3. Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study.

    Science.gov (United States)

    Peyrot, M; Barnett, A H; Meneghini, L F; Schumm-Draeger, P-M

    2012-05-01

    To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens. Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA. One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives. Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  4. Pediatric drug-related problems: a multicenter study in four French-speaking countries.

    Science.gov (United States)

    Prot-Labarthe, Sonia; Di Paolo, Ermindo R; Lavoie, Annie; Quennery, Stefanie; Bussières, Jean-François; Brion, Françoise; Bourdon, Olivier

    2013-04-01

    Pediatric intensive care patients represent a population at high risk for drug-related problems. There are few studies that compare the activity of clinical pharmacists between countries. To describe the drug-related problems identified and interventions by four pharmacists in a pediatric cardiac and intensive care unit. Four pediatric centers in France, Quebec, Switzerland and Belgium. This was a six-month multicenter, descriptive and prospective study conducted from August 1, 2009 to January 31, 2010. Drug-related problems and clinical interventions were compiled from four pediatric centers in France, Quebec, Switzerland and Belgium. Data on patients, drugs, intervention, documentation, approval and estimated impact were compiled. Number and type of drug-related problems encountered in a large pediatric inpatient population. A total of 996 interventions were recorded: 238 (24 %) in France, 278 (28 %) in Quebec, 351 (35 %) in Switzerland and 129 (13 %) in Belgium. These interventions targeted 270 patients (median 21 months old, 53 % male): 88 (33 %) in France, 56 (21 %) in Quebec, 57 (21 %) in Switzerland and 69 (26 %) in Belgium. The main drug-related problems were inappropriate administration technique (29 %), untreated indication (25 %) and supra-therapeutic dose (11 %). The pharmacists' interventions were mostly optimizing the mode of administration (22 %), dose adjustment (20 %) and therapeutic monitoring (16 %). The two major drug classes that led to interventions were anti-infectives for systemic use (23 %) and digestive system and metabolism drugs (22 %). Interventions mainly involved residents and all clinical staff (21 %). Among the 878 (88 %) proposed interventions requiring physician approval, 860 (98 %) were accepted. This descriptive study illustrates drug-related problems and the ability of clinical pharmacists to identify and resolve them in pediatric intensive care units in four French-speaking countries.

  5. Peramivir injection in the treatment of acute influenza: a review of the literature

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    Wester A

    2016-08-01

    Full Text Available Ashley Wester,1 Avinash K Shetty2 1Department of Pharmacy, 2Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA Abstract: Influenza virus infection is a major cause of morbidity and mortality in children and adults globally. Seasonal epidemics are common due to the rapid virus evolution, whereas the frequent emergence of antigenic variants can result in pandemics and sporadic/endemic avian influenza virus infections. Although annual vaccination is the mainstay for influenza prevention and control, the use of antiviral agents must be considered for treatment and prophylaxis against influenza. Currently available antiviral drugs include neuraminidase inhibitors (NAIs, adamantanes, and a novel polymerase inhibitor (favipiravir. Peramivir is a recently US Food and Drug Administration-approved NAI for the treatment of acute uncomplicated influenza in adults. The chemical structure of peramivir allows it to bind to the influenza neuraminidase with much higher affinity than oseltamivir. Peramivir is effective against a variety of influenza A and B subtypes and has a lower half-maximal inhibitory concentration compared to other NAIs in in vitro studies. Peramivir can be administered intravenously, a route that is favorable for hospitalized, critically ill patients with influenza. The long half-life of peramivir allows for once-daily dosing. The drug is eliminated primarily by the kidneys, warranting dose adjustments in patients with renal dysfunction. Studies have assessed the clinical efficacy of peramivir for treatment of pandemic influenza A (H1N1. Although anecdotal evidence supports the use of peramivir in pediatric patients, pregnant women, and hospitalized patients with severe influenza receiving continuous renal replacement therapy and extracorporeal membrane oxygenation, well-designed, controlled clinical trials should be conducted in order to assess its clinical efficacy in these patient populations. Keywords

  6. Peramivir injection in the treatment of acute influenza: a review of the literature.

    Science.gov (United States)

    Wester, Ashley; Shetty, Avinash K

    2016-01-01

    Influenza virus infection is a major cause of morbidity and mortality in children and adults globally. Seasonal epidemics are common due to the rapid virus evolution, whereas the frequent emergence of antigenic variants can result in pandemics and sporadic/endemic avian influenza virus infections. Although annual vaccination is the mainstay for influenza prevention and control, the use of antiviral agents must be considered for treatment and prophylaxis against influenza. Currently available antiviral drugs include neuraminidase inhibitors (NAIs), adamantanes, and a novel polymerase inhibitor (favipiravir). Peramivir is a recently US Food and Drug Administration-approved NAI for the treatment of acute uncomplicated influenza in adults. The chemical structure of peramivir allows it to bind to the influenza neuraminidase with much higher affinity than oseltamivir. Peramivir is effective against a variety of influenza A and B subtypes and has a lower half-maximal inhibitory concentration compared to other NAIs in in vitro studies. Peramivir can be administered intravenously, a route that is favorable for hospitalized, critically ill patients with influenza. The long half-life of peramivir allows for once-daily dosing. The drug is eliminated primarily by the kidneys, warranting dose adjustments in patients with renal dysfunction. Studies have assessed the clinical efficacy of peramivir for treatment of pandemic influenza A (H1N1). Although anecdotal evidence supports the use of peramivir in pediatric patients, pregnant women, and hospitalized patients with severe influenza receiving continuous renal replacement therapy and extracorporeal membrane oxygenation, well-designed, controlled clinical trials should be conducted in order to assess its clinical efficacy in these patient populations.

  7. Management of influenza infection in solid-organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI).

    Science.gov (United States)

    López-Medrano, Francisco; Cordero, Elisa; Gavaldá, Joan; Cruzado, Josep M; Marcos, M Ángeles; Pérez-Romero, Pilar; Sabé, Nuria; Gómez-Bravo, Miguel Ángel; Delgado, Juan Francisco; Cabral, Evelyn; Carratalá, Jordi

    2013-10-01

    Solid organ transplant (SOT) recipients are at greater risk than the general population for complications and mortality from influenza infection. Researchers and clinicians with experience in SOT infections have developed this consensus document in collaboration with several Spanish scientific societies and study networks related to transplant management. We conducted a systematic review to assess the management and prevention of influenza infection in SOT recipients. Evidence levels based on the available literature are given for each recommendation. This article was written in accordance with international recommendations on consensus statements and the recommendations of the Appraisal of Guidelines for Research and Evaluation II (AGREE II). Recommendations are provided on the procurement of organs from donors with suspected or confirmed influenza infection. We highlight the importance of the possibility of influenza infection in any SOT recipient presenting upper or lower respiratory symptoms, including pneumonia. The importance of early antiviral treatment of SOT recipients with suspected or confirmed influenza infection and the necessity of annual influenza vaccination are emphasized. The microbiological techniques for diagnosis of influenza infection are reviewed. Guidelines for the use of antiviral prophylaxis in inpatients and outpatients are provided. Recommendations for household contacts of SOT recipients with influenza infection and health care workers in close contact with transplant patients are also included. Finally antiviral dose adjustment guidelines are presented for cases of impaired renal function and for pediatric populations. The latest scientific information available regarding influenza infection in the context of SOT is incorporated into this document. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  8. A Patient with Supraclavicular Lymphadenopathy and Anterior Mediastinal Mass Presenting as a Rare Case of Composite Lymphoma: A Case Report and Literature Review

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    Alex Raufi

    2016-12-01

    Full Text Available Composite lymphoma (CL is a rare disease with 2 distinct lymphomas concurrently arising in a single patient with an estimated incidence of 1–4.7% of newly diagnosed lymphomas per year. CL most commonly involves 2 B-cell non-Hodgkin lymphomas (NHL or a B-cell NHL with a Hodgkin lymphoma. Our case is unique in that it was a bilineage CL with both a T-cell and B-cell NHL, which has only been reported in a few case reports. A 49-year-old woman presented with several months of progressive cough, weight loss, dyspnea, and supraclavicular lymphadenopathy. Computed tomographic imaging done upon admission to the hospital found that she had extensive anterior and middle mediastinal lymphadenopathy as well as bilateral supraclavicular lymphadenopathy. The patient underwent an excisional biopsy on the supraclavicular lymph node and was found to have a composite lymphoma involving both a T-cell and B-cell NHL. Her final pathological diagnosis was peripheral T-cell lymphoma and lymphoplasmacytic lymphoma. The patient was found to have stage IIIB disease. Her HIV, hepatitis panel, and tuberculosis tests were all negative. She then underwent chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. The patient showed a complete response and was then referred to a bone marrow transplant center for an autologous hematopoietic stem cell transplant. CL is a rare disease composed of at least 2 distinct lymphomas concurrently arising in a single patient. Due to the complexity in having to treat multiple types of lymphoma simultaneously CL presents challenges with treatment and assessing prognosis.

  9. Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study

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    Mehta R

    2014-12-01

    Full Text Available Rashmi Mehta,1 Kelly Hardes,2 Noushin Brealey,3 Lee Tombs,4 Andrew Preece,2 Dennis Kelleher1 1Respiratory Medicines Development Center, GSK, Research Triangle Park, NC, USA; 2Clinical Pharmacology Science and Study Operations, 3Respiratory Medicines Development Centre, GSK, Stockley Park, UK; 4Statistics and Programming, Synergy, Slough, Berkshire, UKBackground: Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney.Objectives: To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol.Methods: Nine patients with severe renal impairment (creatinine clearance <30 mL/min and nine matched healthy volunteers received a single dose of umeclidinium 125 µg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 µg.Results: No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration were observed following umeclidinium 125 µg or umeclidinium/vilanterol 125/25 µg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval was 88% (81%–93% and 89% (81%–93% lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 µg and umeclidinium/vilanterol 125/25 µg administration, respectively. Treatments were well tolerated in both populations.Conclusion: Umeclidinium 125 µg or umeclidinium/vilanterol 125/25 µg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal

  10. The difference in pharmacists' interventions across the diverse settings in a children's hospital.

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    Hesty Utami Ramadaniati

    Full Text Available AIMS: This study aimed to document and compare the nature of clinical pharmacists' interventions made in different practice settings within a children's hospital. METHODS: The primary investigator observed and documented all clinical interventions performed by clinical pharmacists for between 35-37 days on each of the five study wards from the three practice settings, namely general medical, general surgical and hematology-oncology. The rates, types and significance of the pharmacists' interventions in the different settings were compared. RESULTS: A total of 982 interventions were documented, related to the 16,700 medication orders reviewed on the five wards in the three practice settings over the duration of the study. Taking medication histories and/or patient counselling were the most common pharmacists' interventions in the general settings; constituting more than half of all interventions. On the Hematology-Oncology Ward the pattern was different with drug therapy changes being the most common interventions (n = 73/195, 37.4% of all interventions. Active interventions (pharmacists' activities leading to a change in drug therapy constituted less than a quarter of all interventions on the general medical and surgical wards compared to nearly half on the specialty Hematology-Oncology Ward. The majority (n = 37/42, 88.1% of a random sample of the active interventions reviewed were rated as clinically significant. Dose adjustment was the most frequent active interventions in the general settings, whilst drug addition constituted the most common active interventions on the Hematology-Oncology Ward. The degree of acceptance of pharmacists' active interventions by prescribers was high (n = 223/244, 91.4%. CONCLUSIONS: The rate of pharmacists' active interventions differed across different practice settings, being most frequent in the specialty hematology-oncology setting. The nature and type of the interventions documented in the

  11. [A new joint approach to drug management: clinical pharmacy services and risk management unit].

    Science.gov (United States)

    Schwartz, Vardit; Kravitz, Martine Szyper

    2015-04-01

    According to the "To Err is Human" report, medication-related errors are common in medicine and may have several and different effects. Clinical Pharmacy is a leading worldwide established pharmacy service which has been improving the quality of care for the last 30 years. The accumulated experience shows improved quality of care, improved patient safety and economic benefit. These understandings led to the definition and expansion of the Clinical Pharmacist Intervention Program and a joint project with the Risk Management Unit was created. A characterization process was conducted, parameters were defined for monitoring and surveillance and interventions were devised. The relevant data requiring pharmacist intervention was defined (e.g., dose adjustments, contraindications, side-effects); a report was devised, based on the patient's electronic medical record; daily follow-up included analysis, stratification, quantification and understanding of the different types of pharmacist interventions. The pharmacist interventions were summed up and assessed for performance and quality control. Between March 2013 and February 2014 the medical records of 14,499 patients were examined in our hospital Only in 16% of the records an active pharmacist intervention was performed, according to the parameters defined. Interventions for potentially high risk events such as therapeutic duplication, drug administration in spite of contraindication and in spite of documented allergy were very rare, less than 2% of all the pharmacist interventions. This joint venture, which is based on an existing platform, reflects an up-to-date view of an important facet of the clinical work performed at the hospital, helps identify trends, potential failures and vulnerabilities with regard to medication treatment and allows the formulation of intervention programs to improve the quality and safety of drug therapy.

  12. Clinic and ambulatory heart rates in patients with ischaemic heart disease and/or chronic heart failure taking rate-limiting medications: are they interchangeable?

    Science.gov (United States)

    Javed, Omar; Koo, Kenneth; El-Omar, Omar; Allen, Stuart; Squires, Alexander; El-Omar, Magdi

    2015-01-01

    The prognostic benefit from heart rate (HR) reduction in patients with ischaemic heart disease (IHD) and/or chronic heart failure (CHF) is now firmly established. Most decisions regarding initiation and/or dose adjustment of HR-limiting medications in such patients are based on clinic HR. Yet, this is a highly variable parameter that may not necessarily reflect HR control over the 24 h period. To examine the level of agreement between mean clinic and mean ambulatory HRs in patients with IHD and/or CHF taking rate-limiting medications. Prospective, observational study. Fifty patients with IHD and/or CHF who attended cardiology outpatient clinics at the Manchester Heart Centre and underwent same-day 24 h continuous ECG recording between March and October 2013 were included in the study. Mean clinic HR was compared with mean 24 h, daytime and night-time HRs. Limits-of-agreement plots were constructed to examine the relationship between the two HR measures in more detail. The mean clinic HR was numerically similar to the mean HRs of all ambulatory time periods examined. However, on Bland-Altman plots, the limits of agreement between clinic and ambulatory HR means were quite wide, with the mean clinic HR ranging between 10.93 and 13.58 bpm below and 8.4 and 18.15 bpm above the mean ambulatory HR. Although numerically similar, the means of clinic and ambulatory HRs in patients with IHD and/or CHF display wide limits of agreement. As such, the two measures cannot be regarded as interchangeable. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine.

    Science.gov (United States)

    Wang, Xue Yan; Lim-Jurado, Margaret; Prepageran, Narayanan; Tantilipikorn, Pongsakorn; Wang, De Yun

    2016-01-01

    Allergic rhinitis and urticaria are common allergic diseases that may have a major negative impact on patients' quality of life. Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug-drug interactions, and does not require dose adjustment in renal impairment. As bilastine is not metabolized and is excreted largely unchanged, hepatic impairment is not expected to increase systemic exposure above the drug's safety margin. Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis. It has also shown significant efficacy (similar to that of cetirizine) and safety in the long-term treatment of perennial allergic rhinitis. Bilastine showed similar efficacy to levocetirizine in patients with chronic spontaneous urticaria and can be safely used at doses of up to fourfold higher than standard dosage (80 mg once daily). The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines. Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity. Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria.

  14. CYP2C9 genotype vs. metabolic phenotype for individual drug dosing--a correlation analysis using flurbiprofen as probe drug.

