Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)

NARCIS (Netherlands)

Rubbert-Roth, Andrea; Tak, Paul P.; Zerbini, Cristiano; Tremblay, Jean-Luc; Carreño, Luis; Armstrong, Gillian; Collinson, Neil; Shaw, Tim M.

2010-01-01

Methods. Patients with active RA despite stable MTX (10-25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 x 500 and 2 x 500 mg; 2 x 500 and 2 x 1000 mg (dose escalation); and 2 x 1000 and 2 x 1000 mg. The primary endpoint

Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

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Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-23

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

Comparison of two dose regimens of misoprostol for second-trimester pregnancy termination

NARCIS (Netherlands)

Brouns, Joseph Franciscus Gertrudis Maria; van Wely, Madelon; Burger, Mattheus Petrus Maria; van Wijngaarden, Willem Jacobus

2010-01-01

Objective: The study was conducted to compare the efficacy of two different dose regimens of misoprostol administered vaginally in combination with mifepristone for second trimester termination of viable and non-viable pregnancies. Design: Double-blind randomized controlled trial conducted at the

The effect of dosing regimen on the pharmacokinetics of risedronate

Science.gov (United States)

Mitchell, David Y; Heise, Mark A; Pallone, Karen A; Clay, Marian E; Nesbitt, John D; Russell, Darrell A; Melson, Chad W

1999-01-01

Aims To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. Methods A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. Results Extent of risedronate absorption (AUC and Ae) was comparable (P = 0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. Conclusions The comparable extent of risedronate absorption when administered either 0.5–1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine. PMID:10583024

High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting

DEFF Research Database (Denmark)

Herrstedt, Jørn; Hannibal, J; Hallas, Jesper

1991-01-01

In a randomized double-blind, cross-over trial of 34 patients receiving cisplatin-based chemotherapy (20-100 mg/m2), the antiemetic effect of high-dose metoclopramide (HDM) (10 mg/kg iv. loading dose + 7 hours continuous infusion) + lorazepam (L) (2.5 mg x 4 po) was compared with low......-dose metoclopramide (LDM) (70 mg) + L (2.5 mg x 2 po) + dehydrobenzperidol (5 mg x 2 im). Among the 29 patients who completed the cross-over, HDM significantly reduced the number of vomiting episodes (p = 0.002) and the degree of nausea (p = 0.004). Seventeen patients preferred the HDM and 4 the LDM regimen (p = 0.......01). Sedation was seen in all but 1 patient, and was graded as severe in 6 patients receiving the HDM and in 2 patients receiving the LDM regimen. No extrapyramidal adverse reactions were seen. We conclude that high-dose metoclopramide + lorazepam is a safe antiemetic regimen and significantly superior to low...

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma

DEFF Research Database (Denmark)

Xu, Xu Steven; Yan, Xiaoyu; Puchalski, Thomas

2017-01-01

New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen...... for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM. This article is protected by copyright. All...

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns,

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Laura Vargas Dornelles

2016-06-01

Full Text Available Abstract Objective: To compare the efficacy of intravenous ibuprofen at high (20-10-10 mg/kg/dose and low doses (10-5-5 mg/kg/dose the closure of patent ductus arteriosus in preterm newborns. Methods: A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Results: Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8% low-dose patients and in 17 (51.5% high-dose patients (p > 0.99. Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p > 0.99. Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p = 0.22. Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p > 0.99. Twenty-two (50% low-dose patients died vs. 15 (45.5% high-dose patients (p = 0.86. Conclusions: There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns.

Science.gov (United States)

Dornelles, Laura Vargas; Corso, Andréa Lúcia; Silveira, Rita de Cássia; Procianoy, Renato Soibelmann

2016-01-01

To compare the efficacy of intravenous ibuprofen at high (20-10-10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Lean body mass as an independent determinant of dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX regimens

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Ali, Raafi; Sawyer, Michael B.; Bianchi, Laurent; Roberts, Sarah; Mollevi, Caroline; Senesse, Pierre; Baracos, Vickie E.; Assenat, Eric

2016-01-01

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing

A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design.

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Vincent H Tam

Full Text Available Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens or time-dependent (for which more frequent dosing is preferred. While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing. A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T>MIC could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem. The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection.

Vitamin D supplementation in nursing home patients: randomized controlled trial of standard daily dose versus individualized loading dose regimen.

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Wijnen, Hugo; Salemink, Dayenne; Roovers, Lian; Taekema, Diana; de Boer, Hans

2015-05-01

Supplementation of cholecalciferol 800 IU daily appears to be insufficient to raise vitamin D levels to >75 nmol/l in nursing home (NH) patients. Our objective was to compare the efficacy of an individualized cholecalciferol loading dose (LD) regimen and a daily dose (DD) regimen of cholecalciferol 800 IU in reaching 25-OH vitamin D (25OHD) levels >75 nmol/l. A total of 30 NH patients with 25OHD levels 50 nmol/l were included. Patients were randomized using the minimization method in the LD or DD group. The cholecalciferol LD, calculated with an algorithm based on serum 25OHD level and body weight, was administered in divided doses of 50,000 IU twice a week, followed by a monthly maintenance dose of either 50,000 or 25,000 IU. The DD regimen consisted of cholecalciferol 800 IU daily for 26 weeks. Serum 25OHD, calcium, creatinine, phosphate, and parathyroid hormone were measured, and 2-minute walking test, handgrip strength, and timed get up and go test were assessed at baseline (T 0), after 5 weeks (T 5), 12 weeks (T 12), and 26 weeks (T 26). The primary endpoint was the percentage of patients with 25OHD levels >75 nmol/l at T 5. Secondary endpoints were the proportion of patients with 25OHD levels >75 nmol/l at T 26, safety of LD regimen, and improvement of performance tests with normalization of vitamin D levels. Median baseline 25OHD levels (interquartile range) were comparable between the 14 DD and 16 LD patients: 20.9 (15.9-29.6) and 21.7 (16.4-32.8) nmol/l, respectively. Levels of 25OHD >75 nmol/l at T 5 were reached in 79 % of the 14 LD patients, but in none of the 13 DD patients (p 75 nmol/l were reached in 83 % of the 12 LD patients and in 30 % of the ten DD patients (p tests was observed. In NH patients with severe 25OHD deficiency, an individualized calculated cholecalciferol LD is likely to be superior to a DD of cholecalciferol 800 IU in terms of the ability to rapidly normalize vitamin D levels.

[Influence of dose regimen on gentamycin nephrotoxicity in rats].

Science.gov (United States)

Oliveira, V C; Tejos, C R; Hosaka, E M; Andrade, S C; Araújo, M; Vattimo, M F

2001-06-01

The acute renal failure (ARF), that still presents a right mortality rate (50%) can be defined as an abrupt decline of the glomerular filtration, resultant of ischemic or toxicity event. The drugs nephrotoxicity is one of the most frequent cause (27%) of ARF and it is suggested that the interval of administration of the drug can interfere in this side effect, however the best administration regimen is not very well established. This study evaluated the renal function of rats that received gentamicin (100 mg/kg) in one dose or in two doses (2 x 50 mg/kg), by intraperitoneal infusion. The results obtained in this research, indicated that the single infusion of gentamicin determined smaller nephrotoxicity by the reduction of serum concentration of this drug in 24 hours, decreasing the intracellular accumulation of this gentamicin, which is one of the main cellular mechanisms of this renal injury. The single dose treatment regime, otherwise, shows advantages not only related to the nephrotoxicity effect, but also it is relevant to the cost and safety, which can be rationable factors in the administration of this drug.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

Science.gov (United States)

Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

2015-06-01

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

The effectiveness of low-dose and high-dose tranexamic acid in posterior lumbar interbody fusion: a double-blinded, placebo-controlled randomized study.

Science.gov (United States)

Kim, Ki-Tack; Kim, Cheung-Kue; Kim, Yong-Chan; Juh, Hyung-Suk; Kim, Hyo-Jong; Kim, Hyeon-Soo; Hong, Se Jung; Hey, Hwee Weng Dennis

2017-11-01

Tranexamic acid is a proven drug used for reduction of intraoperative blood loss in spinal surgery. However, optimal dosing considering risk/benefits is not well established owing to the heterogeneity in patient selection and surgical procedures of previous studies. This study aimed to evaluate the effectiveness and safety of various tranexamic acid regimens in reducing perioperative blood loss in single-level posterior lumbar interbody fusion (PLIF). Patients were randomly grouped into three different interventions: low-dose tranexamic acid (LD), high-dose tranexamic acid (HD), and placebo-controlled (PC) groups. The HD and LD groups received 10 and 5 mg/kg of bolus loading dose and 2 and 1 mg/kg of continuous infusion until 5 h after surgery, respectively. Data on patient demographics and preoperative and 24-h postoperative laboratory values were collected. Outcome parameters include intraoperative blood loss, 24-h postoperative blood loss, and blood loss during removal of the last drain. Seventy-two patients (mean age 63.3 ± 7.6 years) showed similar baseline characteristics. Intraoperatively, blood loss was reduced by the administration of tranexamic acid (P = 0.04), contributed predominantly by a difference between the LD and HD groups (123 mL; P tranexamic acid use were noted. Tranexamic acid administration for single-level PLIF was effective and safe in reducing perioperative blood loss in a dose-dependent manner. An HD regimen comprising 10 mg/kg of bolus loading dose and 2 mg/kg/h of continuous infusion is recommended. Level 1 study according to Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

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Olivia Taylor

Full Text Available Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

Science.gov (United States)

Taylor, Olivia; Van Laeken, Nick; Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog.

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Jeunesse, Elisabeth C; Schneider, Marc; Woehrle, Frederique; Faucher, Mathieu; Lefebvre, Herve P; Toutain, Pierre-Louis

2013-12-11

Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin-induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg

Alcohol dose dumping: The influence of ethanol on hot-melt extruded pellets comprising solid lipids.

Science.gov (United States)

Jedinger, N; Schrank, S; Mohr, S; Feichtinger, A; Khinast, J; Roblegg, E

2015-05-01

The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol® and Precirol®) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol dose dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced dose dumping for certain API's. Copyright © 2015 Elsevier B.V. All rights reserved.

Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C.

Science.gov (United States)

Brennan, Barbara J; Lemenuel-Diot, Annabelle; Snoeck, Eric; McKenna, Michael; Solsky, Jonathan; Wat, Cynthia; Mallalieu, Navita L

2016-04-01

The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin. Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients. © 2015 The British Pharmacological Society.

The effect of the second dose 131I in patients with Grave's disease, treated with 185 MBq low-fixed dose regimen

International Nuclear Information System (INIS)

Bochev, P.; Klissarova, A.; Hristozov, H.; Chaushev, B.; Cvetanova, B.

2006-01-01

Full text: The aim of the study was to evaluate the success rate after application of a second dose 131 I in patients with Grave's disease, treated with a fixed dose 185 MBq 131 I and still hyperthyroid. 27 patients with Grave's disease, treated with 185 MBq 131 I. Each patient was followed up by physical exam, ultrasonography and hormone levels for a period of at least one year. On the sixth month after the initial treatment 14 patients (52%) were still hyperthyroid. Based on hormone levels and reduction of gland size a decision for applying a second dose 131 I was taken for 8 patients. The remaining six patients with persistent hyperthyroidism were treated with antithyroid drugs till the end of the first year. By the time of the study 12.5% of the patients being treated with a second dose are still hyperthyroid, 37.5% - euthyroid and 50% -hypothyroid with total success rate (hypo+euthyroid) of 87%. In comparison 16 % of the patients treated with antithyroid drugs are euthyroid. The use of a second dose 131 I in patients with Graves disease being treated with low-fixed dose regimen and still hyperthyroid by the sixth month after the initial treatment leads to a high overall success rate in one year

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

Directory of Open Access Journals (Sweden)

Galactéros Frédéric

2011-05-01

Full Text Available Abstract Background Hydroxyurea (HU is the first approved pharmacological treatment of sickle cell anemia (SCA. The objectives of this study were to develop population pharmacokinetic(PK-pharmacodynamic(PD models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF% and mean corpuscular volume (MCV were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV of clearance was 11.6 L/h (30%, the central volume was 45.3 L (35%. PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%; the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil.

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Ferreira, Anna Carolina Galvão; Silva Júnior, José Laerte Rodrigues da; Conde, Marcus Barreto; Rabahi, Marcelo Fouad

2013-01-01

To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil *

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Ferreira, Anna Carolina Galvão; da Silva, José Laerte Rodrigues; Conde, Marcus Barreto; Rabahi, Marcelo Fouad

2013-01-01

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health-rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months-involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (≥ 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous basic regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%). PMID:23503489

Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen.

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Lobel, H O; Bernard, K W; Williams, S L; Hightower, A W; Patchen, L C; Campbell, C C

1991-01-16

To measure the effectiveness and tolerance of long-term malaria prophylaxis with mefloquine, the incidence of Plasmodium falciparum malaria and of adverse reactions was compared in Peace Corps volunteers in West Africa who took mefloquine every 2 weeks and in volunteers who took chloroquine phosphate weekly. Mefloquine was only 63% more effective than chloroquine; the monthly incidence of P falciparum infections was one case per 100 volunteers who took mefloquine and 2.7 cases per 100 volunteers who took chloroquine. Using daily proguanil (chloroguanide) hydrochloride in addition to chloroquine did not provide additional protection. All mefloquine prophylaxis failures occurred during the second week of the every-2-weeks dosing regimen in volunteers who had used mefloquine for more than 2 months. Blood concentrations of mefloquine were lower during the second week of the alternate-week regimen than during the first week, suggesting that blood levels are too low during the second week to suppress parasitemia. No serious adverse reactions were observed. The results indicate that a dosing regimen of 250 mg of mefloquine weekly should be considered for travelers to areas with chloroquine-resistant P falciparum malaria.

Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

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Xu, Yuhui; Wu, Jianan; Liao, Sha; Sun, Zhaogang

2017-10-03

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis.

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Wang, Caixia; Ye, Yuqiu; Liu, Chunyong; Zhou, Yongming; Lv, Linsheng; Cheng, Cailian; Li, Shaomin; Lou, Tanqi; Liu, Xun

2017-08-01

Evening dosing regimen drug therapy on blood pressure (BP) control is used widely, but its clinical benefits and preservation or re-establishment of the normal 24-h BP dipping pattern in chronic kidney disease (CKD) patients is not known. To investigate the effect of an evening dosing regimen of antihypertensive drugs on BP patterns of CKD patients with hypertension. A systematic review was conducted by searching PUBMED, EMBASE, ASN-ONLINE, the Cochrane Library and the reference lists of relevant articles of published papers. All trials designed to evaluate the effects of evening versus morning dosing regimen drug therapy for CKD patients with hypertension were included. Meta-analysis was performed using random or fixed effects models. Five randomised controlled trials and one comparative study, including 3732 patients, met the inclusion criteria. Compared with morning dosing regimen drug therapy, evening administration of antihypertensive medication was associated with a significant reduction of 40% in non-dipper BP patterns (risk ratio (RR), 95% CI, (0.43, 0.84)). We noted a significant decrease in nocturnal systolic blood pressure (SBP) (MD -3.17 mmHg, 95% CI (-5.41, -0.94)), a significant reduction in nocturnal diastolic blood pressure (DBP) (MD -1.37 mmHg, 95% CI (-2.05, -0.69)) and a significant increase in awake SBP (MD 1.15 mmHg, 95% CI (0.10, 2.19)) in patients assigned to the evening dosing regimen drug therapy group. Patients showed no significant differences for all-cause mortality and cardiovascular mortality. This review shows that evening dosing regimen drug therapy could reverse non-dipper BP patterns in hypertensive CKD patients. © 2017 Royal Australasian College of Physicians.

Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis.

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Bartacek, A; Schütt, D; Panosch, B; Borek, M

2009-06-01

To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB). This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations. Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups. The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

International Nuclear Information System (INIS)

Hall, Matthew D.; Schultheiss, Timothy E.; Smith, David D.; Nguyen, Khanh H.; Wong, Jeffrey Y.C.

2015-01-01

Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the

Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

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Hall, Matthew D. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Schultheiss, Timothy E., E-mail: schultheiss@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Smith, David D. [Division of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Nguyen, Khanh H. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Department of Radiation Oncology, Bayhealth Cancer Center, Dover, Delaware (United States); Wong, Jeffrey Y.C. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States)

2015-01-01

Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the

Delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen: a case report.

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Sokolova, Alexandra; Chan, Onyee; Ullah, Waqas; Hamdani, Auon Abbas; Anwer, Faiz

2017-04-11

High-dose chemotherapy with autologous stem cell rescue is commonly used for the treatment of relapsed germ cell tumors. We report the first case of delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen. We report a case of a 21-year-old African-American man diagnosed with relapsed non-seminomatous germ cell tumor who received high-dose chemotherapy with carboplatin and etoposide following TIGER trial arm B off-protocol. His course was complicated by muscle pain and rhabdomyolysis after cycle 4 on day +12 after infusion of autologous stem cells. To the best of our knowledge, this complication has not been reported with this regimen. A differential diagnosis of sepsis and neutropenic fever along with side effects of high-dose chemotherapy were considered, but based on the timing of events, it was concluded that the etiology of rhabdomyolysis is high-dose chemotherapy. Rhabdomyolysis was successfully treated with hydration and did not recur during subsequent cycle 5. Delayed rhabdomyolysis after high-dose chemotherapy with paclitaxel, ifosfamide, carboplatin, and etoposide regimen has not been previously reported and needs to be considered for preventive strategy and prompt diagnosis and treatment to avoid renal complications. Physicians should have a low threshold to check creatine kinase enzymes in patients with unexplained muscle pain or renal insufficiency after high-dose chemotherapy.

Assessment of serum magnesium levels and its outcome in neonates of eclamptic mothers treated with low-dose magnesium sulfate regimen

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Das, Monalisa; Chaudhuri, Patralekha Ray; Mondal, Badal C.; Mitra, Sukumar; Bandyopadhyay, Debasmita; Pramanik, Sushobhan

2015-01-01

Objectives: Magnesium historically has been used for treatment and/or prevention of eclampsia. Considering the low body mass index of Indian women, a low-dose magnesium sulfate regime has been introduced by some authors. Increased blood levels of magnesium in neonates is associated with increased still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, gastrointestinal hypomotility. The objective of this study was to assess safety of low-dose magnesium sulfate regimen in neonates of eclamptic mothers treated with this regimen. Materials and Methods: This was a cross-sectional observational study of 100 eclampsia patients and their neonates. Loading dose and maintenance doses of magnesium sulfate were administered to patients by combination of intravenous and intramuscular routes. Maternal serum and cord blood magnesium levels were estimated. Neonatal outcome was assessed. Results: Bradycardia was observed in 18 (19.15%) of the neonates, 16 (17.02%) of the neonates were diagnosed with hypotonia. Pearson Correlation Coefficient showed Apgar scores decreased with increase in cord blood magnesium levels. Unpaired t-test showed lower Apgar scores with increasing dose of magnesium sulfate. The Chi-square/Fisher's exact test showed significant increase in hypotonia, birth asphyxia, intubation in delivery room, Neonatal Intensive Care Unit (NICU) care requirement, with increasing dose of magnesium sulfate. (P ≤ 0.05). Conclusion: Several neonatal complications are significantly related to increasing serum magnesium levels. Overall, the low-dose magnesium sulfate regimen was safe in the management of eclamptic mothers, without toxicity to their neonates. PMID:26600638

Hypofractionation Regimens for Stereotactic Radiotherapy for Large Brain Tumors

International Nuclear Information System (INIS)

Yuan Jiankui; Wang, Jian Z.; Lo, Simon; Grecula, John C.; Ammirati, Mario; Montebello, Joseph F.; Zhang Hualin; Gupta, Nilendu; Yuh, William T.C.; Mayr, Nina A.

2008-01-01

Purpose: To investigate equivalent regimens for hypofractionated stereotactic radiotherapy (HSRT) for brain tumor treatment and to provide dose-escalation guidance to maximize the tumor control within the normal brain tolerance. Methods and Materials: The linear-quadratic model, including the effect of nonuniform dose distributions, was used to evaluate the HSRT regimens. The α/β ratio was estimated using the Gammaknife stereotactic radiosurgery (GKSRS) and whole-brain radiotherapy experience for large brain tumors. The HSRT regimens were derived using two methods: (1) an equivalent tumor control approach, which matches the whole-brain radiotherapy experience for many fractions and merges it with the GKSRS data for few fractions; and (2) a normal-tissue tolerance approach, which takes advantages of the dose conformity and fractionation of HSRT to approach the maximal dose tolerance of the normal brain. Results: A plausible α/β ratio of 12 Gy for brain tumor and a volume parameter n of 0.23 for normal brain were derived from the GKSRS and whole-brain radiotherapy data. The HSRT prescription regimens for the isoeffect of tumor irradiation were calculated. The normal-brain equivalent uniform dose decreased as the number of fractions increased, because of the advantage of fractionation. The regimens for potential dose escalation of HSRT within the limits of normal-brain tolerance were derived. Conclusions: The designed hypofractionated regimens could be used as a preliminary guide for HSRT dose prescription for large brain tumors to mimic the GKSRS experience and for dose escalation trials. Clinical studies are necessary to further tune the model parameters and validate these regimens

A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris

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Dhaked, Daulat Ram; Meena, Ram Singh; Maheshwari, Anshul; Agarwal, Uma Shankar; Purohit, Saroj

2016-01-01

Background: Oral isotretinoin is highly effective in all forms and grades of acne, even in lower dosages (acne vulgaris. Materials and Methods: A total of 240 patients with moderate to severe acne vulgaris were selected and randomized into two groups and treated with a fixed dose of 20 mg of isotretinoin (Group A - daily and Group B - alternate days) for 24 weeks and followed up for 12 weeks post therapy. Results: A total of 234 patients completed the study. At the end of therapy, decrease in the total acne loads up to 98.99% (Group A) and 97.69% (Group B) was achieved from the baseline (P acne, Group A performed significantly better than Group B until the end of 36 weeks. While in the moderate acne, significant difference in the response between both groups was observed only up to 12 weeks. No serious side effect was observed. Conclusion: Both isotretinoin regimens were well tolerated and found to be an effective treatment for moderate to severe acne vulgaris. However, in moderate acne 20 mg alternate day regimen may be preferred. A 20 mg daily regimen is a better choice for severe acne in terms of response. Limitation: Small sample size and short follow-up period. PMID:27730033

Microbiological efficacy and tolerability of a single-dose regimen of 1 g of ceftriaxone in men with gonococcal urethritis.

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Ito, Shin; Yasuda, Mitsuru; Hatazaki, Kyoko; Mizutani, Kosuke; Tsuchiya, Tomohiro; Yokoi, Shigeaki; Nakano, Masahiro; Deguchi, Takashi

2016-09-01

We treated men with gonococcal urethritis with a single-dose regimen of 1 g of ceftriaxone, which is recommended as the first-line treatment for gonorrhoea in Japan, to determine its microbiological outcomes and tolerability. We enrolled 255 men with gonococcal urethritis and treated them with a single-dose regimen of 1 g of ceftriaxone. We evaluated its microbiological outcomes and tolerability. We also determined ceftriaxone MICs for pretreatment isolates of Neisseria gonorrhoeae collected from the patients. The microbiological efficacy of the ceftriaxone regimen, which was determined between 5 and 9 days after treatment in 111 men based on the Japanese guideline for clinical research on antimicrobial agents in urogenital infections, was 100%. In the 194 men who returned to the clinic between 2 and 41 days after treatment, 191 (98.5%; 95% CI 96.8%-100%) were negative for N. gonorrhoeae after treatment. Ceftriaxone MICs determined for 136 pretreatment isolates obtained from these 194 men ranged from 0.001 to 0.25 mg/L. One isolate persisting after treatment exhibited a ceftriaxone MIC of 0.008 mg/L. For two isolates persisting after treatment, ceftriaxone MICs were not determined. Seven adverse events were observed in 7 (3.2%) of the 220 men treated with the ceftriaxone regimen. Four men had diarrhoea classified as grade 1. Three had urticaria during ceftriaxone administration, with one event classified as grade 1 and two events classified as grade 3. A single-dose regimen of 1 g of ceftriaxone was microbiologically effective against gonococcal urethritis and was safe and tolerable. © 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.

A rational quantitative approach to determine the best dosing regimen for a target therapeutic effect: a unified formalism for antibiotic evaluation.

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Li, Jun; Nekka, Fahima

2013-02-21

The determination of an optimal dosing regimen is a critical step to enhance the drug efficacy and avoid toxicity. Rational dosing recommendations based on mathematical considerations are increasingly being adopted in the process of drug development and use. In this paper, we propose a quantitative approach to evaluate the efficacy of antibiotic agents. By integrating both pharmacokinetic (PK) and pharmacodynamic (PD) information, this approach gives rise to a unified formalism able to measure the cause-effect of dosing regimens. This new pharmaco-metric allows to cover a whole range of antibiotics, including the two well known concentration and time dependent classes, through the introduction of the Hill-dependency concept. As a direct fallout, our formalism opens a new path toward the bioequivalence evaluation in terms of PK and PD, which associates the in vivo drug concentration and the in vitro drug effect. Using this new approach, we succeeded to reveal unexpected, but relevant behaviors of drug performance when different drug regimens and drug classes are considered. Of particular notice, we found that the doses required to reach the same therapeutic effect, when scheduled differently, exhibit completely different tendencies for concentration and time dependent drugs. Moreover, we theoretically confirmed the previous experimental results of the superiority of the once daily regimen of aminoglycosides. The proposed methodology is appealing for its computational features and can easily be applicable to design fair clinical protocols or rationalize prescription decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluation of Low- Versus High-dose Valganciclovir for Prevention of Cytomegalovirus Disease in High-risk Renal Transplant Recipients.

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Gabardi, Steven; Asipenko, Natalya; Fleming, James; Lor, Kevin; McDevitt-Potter, Lisa; Mohammed, Anisa; Rogers, Christin; Tichy, Eric M; Weng, Renee; Lee, Ruth-Ann

2015-07-01

Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR). Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed. Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar. Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

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Kampouraki, Emmanouela; Avery, Peter J; Wynne, Hilary; Biss, Tina; Hanley, John; Talks, Kate; Kamali, Farhad

2017-09-01

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients. © 2017 John Wiley & Sons Ltd.

RESULTS OF LONG-TERM THERAPY WITH GROWTH-HORMONE IN 2 DOSE REGIMENS IN TURNER SYNDROME

NARCIS (Netherlands)

NIENHUIS, HE; RONGENWESTERLAKEN, C; WIT, JM; OTTEN, BJ; KEIZERSCHRAMA, SMPFD; DRAYER, NM; DELEMARREVANDEWAAL, HA; VULSMA, T; OOSTDIJK, W; WAELKENS, JJJ

1993-01-01

Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (A1 and B1, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/M2/week, with an increase in height velocity, though

Provider knowledge of treatment policy and dosing regimen with artemether-lumefantrine and quinine in malaria-endemic areas of western Kenya

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Watsierah Carren A

2012-12-01

Full Text Available Abstract Background Due to widespread anti-malarial drug resistance in many countries, Kenya included, artemisinin-based Combination Therapy (ACT has been adopted as the most effective treatment option against malaria. Artemether-lumefantrine (AL is the first-line ACT for treatment of uncomplicated malaria in Kenya, while quinine is preferred for complicated and severe malaria. Information on the providers’ knowledge and practices prior to or during AL and quinine implementation is scanty. The current study evaluated providers’ knowledge and practices of treatment policy and dosing regimens with AL and quinine in the public, private and not-for-profit drug outlets. Methods A cross-sectional survey using three-stage sampling of 288 (126 public, 96 private and 66 not-for-profits providers in drug outlets was conducted in western Kenya in two Plasmodium falciparum-endemic regions with varying malarial risk. Information on provider in-service training, knowledge (qualification, treatment policy, dosing regimen, recently banned anti-malarials and on practices (request for written prescription, prescription of AL, selling partial packs and advice given to patients after prescription, was collected. Results Only 15.6% of providers in private outlets had received any in-service training on AL use. All (100% in public and majority (98.4% in not-for-profit outlets mentioned AL as first line-treatment drug. Quinine was mentioned as second-line drug by 47.9% in private outlets. A total of 92.0% in public, 57.3% in private and 78.8% in not-for-profit outlets stated correct AL dose for adults. A total of 85.7% of providers in public, 30.2% in private and 41.0% in not-for-profit outlets were aware that SP recommendations changed from treatment for mild malaria to IPTp in high risk areas. In-service training influenced treatment regimen for uncomplicated malaria (P = 0.039 and P = 0.039 and severe malaria (P P = 0.002 in children and adults

Switch from a ZDV/3TC-based regimen to a completely once daily (QD regimen of emtricitabine/tenofovir DF fixed dose combination plus a third QD agent (SONETT

Directory of Open Access Journals (Sweden)

Arasteh K

2009-05-01

Full Text Available Abstract Objectives To assess the efficacy and safety of a treatment switch from a twice-daily (BID regimen containing zidovudine (ZDV and lamivudine (3TC plus a third agent to a once daily (QD regimen containing the fixed-dose combination of tenofovir DF/emtricitabine (TDF/FTC, Truvada® plus a divergent third QD agent in HIV-1 infected patients. Methods Prospective, 48-week, non-randomised, single-group, open-label, study. Fifty-one patients on stable ZDV/3TC-containing HAART, with HIV-1 RNA 50 cells/μl, were switched to TDF/FTC plus a third agent. Plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts were assessed at baseline and weeks 4, 12, 24, 36 and 48 post-switch. Results During the 48-week study, 10 patients discontinued prematurely, including three due to adverse events (AEs. At week 48, plasma HIV-1 RNA was p Conclusions Results from this study support switching from a ZDV/3TC-containing HAART regimen to a completely QD regimen of TDF/FTC plus a third agent. Virologic and immunologic control are maintained, with apparent benefits in haemoglobin.

Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy.

Directory of Open Access Journals (Sweden)

Elizabeth A Brezinski

Full Text Available OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent

The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular-weight heparin in the initial treatment of acute coronary syndromes

NARCIS (Netherlands)

Bijsterveld, Nick R.; Moons, Arno H.; Meijers, Joost C. M.; Levi, Marcel; Büller, Harry R.; Peters, Ron J. G.

2003-01-01

OBJECTIVES We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS). BACKGROUND It is unclear whether an intravenous (M loading dose of enoxaparin should be added to a subcutaneous (SQ) regimen in

A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan

DEFF Research Database (Denmark)

Adam, Ishag; Magzoub, Mamoun; Osman, Maha E

2006-01-01

-sulfamethoxypyrazine-pyrimethamine (AS+SMP f) administered at time intervals of 12 hours for a 24-hour therapy was compared with the efficacy of the same drug given as a loose combination (AS+SMP l) with a dose interval of 24 hours for 3 days for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. RESULTS...... of the patients. CONCLUSION: both regimens of AS+SMP were effective and safe for the treatment of uncomplicated P. falciparum malaria in eastern Sudan. Due to its simplicity, the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice....

Evaluation of the Efficacy and Safety of High Dose Short Duration Enrofloxacin Treatment Regimen for Uncomplicated Urinary Tract Infections in Dogs

Science.gov (United States)

Westropp, JL; Sykes, JE; Irom, S; Daniels, JB; Smith, A; Keil, D; Settje, T; Wang, Y; Chew, DJ

2012-01-01

Background Uncomplicated urinary tract infections (UTI) in dogs usually are treated with antimicrobial drugs for 10–14 days. Shorter duration antimicrobial regimens have been evaluated in human patients. Hypothesis A high dose short duration (HDSD) enrofloxacin protocol administered to dogs with uncomplicated UTI will not be inferior to a 14-day treatment regimen with amoxicillin-clavulanic acid. Animals Client-owned adult, otherwise healthy dogs with aerobic bacterial urine culture yielding ≥103 CFU/mL of bacteria after cystocentesis. Methods Prospective, multicenter, controlled, randomized blinded clinical trial. Enrolled dogs were randomized to group 1 (enrofloxacin 18–20 mg/kg PO q24h for 3 days) or group 2 (amoxicillin-clavulanic acid 13.75–25 mg/kg PO q12h for 14 days). Urine cultures were obtained at days 0, 10, and 21. Microbiologic and clinical cure rates were evaluated 7 days after antimicrobial treatment was discontinued. Lower urinary tract signs and adverse events also were recorded. Results There were 35 dogs in group 1 and 33 in group 2. The microbiologic cure rate was 77.1 and 81.2% for groups 1 and 2, respectively. The clinical cure rate was 88.6 and 87.9% for groups 1 and 2, respectively. Cure rates between groups did not differ according to the selected margin of noninferiority. Conclusions and Clinical Importance HDSD enrofloxacin treatment was not inferior to a conventional amoxicillin-clavulanic acid protocol for the treatment of uncomplicated bacterial UTI in dogs. Further research is warranted to determine if this protocol will positively impact owner compliance and decrease the emergence of antimicrobial resistance. PMID:22486931

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception.

Science.gov (United States)

Shohel, Mohammad; Rahman, Mohammad Mahfuzur; Zaman, Asif; Uddin, Mir Muhammad Nasir; Al-Amin, Md Mamun; Reza, Hasan Mahmud

2014-04-04

Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12-24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients

International Nuclear Information System (INIS)

Penoncello, Gregory P.; Ding, George X.

2016-01-01

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2 cm"3 for head and neck plans and brain plans and a contiguous volume of 5 cm"3 for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

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Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

[Combination of busulfan with increased-dose of fludarabine as conditioning regimen for MDS and MDS-AML patients with allo-HSCT].

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Yuan, Jing; Ren, Hanyun; Qiu, Zhixiang; Li, Yuan; Wang, Mangju; Liu, Wei; Xu, Weilin; Sun, Yuhua; Wang, Lihong; Liang, Zeyin; Dong, Yujun; Ou, Jinping; Wang, Wensheng; Yin, Yue; Cen, Xinan; Wang, Qian

2015-06-01

To investigate the safety and efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (MDS-AML) using conditioning regimen with busulfan (Bu) and increased-dose of fludarabine (ID-Flu). A total of 49 patients with MDS or MDS-AML were treated by allo-HSCT, the clinical data was analyzed retrospectively. All patients achieved hematopoietic reconstitution. Neutrophil engraftment was at 10 - 22 days (median 13 days), and platelet engraftment was at 8 - 66 days (median 16 days). The cumulative incidences of Ⅱ-Ⅳ degree acute graft-versus-host disease (GVHD), hemorrhagic cystitis (HC), and hepatic venous occlusive disease (VOD) were 28.6%, 14.3% and 2.0%, respectively. The transplant-related mortality (TRM) was only 4.1% at 100d and 8.2% at 1-92 months of followed-up (median 14 months) period. Overall survival (OS) and disease free survival (DFS) was 75.5%, 73.5%, respectively. Kaplan-Meier curve showed that 3-year OS and 3-year DFS was (71.1 ± 7.8)%, (66.7 ± 8.3)%, respectively, with a relapse incidence (RI) 16.3%. OS for MDS and MDS-AML was 81.5% and 68.2%, and RI in two settings was 3.7%, 31.8%, respectively. OS for MDS-AML at complete remission (CR) and non-CR subgroup was 83.3% and 50.0%, respectively, while cumulative RR was 16.7% and 50.0%, respectively. OS and RI except for non-CR subgroup were 82.1% and 7.7%. Univariate analysis showed that pre-HSCT disease status had correlation with OS (P=0.031), but age, decitabine in conditioning regimen, stem cell source, HLA matching, patient-donor gender, dose of mononuclear cells and GVHD had no correlation with OS. Bu/ID-Flu conditioning regimen for MDS and MDS-AML has high efficiency, fewer complications, lower toxicity and TRM. The OS and DFS were higher and RI was lower except for refractory MDS-AML patients. The regimen is valuable for clinical application.

Characteristics of HIV antiretroviral regimen and treatment adherence

Directory of Open Access Journals (Sweden)

Vera Lúcia da Silveira

Full Text Available The relationship between characteristics of HIV antiretroviral regimens and treatment adherence was studied in adolescent and adult patients who underwent antiretroviral therapy from January 1998 to September 2000, at the Service for Specialized Assistance in Pelotas. The patients were interviewed on two occasions, and the use of antiretrovirals during the previous 48 hours was investigated by a self-report. Adherence was defined as use of 95% or more of the prescribed medication. Social-demographic variables were collected through direct questionnaires. The antiretroviral regimen and clinical data were copied from the patients' records. Associations between the independent variables and adherence were analyzed by means of logistic regression. The multivariate analysis included characteristics of the antiretroviral regimens, social-demographic variables, as well as perception of negative effects, negative physiological states, and adverse effects of the treatment. Among the 224 selected patients, 194 participated in our study. Their ages varied from 17 to 67 years; most patients were men, with few years of schooling and a low family income. Only 49% adhered to the treatment. Adherence to treatment regimens was reduced when more daily doses were indicated: three to four doses (odds ratio of adherence to treatment (OR=0.47, 95% confidence interval (CI 0.22-1.01 and five to six (OR=0.24, 95% CI 0.09-0.62; two or more doses taken in a fasting state (OR=0.59, 95% CI 0.11-0.68, and for patients who reported adverse effects to the treatment (OR=0.39, 95% CI 0.19-0.77. Most of the regimens with more than two daily doses of medication included at least one dose apart from mealtimes. The results suggest that, if possible, regimens with a reduced number of doses should be chosen, with no compulsory fasting, and with few adverse effects. Strategies to minimize these effects should be discussed with the patients.

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial.

Science.gov (United States)

Ladenstein, Ruth; Pötschger, Ulrike; Pearson, Andrew D J; Brock, Penelope; Luksch, Roberto; Castel, Victoria; Yaniv, Isaac; Papadakis, Vassilios; Laureys, Geneviève; Malis, Josef; Balwierz, Walentyna; Ruud, Ellen; Kogner, Per; Schroeder, Henrik; de Lacerda, Ana Forjaz; Beck-Popovic, Maja; Bician, Pavel; Garami, Miklós; Trahair, Toby; Canete, Adela; Ambros, Peter F; Holmes, Keith; Gaze, Mark; Schreier, Günter; Garaventa, Alberto; Vassal, Gilles; Michon, Jean; Valteau-Couanet, Dominique

2017-04-01

High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m 2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m 2 ) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m 2 per day for 4 days, and melphalan 70 mg/m 2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients.

Science.gov (United States)

Penoncello, Gregory P; Ding, George X

2016-01-01

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2cm(3) for head and neck plans and brain plans and a contiguous volume of 5cm(3) for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens. Copyright © 2016 American Association of Medical Dosimetrists. Published by

A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment.

Science.gov (United States)

Devane, John G; Martin, Mary L; Matson, Mark A

2014-06-01

during week 1 treatment, indicating an early peak in FLS severity during the No Titration treatment and subsequent development of tolerance. In contrast, titration results in near baseline severity scores throughout the treatment period. Similar trends were seen for 4 and 12 hour FLS severity scores. Of the individual FLS, difference in fever severity was most marked. Safety profiles for both regimens were consistent with the approved prescribing information for interferon gamma-1b. Study limitations included the use of healthy subjects rather than disease subjects, the lack of a validated assessment tool for evaluating FLS and the relatively high discontinuation rate. A short 2 week, dose-titration regimen reduces FLS severity following interferon gamma-1b treatment initiation in normal subjects.

Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration

OpenAIRE

McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

2011-01-01

Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent (i.e., postnatal day (PND) 40) rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a “challenge” high-dose METH regimen when administered ...

Comparison of current recommended regimens of atropinization in organophosphate poisoning.

Science.gov (United States)

Connors, Nicholas J; Harnett, Zachary H; Hoffman, Robert S

2014-06-01

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.'s work, texts of Internal and Emergency Medicine, and electronic resources were reviewed for atropine dosing recommendations. For comparison, recommendations were assessed using the same mean dose (23.4 mg) and the highest dose (75 mg) of atropine as used in the original paper. Recommendations were also compared with the dosing regimen from the World Health Organization (WHO). Thirteen of the original recommendations were updated and 15 additional references were added giving a convenience sample of 28. Sufficient information to calculate time to targeted dose was provided by 24 of these samples. Compared to 2004, current recommendations have greatly increased the speed of atropinization with 13/24 able to reach the mean and high atropine dose within 30 min compared to 1/36 in 2004. In 2004, there were 13 regimens where the maximum time to reach 75 mg was over 18 h, whereas now, there are 2. While only one recommendation called for doubling the dose for faster escalation in 2004, 15 of the 24 current works include dose doubling. In 2004, Eddleston et al. called for an evidence-based guideline for the treatment of OP poisoning that could be disseminated worldwide. Many current recommendations can adequately treat patients within 1 h. While the WHO recommendations remain slow to treat patients with OP poisoning, other authorities are close to a consensus on rapid atropinization.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns

Directory of Open Access Journals (Sweden)

Laura Vargas Dornelles

2016-05-01

Full Text Available Objective: To compare the efficacy of intravenous ibuprofen at high (20-10-10 mg/kg/dose and low doses (10-5-5 mg/kg/dose the closure of patent ductus arteriosus in preterm newborns. Methods: A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Results: Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8% low-dose patients and in 17 (51.5% high-dose patients (p > 0.99. Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p > 0.99. Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p = 0.22. Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p > 0.99. Twenty-two (50% low-dose patients died vs. 15 (45.5% high-dose patients (p = 0.86. Conclusions: There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Resumo: Objetivo: Comparar a eficácia do ibuprofeno endovenoso em doses altas (20, 10 e 10 mg/kg/dose e em doses baixas (10, 5 e 5 mg/kg/dose para o fechamento do canal arterial em recém-nascidos pré-termo. Métodos: Estudo de coorte com controle histórico pesquisando recém-nascidos que receberam ibuprofeno endovenoso, no período de 2010 à 2013 na unidade de internação neonatal, em doses altas e baixas para o fechamento do canal arterial, documentado por

Optimization of inactivated H5N9 highly pathogenic avian influenza vaccine and inactivated Salmonella enterica serovar Typhimurium vaccine with antigen dose and prime-boost regimen in domestic ducks.