    Directory of Open Access Journals (Sweden)

    Silvia Vogl

    Full Text Available Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects, correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen determined two hours after flurbiprofen (8.75 mg administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type, and 0.113 for CYP2C9*3 (19 % of wild type. If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19 % would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation ≥ 20 % and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40 % off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.

  15. Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder.

    Science.gov (United States)

    Ulrich, S; Neuhof, S; Braun, V; Meyer, F P

    1998-09-01

    Although several studies have been performed on the serum level-therapeutic effect relationship of neuroleptic drugs, the application of therapeutic drug-monitoring of neuroleptics is still a matter of controversy. Until now, haloperidol provided the most promising results. For this reason, an investigation of the dependence of clinical improvement on haloperidol serum levels was conducted in an acute psychiatric ward (Landeskrankenhaus Bernburg). In an open clinical trial haloperidol serum levels were measured in 57 acute schizophrenic patients for at least three weeks and correlated with clinical outcome (percent change of Brief Psychiatric Rating Scale, BPRS). A bisigmoidal model was used for data analysis. After three weeks of treatment, the major result proved to be a significant relationship between haloperidol serum level and therapeutic effect with pseudo-r2=0.316 and p=0.0031. Clinical improvement is enhanced by increasing haloperidol concentration up to about 10 ng/ml. It attains a maximum at about 10 ng/ml and decreases at haloperidol serum levels in a range of 10 ng/ml to 50 ng/ml. A simulation of this dependence of clinical improvement on serum levels, mediated by the variable dose design, can be excluded because of the results of a retrospective analysis of dosing behavior. Further evidence is thus provided for the dependence of therapeutic effect on the serum haloperidol concentration in acute schizophrenia. For practical application the position of a therapeutic window can be defined by a lower threshold level of about 5 ng/ml and an upper threshold of about 17 ng/ml. However, a maximal therapeutic effect is assured at 10 ng/ml. This should be the target value in serum level-guided dose adjustments.

  16. Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases.

    Science.gov (United States)

    Chapdelaine, Aurélie; Mansour, Anne-Marie; Troyanov, Yves; Williamson, David R; Doré, Maxime

    2017-01-27

    6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 10(8) erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 10(8) erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP 5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.

  17. Assessment of the pharmacokinetic interaction between eltrombopag and lopinavir-ritonavir in healthy adult subjects.

    Science.gov (United States)

    Wire, Mary B; McLean, Heidi B; Pendry, Carolyn; Theodore, Dickens; Park, Jung W; Peng, Bin

    2012-06-01

    Eltrombopag is an orally bioavailable thrombopoietin receptor agonist that is approved for the treatment of chronic idiopathic thrombocytopenic purpura. It is being developed for other medical disorders that are associated with thrombocytopenia. Patients with human immunodeficiency virus (HIV) may suffer from thrombocytopenia as a result of their HIV disease or coinfection with hepatitis C virus (HCV). HIV medications, particularly ritonavir (RTV)-boosted HIV protease inhibitors, are involved in many drug interactions. This study evaluated the potential drug-drug interaction between eltrombopag and lopinavir (LPV)/RTV. Forty healthy adult subjects enrolled in this open-label, three-period, single-sequence crossover study received a single 100-mg dose of eltrombopag (period 1), LPV/RTV at 400/100 mg twice daily (BID) for 14 days (period 2), and LPV/RTV at 400/100 mg BID (2 doses) with a single 100-mg dose of eltrombopag administered with the morning LPV/RTV dose (period 3). There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected during 72 h in periods 1 and 3 and during 12 h in period 2. The coadministration of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag decreased the plasma eltrombopag area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) by 17%, on average, with no change in plasma LPV/RTV exposure. Adverse events (AEs) reported in period 2 were consistent with known LPV/RTV AEs, such as diarrhea, abdominal pain, nausea, vomiting, rash, and fatigue. No subjects withdrew due to AEs, and no serious AEs were reported. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued.

  18. Effect of telaprevir on the pharmacokinetics of buprenorphine in volunteers on stable buprenorphine/naloxone maintenance therapy.

    Science.gov (United States)

    Luo, Xia; Trevejo, Jose; van Heeswijk, Rolf P G; Smith, Frances; Garg, Varun

    2012-07-01

    This was an open-label, single-sequence trial in hepatitis C virus-negative volunteers on stable, individualized, buprenorphine maintenance therapy. Telaprevir at 750 mg every 8 h was coadministered with buprenorphine/naloxone (4:1 ratio as sublingual tablets) for 7 days with food. Pharmacokinetic profiles of buprenorphine, norbuprenorphine, and naloxone were measured over the 24-hour dosing interval on day -1 (buprenorphine/naloxone alone, reference) and day 7 of telaprevir coadministration (test). Geometric least-squares mean ratios and associated 90% confidence intervals of treatment ratios (test/reference) were calculated using log-transformed pharmacokinetic parameters. Opioid withdrawal symptoms were evaluated throughout the study (via questionnaires and pupillometry). Pharmacokinetic data were available for 14 and 13 volunteers on day -1 and day 7, respectively. The area under the concentration-time curve (AUC) for buprenorphine was unchanged and the maximum concentration of drug in serum (C(max)) for buprenorphine, C(max) and AUC for norbuprenorphine, and C(max) naxolone were modestly decreased during coadministration with telaprevir. Geometric least-squares mean ratios (90% confidence intervals) for buprenorphine were 0.80 (0.69, 0.93) for the C(max) and 0.96 (0.84, 1.10) for the AUC from 0 to 24 h (AUC(0-24)); for norbuprenorphine, values were 0.85 (0.66, 1.09) for C(max) and 0.91 (0.71, 1.16) for AUC(0-24); for naloxone, the C(max) was 0.84 (0.62, 1.13). Coadministration of telaprevir did not increase withdrawal symptom frequency, and there were no serious adverse events reported during or after completion of telaprevir coadministration. Results suggest dose adjustment may not be necessary when telaprevir and buprenorphine/naloxone are coadministered.

  19. Effects of etravirine on the pharmacokinetics of the integrase inhibitor S/GSK1265744.

    Science.gov (United States)

    Ford, Susan L; Gould, Elizabeth; Chen, Shuguang; Lou, Yu; Dumont, Etienne; Spreen, William; Piscitelli, Stephen

    2013-01-01

    HIV integrase inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase inhibitor etravirine (ETR) may be used in combination with integrase inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational integrase inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.

  20. Effect of fosamprenavir-ritonavir on the pharmacokinetics of dolutegravir in healthy subjects.

    Science.gov (United States)

    Song, Ivy; Borland, Julie; Chen, Shuguang; Peppercorn, Amanda; Wajima, Toshihiro; Piscitelli, Stephen C

    2014-11-01

    Dolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established "no-effect" boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier NCT01209065.).

  1. Lack of clinically significant pharmacokinetic interaction between the thrombopoietin receptor agonist eltrombopag and hepatitis C virus protease inhibitors boceprevir and telaprevir.

    Science.gov (United States)

    Wire, Mary Beth; Fang, Lei; Hussaini, Azra; Kleha, Joseph F; Theodore, Dickens

    2014-11-01

    Eltrombopag is an orally bioavailable thrombopoietin receptor agonist approved for the treatment of thrombocytopenia associated with chronic immune (idiopathic) thrombocytopenic purpura and chronic hepatitis C virus (HCV) infection. This study evaluated the potential drug-drug interactions between eltrombopag and the HCV protease inhibitors boceprevir and telaprevir. In this open-label, 3-period, single-sequence, and crossover study, 56 healthy adult subjects were randomized 1:1 to cohort 1 (boceprevir) or 2 (telaprevir). The dosing was as follows: period 1, single 200-mg dose of eltrombopag; period 2, 800 mg boceprevir or 750 mg telaprevir every 8 hours (q8h) for 10 days; and period 3, single 200-mg dose of eltrombopag with either 800 mg boceprevir or 750 mg telaprevir q8h (3 doses). All doses were administered with food, and eltrombopag was administered specifically with low-calcium food. There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected for 72 h in periods 1 and 3 and for 8 h in period 2. The coadministration of eltrombopag increased the rate of boceprevir absorption, resulting in a 20% increase in the maximum concentration in plasma (Cmax), a 1-h-earlier time to Cmax (Tmax) for boceprevir, a 32% decrease in the concentration at the end of the dosing interval (Cτ), and no change in the area under the concentration-time curve over the dosing interval (AUC0-τ). The coadministration of eltrombopag did not alter telaprevir pharmacokinetics, and the coadministration of boceprevir or telaprevir did not alter eltrombopag pharmacokinetics. Dysgeusia, headache, and somnolence occurred in ≥2 subjects. One subject withdrew because of nausea, headache, dizziness, sinus pressure, and vomiting. There were no severe or serious adverse events. Dose adjustment is not required when eltrombopag is coadministered with boceprevir or telaprevir given the lack of clinically significant

  2. Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study.

    Science.gov (United States)

    Quach, Hang; White, Darrell; Spencer, Andrew; Ho, P Joy; Bhutani, Divaya; White, Mike; Inamdar, Sandeep; Morris, Chris; Ou, Ying; Gyger, Martin

    2017-06-01

    The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m(2). This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m(2) in normal renal function and ESRD patients. Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m(2) (cycle 1 day 1-2), escalated to 27 mg/m(2) on cycle 1 day 8; if tolerated, 56 mg/m(2) starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively. 26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients. There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure-response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

  3. NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Yi, Eun Sang; Choi, Young Bae; Choi, Rihwa; Lee, Na Hee; Lee, Ji Won; Yoo, Keon Hee; Sung, Ki Woong; Lee, Soo-Youn; Koo, Hong Hoe

    2017-09-13

    We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normal-activity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

  4. Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

    Science.gov (United States)

    Lalande, L; Bourguignon, L; Bihari, S; Maire, P; Neely, M; Jelliffe, R; Goutelle, S

    2015-09-01

    Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

  5. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    Science.gov (United States)

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    statin dose adjustment in clinical practice. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Diabetic nephropathy: new approaches for improving glycemic control and reducing risk.

    Science.gov (United States)

    Schernthaner, Guntram; Schernthaner, Gerit Holger

    2013-01-01

    Nephropathy is a common consequence of diabetes, with a high prevalence in patients with type 1 (15%-25%) and type 2 diabetes mellitus (T2DM; 30%-40%). Nephropathy is associated with a poor prognosis and high economic burden. The risk of developing nephropathy increases with the duration of diabetes, and early diagnosis and treatment of risk factors for nephropathy (e.g., tight control of glycemia and hypertension) can reduce the development and progression of diabetic nephropathy. Advances in our understanding of the mechanisms of renal complications associated with diabetes and the etiology of nephropathy have identified additional risk factors for nephropathy, and novel therapeutic options are being explored. This review discusses the pathophysiology of diabetic nephropathy and common risk factors. Furthermore, we discuss emerging treatments for T2DM that could potentially slow or prevent the progression of diabetic nephropathy. The use of incretin-based therapies, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, is growing in patients with T2DM, due to their efficacy and tolerability profiles. As renal safety is a key factor when choosing treatment options to manage patients with T2DM, drugs that are suitable for use in patients with varying degrees of renal impairment without a requirement for dose adjustment, such as the DPP-4 inhibitor linagliptin, are of particular use. The ongoing advances in T2DM therapy may allow optimization of glycemic control in a wide range of patients, thereby helping to reduce the increasing morbidity and mortality associated with diabetic nephropathy.

  7. Polydrug abuse among opioid maintenance treatment patients is related to inadequate dose of maintenance treatment medicine.

    Science.gov (United States)

    Heikman, Pertti Kalevi; Muhonen, Leea Hellevi; Ojanperä, Ilkka Antero

    2017-07-06

    Polydrug abuse is a known problem among opioid-dependent patients receiving opioid maintenance treatment (OMT). However, improved laboratory diagnostics is required to reveal polydrug abuse in its current scope. Furthermore, there are few studies focusing on the relationship between polydrug abuse and adequacy of the dose of OMT medicine. This study aimed to evaluate the polydrug abuse among opioid-dependent patients receiving OMT with inadequate (Group IA) and adequate (Group A) doses of OMT medicine as experienced by the patients. Craving for opioids and withdrawal symptoms were evaluated as indicators of the adequacy rating. This is a retrospective register-based study of 60 OMT patients on either methadone or sublingual buprenorphine/naloxone medication, whose polydrug abuse was studied from urine samples by means of a comprehensive high-resolution mass spectrometry method. Inadequate doses of the OMT medicines were associated with higher subjective withdrawal scores and craving for opioids. Six groups of abused substances (benzodiazepines, amphetamines, opioids, cannabis, new psychoactive substances, and non-prescribed psychotropic medicines) were found among OMT patients. Group IA patients showed significantly more abuse of benzodiazepines and amphetamines than the Group A patients. All the new psychoactive substances and most of the non-prescribed psychotropic medicines were detected from the Group IA patients. There was no difference in the doses of the OMT medicine between Groups IA and A patients. Polydrug abuse, detected by definitive laboratory methods, was widespread and more common among Group IA than Group A patients, emphasizing the requirement for individual OMT medicine dose adjustment.

  8. Non-Vitamin K Antagonist Oral Anticoagulants for Cardioversion in Atrial Fibrillation: An Updated Meta-analysis.

    Science.gov (United States)

    Renda, Giulia; Ricci, Fabrizio; De Caterina, Raffaele

    2017-04-01

    Non-vitamin K oral anticoagulants are now proven alternatives to vitamin K antagonists for stroke prevention in atrial fibrillation. However, there are few data on the efficacy and safety of their use for cardioversion, in which the risk of thromboembolic events is heightened. We performed a random-effects meta-analysis of patients undergoing both electrical and pharmacologic cardioversion for atrial fibrillation in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48, X-VeRT, and ENSURE-AF trials. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for stroke/systemic embolism and major bleeding at ≤42 days of follow-up. The analysis pooled 6148 patients in whom 6854 cardioversions for atrial fibrillation were performed. Compared with vitamin K antagonists, non-vitamin K antagonist oral anticoagulant therapy was associated with a similar risk of stroke/systemic embolism (RR, 0.82; 95% CI, 0.38-1.75) and major bleeding (RR, 0.98; 95% CI, 0.51-1.87). We found no significant statistical heterogeneity among studies (Cochrane Q P = .75, I(2) = 0% for stroke/systemic embolism; P = .54; I(2) = 0% for major bleeding). The short-term incidence of thromboembolism and major bleeding after cardioversion on non-vitamin K antagonist oral anticoagulants was comparable to the incidence observed on dose-adjusted vitamin K antagonist therapy. Non-vitamin K antagonist oral anticoagulants are a reasonable alternative to vitamin K antagonists in patients undergoing cardioversion. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Pharmacokinetics of a single dose of voriconazole administered orally with and without food to red-tailed hawks (Buteo jamaicensus).

    Science.gov (United States)

    Parsley, Ruth A; Tell, Lisa A; Gehring, Ronette

    2017-04-01

    OBJECTIVE To determine the pharmacokinetics of voriconazole administered PO with or without food to red-tailed hawks (Buteo jamaicensus) and whether any observed variability could be explained by measured covariates to inform dose adjustments. ANIMALS 7 adult red-tailed hawks. PROCEDURES In a crossover study design, hawks were randomly assigned to first receive voriconazole (15 mg/kg, PO) injected into a dead mouse (n = 3; fed birds) or without food (4; unfed birds). Sixteen days later, treatments were reversed. Blood samples were collected at various points to measure plasma voriconazole concentrations by ultraperformance liquid chromatography. Pharmacokinetic data were analyzed by noncompartmental methods and fit to a compartmental model through nonlinear mixed-effects regression, with feeding status and body weight investigated as covariates. RESULTS Voriconazole was well absorbed, with quantifiable plasma concentrations up to 24 hours after administration. Mean plasma half-life was approximately 2 hours in fed and unfed birds. Administration of the voriconazole in food delayed absorption, resulting in a significant delay in time to maximum plasma concentration. The final compartmental model included a categorical covariate to account for this lag in absorption as well as body weight as a covariate of total body clearance (relative to unknown bioavailability). CONCLUSIONS AND CLINICAL RELEVANCE A single dose of voriconazole (15 mg/kg) administered PO to red-tailed hawks resulted in mean plasma voriconazole concentrations greater than the targeted value (1 μg/mL). Additional studies with larger sample sizes and multidose regimens are required before the model developed here can be applied in clinical settings.

  10. Dosing of chemotherapy in obese and cachectic patients: results of a national survey.

    Science.gov (United States)

    Anglada-Martínez, Helena; Riu-Viladoms, Gisela; do Pazo-Oubiña, Fernando; Molas-Ferrer, Gloria; Mangues-Bafalluy, Irene; Codina-Jané, Carles; Creus-Baró, Natàlia

    2014-06-01

    It is not unusual to find obese and cachectic patients in the hematology oncology setting. However, information on dosage in these groups is scarce. The objectives of our study were to explore the dosing strategies applied in the treatment of obese and cachectic cancer patients and to determine whether these strategies are applied in clinical trials. Members of the Spanish Group for the Development of Hematology-Oncology Pharmacy (GEDEFO). We invited all cancer hospital pharmacists to participate in a survey. Descriptive statistics of the dosing strategies approaches. We invited 159 eligible hospitals to participate, and 38 responded to the survey. A total of 50 surveys were received: different strategies were applied by different physicians from the same hospital and by hematology and oncology departments. Body mass index was used to define obesity and cachexia in 40 and 30 % of the cases, respectively. Capping the body surface area (BSA) was the approach most commonly followed (64.1 %) in obese patients, whereas no specific approach was adopted in cachectic patients. In hematology patients, the BSA calculation was based on ideal body weight or adjusted body weight in 16.0 % of cases (n = 2) and 50.0 % of cases (n = 6), respectively; in oncology patients, use of adjusted or ideal body weight was negligible. Actual body weight was the main approach in obese patients (35 surveys) and cachectic patients (48 surveys). Creatinine clearance was assessed mainly using the Cockcroft and Gault equation (around 76.0 % of responses). As for clinical trials, 64.1 % of the respondents (n = 25 hospitals) considered the criteria from each clinical trial individually. Dose adjustments are more frequent in obese patients than in cachectic patients. In cancer oncology patients, dose is adjusted mainly by hematology and hematopoietic cell transplant teams. Capping BSA is the most frequent strategy, followed by calculating actual body weight.

  11. Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world perspective

    Directory of Open Access Journals (Sweden)

    Vidal Hector O

    2011-07-01

    Full Text Available Abstract Warfarin has a long history of benefit and has become the gold standard medication for the prevention of ischemic stroke in patients with atrial fibrillation. Nevertheless, it is far from perfect and there is no doubt that new drugs must be found to replace warfarin. The new oral anticoagulants that are on the market or awaiting approval or under research offer some benefits but not enough to replace warfarin until results of additional studies can show an adequate balance between effectiveness/safety and cost/benefit. There are several issues concerning the new oral anticoagulants. It is essential that the effect of any anticoagulant can be measured in plasma. But to date, there is no test to assess the effect or therapeutic range for the new oral anticoagulants. There is no antidote to neutralize the action of the new drugs in cases of bleeding or when acute surgical intervention is necessary. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal failure. Rivaroxaban should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not yet been determined. How anticoagulant bridging can be done before surgery has not yet been established. In conclusion, although thousands of patients have been treated in phase III studies, additional data are necessary before conclusions can be drawn on the potential for these new anticoagulant drugs to replace warfarin in patients with atrial fibrillation.

  12. Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach.

    Science.gov (United States)

    Serdjebi, Cindy; Gattacceca, Florence; Seitz, Jean-François; Fein, Francine; Gagnière, Johan; François, Eric; Abakar-Mahamat, Abakar; Deplanque, Gael; Rachid, Madani; Lacarelle, Bruno; Ciccolini, Joseph; Dahan, Laetitia

    2017-06-01

    Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.

  13. Efficacy of generic levetiracetam (epiterra in monotherapy for epilepsy in adult patients: preliminary results

    Directory of Open Access Journals (Sweden)

    V. A. Karlov

    2015-01-01

    Full Text Available Objective: to evaluate the efficacy and tolerability of levetiracetam (LEV (epiterra, TEVA in adult patients with focal epilepsy (FE or juvenile myoclonic epilepsy (JME who took the drug for і6 months as of December 15, 2014. Patients and methods. The efficacy of LEV as a generic (epiterra used in monotherapy was analyzed in 23 patients with FE and in 4 female patients with JME who had taken the drug for ≥6 months. In FE, LEV was switched to epiterra because of the high cost of the former and inadequate efficacy/poor tolerability of initial antiepileptic drugs (AEDs in 17 and 6 cases, respectively. In JMA, epiterra was prescribed as initial therapy in 2 cases and, with the diagnosis being changed, in 2 more patients. Results and discussion. When LEV was switched to its generic, the indicators of efficacy, tolerability, quality of life, and a plain electroencephalogram (EEG were significantly unchanged. When epiterra was substituted for other AEDs, the efficiency of its therapy was also significantly unchanged and tolerance, quality of life, and EEG characteristics were improved. Epiterra’s adverse reactions as sleepiness (n = 1 and a higher rate of mental processes (n=1 were observed exclusively when it was switched from another AED. However, they were transient (for 2–3 weeks and seen during either dose adjustment or at the stage of transitional combined therapy. Dual therapy (valproate + epiterra had to be used in only 1 female patient. Thus, the 6-month use of epiterra in adult patients with FE as an alternative to brand LEV did not deteriorate the clinical picture of the disease (remission rates and injury frequency and severity were significantly unchanged baseline tolerability, quality of life, or plain EEG values. The findings suggest that the use of epiterra is highly promising in epileptology, particularly in FE and JME in adult patients. 

  14. Prescribing of FDA-approved and compounded hormone therapy differs by specialty.

    Science.gov (United States)

    Constantine, Ginger D; Archer, David F; Graham, Shelli; Bernick, Brian A; Mirkin, Sebastian

    2016-10-01

    To determine the prescribing patterns of general practitioners (GPs), obstetrician/gynecologists (OB/GYNs), and wellness physicians (WPs) of menopausal hormone therapy (HT) for both compounded (CHT) and Food and Drug Administration (FDA)-approved products, using a survey of US physicians. Nine thousand one US physicians were invited to participate in a survey to report on their HT-prescribing patterns. Physicians were eligible if they prescribed HT for at least six patients per month. The survey was completed by 440 eligible physicians (893 responded of 9,001 invited) including 171 GPs, 170 OB/GYNs, and 84 WPs. Physicians prescribed HT for 15% to 30% of their female patients, with WPs numerically most likely to prescribe HT. Menopausal symptoms were the leading reason for HT prescriptions among all specialties. WPs seemed more likely to prescribe HT for general/cardiovascular health (28%), and for shorter durations, than other specialties. WPs prescribed proportionally more compounded (vs FDA-approved) estrogens/progestogens than GPs or OB/GYNs, but OB/GYNs seemed to prescribe more compounded dehydroepiandrosterone and testosterone (prescribed alone) than did others. OB/GYNs seemed least likely to consider CHT being more safe or effective than FDA-approved HT. Symptom relief was the main determinant of efficacy for all specialties; WPs also used blood (61%) or saliva testing (25%) for dose adjustment. Although all physician specialties surveyed prescribed HT, differences in prescribing CHT versus FDA-approved formulations by medical specialty/practice seemed to exist. Of those surveyed, OB/GYNs and GPs prescribed proportionally more FDA-approved HT, whereas WPs, similarly, prescribed more CHT. More discussion is needed concerning physicians' decisions to prescribe CHT versus FDA-approved formulations.

  15. Characterization and application of restricted access carbon nanotubes in online extraction of anticonvulsant drugs from plasma samples followed by liquid chromatography analysis.

    Science.gov (United States)

    Dos Santos, Rodrigo Campos; Kakazu, Adriana Kaori; Santos, Mariane Gonçalves; Belinelli Silva, Fábio Antônio; Figueiredo, Eduardo Costa

    2017-06-01

    Anticonvulsant drugs are often used in the treatment of epilepsy. However, their therapeutic monitoring is often necessary in order to obtain an appropriate dose adjustment, due to the proximity between their therapeutic and toxic ranges. The aim of this study was to carry out the synthesis, characterization and use of restricted access carbon nanotubes (RACNTs) in an online method for the analyses of phenobarbital and carbamazepine and primidone from untreated human blood plasma by column switching liquid chromatography. Therefore, the synthesis of RACNTs was carried out through coating commercial Carbon nanotubes with bovine serum albumin (BSA) to subsequently use them as adsorbents in a column switching system operating in the backflush mode. This material was evaluated through the construction of the kinetic and isotherm curves. The experimental data for the interaction of primidone with RACNTs were adequately adjusted to the chemisorption and Sips models for the kinetic and adsorption studies, respectively. The analytical curves ranged from 2.0 to 40.0mgL(-1), with correlation coefficients higher than 0.99, for all the analytes. The LODs of 0.1, 0.1 and 0.01μgmL(-1) were defined for PHB, PRM and CBZ, respectively. The relative standard deviation values ranged from 1.0% to 8.4% for the intra assay precision and from 2.7% to 7.6% for inter assay precision. The relative error values ranged from -13.4% to 7.7% for the intra assay accuracy and from -8.6% to 2.5% for the inter assay accuracy. The method was adequately used in the therapeutic monitoring of anticonvulsant drugs in human plasma samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Variables Influencing the Depth of Conscious Sedation in Plastic Surgery: A Prospective Study

    Science.gov (United States)

    Kim, Wonwoo; Park, Hyochun; Kim, Hoonnam

    2017-01-01

    Background Conscious sedation has been widely utilized in plastic surgery. However, inadequate research has been published evaluating adequate drug dosage and depth of sedation. In clinical practice, sedation is often inadequate or accompanied by complications when sedatives are administered according to body weight alone. The purpose of this study was to identify variables influencing the depth of sedation during conscious sedation for plastic surgery. Methods This prospective study evaluated 97 patients who underwent plastic surgical procedures under conscious sedation. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and glucose levels were measured. Midazolam and ketamine were administered intravenously according to a preset protocol. Bispectral index (BIS) recordings were obtained to evaluate the depth of sedation 4, 10, 15, and 20 minutes after midazolam administration. Associations between variables and the BIS were assessed using multiple regression analysis. Results Alcohol intake and female sex were positively associated with the mean BIS (P<0.01). Age was negatively associated with the mean BIS (P<0.01). Body mass index (P=0.263), creatinine clearance (P=0.832), smoking history (P=0.398), glucose (P=0.718), AST (P=0.729), and ALT (P=0.423) were not associated with the BIS. Conclusions Older patients tended to have a greater depth of sedation, whereas females and patients with greater alcohol intake had a shallower depth of sedation. Thus, precise dose adjustments of sedatives, accounting for not only weight but also age, sex, and alcohol consumption, are required to achieve safe, effective, and predictable conscious sedation. PMID:28194341

  17. Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients.

    Science.gov (United States)

    Kline, Christina Leah; Sheikh, Hassan S; Scicchitano, Angelique; Gingrich, Rebecca; Beachler, Cheryl; Finnberg, Niklas K; Liao, Jason; Sivik, Jeffrey; El-Deiry, Wafik S

    2011-10-01

    Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-Fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS, BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6 + Avastin (N = 8), FOLFOX6 (N = 11), FOLFIRI (N = 1) and FOLFOX4 (N = 1). Mutations identified in tumors included G12V KRAS (N = 2), G12A KRAS (N = 1), and V600E BRAF (N = 3). Six-of-eleven patients with normalized tumor TS mRNA levels 5-FU AUC of 20 mg.h/L or greater, and 80% of patients (4 of 5) with TS levels > 4.0 had a plasma 5-FU AUC of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AUC levels with 0-2 dose adjustments while a sub-group of ~1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AUC optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.

  18. Combined treatment with everolimus and fulvestrant reversed anti-HER2 resistance in a patient with refractory advanced breast cancer: a case report

    Directory of Open Access Journals (Sweden)

    Sun B

    2016-07-01

    Full Text Available Bing Sun,1 Lijuan Ding,1 Shikai Wu,1 Xiangying Meng,1 Santai Song2 1Department of Radiotherapy, 2Department of Breast Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China Background: Everolimus, an inhibitor of the mammalian target of rapamycin, shows promising antitumor activity when combined with trastuzumab and chemotherapy for human epidermal growth factor receptor-2 (HER2-positive breast cancer or when combined with endocrine agents for hormone receptor (HR-positive tumors. However, data are limited regarding the effect of everolimus in combination with endocrine drugs in HER2-positive advanced breast cancer regardless of the HR status.Case presentation: A 44-year-old female was diagnosed with recurrent HER2-positive breast cancer. The primary tumor was HR positive; however, the metastatic tumor was HR negative. The patient was resistant to classical chemotherapeutic agents and anti-HER2 treatment. Thus, the combination of everolimus and fulvestrant, a selective estrogen receptor downregulator, was chosen to reverse the resistance to anti-HER2 therapy. Indeed, the patient experienced long-term disease stabilization. Adverse events associated with the treatment were manageable by dose adjustments. We performed genetic testing of the metastatic tumor, which harbored a PIK3CA gene mutation but was positive for phosphatase and tensin homologue expression, which might result in resistance to the mammalian target of rapamycin inhibitor.Conclusion: This case study indicates that combined treatment with everolimus and fulvestrant might be a viable option for the treatment of metastatic breast cancer patients who are HER2 positive and carry a PIK3CA gene mutation but are resistant to anti-HER2 therapy and classical chemotherapeutic agents. Further prospective randomized trials are needed to confirm this finding. Keywords: mTOR inhibitor, PIK3CA gene, genetic testing, PI3K Akt mTOR pathway

  19. Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients.

    Science.gov (United States)

    Moltó, José; Valle, Marta; Miranda, Cristina; Cedeño, Samandhy; Negredo, Eugenia; Barbanoj, Manuel José; Clotet, Bonaventura

    2011-01-01

    The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m(2). Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

  20. Herb-Drug Interaction between Echinacea purpurea and Darunavir-Ritonavir in HIV-Infected Patients▿

    Science.gov (United States)

    Moltó, José; Valle, Marta; Miranda, Cristina; Cedeño, Samandhy; Negredo, Eugenia; Barbanoj, Manuel José; Clotet, Bonaventura

    2011-01-01

    The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting. PMID:21078942

  1. Herb-drug interaction between Echinacea purpurea and etravirine in HIV-infected patients.

    Science.gov (United States)

    Moltó, José; Valle, Marta; Miranda, Cristina; Cedeño, Samandhy; Negredo, Eugenia; Clotet, Bonaventura

    2012-10-01

    The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement Echinacea purpurea to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV. Fifteen HIV-infected patients receiving antiretroviral therapy with etravirine (400 mg once daily) for at least 4 weeks were included. E. purpurea root/extract-containing capsules were added to the antiretroviral treatment (500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus E. purpurea on day 14. Individual etravirine pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 46 years (interquartile range, 41 to 50), and the median body weight was 76 kg (interquartile range, 68 to 92). Echinacea was well tolerated, and all participants completed the study. The GMR for etravirine coadministered with E. purpurea relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration, 1.04 (90% CI, 0.79 to 1.38) for the area under the concentration-time curve from 0 to 24 h, and 1.04 (90% CI, 0.74 to 1.44) for the concentration at the end of the dosing interval. In conclusion, the coadministration of E. purpurea with etravirine was safe and well tolerated in HIV-infected patients; our data suggest that no dose adjustment for etravirine is necessary.