Science.gov (United States)

Yuk, Seong-Su; To, Eredene-Ochir; Kwon, Jung-Hoon; Noh, Jin-Yong; Hong, Woo-Tack; Jeong, Jei-Hyun; Gwon, Gyeong-Bin; Song, Chang-Seon

2017-09-01

Owing to the increase in the number of diseases affecting ducks and the demand for food safety by consumers, vaccination has become one of the factors that influence duck meat productivity. The highly pathogenic avian influenza (HPAI) virus is one of the most prevalent and causes one of the most lethal diseases in domestic ducks, and Salmonella enterica serovar Typhimurium is a food-borne pathogen persistent in the domestic duck population. To better understand the optimal usage of HPAI and S. enterica serovar Typhimurium vaccines, we aimed to determine antigen dose, oil and gel adjuvant usage with prime-boost regimen, and vaccination age, inducing the best immune response in ducks, without an effect on body weight gain. In the case of the inactivated H5N9 vaccine, a single dose of vaccine was inadequate to induce proper antibody titer when administered to day-old ducks, which necessitates boost vaccination. Administration of the oil-adjuvanted H5N9 vaccine administration in day-old and 2-week-old ducks resulted in a lower body weight at the time of slaughtering, compared to that of gel-adjuvanted H5N9 vaccine. However, gel-adjuvanted H5N9 vaccine failed to induce proper immune response to an extent recommend by OIE-World Organization for Animal Health. In the case of the Salmonella enterica serovar Typhimurium vaccine, a moderate or low dose of vaccine was appropriate for day-old ducks receiving the gel prime-oil boost vaccination. Single vaccination with oil adjuvants affects the mean body weight of 7-week-old ducks, suggesting that the gel adjuvant is more suitable for meat production. We expect that the use of adjuvants in a prime-boost regimen and at antigen doses set in this study will be helpful to maximize body weight in the case of domestic duck production at the actual farm site. © 2017 Poultry Science Association Inc.

IIVP salvage regimen induces high response rates in patients with relapsed lymphoma before autologous stem cell transplantation.

Science.gov (United States)

Abali, Huseyin; Oyan, Basak; Koc, Yener; Kars, Ayse; Barista, Ibrahim; Uner, Aysegul; Turker, Alev; Demirkazik, Figen; Tekin, Fatma; Tekuzman, Gulten; Kansu, Emin

2005-06-01

Patients with relapsed lymphoma can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). New therapeutic approaches with better cytoreductive capacity are needed for relapsed patients to keep their chance for cure with transplantation. We report 30 patients with relapsed lymphoma, median age 43 years, treated with IIVP salvage regimen consisting of ifosfamide, mesna, idarubicin, and etoposide for 2 or 3 cycles. Seventeen patients had non-Hodgkin lymphoma (NHL) and 13 patients had Hodgkin disease (HD). Fourteen (47%) patients were at their first relapse. Overall response rate was 86.6% (n = 26) with 19 patients (63.3%) achieving complete response. Overall response rate was 92% in patients with HD and 82% in NHL. The most frequent side effects observed were grade III-IV neutropenia (87%) and thrombocytopenia (73%). IIVP regimen is a highly effective salvage therapy for patients with relapsed HD or NHL who are candidates for autologous HSCT. Close follow up is necessary because of the high incidence of grade III-IV hematologic toxicity.

Comparison of two dose regimens of growth hormone (GH) with different target IGF-1 levels on glucose metabolism, lipid profile, cardiovascular function and anthropometric parameters in gh-deficient adults.

Science.gov (United States)

Cenci, Maria Claudia Peixoto; Soares, Débora Vieira; Spina, Luciana Diniz Carneiro; Brasil, Rosane Resende de Lima Oliveira; Lobo, Priscila Marise; Michmacher, Eduardo; Vaisman, Mario; Boguszewski, Cesar Luiz; Conceição, Flávia Lúcia

2012-01-01

To compare the effects of two regimens of GH therapy with different target IGF-1 levels on anthropometric parameters, glucose metabolism, lipid profile and cardiac function in adults with GH deficiency (GHD). Retrospective analysis of 14 GHD adults from Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil, who were treated with a GH regimen aimed at maintaining serum IGF-1 levels between the median and upper reference limit (high dose group - HDGH) and 18 GHD adults from Federal University Hospital, Curitiba, Brazil, who received a fixed GH dose of 0.2mg/day in the first year of treatment, followed by titration to maintain serum IGF-1 levels between the median and lower reference limit (low dose group - LDGH). All patients were followed for 2 years with analysis of anthropometric parameters, serum levels of IGF-1, glucose, insulin, HOMA-IR, lipid profile, and transthoracic echocardiography. Changes on weight, BMI and waist circumference were similar between the two groups. Insulin levels increased and HOMA-IR worsened in the LDGH group at 1year and improved thereafter. Total cholesterol and triglycerides did not change with therapy. LDL cholesterol reduced in both groups, while HDL-cholesterol significantly increased only in the HDGH group (p=0.007 vs LDGH). No significant variations on echocardiographic parameters were observed. The HDGH and LDGH regimens resulted in similar changes on anthropometric, echocardiographic, glucose and lipid parameters in GHD adults, except for increase in HDL cholesterol that was only observed in the HDGH regimen. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cluster-randomized non-inferiority trial to compare supplement consumption and adherence to different dosing regimens for antenatal calcium and iron-folic acid supplementation to prevent preeclampsia and anaemia: rationale and design of the Micronutrient Initiative study

Directory of Open Access Journals (Sweden)

Moshood O. Omotayo

2015-11-01

Full Text Available Background: To prevent pre-eclampsia in populations with insufficient dietary calcium (Ca intake, the World Health Organisation (WHO recommends routine Ca supplementation during antenatal care (ANC. WHO guidelines suggest a complex dosing regimen, requiring as many as 5 pill-taking events per day when combined with iron and folic acid (IFA supplements. Poor adherence may undermine public health effectiveness, so simpler regimens may be preferable. This trial will compare the effect of the WHO-recommended (higher-dose regimen vs. a simpler, lower-dose regimen on supplement consumption and pill-taking behaviours in Kenyan ANC clients. Design and methods: This is a parallel, non-inferiority, cluster-randomized trial; we examined 16 primary care health facilities in Kenya, 1047 pregnant women between 16-30 weeks gestational age. Higher-dose regimen: 1.5 g elemental calcium in 3 separate doses (500 mg Ca/pill and IFA (60 mg Fe + 400 μg folic acid taken with evening dose. Lower-dose regimen: 1.0 g calcium in 2 separate doses (500 mg Ca/pill with IFA taken as above. Measurements: Primary outcome is Ca pills consumed per day, measured by pill counts. Secondary outcomes include IFA pills consumed per day, client knowledge, motivation, social support, and satisfaction, measured at 4 to 10 weeks post-enrolment. Statistical analyses: Unit of randomization is the health-care facility; unit of analysis is individual client. Intent-to-treat analysis will be implemented with multi-level models to account for clustering. Expected public health impact: If pregnant women prescribed lower doses of Ca ingest as many pills as women prescribed the WHO-recommended regimen, developing a lower-dose recommendation for antenatal Ca and IFA supplementation programs could save resources.

Prophylactic antibiotic regimens in tumour surgery (PARITY)

DEFF Research Database (Denmark)

Petersen, Michael Mørk; Hettwer, Werner H; Grum-Schwensen, Tomas

2015-01-01

-day regimen of post-operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours. METHODS: We performed a pilot international multi-centre RCT. We used central randomisation...... to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens. RESULTS: We screened 96 patients and enrolled 60 participants......% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post-operatively, but 93% of all post-operative doses were administered per protocol. CONCLUSIONS: It is feasible to conduct a definitive multi-centre RCT of post...

Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens

DEFF Research Database (Denmark)

Siqueira, Scheyla D V S; Müllertz, Anette; Gräeser, Kirsten

2017-01-01

The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were......, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption...

Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation

International Nuclear Information System (INIS)

Belkacemi, Yazid; Labopin, Myriam; Hennequin, Christophe; Hoffstetter, Sylvette; Mungai, Raffaello; Wygoda, Marc; Lundell, Marie; Finke, Jurgen; Aktinson, Chris; Lorchel, Frederic; Durdux, Catherine; Basara, Nadezda

2007-01-01

Purpose: The high rate of toxicity is the limitation of myelobalative regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. Methods and Materials: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). Results: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). Conclusions: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population

High-dose buprenorphine: perioperative precautions and management strategies.

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Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

Cycloplegic Refraction in Hyperopic Children: Effectiveness of a 0.5% Tropicamide and 0.5% Phenylephrine Addition to 1% Cyclopentolate Regimen.

Science.gov (United States)

Yoo, Seul Gi; Cho, Myung Jin; Kim, Ungsoo Samuel; Baek, Seung Hee

2017-06-01

To evaluate the effectiveness of a cycloplegic regimen using 0.5% tropicamide and 0.5% phenylephrine (Tropherine, Hanmi Pharm), in addition to 1% cyclopentolate, in hyperopic children. The medical records of hyperopic patients below the age of 14 years who had undergone cycloplegic retinoscopy were retrospectively reviewed. Cycloplegic refractions were performed using one of two cycloplegic regimens. Regimen 1 was a Tropherine-added regimen comprising the administration of one drop of 1% cyclopentolate followed by two to three drops of Tropherine added at 15-minute intervals. Regimen 2 was a cyclopentolate-only regimen comprising the administration of three to four drops of 1% cyclopentolate at 15-minute intervals. The mean difference between noncycloplegic and cycloplegic refraction was compared between the two regimens. A total of 308 eyes of 308 hyperopic children were included. The mean difference (±standard deviation) in the spherical equivalent (SE) between cycloplegic and noncycloplegic refraction was significantly larger in regimen 2 than in regimen 1, with values of +1.70 ± 1.03 diopters (D) and +1.25 ± 0.89 D, respectively (p=0.001). The SE change after cycloplegia was significantly different between the two regimens only in patients aged 5 years or younger (p=0.001), particularly in those with high hyperopia with an SE ≥5 D (p=0.005) or fully accommodative esotropia (p=0.009). There was no significant difference between the two regimens in patients older than 5 years, regardless of the presence of high hyperopia or fully accommodative esotropia. The Tropherine-added regimen exerted a weaker cycloplegic effect than the cyclopentolate-only regimen, particularly in children under the age of 5 years with high hyperopia or fully accommodative esotropia. However, the difference in refraction between the two regimens was small. A Tropherine-added regimen can be effective in hyperopic children, with less associated discomfort than the instillation of

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

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Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study.

Science.gov (United States)

Popov, I P; Jelić, S B; Krivokapić, Z V; Jezdić, S D; Pesko, P M; Micev, M T; Babić, D R

2008-01-01

To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. Histologically confirmed measurable advanced gastric cancer, age EAP arm: doxorubicin (40 mg/m(2)), etoposide (360 mg/m(2)), and cisplatin (80 mg/m(2)) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m(2) 24 h infusion, biweekly. Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2-8), HD 5-FU arm 2 (1-8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16-50%]/HD 5-FU arm 10% (0-21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3-27], HD 5-FU arm 6 mo (4-25). Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.

The Effect of a New Sodium Bicarbonate Loading Regimen on Anaerobic Capacity and Wrestling Performance

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Krzysztof Durkalec-Michalski

2018-05-01

Full Text Available Gastrointestinal side effects are the main problem with sodium bicarbonate (SB use in sports. Therefore, our study assessed the effect of a new SB loading regimen on anaerobic capacity and wrestling performance. Fifty-eight wrestlers were randomized to either a progressive-dose regimen of up to 100 mg∙kg−1 of SB or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first Wingate, dummy throw, and second Wingate tests. Blood samples were taken pre- and post-exercise. No gastrointestinal side effects were reported during the study. After SB treatment, there were no significant improvements in the outcomes of the Wingate and dummy throw tests. The only index that significantly improved with SB, compared to the placebo (p = 0.0142, was the time-to-peak power in the second Wingate test, which decreased from 3.44 ± 1.98 to 2.35 ± 1.17 s. There were also no differences in blood lactate or glucose concentrations. In conclusion, although the new loading regimen eliminated gastrointestinal symptoms, the doses could have been too small to elicit additional improvements in anaerobic power and wrestling performance. However, shortening the time-to-peak power during fatigue may be particularly valuable and is one of the variables contributing to the final success of a combat sports athlete.

The Effect of a New Sodium Bicarbonate Loading Regimen on Anaerobic Capacity and Wrestling Performance.

Science.gov (United States)

Durkalec-Michalski, Krzysztof; Zawieja, Emilia Ewa; Podgórski, Tomasz; Zawieja, Bogna Ewa; Michałowska, Patrycja; Łoniewski, Igor; Jeszka, Jan

2018-05-30

Gastrointestinal side effects are the main problem with sodium bicarbonate (SB) use in sports. Therefore, our study assessed the effect of a new SB loading regimen on anaerobic capacity and wrestling performance. Fifty-eight wrestlers were randomized to either a progressive-dose regimen of up to 100 mg∙kg -1 of SB or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first Wingate, dummy throw, and second Wingate tests. Blood samples were taken pre- and post-exercise. No gastrointestinal side effects were reported during the study. After SB treatment, there were no significant improvements in the outcomes of the Wingate and dummy throw tests. The only index that significantly improved with SB, compared to the placebo ( p = 0.0142), was the time-to-peak power in the second Wingate test, which decreased from 3.44 ± 1.98 to 2.35 ± 1.17 s. There were also no differences in blood lactate or glucose concentrations. In conclusion, although the new loading regimen eliminated gastrointestinal symptoms, the doses could have been too small to elicit additional improvements in anaerobic power and wrestling performance. However, shortening the time-to-peak power during fatigue may be particularly valuable and is one of the variables contributing to the final success of a combat sports athlete.

Gonadal status following bone marrow transplantation with low dose busulfan-cyclophosphamide regimen

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Mohsen Khosh niat Nikoo

2006-02-01

Full Text Available Background: Gonadal dysfunction is one of the short and long-term side effects following bone marrow transplantation (BMT. We assessed hypophyseal-gonadal axis after BMT by low dose busulfan-cyclophosphamide conditioning regimen (120 mg/kg. Methods: In this cohort study, we evaluated gonadal function in 48 patients (25 pubert males and 23 pubert females. Data were obtained by history, physical examination, LH, FSH, prolactin, estradiol (E2, progesterone, testosterone and semen analysis before BMT and in 6 and 12 months of post-BMT. Results: Gonadal axis in 16 male subjects (64% was normal before BMT and remained normal in 6 subjects (37% 12 months post BMT. In another 10 patients (63%, hypogonadism was started in 6 months post BMT. Spermatogenesis failure (31%, low level of testosterone (25% and spermatogenesis failure plus low level of testosterone in 12.5% were found. Gonadal axis in 20 female subjects (87% was normal before BMT, but remained normal only in 10% of subject until the end of the study. Other patients (90% had primary hypogonadism in 6 months of post BMT. Conclusion: There is a high prevalence of gonadal dysfunction following BMT in both adult sexes (especially in female patients. Therefore, regular gonadal assessment is recommended following BMT.

The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease.

Science.gov (United States)

Tawfic, Qutaiba A; Faris, Ali S; Kausalya, Rajini

2014-02-01

Acute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. We studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. A retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2-0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5-1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. Nine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). Low-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect. Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Comparison of different glucocorticoid regimens in the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

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Ajish, T P; Praveen, V P; Nisha, B; Kumar, Harish

2014-11-01

There are recommendations regarding the total dose of hydrocortisone to be administered in the treatment of classical congenital adrenal hyperplasia (CAH) to achieve the twin objectives of glucocorticoid replacement and control of hyperandrogenism. However, there is evidence gap regarding the breakup, timing and type of the steroid regimen. Efficacy of three different glucocorticoid regimens having the same total dose of steroid, differing in either the timing or type of evening steroid administered, in achieving biochemical control of the disease was assessed. The study was done in 13 prepubertal children with classical CAH over a 6-month period with 2 months devoted to each regimen. We used a prospective cross-over design using 10-15 mg/m(2) total dose of hydrocortisone. Two-fifths of the total dose of hydrocortisone was administered in the morning and one-fifth of the total dose was administered at noon in all the regimens. The regimens differed in the timing of the evening dose of hydrocortisone, 06.00-07.00 pm in regimen 1 and 09.00-10.00 pm in regimen 2. The third regimen had the evening dose of hydrocortisone replaced by an equivalent dose of prednisolone suspension which was administered at 10.00 pm. Serum 17-hydroxyprogesterone and testosterone levels were compared to assess the efficacy of treatment regimens. The three different regimens were found to be similar in their ability to control 17-hydroxyprogesterone and testosterone levels. The percentage of patients with predefined criteria for biochemically controlled disease was similar in all the three regimens. However, there was a trend toward better control of 17-hydroxyprogesterone levels in patients receiving evening dose of prednisolone. There is no significant advantage in administering the hydrocortisone dose late at night in patients with classical CAH.

Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

Science.gov (United States)

Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

2002-09-01

The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen.

LENUS (Irish Health Repository)

Cassidy, Eugene M

2012-10-01

The aim of the study was to compare symptom-triggered and standard benzodiazepine regimens for the treatment of alcohol withdrawal syndrome in an emergency department clinical decision unit. The authors found that the symptom-triggered approach reduced cumulative benzodiazepine dose and length of stay.

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

Science.gov (United States)

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Involved field radiation therapy for Hodgkin's disease autologous bone marrow transplantation regimens

International Nuclear Information System (INIS)

Pezner, Richard D.; Nademanee, Auayporn; Niland, Joyce C.; Vora, Nayana; Forman, Stephen J.

1995-01-01

From 1986 through 1992, involved-field radiation therapy (IF-RT) was administered to 29 of 86 patients with recurrent Hodgkin's disease (HD) who received a high-dose cyclophosphamide/etoposide regimen with autologous bone marrow transplantation (A-BMT). Patients without a significant history of prior RT received total body irradiation (TBI), initially as a single dose 5-7.5 Gy, and subsequently with fractionated TBI (F-TBI) delivering 12 Gy. Previously irradiated patients received a high-dose BCNU regimen instead of TBI. IF-RT was employed selectively, usually for sites of bulky disease (> 5 cm). IF-RT doses were typically 20 Gy at 2 Gy per fraction for TBI patients and 30-40 Gy at 1.8-2.0 Gy per fraction for non-TBI Patients. Fatal complications developed in four patients while second malignancies have developed in two. The region which received IF-RT was the site of first recurrence in only two cases (7%). With a median follow-up of 28 months, the two-year disease-free survival rate was 44%. For the 22 patients treated by either F-TBI or high-dose BCNU, the 2-year disease-free survival rate was 50% with a median follow up of 29 months. Selective use of IF-RT may increase the chances of complete remission and disease free survival in HD patients with a history of bulky disease

Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.

Science.gov (United States)

Shiber, Shachaf; Stiebel-Kalish, Hadas; Shimon, Ilan; Grossman, Alon; Robenshtok, Eyal

2014-10-01

Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], phyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis.

Science.gov (United States)

Chirehwa, Maxwell T; McIlleron, Helen; Rustomjee, Roxana; Mthiyane, Thuli; Onyebujoh, Philip; Smith, Peter; Denti, Paolo

2017-08-01

Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively. Copyright © 2017 American Society for Microbiology.

Classifying insulin regimens

DEFF Research Database (Denmark)

Neu, A; Lange, K; Barrett, T

2015-01-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1...

Leveraging protein binding and the EPR effect in legacy chemotherapy regimens

Directory of Open Access Journals (Sweden)

Shireesh Apte

2016-12-01

Full Text Available Legacy chemotherapy regimens have the potential to be significantly more effective and less toxic if the dosage is titrated so that the mole ratio of drugs to circulating albumin is less than or equal to 1 and the order of administration of the drugs within each course of the regimen follows the sequence most hydrophobic (usually the least dose to least hydrophobic (usually the largest dose

Single Dose Versus 3 Doses of Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial.

Science.gov (United States)

Andrade, Roberto; Rodriguez-Barradas, Maria C; Yasukawa, Kosuke; Villarreal, Erick; Ross, Michael; Serpa, Jose A

2017-03-15

Patients coinfected with syphilis and human immunodeficiency virus (HIV) may have a slower decrease in rapid plasma reagin (RPR) titers. Currently a single dose of 2.4 million units of intramuscular benzathine penicillin G (BPG) is recommended for the treatment of early syphilis. Some observational studies have suggested that this regimen may lead to high failure rates in coinfected patients. We conducted an open-label randomized clinical trial to compare the efficacy of single-dose and 3-dose regimens of BPG for the treatment of early syphilis in HIV-infected individuals. RPR titers were monitored every 3 months. Treatment success was defined as a decrease in RPR titers of ≥2 dilutions (4-fold) during a 12-month follow-up period. Sixty-four patients were included. In the intention-to-treat analysis, treatment success rates were 80% (28 of 35 subjects) and 93% (27 of 29 subjects) in the single-dose and 3-dose regimens, respectively (absolute difference, 13% [95% confidence interval {CI}, -5% to 30%; P = .17). In the per-protocol analysis, success rates were 93% (27 of 29) and 100% in the single-dose and 3-dose regimens, respectively (absolute difference, 7% [95% CI, -7% to 22%]; P = .49). CD4 T-cell count, RPR titer and syphilis stage did not affect treatment results. When compared with a single dose of BPG, a 3-dose regimen did not improve syphilis serological outcomes. Our results support the Centers for Disease Control and Prevention recommendation of a single dose of BPG in HIV-infected patients with early syphilis. NCT02611765. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects.

Science.gov (United States)

Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

2017-06-03

To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China.

Influence of control group therapy on the benefit from dose-dense chemotherapy in early breast cancer: a systemic review and meta-analysis.

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Goldvaser, Hadar; Majeed, Habeeb; Ribnikar, Domen; Šeruga, Boštjan; Ocaña, Alberto; Cescon, David W; Amir, Eitan

2018-02-08

Results from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent. A systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta-regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy. The primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group.

High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial.

Science.gov (United States)

Pearson, Andrew D J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Ellershaw, Caroline; Machin, David

2008-03-01

The current standard treatment for patients with high-risk neuroblastoma includes initial induction chemotherapy with a 21-day interval between induction treatments. We aimed to assess whether an intensive chemotherapy protocol that had a 10-day interval between treatments would improve event-free survival (EFS) in patients aged 1 year or over with high-risk neuroblastoma. Between Oct 30, 1990, and March 18, 1999, patients with stage 4 neuroblastoma who had not received previous chemotherapy were enrolled from 29 centres in Europe. Patients were randomly assigned to rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC) or standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC). Both regimens used the same total cumulative doses of each drug (except vincristine), but the dose intensity of the rapid regimen was 1.8-times higher than that of the standard regimen. The standard regimen was given every 21 days if patients showed haematological recovery, whereas the rapid regimen was given every 10 days irrespective of haematological recovery. Response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC). In responders, surgical excision of the primary tumour was attempted, followed by myeloablation (with 200 mg/m2 of melphalan) and haemopoietic stem-cell rescue. Primary endpoints were 3-year, 5-year, and 10-year EFS. Data were analysed by intention to treat. This trial is registered on the clinical trials site of the US National Cancer Institute website, number NCT00365755, and also as EU-20592 and CCLG-NB-1990-11. 262 patients, of median age 2.95 years (range 1.03-20.97), were randomly assigned-132 patients to standard and 130 patients to rapid treatment. 111 patients in the standard group and 109

Split-Course, High-Dose Palliative Pelvic Radiotherapy for Locally Progressive Hormone-Refractory Prostate Cancer

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Gogna, Nirdosh Kumar, E-mail: kumar_gogna@health.qld.gov.au [Radiation Oncology Services, Mater Centre, Brisbane, Queensland (Australia); Baxi, Siddhartha; Hickey, Brigid; Baumann, Kathryn [Radiation Oncology Services, Mater Centre, Brisbane, Queensland (Australia); Burmeister, Elizabeth [Princess Alexandra Hospital, Brisbane, Queensland (Australia); Holt, Tanya [Radiation Oncology Services, Mater Centre, Brisbane, Queensland (Australia)

2012-06-01

Purpose: Local progression, in patients with hormone-refractory prostate cancer, often causes significant morbidity. Pelvic radiotherapy (RT) provides effective palliation in this setting, with most published studies supporting the use of high-dose regimens. The aim of the present study was to examine the role of split-course hypofractionated RT used at our institution in treating this group of patients. Methods and Materials: A total of 34 men with locoregionally progressive hormone-refractory prostate cancer, treated with a split course of pelvic RT (45-60 Gy in 18-24 fractions) between 2000 and 2008 were analyzed. The primary endpoints were the response rate and actuarial locoregional progression-free survival. Secondary endpoints included overall survival, compliance, and acute and late toxicity. Results: The median age was 71 years (range, 53-88). Treatment resulted in an overall initial response rate of 91%, a median locoregional progression-free survival of 43 months, and median overall survival of 28 months. Compliance was excellent and no significant late toxicity was reported. Conclusions: The split course pelvic RT described has an acceptable toxicity profile, is effective, and compares well with other high-dose palliative regimens that have been previously reported.

"Time sequential high dose of Cytarabine in acute myelocytic leukemia "

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Ghavamzadeh A

2003-05-01

Full Text Available Given preliminary evidence of timed, sequential chemotherapy of high dose cytosine arabinoside the current study was initiated to assess the side effects and efficacy of this regimen in patients with newly acute myelocytic leukemia (AML. Nineteen adults who referred to Hematology-Oncology and Bone Marrow Transplantation (BMT research center of Tehran University of Medical Sciences were enrolled in a trial from Aug 1999 to Nov 2000. All patients had a Karnofski classification above 60%. At this time induction therapy consisted of daunorubicin or idarubicin given at a dose of 60 mg/m² and 12 mg/m² IV respectively on days 1-3, and cytarabine (Ara-C 100 mg/m² intravenously by continuous infusion on days 1-7, followed by Ara-C 1000 mg/m² given on day 8-10 every 12 hours by IV infusion. Consolidation therapy started after 35th day. Of 19 fully evaluable patients, 10 patients achieved a complete remission, whereas 36.6% patients succumbed to death due to regeneration failure. The clinical data show that the overall survival rate from diagnosis 55.5% (95% CI, 30.8-78.5 at 6 months for the entire cohort of the patients. Disease free survival is also 50% (95% CI, 26-74. Mean duration of death due to treatment was 20 days (range 17-29 after beginning the regimen. Presenting WBC counts, French-American-British (FAB classification, sex and age were not useful prognostic variables. Fever, diarrhea, nausea and vomiting and GI hemorrhage were seen in 19, 6, 4, 7 patients respectively. It seems the 3+7+3 regimen is a promising approach for the AML patients regarding to high complete remission rate, but more supportive care should be considered. Furthermore any, benefit in long-term outcome can’t be determined regardless to the choice of post remission therapy (e.g., GCSF, appropriate antibiotics and etc.

Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

Science.gov (United States)

Salerno, Francesco; Navickis, Roberta J; Wilkes, Mahlon M

2015-11-25

Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of

Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

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Zhu Xiongpeng

2010-04-01

Full Text Available Abstract Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML. However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine, FLT3 inhibitor (sorafenib, farnesyl-transferase inhibitor (tipifarnib, histone deacetylase inhibitor (vorinostat, lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine, were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421 from the 2009 ASH annual meeting.

Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

Science.gov (United States)

Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

2014-01-01

Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

Dose escalation by image-guided intensity-modulated radiotherapy leads to an increase in pain relief for spinal metastases: a comparison study with a regimen of 30 Gy in 10 fractions.

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He, Jinlan; Xiao, Jianghong; Peng, Xingchen; Duan, Baofeng; Li, Yan; Ai, Ping; Yao, Min; Chen, Nianyong

2017-12-22

Under the existing condition that the optimum radiotherapy regimen for spinal metastases is controversial, this study investigates the benefits of dose escalation by image-guided intensity-modulated radiotherapy (IG-IMRT) with 60-66 Gy in 20-30 fractions for spinal metastases. In the dose-escalation group, each D50 of planning gross tumor volume (PGTV) was above 60 Gy and each Dmax of spinal cord planning organ at risk volume (PRV) was below 48 Gy. The median biological effective dose (BED) of Dmax of spinal cord was lower in the dose-escalation group compared with that in the 30-Gy group (69.70 Gy vs. 83.16 Gy, p pain responses were better in the dose-escalation group than those in the 30-Gy group ( p = 0.005 and p = 0.024), and the complete pain relief rates were respectively 73.69% and 34.29% ( p = 0.006), 73.69% and 41.38% ( p = 0.028) in two compared groups. In the dose-escalation group, there is a trend of a longer duration of pain relief, a longer overall survival and a lower incidence of acute radiation toxicities. No late radiation toxicities were observed in both groups. Dosimetric parameters and clinical outcomes, including pain response, duration of pain relief, radiation toxicities and overall survival, were compared among twenty-five metastatic spinal lesions irradiated with the dose-escalation regimen and among forty-four lesions treated with the 30-Gy regimen. Conventionally-fractionated IG-IMRT for spinal metastases could escalate dose to the vertebral lesions while sparing the spinal cord, achieving a better pain relief without increasing radiation complications.

Hyperfractionated high-dose total body irradiation in bone marrow transplantation for Ph{sup 1}-positive acute lymphoblastic leukemia

Energy Technology Data Exchange (ETDEWEB)

Kikuchi, Akira; Ebihara, Yasuhiro; Mitsui, Tetsuo [Tokyo Univ. (Japan). Hospital of the Institute of Medical Science] [and others

1998-12-01

In two cases of Philadelphia-positive childhood acute lymphoblastic leukemia (Ph{sup 1} ALL), we performed allogeneic bone marrow transplantation (AlloBMT) with preconditioning regimen, including hyperfractionated high-dose total body irradiation (TBI) (13.5 Gy, in 9 fractions). Their disease statuses at BMT were hematological relapse in case 1 and molecular relapse in case 2. Bone marrow donors were unrelated in case 1, and HLA was a partially mismatched mother in case 2. Regimen-related toxicity was tolerable in both cases. Hematological recovery was rapid, and engraftment was obtained on day 14 in case 1 and on day 12 in case 2. BCR/ABL message in bone marrow disappeared on day 89 in case 1 and on day 19 in case 2 and throughout their subsequent clinical courses. Although short-term MTX and Cy-A continuous infusion were used for GVHD prophylaxis, grade IV GVHD was observed in case 1 and grade III in case 2. Both cases experienced hemorrhagic cystitis because of adenovirus type 11 infection. Although case 1 died of interstitial pneumonitis on day 442, case 2 has been free of disease through day 231. AlloBMT for Ph{sup 1} ALL with preconditioning regimen including hyperfractionated high-dose TBI is considered to be worth further investigation. (author)

Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

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Seyed Amir Dadkhahi

2017-05-01

Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

Treatment outcomes of fixed-dose combination versus separate tablet regimens in pulmonary tuberculosis patients with or without diabetes in Qatar.

Science.gov (United States)

Al-Shaer, Mohammad H; Mansour, Hanine; Elewa, Hazem; Salameh, Pascale; Iqbal, Fatima

2017-02-02

Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB. A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups. The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics. ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

Science.gov (United States)

Taylor, W Robert; Naw, Htee Khu; Maitland, Kathryn; Williams, Thomas N; Kapulu, Melissa; D'Alessandro, Umberto; Berkley, James A; Bejon, Philip; Okebe, Joseph; Achan, Jane; Amambua, Alfred Ngwa; Affara, Muna; Nwakanma, Davis; van Geertruyden, Jean-Pierre; Mavoko, Muhindo; Lutumba, Pascal; Matangila, Junior; Brasseur, Philipe; Piola, Patrice; Randremanana, Rindra; Lasry, Estrella; Fanello, Caterina; Onyamboko, Marie; Schramm, Birgit; Yah, Zolia; Jones, Joel; Fairhurst, Rick M; Diakite, Mahamadou; Malenga, Grace; Molyneux, Malcolm; Rwagacondo, Claude; Obonyo, Charles; Gadisa, Endalamaw; Aseffa, Abraham; Loolpapit, Mores; Henry, Marie-Claire; Dorsey, Grant; John, Chandy; Sirima, Sodiomon B; Barnes, Karen I; Kremsner, Peter; Day, Nicholas P; White, Nicholas J; Mukaka, Mavuto

2018-01-18

In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244

A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis.

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Marcus B Conde

Full Text Available The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg plus moxifloxacin (investigational arm, or rifampin (approximately 10 mg/kg plus ethambutol (control daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.121 participants (56% of accrual target were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ medium occurred in 47/60 (78% participants in the investigational arm vs. 43/51 (84%, p = 0.47 in the control arm; negative cultures using liquid medium occurred in 37/47 (79% in the investigational arm vs. 27/41 (66%, p = 0.23 in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03, but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24 was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04 although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the

[High-dosed gestagen therapy of the metastatic mammary carcinoma (author's transl)].

Science.gov (United States)

Firusian, N; Becher, R

1981-12-01

Thirty patients with histologically proven metastatic mammary carcinoma were treated, after exhaustion of hormonal and cytostatic therapeutic means, with high-dosed medroxyprogesterone acetate (MPA) during a ten-day induction phase with 1000 mg MPAi.m. per day and then with 600 mg oral MPA per day. In eleven patients a complete or partial remission was achieved. The median period of remission comprised ten months. A positive relationship was found between the response to high-dosed MPA therapy and the length of free intervals. Side effects were tolerable.

Cancer-Associated Fibroblasts from lung tumors maintain their immuno-suppressive abilities after high-dose irradiation

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Laia eGorchs

2015-05-01

Full Text Available Accumulating evidence supports the notion that high-dose (>5 Gy radiotherapy (RT regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study we have investigated the effects of high-dose irradiation (HD-RT on the immunomodulating functions of cancer-associated fibroblasts (CAFs. Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays and T-cell cytokine production. Additionally, CAF-secreted immuno-regulatory factors were studied by multiplex protein arrays, ELISAs and by LC-MS/MS proteomics. In all functional assays we observed a powerful immuno-suppressive effect exerted by CAF-conditioned medium on activated T-cells (p>0,001, and this effect was sustained after a single radiation dose of 18 Gy. Relevant immuno-suppressive molecules such as prostaglandin E2, interleukin-6 and -10, or transforming growth factor-β were found in CAF conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immuno-suppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence.

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Strohal, Robert; Chimenti, Sergio; Vena, Gino Antonio; Girolomoni, Giampiero

2013-06-01

The treatment of psoriasis requires long-lasting intervention. Conventional treatments for psoriasis comprise topical, phototherapeutic and systemic modalities, such as methotrexate or cyclosporine. Biological therapies are advocated by treatment guidelines for the use in moderate-to-severe psoriasis, when conventional treatments have failed, are contraindicated or are associated with severe adverse events. Etanercept is an anti-TNF recombinant fusion protein that has emerged as a standard biologic treatment option for moderate-to-severe psoriasis. The present review summarizes data from pivotal and post-marketing randomized controlled etanercept trials to treat moderate-to-severe psoriasis for 24 weeks and longer. During the first 12 weeks, etanercept can be administered in different dosing regimens: 50 mg twice weekly (BIW) and 50 mg once weekly. Although both regimens are effective, it has been shown that the 50 mg BIW dosage leads to higher response rates at week 24. In addition, after 24 weeks' treatment etanercept provides the unique possibility of continuous or intermittent long-term treatment programmes. The medium- to long-term efficacy of etanercept was consistent, regardless of whether etanercept therapy was interrupted or continuous. Taking the chronic nature of psoriasis into account, this flexibility in dosing regimen bestows a key advantage in facilitating individualisation of long-term treatment according to patient needs.

Comparative study of SOI/Si hybrid substrates fabricated using high-dose and low-dose oxygen implantation

International Nuclear Information System (INIS)

Dong Yemin; Chen Meng; Chen Jing; Wang Xiang; Wang Xi

2004-01-01

Hybrid substrates comprising both silicon-on-insulator (SOI) and bulk Si regions have been fabricated using the technique of patterned separation by implantation of oxygen (SIMOX) with high-dose (1.5 x 10 18 cm -2 ) and low-dose ((1.5-3.5) x 10 17 cm -2 ) oxygen ions, respectively. Cross-sectional transmission electron microscopy (XTEM) was employed to examine the microstructures of the resulting materials. Experimental results indicate that the SOI/Si hybrid substrate fabricated using high-dose SIMOX is of inferior quality with very large surface height step and heavily damaged transitions between the SOI and bulk regions. However, the quality of the SOI/Si hybrid substrate is enhanced dramatically by reducing the implant dose. The defect density in transitions is reduced considerably. Moreover, the expected surface height difference does not exist and the surface is exceptionally flat. The possible mechanisms responsible for the improvements in quality are discussed

Total Skin Electron Beam Therapy in the Treatment of Mycosis Fungoides: A Review of Conventional and Low-Dose Regimens.

Science.gov (United States)

Chowdhary, Mudit; Chhabra, Arpit M; Kharod, Shivam; Marwaha, Gaurav

2016-12-01

Mycosis fungoides (MF) is the most prevalent subtype of cutaneous T-cell lymphoma, which is characterized by the proliferation of CD4 + T cells. While often an indolent disease, most patients eventually develop progression from isolated patches to tumors and finally nodal or visceral involvement. Treatment choice is largely based on disease burden, though prognostic factors such as disease stage, patient age, and extracutaneous involvement must be taken into consideration. Radiotherapy represents one of the most effective therapeutic modalities in the treatment of MF. Lymphocytes are exquisitely radiosensitive, and excellent responses are observed even with low doses of radiation. Total skin electron beam therapy (TSEBT) is a special technique that allows for the homogenous irradiation of the entire skin. There are well-documented radiation dose-response relationships for achieving a complete response. As such, TSEBT doses ≥ 30 Gy comprise the current standard of care. Although highly effective, most patients experience recurrent disease even after conventional-dose (≥ 30 Gy) TSEBT. In addition, toxicity is cumulatively dose dependent, and there is reluctance to administer multiple courses of conventional-dose TSEBT. Consequently, there has been renewed interest in determining the utility of TSEBT at lower total (≤ 30 Gy) doses. Advantages of low-total-dose (with standard dose per fraction) TSEBT include a shortened treatment course, the potential to minimize the risk of adverse events, and the opportunity to allow for retreatment in cases of disease recurrence. This comprehensive review compares the impact of different TSEBT dosing schemes on clinical outcomes of MF. Copyright © 2016 Elsevier Inc. All rights reserved.

Pentobarbital quantitation using EMIT serum barbiturate assay reagents: application to monitoring of high-dose pentobarbital therapy.

Science.gov (United States)

Pape, B E; Cary, P L; Clay, L C; Godolphin, W

1983-01-01

Pentobarbital serum concentrations associated with a high-dose therapeutic regimen were determined using EMIT immunoassay reagents. Replicate analyses of serum controls resulted in a within-assay coefficient of variation of 5.0% and a between-assay coefficient of variation of 10%. Regression analysis of 44 serum samples analyzed by this technique (y) and a reference procedure (x) were y = 0.98x + 3.6 (r = 0.98; x = ultraviolet spectroscopy) and y = 1.04x + 2.4 (r = 0.96; x = high-performance liquid chromatography). Clinical evaluation of the results indicates the immunoassay is sufficiently sensitive and selective for pentobarbital to allow accurate quantitation within the therapeutic range associated with high-dose therapy.

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

Science.gov (United States)

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046

Immune reactivity after high-dose irradiation

International Nuclear Information System (INIS)

Gassmann, W.; Wottge, H.U.; von Kolzynski, M.; Mueller-Ruchholtz, W.

1986-01-01

Immune reactivity after total-body irradiation was investigated in rats using skin graft rejection as the indicator system. After sublethal irradiation with 10.5 Gy (approximately 50% lethality/6 weeks) the rejection of major histocompatibility complex allogeneic skin grafts was delayed significantly compared with nonirradiated control animals (28 versus 6.5 days). In contrast, skin grafts were rejected after 7.5 days in sublethally irradiated animals and 7 days in lethally irradiated animals if additional skin donor type alloantigens--namely, irradiated bone marrow cells--were given i.v. either simultaneously or with a delay of not more than 24 hr after the above conditioning regimen. These reactions were alloantigen-specific. They were observed in six different strain combinations with varying donors and recipients. Starting on day 2 after irradiation, i.v. injection of bone marrow gradually lost its effectivity and skin grafts were no longer rejected with uniform rapidity; skin donor marrow given on days 4 or 8 did not accelerate skin graft rejection at all. These data show that for approximately 1-2 days after high-dose total-body irradiation rats are still capable of starting a vigorous immune reaction against i.v.-injected alloantigens. The phenomenon of impaired rejection of skin grafted immediately after high-dose irradiation appears to result from the poor accessibility of skin graft alloantigens during the early postirradiation phase when vascularization of the grafted skin is insufficient

High-dose vitamin C and cancer

Directory of Open Access Journals (Sweden)

Ahmet Unlu, M.D.

2016-01-01

Full Text Available Vitamin C (ascorbic acid, ascorbate is a basic compound that is of great importance with its role in various enzymatic reactions including the synthesis of collagen, as well as with its redox functions. Vitamin C has become the center of interest in cancer studies, in consequence of the facts that connective tissue changes and vitamin C deficiency were first alleged to be associated with cancer in the 1950s; and that high doses of vitamin C was asserted to be cytotoxic for cancer cells, later on. The results of the first study carried out in the 1970s were promising; but afterwards, the studies were ascertained to be faulty. Despite the positive results achieved from some laboratory and animal experiments, randomized clinical trials did not verify those findings, and no clear benefit of vitamin C for cancer treatment could be demonstrated. As for studies, where its use in combination with other cancer treatment regimens was assessed, conflicting results were obtained. Although intake of high doses of vitamin C is alleged to be harmless, based on that it is in the group of water soluble vitamins and is not stored in the body, there are many side effects and drug interactions reported in the literature. For now, it is better to abstain from this treatment, until the benefit of the treatment (if any is clearly demonstrated, considering the potential side effects and interactions.

Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the randomized Trial to Assess Chelation Therapy (TACT).

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Issa, Omar M; Roberts, Rhonda; Mark, Daniel B; Boineau, Robin; Goertz, Christine; Rosenberg, Yves; Lewis, Eldrin F; Guarneri, Erminia; Drisko, Jeanne; Magaziner, Allan; Lee, Kerry L; Lamas, Gervasio A

2018-01-01

In a prespecified subgroup analysis of participants not on statin therapy at baseline in the TACT, a high-dose complex oral multivitamins and multimineral regimen was found to have a large unexpected benefit compared with placebo. The regimen tested was substantially different from any vitamin regimen tested in prior clinical trials. To explore these results, we performed detailed additional analyses of participants not on statins at enrollment in TACT. TACT was a factorial trial testing chelation treatments and a 28-component high-dose oral multivitamins and multiminerals regimen versus placebo in post-myocardial infarction (MI) patients 50 years or older. There were 460 (27%) of 1,708 TACT participants not taking statins at baseline, 224 (49%) were in the active vitamin group and 236 (51%) were in the placebo group. Patients were enrolled at 134 sites around the United States and Canada. Daily high-dose oral multivitamins and multiminerals (6 tablets, active or placebo). The primary end point of TACT was time to the first occurrence of any component of the composite end point: all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for angina. The primary end point occurred in 137 nonstatin participants (30%), of which 51 (23%) of 224 were in the active group and 86 (36%) of 236 were taking placebo (hazard ratio, 0.62; 95% confidence interval, 0.44-0.87; P=.006). Results in the key TACT secondary end point, a combination of cardiovascular mortality, stroke, or recurrent MI, was consistent in favoring the active vitamin group (hazard ratio, 0.46; 95% confidence interval, 0.28-0.75; P=.002). Multiple end point analyses were consistent with these results. High-dose oral multivitamin and multimineral supplementation seem to decrease combined cardiac events in a stable, post-MI population not taking statin therapy at baseline. These unexpected findings are being retested in the ongoing TACT2. Copyright © 2017 The Authors. Published by Elsevier

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

International Nuclear Information System (INIS)

Ribeiro, Rodrigo Antonini; Duncan, Bruce Bartholow; Ziegelmann, Patricia Klarmann; Stella, Steffan Frosi; Vieira, Jose Luiz da Costa; Restelatto, Luciane Maria Fabian; Polanczyk, Carisi Anne

2015-01-01

Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective. We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied. Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

Energy Technology Data Exchange (ETDEWEB)

Ribeiro, Rodrigo Antonini, E-mail: rodrigo.ribeiro@htanalyze.com [Programa de Pós-Graduação em Epidemiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Duncan, Bruce Bartholow [Programa de Pós-Graduação em Epidemiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Cardiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Ziegelmann, Patricia Klarmann [Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Departamento de Estatística da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Stella, Steffan Frosi [Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Cardiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Vieira, Jose Luiz da Costa [Instituto de Cardiologia / Fundação Universitária de Cardiologia, Porto Alegre, RS (Brazil); Restelatto, Luciane Maria Fabian [Serviço de Medicina Interna do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS (Brazil); Polanczyk, Carisi Anne [Programa de Pós-Graduação em Epidemiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Instituto de Avaliação de Tecnologia em Saúde, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Cardiologia da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil)

2015-01-15

Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective. We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied. Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil.

Characteristics and risk factors of oral mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2.

Science.gov (United States)

Vokurka, S; Steinerova, K; Karas, M; Koza, V

2009-11-01

The fludarabine (FLU)/melphalan (MEL) conditioning regimen containing FLU and high-dose MEL was analyzed in comparison with the BU/CY2 regimen to characterize oral mucositis (OM) and risk factors. OM incidence significantly varied between BU/CY2 and FLU/MEL (100 vs 78%, P=0.004), but the incidence of severe OM grades 3-4 WHO and kinetics of OM were fully comparable. Patients with OM persisting on day +21 had more acute GVHD (68 vs 32%, P=0.005), which tended to occur earlier than among those without such prolonged OM. Multivariate analysis showed significant dependency of acute GVHD on severity and prolonged duration of OM and significant correlation between OM severity and its prolonged duration. Body surface area-based dosing in the FLU/MEL regimen led to a wide range of MEL doses administered per kilogram body weight (2.5-5.2 mg/kg, median 3.5). In multivariate analysis, MEL dose per kilogram of body weight was found to be a significant predictor of OM incidence and severity. Female gender and lower body mass index were less important variables than the fact that the actual dose of MEL administered per kilogram of body weight was relatively high when the dosage was calculated on the basis of body surface area.

Radiobiological effect of different irradiation fractionated regimens in human brain glioma

International Nuclear Information System (INIS)

Gai Xue; Yang Weizhi; Gao Li; Jiang Heng; Wang Mianrong; Shi Huizhen

2010-01-01

Objective: To evaluate the radiobiological effect of different irradiation fractionated regimens in human glioma cells (BT 325 cell line). Methods: The xenografts in Balb/c-nude mice were irradiated with different single and fractionated regimens. The single fraction dose was 10, 20, 30, 40 and 60 Gy, respectively. The fractionated regimens were 2 Gy x 5 fractions ( irradiated every day), and 3 Gy x 3 fractions (irradiated every other day), 3 Gy x 5 fractions (irradiated every day) and 4 Gy x 3 fractions (irradiated every other day), with total doses of 125 Gy, 114 Gy, 126 Gy and 112 Gy, respectively. The growth curve was used to evaluate the tumor doubling time. clonogenic assays was performed to draw the cell survival curve and analyze the radiobiological parameters with doses of 1, 2, 4, 6, 8 and 10 Gy. T 1/2 was measured by comet assay. Results: Tumor regression were not observed by single fraction irradiation, 2 Gy x 5 fractions and 3 Gy x 3 fractions irradiation regimens. The tumor regress was more significant with the increas of fraction dose. The 4 Gy x 3 fractions inhibited tumor more though not curing tumor. The cell doubling time of the BT 325 cell was 30. 16 h and the tumor doubling time of the xenograft was 43 days.When fitted with L-Q model, α was 0. 36 Gy -1 and β was 0. 057 Gy -2 . When fitted with the single-hit multi target model, D 0 was 1. 394 Gy, Dq was 2. 127 Gy and SF 2 was 0.714, respectively. The T 1/2 was 9.999 min. Conclusions: Glioma is a radioresistant tumor. Increase of the fraction dose improves recent effect.Further study is needed to control the tumor stem cells. (authors)

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study.

Science.gov (United States)

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

Analysis of factors affecting the outcome of Graves disease patients treated with two regimens of fixed Iodine-131 doses (10 mCi and 15 mCi)

International Nuclear Information System (INIS)

Machado, Ana C.B.; Santos, Roberto B.; Chaves, Fatima R.; Romaldini, Joao H.; Ward, Laura S.

2005-01-01

Full text: The use of fixed doses of radioiodine ( 131 I) simplifies the approach to treatment for Graves' disease (GD) patients with potential cost savings. In order to evaluate factors that may affect the outcome of 2 different regimens of 131 I, we prospectively examined 128 patients with overt thyrotoxicosis from GD, as confirmed by suppressed serum TSH, presence of TRAb, increased serum T 3 and FT 4 values. Group 1 comprised 76 patients who received a fixed dose of 10 mCi and Group 2=52 patients who received a fixed dose of 15 mCi. 36 patients did not use any antithyroid drugs and 92 patients used methimazole that was withdrawn at least 5 days before radioiodine administration. Antithyroid drugs treatment was restarted at least 7 days following 131 I therapy when needed. Baseline serum TSH and FT 4 levels were measured at 3, 6, 9 and 12 months after treatment. The groups were similar concerning age, gender, smoke, eye disease, goiter size, serum T 3 , FT 4 , TRAb, anti-Tg and anti-TPO levels as well as 24-hour 131 I or Tec-uptake values and thyroid scan. Clinical outcome was evaluated at the end of 1-year follow-up and cure of hyperthyroidism was defined as clinical and laboratory evidence of either euthyroidism or hypothyroidism in the absence of antithyroid drugs. The cure rate obtained was similar in groups 1 and 2: 73.7% and 80.8%, respectively (p=0.35). Hypothyroidism was diagnosed in 56.5% and 71.15% of the patients from groups 1 and 2, respectively (p=0.13). There was no correlation between clinical features, thyroid uptake, antibodies, serum hormones and outcome. However, logistic regression analysis demonstrated that patients with larger thyroids (weight >60 g) that, consequently, received a lower dose of radioiodine in MBq/g, had 2.4 times less chance to cure (95% Cl=1.18-4.96). The use of fixed doses of radioiodine ( 131 I) simplifies the approach to treatment for Graves' disease (GD) patients with potential cost savings. In order to evaluate

Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

Science.gov (United States)

Ren, Jun; Di, Lijun; Song, Guohong; Yu, Jing; Jia, Jun; Zhu, Yuling; Yan, Ying; Jiang, Hanfang; Liang, Xu; Che, Li; Zhang, Jie; Wan, Fengling; Wang, Xiaoli; Zhou, Xinna; Lyerly, Herbert Kim

2013-10-01

We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

Science.gov (United States)

Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Early intravenous immunoglobin (two-dose regimen) in the management of severe Rh hemolytic disease of newborn--a prospective randomized controlled trial.

Science.gov (United States)

Elalfy, Mohsen Saleh; Elbarbary, Nancy Samir; Abaza, Heba Wegdan

2011-04-01

Phototherapy is the standard treatment in moderately severe hemolytic disease of newborn (HDN), whereas exchange transfusion (ET) is the second line in progressive cases. Intravenous immunoglobin (IVIG) has been suggested to decrease the need for ET. We aimed at assessing the efficacy of early two-dose regimens of IVIG to avoid unnecessary ET in severe Rh HDN. The study included 90 full-term neonates with Rh incompatibility unmodified by antenatal treatment and not eligible for early ET and which were randomly assigned into one of three groups: group (I), treated by conventional method; groups IIa and IIb received IVIG once at 12 h postnatal age if PT was indicated, in a dose of 0.5 and 1 g/kg, respectively. Analysis revealed 11 neonates (22%) in the conventional group and 2 (5%) in the intervention group who administered low-dose IVIG at 12 h, while none in group IIb required exchange transfusion (p = 0.03). Mean bilirubin levels were significantly lower during the first 96 h in the intervention group compared to the conventional group (p < 0.0001). Shorter duration of phototherapy (52.8 ± 12.39 h) and hospital stay (3.25 ± 0.71 days) in the IVIG group compared to conventional group (84 ± 12.12 h and 4.72 ± 0.78 days, p < 0.0001, respectively) were observed. We conclude that IVIG administration at 12 h was effective in the treatment of severe Rh HDN; the low-dose IVIG (0.5 g/kg) was as effective as high dose (1 g/kg) in reducing the duration of phototherapy and hospital stay, but less effective in avoiding exchange transfusion.

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

Directory of Open Access Journals (Sweden)

Rodrigo Antonini Ribeiro

2015-01-01

Full Text Available Background: Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. Objective: To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS perspective. Methods: We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg, intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg, high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$. A willingness-to-pay (WTP threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770 was applied. Results: Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Conclusions: Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil.

Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

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Aisa, Yoshinobu; Mori, Takehiko; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Yokoyama, Akihiro; Ikeda, Yasuo; Okamoto, Shinichiro

2005-04-01

The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

A phase II study of V-BEAM as conditioning regimen before second auto-SCT for multiple myeloma.

Science.gov (United States)

Wang, T-F; Fiala, M A; Cashen, A F; Uy, G L; Abboud, C N; Fletcher, T; Wu, N; Westervelt, P; DiPersio, J F; Stockerl-Goldstein, K E; Vij, R

2014-11-01

High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

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Wen-Jen Hwu

2011-12-01

Full Text Available Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dosedense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon- alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dosedense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

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Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

(typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

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Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

2017-06-01

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Beneficial Effects of an Alternating High- Fat Dietary Regimen on Systemic Insulin Resistance, Hepatic and Renal Inflammation and Renal Function

NARCIS (Netherlands)

Yakala, G.K.; Heijden, R. van der; Molema, G.; Schipper, M.; Wielinga, P.Y.; Kleemann, R.; Kooistra, T.; Heeringa, P.

2012-01-01

Background: An Alternating high- cholesterol dietary regimen has proven to be beneficial when compared to daily high- cholesterol feeding. In the current study we explored whether the same strategy is applicable to a high- fat dietary regimen. Objective: To investigate whether an alternating high-

Beneficial Effects of an Alternating High- Fat Dietary Regimen on Systemic Insulin Resistance, Hepatic and Renal Inflammation and Renal Function

NARCIS (Netherlands)

Yakala, Gopala K.; van der Heijden, Roel; Molema, Grietje; Schipper, Martin; Wielinga, Peter Y.; Kleemann, Robert; Kooistra, Teake; Heeringa, Peter

2012-01-01

Background: An Alternating high-cholesterol dietary regimen has proven to be beneficial when compared to daily high-cholesterol feeding. In the current study we explored whether the same strategy is applicable to a high-fat dietary regimen. Objective: To investigate whether an alternating high-fat

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

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Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID:25692350

Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States

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Shepardson, D.; Marks, S. M.; Chesson, H.; Kerrigan, A.; Holland, D. P.; Scott, N.; Tian, X.; Borisov, A. S.; Shang, N.; Heilig, C. M.; Sterling, T. R.; Villarino, M. E.; Mac Kenzie, W. R.

2017-01-01

SUMMARY SETTING A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H). OBJECTIVES To assess the cost-effectiveness of 3HP compared to 9H. DESIGN A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H. RESULTS Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21 525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained. CONCLUSIONS 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease. PMID:24200264

Body friendly, safe and effective regimen of MgSO4 for eclampsia

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Gautam S. Aher, Urmila Gavali

2013-01-01

Full Text Available Pre-eclampsia and eclampsia are major health problems in developing countries. MgSO4 is the standard drug in the control of convulsions in eclampsia. Our study carried out at PDVVPF’s hospital is based on the low dose regimen than Pritchard, which is suitable for Indian women who are of smaller built thanwomen in western world. This prospective study included 50 eclampsia patients receiving low dose MgSO4 therapy. The loading dose of MgSO4 was 9gm. Following this 2.5 gm was given intramuscularly every 6 hourly for 24 hours after administration of the loading dose. Patients were monitored hourly by observing their respiratory rate, knee jerk and urine output. Out of 50, two patients required Pritchard regimen, rest completely recovered from eclampsia. The maternal and perinatal morbidity and mortality were comparable to those of the standard Pritchard regime. The study did not find a single case of magnesium related toxicity with low dose MgSO4 regime. Low dose magnesium sulphate regime was found to be safe and effective in eclampsia

Management of factor VII-deficient patients undergoing joint surgeries--preliminary results of locally developed treatment regimen.

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Windyga, J; Zbikowski, P; Ambroziak, P; Baran, B; Kotela, I; Stefanska-Windyga, E

2013-01-01

Inherited factor VII (FVII) deficiency is a rare coagulation disorder with variable haemorrhagic manifestations. In severely affected cases spontaneous haemarthroses leading to advanced arthropathy have been observed. Such cases may require surgery. Therapeutic options for bleeding prevention in FVII deficient patients undergoing surgery comprise various FVII preparations but the use of recombinant activated factor VII (rFVIIa) seems to be the treatment of choice. To present the outcome of orthopaedic surgery under haemostatic coverage of rFVIIa administered according to the locally established treatment regimen in five adult patients with FVII baseline plasma levels below 10 IU dL(-1). Two patients required total hip replacement (THR); three had various arthroscopic procedures. Recombinant activated factor VII was administered every 8 h on day of surgery (D0) followed by every 12-24 h for the subsequent 9-14 days, depending on the type of surgery. Factor VII plasma coagulation activity (FVII:C) was determined daily with no predefined therapeutic target levels. Doses of rFVIIa on D0 ranged from 18 to 37 μg kg(-1) b.w. and on the subsequent days--from 13 to 30 μg kg(-1) b.w. Total rFVIIa dose per procedure ranged from 16 to 37.5 mg, and the total number of doses per procedure was 16-31. None of our patients developed excessive bleeding including those in whom FVII:C trough levels returned nearly to the baseline level on the first post-op day. Preliminary results demonstrate that rFVIIa administered according to our treatment regimen is an effective and safe haemostatic agent for hypoproconvertinaemia patients undergoing orthopaedic surgery. © 2012 Blackwell Publishing Ltd.

Successful Desensitization of T cell Flow Cytometry Crossmatch Positive Renal Transplant Recipients Using Plasmapheresis and Super High-Dose Intravenous Immunoglobulin

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Yoichi Kakuta, MD, PhD

2018-01-01

Full Text Available Background. High-dose IVIG (2 g/kg alone or low-dose IVIG (100 mg/kg in conjunction with plasma exchange is typically administered as a renal transplantation desensitization therapy. Herein, we monitored changes in T cell and B cell flow cytometry crossmatch (FCXM to assess the effects of short-term super high-dose IVIG (4 g/kg administration with plasmapheresis before living-donor renal transplantation. Methods. Seventeen patients, each showing positive T cell FCXM (median ratio, ≥ 1.4 after 2 rounds of double-filtration plasmapheresis, received 4-day regimens of IVIG (1 g/kg per day over 1-week periods. T cell and B cell FCXM determinations were obtained after every IVIG dose and again up to 4 weeks after initiating IVIG to ascertain negative conversion of T cell FCXM (median ratio < 1.4. The primary study endpoint was the percentage of patients achieving T cell FCXM-negative status after the 4-dose IVIG regimen. Results. Upon completion (4 g/kg total or discontinuation of IVIG administration, 8 (47.1% of 17 patients displayed negative T cell FCXM. Based on Kaplan-Meier estimates, the cumulative T cell FCXM-negative conversion rate 4 weeks after IVIG administration initiation was 60.3%. The T cell FCXM-negative conversion rates after cumulative doses of 1, 2, 3, and 4 g/kg IVIG were 29.4%, 35.3%, 56.3%, and 46.7%, respectively. Conclusions. Desensitization of donor-specific antibody-positive renal transplant recipients seems achievable in only a subset of recipients through IVIG dosing (1 g/kg × 4 within 1 week after double-filtration plasmapheresis. The T cell FCXM-negative conversion rate resulting from a cumulative IVIG dose of 3 g/kg or greater surpassed that attained via conventional single-dose IVIG (2 g/kg protocol. This short-term high-dose IVIG desensitization protocol may be an alternative to conventional protocols for recipients with donor-specific antibody.

Fourteen-day high-dose esomeprazole, amoxicillin and metronidazole as third-line treatment for Helicobacter pylori infection.

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Puig, Ignasi; González-Santiago, Jesús M; Molina-Infante, Javier; Barrio, Jesús; Herranz, Maria Teresa; Algaba, Alicia; Castro, Manuel; Gisbert, Javier P; Calvet, Xavier

2017-09-01

The efficacy of currently recommended third-line therapies for Helicobacter pylori is suboptimal, even that of culture-guided treatments. Resistance to multiple antibiotics is the major factor related to treatment failure. The aim of this study was to evaluate the effectiveness and safety of a 14-day therapy using high-dose of amoxicillin, metronidazole and esomeprazole. Multicenter open-label study as a register in routine clinical practice in patients with two previous failures of eradication therapy. A triple therapy with esomeprazole 40 mg b.d., amoxicillin 1 g t.d.s and metronidazole 500 mg t.d.s for 2 weeks was administered as a third-line therapy after a first treatment including clarithromycin and a second treatment including a quinolone. Helicobacter pylori status was determined by either histology or 13 C-UBT both before and after treatment. A total of 68 patients were included in this study. An interim analysis showed that only three out of eight patients who had received metronidazole in previous eradication regimens were cured (37%, 95% CI 8-75); as a result, after this interim analysis only metronidazole-naïve patients were included. The ITT eradication rate in metronidazole-naive patients was 64% (95% CI 51-76). Adverse events occurred in 58% of patients, all of them mild-to-moderate. Two patients (3%) did not complete >90% of the treatment because of side effects. No severe adverse events occurred. Cure rates of this 14-day schedule using high-dose esomeprazole, amoxicillin and metronidazole as a third-line eradication regimen were suboptimal, especially in patients who had received metronidazole in previous failed eradication regimens. © 2017 John Wiley & Sons Ltd.

A study to determine the optimum romurtide regimen to prevent radiation-induced leukopenia

International Nuclear Information System (INIS)

Inoue, Toshihiko; Teshima, Teruki; Ohtani, Masatoshi

1994-01-01

To evaluate the best dose of romurtide to counter radiation-induced leukopenia, two romurtide regimens have been studied in 69 patients undergoing radiation therapy, said patients divided into two groups. Those assigned to Group A, consisting of 33 patients, received a daily subcutaneous injection of 200 μg of romurtide for 10 consecutive days, and those assigned to Group B, consisting of 36 patients, received the same injection dose of romurtide every other day. Three weeks after the start of this study, it was found that both the leukocyte count and neutrophil count were significantly higher in the Group B patients (p<0.05). These results suggest that leukopenia resulting from exposure to radiotherapy can be prevented from developing over a longer period by the every other day romurtide injection regimen, compared to the daily romurtide injection regimen. (author)

Comparing two service delivery models for the prevention of mother-to-child transmission (PMTCT of HIV during transition from single-dose nevirapine to multi-drug antiretroviral regimens

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Mugwaneza Placidie

2010-12-01

Full Text Available Abstract Background Mother-to-child transmission (MTCT of HIV has been eliminated from the developed world with the introduction of multi-drug antiretroviral (md-ARV regimens for the prevention of MTCT (PMTCT; but remains the major cause of HIV infection among sub-Saharan African children. This study compares two service delivery models of PMTCT interventions and documents the lessons learned and the challenges encountered during the transition from single-dose nevirapine (sd-nvp to md-ARV regimens in a resource-limited setting. Methods Program data collected from 32 clinical sites was used to describe trends and compare the performance (uptake of HIV testing, CD4 screening and ARV regimens initiated during pregnancy of sites providing PMTCT as a stand-alone service (stand-alone site versus sites providing PMTCT as well as antiretroviral therapy (ART (full package site. CD4 cell count screening, enrolment into ART services and the initiation of md-ARV regimens during pregnancy, including dual (zidovudine [AZT] +sd-nvp prophylaxis and highly active antiretroviral therapy (HAART were analysed. Results From July 2006 to December 2008, 1,622 pregnant women tested HIV positive (HIV+ during antenatal care (ANC. CD4 cell count screening during pregnancy increased from 60% to 70%, and the initiation of md-ARV regimens increased from 35.5% to 97% during this period. In 2008, women attending ANC at full package sites were 30% more likely to undergo CD4 cell count assessment during pregnancy than women attending stand-alone sites (relative risk (RR = 1.3; 95% confidence interval (CI: 1.1-1.4. Enrolment of HIV+ pregnant women in ART services was almost twice as likely at full package sites than at stand-alone sites (RR = 1.9; 95% CI: 1.5-2.3. However, no significant differences were detected between the two models of care in providing md-ARV (RR = 0.9; 95% CI: 0.9-1.0. Conclusions All sites successfully transitioned from sd-nvp to md-ARV regimens for PMTCT

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

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Setyawan, Juliana; Hodgkins, Paul; Guérin, Annie; Gauthier, Geneviève; Cloutier, Martin; Wu, Eric; Erder, M Haim

2013-10-01

To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically

A randomized controlled trial of increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti microfilaremics in Odisha, India.

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Kar, Shantanu Kumar; Dwibedi, Bhagirathi; Kerketa, Anna Salomi; Maharana, Antaryami; Panda, Sudanshu S; Mohanty, Prafulla Chandra; Horton, John; Ramachandran, Cherubala P

2015-03-01

Although current programmes to eliminate lymphatic filariasis have made significant progress it may be necessary to use different approaches to achieve the global goal, especially where compliance has been poor and 'hot spots' of continued infection exist. In the absence of alternative drugs, the use of higher or more frequent dosing with the existing drugs needs to be explored. We examined the effect of higher and/or more frequent dosing with albendazole with a fixed 300 mg dose of diethylcarbamazine in a Wuchereria bancrofti endemic area in Odisha, India. Following screening, 104 consenting adults were randomly assigned to treatment with the standard regimen annually for 24 months (S1), or annually with increased dose (800 mg albendazole)(H1) or with increased frequency (6 monthly) with either standard (S2) or increased (H2) dose. Pre-treatment microfilaria counts (GM) ranged from 348 to 459 mf/ml. Subjects were followed using microfilaria counts, OG4C3 antigen levels and ultrasound scanning for adult worm nests. Microfilarial counts tended to decrease more rapidly with higher or more frequent dosing at all time points. At 12 months, Mf clearance was marginally greater with the high dose regimens, while by 24 months, there was a trend to higher Mf clearance in the arm with increased frequency and 800 mg of albendazole (76.9%) compared to other arms, (S1:64%, S2:69.2% & H1:73.1%). Although higher and/or more frequent dosing showed a trend towards a greater decline in antigenemia and clearance of "nests", all regimens demonstrated the potential macrofilaricidal effect of the combination. The higher doses of albendazole did not result in a greater number or more severe side effects. The alternative regimens could be useful in the later stages of existing elimination programmes or achieving elimination more rapidly in areas where programmes have yet to start.

Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.

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Clark, Robert E; Kuczenski, Ronald; Segal, David S

2007-07-01

Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.

High-doses of proton pump inhibitors in refractory gastro-intestinal cancer: A case series and the state of art.

Science.gov (United States)

Falcone, Rosa; Roberto, Michela; D'Antonio, Chiara; Romiti, Adriana; Milano, Annalisa; Onesti, Concetta Elisa; Marchetti, Paolo; Fais, Stefano

2016-12-01

In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumour microenvironment acidification thus restoring chemotherapeutic sensitivity. Moreover, several clinical data supports the role of cytotoxic drugs at low-dose continuously delivered as anticancer therapy. Clinical records of three patients affected with gastrointestinal cancer refractory to standard treatments, who had received a combination of high-dose rabeprazole and metronomic chemotherapy were reviewed. The first case, a 78-year-old man was treated for lung metastasis from colon adenocarcinoma. The second case, a 73-year-old man was treated for metastatic rectal cancer to the liver. The third one, a 68-year-old man, underwent the combination regimen for colon cancer with lung, liver and peritoneal metastases. Despite the failure of previous standard chemotherapy for metastatic disease, good clinical outcome was shown in these patients treated with an unconventional association of high-dose PPIs and metronomic chemotherapy. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

A simple high-dose gentamicin regimen showed no side effects among neonates

DEFF Research Database (Denmark)

Blaabjerg, Anne Sofie; Kofoed, Poul-Erik; Dalegaard, Mette Correll

2017-01-01

INTRODUCTION: Treatment of infections in neonates with gentamicin is a balance between optimising bactericidal effect and minimising adverse effects. Previously, at the Neonatal Intensive Care Unit (NICU) at Kolding Hospital, Denmark, neonates suspected of having infections were treated daily...... and 2012 and treated with gentamicin were included retrospectively in the study. Neonates with trough serum (S)-gentamicin level ≥ 2.0 mg/l before the third dose were reviewed in detail. RESULTS: In total, S-gentamicin level was measured in 253 treated neonates of whom 7% displayed elevated trough values....... Neonates elevated S...

EXPERIMENTAL CONFIRMATION FOR SELECTION OF IRRADIATION REGIMENS FOR INTRAPERITONEAL PHOTODYNAMIC THERAPY WITH PORPHYRIN AND PHTHALOCYANINE PHOTOSENSITIZERS

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A. A. Pankratov

2017-01-01

Full Text Available Optimized irradiation regimens for intraperitoneal photodynamic therapy with porphyrin and phthalocyanine photosensitizers are determined in in vitro and in vivo studies.The experimental  study on НЕр2 cell line showed that reduce of power density for constant  light dose increased significantly the efficacy of photodynamic therapy (the reduce of power density from 20-80 mW/cm2 to 10 mW/cm2 had the same results (90% cell death for half as much concentration of the photosensitizer.The obtained results were confirmed in vivo in mice with grafted tumor S-37. For light dose of 90 J/cm2  and power density of 25 mW/cm2 none of animals in the experimental  group had total resorption of the tumor. For the same light dose and decrease  of power density to 12 mW/cm2  total tumor resorption was achieved in 34% of animals, 66% of animals died from phototoxic  shock. For twofold decrease  of light dose – to 45 J/cm2  with the same low-intensity power density (12 mW/cm2 we managed total tumor resorption in 100% of animals.In the following studies of optimized irradiation regimen for intrapleural photodynamic therapy the reaction of intact peritoneum of rats on photodynamic exposure was assessed and optimized parameters of laser irradiation, which did not cause necrosis and intense inflammatory reaction of peritoneum, were determined – light dose of 10 J/cm2  with power density of mW/cm2.Thus, the reasonability for use of low-intensity regimens of irradiation for intraperitoneal photodynamic therapy was confirmed experimentally with possibility of high efficacy of treatment without inflammatory reactions of peritoneum.

Mitigation of Initial Cardiodynamic Effects of the S1P1 Receptor Modulator Ponesimod Using a Novel Up-Titration Regimen.

Science.gov (United States)

Juif, Pierre-Eric; Hoch, Matthias; Vaclavkova, Andrea; Krause, Andreas; Bush, Jim; Dingemanse, Jasper

2017-03-01

Ponesimod, a potent selective sphingosine-1-phosphate receptor 1 modulator, leads to a reduction in circulating total lymphocyte count and transient decreases in heart rate (HR). Based on a modeling and simulation approach, this study was conducted to investigate whether a gradual up-titration regimen may mitigate these cardiodynamic effects. In this double-blind, placebo-controlled, randomized, 2-way crossover study, 32 healthy participants (15 males) received placebo on day 1 followed by multiple-dose administration of either ponesimod or placebo (ratio 3:1). Ponesimod was administered alternately using regimen A (incremental dose increase from 2 to 20 mg in 9 steps) or B (10 mg for 7 days followed by a single-dose administration of 20 mg). Cardiodynamic (Holter and 12-lead ECG), pharmacokinetic, pharmacodynamic (total lymphocyte count), and safety variables were assessed. After first-dose ponesimod administration (day 2), a transient decrease in HR was observed (nadir 2-3 hours postdose, back to predose values within 4-5 hours) of approximately 6 and 12 beats/min (bpm) (mean) following regimens A and B, respectively. On day 2, occurrence of HR 20 ms, was lower following regimen A than B (14 vs 43 events). During the course of the study, incidence of HR <45 bpm was lower following regimen A than B (20 vs 58 events). Fewer participants reported adverse events following regimen A than B. Pharmacokinetics and pharmacodynamics were similar between the regimens. The novel gradual up-titration with ponesimod markedly mitigated initial cardiodynamic effects. © 2016, The American College of Clinical Pharmacology.

Pharmacokinetic/pharmacodynamic based dosing of ciprofloxacin in complicated urinary tract infections

Directory of Open Access Journals (Sweden)

Ana Sabo

2015-08-01

Full Text Available Ciprofloxacin is often used in treatment of complicated urinary tract infections in areas with high rates of resistance to first line agents. The aim of this study was to evaluate efficacy of ciprofloxacin in standard dosing regimens in treatment of complicated urinary tract infections. Plasma concentration curves were simulated and minimum inhibitory concentration (MIC and post-antibiotic effect were determined. Ciprofloxacin MIC ranged from 0.0156 for Gram-negative and to 0.125-0.5 µg/mL for Gram-positive bacteria. Both dosing regimens were suitable for eradication of Gram-negative bacteria, with slight supremacy of 750 mg/12 hours over 500 mg/12 hours dosing regimen. Even though all strains were fully susceptible to ciprofloxacin, pharmaco-kinetic/pharmacodynamic parameters did not meet target thresholds for pathogens with MIC over 0.1-0.2 µg/mL regardless of the administered dose. Ciprofloxacin remains an excellent choice for treatment of complicated urinary tract infections caused by Gram-negative bacteria, but in infection caused by Gram-positive strains, deeper analysis is necessary in order to achieve optimal results.

A comparison of twice-weekly MPD-PUVA and three times-weekly skin typing-PUVA regimens for the treatment of psoriasis

Energy Technology Data Exchange (ETDEWEB)

Buckley, D.A.; Rogers, S. [City of Dublin Skin and Cancer Hospital, Dublin (Ireland); Healy, E. [Royal Victoria Infirmary, Newcastle upon Tyne (United Kingdom)

1995-09-01

The most frequent PUVA treatment regimen in current use is three times weekly, using skin typing to estimate the starting dose. Recently, it was suggested that twice-weekly treatment, using the minimal phototoxic dose- (MPD) to calculate suberythmal starting doses of UVA, achieved similar clearance rates with fewer treatments and a lower cumulative UVA dose. We have carried out a trial on 83 patients, comparing twice-weekly MPD-PUVA with three times-weekly skin typing-PUVA, in order to test this hypothesis. Although clearance rates were comparable between the two regimens, there was no overall significant difference in the number of treatments or in the cumulative UVA doses at clearance. However, for patients with skin types I and II the cumulative UVA dose was significantly higher using the twice-weekly MPD regimen (70.OJ/cm{sup 2} vs. 55.8J/cm{sup 2}; P<0.05). Our results do not confirm that there is a reduction in cumulative UVA dosage with twice-weekly MPD-PUVA. (Author).

High dose rate brachytherapy for the treatment of soft tissue sarcoma of the extremity

International Nuclear Information System (INIS)

Speight, J.L.; Streeter, O.E.; Chawla, S.; Menendez, L.E.

1996-01-01

15 months. During this period, 2 patients (18%) failed at distant sites on this treatment regimen; however, no patient had a local recurrence. Conclusions: 1. Early local control of soft tissue sarcoma is essential to maximize overall survival and prevent metastatic spread. 2. HDR IBT reduces local recurrence of high risk soft tissue sarcomas of the extremity following en bloc resection. 3. Adjuvant chemotherapy may play a role in local control; studies suggest significant overall and distant disease-free survival benefits. 4. Cooperative phase I/II trials are needed to establish the maximum tolerated dose (MTD) for both chemotherapy and radiation, as well as the optimum dosing regimen

Comparison of fixed low dose versus high dose radioactive iodine for the treatment of hyperthyroidism: retrospective multifactorial analysis impacting the outcome of therapy

International Nuclear Information System (INIS)

Suresh Kumar, A.C.; Malhotra, G.; Basu, S.; Asopa, R.V.

2010-01-01

Full text: Radioactive iodine ( 131 I) as a fixed dose protocol is widely used for treatment of hyperthyroidism. However, there is no consensus on the best optimum dose for an individual patient. The objectives of this study were to observe the outcome of 131 I therapy in patients of primary hyperthyroidism in relation to fixed low dose versus high dose regimen, impact of antithyroid drugs and influence of thyroid gland size on therapy outcome. Materials and Methods: Study design: Retrospective analysis. Study group included 287 diagnosed patients of primary hyperthyroidism who had undergone 131 I therapy for the first time (68 M, 219 F; Mean age ± S.D.: 43.84 ± 12.53). All patients with low RAIU, thyrocardiac disease were excluded. Details of antithyroid (ATD) drug treatment were recorded. Analysis was done from 2002 till patients became euthyroid/hypothyroid or until January 2010. Each patient's response was evaluated initially at 6 weeks and thereafter every three months. Appropriate statistical tests were applied to compare treatment response between the groups. A P value<0.05 was considered significant. Results: Of 287 patients, 209 patients had been administered low dose (Mean ± S.D.: 4.68 ± 0.62 mCi) while 78 patients had received high dose (Mean ± S.D.: 9.15 ± 1.05 mCi) of radioiodine. 57.9% (121/ 209) patients in the low dose group responded as compared to 75.6% (59/78) in high dose group after a follow up of more than 36 months. Similarly, among patients with and without antithyroid drug treatment, grade II and above goiters the response rates were significantly higher for high dose group as compared to low dose group. Conclusion: We suggest that high dose radioiodine treatment with 8 to 10 mCi is effective in treating hyperthyroidism in patients with a better success rate than the low dose treatment with 3 to 5 mCi. This is also likely to be helpful in patients who have not received antithyroid drugs. It appears that clinically relevant

Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

Science.gov (United States)

Brown, Tanya; Parasrampuria, Ridhi; Brazeau, Daniel A.; Forrest, Alan; Kelchlin, Pamela A.; Holden, Patricia N.; Peloquin, Charles A.; Hanna, Debra; Bulitta, Jurgen B.

2012-01-01

Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 106 CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log10 CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of −6.15 and −6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary. PMID:22526313

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

Science.gov (United States)

Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

2014-12-01

Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

Science.gov (United States)

Mallat, Samir G; Tanios, Bassem Y; Itani, Houssam S; Lotfi, Tamara; McMullan, Ciaran; Gabardi, Steven; Akl, Elie A; Azzi, Jamil R

2017-08-07

The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m 2 ; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. We found

An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients

NARCIS (Netherlands)

Vollebergh, M. A.; Lips, E. H.; Nederlof, P. M.; Wessels, L. F. A.; Schmidt, M. K.; van Beers, E. H.; Cornelissen, S.; Holtkamp, M.; Froklage, F. E.; de Vries, E. G. E.; Schrama, J. G.; Wesseling, J.; van de Vijver, M. J.; van Tinteren, H.; de Bruin, M.; Hauptmann, M.; Rodenhuis, S.; Linn, S. C.

Patients and methods: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss

Efficacy, safety and proper dose analysis of PEGylated granulocyte colony-stimulating factor as support for dose-dense adjuvant chemotherapy in node positive Chinese breast cancer patients.

Science.gov (United States)

Zhang, Fan; LingHu, RuiXia; Zhan, XingYang; Li, Ruisheng; Feng, Fan; Gao, Xudong; Zhao, Lei; Yang, Junlan

2017-10-03

For high-risk breast cancer patients with positive axillary lymph nodes, dose-dense every-two-week epirubicin/cyclophosphamide-paclitaxel (ddEC-P) regimen is the optimal postoperative adjuvant therapy. However, this regimen is limited by the grade 3/4 neutropenia and febrile neutropenia (FN). There is an urgent need to explore the efficacy, safety and proper dosage of PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) as support for ddEC-P in Chinese breast cancer patients with positive axillary lymph nodes. Prospectively, 40 women with stage IIIA to IIIC breast cancer received ddEC-P ± trastuzumab as adjuvant treatment. PEG-G-CSF was injected subcutaneously in a dose of 6 mg or 3 mg on the 2 th day of each treatment cycle. With administration of PEG-G-CSF, all of the 40 patients completed 8 cycles of ddEC-P ± trastuzumab regimen without dose reductions or treatment delays. Moreover, no FN cases were observed. Further analysis showed that the proper dosage of PEG-G-CSF was 6 mg for ddEC treatment, and 3 mg for ddP treatment. PEG-G-CSF exhibits advantages compared with G-CSF in convenient of administration and tolerance for high risk Chinese breast cancer patients. More importantly, the proper dose of PEG-G-CSF for high risk Chinese breast cancer patients during ddEC-P chemotherapy may be 6 mg for ddEC treatment and 3 mg for ddP treatment.

Comparison of Current Recommended Regimens of Atropinization in Organophosphate Poisoning

OpenAIRE

Connors, Nicholas J.; Harnett, Zachary H.; Hoffman, Robert S.

2013-01-01

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.’s work, texts of Internal ...

Clinical and microbiological outcomes in treatment of men with non-gonococcal urethritis with a 100-mg twice-daily dose regimen of sitafloxacin.

Science.gov (United States)

Ito, Shin; Yasuda, Mitsuru; Seike, Kensaku; Sugawara, Takashi; Tsuchiya, Tomohiro; Yokoi, Shigeaki; Nakano, Masahiro; Deguchi, Takashi

2012-06-01

Several microorganisms cause non-gonococcal urethritis (NGU). Failure to eradicate Mycoplasma genitalium from the urethra could be associated with persistent or recurrent urethritis; thus, the choice of antibiotics with activities potent enough to eradicate M. genitalium is crucial in the treatment of NGU. In in vitro studies, sitafloxacin has been shown to be highly active against Chlamydia trachomatis and M. genitalium. We treated 89 males with NGU, including 15 patients with persistent or recurrent NGU and 1 patient with post-gonococcal urethritis, with a 100-mg twice-daily dose regimen of sitafloxacin to assess its efficacy against NGU. We examined first-void urine samples for the presence of C. trachomatis, M. genitalium, Ureaplasma parvum, and Ureaplasma urealyticum. After treatment, we evaluated 73 patients for clinical outcomes and 44 for microbiological outcomes. Symptoms were alleviated in 62 (84.9%) patients, who were judged clinically cured. Microorganisms detected before treatment were eradicated in 42 (95.5%) patients, who were judged microbiologically cured. Regarding microbiological outcomes of specific microorganisms, eradication rates of C. trachomatis (n = 33), M. genitalium (n = 11), and U. urealyticum (n = 10) were 100%, 100%, and 80.0%, respectively. In all 5 patients with M. genitalium-positive persistent or recurrent NGU who had experienced treatment failures with antibiotics, the mycoplasma was eradicated. These results suggested that the sitafloxacin regimen used, which was effective on both M. genitalium and C. trachomatis infections, could be useful as an appropriate option as first- and second-line treatment of NGU.

High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity

DEFF Research Database (Denmark)

Hansen, A; Kemp, K; Kemp, E

2001-01-01

of high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population...

Standard effective doses for proliferative tumours

International Nuclear Information System (INIS)

Jones, L.C.; Hoban, P.