  2. [Dalbavancin: pharmacokinetic and pharmacodynamic parameters].

    Science.gov (United States)

    Azanza, José Ramón; Sádaba, Belén; Reis, Joana

    2017-01-01

    Dalbavancin is a new lipoglycopeptide antibiotic whose structure influences its pharmacokinetic profile. It is not absorbed after oral administration and is therefore administered intravenously. It is distributed through intracellular fluid, reaching adequate concentrations in the skin, bone, blister fluid and synovial fluid. Plasma protein binding is very high. Concentrations in brain tissue and cerebrospinal fluid (CSF) are inadequate. Excretion is through non-microsomal metabolism with inactive metabolites and through the kidneys by glomerular filtration. Dalbavancin is eliminated slowly, as shown by its clearance value and its terminal elimination half-life, which exceeds 300 hours. This means that adequate concentrations of the drug remain in plasma and tissues for a prolonged period and explains the dosing regimen: a first dose of 1g followed 7 days later by a 500mg dose. The pharmacokinetics are linear and show little intra- and interindividual variability. There are no pharmacokinetic interactions. Dose adjustment is not required for patients with mild or moderate renal insufficiency (creatinine clearance ≥ 30 to 79ml/min). Dosage adjustment is not required in patients regularly receiving elective haemodialysis (3 times/week) and the drug can be administered without consideration of haemodialysis times. In patients with chronic renal insufficiency, whose creatinine clearance is < 30ml/min and who are not regularly receiving elective haemodialysis, the recommended dose should be reduced to 750mg per week, followed 1 week later by 375mg. Dosage adjustment does not seem necessary in patients with liver failure or in older patients. There is no information on the most appropriate dosage in children. The pharmacokinetic/pharmacodynamics parameter that best describes the effectiveness of dalbavancin is the ratio between the area under the curve and the minimum inhibitory concentration.

  3. Workshop: Patient Self-Management: Update of Ongoing Studies in Sweden.

    Science.gov (United States)

    Stigendal; André

    1998-01-01

    Anti-vitamin K (AVK) therapy (e.g., warfarin) requires regular blood tests for adequate dosing of the drug. The therapeutic window for these drugs is narrow, with a risk of bleeding if the dose is too high and of thrombotic complications if the dose is too low. Moreover, the required dose to achieve an optimal level of anticoagulation is individual and depends on such factors as the general health of the patient, food intake, and concomitant medication. Although control requires regular monitoring, most patients are reluctant to visit an anticoagulation clinic (ACC) more than 6-12 times yearly because each visit costs the patient both money and time. The development of prothrombin time (PT) monitors that are simple to operate and highly portable has made self-management possible for large groups of patients on long-term AVK therapy. Self-management increases the safety of AVK therapy through frequent testing (3-4 times per month) and timely dose adjustments when they are indicated. The concept of self-management of AVK therapy was introduced in Germany a decade ago with great success. Swedish patient education in self-management was started in September 1996. As of May 1997, 38 patients have completed the training program, 37 of whom have continued with self-management. Experience with the first seven groups of patients has convinced us that self-management is possible and has great potential. Randomized controlled studies are needed to determine the cost effectiveness of self-management with regard to a reduction in bleeding and thrombotic complications.

  4. A survey of resistance to colchicine treatment for French patients with familial Mediterranean fever.

    Science.gov (United States)

    Corsia, Alice; Georgin-Lavialle, Sophie; Hentgen, Véronique; Hachulla, Eric; Grateau, Gilles; Faye, Albert; Quartier, Pierre; Rossi-Semerano, Linda; Koné-Paut, Isabelle

    2017-03-16

    Colchicine is the standard treatment for familial Mediterranean fever (FMF), preventing attacks and inflammatory complications. True resistance is rare and yet not clearly defined. We evaluated physicians' definition of colchicine resistance and report how they manage it. We recruited patients with a clinical diagnosis of FMF, one exon-10 Mediterranean fever (MEFV) gene mutation and considered resistant to colchicine, via networks of expert physicians. Clinical, biological characteristics and information about colchicine treatment (dose adjustment, compliance) were collected. The severity of FMF was assessed by the Tel Hashomer criteria. We included 51 patients, most females (55%), mean age 34 ± 23.1 years years (range 4.7-86.3). Overall, 58% (27/47) patients had homozygous M694 MEFV gene mutations. Seventeen of 42 patients (40%) declared full adherence to colchicine treatment, greater for children (48%) than adults (22%). Physicians considered colchicine resistance with > 6 attacks/year (n = 21/51, 42%), > 4 attacks in the last 6 months (n = 13/51, 26%), persistent inflammation (n = 23/51, 45%), renal amyloidosis in (n = 6/28, 22%) of adult patients and intolerance to an increase in colchicine dose (n = 10/51, 19%), and other reasons (n = 13/51, 23%), including chronic arthralgia (n = 6/51, 12%). Interleukin 1-targeting drugs represented the only alternative treatments in addition to daily colchicine. Resistance to colchicine is rare (treatment is a key component of resistance.

  5. Pharmacokinetic interaction study between riociguat and the combined oral contraceptives levonorgestrel and ethinylestradiol in healthy postmenopausal women.

    Science.gov (United States)

    Frey, Reiner; Unger, Sigrun; van der Mey, Dorina; Becker, Corina; Saleh, Soundos; Wensing, Georg; Mück, Wolfgang

    2016-03-01

    Female patients requiring treatment for pulmonary arterial hypertension (PAH) are advised to avoid pregnancy because of the high associated mortality rate. Oral contraception is one of the main methods of preventing pregnancy in this context, mandating pharmacokinetic and safety studies for new agents in this setting. Riociguat is a soluble guanylate cyclase stimulator approved for treatment of PAH and inoperable and persistent or recurrent chronic thromboembolic pulmonary hypertension. This single-center, randomized, nonblinded study involving healthy postmenopausal women investigated the effect of riociguat on plasma concentrations of levonorgestrel (0.15 mg) and ethinylestradiol (0.03 mg) in a combined oral contraceptive. Treatment A was a single oral tablet of levonorgestrel-ethinylestradiol. In treatment B, subjects received 2.5 mg riociguat 3 times daily for 12 days. On the eighth day, they also received a single oral tablet of levonorgestrel-ethinylestradiol. Subjects received both regimens in a crossover design. There was no change in area under the plasma concentration-time curves of levonorgestrel or ethinylestradiol or maximum concentration in plasma (C max) of levonorgestrel during combined administration versus levonorgestrel-ethinylestradiol alone. A 20% increase in the C max of ethinylestradiol was noted during coadministration; this is not anticipated to adversely impact the contraceptive efficacy or to require any dose adjustment for ethinylestradiol. Plasma concentrations and exposures of riociguat were within the expected range and were not influenced by coadministration with levonorgestrel-ethinylestradiol. Combined treatment was safe and well tolerated. In conclusion, riociguat did not change the exposure to levonorgestrel or ethinylestradiol relative to oral contraceptive administered alone.

  6. The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain.

    Science.gov (United States)

    Lasheen, Wael; Walsh, Declan; Mahmoud, Fade; Sarhill, Nabeel; Rivera, Nilo; Davis, Mellar; Lagman, Ruth; Legrand, Susan

    2010-01-01

    Morphine (M) is the opioid analgesic of choice for severe cancer pain. The IV to PO M equipotent switch ratio (CR) is controversial. We designed this prospective observational cohort to confirm the efficacy and safety of M IV to PO CR of 1:3. Consecutive cancer patients admitted to an inpatient palliative medicine unit were screened for inclusion. Pain was managed by palliative medicine specialists. They were blinded to the patient data collected, and the calculated CR. The switch was considered successful if the following criteria were met: (1) Pain adequately controlled: pain rated as none or mild (2) Number of RD less than 4 (for non incident pain) per 24 hours (3) No limiting side effects. We used Day 3 ATC M dose for CR calculations. The major outcome measures were the IV : PO CR ratio, morphine doses (mg/day), pain severity, number of PRN doses, and day 1 and day 3side effects. Descriptive statistics were used to report mean, median, standard deviation and range of different variables. Two hundred and fifty six consecutive admissions were screened, and 106 were eligible for the study. Sixty two underwent a successful M route switch and were included in this analysis. A ratio of 1:3 was safely implemented over a wide M dose range. About 80% were successfully switched with a calculated CR of 1:3. 20% required an oral M dose adjustment after route switch either to better pain control or reduce side effects with a resultant higher (e.g. 1:4) or lower (e.g. 1:2) calculated potency ratios respectively. A potency ratio of 1:3 was safe as evaluated by common M side-effects, the dose also easy to calculate. The 1: 3 M IV to PO relative milligram potency ratio appears correct and practical for most patients over a wide M dose range.

  7. Herb-Drug Interaction between Echinacea purpurea and Etravirine in HIV-Infected Patients

    Science.gov (United States)

    Valle, Marta; Miranda, Cristina; Cedeño, Samandhy; Negredo, Eugenia; Clotet, Bonaventura

    2012-01-01

    The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement Echinacea purpurea to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV. Fifteen HIV-infected patients receiving antiretroviral therapy with etravirine (400 mg once daily) for at least 4 weeks were included. E. purpurea root/extract-containing capsules were added to the antiretroviral treatment (500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus E. purpurea on day 14. Individual etravirine pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 46 years (interquartile range, 41 to 50), and the median body weight was 76 kg (interquartile range, 68 to 92). Echinacea was well tolerated, and all participants completed the study. The GMR for etravirine coadministered with E. purpurea relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration, 1.04 (90% CI, 0.79 to 1.38) for the area under the concentration-time curve from 0 to 24 h, and 1.04 (90% CI, 0.74 to 1.44) for the concentration at the end of the dosing interval. In conclusion, the coadministration of E. purpurea with etravirine was safe and well tolerated in HIV-infected patients; our data suggest that no dose adjustment for etravirine is necessary. PMID:22869560

  8. Continuous quality improvement in daily clinical practice: a proof of concept study.

    Directory of Open Access Journals (Sweden)

    Jonathan A Lorch

    Full Text Available Continuous Quality Improvement (CQI is an iterative process of: planning to improve a product or process, plan implementation, analyzing and comparing results against those expected, and corrective action on differences between actual and expected results. It is little used in clinical medicine. Anemia, a complex problem in End Stage Renal Disease patients, served to test the ability of an unique electronic medical record (EMR optimized for daily care to empower CQI in practice. We used data collected during daily care, stored in the EMR, and organized to display temporal relationships between clinical, laboratory, and therapeutic events. Our aims were optimal hemoglobin with minimum epoetin, and maintaining stable hemoglobin and epoetin. The study was done on 250 patients treated by maintenance hemodialysis (HD, receiving epoetin prior to February 1, 2010 and followed to July 31, 2011. Repleting iron, ensuring iron sufficiency, slow epoetin reduction, and decision support tools enabling data display over long periods in patient-centered reports were key elements. Epoetin dose, adjusted 6-8 weekly, was based on current clinical conditions and past responses. Hemoglobin increased by months 1-2; epoetin decreased from month 4. By months 16-18, epoetin had decreased 42% to 9,720 units/week while hemoglobin increased 8% to 123.6 g/L. Hemoglobin and epoetin were stable from month 7 onward. New epoetin orders decreased 83%. Transferrin saturation increased after the study start. Individual patient hemoglobin variation decreased by 23%, range by 27%. Mortality, 11.78 per 100 patient years, was 42% less than United States dialysis patient mortality. Allowable epoetin charges decreased by $15.33 per treatment and were $22.88 less than current Medicare allowance. The study validates the hypothesis that an EMR optimized for daily patient care can empower CQI in clinical medicine and serve to monitor medical care quality and cost.

  9. Pharmacokinetics of sugammadex in subjects with moderate and severe renal impairment
.

    Science.gov (United States)

    Min, K Chris; Lasseter, Kenneth C; Marbury, Thomas C; Wrishko, Rebecca E; Hanley, William D; Wolford, Dennis G; Udo de Haes, Joanna; Reitmann, Christina; Gutstein, David E

    2017-09-01

    Sugammadex rapidly reverses moderate and deep rocuronium- or vecuronium-induced neuromuscular blockade at doses of 4 mg/kg and 2 mg/kg, respectively. Sugammadex is renally eliminated. This study evaluated the pharmacokinetics of sugammadex in subjects with renal impairment versus those with normal renal function. This open-label, two-part, phase 1 study included adults with moderate (creatinine clearance (CLcr) 30 - cr cr ≥ 80 mL/min). A single intravenous (IV) bolus injection of sugammadex 4 mg/kg was administered into a peripheral vein over 10 seconds directly by straight needle in part 1 (n = 24; 8/group), and via an IV catheter followed by a saline flush in part 2 (n = 18; 6/group). Plasma concentrations of sugammadex were collected after drug administration. Due to dosing issues in part 1, pharmacokinetic parameters were determined for part 2 only. Safety was assessed throughout the study. Pharmacokinetic data were obtained from 18 subjects. Mean sugammadex exposure (AUC0-∞) in subjects with moderate and severe renal impairment was 2.42- and 5.42-times, respectively, that of healthy controls. Clearance decreased and apparent terminal half-life was prolonged with increasing renal dysfunction. Similar Cmax values were observed in subjects with renal impairment and healthy controls. There were no serious adverse events. Sugammadex exposure is increased in subjects with moderate and severe renal insufficiency due to progressively decreased clearance as a function of worsening renal function. Sugammadex 4 mg/kg was well tolerated in subjects with renal impairment, with a safety profile similar to that of healthy subjects. These results indicate that dose adjustment of sugammadex is not required in patients with moderate renal impairment; however, current safety experience is insufficient to support the use of sugammadex in patients with CLcr < 30 mL/min.
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  10. An integrated safety analysis of intravenous ibuprofen (Caldolor® in adults

    Directory of Open Access Journals (Sweden)

    Southworth SR

    2015-10-01

    Full Text Available Stephen R Southworth,1 Emily J Woodward,2 Alex Peng,2 Amy D Rock21North Mississippi Sports Medicine and Orthopaedic Clinic, PLLC, Tupelo, MS, 2Department of Research and Development, Cumberland Pharmaceuticals Inc., Nashville, TN, USAAbstract: Intravenous (IV nonsteroidal anti-inflammatory drugs such as IV ibuprofen are increasingly used as a component of multimodal pain management in the inpatient and outpatient settings. The safety of IV ibuprofen as assessed in ten sponsored clinical studies is presented in this analysis. Overall, 1,752 adult patients have been included in safety and efficacy trials over 11 years; 1,220 of these patients have received IV ibuprofen and 532 received either placebo or comparator medication. The incidence of adverse events (AEs, serious AEs, and changes in vital signs and clinically significant laboratory parameters have been summarized and compared to patients receiving placebo or active comparator drug. Overall, IV ibuprofen has been well tolerated by hospitalized and outpatient patients when administered both prior to surgery and postoperatively as well as for nonsurgical pain or fever. The overall incidence of AEs is lower in patients receiving IV ibuprofen as compared to those receiving placebo in this integrated analysis. Specific analysis of hematological and renal effects showed no increased risk for patients receiving IV ibuprofen. A subset analysis of elderly patients suggests that no dose adjustment is needed in this higher risk population. This integrated safety analysis demonstrates that IV ibuprofen can be safely administered prior to surgery and continued in the postoperative period as a component of multimodal pain management.Keywords: NSAID, surgical pain, fever, perioperative analgesia, critical care, multimodal pain management

  11. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies.