1999-01-01

This study was undertaken to investigate the treatment schedules used clinically for highly proliferative tumours, particularly with reference to the effects of fraction size, fraction number and treatment duration. The linear quadratic model (with time component) is used here to compare non-standard treatment regimens (e.g. accelerated and hyperfractionated schedules), currently the focus of randomized trials, with each other and some common 'standard regimens'. To ensure easy interpretation of results, two parameters known as proliferative standard effective dose one (PSED 1 ) and proliferative standard effective dose two (PSED 2 ) have been calculated for each regimen. Graphs of PSED 1 and PSED 2 versus potential doubling time (T p ) have been generated for a range of fractionation regimens which are currently under trial in various randomized studies. From these graphs it can be seen that the highly accelerated schedules (such as CHART) only show advantages for tumours with very short potential doubling times. Calculations for most of the schedules considered showed at least equivalent tumour control expected for the trial schedule compared with the control arm used and these values agree quite well with clinical results. These calculations are in good agreement with clinical results available at present. The greater the PSED 1 or PSED 2 for the schedule considered the greater the tumour control, which can be expected. However, as has been seen with clinical trials, this higher cell kill also results in higher acute effects which have proved too great for some accelerated schedules to continue. (author)

Primary radiotherapy of stage IIA/B-IIIB cervical carcinoma. A comparison of continuous versus sequential regimens

International Nuclear Information System (INIS)

Mayer, A.; Nemeskeri, C.; Petnehazi, C.; Varga, S.; Naszaly, A.; Borgulya, G.

2004-01-01

Background: comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. Patients and methods: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i.e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. Results: progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). Conclusion: for the patients included in this study, no advantage has been found so far in using CRT, i.e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per

An integrated disease/pharmacokinetic/pharmacodynamic model suggests improved interleukin-21 regimens validated prospectively for mouse solid cancers.

Directory of Open Access Journals (Sweden)

Moran Elishmereni

2011-09-01

Full Text Available Interleukin (IL-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK and pharmacodynamic (PD data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected "training" data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent "validation" data in melanoma and renal cell carcinoma-challenged mice (R(2>0.90. Simulations of the verified model surfaced important therapeutic insights: (1 Fractionating the standard daily regimen (50 µg/dose into a twice daily schedule (25 µg/dose is advantageous, yielding a significantly lower tumor mass (45% decrease; (2 A low-dose (12 µg/day regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R(2>0.89, thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic.

Modification of Enrofloxacin Treatment Regimens for Poultry Experimentally Infected with Salmonella enterica Serovar Typhimurium DT104 To Minimize Selection of Resistance▿

Science.gov (United States)

Randall, Luke P.; Cooles, Sue W.; Coldham, Nick C.; Stapleton, Ken S.; Piddock, Laura J. V.; Woodward, Martin J.

2006-01-01

We hypothesized that higher doses of fluoroquinolones for a shorter duration could maintain efficacy (as measured by reduction in bacterial count) while reducing selection in chickens of bacteria with reduced susceptibility. Chicks were infected with Salmonella enterica serovar Typhimurium DT104 and treated 1 week later with enrofloxacin at the recommended dose for 5 days (water dose adjusted to give 10 mg/kg of body weight of birds or equivalence, i.e., water at 50 ppm) or at 2.5 or 5 times the recommended dose for 2 days or 1 day, respectively. The dose was delivered continuously (ppm) or pulsed in the water (mg/kg) or by gavage (mg/kg). In vitro in sera, increasing concentrations of 0.5 to 8 μg/ml enrofloxacin correlated with increased activity. In vivo, the efficacy of the 1-day treatment was significantly less than that of the 2- and 5-day treatments. The 2-day treatments showed efficacy similar to that of the 5-day treatment in all but one repeat treatment group and significantly (P < 0.01) reduced the Salmonella counts. Dosing at 2.5× the recommended dose and pulsed dosing both increased the peak antibiotic concentrations in cecal contents, liver, lung, and sera as determined by high-pressure liquid chromatography. There was limited evidence that shorter treatment regimens (in particular the 1-day regimen) selected for fewer strains with reduced susceptibility. In conclusion, the 2-day treatment would overall require a shorter withholding time than the 5-day treatment and, in view of the increased peak antibiotic concentrations, may give rise to improved efficacy, in particular for treating respiratory and systemic infections. However, it would be necessary to validate the 2-day regimen in a field situation and in particular against respiratory and systemic infections to validate or refute this hypothesis. PMID:17030564

Renexin as a rescue regimen for noise-induced hearing loss

Directory of Open Access Journals (Sweden)

So Young Park

2014-01-01

Full Text Available Renexin, a compound of cilostazol and ginkgo biloba extract, has been reported to produce neuroprotective effects through antioxidant, antiplatelet, and vasodilatory mechanisms. This study was designed to investigate the protective effects of renexin on hearing, the organ of Corti (OC, and medial olivocochlear efferents against noise-induced damage. C57BL/6 mice were exposed to 110 dB SPL white noise for 60 min and then randomly divided into three groups: high- and low-dose renexin-treated groups and noise only group. Renexin were administered for 7 days: 90 mg/kg to the low-dose, and 180 mg/kg to the high-dose groups. All mice, including the controls underwent hearing tests on postnoise day 8 and were killed for cochlear harvest. We compared the hearing thresholds and morphology of the OC and cochlear efferents across the groups. The renexin-treated groups recovered from the immediate threshold shifts in a dose-dependent manner, while the noise group showed a permanent hearing loss. The renexin-treated ears demonstrated less degeneration of the OC. The diameters of the efferent terminals labeled with α-synuclein were preserved in the high-dose renexin-treated group. In the western blot assay of the cochlear homogenates, the treated groups displayed stronger expressions of α-synuclein than the noise and control groups, which may indicate that noise-induced enhanced activity of the cochlear efferent system was protected by renexin. Our results suggest that pharmacologic treatment with renexin is hopeful to reduce or prevent noise-induced hearing loss as a rescue regimen after noise exposure.

Impact of Drug Therapy, Radiation Dose, and Dose Rate on Renal Toxicity Following Bone Marrow Transplantation

International Nuclear Information System (INIS)

Cheng, Jonathan C.; Schultheiss, Timothy E.; Wong, Jeffrey Y.C.

2008-01-01

Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age ≥18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function

German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients.

Science.gov (United States)

Möbus, V; von Minckwitz, G; Jackisch, C; Lück, H-J; Schneeweiss, A; Tesch, H; Elling, D; Harbeck, N; Conrad, B; Fehm, T; Huober, J; Müller, V; Bauerfeind, I; du Bois, A; Loibl, S; Nekljudova, V; Untch, M; Thomssen, C

2017-08-01

Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine. Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4. From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10). Adding

Tissue repair capacity and repair kinetics deduced from multifractionated or continuous irradiation regimens with incomplete repair

International Nuclear Information System (INIS)

Thames, H.D. Jr.; Peters, L.J.

1984-01-01

A model is proposed for cell survival after multiple doses, when the interfraction interval is insufficient for complete Elkind repair. In the limit of ever-increasing number of ever-smaller fractional doses, the model transforms into the accumulation model of survival after continuous irradiation. When adapted to describe tissue responses to isoeffective multifractionated regimens, wherein repair is incomplete, a generalization of the usually linear plot of reciprocal total dose versus dose per fraction is obtained, in which downward curvature is evident. There is an advantage in studying tissue responses to multifractionated regimens with incomplete repair in the interfraction intervals, or continuous exposures at various dose rates since, in addition to determination of repair capacity, there is an estimate of repair kinetics. Results of analyses of previously published data are presented as illustration. Estimated from the response of three acutely responding normal tissues in the mouse (jejunum, colon and bone marrow), repair halftimes ranged from 0.3-0.9 h and values of β/delta were approximately 0.1 Gy -1 . From the response of mouse lung (LD50 for pneumonitis) to multifractionated regimens with incomplete repair, the repair halftime was estimated at 1.5 h and β/delta was 0.27 Gy -1 . In the rat spinal cord β/delta was 0.7 Gy -1 and Tsub(1/2) was 1.5 h. (U.K.)

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer

International Nuclear Information System (INIS)

Chen, Yuhchyau; Pandya, Kishan J.; Feins, Richard; Johnstone, David W.; Watson, Thomas; Smudzin, Therese; Keng, Peter C.

2008-01-01

Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m 2 , 20 mg/m 2 , and 25 mg/m 2 were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m 2 ), II (20 mg/m 2 ), and III (25 mg/m 2 ), the mean peak plasma level was 0.23 ± 0.06 μmol/l, 0.32 ± 0.05 μmol/l, and 0.52 ± 0.14 μmol/l, respectively; AUC was 0.44 ± 0.09 μmol/l, 0.61 ± 0.1 μmol/l, and 0.96 ± 0.23 μmol/l, respectively; and duration of drug concentration >0.05 μmol/l (t > 0.05 μmol/l) was 1.6 ± 0.3 h, 1.9 ± 0.2 h, and 3.0 ± 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 μmol/l for a minimum of 1.6 h was sufficient for effective radiosensitization

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

Directory of Open Access Journals (Sweden)

Mary J Warrell

2008-04-01

Full Text Available The need for economical rabies post-exposure prophylaxis (PEP is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90; or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

Science.gov (United States)

Warrell, Mary J; Riddell, Anna; Yu, Ly-Mee; Phipps, Judith; Diggle, Linda; Bourhy, Hervé; Deeks, Jonathan J; Fooks, Anthony R; Audry, Laurent; Brookes, Sharon M; Meslin, François-Xavier; Moxon, Richard; Pollard, Andrew J; Warrell, David A

2008-04-23

The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Controlled

Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation

International Nuclear Information System (INIS)

Kal, H.B.; Kempen-Harteveld, M.L. van; Heijenbrok-Kal, M.H.; Struikmans, H.

2006-01-01

Background and Purpose: Total-body irradiation (TBI) is an important part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The results after treatment with various TBI regimes were compared, and dose-effect relationships for the endpoints relapse incidence, disease-free survival, treatment-related mortality, and overall survival were derived. The aim was to define requirements for an optimal treatment schedule with respect to leukemic cell kill and late normal-tissue morbidity. Material and Methods: A literature search was performed. Three randomized studies, four studies comparing results of two or three TBI regimens, and nine reports with results of one specific TBI regimen were identified. Biologically effective doses (BEDs) were calculated. The results of the randomized studies and the studies comparing results of two or three TBI regimens were pooled, and the pooled relative risk (RR) was calculated for the treatments with high BED values versus treatments with a low BED. BED-effect relationships were obtained. Results: RRs for the high BED treatments were significantly lower for relapse incidence, not significantly different for disease-free survival and treatment-related mortality, and significantly higher for overall survival. BED-effect relationships indicate a decrease in relapse incidence and treatment-related mortality and an increase in disease-free and overall survival with higher BED values. Conclusion: 'More dose is better', provided that a TBI setting is used limiting the BEDs of lungs, kidneys, and eye lenses. (orig.)

Outcomes after chemotherapy with WHO category II regimen in a population with high prevalence of drug resistant tuberculosis.

Directory of Open Access Journals (Sweden)

Francine Matthys

Full Text Available Standard short course chemotherapy is recommended by the World Health Organization to control tuberculosis worldwide. However, in settings with high drug resistance, first line standard regimens are linked with high treatment failure. We evaluated treatment outcomes after standardized chemotherapy with the WHO recommended category II retreatment regimen in a prison with a high prevalence of drug resistant tuberculosis (TB. A cohort of 233 culture positive TB patients was followed through smear microscopy, culture, drug susceptibility testing and DNA fingerprinting at baseline, after 3 months and at the end of treatment. Overall 172 patients (74% became culture negative, while 43 (18% remained positive at the end of treatment. Among those 43 cases, 58% of failures were determined to be due to treatment with an inadequate drug regimen and 42% to either an initial mixed infection or re-infection while under treatment. Overall, drug resistance amplification during treatment occurred in 3.4% of the patient cohort. This study demonstrates that treatment failure is linked to initial drug resistance, that amplification of drug resistance occurs, and that mixed infection and re-infection during standard treatment contribute to treatment failure in confined settings with high prevalence of drug resistance.

Comparison between chloral hydrate and propofol-ketamine as sedation regimens for pediatric auditory brainstem response testing.

Science.gov (United States)

Abulebda, Kamal; Patel, Vinit J; Ahmed, Sheikh S; Tori, Alvaro J; Lutfi, Riad; Abu-Sultaneh, Samer

2017-10-28

The use of diagnostic auditory brainstem response testing under sedation is currently the "gold standard" in infants and young children who are not developmentally capable of completing the test. The aim of the study is to compare a propofol-ketamine regimen to an oral chloral hydrate regimen for sedating children undergoing auditory brainstem response testing. Patients between 4 months and 6 years who required sedation for auditory brainstem response testing were included in this retrospective study. Drugs doses, adverse effects, sedation times, and the effectiveness of the sedative regimens were reviewed. 73 patients underwent oral chloral hydrate sedation, while 117 received propofol-ketamine sedation. 12% of the patients in the chloral hydrate group failed to achieve desired sedation level. The average procedure, recovery and total nursing times were significantly lower in the propofol-ketamine group. Propofol-ketamine group experienced higher incidence of transient hypoxemia. Both sedation regimens can be successfully used for sedating children undergoing auditory brainstem response testing. While deep sedation using propofol-ketamine regimen offers more efficiency than moderate sedation using chloral hydrate, it does carry a higher incidence of transient hypoxemia, which warrants the use of a highly skilled team trained in pediatric cardio-respiratory monitoring and airway management. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor.

Science.gov (United States)

Abbas, Richat; Hug, Bruce A; Leister, Cathie; Sonnichsen, Daryl

2012-07-01

Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects. A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5-7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7. No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28-72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52-90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea. Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

Effectiveness of two different HDR brachytherapy regimens with the same BED value in cervical cancer

Directory of Open Access Journals (Sweden)

Rajesh Vashistha

2010-07-01

Full Text Available Purpose: To analyze the effectiveness of biologically effective dose (BED in two different regimens of HDR brachytherapy keeping the same total BED to point A and to compare the relationship of overall treatment time in terms of local control and bladder and rectal complications.Material and methods: The study included two groups comprising a total of 90 cervical cancer patients who underwent external beam radiotherapy (EBRT followed by HDR intracavitary brachytherapy (ICBT. EBRT treatment was delivered by a Co-60 teletherapy unit to a prescribed dose of 45 Gy with 1.8 Gy per fraction in 25 fractions over a period of five weeks. Parallel opposed anterior–posterior (AP/PA fields with no central shielding were used, followed by the HDR ICBT dose, to point A, of either two fractions of 9.5 Gy with a gap of 10 days, or three fractions of 7.5 Gy with a gap of 7 days between the fractions. Gemcitabine (dose of 150 mg/m2 was given weekly to all the patients as a radiosensitizer. The calculate BED3 to point A was almost the same in both groups to keep the same late complication rates. The doses, and BED10 and BED3, were calculated at different bladder and rectal point as well as at the lymphatictrapezoid points. During and after treatment patients were evaluated for local control and complications for 24 months.Results and Conclusions: Doses and BEDs at different bladder, rectal and lymphatic trapezoid points, local control, and complications in both HDR ICBT groups did not have statistically significant differences (p > 0.05. Both HDR ICBT schedules are well tolerable and equally effective.

Characterization of HIV-1 from patients with virological failure to a boosted protease inhibitor regimen

DEFF Research Database (Denmark)

Lillemark, Marie Rathcke; Gerstoft, Jan; Obel, Niels

2011-01-01

The use of highly active antiretroviral treatment (HAART) regimens with unboosted protease inhibitors (PIs) has resulted in a high level of virological failure primarily due to the development of resistant virus. Current boosted PI regimens combine successfully low-dose ritonavir (r) with a second.......3%) experienced virological failure, of whom 19 (83%) started PI/r treatment before 2001. Patients from Copenhagen (n=19) were selected to study the development of protease (PR) and gag cleavage site (CS) mutations during PI/r treatment and PI plasma levels at the time of virological failure. Three patients (16......%) developed major PI resistance mutations. Mutations in the p7/p1 and p1/p6 gag CS only developed in patients with major or minor mutations in PR. Drug concentrations were low or undetectable in 10 out of the 19 patients. In total PR resistance mutations and low drug levels could account for 12 (63...

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

Science.gov (United States)

Drusano, George L.; Adams, Jonathan R.; Rodriquez, Jaime L.; Jambunathan, Kalyani; Baluya, Dodge L.; Brown, David L.; Kwara, Awewura; Mirsalis, Jon C.; Hafner, Richard; Louie, Arnold

2015-01-01

ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. PMID:26530386

Efficacy, safety and proper dose analysis of PEGylated granulocyte colony-stimulating factor as support for dose-dense adjuvant chemotherapy in node positive Chinese breast cancer patients

OpenAIRE

Zhang, Fan; LingHu, RuiXia; Zhan, XingYang; Li, Ruisheng; Feng, Fan; Gao, Xudong; Zhao, Lei; Yang, Junlan

2017-01-01

For high-risk breast cancer patients with positive axillary lymph nodes, dose-dense every-two-week epirubicin/cyclophosphamide-paclitaxel (ddEC-P) regimen is the optimal postoperative adjuvant therapy. However, this regimen is limited by the grade 3/4 neutropenia and febrile neutropenia (FN). There is an urgent need to explore the efficacy, safety and proper dosage of PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) as support for ddEC-P in Chinese breast cancer patients with posit...

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

Science.gov (United States)

Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen).

Science.gov (United States)

Mahendra, B J; Narayana, Dh Ashwath; Agarkhedkar, Sharad; Ravish, H S; Harish, B R; Agarkhedkar, Shalaka; Madhusudana, S N; Belludi, Ashwin; Ahmed, Khaleel; Jonnalagedda, Rekha; Vakil, Hoshang; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2015-01-01

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.

Efficacy and tolerability of chemotherapy with modified dose-dense TCF regimen (TCF-dd) in locally advanced or metastatic gastric cancer: final results of a phase II trial.

Science.gov (United States)

Tomasello, Gianluca; Liguigli, Wanda; Poli, Rossana; Lazzarelli, Silvia; Brighenti, Matteo; Negri, Federica; Curti, Alessandra; Martinotti, Mario; Olivetti, Lucio; Rovatti, Massimo; Donati, Gianvito; Passalacqua, Rodolfo

2014-10-01

We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC). Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, l-folinic acid 100 mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus days 1 and 2, and then 600 mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14 days, plus pegfilgrastim 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30 %. Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78 % male, 22 % female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48 %, 1, 46 %). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5 %) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61 % (95 % CI 47-75). Median overall survival (OS) was 17.63 months (95 % CI, 13.67-20.67); median progression-free survival was 8.9 months (95 % CI, 6.5-13.4). Twenty-one patients (46.0 %) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20 %), leukopenia (4 %), thrombocytopenia (2 %), anemia (2 %), febrile neutropenia (6 %), asthenia (22 %), diarrhea (4 %), nausea/vomiting (11 %), and hypokalemia (6 %). Overall, TCF-dd was shown to be safe. The TCF-dd regimen in locally advanced or MGC

Dose response and factors related to interstitial pneumonitis after bone marrow transplant

International Nuclear Information System (INIS)

Sampath, Sagus; Schultheiss, Timothy E.; Wong, Jeffrey

2005-01-01

Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The α/β value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D 50 , for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; in the absence of chemotherapy, the estimated D 50 is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding. Shielding the lung

Two low-dose bowel-cleansing regimens: efficacy and safety of senna and sodium phosphorus solution for colonoscopy

Directory of Open Access Journals (Sweden)

Poyrazoglu OK

2015-09-01

Full Text Available Orhan Kursat Poyrazoglu, Mehmet Yalniz Department of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey Background: The aim of the present study was to compare the efficacy, adequacy, side effects, and patient compliance of sodium phosphorus (NaP and senna solutions when preparing the colon before colonoscopy.Methods: A total of 137 consecutive patients who were considered for colonoscopy evaluation had randomly received one of two premeditated regimens: 90 mL of oral NaP (NaP group or 500 mL of 1,000 mg of sennosides A and B calcium +66.6 g of sorbitol (senna group. Patients’ compliance with the bowel-cleansing method was determined using a questionnaire prior to the colonoscopic examination. On the other hand, the adequacy of the bowel-cleansing method was evaluated by the colonoscopist who was blind to the bowel-cleansing regimen used prior to the examination of the colon from the rectum to the cecum.Results: Nausea and vomiting complaints were seen more frequently in the NaP group than in the senna group (47 vs 28 and 31 vs 10; P<0.05 and P<0.01, respectively. The response to the question of whether the patients would like to use the same regimen again or not was similar in both groups. The acceptable bowel-cleansing rate was also comparable across both groups. Nevertheless, the number of patients that experienced excellent bowel cleansing in terms of general appraisal of the colonoscopic evaluation was significantly greater in the NaP group than in the senna group (46 vs 25; P<0.001.Conclusion: Although bowel cleansing was better in the NaP group, both cleansing regimens were comparable regarding the admissibility of the preparations for the procedure. The senna regimen is, however, superior to the NaP regimen in terms of application compliance and its side effects, and it may be an effective alternative for cleansing the bowel prior to colonoscopic examination. Keywords: bowel preparation, colonoscopy, side effect

Efficacy of various single-dose regimens of ceftriaxone in ...

African Journals Online (AJOL)

The therapeutic efficacy of single intramuscular doses of ceftriaxone (Rocephin; Roche) (62,S, 125 and 250 mg), administered without probenecid, was evaluated in 167 adult males with uncomplicated acute gonococcal urethritis. Cure rates of 100% were achieved at 62,5 mg and 250 mg. In the 125 mg dose group, ...

Gamma dosimetry of high doses

International Nuclear Information System (INIS)

Martinez C, T.; Galvan G, A.; Canizal, G.

1991-01-01

The gamma dosimetry of high doses is problematic in almost all the classic dosemeters either based on the thermoluminescence, electric, chemical properties, etc., because they are saturated to very high dose and they are no longer useful. This work carries out an investigation in the interval of high doses. The solid system of heptahydrate ferrous sulfate, can be used as solid dosemeter of routine for high doses of radiation. The proposed method is simple, cheap and it doesn't require sophisticated spectrophotometers or spectrometers but expensive and not common in some laboratories

Effectiveness of two different doses of rituximab for the treatment of rheumatoid arthritis in an international cohort

DEFF Research Database (Denmark)

Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny

2016-01-01

months. DAS28 reductions at 6 months were comparable in the 2 dose regimens [mean DeltaDAS28 ± SD -2.0 ± 1.3 (high dose) vs. -1.7 ± 1.4 (low dose), p = 0.23 adjusted for baseline differences]. Similar percentages of patients achieved EULAR good response in the two dose groups, 18.4 % vs. 17...

Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience.

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Jalaeikhoo, Hasan; Rajaeinejad, Mohsen; Keyhani, Manoutchehr; Zokaasadi, Mohammad; Dehghani Firoozabadi, Mohammad Mehdi

2018-03-01

Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1-57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Prophylactic CNS therapy in childhood leukemia. Randomized controlled study of high-dose intravenous methotrexate and cranial irradiation

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Yokoyama, Takashi; Hiyoshi, Yasuhiko [Kurume Univ., Fukuoka (Japan). School of Medicine; Fujimoto, Takeo

1982-12-01

This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm/sup 3/) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm/sup 3/) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m/sup 2/) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m/sup 2/, the CSF concentration of MTX rose to 2.3 +- 2.4 x 10/sup -6/M after initiation of infusion and remained in 10/sup -7/ M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% in Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC.

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas.

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Nieto, Yago; Valdez, Benigno C; Thall, Peter F; Ahmed, Sairah; Jones, Roy B; Hosing, Chitra; Popat, Uday; Shpall, Elizabeth J; Qazilbash, Muzaffar; Gulbis, Alison; Anderlini, Paolo; Alousi, Amin; Shah, Nina; Bashir, Qaiser; Liu, Yan; Oki, Yasuhiro; Hagemeister, Frederick; Fanale, Michelle; Dabaja, Bouthaina; Pinnix, Chelsea; Champlin, Richard; Andersson, Borje S

2015-11-01

More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days -8 to -3). Gemcitabine was infused continuously at 10 mg/m(2)/minute over 4.5 hours (days -8 and -3). Busulfan dosing targeted 4000 μM-minute/day (days -8 to -5). Melphalan was infused at 60 mg/m(2)/day (days -3 and -2). Patients with CD20(+) tumors received rituximab (375 mg/m(2), days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography-positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. This trial was registered at ClinicalTrials.gov (NCI-2011-02891). Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights

Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration.

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McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

2011-08-01

Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent [i.e., postnatal day (PND) 40] rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a "challenge" high-dose METH regimen when administered at PND90. Mechanisms underlying this "resistance" were thus investigated. Results revealed that biweekly METH treatment throughout development attenuated both the acute and persistent deficits in VMAT2 function, as well as the acute hyperthermia, caused by a challenge METH treatment. Pharmacokinetic alterations did not appear to contribute to the protection afforded by the biweekly treatment. Maintenance of METH-induced hyperthermia abolished the protection against both the acute and persistent VMAT2-associated deficits suggesting that alterations in thermoregulation were caused by exposure of rats to METH during development. These findings suggest METH during development prevents METH-induced hyperthermia and the consequent METH-related neurotoxicity. Copyright © 2011 Wiley-Liss, Inc.

Optimization of the fractionated irradiation scheme considering physical doses to tumor and organ at risk based on dose–volume histograms

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Sugano, Yasutaka [Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0812 (Japan); Mizuta, Masahiro [Laboratory of Advanced Data Science, Information Initiative Center, Hokkaido University, Kita-11, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0811 (Japan); Takao, Seishin; Shirato, Hiroki; Sutherland, Kenneth L. [Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-8638 (Japan); Date, Hiroyuki, E-mail: date@hs.hokudai.ac.jp [Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0812 (Japan)

2015-11-15

Purpose: Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose–volume histograms for tumor and normal tissues of organs around the tumor. Methods: Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of the tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose–volume histogram. Results: It was found that the optimization of fractionation scheme incorporating the dose–volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8–32 fractions with a daily dose of 2.2–6.3 Gy. Conclusions: It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose–volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.

Therapeutical evaluation of different dose regimens of praziquantel in schistosomiasis mansoni, based on the quantitative oogram technique

Directory of Open Access Journals (Sweden)

Aloísio Sales da Cunha

1987-10-01

Full Text Available A clinical trial involving 80 patients of both sexes, from ages 15 to 55, with chronic intestinal or hepatointestinal schistosomiasis mansoni, was carried out to evaluate the therapeutical efficacy of different dose regimens of praziquantel. The patients were randomly allocated into four groups with an equal number of cases and were then treated with one of the following dosages: 60 mg/kg for 1 day; 60 mg/kg daily for 2 days; 60 mg/kg daily for 3 days; and 30 mg/kg daily for 6 days. The assessment of parasitological cure was based on the quantitative oogram technique through rectal mucosa biopsies which were undertaken prior to, as well as, 1,2,4 and 6 months post-treatment. Concurrently, stool examinations according to the qualitative Hoffman, Pons & Janer (HPJ and the quantitative Kato-Katz (K-K methods were also performed. The best tolerability was observed with 30 mg/kg daily for 6 days whereas the highest incidence of side-effects (mainly dizziness and nausea was found with 60 mg/kg daily for 3 days. No serious adverse drug reaction has occurred. The achieved cure rates were: 25% with 60 mg/kg for 1 day; 60% with 60 mg/kg daily for 2 days; 89.5% with 60 mg/kg daily for 3 days; and 90% with 30 mg/kg daily for 6 days. At the same time there has been a downfall of 64%, 73%, 87% and 84% respectively, in the median number of viable S. mansoni ova per gram of tissue. Thus, a very clear direct correlation between dose and effect could be seen. The corresponding cure rates according to stool examinations by HPJ were 39%, 80%, 100% and 95%; by K-K 89%, 100%, 100% and 100%. This discrepancy in results amongst the three parasitological methods is certainly due to their unequal accuracy. In fact, when the number of viable eggs per gram of tissue fell below 5,000 the difference in the percentage of false negative findings between HPJ (28% and K-K (80% became significative. When this number dropped to less than 2,000 the percentage of false negative

High Dose Cyclophosphamide without Stem Cell Rescue in 207 Patients with Aplastic anemia and other Autoimmune Diseases

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DeZern, Amy E.; Petri, Michelle; Drachman, Daniel B.; Kerr, Doug; Hammond, Edward R.; Kowalski, Jeanne; Tsai, Hua-Ling; Loeb, David M.; Anhalt, Grant; Wigley, Fredrick; Jones, Richard J.; Brodsky, Robert A.

2011-01-01

High-dose cyclophosphamide has long been used an anticancer agent, a conditioning regimen for hematopoietic stem cell transplantation and as potent immunosuppressive agent in autoimmune diseases including aplastic anemia. High-dose cyclophosphamide is highly toxic to lymphocytes but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, the major mechanism of cyclophosphamide inactivation. High dose cyclophosphamide therapy induces durable remissions in most patients with acquired aplastic anemia. Moreover, high-dose cyclophosphamide without hematopoietic stem cell rescue has shown activity in a variety of other severe autoimmune diseases. Here we review the history of cyclophosphamide as is applies to aplastic anemia (AA) and other autoimmune diseases. Included here are the historical data from early patients treated for AA as well as an observational retrospective study in a single tertiary care hospital. This latter component was designed to assess the safety and efficacy of high-dose cyclophosphamide therapy without stem cell rescue in patients with refractory autoimmune diseases. We analyzed fully the 140 patients with severe, progressive autoimmune diseases treated. All patients discussed here received cyclophosphamide, 50 mg/kg per day for 4 consecutive days. Response, relapse and overall survival were measured. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune modulating drugs. Relapse was defined as worsening disease activity and/or a requirement of an increase in dose of, or administration of new, immunosuppressive medications. Hematologic recovery occurred in all patients. The overall response rate of the was 95%, and 44% of those patients remain progression-free with a median follow up time of 36 (range 1–120) months for the 140 patients analyzed together. The overall actuarial and event free survival across all diseases at 60 months is 90.7% and 20

A heterologous prime-boost Ebola virus vaccine regimen induces durable neutralizing antibody response and prevents Ebola virus-like particle entry in mice.

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Chen, Tan; Li, Dapeng; Song, Yufeng; Yang, Xi; Liu, Qingwei; Jin, Xia; Zhou, Dongming; Huang, Zhong

2017-09-01

Ebola virus (EBOV) is one of the most virulent pathogens known to humans. Neutralizing antibodies play a major role in the protection against EBOV infections. Thus, an EBOV vaccine capable of inducing a long-lasting neutralizing antibody response is highly desirable. We report here that a heterologous prime-boost vaccine regimen can elicit durable EBOV-neutralizing antibody response in mice. A chimpanzee serotype 7 adenovirus expressing EBOV GP (denoted AdC7-GP) was generated and used for priming. A truncated version of EBOV GP1 protein (denoted GP1t) was produced at high levels in Drosophila S2 cells and used for boosting. Mouse immunization studies showed that the AdC7-GP prime/GP1t boost vaccine regimen was more potent in eliciting neutralizing antibodies than either the AdC7-GP or GP1t alone. Neutralizing antibodies induced by the heterologous prime-boost regimen sustained at high titers for at least 18 weeks after immunization. Significantly, in vivo challenge studies revealed that the entry of reporter EBOV-like particles was efficiently blocked in mice receiving the heterologous prime-boost regimen even at 18 weeks after the final dose of immunization. These results suggest that this novel AdC7-GP prime/GP1t boost regimen represents an EBOV vaccine approach capable of establishing long-term protection, and therefore warrants further development. Copyright © 2017 Elsevier B.V. All rights reserved.

High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment.

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Sivadasan, Ajith; Abraham, O C; Rupali, Priscilla; Pulimood, Susanne A; Rajan, Joyce; Rajkumar, S; Zachariah, Anand; Kannangai, Rajesh; Kandathil, Abraham Joseph; Sridharan, G; Mathai, Dilip

2009-05-01

To determine the rates, reasons and predictors of treatment change of the initial antiretroviral treatment (ART) regimen in HIV-infected south Indian adults. In this prospective cohort study, ART-naive adults initiated on generic, fixed dose combination ART as per the National AIDS Control Organization guidelines were followed up at an academic medical center. Treatment change was defined as any event which necessitated a change in or discontinuation of the initial ART regimen. Two hundred and thirty persons with HIV infection (males 74.8% and median age 37 years) were followed up for median duration of 48 weeks. The majority (98.7%) had acquired HIV infection through the heterosexual route. Most (70.4%) had advanced IV infection (WHO clinical stage 3 or 4) and 78% had CD4+ T-lymphocyte counts below 200 cells/microL. The initial ART regimens used were: Lamivudine (3TC) with Stavudine (d4T) (in 76%) or Azidothymidine (AZT) and Nevirapine (NVP) (in 86%) or Efavirenz (EFV). The cumulative incidence of treatment change was 39.6% (91 patients). Drug toxicity (WHO grade 3 or 4) was the reason for treatment change among 62 (27%) (incidence rate 35.9/100 person-years). The most common toxicities were attributable to the thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs), d4T and AZT [lactic acidosis (8.7%), anemia (7%) and peripheral neuropathy (5.2%)]. The other toxicities were rash (3.9%) and hepatitis (1.3%) due to NVP. The mortality (4.6/100 person-years) and disease progression rates (4.1/100 person-years) were low. The ART regimens used in this study were effective in decreasing disease progression and death. However, they were associated with high rates of drug toxicities, particularly those attributable to thymidine analogue NRTI. As efforts are made to improve access to ART, treatment regimens chosen should not only be potent, but also safe.

[Pretreatment doses of antithymocyte globubin-fresenius for allogeneic hematopoietic stem cell transplantation for beta-thalassemia major].

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Li, Chunfu; Wang, Yanhua; Wu, Xuedong; Pei, Fuyu; He, Yuelin; Feng, Xiaoqin; Liu, Huaying

2012-05-01

To investigate the effects of different doses of antithymocyte globubin-fresenius (ATG-F) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with beta-thalassemia Major. Sixty-four children with beta-thalassemia major undergoing allo-HSCT were divided into two equal groups to receive ATG-F pretreatments at high (30 mg/kg) or low (15 mg/kg) doses as part of the conditioning regimen including mainly cyclophosphamide, busulfan, fludarabine, and thiotepa. The outcomes of the patients were compared between the two groups. No obvious difference were noted in the time to leukocyte and platelet engraftment between the two groups. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) appeared to be higher in the low-dose group than in the high-dose group (12.5% vs 9.4%). The incidence of grade III-IV aGVHD was also higher in the low dose group (12.5% vs 6.3%), but the difference was not statistically significant. Application of high-dose ATG-F was associated with a higher rate of probable and possible fungal infection (P<0.05). The two doses of ATG-F is feasible as a part of the conditioning regimen for allo-HSCT in children with beta-thalassemia major.

Influence of the number of daily pills and doses on adherence to antiretroviral treatment: a 7-year study.

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Hernández Arroyo, M J; Cabrera Figueroa, S E; Sepúlveda Correa, R; Valverde Merino, M P; Luna Rodrigo, G; Domínguez-Gil Hurlé, A

2016-02-01

Antiretroviral treatment (ART) is hampered by complicated regimens, high pill burden, drug-drug interactions, and frequent short- and long-term adverse effects, leading to decreased adherence. Over recent years, considerable effort has been directed at developing regimens that are less burdening. We undertook a 7-year retrospective study of the records of 264 HIV-infected subjects enrolled in a pharmaceutical care programme to document the progress made and to study the influence of the number of ART pills and doses on the level of treatment adherence. Antiretroviral dispensing records were analysed for the number of pills and doses administered and the ART adherence rate estimated. In 2005, the patients took a mean of 6·2 pills daily (CI 95%: 5·9-6·6), and 92·9% of them were on a twice-a-day (BID) dosage regimen. By 2012, the mean number of pills was reduced to 4·1 (CI 95%: 3·8-4·4), and only 50·9% were on a BID regimen. No statistically significant relation was observed between number of daily pills and doses and ART adherence reached by the patients in any of the analyses performed. There has been a continuous reduction in the number of pills and doses of antiretrovirals taken by individual patients over the last 7 years due largely to the introduction of improved treatments and regimens. More daily pills or doses was not associated with worse ART adherence in our pharmaceutical care programme. © 2015 John Wiley & Sons Ltd.

Desfechos clínicos do tratamento de tuberculose utilizando o esquema básico recomendado pelo Ministério da Saúde do Brasil com comprimidos em dose fixa combinada na região metropolitana de Goiânia Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil

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Anna Carolina Galvão Ferreira

2013-02-01

years of age treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47% reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%.

Low-dose total skin electron beam therapy for cutaneous lymphoma : Minimal risk of acute toxicities.

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Kroeger, Kai; Elsayad, Khaled; Moustakis, Christos; Haverkamp, Uwe; Eich, Hans Theodor

2017-12-01

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T‑cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.

Desensitization Using Bortezomib and High-dose Immunoglobulin Increases Rate of Deceased Donor Kidney Transplantation.

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Jeong, Jong Cheol; Jambaldorj, Enkthuya; Kwon, Hyuk Yong; Kim, Myung-Gyu; Im, Hye Jin; Jeon, Hee Jung; In, Ji Won; Han, Miyeun; Koo, Tai Yeon; Chung, Junho; Song, Eun Young; Ahn, Curie; Yang, Jaeseok

2016-02-01

Combination therapy of intravenous immunoglobulin (IVIG) and rituximab showed a good transplant rate in highly sensitized wait-listed patients for deceased donor kidney transplantation (DDKT), but carried the risk of antibody-mediated rejection. The authors investigated the impact of a new combination therapy of bortezomib, IVIG, and rituximab on transplantation rate.This study was a prospective, open-labeled clinical trial. The desensitization regimen consisted of 2 doses of IVIG (2  g/kg), a single dose of rituximab (375  mg/m), and 4 doses of bortezomib (1.3  mg/m). The transplant rate was analyzed. Anti-Human leukocyte antigen (HLA) DRB antibodies were determined by a Luminex solid-phase bead assay at baseline and after 2, 3, and 6 months in the desensitized patients.There were 19 highly sensitized patients who received desensitization and 17 patients in the control group. Baseline values of class I and II panel reactive antibody (%, peak mean fluorescence intensity) were 83  ±  16.0 (14952  ±  5820) and 63  ±  36.0 (10321  ±  7421), respectively. Deceased donor kidney transplantation was successfully performed in 8 patients (42.1%) in the desensitization group versus 4 (23.5%) in the control group. Multivariate time-varying covariate Cox regression analysis showed that desensitization increased the probability of DDKT (hazard ratio, 46.895; 95% confidence interval, 3.468-634.132; P = 0.004). Desensitization decreased mean fluorescence intensity values of class I panel reactive antibody by 15.5% (20.8%) at 2 months. In addition, a liberal mismatch strategy in post hoc analysis increased the benefit of desensitization in donor-specific antibody reduction. Desensitization was well tolerated, and acute rejection occurred only in the control group.In conclusion, a desensitization protocol using bortezomib, high-dose IVIG, and rituximab increased the DDKT rate in highly sensitized, wait-listed patients.

Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

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Suputtamongkol, Yupin; Premasathian, Nalinee; Bhumimuang, Kid; Waywa, Duangdao; Nilganuwong, Surasak; Karuphong, Ekkapun; Anekthananon, Thanomsak; Wanachiwanawin, Darawan; Silpasakorn, Saowaluk

2011-01-01

Background Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined. Methods A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up. Results Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin

Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study

NARCIS (Netherlands)

van Heeswijk, R. P.; Veldkamp, A. I.; Mulder, J. W.; Meenhorst, P. L.; Lange, J. M.; Beijnen, J. H.; Hoetelmans, R. M.

2000-01-01

To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. Open-label, multi-dose, pharmacokinetic pilot study. Seven HIV-1-infected individuals who were treated with

Efficacy of three-week oxytetracycline or rifampin monotherapy compared with a combination regimen against the filarial nematode Onchocerca ochengi.

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Bah, Germanus S; Ward, Emma L; Srivastava, Abhishek; Trees, Alexander J; Tanya, Vincent N; Makepeace, Benjamin L

2014-01-01

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a major cause of visual impairment and dermatitis in sub-Saharan Africa. As O. volvulus contains an obligatory bacterial symbiont (Wolbachia), it is susceptible to antibiotic chemotherapy, although current regimens are considered too prolonged for community-level control programs. The aim of this study was to compare the efficacies of oxytetracycline and rifampin, administered separately or in combination, against a close relative of O. volvulus (Onchocerca ochengi) in cattle. Six animals per group were treated with continuous or intermittent oxytetracycline regimens, and effects on adult worm viability, dermal microfilarial loads, and Wolbachia density in worm tissues were assessed. Subsequently, the efficacies of 3-week regimens of oxytetracycline and rifampin alone and a combination regimen were compared, and rifampin levels in plasma and skin were quantified. A 6-month regimen of oxytetracycline with monthly dosing was strongly adulticidal, while 3-week and 6-week regimens exhibited weaker adulticidal effects. However, all three regimens achieved >2-log reductions in microfilarial load. In contrast, rifampin monotherapy and oxytetracycline-rifampin duotherapy failed to induce substantive reductions in either adult worm burden or microfilarial load, although a borderline effect on Wolbachia density was observed following duotherapy. Dermal rifampin levels were maintained above the MIC for >24 h after a single intravenous dose. We conclude that oxytetracycline-rifampin duotherapy is less efficacious against O. ochengi than oxytetracycline alone. Further studies will be required to determine whether rifampin reduces oxytetracycline bioavailability in this system, as suggested by human studies using other tetracycline-rifampin combinations.

Current regimen of pulse therapy for pemphigus: Minor modifications, improved results

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Pasricha J

2008-01-01

Full Text Available Background: If administered properly, dexamethasone cyclophosphamide pulse (DCP therapy has the potential to effect lifelong recovery from pemphigus. Aims: The objective of this paper is to highlight various parameters of DCP therapy and also, to report the effects of a few modifications in the regimen. Methods: An analysis of 123 patients treated with the DCP/DP regimen over a period of five years (1998 to 2002 is presented here. Seventeen patients who did not start/continue the treatment and three patients who died during the treatment have been excluded from the analysis. Twenty patients who had not yet started families were given only dexamethasone pulses (DPs while 103 patients received DCPs. Low dose (50 mg/day cyclophosphamide was used as in the standard regimen. The three modifications introduced into the regimen were: (1 an additional daily dose of oral betamethasone sufficient to control the disease activity during phase I, which was progressively tapered off completely as the patient recovered, (2 use of systemic antibiotics if the patient had skin lesions, and oral anti-candida drugs if the patient had oral ulcers until complete healing, and (3 insistence on thorough cleaning of the skin and scalp with a normal soap and shampoo, and proper maintenance of oral hygiene in spite of skin/mucosal lesions. The regimen consisted of DCP/DP repeated in exactly 28-day cycles, along with 50 mg cyclophosphamide per day, insistence on completing the treatment and avoiding irregular pulses in all patients. The number of DCPs/DPs during phase I varied in different patients depending upon the dose of betamethasone used and the rate of recovery, but phase II (nine DCPs/DPs in exactly 28-day cycles along with 50 mg cyclophosphamide per day and phase III (only 50 mg cyclophosphamide per day was fixed at nine months each. This was followed by posttreatment follow-up (phase IV. Results: At present, all the patients are in complete remission. The

High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution

Science.gov (United States)

Seldin, D. C.; Andrea, N.; Berenbaum, I.; Berk, J. L.; Connors, L.; Dember, L. M.; Doros, G.; Fennessey, S.; Finn, K.; Girnius, S.; Lerner, A.; Libbey, C.; Meier-Ewert, H. K.; O’Connell, R.; O’Hara, C.; Quillen, K.; Ruberg, F. L.; Sam, F.; Segal, A.; Shelton, A.; Skinner, M.; Sloan, J. M.; Wiesman, J. F.; Sanchorawala, V.

2017-01-01

Treatment with high-dose melphalan chemotherapy supported by hematopoietic rescue with autologous stem cells produces high rates of hematologic responses and improvement in survival and organ function for patients with AL amyloidosis. Ongoing clinical trials explore pre-transplant induction regimens, post-transplant consolidation or maintenance approaches, and compare transplant to non-transplant regimens. To put these studies into context, we reviewed our recent experience with transplant for AL amyloidosis in the Amyloid Treatment and Research Program at Boston Medical Center and Boston University School of Medicine. Over the past 10 years, there was a steady reduction in rates of treatment-related mortality and improvement in 1-year survival, now approximately 5% and 90%, respectively, based upon an intention-to-treat analysis. Median overall survival of patients treated with this approach at our center exceeds 7.5 years. PMID:21838459

Biological dose estimation for accidental supra-high dose gamma-ray exposure

International Nuclear Information System (INIS)

Chen, Y.; Yan, X.K.; Du, J.; Wang, Z.D.; Zhang, X.Q.; Zeng, F.G.; Zhou, P.K.

2011-01-01

To correctly estimate the biological dose of victims accidentally exposed to a very high dose of 60 Co gamma-ray, a new dose-effect curve of chromosomal dicentrics/multicentrics and rings in the supra-high dose range was established. Peripheral blood from two healthy men was irradiated in vitro with doses of 60 Co gamma-rays ranging from 6 to 22 Gy at a dose rate of 2.0 Gy/min. Lymphocytes were concentrated, cultured and harvested at 52 h, 68 h and 72 h. The numbers of dic + r were counted. The dose-effect curves were established and validated using comparisons with doses from the Tokai-mura accident and were then applied to two victims of supra-high dose exposure accident. The results indicated that there were no significant differences in chromosome aberration frequency among the different culture times from 52 h to 72 h. The 6-22 Gy dose-effect curve was fitted to a linear quadratic model Y = -2.269 + 0.776D - 7.868 x l0 -3 D 2 . Using this mathematic model, the dose estimates were similar to data from Tokai-mura which were estimated by PCC ring. Whole body average doses of 9.7 Gy and 18.1 Gy for two victims in the Jining accident were satisfactorily given. We established and successfully applied a new dose-effect curve of chromosomal dicentrics plus ring (dic + r) after 6-22 Gy γ-irradiation from a supra-high dose 60 Co gamma-ray accident.

Different Nebulized Budesonide Dosing Regimens in a Mouse Model of Chronic Asthma

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Pınar Uysal

2016-12-01

Full Text Available Objective: The aim of this study was to compare the effectiveness of different inhaled steroid regimens on the lungs and their potential side effects on the bone tissues in chronic asthma model. Materials and Methods: Thirty-five specific pathogen-free BALB/c mice were divided into five groups. The mice in all of the study groups except the control group were sensitized with chicken egg albumin. After sensitization, the mice in group 2 were treated with saline modeling twice daily, the mice in group 3 were treated with 250 mcg of nebulized budesonide twice daily, the mice in group 4 were treated with 500 mcg of budesonide once daily, and the mice in group 5 were treated with 1000 mcg of budesonide every other day for the last 14 days of the challenge period. After challenge, the mice were sacrificed and lung and tibia samples were histologically examined. Results: Pulmonary parameters, including subepithelial smooth muscle thickness, goblet cell count, mast cell count and epithelial thickness, were the lowest in group 5 compared to other groups (p0.01. Conclusion: The beneficial effect on lung tissue was highest in the treatment group receiving budesonide every other day (group 5 and no further measureable side effects on bone mineralization were observed in this group compared with the other treatment groups. Every-other-day treatment application seems to be the most effective regimen in chronic asthma model.

Intravenous administration of high-dose Paclitaxel reduces gut-associated lymphoid tissue cell number and respiratory immunoglobulin A concentrations in mice.

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Moriya, Tomoyuki; Fukatsu, Kazuhiko; Noguchi, Midori; Okamoto, Koichi; Murakoshi, Satoshi; Saitoh, Daizoh; Miyazaki, Masaru; Hase, Kazuo; Yamamoto, Junji

2014-02-01

Chemotherapy remains a mainstay of treatment for cancer patients. However, anti-cancer drugs frequently cause a wide range of side effects, including leukopenia and gastrointestinal toxicity. These adverse effects can lead to treatment delays or necessitate temporary dose reductions. Although chemotherapy-related changes in gut morphology have been demonstrated, the influences of chemotherapeutic regimens on gut immunity are understood poorly. This study aimed to examine whether the anti-cancer drug paclitaxel (PTX) impairs gut immunity in mice. Male ICR mice were randomized into three groups: Control, low-dose PTX (low PTX; 2 mg/kg), or high-dose PTX (high PTX; 4 mg/kg). A single intravenous dose was given. On day seven after the injection, lymphocytes from Peyer patches (PP), intraepithelial (IE) spaces, and the lamina propria (LP) were counted and analyzed by flow cytometry (CD4(+), CD8(+), αβTCR(+), γδTCR(+), B220(+)). Immunoglobulin A (IgA) concentrations were measured in small intestinal and respiratory tract washings. Total, CD4(+) and γδTCR(+) lymphocyte numbers in PPs were significantly lower in the high PTX than in the control group. The CD4(+) lymphocyte numbers in the IE spaces were significantly lower in both PTX groups than in the control group. Respiratory tract IgA concentrations were lower in the high PTX than in the control group. The present data suggest high-dose PTX impairs mucosal immunity, possibly rendering patients more vulnerable to infection. Careful dose selection and new therapies may be important for maintaining mucosal immunity during PTX chemotherapy.

Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

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Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso: effect of adding a third dose to the standard two-dose regimen on low birth weight, anaemia and pregnancy outcomes

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Roberfroid Dominique

2010-11-01

Full Text Available Abstract Background Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome. Methods Pregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2 or 3 doses (SP3 of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW ( Results Data from 1274 singleton pregnancies were analysed (641 in the SP3 and 633 in the SP2 group. The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24 in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 - 0.90. The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance. Conclusion The risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal.

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso: effect of adding a third dose to the standard two-dose regimen on low birth weight, anaemia and pregnancy outcomes.

Science.gov (United States)

Valea, Innocent; Tinto, Halidou; Drabo, Maxime K; Huybregts, Lieven; Henry, Marie-Claire; Roberfroid, Dominique; Guiguemde, Robert T; Kolsteren, Patrick; D'Alessandro, Umberto

2010-11-12

Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW) and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome. Pregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2) or 3 doses (SP3) of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW (anaemia (Hb pregnancies were analysed (641 in the SP3 and 633 in the SP2 group). The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24) in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 - 0.90). The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance. The risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal.

Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric Acute Lymphocytic Leukemia (ALL): Review from an International Consensus Conference

NARCIS (Netherlands)

T.M. Horton (Terzah); R. Sposto (Richard); P. Brown (Patrick); C.P. Reynolds (Patrick); S.P. Hunger (Stephen); N.J. Winick (Naomi); E.A. Raetz (Elizabeth); W.L. Carroll (William); R.J. Arceci (Robert); M.J. Borowitz (Michael); P.S. Gaynon (Paul); L. Gore (Lia); S. Jeha (Sima); B.J. Maurer (Barry); S.E. Siegel (Stuart); A. Biondi (Andrea); P. Kearns (Pamela); A. Narendran (Aru); L.B. Silverman (Lewis); M.A. Smith (Malcolm); C.M. Zwaan (Christian Michel); J.A. Whitlock (James)

2010-01-01

textabstractOne of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute

Tradução e validação para o português do Medication Regimen Complexity Index Translation and validation into portuguese Language of the Medication Regimen Complexity Index

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Ana Carolina Melchiors

2007-10-01

Full Text Available FUNDAMENTO: A complexidade da farmacoterapia consiste de múltiplas características do regime prescrito, incluindo o número de diferentes medicações no esquema, o número de unidades de dosagem por dose, o número total de doses por dia e os cuidados na administração dos medicamentos. O Medication Regimen Complexity Index (MRCI é um instrumento específico, validado e utilizado para medir a complexidade da farmacoterapia, desenvolvido originalmente em língua inglesa. OBJETIVO: Tradução transcultural e validação desse instrumento para o português do Brasil. MÉTODOS: Foi desenvolvido um estudo transversal envolvendo 95 pacientes com diabete do tipo 2 utilizando múltiplas medicações. O processo de validação teve início pela tradução, retrotradução e pré-teste do instrumento, gerando uma versão adaptada chamada Índice de Complexidade da Farmacoterapia (ICFT. Em seguida foram analisados parâmetros psicométricos, incluindo validade convergente, validade divergente, confiabilidade entre avaliadores e teste-reteste. RESULTADOS: A complexidade da farmacoterapia medida pelo ICFT obteve média de 15,7 pontos (desvio padrão = 8,36. O ICFT mostrou correlação significativa com o número de medicamentos em uso (r = 0,86; p BACKGROUND: The complexity of pharmacotherapy is a result of a multiplicity of prescribed regimen factors, including the number of different drugs in the regimen, the number of dosage units per dose, the total number of prescribed doses per day and administration instructions. The Medication Regimen Complexity Index (MRCI is a specific, reliable and valid tool used to measure the complexity of pharmacotherapy, originally developed in English language. OBJECTIVE: Transcultural translation and validation of this tool into Brazilian Portuguese. METHODS: A cross-sectional study was developed with 95 type-2 diabetes patients, receiving multiple medications. The validation process included translation into

Low dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis

NARCIS (Netherlands)

Youssef, Mohamed Abdel-Fattah; van Wely, Madelon; Mochtar, Monique; Fouda, Usama Mohamed; Eldaly, Ashraf; El Abidin, Eman Zein; Elhalwagy, Ahmed; Mageed Abdallah, Ahmed Abdel; Zaki, Sherif Sameh; Abdel Ghafar, Mohamed Sayed; Mohesen, Mohamed Nagi; van der Veen, Fulco

2018-01-01

Objective: To evaluate the effectiveness of low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens in terms of ongoing pregnancy per fresh IVF attempt in women with poor ovarian reserve undergoing

Optimized dose distribution of a high dose rate vaginal cylinder

International Nuclear Information System (INIS)

Li Zuofeng; Liu, Chihray; Palta, Jatinder R.

1998-01-01

Purpose: To present a comparison of optimized dose distributions for a set of high-dose-rate (HDR) vaginal cylinders calculated by a commercial treatment-planning system with benchmark calculations using Monte-Carlo-calculated dosimetry data. Methods and Materials: Optimized dose distributions using both an isotropic and an anisotropic dose calculation model were obtained for a set of HDR vaginal cylinders. Mathematical optimization techniques available in the computer treatment-planning system were used to calculate dwell times and positions. These dose distributions were compared with benchmark calculations with TG43 formalism and using Monte-Carlo-calculated data. The same dwell times and positions were used for a quantitative comparison of dose calculated with three dose models. Results: The isotropic dose calculation model can result in discrepancies as high as 50%. The anisotropic dose calculation model compared better with benchmark calculations. The differences were more significant at the apex of the vaginal cylinder, which is typically used as the prescription point. Conclusion: Dose calculation models available in a computer treatment-planning system must be evaluated carefully to ensure their correct application. It should also be noted that when optimized dose distribution at a distance from the cylinder surface is calculated using an accurate dose calculation model, the vaginal mucosa dose becomes significantly higher, and therefore should be carefully monitored

Dose rate and dose fractionation studies in total body irradiation of dogs

International Nuclear Information System (INIS)

Kolb, H.J.; Netzel, B.; Schaffer, E.; Kolb, H.

1979-01-01

Total body irradiation (TBI) with 800-900 rads and allogeneic bone marrow transplantation according to the regimen designated by the Seattle group has induced remissions in patients with otherwise refractory acute leukemias. Relapse of leukemia after bone marrow transplantation remains the major problem, when the Seattle set up of two opposing 60 Co-sources and a low dose rate is used in TBI. Studies in dogs with TBI at various dose rates confirmed observations in mice that gastrointestinal toxicity is unlike toxicity against hemopoietic stem cells and possibly also leukemic stem cells depending on the dose rate. However, following very high single doses (2400 R) and marrow infusion acute gastrointestinal toxicity was not prevented by the lowest dose rate studied (0.5 R/min). Fractionated TBI with fractions of 600 R in addition to 1200 R (1000 rads) permitted the application of total doses up to 300 R followed by marrow infusion without irreversible toxicity. 26 dogs given 2400-3000 R have been observed for presently up to 2 years with regard to delayed radiation toxicity. This toxicity was mild in dogs given single doses at a low dose rate or fractionated TBI. Fractionated TBI is presently evaluated with allogeneic transplants in the dog before being applied to leukemic patients

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

Science.gov (United States)

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Reyes, Antonio; Majercak, Ivan; Andreka, Peter; Shehova-Yankova, Nina; Anand, Inder; Yilmaz, Mehmet B; Gogia, Harinder; Martinez-Selles, Manuel; Fischer, Steffen; Zilahi, Zsolt; Cosmi, Franco; Gelev, Valeri; Galve, Enrique; Gómez-Doblas, Juanjo J; Nociar, Jan; Radomska, Maria; Sokolova, Beata; Volterrani, Maurizio; Sarkar, Arnab; Reimund, Bernard; Chen, Fabian; Charney, Alan

2016-09-01

To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure 5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose

Camptothecin-Based Regimens for Treatment of Ewing Sarcoma: sPast Studies and Future Directions

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Lars Wagner

2011-01-01

Full Text Available New therapies are needed to improve survival for patients with Ewing sarcoma. Over the past decade, camptothecin agents such as topotecan and irinotecan have demonstrated activity against Ewing sarcoma, especially in combination with alkylating agents. Previous studies have shown camptothecin-based combinations to be tolerable outpatient strategies that are attractive for salvage therapy. This paper highlights important issues related to drug dosing, schedule of administration, pharmacokinetics, toxicity, and activity of commonly used camptothecin-based regimens. Also discussed are strategies for incorporating these regimens into therapy for newly diagnosed patients, including several potential possibilities for combination with targeted agents.

Progress in high-dose radiation dosimetry

International Nuclear Information System (INIS)

Ettinger, K.V.; Nam, J.W.; McLaughlin, W.L.; Chadwick, K.H.

1981-01-01

The last decade has witnessed a deluge of new high-dose dosimetry techniques and expanded applications of methods developed earlier. Many of the principal systems are calibrated by means of calorimetry, although production of heat is not always the final radiation effect of interest. Reference systems also include a number of chemical dose meters: ferrous sulphate, ferrous-cupric sulphate, and ceric sulphate acidic aqueous solutions. Requirements for stable and reliable transfer dose meters have led to further developments of several important high-dose systems: amino acids and saccharides analysed by ESR or lyoluminescence, thermoluminescent materials, radiochromic dyes and plastics, ceric-cerous solutions analysed by potentiometry, and ethanol-chlorobenzene solutions analysed by high-frequency oscillometry. A number of other prospective dose meters are also treated in this review. In addition, an IAEA programme of high-dose standardization and intercomparison for industrial radiation processing is described. (author)

Dose rate and fractionation: Relative importance in radiation for bone marrow transplantation

International Nuclear Information System (INIS)

Tarbell, N.J.; Rosenblatt, M.; Mauch, P.; Hellman, S.

1987-01-01

The optimal dose rate and fractionation schedules for total body irradiation (TBI) in bone marrow transplantation (BMT) are presently unknown. This study compares several fractionation and dose rate schedules that are currently in clinical use. C/sub 3/H/HeJ were given TBI and the bone marrow survival fraction was calculated using the CFU's assay. Irradiation was given as low dose rate (LDR) at 5 cGy/min or high dose rate (HDR) at 80 cGy/min, in single fraction (SF) and fractionated (FX) regimens. These results indicate no increase in survival for the normal bone marrow stem cells with fractionation either at high or low dose-rates. In fact, fractionation seemed to decrease the bone marrow survival over single fraction radiation

Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers.

Science.gov (United States)

Polepally, Akshanth R; King, Jennifer R; Ding, Bifeng; Shuster, Diana L; Dumas, Emily O; Khatri, Amit; Chiu, Yi-Lin; Podsadecki, Thomas J; Menon, Rajeev M

2016-08-01

The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments. Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC). Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP. Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

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Catherine Weber

2012-01-01

Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

High-dose cisplatin with dipyridamole in advanced non-small cell lung cancer. A Grupo Oncológico Cooperativo del Sur study.

Science.gov (United States)

Vallejo, C T; Rabinovich, M G; Perez, J E; Rodriguez, R; Machiavelli, M R; Leone, B A; Romero, A D; Lacava, J A; Cuevas, M A; Langhi, M J

1995-06-01

From March 1991 to October 1992, 41 patients with advanced non-small cell lung cancer (NSCLC) (20 stage IIIB and 21 stage IV) received a regimen consisting of cisplatin (CP) 100 mg/m2 i.v. days 1 and 8, and dipyridamole (DPD) 100 mg p.o. 75 minutes before CP, and then at hours 6, 12, and 18 as first-line chemotherapy. Cycles were repeated every 28 days for a total of 3. Median age was 56 years (range: 40-70). All patients had a performance status 0 to 1 and a weight loss < or = 10%. Squamous-cell carcinoma was diagnosed in 19 patients; adenocarcinoma in 16, and large-cell carcinoma in 6. A total of 37 patients were fully evaluable for response, whereas 39 were assessable for toxicity. No complete responses were observed: 5 patients (14%) achieved partial response; 23 patients (62%) showed no change, and progressive disease was observed in 9 (24%). The median time to treatment failure was 4 months, whereas median survival was 8 months. The average dose intensity received at the end of the third course of therapy was 46 mg/m2/week. There were no drug-related deaths. Toxicity was mild to moderate, with a high incidence of ototoxicity (54%) and emesis (67%). In conclusion, these results failed to demonstrate any significant advantage from a high-dose CP regimen modulated by DPD in patients with advanced NSCLC.

A randomized open-labeled study to demonstrate the non-inferiority of purified chick-embryo cell rabies vaccine administered in the Zagreb regimen (2-1-1) compared with the Essen regimen in Chinese adults.

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Ma, Jingchen; Wang, Hongchang; Li, Jun; Chang, Likuan; Xie, Yun; Liu, Zhonglin; Zhao, Yuliang; Malerczyk, Claudius; Claudius, Malerczyk

2014-01-01

The Zagreb regimen has been used for 20 years in various countries. In China, until 2010, the Zagreb schedule was only approved for purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccines (PVRV). In this phase III clinical trial, we aimed to demonstrate the safety and immunogenic non-inferiority of the Zagreb regimen compared with the Essen regimen in healthy adult Chinese immunized with PCECV (Rabipur®). The study enrolled 825 subjects aged 18 to 50 years; serum samples were collected on Days 0, 7, 14, 42, and at 13 months to assess rabies virus neutralizing antibody (RVNA) concentrations. Solicited and unsolicited local and systemic reactions were recorded for 6 days following the day of vaccination, and collected throughout the entire study period (Day 1 until Month 13). The Zagreb regimen was non-inferior to the Essen regimen with regard to RVNA concentrations after 7, 14, and 42 days, and 13 months of immunization. The non-inferiority of seroconversion was established at Days 14 and 42. The incidence of local and systemic reactions was similar between groups, and mostly of mild or moderate severity. Vaccine-related adverse events occurred more frequently in the Essen group than in the Zagreb group. Vaccination with PCECV under a 2-1-1 regimen is as safe and immunogenic as under the traditional 5-dose Essen regimen for rabies post-exposure prophylaxis, and is a more cost-effective option, has a more practical vaccination schedule, and can potentially increase compliance.

Dose-response relationship in the treatment of gastrointestinal disorders.

Science.gov (United States)

Weihrauch, T R; Demol, P

1989-08-01

Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

Science.gov (United States)

Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

2015-09-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intracranial meningiomas after high-dose irradiation

International Nuclear Information System (INIS)

Soffer, D.; Gomori, J.M.; Siegal, T.; Shalit, M.N.

1989-01-01

Three patients who presented with intracranial meningiomas 12, 15, and 20 years, respectively, after therapeutic high-dose irradiation of a primary brain tumor are described. Analysis of these cases and similar documented cases suggests that meningiomas after high-dose irradiation constitute a recognizable entity. Patients with such tumors received radiation therapy at a young age (mean age, 9.4 years). After a latent period of 2 to 47 years (mean, 19.8 years) they developed meningiomas at the site of irradiation, at a much younger age than patients with ''spontaneous'' meningiomas. Similar to the situation with meningiomas after low-dose irradiation, a relatively high proportion of meningiomas induced by high-dose irradiation tend to be malignant and biologically aggressive. A very young age at the time of irradiation seems to predispose to the induction of malignant meningiomas, rather than benign tumors. These unusual features provide indirect evidence that high-dose radiation may play a role in the pathogenesis of meningiomas.41 references

Targeted ultraviolet B phototherapy in vitiligo: A comparison between once-weekly and twice-weekly treatment regimens

Directory of Open Access Journals (Sweden)

Imran Majid

2015-01-01

Full Text Available Background: Targeted ultraviolet B (T-UVB phototherapy in vitiligo is usually administered twice or thrice a week on non-consecutive days. It is difficult for many patients to adhere to this regimen, forcing them to discontinue treatment. Aim: The study aimed to compare the efficacy of twice-weekly and once-weekly targeted ultraviolet B phototherapy regimens in vitiligo. Methods: Sixty patients with non-segmental vitiligo on the face, neck or trunk were divided into two groups of 30 patients each. The patients in group A received targeted ultraviolet B twice weekly, while those in group B received targeted ultraviolet B once weekly. Repigmentation was monitored and graded as excellent (≥75% repigmentation, good (50−74% repigmentation and poor (<50% repigmentation. The extent of repigmentation at each body site (primary outcome measure, the number of doses required for initiation of pigmentation, and the cumulative dose of targeted ultraviolet B administered was calculated and compared between both groups. Results: A total of 90 lesions (48 in the twice weeklygroup and 42 in the once weekly group were treated on the face, neck and trunk. Excellent results were obtained in 62.5% (30/48 of lesions treated twice weekly, and 64.3% (27/42 in lesions treated once weekly. The mean number of doses required for initiation of pigmentation was 4.69 in the twice weekly group, and 4.35 in the once weekly group. The patients in the twice weekly group received a mean cumulative dose of 8.26 J/cm 2, while the once weekly group received 7.69 J/cm 2. No statistically significant differences were observed between the two groups with respect to the outcome, with respect to the total repigmentation, the number of doses till onset of pigmentation, as well as the cumulative dose of targeted UVB. Conclusion: Once-weekly targeted ultraviolet B phototherapy appears to be as efficacious as the twice-weekly regimen in vitiligo.

Inactivated H9N2 avian influenza virus vaccine with gel-primed and mineral oil-boosted regimen could produce improved immune response in broiler breeders.

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Lee, D-H; Kwon, J-S; Lee, H-J; Lee, Y-N; Hur, W; Hong, Y-H; Lee, J-B; Park, S-Y; Choi, I-S; Song, C-S

2011-05-01

The frequent economic losses incurred with H9N2 low pathogenic avian influenza viruses (LPAI) infection have raised serious concerns for the poultry industry. A 1-dose regimen with inactivated H9N2 LPAI vaccine could not prevent vaccinated poultry from becoming infected and from shedding wild viruses. A study was conducted to determine whether a 2-dose regimen of inactivated H9N2 LPAI vaccine could enhance the immunologic response in chickens. Such gel-primed and mineral oil-boosted regimen has produced encouraging results associated with improved immune responses to an H9N2 LPAI. This strategy could be cost effective and helpful for preventing avian influenza virus in the poultry industry.

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

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Thanos Manos

2018-04-01

Full Text Available In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization.

Science.gov (United States)

Manos, Thanos; Zeitler, Magteld; Tass, Peter A

2018-01-01

In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long

Relationship between person's health beliefs and diabetes self-care management regimen.

Science.gov (United States)

Albargawi, Moudi; Snethen, Julia; Al Gannass, Abdulaziz; Kelber, Sheryl

2017-12-01

To examine the relationship between the health beliefs of Saudi adults with type 2 diabetes mellitus (T2DM) and their adherence to daily diabetes self-care management regimen. A secondary aim was to examine the health beliefs of adults with a diabetic foot ulcer (DFU) and participants without a DFU. Descriptive correlational design with a convenience sample of 30 participants. Participants were recruited for this pilot study from an outpatient clinic at King Abdulaziz Medical City in Riyadh. The participants completed self-reported questionnaires about their health beliefs, daily diabetes self-care management regimen, and demographic characteristics. Hierarchical multiple regression analysis was used to test the interaction effects. Participants who reported having a high internal health locus of control (IHLoC) and a high level of self-efficacy (SE) adhered well to their foot care regimen (P = .038). The more the participants believed that God controls their health, and the higher their SE, the greater the participant's adherence to their medication regimen (P = .035). The stronger the participant's belief that following their diabetes treatment regimen will lead to good outcomes, the greater the participant's adherence to their dietary regimen for those with a low IHLoC (P = .015). Participants with a high SE and reported that their doctor is able to help them control their diabetes were more likely to follow their dietary regimen (P = .048). Participants with a DFU reported having additional health conditions besides T2DM (P = .018) and had less than a college education (P = .015). Although participants with a DFU reported that they were responsible for their diabetes (P = .21), they stated that God manages their diabetes (P = .29), and the disease can be controlled based on luck (P = .10). Participants' beliefs were found to influence their daily self-care management regimen. Further studies are needed using a larger sample. Copyright © 2017

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.

Science.gov (United States)

Deshpande, Devyani; Srivastava, Shashikant; Nuermberger, Eric; Pasipanodya, Jotam G; Swaminathan, Soumya; Gumbo, Tawanda

2016-11-01

 The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination.  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (T MIC ) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression.  TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem T MIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem T MIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment.  We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

High-dose irradiation of food

International Nuclear Information System (INIS)

Diehl, J.F.

1999-01-01

Studies performed on behalf of the International Project on Food Irradiation in the period from 1971 until 1980 resulted in the concluding statement that ''.the irradiation of any food commodity up to an overall average dose of 10 kGy presents no toxicological hazard; hence, toxicological testing of foods so treated is no longer required.'' Since then, licenses for food irradiation have been restricted to this maximum dose in any country applying this technology. Further testing programmes have been carried out investigating the wholesomeness or hazards of high-dose irradiation, but there has been little demand so far by the food industry for licensing of high-dose irradiation, as there is only a small range of products whose irradiation at higher doses offers advantages for given, intended use. These include eg. spices, dried herbs, meat products in flexible pouch packagings for astronauts, or patients with immune deficiencies. (orig./CB) [de

''Low dose'' and/or ''high dose'' in radiation protection: A need to setting criteria for dose classification

International Nuclear Information System (INIS)

Sohrabi, M.

1997-01-01

The ''low dose'' and/or ''high dose'' of ionizing radiation are common terms widely used in radiation applications, radiation protection and radiobiology, and natural radiation environment. Reading the title, the papers of this interesting and highly important conference and the related literature, one can simply raise the question; ''What are the levels and/or criteria for defining a low dose or a high dose of ionizing radiation?''. This is due to the fact that the criteria for these terms and for dose levels between these two extreme quantities have not yet been set, so that the terms relatively lower doses or higher doses are usually applied. Therefore, setting criteria for classification of radiation doses in the above mentioned areas seems a vital need. The author while realizing the existing problems to achieve this important task, has made efforts in this paper to justify this need and has proposed some criteria, in particular for the classification of natural radiation areas, based on a system of dose limitation. (author)

Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: A modelling study

NARCIS (Netherlands)

M.A. Irvine (Michael A.); W.A. Stolk (Wilma); Smith, M.E. (Morgan E); S.V. Subramanian; B.K. Singh (Brajendra K.); G.J. Weil (Gary); E. Michael (Edwin); T.D. Hollingsworth (T. Déirdre)

2017-01-01

textabstractBackground: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen

Low-dose hydrocortisone (HC) replacement therapy is associated with improved bone remodeling balance in hypopituitary subjects

LENUS (Irish Health Repository)

Behan, L A

2011-06-01

The effect of commonly used glucocorticoid replacement regimens on bone health in hypopituitary subjects is not well known. We aimed to assess the effect of 3 hydrocortisone (HC) replacement dose regimens on bone turnover in this group.10 hypopituitary men with severe ACTH deficiency were randomised in a crossover design to 3 HC dose regimens, Dose A (20mg mane, 10mg tarde), Dose B (10mg twice daily) and Dose C (10mg mane, 5mg tarde). Following 6 weeks of each regimen participants underwent fasting sampling of bone turnover markers.Data from matched controls were used to produce a Z score for subject bone formation and resorption markers and to calculate the bone remodeling balance (formation Z score-resorption Z score) and turnover index ((formation Z + resorption Z)\\/2). A positive bone remodeling balance with increased turnover is consistent with a favourable bone cycle. Data are expressed as median (range).The Pro Collagen Type 1 Peptide (PINP) bone formation Z-score was significantly increased in Dose C, (1.805 (-0.6-10.24)) compared to Dose A (0.035 (-1.0-8.1)) p<0.05 while there was no difference in the C-terminal crosslinking telopeptide (CTx) resorption Z score. The bone remodeling balance was significantly lower for dose A -0.02 (-1.05-4.12) compared to dose C 1.13 (0.13-6.4) (p<0.05). Although there was a trend to an increased bone turnover index with the lower dose regimen, this was not statistically significant.Low dose HC replacement (10mg mane\\/5 mg tarde) was associated with increased bone formation and improved bone remodeling balance which is associated with a more favourable bone cycle. This may have a long term beneficial effect on bone health.

Optimal use of β-blockers in high-risk hypertension: A guide to dosing equivalence

Directory of Open Access Journals (Sweden)

Janet B McGill

2010-05-01

Full Text Available Janet B McGillDepartment of Medicine, Washington University School of Medicine, St. Louis, Missouri, USAAbstract: Hypertension is the number one diagnosis made by primary care physicians, placing them in a unique position to prescribe the antihypertensive agent best suited to the individual patient. In individuals with diabetes mellitus, blood pressure (BP levels > 130/80 mmHg confer an even higher risk for cardiovascular and renal disease, and these patients will benefit from aggressive antihypertensive treatment using a combination of agents. β‑blockers are playing an increasingly important role in the management of hypertension in high-risk patients. β‑blockers are a heterogeneous class of agents, and this review presents the differences between β‑blockers and provides evidence-based protocols to assist in understanding dose equivalence in the selection of an optimal regimen in patients with complex needs. The clinical benefits provided by β‑blockers are only effective if patients adhere to medication treatment long term. β‑blockers with proven efficacy, once-daily dosing, and lower side effect profiles may become instrumental in the treatment of hypertensive diabetic and nondiabetic patients.Keywords: antihypertensive, blood pressure, atenolol, carvedilol, labetalol, metoprolol, nebivolol

Maternal methadone dosing schedule and fetal neurobehavior

Science.gov (United States)

Jansson, Lauren M.; DiPietro, Janet A.; Velez, Martha; Elko, Andrea; Knauer, Heather; Kivlighan, Katie T.

2008-01-01

Objective Daily methadone maintenance is the standard of care for opiate dependency during pregnancy. Previous research has indicated that single-dose maternal methadone administration significantly suppresses fetal neurobehaviors. The purpose of this study was to determine if split-dosing would have less impact on fetal neurobehavior than single-dose administration. Methods Forty methadone-maintained women were evaluated at peak and trough maternal methadone levels on single- and split-dosing schedules. Monitoring sessions occurred at 36 and 37 weeks gestation in a counterbalanced study design. Fetal measures included heart rate, variability, accelerations, motor activity and fetal movement-heart rate coupling (FM-FHR). Maternal measures included heart period, variability, skin conductance, respiration and vagal tone. Repeated measure analysis of variance was used to evaluate within-subject changes between split- and single-dosing regimens. Results All fetal neurobehavioral parameters were suppressed by maternal methadone administration, regardless of dosing regimen. Fetal parameters at peak were significantly lower during single vs. split methadone administration. FM-FHR coupling was less suppressed from trough to peak during split-dosing vs. single-dosing. Maternal physiologic parameters were generally unaffected by dosing condition. Conclusion Split- dosed fetuses displayed less neurobehavioral suppression from trough to peak maternal methadone levels as compared to single-dosed fetuses. Split-dosing may be beneficial for methadone-maintained pregnant women. PMID:19085624

AUC versus peak-trough dosing of vancomycin: applying new pharmacokinetic paradigms to an old drug.

Science.gov (United States)

Brown, Daniel L; Lalla, Christina D; Masselink, Andrew J

2013-08-01

To compare and contrast the pharmacokinetic/pharmacodynamic foundations of traditional "peak-trough" vancomycin dosing methods versus newer "area under the curve" (AUC) strategies. To propose a new AUC-based dosing chart for empirically determining an initial vancomycin dosing regimen designed to achieve a desired AUC24 using the minimum inhibitory concentration (MIC), creatinine clearance (CrCl), and vancomycin clearance (ClVanco). Peak-trough vancomycin dosing is designed to achieve a Cpeak of 20-40 mg/L and a Ctrough of 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. New treatment guidelines for vancomycin suggest that therapy should achieve an AUC24/MIC of ≥400. AUC-based vancomycin dosing derives the daily dose from ClVanco, MIC, and the desired AUC24/MIC, without consideration of the patient's weight. A vancomycin dosing chart is proposed that estimates ClVanco using the following formula developed by Matzke et al: ClVanco in L/h = [(CrClmL/min × 0.689) + 3.66] × 0.06, which simplifies to (CrClmL/min × 0.41) + 0.22. Two levels of dosing are included-high dose (Ctrough: 15-20 mg/L) and moderate dose (Ctrough: 10-15 mg/L). Although the chart has not been validated clinically, it represents the product of standard dosing equations that are used to determine a starting dosing regimen based on well-established vancomycin pharmacokinetic parameters. An understanding of pharmacokinetic and pharmacodynamic principles, including the relevance of AUC in relation to MIC, enables clinicians to make the best use of vancomycin dosing options. The proposed dosing chart is pharmacokinetically valid but has yet to be applied clinically. It provides a foundation for further study of how clinicians can determine an optimal AUC-based starting vancomycin dosing regimen without having to derive ClVanco or AUC24.

Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia.

Science.gov (United States)

Ramirez, Julio; Dartois, Nathalie; Gandjini, Hassan; Yan, Jean Li; Korth-Bradley, Joan; McGovern, Paul C

2013-04-01

In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.).

Dose-reduction techniques for high-dose worker groups in nuclear power plants

International Nuclear Information System (INIS)

Khan, T.A.; Baum, J.W.; Dionne, B.J.

1991-03-01

This report summarizes the main findings of a study of the extent of radiation dose received by special work groups in the nuclear power industry. Work groups which chronically get large doses were investigated, using information provided by the industry. The tasks that give high doses to these work groups were examined and techniques described that were found to be particularly successful in reducing dose. Quantitative information on the extent of radiation doses to various work groups shows that significant numbers of workers in several critical groups receive doses greater than 1 and even 2 rem per year, particularly contract personnel and workers at BWR-type plants. The number of radiation workers whose lifetime dose is greater than their age is much less. Although the techniques presented would go some way in reducing dose, it is likely that a sizeable reduction to the high-dose work groups may require development of new dose-reduction techniques as well as major changes in procedures. 10 refs., 26 tabs

Performance of thermoluminescent materials for high dose dosimetry

International Nuclear Information System (INIS)

Texeira, Maria I.; Cecatti, Sonia G.P.; Caldas, Linda V.E.

2008-01-01

Cases involving high-doses of ionizing radiation are becoming increasingly common.The objective of this work was to characterize thermoluminescent materials for the dosimetry of workers exposed to high doses. Samples of TLD-200, TLD-400 and TLD-800 pellets from Thermo Electron Corporation were studied in gamma high-doses. Dose-response curves were obtained for doses between 100 mGy and 100 Gy. The reproducibility, the lower detection limits and dose-response curves were obtained for all three materials. The different kinds of detectors show usefulness for dosimetry of workers exposed accidentally to high doses. (author)

Pulsed dose rate and fractionated high dose rate brachytherapy: choice of brachytherapy schedules to replace low dose rate treatments

International Nuclear Information System (INIS)

Visser, Andries G.; Aardweg, Gerard J.M.J. van den; Levendag, Peter C.

1996-01-01

Purpose: Pulsed dose rate (PDR) brachytherapy is a new type of afterloading brachytherapy (BT) in which a continuous low dose rate (LDR) treatment is simulated by a series of 'pulses,' i.e., fractions of short duration (less than 0.5 h) with intervals between fractions of 1 to a few hours. At the Dr. Daniel den Hoed Cancer Center, the term 'PDR brachytherapy' is used for treatment schedules with a large number of fractions (at least four per day), while the term 'fractionated high dose rate (HDR) brachytherapy' is used for treatment schedules with just one or two brachytherapy fractions per day. Both treatments can be applied as alternatives for LDR BT. This article deals with the choice between PDR and fractionated HDR schedules and proposes possible fractionation schedules. Methods and Materials: To calculate HDR and PDR fractionation schedules with the intention of being equivalent to LDR BT, the linear-quadratic (LQ) model has been used in an incomplete repair formulation as given by Brenner and Hall, and by Thames. In contrast to earlier applications of this model, both the total physical dose and the overall time were not kept identical for LDR and HDR/PDR schedules. A range of possible PDR treatment schedules is presented, both for booster applications (in combination with external radiotherapy (ERT) and for BT applications as a single treatment. Because the knowledge of both α/β values and the half time for repair of sublethal damage (T (1(2)) ), which are required for these calculations, is quite limited, calculations regarding the equivalence of LDR and PDR treatments have been performed for a wide range of values of α/β and T (1(2)) . The results are presented graphically as PDR/LDR dose ratios and as ratios of the PDR/LDR tumor control probabilities. Results: If the condition that total physical dose and overall time of a PDR treatment must be exactly identical to the values for the corresponding LDR treatment regimen is not applied, there appears

Dose evaluation of narrow-beam

International Nuclear Information System (INIS)

Goto, Shinichi

1999-01-01

Reliability of the dose from the narrow photon beam becomes more important since the single high-dose rate radiosurgery becoming popular. The dose evaluation for the optimal dose is difficult due to absence of lateral electronic equilibrium. Data necessary for treatment regimen are TMR (tissue maximum ratio), OCR (off center ratio) and S c,p (total scatter factor). The narrow-beam was 10 MV X-ray from Varian Clinac 2100C equipped with cylindrical Fischer collimator CBI system. Detection was performed by Kodak XV-2 film, a PTW natural diamond detector M60003, Scanditronics silicon detector EDD-5 or Fujitec micro-chamber FDC-9.4C. Phantoms were the water equivalent one (PTW, RW3), water one (PTW, MP3 system) and Wellhofer WP600 system. Factors above were actually measured to reveal that in the dose evaluation of narrow photon beam, TMR should be measured by micro-chamber, OCR, by film, and S c,p , by the two. The use of diamond detector was recommended for more precise measurement and evaluation of the dose. The importance of water phantom in the radiosurgery system was also shown. (K.H.)

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Cost-Utility Analysis.

Science.gov (United States)

Dawoud, Dalia; Fenu, Elisabetta; Higgins, Bernard; Wonderling, David; Amiel, Stephanie A

2017-12-01

To assess the cost-effectiveness of basal insulin regimens for adults with type 1 diabetes mellitus in England. A cost-utility analysis was conducted in accordance with the National Institute for Health and Care Excellence reference case. The UK National Health Service and personal and social services perspective was used and a 3.5% discount rate was applied for both costs and outcomes. Relative effectiveness estimates were based on a systematic review of published trials and a Bayesian network meta-analysis. The IMS CORE Diabetes Model was used, in which net monetary benefit (NMB) was calculated using a threshold of £20,000 per quality-adjusted life-year (QALY) gained. A wide range of sensitivity analyses were conducted. Insulin detemir (twice daily) [iDet (bid)] had the highest mean QALY gain (11.09 QALYs) and NMB (£181,456) per patient over the model time horizon. Compared with the lowest cost strategy (insulin neutral protamine Hagedorn once daily), it had an incremental cost-effectiveness ratio of £7844/QALY gained. Insulin glargine (od) [iGlarg (od)] and iDet (od) were ranked as second and third, with NMBs of £180,893 and £180,423, respectively. iDet (bid) remained the most cost-effective treatment in all the sensitivity analyses performed except when high doses were assumed (>30% increment compared with other regimens), where iGlarg (od) ranked first. iDet (bid) is the most cost-effective regimen, providing the highest QALY gain and NMB. iGlarg (od) and iDet (od) are possible options for those for whom the iDet (bid) regimen is not acceptable or does not achieve required glycemic control. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand.