    Science.gov (United States)

    Di Nisio, Marcello; Vedovati, Maria C; Riera-Mestre, Antoni; Prins, Martin H; Mueller, Katharina; Cohen, Alexander T; Wells, Philip S; Beyer-Westendorf, Jan; Prandoni, Paolo; Bounameaux, Henri; Kubitza, Dagmar; Schneider, Jonas; Pisters, Ron; Fedacko, Jan; Fontes-Carvalho, Ricardo; Lensing, Anthonie W A

    2016-09-27

    The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

  12. Intraoperative blood glucose management: impact of a real-time decision support system on adherence to institutional protocol.

    Science.gov (United States)

    Nair, Bala G; Grunzweig, Katherine; Peterson, Gene N; Horibe, Mayumi; Neradilek, Moni B; Newman, Shu-Fang; Van Norman, Gail; Schwid, Howard A; Hao, Wei; Hirsch, Irl B; Patchen Dellinger, E

    2016-06-01

    Poor perioperative glycemic management can lead to negative surgical outcome. Improved compliance to glucose control protocol could lead to better glucose management. An Anesthesia Information Management System based decision support system-Smart Anesthesia Manager™ (SAM) was used to generate real-time reminders to the anesthesia providers to closely adhere to our institutional glucose management protocol. Compliance to hourly glucose measurements and correct insulin dose adjustments was compared for the baseline period (12 months) without SAM and the intervention period (12 months) with SAM decision support. Additionally, glucose management parameters were compared for the baseline and intervention periods. A total of 1587 cases during baseline and 1997 cases during intervention met the criteria for glucose management (diabetic patients or non-diabetic patients with glucose level >140 mg/dL). Among the intervention cases anesthesia providers chose to use SAM reminders 48.7 % of the time primarily for patients who had diabetes, higher HbA1C or body mass index, while disabling the system for the remaining cases. Compliance to hourly glucose measurement and correct insulin doses increased significantly during the intervention period when compared with the baseline (from 52.6 to 71.2 % and from 13.5 to 24.4 %, respectively). In spite of improved compliance to institutional protocol, the mean glucose levels and other glycemic management parameters did not show significant improvement with SAM reminders. Real-time electronic reminders improved intraoperative compliance to institutional glucose management protocol though glycemic parameters did not improve even when there was greater compliance to the protocol.

  13. Arsenic trioxide: safety issues and their management

    Institute of Scientific and Technical Information of China (English)

    Wing-Yan AU; Yok-Lam KWONG

    2008-01-01

    Arsenic trioxide (As2O3) has been used medicinally for thousands of years.Its therapeutic use in leukaemia was described a century ago.Recent rekindling in the interest of As2O3 is due to its high efficacy in acute promyelocytic leukaemia (APL).As2O3 has also been tested clinically in other blood and solid cancers.Most studies have used intravenous As2O3,although an oral As2O3 is equally efficacious.Side effects of As2O3 are usually minor,including skin reactions,gastrointestinal upset,and hepatitis.These respond to symptomatic treatment or temporary drug cessation,and do not compromise subsequent treatment with As2O3.During induction therapy in APL,a leucocytosis may occasionally occur,which can be associated with fluid accumulation and pulmonary infiltration.The condition is similar to the APL differentiation syndrome during treatment with all-trans retinoic acid,and responds to cytoreductive treatment and corticosteroids.Intravenous As2O3 treatment leads to QT prolongation.In the presence of under-lying cardiopulmonary diseases or electrolyte disturbances,particularly hypokalaemia and hypomagnesaemia,serious arrhythmias may develop,with torsades du pointes reported in 1% of cases.This may be related to a dose-dependent arsenic-mediated inhibition of potassium ion channels that compro-mises cardiac repolarization.Because of slow intestinal absorption,oral-As2O3 gives a lower plasma arsenic concentration,which is associated with lesser QT prolongation and hence a more favorable cardiac safety profile.As2O3 does not appear to enter the central nervous system.However,if the blood brain barrier is breached,elemental arsenic may enter the cerebrospinal fluid.As2O3 is predomi-nantly excreted in the kidneys,and dose adjustment is required when renal func-tion is impaired.

  14. Application of Biodegradable Nanoparticles in Liver Targeting of Tacrolimus

    Science.gov (United States)

    Affifi, Nagia N.; Heikal, Ola A.; Hanafi, Rasha S.; Tammam, Salma N.

    2011-06-01

    Tacrolimus is a potent immunosuppressant used in liver transplantation to avoid graft rejection. Tacrolimus has a narrow therapeutic index and variable pharmacokinetics, making dose adjustment and therapeutic drug monitoring a complicated task. Increasing the occurrence of adverse effects, especially nephrotoxicity are another concerns. In graft rejection, antigen presentation occurs in the graft and lymphatics. Therefore, by targeting tacrolimus to the liver and spleen, graft survival could be achieved with a decrease in nephrotoxicity. Poly(lactide) tacrolimus nanoparticles (PLA-TAC-NP) were formulated and characterized with the aim of targeting tacrolimus to the liver and spleen and therefore decreasing its nephrotoxicity. To evaluate the targeting efficiency of PLA-TAC-NP, rats were divided into two groups. They were intravenously injected either PLA-TAC-NP or free tacrolimus. At assigned time intervals, blood, liver, spleen and kidney samples were collected from each rat. Drug extraction and HPLC analysis were used to evaluate tacrolimus tissue distribution and consequently the targeting efficiency of the prepared PLA-TAC-NP. PLA-TAC-NP proved their success in targeting liver and spleen, by showing significantly higher drug amounts compared to the rats injected with free tacrolimus. PLA-TAC-NP increased tacrolimus concentration in the liver 24 fold and in the spleen 1.94 fold whereas tacrolimus concentration in the kidneys decreased by 7.12 fold. Transmission electron microscopy (TEM) was used to examine a liver section, obtained from a rat that has received PLA-TAC-NP. TEM images showed PLA-TAC-NP in a Kupffer cell and in the liver sinusoids. Therefore, PLA-TAC-NP are promising drug delivery systems for achieving localized immunosuppression and minimizing nephrotoxicity in liver transplant patients.

  15. Retrospective study evaluating dose standards for infliximab in patients with rheumatoid arthritis at Hospital Israelita Albert Einstein, São Paulo, Brazil.

    Science.gov (United States)

    Scheinberg, Morton; Goldenberg, José; Feldman, Daniel P; Nóbrega, João Luiz

    2008-08-01

    We determined, in our surrounding environment, the proportion of patients being treated with infliximab who required a therapeutic scheme escalation (an infliximab dose increase surpassing the level of 3 mg/kg every 8 weeks and/or a decrease on the current between infusions' interval). This was a study of the retrospective analysis of data from the 41 rheumatoid arthritis (RA) patients receiving an infliximab therapy at the Albert Einstein Israelita Hospital, from January 2001 up to December 2005. A questionnaire was applied to these patients, assessing their clinical and laboratory data, adverse events, and individual information regarding the infliximab administration. Therapeutic dose information was available in 68% (28/41) of the RA patients, with 46% of these (13/28) receiving a dose increase, and 30% (8/27) experiencing a shortening of the between infusions' interval. The average final infliximab dose (4.21 mg/kg) was significantly greater than their average initial dose (3.29 mg/kg). The average time intervals between the initial and final infusions, though shortened, were not significantly different. A proportion of 73% (30/41) of these patients demonstrated improvement in at least one of the assessed clinical parameters, and 50% of these patients (15/30) experienced a dose increase, while 20% (6/30) experienced shortening of the between treatments' interval. A total of 20% (8/41) of the original patients experienced adverse events. Although infliximab is effective in the control of RA, dose adjustment and/or shortening of the between treatments' interval is frequently required.

  16. XIMELAGATRAN: A NEW DIRECT THROMBIN INHIBITOR

    Directory of Open Access Journals (Sweden)

    Mehta Hiren R

    2011-04-01

    Full Text Available Venous thromboembolism is a serious illness that affects patient morbidity and mortality and presents a significant management challenge to healthcare providers world-wide. Despite major achievements in the significant reduction of thromboembolic complications, the most common therapies currently used for prevention and treatment of venous thromboembolism – heparins and vitamin K antagonists such as warfarin – have several limitations. Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Unlike warfarin and heparin, these direct thrombin inhibitors are able to inhibit fibrin-bound thrombin and so produce more effective inhibition of coagulation. Importantly, some members of this class of drugs have been developed for oral administration. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal.

  17. Kinsale Community Hospital, Kinsale, Cork.

    LENUS (Irish Health Repository)

    Casey, Dympna

    2011-08-30

    Abstract Background The literature reveals that structured education programmes, such as DAFNE, result in many positive outcomes for people with Type 1 diabetes including a decrease in HbA1c levels and reductions in hypoglycaemia. While there is evidence that some of these outcomes are maintained we do not know at present what factors are most important over time. The study aim was to identify the key factors impacting on persons with Type 1 diabetes ability to assimilate the Dose Adjustment For Normal Eating (DAFNE) DAFNE principles into their daily lives and how these factors change over time. Methods This is a longitudinal descriptive qualitative study. Interviews were undertaken with 40 participants who had attended DAFNE in one of 5 study sites across the Island of Ireland, at 6 weeks, 6 and 12 months after completion of the programme. The interviews lasted from 30 to 60 minutes and were transcribed verbatim. Data were analysed in three ways, a within time analysis, a cross sectional analysis for each participant and a thematic analysis which focused on examining changes over time Results Four themes that influenced participants\\' ability to assimilate DAFNE into their daily lives over time were identified. These were: embedded knowledge, continued responsive support, enduring motivation and being empowered. Support at the 6 month period was found to be crucial to continued motivation. Conclusions Understanding the factors that influence people\\'s ability to assimilate DAFNE principles over time into their daily lives can help health professionals give focused responsive support that helps people with diabetes become more empowered. Understanding that continued support matters, particularly around 6 months, is important as health professionals can influence good management by providing appropriate support and enhancing motivation. Trial registration ISRCTN79759174

  18. Insulin-based strategies to prevent hypoglycaemia during and after exercise in adult patients with type 1 diabetes on pump therapy: the DIABRASPORT randomized study.

    Science.gov (United States)

    Franc, S; Daoudi, A; Pochat, A; Petit, M-H; Randazzo, C; Petit, C; Duclos, M; Penfornis, A; Pussard, E; Not, D; Heyman, E; Koukoui, F; Simon, C; Charpentier, G

    2015-12-01

    To validate strategies to prevent exercise-induced hypoglycaemia via insulin-dose adjustment in adult patients with type 1 diabetes (T1D) on pump therapy. A total of 20 patients randomly performed four 30-min late post-lunch (3 h after lunch) exercise sessions and a rest session: two moderate sessions [50% maximum oxygen consumption (VO2 max)] with 50 or 80% basal rate (BR) reduction during exercise + 2 h and two intense sessions (75% VO2 max) with 80% BR reduction or with their pump stopped. Two additional early post-lunch sessions (90 min after lunch) were analysed to compare hypoglycaemia incidence for BR reduction versus bolus reduction. In all, 100 late post-lunch sessions were analysed. Regardless of exercise type and BR reduction, no more hypoglycaemic events occurred in the period until the next morning than occurred after the rest sessions. In the afternoon, no more hypoglycaemic events occurred with 80% BR reduction/moderate exercise or with pump discontinuation/intense exercise than for the rest session, whereas more hypoglycaemic events occurred with 50% BR reduction/moderate exercise and 80% BR reduction/intense exercise. After early post-lunch exercise (n = 37), a trend towards fewer hypoglycaemic episodes was observed with bolus reduction versus BR reduction (p = 0.07). Mean blood glucose fell by ∼3.3 mmol/l after 30 min of exercise, irrespective of dose reduction, remaining stable until the next morning with no rebound hyperglycaemia. In adults with T1D, to limit the hypoglycaemic risk associated with 30 min of exercise 3 h after lunch, without carbohydrate supplements, the best options seem to be to reduce BR by 80% or to stop the pump for moderate or intense exercise, or for moderate exercise 90 min after lunch, to reduce the prandial bolus rather than the BR. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  19. Venous thromboembolism: identifying patients at risk and establishing prophylaxis.

    Science.gov (United States)

    Shirvanian, Shant; Tapson, Victor F

    2015-12-01

    Venous thromboembolism (VTE) is a major cause of morbidity and mortality and is associated with substantial healthcare costs. Identification of patients at risk of developing VTE enables appropriate thromboprophylaxis to be implemented. Although no predisposing risk factors can be identified in many patients in whom VTE develops, most have at least one underlying risk factor which can be categorized according to whether it confers low, moderate, or high risk. Clinical trials have demonstrated the effectiveness of thromboprophylaxis, both non-pharmacological and pharmacological, in a host of medical settings and there is sufficient evidence to support routine prophylaxis in many groups of patients. The implementation of decision making tools based on risk factor assessment improves the prescription of appropriate VTE prophylaxis. Nonetheless, thromboprophylaxis is often inadequate, with haphazard risk assessment and application of guidelines, leading to easily preventable instances of VTE. The most commonly used agents for pharmacological thromboprophylaxis of VTE are low dose unfractionated heparin; a low molecular weight heparin such as dalteparin, enoxaparin or tinzaparin; fondaparinux; warfarin; or aspirin. However, these have a number of drawbacks, principally the need for parenteral administration (with heparins) and frequent coagulation monitoring (with warfarin). The optimal anticoagulant would be orally administered, with a wide therapeutic window, rapid onset of action, predictable pharmacodynamics and pharmacokinetics, minimal interactions with food and other drugs, an ability to inhibit free and clot-bound coagulation factors, low, non-specific binding, and no requirement for routine coagulation monitoring or dose adjustment. A number of novel, single-target oral anticoagulants have been developed that appear to fulfill many of these requirements. This narrative review discusses the use of guidelines and risk assessment tools to identify patients at risk

  20. Etravirine Pharmacokinetics In HIV-Infected Pregnant Women

    Directory of Open Access Journals (Sweden)

    Nikki Mulligan

    2016-08-01

    Full Text Available Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. Methods: IMPAACT P1026s and PANNA are on-going, nonrandomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12 or 24 hour pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 mcg/mL and 0.026 mcg/mL. Results: Fifteen women took etravirine 200 mg twice-daily dosing and one took 400 mg once-daily. Etravirine AUC0-12 was significantly higher in the 3rd trimester compared to paired postpartum data by 45% (median 8.3 mcg*hr/mL versus 5.7 mcg*hr/mL, p = 0.086. Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data (median 24 L/h versus 35 L/h, p = 0.038. The median ratio of cord blood to maternal plasma concentration at delivery was 0.56 (range: 0.19 - 4.25 and no perinatal transmission occurred. Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.

  1. Clinical role of brexpiprazole in depression and schizophrenia

    Science.gov (United States)

    Parikh, Nishant B; Robinson, Diana M; Clayton, Anita H

    2017-01-01

    Brexpiprazole, a serotonin–dopamine activity modulator, is the second D2 partial agonist to come to market and has been approved for the treatment of schizophrenia and as an adjunctive treatment in major depressive disorder. With less intrinsic activity than aripiprazole at the D2 receptor and higher potency at 5-HT2A, 5-HT1A, and α1B receptors, the pharmacological properties of brexpiprazole suggest a more tolerable side effect profile with regard to akathisia, extrapyramidal dysfunction, and sedation. While no head-to-head data are currently available, double-blind placebo-controlled studies show favorable results, with the number needed to treat (NNT) vs placebo of 6–15 for response in acute schizophrenia treatment and 4 for maintenance. NNT is 12 for response and 17–31 for remission vs placebo in major depression. In schizophrenia trials, treatment-emergent adverse effects (TEAEs) and discontinuation rates due to TEAEs were lower in treatment groups vs placebo (7.1%–9.2% vs 14.7%, respectively). Meanwhile, discontinuation rates due to TEAEs in depression studies were higher in treatment groups vs placebo (1.3%–3.5% vs 0–1.4%, respectively) and appeared dose dependent. Rates of akathisia are lower compared to those with aripiprazole and cariprazine, weight gain is more prominent than with aripiprazole, cariprazine, or ziprasidone, and sedation is less than with aripiprazole but more than with cariprazine. Brexpiprazole target dosing is 2–4 mg in schizophrenia and 2 mg in depression augmentation. Dose adjustments should be considered in hepatic or renal dysfunction and/or in poor cytochrome P450 2D6 metabolizers. While brexpiprazole represents an exciting second entry for D2 partial agonists with positive studies thus far, direct head-to-head comparisons will shed more light on the efficacy and side effect profile of brexpiprazole. PMID:28331332

  2. Pegvisomant bioavailability of single 30 mg/mL subcutaneous injection compared to two 15 mg/mL subcutaneous injections: a pharmacokinetic, safety and tolerability study.