Science.gov (United States)

Werayingyong, Pitsaphun; Phanuphak, Nittaya; Chokephaibulkit, Kulkunya; Tantivess, Sripen; Kullert, Nareeluk; Tosanguan, Kakanang; Butchon, Rukmanee; Voramongkol, Nipunporn; Boonsuk, Sarawut; Pilasant, Songyot; Kulpeng, Wantanee; Teerawattananon, Yot

2015-03-01

The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd-NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation. © 2013 APJPH.

Radiobiological responses for two cell lines following continuous low dose-rate (CLDR) and pulsed dose rate (PDR) brachytherapy

International Nuclear Information System (INIS)

Hanisch, Per Henrik; Furre, Torbjoern; Olsen, Dag Rune; Pettersen, Erik O.

2007-01-01

The iso-effective irradiation of continuous low-dose-rate (CLDR) irradiation was compared with that of various schedules of pulsed dose rate (PDR) irradiation for cells of two established human lines, T-47D and NHIK 3025. Complete single-dose response curves were obtained for determination of parameters α and β by fitting of the linear quadratic formula. Sublethal damage repair constants μ and T 1/2 were determined by split-dose recovery experiments. On basis of the acquired parameters of each cell type the relative effectiveness of the two regimens of irradiation (CLDR and PDR) was calculated by use of Fowler's radiobiological model for iso-effect irradiation for repeated fractions of dose delivered at medium dose rates. For both cell types the predicted and observed relative effectiveness was compared at low and high iso-effect levels. The results indicate that the effect of PDR irradiation predicted by Fowler's model is equal to that of CLDR irradiation for both small and large doses with T-47D cells. With NHIK 3025 cells PDR irradiation induces a larger effect than predicted by the model for small doses, while it induces the predicted effect for high doses. The underlying cause of this difference is unclear, but cell-cycle parameters, like G2-accumulation is tested and found to be the same for the two cell lines

The optimal fraction size in high-dose-rate brachytherapy: dependency on tissue repair kinetics and low-dose rate

International Nuclear Information System (INIS)

Sminia, Peter; Schneider, Christoph J.; Fowler, Jack F.

2002-01-01

Background and Purpose: Indications of the existence of long repair half-times on the order of 2-4 h for late-responding human normal tissues have been obtained from continuous hyperfractionated accelerated radiotherapy (CHART). Recently, these data were used to explain, on the basis of the biologically effective dose (BED), the potential superiority of fractionated high-dose rate (HDR) with large fraction sizes of 5-7 Gy over continuous low-dose rate (LDR) irradiation at 0.5 Gy/h in cervical carcinoma. We investigated the optimal fraction size in HDR brachytherapy and its dependency on treatment choices (overall treatment time, number of HDR fractions, and time interval between fractions) and treatment conditions (reference low-dose rate, tissue repair characteristics). Methods and Materials: Radiobiologic model calculations were performed using the linear-quadratic model for incomplete mono-exponential repair. An irradiation dose of 20 Gy was assumed to be applied either with HDR in 2-12 fractions or continuously with LDR for a range of dose rates. HDR and LDR treatment regimens were compared on the basis of the BED and BED ratio of normal tissue and tumor, assuming repair half-times between 1 h and 4 h. Results: With the assumption that the repair half-time of normal tissue was three times longer than that of the tumor, hypofractionation in HDR relative to LDR could result in relative normal tissue sparing if the optimum fraction size is selected. By dose reduction while keeping the tumor BED constant, absolute normal tissue sparing might therefore be achieved. This optimum HDR fraction size was found to be largely dependent on the LDR dose rate. On the basis of the BED NT/TUM ratio of HDR over LDR, 3 x 6.7 Gy would be the optimal HDR fractionation scheme for replacement of an LDR scheme of 20 Gy in 10-30 h (dose rate 2-0.67 Gy/h), while at a lower dose rate of 0.5 Gy/h, four fractions of 5 Gy would be preferential, still assuming large differences between tumor

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

Science.gov (United States)

Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

2018-04-01

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

Fiber optics in high dose radiation fields

International Nuclear Information System (INIS)

Partin, J.K.

1985-01-01

A review of the behavior of state-of-the-art optical fiber waveguides in high dose (greater than or equal to 10 5 rad), steady state radiation fields is presented. The influence on radiation-induced transmission loss due to experimental parameters such as dose rate, total dose, irradiation history, temperature, wavelength, and light intensity, for future work in high dose environments are given

Eruptive furunculosis following the soak and smear regimen.

Science.gov (United States)

Martires, Kathryn; Sukhdeo, Kumar; Meinhardt, Eric

2015-02-18

The 'soak and smear' regimen is a highly effective method for localised topical therapy employed by dermatologists for widespread inflammatory skin conditions. The regimen involves application of topical medication under occlusion after soaking in water. Complications from this treatment method are rare. We present a case of multiple, generalised methicillin-resistant Staphylococcus aureus (MRSA)-positive furuncles arising in a patient as an unexpected consequence of therapy. The case highlights an unanticipated risk of a commonly employed treatment amid an epidemic of MRSA in the community. 2015 BMJ Publishing Group Ltd.

Radiophotoluminescence light scope for high-dose dosimetry

International Nuclear Information System (INIS)

Sato, Fuminobu; Zushi, Naoki; Sakiyama, Tomoki; Kato, Yushi; Murata, Isao; Shimizu, Kikuo; Yamamoto, Takayoshi; Iida, Toshiyuki

2015-01-01

A radiophotoluminescence (RPL) light scope is a remote-sensing technique for measuring in situ the radiation dose in an RPL detector placed at a distance. The RPL light scope is mainly composed of an ultraviolet (UV) pulse laser, telescopic lenses, a photomultiplier tube, and camera modules. In a performance test, some RPL detectors were placed at distances up to 30 m and were illuminated with a pulsed UV laser beam. The photoluminescence responses of the RPL detectors were analyzed using this scope. Their radiation doses were determined from the amplitude of the given component of the photoluminescence responses. The RPL readout could be repeated without fading, and its amplitude exhibited good linearity at a dose ranging from 0.1 to 60 Gy. Furthermore, a two-dimensional distribution of radiation dose was obtained by laser scanning on an RPL detector. It was confirmed that the RPL light scope was a useful remote-sensing tool for high-dose dosimetry. - Highlights: • A radiophotoluminescence (RPL) light scope was developed for high-dose dosimetry. • The RPL light scope has high sensitivity and accuracy in high-dose dosimetry. • Two-dimensional radiation dose distribution was obtained by the RPL light scope.

Febrile Neutropenia Risk Assessment and Granulocyte-Colony Stimulating Factor Support in Patients with Diffuse Large B Cell Lymphoma Receiving R-CHOP Regimens

DEFF Research Database (Denmark)

Salar, Antonio; Haioun, Corinne; Rossi, Francesca Gaia

2009-01-01

BACKGROUND: ASCO and EORTC guidelines recommend granulocyte colony-stimulating factor (G-CSF) primary prophylaxis for cancer patients with a ≥20% overall risk of febrile neutropenia (FN), and to support delivery of dose-dense regimens. CHOP-like regimens (with rituximab [R]) are the current...... standard of care for the management of aggressive non-Hodgkin lymphoma (NHL), but they are often associated with significant myelosuppression. Neutropenic events, particularly febrile neutropenia (FN), can be life-threatening and may lead to dose delays or reductions that compromise the efficacy......-CSF primary prophylaxis. Across all cycles, 29% of R-CHOP-21 patients had an unplanned hospitalization, with neutropenia/FN being the main reason. Subsequently, 67% of patients achieved a relative dose intensity (RDI) of ≥90% of their planned treatment (with respect to cyclophosphamide, doxorubicin...

High-dose dosimetry using natural silicate minerals

International Nuclear Information System (INIS)

Carmo, Lucas S. do; Mendes, Leticia; Watanabe, Shigueo; Rao, Gundu; Lucas, Natasha; Sato, Karina; Barbosa, Renata F.

2015-01-01

In the present study, certain natural silicate minerals such as aquamarine (AB), morganite (PB), goshenite (WB), white jadeite (JW), green jadeite (JG), pink tourmaline (PT) and two varieties of jadeite-like quartz, denoted here by JQ1 and JQ2, were investigated using the thermoluminescence technique to evaluate their potential for use as very-high- and high-dose dosimeters. These minerals respond to high doses of γ-rays of up to 1000 kGy and often to very high doses of up to 3000 kGy. The TL response of these minerals may be considered to be satisfactory for applications in high-dose dosimetry. Investigations of electron paramagnetic resonance and optically stimulated luminescence dosimetry are in progress. (author)

High-dose dosimetry using natural silicate minerals

Energy Technology Data Exchange (ETDEWEB)

Carmo, Lucas S. do; Mendes, Leticia, E-mail: isatiro@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Watanabe, Shigueo; Rao, Gundu; Lucas, Natasha; Sato, Karina, E-mail: lacifid@if.usp.br [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Instituto de Fisica. Departamento de Fisica Nuclear; Barbosa, Renata F., E-mail: profcelta@hotmail.com [Universidade Federal de Sao Paulo (UNIFESP), Santos, SP (Brazil). Departamento de Ciencias do Mar

2015-07-01

In the present study, certain natural silicate minerals such as aquamarine (AB), morganite (PB), goshenite (WB), white jadeite (JW), green jadeite (JG), pink tourmaline (PT) and two varieties of jadeite-like quartz, denoted here by JQ1 and JQ2, were investigated using the thermoluminescence technique to evaluate their potential for use as very-high- and high-dose dosimeters. These minerals respond to high doses of γ-rays of up to 1000 kGy and often to very high doses of up to 3000 kGy. The TL response of these minerals may be considered to be satisfactory for applications in high-dose dosimetry. Investigations of electron paramagnetic resonance and optically stimulated luminescence dosimetry are in progress. (author)

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

Science.gov (United States)

Hodgson, Sam; Larvin, Joseph T; Dearman, Charles

2015-09-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high-dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial: study protocol for a randomized controlled trial

Directory of Open Access Journals (Sweden)

Park Kyung

2012-03-01

Full Text Available Abstract Background Second-generation drug-eluting stents (DES have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES. In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI. A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT is used more commonly than doubling the dose of clopidogrel in high-risk patients. Methods In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES and antiplatelet regimen (TAT vs DDAT. The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen. Discussion The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI. Trial registration ClincalTrials.gov number NCT01267734.

Maximally effective dosing regimens of meropenem in patients with septic shock

DEFF Research Database (Denmark)

Sjövall, Fredrik; Alobaid, Abdulaziz S; Wallis, Steven C

2018-01-01

was required for both empirical and targeted treatment. In patients with a CL CR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. Conclusions: In patients with septic shock and possible augmented renal clearance, doses should be increased and...

In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents

Energy Technology Data Exchange (ETDEWEB)

Langer, R.D., E-mail: rlanger@uaeu.ac.ae [Faculty of Medicine and Health Sciences (FMHS), United Arab Emirates University, Al Ain (United Arab Emirates); Lorke, D.E. [Florida International University, Miami, FL (United States); Neidl van Gorkom, K.F. [Faculty of Medicine and Health Sciences (FMHS), United Arab Emirates University, Al Ain (United Arab Emirates); Petroianu, G. [Florida International University, Miami, FL (United States); Azimullah, S.; Nurulain, S.M.; Singh, S. [Faculty of Medicine and Health Sciences (FMHS), United Arab Emirates University, Al Ain (United Arab Emirates); Fuchsjäger, M. [Al Ain Hospital, MUV-VAMED, Al Ain (United Arab Emirates)

2012-10-15

Aim and objective: Nephrogenic systemic fibrosis (NSF) has been reported in humans to be most likely induced by gadolinium based contrast agents (GBCA), namely by gadodiamide, gadopentetate dimeglumine, and gadoversetamide, rarely by other GBCA. The pathogenesis of NSF remains unclear; different hypotheses are under discussion. The objective of the study is to assess if in the animal model human-like NSF changes can be induced by high-dose, intraperitoneal GBCA injections over four weeks. Materials and methods: After approval by the institutional animal ethics committee, six rats each were randomly assigned to groups, and treated with seven different GBCA. Intraperitoneal (IP) injections – proven in the animal model to be effective – were chosen to prolong the animals’ exposure to the respective GBCA. GBCA doses of previous intravenous (IV) animal studies were applied. After five weeks all rats were sacrificed. Sham controls were treated with IP saline injections, employing the same regimen. Results: No findings comparable with human NSF were observed in all animals after IP treatment with all seven GBCA at daily doses of 2.5 and 5.0 mmol/kg body weight (BW). No histopathological abnormalities of all examined organs were noted. Weight loss was stated in weeks three and four with GBCA injections at doses of 5.0 mmol/kg BW, but rats regained weight after cessation of GBCA treatment. Conclusions: NSF-comparable pathological findings could not be induced by high dose intraperitoneal injection of seven GBCA.

In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents

International Nuclear Information System (INIS)

Langer, R.D.; Lorke, D.E.; Neidl van Gorkom, K.F.; Petroianu, G.; Azimullah, S.; Nurulain, S.M.; Singh, S.; Fuchsjäger, M.

2012-01-01

Aim and objective: Nephrogenic systemic fibrosis (NSF) has been reported in humans to be most likely induced by gadolinium based contrast agents (GBCA), namely by gadodiamide, gadopentetate dimeglumine, and gadoversetamide, rarely by other GBCA. The pathogenesis of NSF remains unclear; different hypotheses are under discussion. The objective of the study is to assess if in the animal model human-like NSF changes can be induced by high-dose, intraperitoneal GBCA injections over four weeks. Materials and methods: After approval by the institutional animal ethics committee, six rats each were randomly assigned to groups, and treated with seven different GBCA. Intraperitoneal (IP) injections – proven in the animal model to be effective – were chosen to prolong the animals’ exposure to the respective GBCA. GBCA doses of previous intravenous (IV) animal studies were applied. After five weeks all rats were sacrificed. Sham controls were treated with IP saline injections, employing the same regimen. Results: No findings comparable with human NSF were observed in all animals after IP treatment with all seven GBCA at daily doses of 2.5 and 5.0 mmol/kg body weight (BW). No histopathological abnormalities of all examined organs were noted. Weight loss was stated in weeks three and four with GBCA injections at doses of 5.0 mmol/kg BW, but rats regained weight after cessation of GBCA treatment. Conclusions: NSF-comparable pathological findings could not be induced by high dose intraperitoneal injection of seven GBCA

High-Dose Vitamin D3 during Tuberculosis Treatment in Mongolia. A Randomized Controlled Trial.

Science.gov (United States)

Ganmaa, Davaasambuu; Munkhzul, Baatar; Fawzi, Wafaie; Spiegelman, Donna; Willett, Walter C; Bayasgalan, Purev; Baasansuren, Erkhembayar; Buyankhishig, Burneebaatar; Oyun-Erdene, Sereeter; Jolliffe, David A; Xenakis, Theodoros; Bromage, Sabri; Bloom, Barry R; Martineau, Adrian R

2017-09-01

Existing trials of adjunctive vitamin D in the treatment of pulmonary tuberculosis (PTB) are variously limited by small sample sizes, inadequate dosing regimens, and high baseline vitamin D status among participants. Comprehensive analyses of the effects of genetic variation in the vitamin D pathway on response to vitamin D supplementation are lacking. To determine the effect of high-dose vitamin D 3 on response to antimicrobial therapy for PTB and to evaluate the influence of single-nucleotide polymorphisms (SNPs) in vitamin D pathway genes on response to adjunctive vitamin D 3 . We conducted a clinical trial in 390 adults with PTB in Ulaanbaatar, Mongolia, who were randomized to receive four biweekly doses of 3.5 mg (140,000 IU) vitamin D 3 (n = 190) or placebo (n = 200) during intensive-phase antituberculosis treatment. The intervention elevated 8-week serum 25-hydroxyvitamin D concentrations (154.5 nmol/L vs. 15.2 nmol/L in active vs. placebo arms, respectively; 95% confidence interval for difference, 125.9-154.7 nmol/L; P vitamin D 3 accelerated sputum culture conversion in patients with one or more minor alleles for SNPs in genes encoding the vitamin D receptor (rs4334089, rs11568820) and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1: rs4646536) (adjusted hazard ratio ≥ 1.47; P for interaction ≤ 0.02). Vitamin D 3 did not influence time to sputum culture conversion in the study population overall. Effects of the intervention were modified by SNPs in VDR and CYP27B1. Clinical trial registered with www.clinicaltrials.gov (NCT01657656).

Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation

Energy Technology Data Exchange (ETDEWEB)

Gluckman, E.; Devergie, A. (Hopital Saint-Louis, 75 - Paris (France)); Dutreix, J. (Institut Gustave Roussy, 94 - Villejuif (France))

1983-07-01

Fanconi anaemia, an autosomal recessive constitutional aplastic anaemia, seems to be related to a DNA repair mechanism defect. Bone marrow transplantation is the only treatment which can cure these patients. Previous attempts at BMT have shown an increased sensitivity to Cyclophosphamide used for the conditioning. Such a sensitivity has also been observed in vitro when Fanconi anaemia cells were incubated with alkylating agents. We have tested the in vivo radiosensitivity and cell repair after skin contact radiotherapy to calculate the irradiation dose which could be tolerated by FA patients. Eight patients have been tested and the results confirmed the suspected increased radiosensitivity in the majority of patients. Following these results, four patients were conditioned with low dose Cyclophosphamide (20 mg/kg) associated with 5 Grays thoraco-abdominal irradiation. All had a take and no major complication of the conditioning regimen. All are alive in good condition from day 51 to day 330 after transplant. Oesophagitis was one major unexpected complication. This study confirms the possibility of curing FA patients with BMT when the conditioning regimen is modified according to the pathophysiology of the disease.

Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation

International Nuclear Information System (INIS)

Gluckman, E.; Devergie, A.; Dutreix, J.

1983-01-01

Fanconi anaemia, an autosomal recessive constitutional aplastic anaemia, seems to be related to a DNA repair mechanism defect. Bone marrow transplantation is the only treatment which can cure these patients. Previous attempts at BMT have shown an increased sensitivity to Cyclophosphamide used for the conditioning. Such a sensitivity has also been observed in vitro when Fanconi anaemia cells were incubated with alkylating agents. We have tested the in vivo radiosensitivity and cell repair after skin contact radiotherapy to calculate the irradiation dose which could be tolerated by FA patients. Eight patients have been tested and the results confirmed the suspected increased radiosensitivity in the majority of patients. Following these results, four patients were conditioned with low dose Cyclophosphamide (20 mg/kg) associated with 5 Grays thoraco-abdominal irradiation. all had a take and no major complication of the conditioning regimen. All are alive in good condition from day 51 to day 330 after transplant. Oesophagitis was one major unexpected complication. This study confirms the possibility of curing FA patients with BMT when the conditioning regimen is modified according to the pathophysiology of the disease. (author)

Cleansing the colon in gallium-67 scintigraphy: a prospective comparison of regimens.

Science.gov (United States)

Novetsky, G J; Turner, D A; Ali, A; Raynor, W J; Fordham, E W

1981-11-01

Colonic accumulation of gallium-67 frequently complicates the interpretation of gallium-67 scintigrams. Although various modes of cleansing the colon prior to scintigraphy have been suggested, there is controversy over their efficacy and none have been tested prospectively. Three hundred nine patients undergoing gallium-67 scintigraphy were randomly assigned to one of four cleansing regimens: (1) a high fiber diet (78 patients); (2) castor oil (76); (3) milk of magnesia and cascara (76); and (4) not preparation (79). Patient compliance rates for the four regimens were 17%, 32%, 36%, and 46%, respectively. After noncompliant patients were excluded, gallium-67 scintigrams were graded for colonic activity on a scale of 0-3 by three independent, experienced observers. Gallium-67 activity in the colon was significantly less after administration of castor oil than after no preparation (p = 0.047). A high fiber diet also resulted in a substantial reduction of colonic activity when compared with no preparation; the difference, however, was not statistically significant (p = 0.083). Regimen 3 did not produce significantly better results than regimen 4 (p = 0.42). A major impediment to the success of any cleansing regimen seems to be poor compliance of patients.

Cleansing the colon in gallium-67 scintigraphy: a prospective comparison of regimens

International Nuclear Information System (INIS)

Novetsky, G.J.; Turner, D.A.; Ali, A.; Raynor, W.J. Jr.; Fordham, E.W.

1981-01-01

Colonic accumulation of gallium-67 frequently complicates the interpretation of gallium-67 scintigrams. Although various modes of cleansing the colon prior to scintigraphy have been suggested, there is controversy over their efficacy and none have been tested prospectively. Three hundred nine patients undergoing gallium-67 scintigraphy were randomly assigned to one of four cleansing regimens: (1) a high fiber diet (78 patients); (2) castor oil (76); (3) milk of magnesia and cascara (76); and (4) not preparation (79). Patient compliance rates for the four regimens were 17%, 32%, 36%, and 46%, respectively. After noncompliant patients were excluded, gallium-67 scintigrams were graded for colonic activity on a scale of 0-3 by three independent, experienced observers. Gallium-67 activity in the colon was significantly less after administration of castor oil than after no preparation (p . 0.047). A high fiber diet also resulted in a substantial reduction of colonic activity when compared with no preparation; the difference, however, was not statistically significant (p . 0.083). Regimen 3 did not produce significantly better results than regimen 4 (p . 0.42). A major impediment to the success of any cleansing regimen seems to be poor compliance of patients

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

Science.gov (United States)

Azman, Andrew S.; Luquero, Francisco J.; Ciglenecki, Iza; Grais, Rebecca F.; Sack, David A.; Lessler, Justin

2015-01-01

Background In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Methods and Findings Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study.

Directory of Open Access Journals (Sweden)

Andrew S Azman

2015-08-01

Full Text Available In 2013, a stockpile of oral cholera vaccine (OCV was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both.Using mathematical models we determined the minimum relative single-dose efficacy (MRSE at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%-56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%. This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%-88% for two doses and 44% (95% CI -27% to 76% for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%-88%, which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943-86,205 cases in Zimbabwe, 78,317 (95% PI 57,435-100,150 in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490-3,170 cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect

Comparison of safety and immunogenicity of purified chick embryo cell vaccine using Zagreb and Essen regimens in patients with category II exposure in China.

Science.gov (United States)

Hu, Quan; Liu, Man-Qing; Zhu, Zheng-Gang; Zhu, Ze-Rong; Lu, Sha

2014-01-01

The aim was to compare the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) with Zagreb 2-1-1 and Essen 1-1-1-1-1 regimens in patients with WHO category II exposure in China. Side effects including systemic and local symptoms were recorded for all patients during vaccination with purified chick embryo cell vaccine (PCECV) under Zagreb 2-1-1 or Essen 1-1-1-1-1 regimens, and the rabies neutralization antibody titers in patients' serum at days 0, 7, 14, 45, 365 post-immunization were measured to determine the immunogenicity. Fever and pain were the most common events for systemic and local symptoms respectively, and most side effects (86.78%, 105/121) occurred after the first dose of vaccination. Safety analysis showed differences in side effects inZagreb and Essen regimens, especially after the first dose of vaccination (P = 0.043). Immunogenicity analysis indicated that Zagreb can achieve higher neutralization antibody titers and a greater seroconversion rate in a shorter time but had less persistence than Essen. When compared with the Essen regimen, the Zagreb regimen had a different immunogenicity in all study subjects, and different safety profile in young children, and a further study with a larger population and longer surveillance is warranted.

Oral antidiabetic therapy in a large Italian sample: drug supply and compliance for different therapeutic regimens

CERN Document Server

Vittorino Gaddi, A; Capello, F; Di Pietro, C; Cinconze, E; Rossi, E; De Sando, V; Cevenini, M; D'Alò, G

2014-01-01

Objectives: To define the main features of patients treated with oral antidiabetics, evaluating monotherapy (MT), loose-dose combination therapy (LDCT) and fixed-dose combination therapy (FDCT); to describe medication adherence to the different therapies; and to evaluate the differences in compliance with the prescribed therapy regimen among prevalent and incident patient cohorts. Study design: This study was a retrospective cohort analysis based on the ARNO database, a national record that tracks reimbursable prescription claims submitted from selected pharmacies to the Italian national health system. In total, 169,375 subjects, from an overall population of 4,040,624 were included in this study. The patients represented 12 different local health units. Each patient had at least one oral antidiabetic prescription claim (A10B ATC code). Methods: Patients were divided into four groups according to their treatment regimen during the recruitment period (1 January 2008-31 December 2008): MT, FDCT, LDCT and swi...

Efficacy of various single-dose regimens of ceftriaxone in ...

African Journals Online (AJOL)

1990-08-18

Aug 18, 1990 ... The therapeutic efficacy of single intramuscular doses of ceftriaxone (Rocephin; Roche) (62,S, 125 and 250 mg), admini- stered without probenecid, was evaluated in 167 adult males with uncomplicated acute gonococcal urethritis. Cure rates of 100% were achieved at 62,5 mg and 250 mg. In the 125 mg.

Comparison of evening and morning dosing of travoprost 0.004%/timolol 0.5% fixed combination in 6 month period.

Science.gov (United States)

Suić, Smiljka Popović; Laus, Katia Novak; Dosen, Vukosava Maricic; Ekert, Miroslav; Mandić, Zdravko; Bojić, Lovro

2010-09-01

An open label, multi-center, 6 months observational study of new fixed combination (travoprost 0.004%/timolol 0.5%), in order to evaluate both efficacy (intraocular pressure lowering) and tolerability (patient and investigator satisfaction) of two dosing regimens--evening (PM) and morning (AM). After screening for enrollment, to 40 patients (79 eyes with primary open angle glaucoma or ocular hypertension), new fixed combination travoprost 0.004%/timolol 0.5% was prescribed once a day in the evening (PM). Patients were enrolled according to each investigator decision on indication for travoprost 0.004%/timolol 0.5% fixed combination once a day, without washout period after previous medication. Intraocular pressure was measured at 9 AM at all time control points: at baseline, after 1 month, after 3 months and after 6 month. After 1 month, screening for nonresponders (criteria: 20% intraocular pressure lowering) and subjects with major side effects was performed. At second control visit, after 3 months PM dosing, intraocular pressure was measured and patients were instructed to continue once a day the same medication, but in the morning (AM) for consequent 3 months. After 1 month, reduction in mean intraocular pressure value was 21.66%. At the visit after 3 month, the mean intraocular pressure was 15.67 +/- 2.17 mm Hg (reduction 21.14%). 3 month after dosing regimen changed to AM (6 month after beginning of travoprost 0.004%/timolol 0.5% combination therapy), reduction in intraocular pressure value was 19.86%. The differences (mean +/- standard deviation) in intraocular pressure values after 1, 3 and 6 month were all highly statistically significant compared to baseline values. The tolerability was evaluated in five steps (Likert scale) ranging from unsatisfactory to excellent by both patient and investigator--taken at 3 and 6 month control visit. 95% of patients and 100% of investigators were satisfied with the possibility of choosing dosing regimen for travoprost 0

The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission.

Science.gov (United States)

Blaise, D; Attal, M; Pico, J L; Reiffers, J; Stoppa, A M; Bellanger, C; Molina, L; Nedellec, G; Vernant, J P; Legros, M; Gabus, R; Huguet, F; Brandely, M; Hercend, T; Olive, D; Maraninchi, D

1997-05-01

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML = 22; ALL = 28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL-2 (RU 49637 from Roussel-Uclaf, Romainville, France) was started after hematological reconstitution an average of 72 +/- 22 days post transplant. The schedule consisted of a continuous infusion over 5 cycles (Cycle 1: 5 days starting on day 1; cycle 2-5: 2 days starting on day 15, 29, 43 and 57). Patients were treated at 4 different dosages (12 (N = 40), 16 (N = 3), 20 (N = 2), 24 (N = 5) x 10(6) IU/m2/day). Toxicities were mainly related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 +/- 49 10(6) IU/m2. Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimu-lation of both T-cells (P < 0.05) and natural killer (NK) cells (P < 0.05) and associated cytolytic functions (P < 0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 +/- 6% overall, 39 +/- 10% and 43 +/- 8% for AML and ALL respectively. Relapse probabilities at 3 years are 59 +/- 11% for AML and 57 +/- 8% for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early after reaching first complete remission.

High dose gamma-ray standard

International Nuclear Information System (INIS)

Macrin, R.; Moraru, R.

1999-01-01

The high gamma-ray doses produced in a gamma irradiator are used, mainly, for radiation processing, i.e. sterilization of medical products, processing of food, modifications of polymers, irradiation of electronic devices, a.s.o. The used absorbed doses depend on the application and cover the range 10 Gy to 100 MGy. The regulations in our country require that the response of the dosimetry systems, used for the irradiation of food and medical products, be calibrated and traceable to the national standards. In order to be sure that the products receive the desired absorbed dose, appropriate dosimetric measurements must be performed, including the calibration of the dosemeters and their traceability to the national standards. The high dose gamma-ray measurements are predominantly based on the use of reference radiochemical dosemeters. Among them the ferrous sulfate can be used as reference dosemeter for low doses (up to 400 Gy) but due to its characteristics it deserves to be considered a standard dosemeter and to be used for transferring the conventional absorbed dose to other chemical dosemeters used for absorbed doses up to 100 MGy. The study of the ferrous sulfate dosemeter consisted in preparing many batches of solution by different operators in quality assurance conditions and in determining for all batches the linearity, the relative intrinsic error, the repeatability and the reproducibility. The principal results are the following: the linear regression coefficient: 0.999, the relative intrinsic error: max.6 %, the repeatability (for P* = 95 %): max.3 %, the reproducibility (P* = 95%): max.5 %. (authors)

APF530 (granisetron injection extended-release) in a three-drug regimen for delayed CINV in highly emetogenic chemotherapy.

Science.gov (United States)

Schnadig, Ian D; Agajanian, Richy; Dakhil, Christopher; Gabrail, Nashat Y; Smith, Robert E; Taylor, Charles; Wilks, Sharon T; Schwartzberg, Lee S; Cooper, William; Mosier, Michael C; Payne, J Yvette; Klepper, Michael J; Vacirca, Jeffrey L

2016-06-01

APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Outcomes of autologous transplantation for multiple myeloma according to different induction regimens

Directory of Open Access Journals (Sweden)

Edvan de Queiroz Crusoe

2014-01-01

Full Text Available Background: Induction therapy followed by high-dose chemotherapy and autologous transplantation is the standard treatment for suitable patients with multiple myeloma. Objective: The aim of this study was to assess whether induction therapy with thalidomidecontaining regimens was associated with improved results compared to vincristine, doxorubicin, and dexamethasone, and whether cyclophosphamide, thalidomide, and dexamethasone were associated with better results than thalidomide and dexamethasone. Methods: The records of 152 patients who underwent autologous transplantation at this institution from August of 2004 to January of 2012 were reviewed, selecting those with at least partial response to a maximum of eight cycles of induction therapy and sufficient follow-up information for analysis. Results: This study included 89 patients; 44 were female, with a mean age of 55 years (there was a significant trend for increasing age over the years of the study.The median number of induction therapy cycles was four, again with a trend of increase over the years.At least a very good partial response to induction therapy was achieved more often in the cyclophosphamide, thalidomide, and dexamethasone group (61.1% and in the thalidomide and dexamethasone group (59.2% than in the vincristine, doxorubicin, and dexamethasone group (16.2%. The overall median progression-free survival was 34 months, with no statistically significant difference between the three groups. The overall median survival was not reached, and there was no significant difference between the three groups; the estimated five-year overall survival was 55%. Conclusion: Although the quality of responses appeared to be better with thalidomidecontaining regimens, these improvements did not translate into improved long-term outcomes. Given its track record, cyclophosphamide, thalidomide, and dexamethasone is currently considered the preferred regimen for first-line induction therapy in the

Dietary regimens of athletes competing at the Delhi 2010 Commonwealth Games.

Science.gov (United States)

Pelly, Fiona E; Burkhart, Sarah J

2014-02-01

The aim of this study was to investigate the dietary regimens reported by athletes competing at a major international competition and report whether these were based on nutrient composition, religious beliefs, cultural eating style, food intolerance or avoidance of certain ingredients. A questionnaire was randomly distributed to 351 athletes in the main dining hall of the athletes' village over the three main meal periods during the Delhi 2010 Commonwealth Games (23rd Sept-14th Oct, 2010). The majority (n = 218, 62%) of athletes reported following one or more dietary regimens, with 50% (n = 174) following a diet based on the nutrient composition of the food. Significantly more athletes from weight category and aesthetic sports (28%, p = .005) and from power/sprint sports (41%, p = .004) followed low fat and high protein regimens respectively. Other specialized dietary regimens were followed by 33% of participants, with avoidance of red meat (13%), vegetarian (7%), Halal (6%), and low lactose regimens (5%) reported most frequently. Significantly more athletes from non-Western regions followed a vegetarian diet (p food items are available at similar events.

Single-dose ceftriaxone for chancroid.

Science.gov (United States)

Bowmer, M I; Nsanze, H; D'Costa, L J; Dylewski, J; Fransen, L; Piot, P; Ronald, A R

1987-01-01

Men with genital ulcers that were culture positive for Haemophilus ducreyi were treated with intramuscular ceftriaxone and randomized to three different dose regimens. All but 1 of 50 men treated with 1 g of intramuscular ceftriaxone were cured. Similarly, 0.5 and 0.25 g cured 43 of 44 men and 37 of 38 men, respectively. A single dose of 250 mg of intramuscular ceftriaxone is an effective treatment for chancroid. PMID:3566241

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

Science.gov (United States)

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Muller, Vincent; Llosa, Augusto E; Uzzeni, Florent; Luquero, Francisco J; Ciglenecki, Iza; Azman, Andrew S

2017-06-01

In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

The incidence of kidney injury for patients treated with a high-potency versus moderate-potency statin regimen after an acute coronary syndrome.

Science.gov (United States)

Sarma, Amy; Cannon, Christopher P; de Lemos, James; Rouleau, Jean L; Lewis, Eldrin F; Guo, Jianping; Mega, Jessica L; Sabatine, Marc S; O'Donoghue, Michelle L

2014-05-01

Observational studies have raised concerns that high-potency statins increase the risk of acute kidney injury. We therefore examined the incidence of kidney injury across 2 randomized trials of statin therapy. PROVE IT-TIMI 22 enrolled 4162 subjects after an acute coronary syndrome (ACS) and randomized them to atorvastatin 80 mg/day versus pravastatin 40 mg/day. A-to-Z enrolled 4497 subjects after ACS and randomized them to a high-potency (simvastatin 40 mg/day × 1 months, then simvastatin 80 mg/day) versus a delayed moderate-potency statin strategy (placebo × 4 months, then simvastatin 20 mg/day). Serum creatinine was assessed centrally at serial time points. Adverse events (AEs) relating to kidney injury were identified through database review. Across both trials, mean serum creatinine was similar between treatment arms at baseline and throughout follow-up. In A-to-Z, the incidence of a 1.5-fold or ≥ 0.3 mg/dL rise in serum creatinine was 11.4% for subjects randomized to a high-potency statin regimen versus 12.4% for those on a delayed moderate-potency regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.76 to 1.10; P=0.33). In PROVE IT-TIMI 22, the incidence was 9.4% for subjects randomized to atorvastatin 80 mg/day and 10.6% for subjects randomized to pravastatin 40 mg/day (OR, 0.88; 95% CI, 0.71 to 1.09; P=0.25). Consistent results were observed for different kidney injury thresholds and in individuals with diabetes mellitus or with moderate renal dysfunction. The incidence of kidney injury-related adverse events (AEs) was not statistically different for patients on a high-potency versus moderate-potency statin regimen (OR, 1.06; 95% CI, 0.68 to 1.67; P=0.78). For patients enrolled in 2 large randomized trials of statin therapy after ACS, the use of a high-potency statin regimen did not increase the risk of kidney injury.

Treatment of small cell carcinoma of lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy

International Nuclear Information System (INIS)

Shank, B.; Natale, R.B.; Hilaris, B.S.; Wittes, R.E.

1981-01-01

Survival of patients with small cell carcinoma of lung, treated on a new combined radiotherapy-chemotherapy protocol, compares favorably with other regimens in the literature and our own previous combined approaches. Radiation, given after induction chemotherapy, consisted of whole brain prophylaxis in all 44 evaluable patients. Patients with limited disease were also treated to the primary and mediastinum to a high dose (5000 rad equivalent) using multiple fields. The new chemotherapy regimen consisted of induction with cyclophosphamide, doxorubicin, and vincristine alternated with cis-platinum and VP-16 (an epipodophyllotoxin) for two cycles, followed by consolidation with low dose cyclophosphamide and vincristine concurrent with irradiation. Patients with limited disease who achieved less than complete response, and all patients with extensive disease were not continued on maintenance chemotherapy. Out of 24 evaluable patients with limited disease, there was 73% survival at 1 year by life-table analysis, measured from treatment initiation. After induction, 16/24 of these limited disease patients were CR (complete responders): 20/24 were CR at completion of their irradiation. Out of 20 evaluable patients with extensive disease, there was 59% survival at 1 year by life-table analysis. Only 4/44 (9%) brain parenchymal relapses occurred, one at 3 months and one at 6 months after local failure and two in patients who did not become CRs, implicating a possible re-seeding mechanism. Five patients had central nervous system relapses outside of brain parenchyma (spinal epidural and leptomeningeal); in three patients this was the initial site of failure. Significant complications included leukopenia (50%) and thrombocytopenia (24%) primarily during induction, and chronic pulmonary fibrosis (25%), possibly contributing to two deaths

Predictive tools for designing new insulins and treatment regimens

DEFF Research Database (Denmark)

Klim, Søren

The thesis deals with the development of "Predictive tools for designing new insulins and treatments regimens" and consists of two parts: A model based approach for bridging properties of new insulin analogues from glucose clamp experiments to meal tolerance tests (MTT) and a second part that des......The thesis deals with the development of "Predictive tools for designing new insulins and treatments regimens" and consists of two parts: A model based approach for bridging properties of new insulin analogues from glucose clamp experiments to meal tolerance tests (MTT) and a second part...... that describes an implemented software program able to handle stochastic differential equations (SDEs) with mixed effects. The thesis is supplemented with scientific papers published during the PhD. Developing an insulin analogue from candidate molecule to a clinical drug consists of a development programme...... and efficacy are investigated. Numerous methods are used to quantify dose and efficacy in Phase II - especially of interest is the 24-hour meal tolerance test as it tries to portray near normal living conditions. Part I describes an integrated model for insulin and glucose which is aimed at simulating 24-hour...

Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations

Directory of Open Access Journals (Sweden)

John Sunyecz

2008-12-01

Full Text Available John SunyeczMenopauseRx, Inc., Hopwood, PA, USAAbstract: Postmenopausal osteoporosis is common and underrecognized among elderly women. Osteoporotic fractures cause disability and disfigurement and threaten patients’ mobility, independence, and survival. Care for incident fractures in this age group must go beyond orthopedic repair, to assessment and treatment of the underlying bone fragility. Fracture risk can be reduced by vitamin D and calcium supplementation along with antiresorptive drug treatment. First-line osteoporosis pharmacotherapy employs nitrogen-containing bisphosphonates. The inconvenience of daily oral treatment has motivated development of weekly, monthly, and intermittent oral regimens, as well as quarterly and yearly intravenous (iv regimens. Ibandronate is the first bisphosphonate to have shown direct anti-fracture efficacy with a non-daily regimen; it was approved for once-monthly oral dosing in 2005 and for quarterly iv dosing in 2006. Intermittent oral risedronate and yearly iv zoledronic acid were approved in 2007. Newly available regimens with extended dosing intervals reduce the inconvenience of bisphosphonate therapy and provide patients with a range of options from which to select a maximally sustainable course of treatment. This review discusses the development, efficacy, safety, and tolerability of extended-interval bisphosphonate regimens and examines their potential to improve patient acceptance and long-term success of osteoporosis treatment.Keywords: ibandronate, alendronate, risedronate, zoledronic acid, adherence, persistence

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center.

Science.gov (United States)

Dodd, C; Watts, R G

2012-07-01

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up. © 2012 Blackwell Publishing Ltd.

Optimizing lithium dosing in hemodialysis

DEFF Research Database (Denmark)

Bjarnason, N H; Munkner, R; Kampmann, J P

2006-01-01

We studied a 62-year-old female hemodialysis patient during initiation and maintenance of lithium carbonate therapy. Three different methods were applied to estimate the regimen: a scenario based on volume of distribution (V(d)), a scenario based on glomerular filtration rate (GFR), and a scenario...... estimates. Furthermore, the maintenance dose estimated from the central compartment (V1) led to plasma concentrations within the therapeutic range. Thus, a regimen where 12.2 mmol lithium was given after each hemodialysis session resulted in stable between-dialysis plasma lithium concentrations...... in this patient with no residual kidney function. We did not observe adverse effects related to this regimen, which was monitored from 18 days to 8 months of therapy, and the patient experienced relief from her severe depressive disorder. In conclusion, dialysis patients may be treated with lithium administrated...

A Phase I Study of Pulse High-Dose Vorinostat (V) plus Rituximab (R), Ifosphamide, Carboplatin, and Etoposide (ICE) in Patients with Relapsed Lymphoma

Science.gov (United States)

Budde, Lihua E.; Zhang, Michelle M.; Shustov, Andrei R.; Pagel, John M.; Gooley, Ted A.; Oliveira, George R.; Chen, Tara L.; Knudsen, Nancy L.; Roden, Jennifer E.; Kammerer, Britt E.; Frayo, Shani L.; Warr, Thomas A.; Boyd, Thomas E.; Press, Oliver W.; Gopal, Ajay K.