    Science.gov (United States)

    Jen, Juif; LaBadie, Robert R; Liang, Yali; Crownover, Penelope H; Gao, Xiang; Hey-Hadavi, Juliana H

    2013-08-01

    The study was conducted to evaluate the pharmacokinetics (PK), relative bioavailability (relBA), safety and tolerability of two single-dose pegvisomant subcutaneous (SC) administrations: one injection of 30 mg/mL (1 × 30 mg/mL) versus two injections of two 15 mg/mL (2 × 15 mg/mL). This was a 2-period, single-dose, crossover study in 14 healthy male and female subjects. All subjects received both administrations during the two treatment periods separated by a two-week washout. Serum samples were collected intensively up to 360 h post injection and were assayed by a validated enzyme linked immunosorbent assay (ELISA) for pegvisomant. PK parameters including AUC and Cmax were derived by noncompartmental analyses. Mixed effects model was used to obtain bioavailability estimates. Safety and tolerability were assessed by clinical monitoring, including adverse events, laboratory assessments and injection site reactions. All subjects completed the study. The relBA of 1 × 30 mg/mL relative to 2 × 15 mg/mL was 123.89% with a 90% CI (112.91-135.93%). Adjusted for the difference in actual pegvisomant amounts in both formulations the dose-adjusted relBA reduced to 112.97% with a 90% CI (103.09-123.80%). Single injection with a higher drug concentration in injection solution might have a role in this 13% higher bioavailability for 1 × 30 mg/mL administration. Other PK parameters for the two administrations were comparable. No laboratory abnormalities, vital signs, ECG, or injection site reactions of clinical concern were observed in either treatment. Comparable BA, safety and tolerability of the new 30 mg/mL strength to the currently marketed 15 mg/mL strength were established in this study. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Impact of Cyclosporine Levels on the Development of Acute Graft versus Host Disease after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Irene García Cadenas

    2014-01-01

    Full Text Available We analyze the impact of cyclosporine (CsA levels in the development of acute graft-versus-host disease (aGVHD after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC. We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10–444, 219 (54–656, 253 (53–910 and 224 (30–699 ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2–4 aGVHD for a cumulative incidence of 45% (95% CI 34–50% at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P=0.02 and development of grade 2–4 aGVHD (HR: 2.5, P<0.01, while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P=0.06. These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

  4. Detection and management of medication errors in internal wards of a teaching hospital by clinical pharmacists.

    Science.gov (United States)

    Abbasinazari, Mohammad; Hajhossein Talasaz, Azita; Eshraghi, Azadeh; Sahraei, Zahra

    2013-08-07

    Any suboptimum treatment in the management of patients can lead to medication errors (MEs) that may increase morbidity and mortality in hospitalized individuals. By establishing well-designed patient care activities within the managed care setting, clinical pharmacists can cooperate with other health care professionals to provide quality care and maximize safety. The aim of this study was to evaluate the frequency and prevention of MEs by clinical pharmacists. This was a cross-sectional interventional study conducted in internal wards of a teaching hospital during a two-month period. During this period, patient records, and physician orders were reviewed by clinical pharmacists. Any prescription error identified was documented. Incorrect drug selection, dose, dosage form, frequency, or route of administration all were considered as medication errors. Then, the clinical pharmacist discuss about findings with the clinical fellows to change faulty orders. The frequency and types of MEs in different wards that were detected and prevented by clinical pharmacists was documented. During the study period, in 132 patients, 262 errors were detected (1.98 per each). Wrong frequency 71 (27%), forget to order 37 (14.1%), wrong selection 33 (12.5%), drug interactions 26 (9.9%), forget to discontinue 25 (9.5%) and inappropriate dose adjustment in renal impairment 25 (9.5%) were the most types of errors. Cardiovascular medications were the class with the highest detected errors (31.6%) followed by gastrointestinal agents (15.6%). Medication errors are common problems in medical wards that their frequency can be restricted by the intervention of clinical pharmacists.

  5. Detection and management of medication errors in internal wards of a teaching hospital by clinical pharmacists.

    Directory of Open Access Journals (Sweden)

    Mohammad Abbasinazari

    2013-07-01

    Full Text Available Any suboptimum treatment in the management of patients can lead to medication errors (MEs that may increase morbidity and mortality in hospitalized individuals. By establishing well-designed patient care activities within the managed care setting, clinical pharmacists can cooperate with other health care professionals to provide quality care and maximize safety. The aim of this study was to evaluate the frequency and prevention of MEs by clinical pharmacists. This was a cross-sectional interventional study conducted in internal wards of a teaching hospital during a two-month period. During this period, patient records, and physician orders were reviewed by clinical pharmacists. Any prescription error identified was documented. Incorrect drug selection, dose, dosage form, frequency, or route of administration all were considered as medication errors. Then, the clinical pharmacist discuss about findings with the clinical fellows to change faulty orders. The frequency and types of MEs in different wards that were detected and prevented by clinical pharmacists was documented. During the study period, in 132 patients, 262 errors were detected (1.98 per each. Wrong frequency 71 (27%, forget to order 37 (14.1%, wrong selection 33 (12.5%, drug interactions 26 (9.9%, forget to discontinue 25 (9.5% and inappropriate dose adjustment in renal impairment 25 (9.5% were the most types of errors. Cardiovascular medications were the class with the highest detected errors (31.6% followed by gastrointestinal agents (15.6%. Medication errors are common problems in medical wards that their frequency can be restricted by the intervention of clinical pharmacists.

  6. Impact of clinical pharmacist in an Indian Intensive Care Unit.

    Science.gov (United States)

    Hisham, Mohamed; Sivakumar, Mudalipalayam N; Veerasekar, Ganesh

    2016-02-01

    A critically ill patient is treated and reviewed by physicians from different specialties; hence, polypharmacy is a very common. This study was conducted to assess the impact and effectiveness of having a clinical pharmacist in an Indian Intensive Care Unit (ICU). It also evaluates the clinical pharmacist interventions with a focus on optimizing the quality of pharmacotherapy and patient safety. The prospective, observational study was carried out in medical and surgical/trauma ICU over a period of 1 year. All detected drug-related problems and interventions were categorized based on the Pharmaceutical Care Network Europe system. During the study period, average monthly census of 1032 patients got treated in the ICUs. A total of 986 pharmaceutical interventions due to drug-related problems were documented, whereof medication errors accounted for 42.6% (n = 420), drug of choice problem 15.4% (n = 152), drug-drug interactions were 15.1% (n = 149), Y-site drug incompatibility was 13.7% (n = 135), drug dosing problems were 4.8% (n = 47), drug duplications reported were 4.6% (n = 45), and adverse drug reactions documented were 3.8% (n = 38). Drug dosing adjustment done by the clinical pharmacist included 140 (11.9%) renal dose, 62 (5.2%) hepatic dose, 17 (1.4%) pediatric dose, and 104 (8.8%) insulin dosing modifications. A total of 577 drug and poison information queries were answered by the clinical pharmacist. Clinical pharmacist as a part of multidisciplinary team in our study was associated with a substantially lower rate of adverse drug event caused by medication errors, drug interactions, and drug incompatibilities.

  7. Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers.

    Science.gov (United States)

    Cho, Doo-Yeoun; Bae, Soo Hyeon; Lee, Joeng Kee; Park, Jung Bae; Kim, Yang-Weon; Lee, Sukhyang; Oh, Euichaul; Kim, Bom-Taeck; Bae, Soo Kyung

    2015-03-01

    1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

  8. Liver volume in thalassaemia major: relationship with body weight, serum ferritin, and liver function

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    Chan Yuleung; Law Manyee; Howard, Robert [Chinese University of Hong Kong, Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, Hong Kong (China); Li Chikong; Chik Kiwai [Chinese University of Hong Kong, Department of Paediatrics, Prince of Wales Hospital, Hong Kong (China)

    2005-02-01

    It is not known whether body weight alone can adjust for the volume of liver in the calculation of the chelating dose in {beta}-thalassaemia major patients, who frequently have iron overload and hepatitis. The hypothesis is that liver volume in children and adolescents suffering from {beta}-thalassaemia major is affected by ferritin level and liver function. Thirty-five {beta}-thalassaemia major patients aged 7-18 years and 35 age- and sex-matched controls had liver volume measured by MRI. Serum alanine aminotransferase (ALT) and ferritin levels were obtained in the thalassaemia major patients. Body weight explained 65 and 86% of the change in liver volume in {beta}-thalassaemia major patients and age-matched control subjects, respectively. Liver volume/kilogram body weight was significantly higher (P<0.001) in thalassaemia major patients than in control subjects. There was a significant correlation between ALT level and liver volume/kilogram body weight (r=0.55, P=0.001). Patients with elevated ALT had significantly higher liver volume/kilogram body weight (mean 42.9{+-}12 cm{sup 3}/kg) than control subjects (mean 23.4{+-}3.6 cm{sup 3}/kg) and patients with normal ALT levels (mean 27.4{+-}3.6 cm{sup 3}/kg). Body weight is the most important single factor for liver-volume changes in thalassaemia major patients, but elevated ALT also has a significant role. Direct liver volume measurement for chelation dose adjustment may be advantageous in patients with elevated ALT. (orig.)

  9. High Variability of Plasma Drug Concentrations in Dual Protease Inhibitor Regimens

    Science.gov (United States)

    Guiard-Schmid, Jean-Baptiste; Poirier, Jean-Marie; Meynard, Jean-Luc; Bonnard, Philippe; Gbadoe, Ayi Hola; Amiel, Corinne; Calligaris, Frédérique; Abraham, Bruno; Pialoux, Gilles; Girard, Pierre-Marie; Jaillon, Patrice; Rozenbaum, Willy

    2003-01-01

    Ritonavir (RTV) strongly increases the concentrations of protease inhibitors (PIs) in plasma in patients given a combination of RTV and another PI. This pharmacological interaction is complex and poorly characterized and shows marked inter- and intraindividual variations. In addition, RTV interacts differently with saquinavir (SQV), indinavir (IDV), amprenavir (APV), and lopinavir (LPV). In this retrospective study on 542 human immunodeficiency virus-infected patients, we compared inter- and intraindividual variability of plasma PI concentrations and correlations between the Cmin (minimum concentration of drug in plasma) values for RTV and the coadministered PI Cmin values. Mean RTV Cmins are significantly lower in patients receiving combinations containing APV or LPV than in combinations with SQV or IDV. With the most common PI dose regimens (600 mg of IDV twice a day [BID], 800 mg of SQV BID, and 400 mg of LPV BID), the interindividual Cmin variability of patients treated with a PI and RTV seemed to be lower with APV and LPV than with IDV and SQV. As regards intraindividual variability, APV also differed from the other PIs, exhibiting lower Cmin variability than with the other combinations. Significant positive correlations between RTV Cmin and boosted PI Cmin were observed with IDV, SQV, and LPV, but not with APV. Individual dose adjustments must take into account the specificity the pharmacological interaction of each RTV/PI combination and the large inter- and intraindividual variability of plasma PI levels to avoid suboptimal plasma drug concentrations which may lead to treatment failure and too high concentrations which may induce toxicity and therefore reduce patient compliance. PMID:12604531

  10. Lack of regulation of 11beta-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism.

    Science.gov (United States)

    Sigurjonsdottir, Helga A; Andrew, Ruth; Stimson, Roland H; Johannsson, Gudmundur; Walker, Brian R

    2009-09-01

    Evidence from long-term clinical studies measuring urinary steroid ratios, and from in vitro studies, suggests that GH administered for longer than 2 months down-regulates 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11beta-HSD1 in liver and adipose tissue in vivo, including using a stable isotope tracer. Observational studies of GH withdrawal and reintroduction in patients with hypopituitarism. Twelve men with benign pituitary disease causing GH and ACTH deficiency on stable replacement therapy for >6 months were studied after GH withdrawal for 3 weeks, and after either placebo or GH injections were reintroduced for another 3 weeks. We measured cortisol kinetics during 9,11,12,12-(2)H(4)-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11beta-HSD1 by appearance of plasma cortisol after oral cortisone, and 11beta-HSD1 mRNA levels in subcutaneous adipose biopsies. GH withdrawal and reintroduction had no effect on 9,12,12-[(2)H](3)-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11beta-HSD1 mRNA. GH withdrawal increased plasma cortisol 30-180 min after oral cortisone, increased d4-cortisol clearance, and decreased relative excretion of 5alpha-reduced cortisol metabolites. In this setting, GH did not regulate 11beta-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11beta-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11beta-HSD1 activity, although dose adjustment may be required in the longer term.

  11. The Total Inotrope Exposure Score: an extension of the Vasoactive Inotrope Score as a predictor of adverse outcomes after paediatric cardiac surgery.

    Science.gov (United States)

    Bangalore, Harish; Gaies, Michael; Ocampo, Elena C; Heinle, Jeffrey S; Guffey, Danielle; Minard, Charles G; Checchia, Paul; Shekerdemian, Lara S

    2017-08-01

    The aim of the present study was to explore and compare the association between a new vasoactive score - the Total Inotrope Exposure Score - and outcome and the established Vasoactive Inotrope Score in children undergoing cardiac surgery with cardiopulmonary bypass DESIGN: The present study was a single-centre, retrospective study. The study was carried out at a 21-bed cardiovascular ICU in a Tertiary Children's Hospital between September, 2010 and May, 2011 METHODS: The Total Inotrope Exposure Score is a new vasoactive score that brings together cumulative vasoactive drug exposure and incorporates dose adjustments over time. The performance of these scores - average, maximum Vasoactive Inotrope Score at 24 and 48 hours, and Total Inotrope Exposure Score - to predict primary clinical outcomes - either death, cardiopulmonary resuscitation, or extra-corporeal membrane oxygenation before hospital discharge - and secondary outcomes - length of invasive mechanical ventilation, length of ICU stay, and hospital stay - was calculated. Main results The study cohort included 167 children under 18 years of age, with 37 (22.2%) neonates and 65 (41.3%) infants aged between 1 month and 1 year. The Total Inotrope Exposure Score best predicted the primary outcome (six of 167 cases) with an unadjusted odds ratio for a poor outcome of 42 (4.8, 369.6). Although the area under curve was higher than other scores, this difference did not reach statistical significance. The Total Inotrope Exposure Score best predicted prolonged invasive mechanical ventilation, length of ICU stay, and hospital stay as compared with the other scores. The Total Inotrope Exposure Score appears to have a good association with poor postoperative outcomes and warrants prospective validation across larger numbers of patients across institutions.

  12. Clinical outcomes of the inclusion of the therapeutic drug monitoring report in the electronic clinical record

    Directory of Open Access Journals (Sweden)

    Marina Sáez Belló

    2016-12-01

    Full Text Available Objectives: To assess the inclusion of the Therapeutic Drug Monitoring Report (TDMR in the Electronic Clinical Record (ECR. Method: An observational ambispective cohort study with a duration of 149 days: PRE (retrospective, 49 days with the TDMR printed in paper, and POST (prospective, 100 days with the TDMR included in the ECR. Exclusion criteria: Patients not hospitalized, applications for Therapeutic Drug Monitoring by Critical Care and Neonatal Units, as well as monitoring with an objective other than dose adjustment. Variables: Number of TDMRs prepared, number of patients admitted with TDMR, time of delay for treatment adjustment, defined as the number of adjustments made to the treatment within over or under 24 hours from the time of TDMR preparation, and medication errors (MEs associated with said delay, as well as the degree of acceptance of the TDMR. Results: 690 TDMRs were conducted in 391 patients, 339 in PRE (n = 206 and 351 in POST (n = 185. The number of treatment modifications made in under 24 hours increased from 73.9% in PRE to 87.3% in POST [RR = 1.2 (CI95% = 0.97-1.43. We identified 35 patients with ME, 9.7% of them in PRE and 8.1% in POST (RR = 0.84 (CI95% = 0.44-1.58]. The degree of acceptance of the pharmacist recommendation increased from 53.3% in PRE to 68.3% in POST [RR = 1.3 (CI95% = 1.02- 1.62]. Conclusions: The inclusion of the Therapeutic Drug Monitoring Report (TDMR in the Electronic Clinical Record increases the degree of acceptance of recommendations, and may reduce the delay in treatment modifications, reducing MEs and improving the process quality in terms of efficacy and safety

  13. Etravirine Pharmacokinetics in HIV-Infected Pregnant Women

    Science.gov (United States)

    Mulligan, Nikki; Schalkwijk, Stein; Best, Brookie M.; Colbers, Angela; Wang, Jiajia; Capparelli, Edmund V.; Moltó, José; Stek, Alice M.; Taylor, Graham; Smith, Elizabeth; Hidalgo Tenorio, Carmen; Chakhtoura, Nahida; van Kasteren, Marjo; Fletcher, Courtney V.; Mirochnick, Mark; Burger, David

    2016-01-01

    Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred. Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. Clinical Trial registration: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929. PMID:27540363

  14. Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives.

    Science.gov (United States)

    Tittle, Victoria; Bull, Lauren; Boffito, Marta; Nwokolo, Nneka

    2015-01-01

    More than 50 % of women living with HIV in low- and middle-income countries are of reproductive age, but there are limitations to the administration of oral contraception for HIV-infected women receiving antiretroviral therapy due to drug-drug interactions caused by metabolism via the cytochrome P450 isoenzymes and glucuronidation. However, with the development of newer antiretrovirals that use alternative metabolic pathways, options for contraception in HIV-positive women are increasing. This paper aims to review the literature on the pharmacokinetics and pharmacodynamics of oral hormonal contraceptives when given with antiretroviral agents, including those currently used in developed countries, older ones that might still be used in salvage regimens, or those used in resource-limited settings, as well as newer drugs. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), the usual backbone to most combined antiretroviral treatments (cARTs) are characterised by a low potential for drug-drug interactions with oral contraceptives. On the other hand non-NRTIs (NNRTIs) and protease inhibitors (PIs) may interact with oral contraceptives. Of the NNRTIs, efavirenz and nevirapine have been demonstrated to cause drug-drug interactions; however, etravirine and rilpivirine appear safe to use without dose adjustment. PIs boosted with ritonavir are not recommended to be used with oral contraceptives, with the exception of boosted atazanavir which should be used with doses of at least 35 µg of estrogen. Maraviroc, an entry inhibitor, is safe for co-administration with oral contraceptives, as are the integrase inhibitors (INIs) raltegravir and dolutegravir. However, the INI elvitegravir, which is given in combination with cobicistat, requires a dose of estrogen of at least 30 µg. Despite the growing evidence in this field, data are still lacking in terms of large cohort studies, randomised trials and correlations to real clinical outcomes, such as pregnancy rates, in women

  15. Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

    Science.gov (United States)

    Borland, Julie; Chen, Shuguang; Peppercorn, Amanda; Wajima, Toshihiro; Piscitelli, Stephen C.

    2014-01-01

    Dolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established “no-effect” boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier NCT01209065.) PMID:25155604

  16. The Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor.

    Science.gov (United States)

    Caro, Luzelena; Wenning, Larissa; Guo, Zifang; Fraser, Iain P; Fandozzi, Christine; Talaty, Jennifer; Panebianco, Deborah; Ho, Maureen; Uemura, Naoto; Reitmann, Christina; Angus, Peter; Gane, Edward; Marbury, Thomas; Smith, William B; Iwamoto, Marian; Butterton, Joan R; Yeh, Wendy W

    2017-09-25

    Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic hepatitis C virus (HCV) genotype 1 or 4 infection. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR 200, 100, and 50 mg in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, versus healthy matched controls (Protocol MK-5172_p013). Participants with mild, moderate, or severe HI and race-, age-, sex-, and body mass index--matched controls (aged 18-65 years) were enrolled in a 3-part, open-label, sequential-panel, pharmacokinetic study. Participants received multiple oral doses of 200 (2×100-mg tablets), 100 (1×100-mg tablet), or 50 mg (2×25-mg tablets) GZR once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls per hepatic cohort. Participants with HI demonstrated higher GZR exposure compared with healthy matched controls, and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0-24 in participants with mild, moderate, or severe HI was ≈2-, ≈5-, and ≈12-fold higher, respectively, than healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated in those with moderate or severe HI (Child-Pugh B or C), as they may have significantly increased GZR exposures that may lead to increased risk of transaminase elevations. Copyright © 2017 American Society for Microbiology.

  17. Teneligliptin in management of type 2 diabetes mellitus.

    Science.gov (United States)

    Sharma, Surendra Kumar; Panneerselvam, A; Singh, K P; Parmar, Girish; Gadge, Pradeep; Swami, Onkar C

    2016-01-01

    Teneligliptin is a recently developed oral dipeptidyl peptidase 4 inhibitor indicated for the management of type 2 diabetes mellitus (T2DM) in adults along with diet and exercise. Teneligliptin has been recently available in Japan (Teneria(®)), Argentina (Teneglucon(®)), and India (Tenepure; Teneza) at relatively affordable price. This is a positive step toward the management of T2DM in developing countries, where the cost of medicine is out-of-pocket expenditure and is a limiting factor for health care. This review evaluates the efficacy and safety of teneligliptin in the management of T2DM. Teneligliptin has been systematically evaluated in T2DM as monotherapy with diet and exercise and in combination with metformin, glimepiride, pioglitazone, and insulin in short-term (12 weeks) and long-term (52 weeks) studies. These studies have reported a reduction in HbA1c of 0.8%-0.9% within 12 weeks of therapy. Two 52-week studies reported sustained improvement in glycemic control with teneligliptin. Teneligliptin has been found to be well tolerated, and the safety profile is similar to other dipeptidyl peptidase 4 inhibitors. Hypoglycemia and constipation are the main adverse events. Teneligliptin can be administered safely to patients with mild, moderate, or severe renal impairment or end-stage renal disease without dose adjustment. Similarly, it can be used in patients with mild-to-moderate hepatic impairment. Teneligliptin is effective and well tolerated and may have an important role in the management of T2DM.

  18. Managing treatment-related peripheral neuropathy in patients with multiple myeloma

    Directory of Open Access Journals (Sweden)

    Grammatico S

    2016-06-01

    Full Text Available Sara Grammatico, Laura Cesini, Maria Teresa Petrucci Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy Abstract: Peripheral neuropathy is one of the most important complications of multiple myeloma treatment. Neurological damage can be observed at the onset of the disease, due to the effect of monoclonal protein or radicular compression, but more often is treatment related. Vinca alkaloids in the past era, and more recently, thalidomide and bortezomib are mainly responsible. Degeneration of dorsal root ganglion is common, prevalently related to angiogenesis inhibition and cytokine modulation in the case of thalidomide and inhibition of the ubiquitin proteasome system in the case of bortezomib. Sensory neuropathy and neuropathic pain are more common; motor neuropathy and autonomic damage are less frequently observed. Neurotoxicity often affects patient's quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, alcohol abuse, vitamin deficiencies, or viral infections and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Effective management of treatment at the emergence of peripheral neuropathy can minimize the incidence and severity of this complication and preserve therapeutic efficacy. Dose adjustment could be necessary during treatment; moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics are suggested according to the pain severity. Some authors reported that patients who develop peripheral neuropathy during their multiple myeloma treatments presented a particular gene expression profile; therefore, future studies could be helpful for a better understanding of possible

  19. Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I.

    Science.gov (United States)

    Giugliani, Roberto; Vieira, Taiane Alves; Carvalho, Clarissa Gutierrez; Muñoz-Rojas, Maria-Veronica; Semyachkina, Alla N; Voinova, Victoria Y; Richards, Susan; Cox, Gerald F; Xue, Yong

    2017-03-01

    Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058-0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment.

  20. A 2016 clinical practice pattern in the management of primary hypothyroidism among doctors from different clinical specialties in New Delhi

    Science.gov (United States)

    Surana, Vineet; Aggarwal, Sameer; Khandelwal, Deepak; Singla, Rajiv; Bhattacharya, Saptarshi; Chittawar, Sachin; Kalra, Sanjay; Dutta, Deep

    2017-01-01

    Background: This study aimed to document practices in managing hypothyroidism among doctors in New Delhi, with special focus on subclinical hypothyroidism, pregnancy, and old age, and to compare it with global practices. Methods: During an academic program attended by 394 doctors, all participants were given a questionnaire designed based on thyroid practices survey done by Burch et al. to evaluate the practice patterns. Questions were based on evaluating doctor's preferred choices in diagnosis, therapy, and follow-up of hypothyroidism in different scenarios. Results: Responses from 308 questionnaires (general physicians [n = 204], obstetricians [n = 51], pediatricians [n = 27], surgeons [n = 12], endocrinologists [n = 10], and others [n = 4]) were analyzed. In the evaluation of 52-year-old female patient with primary hypothyroidism, 52% doctors would prefer thyroid ultrasonography, comparable to global rates. Nearly 96.1% doctors would have initiated levothyroxine, with a large majority of doctors (83.77%) preferred using branded levothyroxine. About 58.74% doctors preferred gradual restoration of euthyroidism. Levothyroxine dose of 25 mcg was the most preferred increment dose (46.07%) during follow-up, with 6 weekly being the most frequent dose adjustment frequency (41.57%). Most preferred target thyroid-stimulating hormone (TSH) in the 52-year-old female patient was 2.5–4.99 mU/L (63.96%), 25-year-old female patient was 1–2.49 mU/L (53.90%), and in 85-year-old female was 2.5–4.99 mU/L (45.45%). Only 68% of doctors in our study preferred keeping TSH branded levothyroxine, widespread use of age-specific TSH targets, and low threshold for treating mild thyroid failure, a highly variable approach to both rates and means of restoring euthyroidism for overt primary hypothyroidism. There is a need for spreading awareness regarding TSH targets in pregnancy. PMID:28217518

  1. Balloon coating with rapamycin using an on-site coating device.

    Science.gov (United States)

    Schmehl, Jörg; von der Ruhr, Jürgen; Dobratz, Markus; Kehlbach, Rainer; Braun, Isabelle; Greiner, Tim-Oliver; Claussen, Claus D; Behnisch, Boris

    2013-06-01

    The efficacy of drug-eluting balloons has been demonstrated in clinical trials. The drug predominantly used is paclitaxel because of its lipophilic properties and the rapid onset of action. The aim of the investigation was to evaluate the feasibility and efficacy of an alternative balloon coating with rapamycin that can be applied on site. The balloon coating (3.0/18 and 3.0/12 mm, Cathy No. 4, Translumina GmbH) with rapamycin was conducted with a coating machine (Translumina GmbH). Concentrations were 2, 2 × 2, 3, and 4 %. Measurements regarding the amount of substance released to the vessel wall were carried out on explanted porcine coronaries by means of ultraviolet and visible-light spectroscopy. Inflation time varied between 30 and 120 s. The biological effect of the coating was evaluated in a porcine peripheral overstretch and stent implantation model. The amount of rapamycin on the balloon surface ranged from 558 ± 108 μg for the 2 % solution to 1,441 ± 228 μg in the 4 % solution. An amount of 95 ± 63-193 ± 113 μg was released into the vessel wall. The quantitative measurements of the angiographic examinations 4 weeks after treatment revealed a reduction of diameter stenosis from 20.6 ± 17.4 % in the control group to 11.6 ± 5.5 % in the drug-eluting balloon group. A balloon coating with rapamycin omitting an excipient is possible with a dose-adjustable coating machine. However, the biological effects are moderate, which make further optimization of the coating process and evaluation of appropriate excipients necessary.

  2. PLEIOTROPIC EFFECTS OF PARATHYROIDECTOMY AND AGONIST CALCIUM-SENSITIVE RECEPTOR, CINACALCET

    Directory of Open Access Journals (Sweden)

    L. V. Egshatyan

    2015-09-01

    Full Text Available Aim. To evaluate the effect of parathyroidectomy and cinacalcet on anemia, lipid profile and blood pressure (BP in uremic hyperparathyroidism.Material and methods. Uremic patients (n=39 treated with hemodialysis and having secondary hyperparathyroidism were included into the study. Radical parathyroidectomy was performed in 21 patients, 18 patients were treated with cinacalcet. BP measurement, determination of blood levels of albumin, total calcium, phosphorus, total cholesterol (TC, low (LDL and high density lipoproteins, triglycerides, intact parathyroid hormone, and hemoglobin were performed in all patients initially and during treatment. Doses of antihypertensive and erythropoiesis-stimulating agents were also assessed.Results. Calcium-phosphorus metabolism indices improved after 6 months of cinacalcet therapy and parathyroidectomy (p<0.05. BP reduction not requiring antihypertensive drugs dose adjustment was found in patients treated with cinacalcet. Significant BP reduction (p<0.05 was observed after parathyroidectomy and it required antihypertensive drugs cancellation or dose lowering. Cinacalcet therapy and parathyroidectomy led to increase in hemoglobin level by 2.02% (p=0.143 and 7.6% (p=0.029, respectively, as well as reduction in weekly dose of erythropoiesis-stimulating drugs by 2.7% (p=0.875 and 8.9% (p=0.751, respectively. Significant (p<0.05 decrease in LDL (5.6%, and triglycerides (23.7% levels was found in patients treated with cinacalcet. Reduction (p<0.05 in total cholesterol (1.4% and LDL (4.3% levels was observed after parathyroidectomy.Conclusion. The pleiotropic effects (reduction in BP and atherogenic lipids levels, as well as decrease in anemia resistant to the action of erythropoiesis-stimulating agents were found after parathyroidectomy and cinacalcet therapy additionally to calcium-phosphorus metabolism improvement.