2013-01-01

SUMMARY Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2.5 μM concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 days in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients (median age 56 years, median 2 prior therapies, 14 chemoresistant [of 27 evaluable], 2 prior transplants) were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 days. Common dose limiting toxicities included infection (n=2), hypokalaemia (n=2), and transaminitis (n=2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4.5 μM (range 4.2–6.0 μM) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted. PMID:23356514

High and low doses of antimony (Sb v in American cutaneous leishmaniasis: a five years follow-up study of 15 patients

Directory of Open Access Journals (Sweden)

MP Oliveira-Neto

1996-04-01

Full Text Available Seventeen patients proceeding from the municipality of Rio de Janeiro, Brazil presenting with the cutaneous ulcerative form of American leishmaniasis were treated with one ampoule of pentavalent antimony daily for 30 days. With this regimen the individuals doses varies greatly: from 3.8 mg/kg of body weight to 22.3 mg/kg. After five years, patients receiving either a smaller dose or a bigger one, showed the same therapeutic result: cutaneous scars and no mucosal lesions.

Estimation of the transit dose component in high dose rate brachytherapy

International Nuclear Information System (INIS)

Garcia Romero, A.; Millan Cebrian, E.; Lozano Flores, F.J.; Lope Lope, R.; Canellas Anoz, M.

2001-01-01

Current high dose rate brachytherapy (HDR) treatment planning systems usually calculate dose only from source stopping positions (stationary component), but fails to account for the administered dose when the source is moving (dynamic component or transit dose). Numerical values of this transit dose depends upon the source velocity, implant geometry, source activity and prescribed dose. In some HDR treatments using particular geometry the transit dose cannot be ignored because it increases the dose at the prescriptions points and also could increase potential late tissue complications as predicted by the linear quadratic model. International protocols recommend to verify this parameter. The aim of this paper has been to establish a procedure for the transit dose calculation for the Gammamed 12i equipment at the RT Department in the Clinical University Hospital (Zaragoza-Spain). A numeric algorithm was implemented based on a dynamic point approximation for the moving HDR source and the calculated results for the entrance-exit transit dose was compared with TLD measurements made in some discrete points. (author) [es

ELDRS Characterization for a Very High Dose Mission

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Harris, Richard D.; McClure, Steven S.; Rax, Bernard G.; Kenna, Aaron J.; Thorbourn, Dennis O.; Clark, Karla B.; Yan, Tsun-Yee

2010-01-01

Evaluation of bipolar linear parts which may have Enhanced Low Dose Rate Sensitivity (ELDRS) is problematic for missions that have very high dose radiation requirements. The accepted standards for evaluating parts that display ELDRS require testing at a very low dose rate which could be prohibitively long for very high dose missions. In this work, a methodology for ELDRS characterization of bipolar parts for mission doses up to 1 Mrad(Si) is evaluated. The procedure employs an initial dose rate of 0.01 rad(Si)/s to a total dose of 50 krad(Si) and then changes to 0.04 rad(Si)/s to a total dose of 1 Mrad(Si). This procedure appears to work well. No change in rate of degradation with dose has been observed when the dose rate is changed from 0.01 to 0.04 rad(Si)/s. This is taken as an indication that the degradation due to the higher dose rate is equivalent to that at the lower dose rate at the higher dose levels, at least for the parts studied to date. In several cases, significant parameter degradation or functional failure not observed at HDR was observed at fairly high total doses (50 to 250 krad(Si)) at LDR. This behavior calls into question the use of dose rate trend data and enhancement factors to predict LDR performance.

Efficacy of Antimicrobial Treatments and Vaccination Regimens for Control of Porcine Reproductive and Respiratory Syndrome Virus and Streptococcus suis Coinfection of Nursery Pigs

Science.gov (United States)

Halbur, P.; Thanawongnuwech, R.; Brown, G.; Kinyon, J.; Roth, J.; Thacker, E.; Thacker, B.

2000-01-01

Seventy-six, crossbred, porcine reproductive and respiratory syndrome virus (PRRSV)-free pigs were weaned at 12 days of age and randomly assigned to seven groups of 10 to 11 pigs each. Pigs in group 1 served as unchallenged controls. Pigs in groups 2 to 7 were challenged intranasally with 2 ml of high-virulence PRRSV isolate VR-2385 (104.47 50% tissue culture infective doses per 2 ml) on day 0 of the study (30 days of age). Seven days after PRRSV challenge, pigs in groups 2 to 7 were challenged intranasally with 2 ml of Streptococcus suis serotype 2 (108.30 CFU/2 ml). Group 2 pigs served as untreated positive controls. Antimicrobial treatments included daily intramuscular injection with 66,000 IU of procaine penicillin G per kg of body weight on days 8 to 10 (group 3), drinking water medication with 23.1 mg of tiamulin per kg during days 8 to 10 (group 4), and daily intramuscular injection of 5.0 mg of ceftiofur hydrochloride per kg on days 8 to 10 (group 5). Vaccination regimens included two intramuscular doses of an autogenous killed S. suis vaccine (group 6) prior to S. suis challenge or a single 2-ml intramuscular dose of an attenuated live PRRSV vaccine (group 7) 2 weeks prior to PRRSV challenge. Mortality was 0, 63, 45, 54, 9, 40, and 81% in groups 1 to 7, respectively. Ceftiofur treatment was the only regimen that significantly (P < 0.05) reduced mortality associated with PRRSV and S. suis coinfection. The other treatments and vaccinations were less effective. We conclude that ceftiofur administered by injection for three consecutive days following S. suis challenge was the most effective regimen for minimizing disease associated with PRRSV and S. suis coinfection. PMID:10699012

Patient and regimen characteristics associated with self-reported nonadherence to antiretroviral therapy.

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Patrick S Sullivan

Full Text Available BACKGROUND: Nonadherence to antiretroviral therapy (ARVT is an important behavioral determinant of the success of ARVT. Nonadherence may lead to virological failure, and increases the risk of development of drug resistance. Understanding the prevalence of nonadherence and associated factors is important to inform secondary HIV prevention efforts. METHODOLOGY/PRINCIPAL FINDINGS: We used data from a cross-sectional interview study of persons with HIV conducted in 18 U.S. states from 2000-2004. We calculated the proportion of nonadherent respondents (took or=4 medications; living in a shelter or on the street; and feeling "blue" >or=14 of the past 30 days. We found weaker associations with having both male-male sex and injection drug use risks for HIV acquisition; being prescribed ARVT for >or=21 months; and being prescribed a protease inhibitor (PI-based regimen not boosted with ritonavir. The median proportion of doses missed was 50%. The most common reasons for missing doses were forgetting and side effects. CONCLUSIONS/SIGNIFICANCE: Self-reported recent nonadherence was high in our study. Our data support increased emphasis on adherence in clinical settings, and additional research on how providers and patients can overcome barriers to adherence.

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Science.gov (United States)

Campbell, Thomas B.; Smeaton, Laura M.; Kumarasamy, N.; Flanigan, Timothy; Klingman, Karin L.; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I.; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F.; Uy, Jonathan; Schooley, Robert T.; De Gruttola, Victor; Hakim, James Gita; Swann, Edith; Barnett, Ronald L.; Brizz, Barbara; Delph, Yvette; Gettinger, Nikki; Mitsuyasu, Ronald T.; Eshleman, Susan; Safren, Steven; Fiscus, Susan A.; Andrade, Adriana; Haas, David W.; Amod, Farida; Berthaud, Vladimir; Bollinger, Robert C.; Bryson, Yvonne; Celentano, David; Chilongozi, David; Cohen, Myron; Collier, Ann C.; Currier, Judith Silverstein; Cu-Uvin, Susan; Eron, Joseph; Flexner, Charles; Gallant, Joel E.; Gulick, Roy M.; Hammer, Scott M.; Hoffman, Irving; Kazembe, Peter; Kumwenda, Newton; Lama, Javier R.; Lawrence, Jody; Maponga, Chiedza; Martinson, Francis; Mayer, Kenneth; Nielsen, Karin; Pendame, Richard B.; Ramratnam, Bharat; Sanne, Ian; Severe, Patrice; Sirisanthana, Thira; Solomon, Suniti; Tabet, Steve; Taha, Taha; van der Horst, Charles; Wanke, Christine; Gormley, Joan; Marcus, Cheryl J.; Putnam, Beverly; Loeliger, Edde; Pappa, Keith A.; Webb, Nancy; Shugarts, David L.; Winters, Mark A.; Descallar, Renard S.; Steele, Joseph; Wulfsohn, Michael; Said, Farideh; Chen, Yue; Martin, John C; Bischofberger, Norbert; Cheng, Andrew; Jaffe, Howard; Sharma, Jabin; Poongulali, S.; Cardoso, Sandra Wagner; Faria, Deise Lucia; Berendes, Sima; Burke, Kelly; Mngqibisa, Rosie; Kanyama, Cecelia; Kayoyo, Virginia; Samaneka, Wadzanai P.; Chisada, Anthony; Faesen, Sharla; Chariyalertsak, Suwat; Santos, Breno; Lira, Rita Alves; Joglekar, Anjali A.; Rosa, Alberto La; Infante, Rosa; Jain, Mamta; Petersen, Tianna; Godbole, Sheela; Dhayarkar, Sampada; Feinberg, Judith; Baer, Jenifer; Pollard, Richard B.; Asmuth, David; Gangakhedkar, Raman R; Gaikwad, Asmita; Ray, M. Graham; Basler, Cathi; Para, Michael F.; Watson, Kathy J.; Taiwo, Babafemi; McGregor, Donna; Balfour, Henry H.; Mullan, Beth; Kim, Ge-Youl; Klebert, Michael K.; Cox, Gary Matthew; Silberman, Martha; Mildvan, Donna; Revuelta, Manuel; Tashima, Karen T.; Patterson, Helen; Geiseler, P. Jan; Santos, Bartolo; Daar, Eric S; Lopez, Ruben; Frarey, Laurie; Currin, David; Haas, David H.; Bailey, Vicki L.; Tebas, Pablo; Zifchak, Larisa; Noel-Connor, Jolene; Torres, Madeline; Sha, Beverly E.; Fritsche, Janice M.; Cespedes, Michelle; Forcht, Janet; O'Brien, William A.; Mogridge, Cheryl; Hurley, Christine; Corales, Roberto; Palmer, Maria; Adams, Mary; Luque, Amneris; Lopez-Detres, Luis; Stroberg, Todd

2012-01-01

Background Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected

Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

Directory of Open Access Journals (Sweden)

Thomas B Campbell

Full Text Available Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.1,571 HIV-1-infected persons (47% women from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV, atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC, or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF (EFV+FTC-TDF. ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18% among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74. Safety endpoints occurred in 243 (46% participants assigned to EFV+FTC-TDF versus 313 (60% assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001 and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01. Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21% among 526 participants assigned to ATV+DDI+FTC and 76 (15% among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007.EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are

Quality control of 192Ir high dose rate after loading brachytherapy dose veracity

International Nuclear Information System (INIS)

Feng Zhongsu; Xu Xiao; Liu Fen

2008-01-01

Recently, 192 Ir high dose rate (HDR) afterloading are widely used in brachytherapy. The advantage of using HDR systems over low dose rate systems are shorter treatment time and higher fraction dose. To guarantee the veracity of the delivery dose, several quality control methods are deseribed in this work. With these we can improve the position precision, time precision and dose precision of the brachytherapy. (authors)

Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-resistant B-precursor Acute Lymphoblastic Leukemia in Mice

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Fatih M. Uckun

2015-04-01

Full Text Available In high-risk remission B-precursor acute lymphoblastic leukemia (BPL patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT even after the use of very intensive total body irradiation (TBI-based conditioning regimens, especially in patients with a high “minimal residual disease” (MRD burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand × soluble TRAIL (“CD19L–sTRAIL” fusion protein. CD19L–sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. Low dose total body irradiation (TBI combined with CD19L–sTRAIL was highly effective against (1 xenografted CD19+ radiochemotherapy-resistant human BPL in NOD/SCID (NS mice challenged with an otherwise invariably fatal dose of xenograft cells derived from relapsed BPL patients as well as (2 radiation-resistant advanced stage CD19+ murine BPL with lymphomatous features in CD22ΔE12xBCR-ABL double transgenic mice. We hypothesize that the incorporation of CD19L–sTRAIL into the pre-transplant TBI regimens of patients with very high-risk BPL will improve their survival outcome after HSCT.

Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

NARCIS (Netherlands)

Attema-de Jonge, M.E. (Milly Ellen)

2004-01-01

Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

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Trakul, Nicholas; Chang, Christine N.; Harris, Jeremy [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Chapman, Christopher [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of Michigan School of Medicine, Ann Arbor, MI (United States); Rao, Aarti [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of California, Davis, School of Medicine, Davis, CA (United States); Shen, John [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of California, Irvine, School of Medicine, Irvine, CA (United States); Quinlan-Davidson, Sean [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Department of Radiation Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario (Canada); Filion, Edith J. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Departement de Medecine, Service de Radio-Oncologie, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada); Wakelee, Heather A.; Colevas, A. Dimitrios [Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA (United States); Whyte, Richard I. [Department of Cardiothoracic Surgery, Division of General Thoracic Surgery, Stanford University School of Medicine, Stanford, CA (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA (United States); and others

2012-09-01

Purpose: Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. Methods and Materials: We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume {>=}12 mL) received multifraction regimens with BED {>=}100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2). Results: The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). Conclusion: A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

Once-daily use of inhaled corticosteroids: A new regimen in the treatment of persistent asthma

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Jeffrey Leflein

2000-01-01

Strict patient adherence with prescribed anti-inflammatory medication is crucial for obtaining optimal therapeutic benefit for patients with asthma. Despite the proven effectiveness of inhaled corticosteroids, patient adherence to prescribed therapy is often low, resulting in increased patient morbidity. Complex dosing regimens contribute greatly to patient non-adherence. Thus, new once-daily regimens of inhaled corticosteroid treatment have been introduced as means to improve patient adherence and provide optimal therapeutic benefit. In the present review, the complex inflammatory and remodeling processes in asthma and their contributions to the clinical manifestations of the disease will be discussed. Currently available, once-daily inhaled corticosteroid treatment options and the advantages of these therapeutic options in the treatment of persistent asthma also will be discussed.

Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine.

Science.gov (United States)

Okamura, Keisuke; Shirai, Kazuyuki; Totake, Nao; Okuda, Tetsu; Urata, Hidenori

2018-01-01

When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group-2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. Group-1 contained 85 patients, Group-2A had 49 patients, and Group-2B had 4 patients. We only analyzed Group-1 and Group-2A due to the small size of Group-2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group-2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group-2A after 3 months, but not at 6 months. Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

Efficacy of two regimens of dexamethasone for management of preterm labour: pilot study

International Nuclear Information System (INIS)

Rasool, A.; Farooq, U.

2017-01-01

Background: Dexamethasone is widely used for prevention of respiratory distress syndrome (RDS), necrotising enterocolitis (NEC) and intra-ventricular haemorrhage (IVH) in preterm babies; decreasing the neonatal mortality rate. There is no consensus on the dose of corticosteroid administered to the mother expected to have a preterm baby. This study is conducted to compare the effectiveness of two popular regimens of dexamethasone administration in decreasing incidence of RDS, necrotizing enterocolitis, IVH and neonatal mortality rate. Methods: Randomized control trial was conducted at Ayub Teaching Hospital, Abbottabad from 1st to 31st August, 2014. Sample size was set at 50. Block randomization was employed in the trial to allocate the patients into corresponding groups 'A' and 'B'. Group A was administered 6mg dexamethasone in 4 doses 12 hours apart and group B was administered 2 doses 12 hours apart. Results: Forty-eight patients participated in the study with 24 patients in each group. Mean age and period gestation of participants were 28.4 years±4.3 SD and 34 weeks±1.9 SD respectively. Four patients in group A gave birth to neonate with RDS compared to two cases in group B. Group B had higher incidence of necrotizing enterocolitis and neonatal mortalities. However, none of these differences observed were statistically significant. No case of IVH was reported in either of the groups. Conclusion: Both the popular regimens of dexamethasone administration are equally effective in decreasing the incidence of neonatal diseases. (author)

Efficacy and safety of a modified intravenous recombinant tissue plasminogen activator regimen in Chinese patients with acute ischemic stroke.

Science.gov (United States)

Pan, Shu-Ming; Liu, Jia-Fu; Liu, Ming; Shen, Sa; Li, Hao-Jun; Dai, Li-Hua; Chen, Xiang-Jun

2013-07-01

Thrombolytic treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA; 0.90 mg/kg, with a maximum dose of 90 mg) has been recommended as the standard management for acute ischemic stroke (AIS) thrombolysis. However, the dose of IV rtPA in Asia remains controversial. This study was designed to verify the safety and efficacy of IV rtPA treatment for AIS with a lower dosage (0.90 mg/kg, with a maximum dose of 50 mg). Patients were divided into 3 dosage groups according to body weight (BW): group 1, 67 kg for descent were included in the study. The baseline characteristics of the 3 dosage groups were well matched. In group 1 (BW 67 kg for <0.75 mg/kg; n = 31; P = .362). There were no significantly statistical differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. This IV rtPA regimen (0.90 mg/kg, with a maximum dose of 50 mg) not only shows sufficient favorable outcome in clinical practice in Chinese patients with AIS but also good health economic savings. This regimen could be suitable for many developing countries. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Cleansing the colon in gallium-67 scintigraphy: a prospective comparison of regimens

International Nuclear Information System (INIS)

Novetsky, G.J.; Turner, D.A.; Ali, A.; Raynor, W.J.; Fordham, E.W.

1981-01-01

Colonic accumulation of gallium-67 frequently complicates the interpretation of gallium-67 scintigrams. Although various modes of cleansing the colon prior to scintigraphy have been suggested, there is controversy over their efficacy and none have been tested prospectively. Three hundred nine patients undergoing gallium-67 scintigraphy were randomly assigned to one of four cleansing regimens: (1) a high fiber diet (78 patients); (2) castor oil (76); (3) milk of magnesia and cascara (76); and (4) no preparation (79). Patient compliance rates for the four regimens were 17%, 32%, 36%, and 46%, respectively. After noncompliant patients were excluded, gallium-67 scintigrams were graded for colonic activity on a scale of 0-3 by three independent, experienced observers. Gallium-67 activity in the colon was significantly less after adminstration of castor oil than after no prepartion (p = 0.083). Regimen 3 did not produce significantly better results than regimen 4 (p = 0.42). A major impediment to the success of any cleansing regimen seems to be poor compliance of patients

Physiological and immunological changes following exposure to low versus high-dose ionizing irradiation; comparative analysis with dose rate and cumulative dose

International Nuclear Information System (INIS)

Heesun, Kim; Heewon, Jang; Soungyeon, Song; Shinhye, Oh; Cukcheul, Shin; Meeseon, Jeong; Chasoon, Kim; Kwnaghee, Yang; Seonyoung, Nam; Jiyoung, Kim; Youngwoo, Jin; Changyoung, Cha

2008-01-01

Full text: While high-dose of ionizing radiation is generally harmful and causes damage to living organisms some reports suggest low-dose of radiation may not be as damaging as previously thought. Despite increasing evidence regarding the protective effect of low-dose radiation, no studies have directly compared the exact dose-response pattern by high- and low-dose of radiation exposed at high-and low-dose rate. This study aims to explore the cellular and molecular changes in mice exposed to low- and high-dose of radiation exposed at low- and high-dose rate. When C57BL/6 mice (Female, 6 weeks) were exposed at high-dose rate, 0.8 Gy/min, no significant change on the level of WBC, RBC, or platelets was observed up to total dose of 0.5 Gy. However, 2 Gy of radiation caused dramatic reduction in the level of white blood cells (WBC) and platelets. This reduction was accompanied by increased DNA damage in hematopoietic environments. The reduction of WBC was mainly due to the reduction in the number of CD4+ T cells and CD19+ B cells. CD8+ T cells and NK cells appeared to be relatively resistant to high-dose of radiation. This change was also accompanied by the reduction of T- and B- progenitor cells in the bone marrow. In contrast, no significant changes of the number of CD4+ T, CD8+ T, NK, and B cells were observed in the spleen of mice exposed at low-dose-rate (0.7 m Gy/h or 3.95 mGy/h) for up to 2 Gy, suggesting that low-dose radiation does not alter cellular distribution in the spleen. Nevertheless, mice exposed to low-dose radiation exhibited elevation of VEGF, MCP-1, IL-4, Leptin, IL-3, and Tpo in the peripheral blood and slight increases in MIP-2, RANTES, and IL-2 in the spleen. This suggests that chronic γ-radiation can stimulate immune function without causing damage to the immune components of the body. Taken together, these data indicate hormesis of low-dose radiation, which could be attributed to the stimulation of immune function. Dose rate rather than total

Polyethylene glycol hydrogel rectal spacer implantation in patients with prostate cancer undergoing combination high-dose-rate brachytherapy and external beam radiotherapy.

Science.gov (United States)

Yeh, Jekwon; Lehrich, Brandon; Tran, Carolyn; Mesa, Albert; Baghdassarian, Ruben; Yoshida, Jeffrey; Torrey, Robert; Gazzaniga, Michael; Weinberg, Alan; Chalfin, Stuart; Ravera, John; Tokita, Kenneth

2016-01-01

To present rectal toxicity rates in patients administered a polyethylene glycol (PEG) hydrogel rectal spacer in conjunction with combination high-dose-rate brachytherapy and external beam radiotherapy. Between February 2010 and April 2015, 326 prostate carcinoma patients underwent combination high-dose-rate brachytherapy of 16 Gy (average dose 15.5 Gy; standard deviation [SD] = 1.6 Gy) and external beam radiotherapy of 59.4 Gy (average dose 60.2 Gy; SD = 2.9 Gy). In conjunction with the radiation therapy regimen, each patient was injected with 10 mL of a PEG hydrogel in the anterior perirectal fat space. The injectable spacer (rectal spacer) creates a gap between the prostate and the rectum. The rectum is displaced from the radiation field, and rectal dose is substantially reduced. The goal is a reduction in rectal radiation toxicity. Clinical efficacy was determined by measuring acute and chronic rectal toxicity using the National Cancer Center Institute Common Terminology Criteria for Adverse Events v4.0 grading scheme. Median followup was 16 months. The mean anterior-posterior separation achieved was 1.6 cm (SD = 0.4 cm). Rates of acute Grade 1 and 2 rectal toxicity were 37.4% and 2.8%, respectively. There were no acute Grade 3/4 toxicities. Rates of late Grade 1, 2, and 3 rectal toxicity were 12.7%, 1.4%, and 0.7%, respectively. There were no late Grade 4 toxicities. PEG rectal spacer implantation is safe and well tolerated. Acute and chronic rectal toxicities are low despite aggressive dose escalation. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Dose volume assessment of high dose rate 192IR endobronchial implants

International Nuclear Information System (INIS)

Cheng, B. Saw; Korb, Leroy J.; Pawlicki, Todd; Wu, Andrew

1996-01-01

Purpose: To study the dose distributions of high dose rate (HDR) endobronchial implants using the dose nonuniformity ratio (DNR) and three volumetric irradiation indices. Methods and Materials: Multiple implants were configured by allowing a single HDR 192 Ir source to step through a length of 6 cm along an endobronchial catheter. Dwell times were computed to deliver a dose of 5 Gy to points 1 cm away from the catheter axis. Five sets of source configurations, each with different dwell position spacings from 0.5 to 3.0 cm, were evaluated. Three-dimensional (3D) dose distributions were then generated for each source configuration. Differential and cumulative dose-volume curves were generated to quantify the degree of target volume coverage, dose nonuniformity within the target volume, and irradiation of tissues outside the target volume. Evaluation of the implants were made using the DNR and three volumetric irradiation indices. Results: The observed isodose distributions were not able to satisfy all the dose constraints. The ability to optimally satisfy the dose constraints depended on the choice of dwell position spacing and the specification of the dose constraint points. The DNR and irradiation indices suggest that small dwell position spacing does not result in a more homogeneous dose distribution for the implant. This study supports the existence of a relationship between the dwell position spacing and the distance from the catheter axis to the reference dose or dose constraint points. Better dose homogeneity for an implant can be obtained if the spacing of the dwell positions are about twice the distance from the catheter axis to the reference dose or dose constraint points

Braquiterapia de alta taxa de dose no Brasil High-dose rate brachytherapy in Brazil

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Sérgio Carlos Barros Esteves

2004-10-01

Full Text Available A braquiterapia de alta taxa de dose foi introduzida em nosso meio em janeiro de 1991. Desde então, houve uma mudança significativa na abordagem das neoplasias malignas em relação às vantagens do novo método, e também resolução da demanda reprimida de braquiterapia para as neoplasias ginecológicas. Nos primeiros dez anos de atividade, o Brasil tratou, em 31 serviços, 26.436 pacientes com braquiterapia, sendo mais de 50% das pacientes portadoras de neoplasias do colo uterino. Este estudo mostra o número e o perfil de pacientes tratados com esse método e a sua distribuição no território nacional, deixando explícito o benefício da braquiterapia de alta taxa de dose para o Brasil.High-dose rate brachytherapy was first introduced in Brazil in January 1991. Significant changes in the management of malignant neoplasms were observed since utilization of high-dose rate brachytherapy. The high number of gynecological patients awaiting for brachytherapy also decreased during this period. In the first ten years 26,436 patients were treated with high-dose rate brachytherapy. More than 50% of these patients presented neoplasms of the uterine cervix. In this study we present the number and profile of the patients treated with high-dose rate brachytherapy as well as the distribution of these patients in the Brazilian territory, proving the benefit of the use of high-dose rate brachytherapy in Brazil.

Low Dose X-Ray Sources and High Quantum Efficiency Sensors: The Next Challenge in Dental Digital Imaging?

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Arnav R. Mistry

2014-01-01

Full Text Available Objective(s. The major challenge encountered to decrease the milliamperes (mA level in X-ray imaging systems is the quantum noise phenomena. This investigation evaluated dose exposure and image resolution of a low dose X-ray imaging (LDXI prototype comprising a low mA X-ray source and a novel microlens-based sensor relative to current imaging technologies. Study Design. A LDXI in static (group 1 and dynamic (group 2 modes was compared to medical fluoroscopy (group 3, digital intraoral radiography (group 4, and CBCT scan (group 5 using a dental phantom. Results. The Mann-Whitney test showed no statistical significance (α=0.01 in dose exposure between groups 1 and 3 and 1 and 4 and timing exposure (seconds between groups 1 and 5 and 2 and 3. Image resolution test showed group 1 > group 4 > group 2 > group 3 > group 5. Conclusions. The LDXI proved the concept for obtaining a high definition image resolution for static and dynamic radiography at lower or similar dose exposure and smaller pixel size, respectively, when compared to current imaging technologies. Lower mA at the X-ray source and high QE at the detector level principles with microlens could be applied to current imaging technologies to considerably reduce dose exposure without compromising image resolution in the near future.

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013

International Nuclear Information System (INIS)

Taylor, Carolyn W.; Wang, Zhe; Macaulay, Elizabeth; Jagsi, Reshma; Duane, Frances; Darby, Sarah C.

2015-01-01

Purpose: Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Methods and Materials: Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this “mean heart dose.” Results: In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Conclusions: Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.

A retrospective evaluation of activity of gemcitabine/platinum regimens in the treatment of recurrent ovarian cancer

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Tran N. Le

2017-11-01

Full Text Available Abstract Background While many of these agents have been compared in prospective clinical trials, the gemcitabine/platinumbased regimens have not been compared in a prospective, randomized clinical trial. While bothgemcitabine/carboplatin and gemcitabine/cisplatin have a similar ORR in separate clinical trials, the tworegimens have never been directly been compared. With overlapping dose-limiting toxicity of thrombocytopenia, the gemcitabine/carboplatin regimen has been challenging to employ in the clinical setting in previously treated ovarian cancer patients and is often associated with treatment delays and/or dose reductions. Gemcitabine/cisplatin can also be a challenge due to its dose limiting neuropathy and renal toxicity, especially in previously treated patients. In the absence of any prospective, head to head comparison this retrospective study was embarked upon to compare the response rate and toxicity profiles of gemcitabine/cisplatin verses gemcitabine/carboplatin for the treatment of platinum-sensitive verses platinum-resistant recurrent ovarian cancer. Methods This was a retrospective chart review study that identified patients that had received either gemcitabine/cisplatin or gemcitabine/carboplatin for treatment of recurrent ovarian cancer and compared documented hematological and non-hematological toxicity and response based on RECIST (v1.1. Data was evaluated based upon platinum sensitivity/resistance as well. Results A total of 93 patients were identified that had received a gemcitabine/platinum regimen with 48 with recurrent ovarian cancer that were included in the study. There were 21 patients in the gemcitabine/cisplatin arm and 27 patients identified in the gemcitabine/carboplatin arm. Objective response rate (ORR was greater in platinum-sensitive patients that received gemcitabine/carboplatin compared to gemcitabine/cisplatin (8 (67% vs 2 (25%, p < 0.05. Conversely, ORR was greater in platinum-resistant patients treated

High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group.

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Pritchard, Jon; Cotterill, Simon J; Germond, Shirley M; Imeson, John; de Kraker, Jan; Jones, David R

2005-04-01

High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test). In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified

Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz.

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Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna; Huang, Liusheng; Natureeba, Paul; Kakuru, Abel; Muhindo, Mary; Nakalembe, Mirium; Havlir, Diane; Kamya, Moses; Aweeka, Francesca; Dorsey, Grant; Rosenthal, Philip J; Savic, Radojka M

2018-03-05

A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), 96% of women, respectively. All regimens were safe, with ≤2% of women predicted to have ≥30 msec QTc increase. For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. NCT02282293. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Dashboard systems: Pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies.

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Mould, Diane R; Dubinsky, Marla C

2015-03-01

Many marketed drugs exhibit high variability in exposure and response. While these drugs are efficacious in their approved indications, finding appropriate dose regimens for individual patients is not straightforward. Similar dose adjustment problems are also seen with drugs that have a complex relationship between exposure and response and/or a narrow therapeutic window. This is particularly true for monoclonal antibodies, where prolonged dosing at a sub-therapeutic dose can also elicit anti-drug antibodies which will further compromise safety and efficacy. Thus, finding appropriate doses quickly would represent a substantial improvement in healthcare. Dashboard systems, which are decision-support tools, offer an improved, convenient means of tailoring treatment for individual patients. This article reviews the clinical need for this approach, particularly with monoclonal antibodies, the design, development, and testing of such systems, and the likely benefits of dashboard systems in clinical practice. We focus on infliximab for reference. © 2015, The American College of Clinical Pharmacology.

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

International Nuclear Information System (INIS)

Trakul, Nicholas; Chang, Christine N.; Harris, Jeremy; Chapman, Christopher; Rao, Aarti; Shen, John; Quinlan-Davidson, Sean; Filion, Edith J.; Wakelee, Heather A.; Colevas, A. Dimitrios; Whyte, Richard I.

2012-01-01

Purpose: Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. Methods and Materials: We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18–25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50–60 Gy in three to four fractions) (Group 2). Results: The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). Conclusion: A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

International Nuclear Information System (INIS)

Fumoleau, Pierre; Trigo, Jose Manuel; Isambert, Nicolas; Sémiond, Dorothée; Gupta, Sunil; Campone, Mario

2013-01-01

Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m 2 , which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in C max and AUC 0–t were dose proportional for the 6–12 mg/m 2 doses. The MTD of weekly cabazitaxel was 12 mg/m 2 and the recommended weekly dose was 10 mg/m 2 . The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. The study was registered with ClinicalTrials.gov as http://www.clinicaltrials.gov/ct2/show/NCT01755390

Loading regimen required to rapidly achieve therapeutic trough plasma concentration of teicoplanin and evaluation of clinical features

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Seki M

2012-11-01

Full Text Available Masafumi Seki,1,* Kaori Yabuno,1,2,* Koji Miyawaki,1,2 Yoshihiro Miwa,2 Kazunori Tomono11Division of Infection Control and Prevention, 2Department of Pharmacy, Osaka University Hospital, Suita, Osaka, Japan*These authors contributed equally to this workBackground: A trough concentration of >20 mg/L is considered the optimal dosage of teicoplanin required to ensure early therapeutic effects against methicillin-resistant Staphylococcus aureus (MRSA infections including those in patients who develop febrile neutropenia after chemotherapy. This study determines appropriate initial doses during the first 2 days of administration and evaluates the therapeutic target teicoplanin trough concentration.Method: A 2-day regimen was evaluated in patients treated with 600 mg and 1200 mg or 1200 mg and 600 mg (total 1800 mg, Group 1, 800 mg and 800 mg (total 1600 mg, Group 2, and 800 mg and 400 mg (total 1200 mg, Group 3 of teicoplanin on Days 1 and 2, respectively. We also compared the efficiency and adverse effects at trough concentrations of 15–20 mg/L (Group A, n = 28 with >20 mg/L (Group B, n = 27 of teicoplanin, and also compared them with those on the similar concentrations of vancomycin (Groups C and D, n = 50 and 34, respectively.Results: The mean trough concentrations of teicoplanin on Days 4 or 5 were 22.2, 17.5, and 16.2 mg/L in Groups 1, 2, and 3, respectively. The clinical efficiency was 85.7%, 81.5%, 92.0%, and 91.5%, in Groups A, B, C, and D, respectively. The rates of adverse effects were not high in teicoplanin (nephrotoxicity, 7.1% and 3.7%, and hepatotoxicity, 14.3% and 11.1% in Groups A and B, respectively. However, more adverse effects tended to arise in patients who received vancomycin in nephrotoxicity (14.0% and 11.8%, in Groups C and D, respectively.Conclusion: These results suggest that the 2-day regimens with total 1800 mg achieved the most effective therapeutic trough plasma concentration of teicoplanin (20 mg/L. However, 15–20

Responses of rat R-1 cells to low dose rate gamma radiation and multiple daily dose fractions

International Nuclear Information System (INIS)

Kal, H.B.; Bijman, J.Th.

1981-01-01

Multifraction irradiation may offer the same therapeutic gain as continuous irradiation. Therefore, a comparison of the efficacy of low dose rate irradiation and multifraction irradiation was the main objective of the experiments to be described. Both regimens were tested on rat rhabdomyosarcoma (R-1) cells in vitro and in vivo. Exponentially growing R-1 cells were treated in vitro by a multifraction irradiation procedure with dose fractions of 2 Gy gamma radiation and time intervals of 1 to 3 h. The dose rate was 1.3 Gy.min -1 . The results indicate that multifractionation of the total dose is more effective with respect to cell inactivation than continuous irradiation. (Auth.)

Case Report: Stevens-Johnson syndrome following a single double dosing of nevirapine-containing regimen once in an HIV-infected woman on long-term antiretroviral therapy.

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Kakande, Betty; Isaacs, Thuraya; Muloiwa, Rudzani; Dlamini, Sipho; Lehloenya, Rannakoe

2015-01-01

A 31-year old HIV-infected African woman on nevirapine, tenofovir and lamivudine for more than 4 years presented with an 8-day history of symptoms and signs of Stevens-Johnson syndrome. She was on no other medication. Her viral load was undetectable and she had maintained a CD4 count of between 356 and 387cells/mm (3) in the preceding 2½ years. She missed her antiretrovirals 10 days before the onset of her symptoms and subsequently doubled her daily dose the following day. She had been on no other medication in the preceding 8 weeks. Her ARVs were stopped and she fully re-epithelialized with the exception of the lips, over the following 10 days. She was started on a daily single tablet of Odimune® (a fixed drug combination antiretroviral containing tenofovir, emtricitabine and efavirenz). Nevirapine is the most common offender in cases of antiretroviral-associated SJS in published literature. Lamivudine is very rarely implicated while there are no similar reports with tenofovir.  We concluded that nevirapine was by far the most likely offender in this case. Nevirapine toxicity is associated with high CD4 counts, undetectable viral load and high drug plasma level. We postulate that the sudden increase of the plasma levels of nevirapine in a patient with a high CD4 count and undetectable viral load created a perfect storm for the development of SJS in our patient, who had been on the NVP-containing regimen for many years. Clinicians should be aware that severe adverse drug reactions are dynamic and can occur even when the drug has been in use for a long time.

Every-other-day Dosing of Oral Viscous Budesonide Is not Effective in the Management of Eosinophlic Esophagitis.

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Rubinstein, Eitan; Hait, Elizabeth E; Mitchell, Paul D; Lee, John J

2018-03-01

Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by esophageal eosinophilia. Oral viscous budesonide (OVB) is an effective treatment with remission rates reported between 55% and 87%; however, topical corticosteroids are associated with increased risk of candidal esophagitis and adrenal suppression. Attempts to decrease the daily dose of topical steroids have resulted in disease relapse. The objective of this study was to determine whether or not reducing the frequency of OVB administration would be effective in controlling esophageal eosinophilia in children and adolescents. Data were obtained by retrospective chart review of patients at Boston Children's Hospital diagnosed with EoE, based on endoscopic findings of >15 eosinophils per high power field (eos/HPF) on esophageal biopsies while on acid blockade. Patients with histologic evidence of response (<15 eos/HPF) while on daily OVB had been offered the option of maintenance therapy based on a Monday-Wednesday-Friday (MWF) dosing regimen. Changes in peak esophageal eosinophil counts over time were examined. Eight male patients ages 5 to 18 years attained clinical response while receiving daily OVB and were subsequently maintained on a MWF OVB dosing regimen for 3 to 7 months. All 8 patients showed an increase in peak esophageal eosinophils, with 7 of 8 (88%) experiencing disease relapse. In fact, the distribution of peak esophageal eosinophils after MWF dosing was not statistically different from peak levels at diagnosis (P = 0.95). An MWF dosing regimen of OVB was not effective at maintaining histologic response in children and adolescents with EoE. Larger prospective studies are warranted to confirm these results.

Antiretroviral Tissue Kinetics: In Vivo Imaging Using Positron Emission Tomography▿

OpenAIRE

Di Mascio, Michele; Srinivasula, Sharat; Bhattacharjee, Abesh; Cheng, Lily; Martiniova, Lucia; Herscovitch, Peter; Lertora, Juan; Kiesewetter, Dale

2009-01-01

Our current knowledge on the antiviral efficacy, dosing, and toxicity of available highly active antiretroviral therapy regimens is mostly derived from plasma or blood kinetics of anti-human immunodeficiency virus (anti-HIV) drugs. However, the blood comprises only 2% of the total target cells in the body. Tissue drug levels may differ substantially from corresponding plasma levels, and drug distribution processes may be characterized by high intertissue variability, leading to suboptimal tar...

Biocatalytic material comprising multilayer enzyme coated fiber

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Kim, Jungbae [Richland, WA; Kwak, Ja Hun [Richland, WA; Grate, Jay W [West Richland, WA

2009-11-03

The present invention relates generally to high stability, high activity biocatalytic materials and processes for using the same. The materials comprise enzyme aggregate coatings having high biocatalytic activity and stability useful in heterogeneous environment. These new materials provide a new biocatalytic immobilized enzyme system with applications in bioconversion, bioremediation, biosensors, and biofuel cells.

Selective Changes in the Immune Profile of Tumor-Draining Lymph Nodes After Different Neoadjuvant Chemoradiation Regimens for Locally Advanced Cervical Cancer

International Nuclear Information System (INIS)

Battaglia, Alessandra; Buzzonetti, Alexia; Martinelli, Enrica; Fanelli, Mara; Petrillo, Marco; Ferrandina, Gabriella; Scambia, Giovanni; Fattorossi, Andrea

2010-01-01

Purpose: To assess how neoadjuvant chemoradiation regimens modulate the immune system state in tumor-draining lymph nodes (TDLN), in the setting of advanced cervical cancer. Methods and Materials: Tumor-draining lymph nodes of patients undergoing chemotherapy only (nonirradiated, NI-TDLN) and chemoradiation with lower-dose (39.6 Gy, LD-TDLN) and higher-dose radiation (50 Gy, HD-TDLN) were analyzed by multicolor flow cytometry. Results: Enlarging our previous data, LD-TDLN showed features overall indicative of an enhanced antitumor response as compared with NI-TDLN, namely a significant Th1 and Tc1 polarization and a lower amount of the potent CD4 + Foxp3 + CD25 high regulatory T cell (Treg) subset identified by neuropilin-1 expression. Conversely, compared with NI-TDLN, HD-TDLN showed features overall indicative of an impaired antitumor response, namely a significantly inverted CD4/CD8 cell ratio, a higher Nrp1 + Treg frequency, and a higher frequency of CCR4 + Treg, a Treg subset facilitated in migrating out from TDLN to suppress the immune response against distant cancer cells. Moreover, the Th1 and Tc1 polarization induced by LD radiation was lost, and there was an unfavorable tolerogenic/immunogenic dendritic cell ratio compared with LD-TDLN. Conclusions: Even minor differences in radiation dose in neoadjuvant regimens for locally advanced cervical cancer are crucial for determining the balance between a tolerogenic and an efficacious antitumor immune response in TDLN. Because most of the anticancer immune response takes place in TDLN, the present findings also emphasize the importance of chemoradiation protocols in the context of immunotherapeutic trials.

Endorectal high dose rate brachytherapy quality assurance

International Nuclear Information System (INIS)

Devic, S.; Vuong, T.; Evans, M.; Podgorsak, E.

2008-01-01

We describe our quality assurance method for preoperative high dose rate (HDR) brachytherapy of endorectal tumours. Reproduction of the treatment planning dose distribution on a daily basis is crucial for treatment success. Due to the cylindrical symmetry, two types of adjustments are necessary: applicator rotation and dose distribution shift along the applicator axis. (author)

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

International Nuclear Information System (INIS)

Martinez, Alvaro A.; Gustafson, Gary; Gonzalez, Jose; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-01-01

Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level ≥10.0 ng/mL, Gleason score ≥7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p<0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p=0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause

Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review.