  3. PLEIOTROPIC EFFECTS OF PARATHYROIDECTOMY AND AGONIST CALCIUM-SENSITIVE RECEPTOR, CINACALCET

    Directory of Open Access Journals (Sweden)

    L. V. Egshatyan

    2013-01-01

    Full Text Available Aim. To evaluate the effect of parathyroidectomy and cinacalcet on anemia, lipid profile and blood pressure (BP in uremic hyperparathyroidism.Material and methods. Uremic patients (n=39 treated with hemodialysis and having secondary hyperparathyroidism were included into the study. Radical parathyroidectomy was performed in 21 patients, 18 patients were treated with cinacalcet. BP measurement, determination of blood levels of albumin, total calcium, phosphorus, total cholesterol (TC, low (LDL and high density lipoproteins, triglycerides, intact parathyroid hormone, and hemoglobin were performed in all patients initially and during treatment. Doses of antihypertensive and erythropoiesis-stimulating agents were also assessed.Results. Calcium-phosphorus metabolism indices improved after 6 months of cinacalcet therapy and parathyroidectomy (p<0.05. BP reduction not requiring antihypertensive drugs dose adjustment was found in patients treated with cinacalcet. Significant BP reduction (p<0.05 was observed after parathyroidectomy and it required antihypertensive drugs cancellation or dose lowering. Cinacalcet therapy and parathyroidectomy led to increase in hemoglobin level by 2.02% (p=0.143 and 7.6% (p=0.029, respectively, as well as reduction in weekly dose of erythropoiesis-stimulating drugs by 2.7% (p=0.875 and 8.9% (p=0.751, respectively. Significant (p<0.05 decrease in LDL (5.6%, and triglycerides (23.7% levels was found in patients treated with cinacalcet. Reduction (p<0.05 in total cholesterol (1.4% and LDL (4.3% levels was observed after parathyroidectomy.Conclusion. The pleiotropic effects (reduction in BP and atherogenic lipids levels, as well as decrease in anemia resistant to the action of erythropoiesis-stimulating agents were found after parathyroidectomy and cinacalcet therapy additionally to calcium-phosphorus metabolism improvement.

  4. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

    Science.gov (United States)

    Scheen, André J

    2015-07-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results

  5. Overnight switch from ropinirole to transdermal rotigotine patch in patients with Parkinson disease

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    Kim Han-Joon

    2011-08-01

    Full Text Available Abstract Background A recent trial involving predominantly Caucasian subjects with Parkinson Disease (PD showed switching overnight from an oral dopaminergic agonist to the rotigotine patch was well tolerated without loss of efficacy. However, no such data have been generated for Korean patients. Methods This open-label multicenter trial investigated PD patients whose symptoms were not satisfactorily controlled by ropinirole, at a total daily dose of 3 mg to 12 mg, taken as monotherapy or as an adjunct to levodopa. Switching treatment from oral ropinirole to transdermal rotigotine was carried out overnight, with a dosage ratio of 1.5:1. After a 28-day treatment period, the safety and tolerability of switching was evaluated. Due to the exploratory nature of this trial, the effects of rotigotine on motor and nonmotor symptoms of PD were analyzed in a descriptive manner. Results Of the 116 subjects who received at least one treatment, 99 (85% completed the 28-day trial period. Dose adjustments were required for 11 subjects who completed the treatment period. A total of 76 treatment-emergent adverse events (AEs occurred in 45 subjects. No subject experienced a serious AE. Thirteen subjects discontinued rotigotine prematurely due to AEs. Efficacy results suggested improvements in both motor and nonmotor symptoms and quality of life after switching. Fifty-two subjects (46% agreed that they preferred using the patch over oral medications, while 31 (28% disagreed. Conclusions Switching treatment overnight from oral ropinirole to transdermal rotigotine patch, using a dosage ratio of 1.5:1, was well tolerated in Korean patients with no loss of efficacy. Trial registration This trial is registered with the ClincalTrails.gov Registry (NCT00593606.

  6. Comparison of predictive accuracy of teicoplanin concentration using creatinine clearance and glomerular filtration rate estimated by serum creatinine or cystatin C.

    Science.gov (United States)

    Kozono, Aki; Hiraki, Yoichi; Adachi, Rui; Nagano, Masahisa; Inoue, Daisuke; Tsuji, Yasuhiro; Kamimura, Hidetoshi; Karube, Yoshiharu

    2016-05-01

    We compared the predictive accuracy of TEIC concentrations (TEIC_conc) calculated using either serum cystatin C (CysC) or serum creatinine (SCr) and the population mean method using the mean population parameter of TEIC_conc for Japan. We also compared the predicted TEIC_conc to measured TEIC_conc. Creatinine clearance (CLCr) predicted using the Cockcroft-Gault (C&G) equation with SCr was 45.23 mL/min (interquartile range [IQR]: 32.12-58.28), and the glomerular filtration rate (GFR) predicted using the Hoek equation with CysC was 45.23 mL/min (IQR: 35.40-53.79). The root mean-squared prediction error (IQR) based on CLCr predicted using the C&G equation with SCr was 6.88 (3.80-9.96) μg/mL, and that based on GFR predicted using the Hoek equation with CysC was 6.72 (3.77-9.68) μg/mL. Predicted TEIC_conc did not differ significantly between the two methods. The predictive accuracy of the TEIC_conc using the Hoek equation with CysC was similar to that of CLCr using the C&G equation with SCr. These findings suggest that the predictive accuracy of the TEIC_conc using CLCr based on the G&G equation and SCr might be sufficient for the initial dose adjustment of TEIC. Given that we were unable to confirm that CysC is the optimal method for predicting TEIC_conc, the expensive measurement of CysC might not be necessary.

  7. A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery.

    Science.gov (United States)

    Gaudreault, François; Drolet, Pierre; Fallaha, Michel; Varin, France

    2012-12-01

    Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93 h after a 100 mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 0.65 h). Interindividual variability (IIV) for these parameters, 58 and 9 %, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F = 77.2 ± 11.5 L, IIV = 26 %) was influenced by body weight (Δ 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 ± 1.0 L/h, 34  IIV = 34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.

  8. A designated centre for people with disabilities operated by St Catherine's Association Limited, Wicklow

    LENUS (Irish Health Repository)

    Casey, Dympna

    2011-08-30

    Abstract Background The literature reveals that structured education programmes, such as DAFNE, result in many positive outcomes for people with Type 1 diabetes including a decrease in HbA1c levels and reductions in hypoglycaemia. While there is evidence that some of these outcomes are maintained we do not know at present what factors are most important over time. The study aim was to identify the key factors impacting on persons with Type 1 diabetes ability to assimilate the Dose Adjustment For Normal Eating (DAFNE) DAFNE principles into their daily lives and how these factors change over time. Methods This is a longitudinal descriptive qualitative study. Interviews were undertaken with 40 participants who had attended DAFNE in one of 5 study sites across the Island of Ireland, at 6 weeks, 6 and 12 months after completion of the programme. The interviews lasted from 30 to 60 minutes and were transcribed verbatim. Data were analysed in three ways, a within time analysis, a cross sectional analysis for each participant and a thematic analysis which focused on examining changes over time Results Four themes that influenced participants\\' ability to assimilate DAFNE into their daily lives over time were identified. These were: embedded knowledge, continued responsive support, enduring motivation and being empowered. Support at the 6 month period was found to be crucial to continued motivation. Conclusions Understanding the factors that influence people\\'s ability to assimilate DAFNE principles over time into their daily lives can help health professionals give focused responsive support that helps people with diabetes become more empowered. Understanding that continued support matters, particularly around 6 months, is important as health professionals can influence good management by providing appropriate support and enhancing motivation. Trial registration ISRCTN79759174

  9. A systematic review of the efficacy and safety experience reported for sorafenib in advanced renal cell carcinoma (RCC in the post-approval setting.

    Directory of Open Access Journals (Sweden)

    Mayer N Fishman

    Full Text Available Sorafenib was FDA approved in 2005 for treatment of renal cell carcinoma (RCC based on the results of the pivotal phase 3 clinical trial, TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial. Since that time, numerous clinical studies have been undertaken that substantially broaden our knowledge of the use of sorafenib for this indication.We systematically reviewed PubMed, Web of Science, Embase, Cochrane Library, and www.clinicaltrials.gov for prospective clinical studies using single agent sorafenib in RCC and published since 2005. Primary endpoints of interest were progression-free survival (PFS and safety. PROSPERO International prospective register of systematic reviews #CRD42014010765.We identified 30 studies in which 2182 patients were treated with sorafenib, including 1575 patients who participated in randomized controlled phase 3 trials. In these trials, sorafenib was administered as first-, second- or third-line treatment. Heterogeneity among trial designs and reporting of data precluded statistical comparisons among trials or with TARGET. The PFS appeared shorter in second- vs. first-line treatment, consistent with the more advanced tumor status in the second-line setting. In some trials, incidences of grade 3/4 hypertension or hand-foot skin reaction (HFSR were more than double that seen in TARGET (4% and 6%, respectively. These variances may be attributable to increased recognition of HFSR, or potentially differences in dose adjustments, that could be consequences of increased familiarity with sorafenib usage. Several small studies enrolled exclusively Asian patients. These studies reported notably longer PFS than was observed in TARGET. However, no obvious corresponding differences in disease control rate and overall survival were seen.Collectively, more recent experiences using sorafenib in RCC are consistent with results reported for TARGET with no marked changes of response endpoints or new safety signals

  10. Pharmacokinetics of conivaptan use in patients with severe hepatic impairment

    Science.gov (United States)

    Marbury, Thomas; Fox, Jerry; Kaelin, Byron; Pavliv, Leo

    2017-01-01

    Purpose Conivaptan is an intravenous dual V1A/V2 vasopressin antagonist approved for the treatment of euvolemic and hypervolemic hyponatremia. Earlier studies showed that patients with moderate liver disease could be safely treated with conivaptan by reducing the dose by 50%, whereas patients with mild hepatic impairment needed no dose adjustment. The objective of this Phase 1, open-label study was to assess the pharmacokinetics, protein binding, and safety of 48 h of conivaptan infusion in individuals with severe hepatic impairment. Patients and methods Eight subjects with severe hepatic impairment (Child–Pugh score 10–15) and nine subjects with normal liver function were enrolled. Intravenous conivaptan (20 mg) was given as a 30 min loading dose on Day 1 followed by two consecutive 20 mg continuous infusions over 24 h each. Subjects were monitored for adverse events and changes in clinical laboratory parameters. Plasma and urine pharmacokinetic samples were collected at defined times. Subjects were followed through Study Day 5. Results Hepatically impaired individuals exhibited higher concentrations of plasma conivaptan throughout the treatment period. Overall exposure, as measured by area under the plasma conivaptan concentration-time curve from time zero through infinity (AUCINF), was ~60% higher in impaired individuals compared to those with normal liver function. Terminal elimination half-life was slightly longer in impaired subjects (12 h) as compared to normal subjects (9 h), and clearance was 65% higher in subjects with normal liver function, while urinary excretion was higher in impaired individuals. Albumin levels directly, and alkaline phosphatase inversely, correlated with conivaptan clearance. Conclusion A 20 mg conivaptan loading dose given >30 min followed by two daily infusions of 20 mg each was well tolerated by patients with severe hepatic impairment as monitored by adverse events and clinical laboratory values. Based on pharmacokinetic data

  11. Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics.

    Science.gov (United States)

    Khalilieh, Sauzanne; Yee, Ka Lai; Liu, Rachael; Fan, Li; Sanchez, Rosa I; Auger, Patrice; Triantafyllou, Ilias; Stypinski, Daria; Lasseter, Kenneth C; Marbury, Thomas; Iwamoto, Marian

    2016-12-27

    Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women). Subjects with hepatic impairment were required to have chronic, stable hepatic impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-∞ , 0.93 (0.74-1.18) for AUC0-24 h , 0.90 (0.66-1.24) for Cmax , and 0.99 (0.74-1.33) for C24 h . Geometric mean apparent terminal t½ was ∼18 hours for both groups, whereas median Tmax was 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that moderate hepatic impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and moderate hepatic impairment.

  12. Educating Families on Real Time Continuous Glucose Monitoring

    Science.gov (United States)

    Messer, Laurel; Ruedy, Katrina; Xing, Dongyuan; Coffey, Julie; Englert, Kimberly; Caswell, Kimberly; Ives, Brett

    2013-01-01

    Purpose The purpose of this article is to describe the process of educating families and children with type 1 diabetes on real time continuous glucose monitoring (RT-CGM) and to note the similarities and differences of training patients using continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). Methods A total of 30 CSII participants and 27 MDI participants were educated using the Navigator RT-CGM in a clinical trial. Time spent with families for visits and calls was tracked and compared between patient groups. The Diabetes Research in Children Network (DirecNet) educators were surveyed to assess the most crucial, time intensive, and difficult educational concepts related to CGM. Results Of the 27 MDI families, an average of 9.6 hours was spent on protocol-prescribed visits and calls (not measured in CSII) and 2 hours on participant-initiated contacts over 3 months. MDI families required an average of 5.4 more phone contacts over 3 months than CSII families. According to the DirecNet educators, lag time and calibrations were the most crucial teaching concepts for successful RT-CGM use. The most time was spent on teaching technical aspects, troubleshooting, and insulin dosing. The most unanticipated difficulties were skin problems including irritation and the sensor not adhering well. Conclusion Educators who teach RT-CGM should emphasize lag time and calibration techniques, technical device training, and sensor insertion. Follow-up focus should include insulin dosing adjustments and skin issues. The time and effort required to introduce RT-CGM provided an opportunity for the diabetes educators to reemphasize good diabetes care practices and promote self-awareness and autonomy to patients and families. PMID:19244568

  13. Population Pharmacokinetic Analysis of Lanreotide Autogel/Depot in the Treatment of Neuroendocrine Tumors: Pooled Analysis of Four Clinical Trials.

    Science.gov (United States)

    Buil-Bruna, Núria; Garrido, María Jesús; Dehez, Marion; Manon, Amandine; Nguyen, Thi Xuan Quyen; Gomez-Panzani, Edda L; Trocóniz, Iñaki F

    2016-04-01

    relevance to potential dose adjustment in clinical practice.

  14. Lanreotide extended-release aqueous-gel formulation, injected by patient, partner or healthcare provider in patients with acromegaly in the United States: 1-year data from the SODA registry.

    Science.gov (United States)

    Salvatori, Roberto; Woodmansee, Whitney W; Molitch, Mark; Gordon, Murray B; Lomax, Kathleen G

    2014-02-01

    Lanreotide depot (LD; commercial name Somatuline(®) Depot) is an injectable, extended-release formulation of the synthetic somatostatin analog (SSA) lanreotide. In recent clinical trials, LD was found to be suitable for self or partner administration, avoiding the need to travel to a medical facility. The Somatuline(®) Depot for Acromegaly (SODA) study is an ongoing, multicenter, observational study in the US investigating the efficacy, safety, convenience and symptom relief provided by LD in patients with acromegaly. Sub-analyses explore outcomes according to who administered the injection: patient, partner, healthcare provider (HCP) or a combination. Data reported here reflect one year of patient experience. Patients are eligible for inclusion if they have a diagnosis of acromegaly, are treated with LD and can give signed informed consent. Baseline data include patient demographics, previous acromegaly treatment and investigations, GH and IGF-I levels, LD dose and dose adjustment frequency. Symptom frequency, injection pain and treatment convenience are assessed using patient-reported questionnaires. As of 18 April 2012, 166 patients had enrolled in SODA. Most (72 %) achieved normal IGF-I levels after 12 months of LD treatment. Disease control was similar in self or partner injectors and in patients who received injections from their HCP, although self or partner injecting was deemed more convenient. LD was well-tolerated irrespective of who performed the injection. Self injection led to more injection-site reactions, but this did not increase the rate of treatment interruption. Acromegaly symptoms remained stable. Biochemical, safety and convenience data support the clinical validity of injecting LD at home.

  15. Pharmacokinetics of Intranasal Scopolamine Gel Formulation During Antiorthostatic Bed Rest, a Microgravity Analog

    Science.gov (United States)

    Singh, Rajendra P.; Daniels, Vernie R.; Crady, Camille J.; Derendorf, H.; Putcha, L.

    2011-01-01

    Statement of Purpose, Innovation or Hypothesis: Space Motion sickness (SMS) is a long-standing problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is frequently used for the treatment of motion sickness (MS), and is available as transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability, thus allowing precise and reduced dosing in addition to offering rescue and treatment options. An intranasal gel dosage formulation of scopolamine (INSCOP) was developed and pharmacokinetics (PK) and bioavailability were determined in clinical trials with human subjects under IND guidelines.Description of Methods and Materials: T