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Charles H King

2011-09-01

Full Text Available Controversy persists about the optimal approach to drug-based control of schistosomiasis in high-risk communities. In a systematic review of published studies, we examined evidence for incremental benefits from repeated praziquantel dosing, given 2 to 8 weeks after an initial dose, in Schistosoma-endemic areas of Africa.We performed systematic searches of electronic databases PubMed and EMBASE for relevant data using search terms 'schistosomiasis', 'dosing' and 'praziquantel' and hand searches of personal collections and bibliographies of recovered articles. In 10 reports meeting study criteria, improvements in parasitological treatment outcomes after two doses of praziquantel were greater for S. mansoni infection than for S. haematobium infection. Observed cure rates (positive to negative conversion in egg detection assays were, for S. mansoni, 69-91% cure after two doses vs. 42-79% after one dose and, for S. haematobium, 46-99% cure after two doses vs. 37-93% after a single dose. Treatment benefits in terms of reduction in intensity (mean egg count were also different for the two species-for S. mansoni, the 2-dose regimen yielded an weighted average 89% reduction in standardized egg counts compared to a 83% reduction after one dose; for S. haematobium, two doses gave a 93% reduction compared to a 94% reduction with a single dose. Cost-effectiveness analysis was performed based on Markov life path modeling.Although schedules for repeated treatment with praziquantel require greater inputs in terms of direct costs and community participation, there are incremental benefits to this approach at an estimated cost of $153 (S. mansoni-$211 (S. haematobium per additional lifetime QALY gained by double treatment in school-based programs. More rapid reduction of infection-related disease may improve program adherence, and if, as an externality of the program, transmission can be reduced through more effective coverage, significant additional benefits are

Association between number of doses per day, number of medications and patient's non-compliance, and frequency of readmissions in a multi-ethnic Asian population

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Ming Ren Toh

2014-01-01

Conclusion: Complex medication regimen (i.e. multiple medications and multiple doses per day is a statistically significant predictor of number of readmissions. Simplifying therapeutic regimens with alternatives such as longer-acting or fixed-dose combination drugs may facilitate better patient adherence and reduce costly readmissions.

A comparison of different antibiotic regimens for the treatment of infective endocarditis.

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Martí-Carvajal, Arturo J; Dayer, Mark; Conterno, Lucieni O; Gonzalez Garay, Alejandro G; Martí-Amarista, Cristina Elena; Simancas-Racines, Daniel

2016-04-19

alone reporting uncertain effects on all-cause mortality (8/31 (26%) with levofloxacin plus standard treatment versus 9/39 (23%) with standard treatment alone; RR 1.12, 95% CI 0.49 to 2.56, very low quality evidence). The second trial compared daptomycin versus low-dose gentamicin plus an anti-staphylococcal penicillin (nafcillin, oxacillin or flucloxacillin) or vancomycin. This showed uncertain effects in terms of cure rates (9/28 (32.1%) with daptomycin versus 9/25 (36%) with low-dose gentamicin plus anti-staphylococcal penicillin or vancomycin, RR 0.89 95% CI 0.42 to 1.89; very low quality evidence). The third trial compared cloxacillin plus gentamicin with a glycopeptide (vancomycin or teicoplanin) plus gentamicin. In participants receiving gentamycin plus glycopeptide only 13/23 (56%) were cured versus 11/11 (100%) receiving cloxacillin plus gentamicin (RR 0.59, 95% CI 0.40 to 0.85; very low quality evidence). The fourth trial compared ceftriaxone plus gentamicin versus ceftriaxone alone and found no conclusive differences in terms of cure (15/34 (44%) with ceftriaxone plus gentamicin versus 21/33 (64%) with ceftriaxone alone, RR 0.69, 95% CI 0.44 to 1.10; very low quality evidence).The trials reported adverse events, need for cardiac surgical interventions, uncontrolled infection and relapse of endocarditis and found no conclusive differences between comparison groups (very low quality evidence). No trials assessed septic emboli or quality of life. Limited and very low quality evidence suggested that there were no conclusive differences between antibiotic regimens in terms of cure rates or other relevant clinical outcomes. However, because of the very low quality evidence, this needs confirmation. The conclusion of this Cochrane review was based on randomised controlled trials with high risk of bias. Accordingly, current evidence does not support or reject any regimen of antibiotic therapy for treatment of infective endocarditis.

Low dose radiation enhance the anti-tumor effect of high dose radiation on human glioma cell U251

International Nuclear Information System (INIS)

Wang Chang; Wang Guanjun; Tan Yehui; Jiang Hongyu; Li Wei

2008-01-01

Objective: To detect the effect on the growth of human glioma cell U251 induced by low dose irradiation and low dose irradiation combined with large dose irradiation. Methods: Human glioma cell line U251 and nude mice carried with human glioma were used. The tumor cells and the mice were treated with low dose, high dose, and low dose combined high dose radiation. Cells growth curve, MTT and flow cytometry were used to detect the proliferation, cell cycle and apoptosis of the cells; and the tumor inhibition rate was used to assess the growth of tumor in vivo. Results: After low dose irradiation, there was no difference between experimental group and control group in cell count, MTT and flow cytometry. Single high dose group and low dose combined high dose group both show significantly the suppressing effect on tumor cells, the apoptosis increased and there was cell cycle blocked in G 2 period, but there was no difference between two groups. In vivo apparent anti-tumor effect in high dose radiation group and the combining group was observed, and that was more significant in the combining group; the prior low dose radiation alleviated the injury of hematological system. There was no difference between single low dose radiation group and control. Conclusions: There is no significant effect on human glioma cell induced by low dose radiation, and low dose radiation could not induce adaptive response. But in vivo experience, low dose radiation could enhance the anti-tumor effect of high dose radiation and alleviated the injury of hematological system. (authors)

Standard dose 131I therapy for hyperthyroidism caused by autonomously functioning thyroid nodules

International Nuclear Information System (INIS)

Fui, S.C.N.T.; Maisey, M.N.

1979-01-01

Thirty-one patients with hyperthyroidism shown on scintigrams to have autonomously functioning thyroid nodules were treated with a standard dose of 15mCi of 131 I. Of thirty patients who have been followed up for at least 6 months to over 3 years, all but one patient were euthyroid after a single dose. Repeat scintigram and Thyrotropin Releasing Hormone test after therapy confirmed that twenty-five patients were cured of the disease. Only one patient developed hypothyroidism. This simplified dose regimen of radioiodine is effective in the treatment of hyperthyroidism caused by autonomously functioning nodules and is not complicated by the high incidence of hyperthyroidism that is observed following radioiodine therapy of Grave's disease. (author)

Novel and Effective Therapeutic Regimens for Helicobacter pylori in an Era of Increasing Antibiotic Resistance

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Yi Hu

2017-05-01

Full Text Available Helicobacter pylori (H. pylori is a common gastrointestinal bacterial strain closely associated with the incidence of chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. A current research and clinical challenge is the increased rate of antibiotic resistance in H. pylori, which has led to a decreased H. pylori eradication rate. In this article, we review recent H. pylori infection and reinfection rates and H. pylori resistance to antibiotics, and we discuss the pertinent treatments. A PubMed literature search was performed using the following keywords: Helicobacter pylori, infection, reinfection, antibiotic resistance, bismuth, proton pump inhibitors, vonoprazan, susceptibility, quintuple therapy, dual therapy, and probiotic. The prevalence of H. pylori has remained high in some areas despite the decreasing trend of H. pylori prevalence observed over time. Additionally, the H. pylori reinfection rate has varied in different countries due to socioeconomic and hygienic conditions. Helicobacter pylori monoresistance to clarithromycin, metronidazole or levofloxacin was common in most countries. However, the prevalence of amoxicillin and tetracycline resistance has remained low. Because H. pylori infection and reinfection present serious challenges and because H. pylori resistance to clarithromycin, metronidazole or levofloxacin remains high in most countries, the selection of an efficient regimen to eradicate H. pylori is critical. Currently, bismuth-containing quadruple therapies still achieve high eradication rates. Moreover, susceptibility-based therapies are alternatives because they may avoid the use of unnecessary antibiotics. Novel regimens, e.g., vonoprazan-containing triple therapies, quintuple therapies, high-dose dual therapies, and standard triple therapies with probiotics, require further studies concerning their efficiency and safety for treating H. pylori.

Non-clinical efficacy and safety of HyVac4:IC31 vaccine administered in a BCG prime-boost regimen.

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Skeiky, Yasir A W; Dietrich, Jes; Lasco, Todd M; Stagliano, Katherine; Dheenadhayalan, Veerabadran; Goetz, Margaret Ann; Cantarero, Luis; Basaraba, Randall J; Bang, Peter; Kromann, Ingrid; McMclain, J Bruce; Sadoff, Jerald C; Andersen, Peter

2010-01-22

Despite the extensive success with the introduction of M. bovis Bacille Calmette-Guérin (BCG), tuberculosis (TB) remains a major global epidemic infecting between 8 and 9 million people annually with an estimated 1.7 million deaths each year. However, because of its demonstrated effectiveness against some of the most severe forms of childhood TB, it is now realized that BCG vaccination of newborns is unlikely to be replaced. Therefore, BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that would enhance and prolong the protective immunity induced by BCG prime immunization. We report on a heterologous booster approach using two highly immunogenic TB antigens comprising Ag85B and TB10.4 (HyVac4) delivered as a fusion molecule and formulated in the proprietary adjuvant IC31. This vaccine was found to be immunogenic and demonstrated greater protection in the more stringent guinea pig model of pulmonary tuberculosis than BCG alone when used in a prime/boost regimen. Significant difference in lung involvement was observed for all animals in the HyVac4 boosted group compared to BCG alone regardless of time to death or sacrifice. A vaccine toxicology study of the HyVac4:IC31 regimen was performed and it was judged safe to advance the vaccine into clinical trials. Therefore, all non-clinical data supports the suitability of HyVac4 as a safe, immunogenic, and effective vaccination in a prime-boost regimen with BCG.

Use of an in vitro pharmacodynamic model to derive a moxifloxacin regimen that optimizes kill of Yersinia pestis and prevents emergence of resistance.

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Louie, A; Heine, H S; VanScoy, B; Eichas, A; Files, K; Fikes, S; Brown, D L; Liu, W; Kinzig-Schippers, M; Sörgel, F; Drusano, G L

2011-02-01

Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the "gold standards" for the treatment of plague. However, streptomycin is not available in many countries, and Y. pestis isolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity against Y. pestis in in vitro and animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted for Y. pestis in an in vitro pharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing of Y. pestis and with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptible Y. pestis, while the C(max) (maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due to Y. pestis in 99.8% of subjects and would prevent resistance amplification. We conclude that in an in vitro pharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment of Y. pestis infections in humans. Studies of moxifloxacin in animal models of plague are warranted.

Advancing tuberculosis drug regimen development through innovative quantitative translational pharmacology methods and approaches.

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Hanna, Debra; Romero, Klaus; Schito, Marco

2017-03-01

The development of novel tuberculosis (TB) multi-drug regimens that are more efficacious and of shorter duration requires a robust drug development pipeline. Advances in quantitative modeling and simulation can be used to maximize the utility of patient-level data from prior and contemporary clinical trials, thus optimizing study design for anti-TB regimens. This perspective article highlights the work of seven project teams developing first-in-class translational and quantitative methodologies that aim to inform drug development decision-making, dose selection, trial design, and safety assessments, in order to achieve shorter and safer therapies for patients in need. These tools offer the opportunity to evaluate multiple hypotheses and provide a means to identify, quantify, and understand relevant sources of variability, to optimize translation and clinical trial design. When incorporated into the broader regulatory sciences framework, these efforts have the potential to transform the development paradigm for TB combination development, as well as other areas of global health. Copyright © 2016. Published by Elsevier Ltd.

NIST high-dose calibration services

International Nuclear Information System (INIS)

Humphreys, J.C.

1989-01-01

There is a need for the standardization of high-dose measurements used in the radiation-processing industry in order to provide assured traceability to national standards. NIST provides dosimetry calibration services to this industry. One of these services involves administration of known absorbed doses of gamma rays to customer-supplied dosimeters. The dosimeters are packaged to provide electron equilibrium conditions and are irradiated in a standard 60 Co calibration facility; this provides a calibration of that batch of dosimeters. Another service consists of supplying to a customer calibrated transfer dosimeters for irradiation with the customer's radiation source. The irradiated transfer dosimeters are then returned to NIST for analysis; the results are reported to the customer, providing a calibration of the dose rate of the customer's source. (orig.)

Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

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Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

2014-05-01

In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial MRI late gadolinium enhancement

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Secchi, Francesco; Di Leo, Giovanni; Papini, Giacomo D.E. [Universita degli Studi di Milano, Dipartimento di Scienze Medico-Chirurgiche, Milan (Italy); IRCCS Policlinico San Donato, Radiology Unit, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy); Giacomazzi, Francesca [IRCCS Policlinico San Donato, Unit of Cardiac Surgery, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy); Di Donato, Marisa [University of Florence, Department of Critical Care Medicine, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy); Sardanelli, Francesco, E-mail: francesco.sardanelli@unimi.it [Universita degli Studi di Milano, Dipartimento di Scienze Medico-Chirurgiche, Milan (Italy); IRCCS Policlinico San Donato, Radiology Unit, Via Morandi 30, 20097 San Donato Milanese, Milan (Italy)

2011-10-15

Objectives: To investigate the time-course of late gadolinium enhancement of infarcted myocardium using gadobenate dimeglumine at different dosages and administration regimens. Materials and methods: After institutional review board approval and informed consent, we studied 13 patients (aged 63 {+-} 11 years) with chronic myocardial infarction. They underwent two gadobenate dimeglumine-enhanced MR examinations (interval 24-48 h) using short-axis inversion-recovery gradient-echo sequences, with the following two different protocols, in randomized order: 0.05 mmol/kg and imaging at the 2.5th, 5th, 7.5th and 10th minute plus 0.05 mmol/kg and imaging at the 12.5th, 15th, 17.5th and 20th minute; the same as before but using 0.1 mmol/kg for both contrast injections. Contrast-to-noise ratios (CNRs) between infarcted myocardium, non-infarcted myocardium and left ventricle cavity were calculated for each time-point (2.5-min steps). Friedman ANOVA was used for comparing the CNR time-course; Wilcoxon test for comparing CNR at the 10th and the 20th minute. Results: The CNR between infarcted and non-infarcted myocardium obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than that obtained at the 10th minute with 0.05 mmol/kg (P = 0.033) while not significantly different from that obtained at the 10th (0.1 mm/kg) or at the 20th minute with 0.1 plus 0.1 mmol/kg. The CNR between infarcted myocardium and the left ventricle cavity obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than all other measured values (P {<=} 0.017). Conclusion: Using gadobenate dimeglumine, 0.05 plus 0.05 mmol/kg allows for a higher CNR between infarcted myocardium and the left ventricle cavity allowing for reliable assessment of the sub-endocardial infarctions.

Comparison of Effectiveness between Rifampicin Ofloxin-Minocycline Regimen and Multidrug Therapy-World Health Organization in Multibacillary Leprosy Patients

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Octawyana Moestopo

2016-12-01

Full Text Available Background: Multidrug therapy (MDT which is recommended by the World Health Organization (WHO for multibacillary (MB leprosy patients has some side effects; it is given in 12 doses over 12-18 months. Patients who refuse or are contraindicated in undertaking MDT-WHO can be given alternative rifampicin-ofloxacin-minocycline (ROM regimen for 24 months, whose side effects are less but more expensive. This study was conducted to compare the effectiveness between ROM and MDT-WHO regimen in the first 12 months based on the derivation in morphological index (MI of acid-fast bacilli (AFB in MB leprosy patient. Methods: This was an observational analytical study with retrospective cohort method. Data was collected from medical records of MB leprosy patients in the Medical Record Installation and Morbus Hansen Clinic, Dr. Hasan Sadikin General Hospital Bandung. The overall derivation in MI in 12 months was assessed according to the type of therapy undertaken by the patient. Data was analyzed by Mann-Whitney U Test. Results: A total of 59 data were selected out of 800 data of new leprosy patients based on the inclusion and exclusion criteria. Among those, 20 patients were treated by ROM and 39 by MDT-WHO. Derivation of MI occurred among both groups, but ROM regimen had higher percentage (94.83% compared with MDT-WHO regimen (79.57% with p value=0.003 (p <0.05. Conclusions: ROM regimen has better effectiveness than MDT-WHO regimen in the first 12 months in MB leprosy patients.

Rectal dose assessment in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer

International Nuclear Information System (INIS)

Oliveira, Jetro Pereira de; Batista, Delano Valdivino Santos; Bardella, Lucia Helena; Carvalho, Arnaldo Rangel

2009-01-01

Objective: The present study was aimed at developing a thermoluminescent dosimetric system capable of assessing the doses delivered to the rectum of patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. Materials and methods: LiF:Mg,Ti,Na powder was the thermoluminescent material utilized for evaluating the rectal dose. The powder was divided into small portions (34 mg) which were accommodated in a capillary tube. This tube was placed into a rectal probe that was introduced into the patient's rectum. Results: The doses delivered to the rectum of six patients submitted to high-dose-rate brachytherapy for uterine cervix cancer evaluated by means of thermoluminescent dosimeters presented a good agreement with the planned values based on two orthogonal (anteroposterior and lateral) radiographic images of the patients. Conclusion: The thermoluminescent dosimetric system developed in the present study is simple and easy to be utilized as compared to other rectal dosimetry methods. The system has shown to be effective in the evaluation of rectal doses in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. (author)

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

Science.gov (United States)

Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-06-01

To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Hand hygiene regimens for the reduction of risk in food service environments.

Science.gov (United States)

Edmonds, Sarah L; McCormack, Robert R; Zhou, Sifang Steve; Macinga, David R; Fricker, Christopher M

2012-07-01

Pathogenic strains of Escherichia coli and human norovirus are the main etiologic agents of foodborne illness resulting from inadequate hand hygiene practices by food service workers. This study was conducted to evaluate the antibacterial and antiviral efficacy of various hand hygiene product regimens under different soil conditions representative of those in food service settings and assess the impact of product formulation on this efficacy. On hands contaminated with chicken broth containing E. coli, representing a moderate soil load, a regimen combining an antimicrobial hand washing product with a 70% ethanol advanced formula (EtOH AF) gel achieved a 5.22-log reduction, whereas a nonantimicrobial hand washing product alone achieved a 3.10log reduction. When hands were heavily soiled from handling ground beef containing E. coli, a wash-sanitize regimen with a 0.5% chloroxylenol antimicrobial hand washing product and the 70% EtOH AF gel achieved a 4.60-log reduction, whereas a wash-sanitize regimen with a 62% EtOH foam achieved a 4.11-log reduction. Sanitizing with the 70% EtOH AF gel alone was more effective than hand washing with a nonantimicrobial product for reducing murine norovirus (MNV), a surrogate for human norovirus, with 2.60- and 1.79-log reductions, respectively. When combined with hand washing, the 70% EtOH AF gel produced a 3.19-log reduction against MNV. A regimen using the SaniTwice protocol with the 70% EtOH AF gel produced a 4.04-log reduction against MNV. These data suggest that although the process of hand washing helped to remove pathogens from the hands, use of a wash-sanitize regimen was even more effective for reducing organisms. Use of a high-efficacy sanitizer as part of a wash-sanitize regimen further increased the efficacy of the regimen. The use of a well-formulated alcohol-based hand rub as part of a wash-sanitize regimen should be considered as a means to reduce risk of infection transmission in food service facilities.

Acute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources

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Mahmoud M. Elzembely

2018-03-01

Full Text Available Purpose: High-dose chemotherapy with autologous stem-cell rescue (SCR is a key component of high-risk neuroblastoma (HRNB therapy. Carboplatin, etoposide, and melphalan (CEM or busulfan and melphalan (Bu/Mel are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT. We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt compared with the resource-rich United States. Patients and Methods: We performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH in the United States (2005 to 2015 versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ in Egypt (2009 to 2015. Results: Forty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05, with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001 and platelets (median 20 days v 18 days, respectively; P < .001. Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033, and four of eight cases were fatal (six of eight patients had underlying hepatitis infection, whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy. Conclusion: Use of autologous stem-cell transplantation is feasible in the context of a resource-limited country.

Successfully Managing Impending Skin Necrosis following Hyaluronic Acid Filler Injection, using High-Dose Pulsed Hyaluronidase

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Kwok Thye David Loh, MBBS

2018-02-01

Full Text Available Summary:. Facial fillers are becoming increasingly popular as aesthetic procedures to temporarily reduce the depth of wrinkles or to contour faces. However, even in the hands of very experienced injectors, there is always a small possibility of vascular complications like intra-arterial injection of filler substance. We present a case report of a patient who developed features of vascular obstruction in right infraorbital artery and tell-tale signs of impending skin necrosis, after hyaluronic acid filler injection by an experienced injector. The diagnosis of a vascular complication was made quickly with the help of clinical features like blanching, livedo reticularis, and poor capillary refill. Patient was treated promptly with “high-dose pulsed hyaluronidase protocol” comprising three 1,000-unit pulses of hyaluronidase, administered hourly. There was no further increase in size of the involved area after the first dose of hyaluronidase. All of the involved area, along with 1 cm overlapping in uninvolved skin area, was injected during each injection pulse, using a combination of cannula and needle. Complete reperfusion and good capillary filling were achieved after completion of 3 pulses, and these were taken as the end-point of high-dose pulsed hyaluronidase treatment. Immediate skin changes after filler injections, as well as after hyaluronidase injections and during the 3-week recovery period, were documented with photographs and clinical notes. Involved skin was found to have been fully recovered from this vascular episode, thus indicating that complete recovery of the ischemic skin changes secondary to possible intra-arterial injection could be achieved using high-dose pulsed hyaluronidase protocol.

Preparations for a major overhaul with equipment for semiautomtic operation on pipework in regions of high radiation dose in nuclear power stations

International Nuclear Information System (INIS)

Hoch, G.

1979-01-01

This paper presents equipment which can be used in the field of high radiation dose on pipeline. This comprises either semi or fully automatic operating machines for the segregation of pipeline, for the treatment of pipeline terminations (weld edges attachments, internal bores), for plating and welding, and also for the testing (ultrasonic and eddy-current testing) of pipelines. (orig./HP) [de

Investigation of polymer composite for high dose dosimetry

International Nuclear Information System (INIS)

Pereira, E.L.M.; Batista, A.S.M.; Ribeiro, F.A.S.; Santos, A.P.; Faria, L.O.; Oliveira, A.H.

2017-01-01

Introduction: This paper presents the efficacy evaluation of PVDF and nanocomposites of the PVDF films for high gamma dosimetry. Our scope in this first part of our studies is the selection of the most promising film for future dosimetry trials, where the proportionality of response of the selected material will be investigated over a large range of doses and dose rates. Methods: Was prepared nanocomposites made by mixing Poly(vinylidene fluoride) (PVDF), zirconium oxide (ZrO 2 ) and multi-walled carbon nanotubes (MWCNTs) aiming to find dosimetric properties for applications in high dose dosimetry. The samples were irradiated with a Co-60 source at constant dose rate (16.7 kGy/h), with doses ranging from 100 to 2750 kGy. The UV-Vis and FTIR spectrophotometry have been used to monitor the appearing of C=C conjugated bonds and radio-oxidation of carbon (C=O). Results: FTIR spectrometry has that the absorbance intensities at 1715 cm -1 and 1730 cm -1 can be used for high dosimetry purposes for gamma doses ranging from 400 to 2750 kGy. In this range, it is possible to observe a linear relationship between Abs & Dose. Fading of signal was evaluated for one month and reproducibility in 2000 kGy dose. Conclusion: FTIR spectroscopic data revealed two optical absorption bands at 1715 cm -1 and 1730 cm -1 whose intensities are unambiguously related to gamma delivered dose ranging from 400 kGy to 2750 kGy. (author)

Statistical behavior of high doses in medical radiodiagnosis

International Nuclear Information System (INIS)

Barboza, Adriana Elisa

2014-01-01

This work has as main purpose statistically estimating occupational exposure in medical diagnostic radiology in cases of high doses recorded in 2011 at national level. For statistical survey of this study, doses of 372 IOE's diagnostic radiology in different Brazilian states were evaluated. Data were extracted from the work of monograph (Research Methodology Of High Doses In Medical Radiodiagnostic) that contains the database's information Sector Management doses of IRD/CNEN-RJ, Brazil. The identification of these states allows the Sanitary Surveillance (VISA) responsible, becomes aware of events and work with programs to reduce these events. (author)

Study of teflon pads as high doses dosemeters

International Nuclear Information System (INIS)

Teixeira, Maria Ines; Caldas, Linda V.E.

2013-01-01

The aim of this work is to study the Teflon, which is used as a binder in the manufacture of dosimetric tablets, for the feasibility of this material as high dose dosemeter. In this paper we used the technique of thermally stimulated luminescence (OSL) to characterize the dosimetric properties of Teflon. Teflon samples were exposed to different doses of radiation, using a source of gamma radiation ( 60 Co). It was obtained dose-response curve between 100 Gy to 50 kGy and reproducibility of OSL response. The preliminary results show that Teflon is a useful material to high dose dosimetry

Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Science.gov (United States)

Krug, L M; Grant, S C; Miller, V A; Ng, K K; Kris, M G

1999-10-01

In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature].

Science.gov (United States)

Zając-Spychała, Olga; Wachowiak, Jacek

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in

Compositions, methods, and systems comprising fluorous-soluble polymers

Science.gov (United States)

Swager, Timothy M.; Lim, Jeewoo; Takeda, Yohei

2015-10-13

The present invention generally relates to compositions, methods, and systems comprising polymers that are fluorous-soluble and/or organize at interfaces between a fluorous phase and a non-fluorous phase. In some embodiments, emulsions or films are provided comprising a polymer. The polymers, emulsions, and films can be used in many applications, including for determining, treating, and/or imaging a condition and/or disease in a subject. The polymer may also be incorporated into various optoelectronic device such as photovoltaic cells, organic light-emitting diodes, organic field effect transistors, or the like. In some embodiments, the polymers comprise pi-conjugated backbones, and in some cases, are highly emissive.

Extended regimen combined oral contraception: A review of evolving concepts and acceptance by women and clinicians.

Science.gov (United States)

Nappi, Rossella E; Kaunitz, Andrew M; Bitzer, Johannes

2016-01-01

The clinical utility of extended regimen combined oral contraceptives (COCs) is increasingly being recognised. Our objective was to understand the attitudes of women and clinicians about the use of these regimens. We present the rationale for extended regimen COCs from a historical perspective, and trace their evolution and growing popularity in light of their clinical benefits. We conclude by offering potential strategies for counselling women about extended regimen COC options. We conducted a MEDLINE search to identify and summarise studies of extended regimen COCs, focusing on attitudes of women and clinicians regarding efficacy, safety/tolerability and fewer scheduled bleeding episodes and other potential benefits. The body of contemporary literature on extended regimen COCs suggests that their contraceptive efficacy is comparable to that of conventional 28-day (i.e., 21/7) regimens. For women seeking contraception that allows infrequent scheduled bleeding episodes, particularly those who suffer from hormone withdrawal symptoms and cyclical symptoms (e.g., headache, mood changes, dysmenorrhoea, heavy menstrual bleeding), extended regimen COCs are an effective and safe option. Although satisfaction with extended regimen COCs in clinical trials is high, misperceptions about continuous hormone use may still limit the widespread acceptance of this approach. Despite the widespread acceptance among clinicians of extended regimen COCs as an effective and safe contraceptive option, these regimens are underused, likely due to a lack of awareness about their availability and utility among women. Improved patient education and counselling regarding the safety and benefits of extended regimen COCs may help women make more informed contraceptive choices.

Ionization chamber for high dose measurements

International Nuclear Information System (INIS)

Rodrigues Junior, Ary de Araujo

2005-01-01

Industrial gamma irradiators facilities are designed for processing large amounts of products, which are exposed to large doses of gamma radiation. The irradiation, in industrial scale, is usually carried out in a dynamic form, where the products go through a 60 Co gamma source with activity of TBq to P Bq (k Ci to MCi). The dose is estimated as being directly proportional to the time that the products spend to go through the source. However, in some situations, mainly for research purposes or for validation of customer process following the ISO 11137 requirements, it is required to irradiate small samples in a static position with fractional deliver doses. The samples are put inside the irradiation room at a fixed distance from the source and the dose is usually determined using dosimeters. The dose is only known after the irradiation, by reading the dosimeter. Nevertheless, in the industrial irradiators, usually different kinds of products with different densities go through between the source and the static position samples. So, the dose rate varies in function of the product density. A suitable methodology would be to monitor the samples dose in real time, measuring the dose on line with a radiation detector, which would improve the dose accuracy and avoid the overdose. A cylindrical ionization chamber of 0.9 cm 3 has been developed for high-doses real-time monitoring, during the sample irradiation at a static position in a 60 Co gamma industrial plant. Nitrogen and argon gas at pressure of 10 exp 5 Pa (1 bar) was utilized to fill the ionization chamber, for which an appropriate configuration was determined to be used as a detector for high-dose measurements. To transmit the signal generated in the ionization chamber to the associated electronic and processing unit, a 20 m mineral insulated cable was welded to the ionization chamber. The signal to noise ratio produced by the detector was about 100. The dosimeter system was tested at a category I gamma

Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.

Science.gov (United States)

Legangneux, Eric; Gardin, Anne; Johns, Donald

2013-03-01

Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min⁻¹; P ≤ 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo. Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg. © 2012 Novartis Institutes for BioMedical Research (NIBIR). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Development of computerized dose planning system and applicator for high dose rate remote afterloading irradiation

Energy Technology Data Exchange (ETDEWEB)

Choi, T. J. [Keimyung Univ., Taegu (Korea); Kim, S. W. [Fatima Hospital, Taegu (Korea); Kim, O. B.; Lee, H. J.; Won, C. H. [Keimyung Univ., Taegu (Korea); Yoon, S. M. [Dong-a Univ., Pusan (Korea)

2000-04-01

To design and fabricate of the high dose rate source and applicators which are tandem, ovoids and colpostat for OB/Gyn brachytherapy includes the computerized dose planning system. Designed the high dose rate Ir-192 source with nuclide atomic power irradiation and investigated the dose characteristics of fabricated brachysource. We performed the effect of self-absorption and determining the gamma constant and output factor and determined the apparent activity of designed source. he automated computer planning system provided the 2D distribution and 3D includes analysis programs. Created the high dose rate source Ir-192, 10 Ci(370GBq). The effective attenuation factor from the self-absorption and source wall was examined to 0.55 of the activity of bare source and this factor is useful for determination of the apparent activity and gamma constant 4.69 Rcm{sup 2}/mCi-hr. Fabricated the colpostat was investigated the dose distributions of frontal, axial and sagittal plane in intra-cavitary radiation therapy for cervical cancer. The reduce dose at bladder and rectum area was found about 20 % of original dose. The computerized brachytherapy planning system provides the 2-dimensional isodose and 3-D include the dose-volume histogram(DVH) with graphic-user-interface mode. emoted afterloading device was built for experiment of created Ir-192 source with film dosimetry within {+-}1 mm discrepancy. 34 refs., 25 figs., 11 tabs. (Author)

Efficacy of combination of glycolic acid peeling with topical regimen in treatment of melasma.

Science.gov (United States)

Chaudhary, Savita; Dayal, Surabhi

2013-10-01

Various treatment modalities are available for management of melasma, ranging from topical and oral to chemical peeling, but none is promising alone. Very few studies are available regarding efficacy of combination of topical treatment with chemical peeling. Combination of chemical peeling and topical regimen can be a good treatment modality in the management of this recalcitrant disorder. To assess the efficacy of combination of topical regimen (2% hydroquinone, 1% hydrocortisone and 0.05% tretinoin) with serial glycolic acid peeling in the treatment of melasma in Indian patients. Forty Indian patients of moderate to severe epidermal variety melasma were divided into two groups of 20 each. One Group i.e. peel group received topical regimen (2% hydroquinone, 1% hydrocortisone and 0.05% tretinoin) with serial glycolic acid peeling and other group i.e. control group received topical regimen (2% hydroquinone, 1% hydrocortisone, 0.05% tretinoin). There was an overall decrease in MASI from baseline in 24 weeks of therapy in both the groups (P value peel with topical regimen showed early and greater improvement than the group which was receiving topical regimen only. This study concluded that combining topical regimen (2% hydroquinone, 1% hydrocortisone and 0.05% tretinoin) with serial glycolic acid peeling significantly enhances the therapeutic efficacy of glycolic acid peeling. The combination of glycolic acid peeling with the topical regimen is a highly effective, safe and promising therapeutic option in treatment of melasma.

Transversus Abdominis Plane Blocks with Single-Dose Liposomal Bupivacaine in Conjunction with a Nonnarcotic Pain Regimen Help Reduce Length of Stay following Abdominally Based Microsurgical Breast Reconstruction.

Science.gov (United States)

Jablonka, Eric M; Lamelas, Andreas M; Kim, Julie N; Molina, Bianca; Molina, Nathan; Okwali, Michelle; Samson, William; Sultan, Mark R; Dayan, Joseph H; Smith, Mark L

2017-08-01

Side effects associated with use of postoperative narcotics for pain control can delay recovery after abdominally based microsurgical breast reconstruction. The authors evaluated a nonnarcotic pain control regimen in conjunction with bilateral transversus abdominis plane blocks on facilitating early hospital discharge. A retrospective analysis was performed of consecutive patients who underwent breast reconstruction using abdominally based free flaps, with or without being included in a nonnarcotic protocol using intraoperative transversus abdominis plane blockade. During this period, the use of locoregional analgesia evolved from none (control), to continuous bupivacaine infusion transversus abdominis plane and catheters, to single-dose transversus abdominis plane blockade with liposomal bupivacaine solution. Demographic factors, length of stay, inpatient opioid consumption, and complications were reported for all three groups. One hundred twenty-eight consecutive patients (182 flaps) were identified. Forty patients (62 flaps) were in the infusion-liposomal bupivacaine group, 48 (66 flaps) were in the single-dose blockade-catheter group, and 40 (54 flaps) were in the control group. The infusion-liposomal bupivacaine patients had a significantly shorter hospital stay compared with the single-dose blockade-catheter group (2.65 ± 0.66 versus 3.52 ± 0.92 days; p plane blocks performed with single injections of liposomal bupivacaine help facilitate early hospital discharge after abdominally based microsurgical breast reconstruction. A trend toward consistent discharge by postoperative day 2 was seen. This could result in significant cost savings for health care systems. Therapeutic, III.

Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus

Directory of Open Access Journals (Sweden)

Hanqing Li

2015-02-01

Full Text Available A hybrid pharmacokinetic/pharmacodynamic (PK/PD model with extended-release (ER process and target mediated drug disposition (TMDD was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG and hemoglobin A1c (HbA1c. Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PK profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol.

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

Directory of Open Access Journals (Sweden)

Rui-Rui Peng

2017-03-01

Full Text Available Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai.Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13% and 0.35% (95% CI: 0.06-1.39%, respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients, fatigue (2 patients, cough (1 patient, sore throat (1 patient, diarrhea (1 patient and erythematous rash (1 patient. The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05. Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia.Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for

Dielectric electroactive polymers comprising an ionic supramolecular structure

DEFF Research Database (Denmark)

2014-01-01

The present invention relates to an ionic interpenetrating polymer network comprising at least one elastomer and an ionic supramolecular structure comprising the reaction product of at least two chemical compounds wherein each of said compounds has at least two functional groups and wherein said ...... compounds are able to undergo Lewis acid-base reactions. The interpenetrating polymer network may be used as dielectric electroactive polymers (DEAPs) having a high dielectric permittivity....

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

Science.gov (United States)

Home, Philip D; Dain, Marie-Paule; Freemantle, Nick; Kawamori, Ryuzo; Pfohl, Martin; Brette, Sandrine; Pilorget, Valérie; Scherbaum, Werner A; Vespasiani, Giacomo; Vincent, Maya; Balkau, Beverley

2015-05-01

It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Open-label observational study to assess the efficacy and safety of aprepitant for chemotherapy-induced nausea and vomiting prophylaxis in Indian patients receiving chemotherapy with highly emetogenic chemotherapy/moderately emetogenic chemotherapy regimens

Directory of Open Access Journals (Sweden)

Hingmire Sachin

2015-01-01

Full Text Available Context: Currently, there is limited data on the prevention of chemotherapy-induced nausea and vomiting (CINV in Indian population with aprepitant containing regimens. Aims: The aim was to assess the Efficacy and Safety of Aprepitant for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy/moderately emetogenic chemotherapy (HEC/MEC regimens. Settings and Design: Investigator initiated, multicentric, open-label, prospective, noncomparative, observational trial. Subjects and Methods: Triple drug regimen with aprepitant, palonosetron, and dexamethasaone administration was assessed for the prevention of CINV during acute, delayed, and the overall phase (OP for HEC/MEC Regimens. The primary endpoint was complete response (CR; no emesis and no use of rescue medication and the key secondary endpoint was the complete control (CC; no emesis, no rescue medication and no more than mild nausea during the OP. Statistical Analysis Used: Perprotocol efficacy was analyzed for the first cycle with results represented in terms of CR/CC rates using descriptive statistics. Results: Seventy-five patients were included in the study with median age of 49.7 years and 89.7% being females. The CR rate (OP for patients administered HEC or MEC regimens during the first cycle were 92% and 90.9%, respectively. Similarly, the CC rates (OP were 75% and 90% for these regimens, respectively. 7 (9.2% patients reported adverse drug reactions that were mild and transient with no reports of any serious adverse events. Conclusions: Use of aprepitant containing regimen for patients receiving HEC/MEC regimen resulted in significantly high CR and CC response rates, which further consolidate its potential role to improve patient quality of life and compliance to disease management.

Placebo HAART Regimen as a Method for Teaching Medication Adherence Issues to Students

OpenAIRE

Sutton, Eliza L; Transue, Emily R; Comes E, Susan; Paauw, Douglas S

2005-01-01

Placebo medication regimens may help educate students about adherence issues. In this randomized trial, 23 third-year medical students took a 2-week placebo regimen mimicking highly active antiretroviral therapy (HAART) during their medicine clerkship; 15 students served as controls. Although no effect was demonstrated from this intervention on an evaluation instrument examining attitudes and beliefs about medication nonadherence, all 23 student-subjects agreed in postintervention interviews ...

Establishment and verification of dose-response curve of chromosomal aberrations after exposure to very high dose γ-ray

International Nuclear Information System (INIS)

Chen Ying; Luo Yisheng; Cao Zhenshan; Liu Xiulin

2006-01-01

To estimate accurately biological dose of the victims exposed to high dose, the dose-response curves of chromosome aberration induced by 6-22 Gy 60 Co γ-ray were established. Human peripheral blood in vitro was irradiated, then lymphocytes were concentrated, cultured 52h, 68h and 72h and harvested. The frequencies of dicentrics (multi-centrics) and rings were counted and compared between different culture times. The dose-response curves and equations were established, as well as verified with high dose exposure accidents. The experiment showed that the culture time should be prolonged properly after high dose exposure, and no significant differences were observed between 52-72h culture. The dose-response curve of 6-22 Gy fitted to linear-square model Y=-2.269 + 0.776D - 7.868 x 10 -3 D 2 and is reliable through verification of the accident dose estimations. In this study, the dose-response curve and equation of chromosome dic + r after 6-22 Gy high dose irradiation were established firstly, and exact dose estimation can be achieved according to it. (authors)

Nonlinear model of high-dose implantation

International Nuclear Information System (INIS)

Danilyuk, A.

2001-01-01

The models of high-dose implantation, using the distribution functions, are relatively simple. However, they must take into account the variation of the function of distribution of the implanted ions with increasing dose [1-4]. This variation takes place owing to the fact that the increase of the concentration of the implanted ions results in a change of the properties of the target. High-dose implantation is accompanied by sputtering, volume growth, diffusion, generation of defects, formation of new phases, etc. The variation of the distribution function is determined by many factors and is not known in advance. The variation within the framework of these models [1-4] is taken into account in advance by the introduction of intuitive assumptions on the basis of implicit considerations. Therefore, these attempts should be regarded as incorrect. The model prepared here makes it possible to take into account the sputtering of the target, volume growth and additional declaration on the implanted ions. Without any assumptions in relation to the variation of the distribution function with increasing dose. In our model it is assumed that the type of distribution function for small doses in a pure target substance is the same as in substances with implanted ions. A second assumption relates to the type of the distribution function valid for small doses in the given substances. These functions are determined as a result of a large number of theoretical and experimental investigations and are well-known at the present time. They include the symmetric and nonsymmetric Gauss distribution, the Pearson distribution, and others. We examine implantation with small doses of up to 10 14 - 10 15 cm -2 when the accurately known distribution is valid

Reduced time for urinary alkalinization before high-dose methotrexate with preadmission oral bicarbonate.

Science.gov (United States)

Kintzel, Polly E; Campbell, Alan D; Yost, Kathleen J; Brinker, Brett T; Arradaza, Nicole V; Frobish, Daniel; Wehr, Alison M; O'Rourke, Timothy J

2012-06-01

Hydration and urinary alkalinization are essential for reducing renal dysfunction with high dose methotrexate (HDMTX). This report presents an analysis of institutional methods used to achieve adequate urinary alkalinization and output for patients receiving single agent HDMTX. Renal and metabolic parameters of tolerance were examined. Medical records of adult patients receiving HDMTX during the calendar years of 2008-2009 were retrospectively reviewed to determine the time to achieve urine pH > 7. Number of hospital days, bicarbonate dose, ordered hydration rate, urine output, and urine pH were assessed. A survival analysis model was run for time to urine pH > 7 using preadmission oral bicarbonate as a predictor variable and including a frailty term. Observational statistics were performed for other parameters. The analysis included 79 encounters for ten patients. Urine pH > 7 was achieved more rapidly in patients receiving preadmission oral bicarbonate (P = 0.012). The number of patients receiving HDMTX on the same day as admission was greater for those receiving preadmission oral bicarbonate (47%) in comparison to those who did not (2%), and they spent less time in the hospital. A standard regimen for hydration and urinary alkalinization based on this project is reported. The nature and frequency of adverse events were as expected for this treatment. At our institution, the time to achieve urinary alkalinization was reduced for patients receiving preadmission oral bicarbonate which facilitated chemotherapy infusion on the same day as admission and decreased the number of calendar days that patients stayed in the hospital.

High-dose gadolinium-enhanced MRI for diagnosis of meningeal metastases

International Nuclear Information System (INIS)

Kallmes, D.F.; Gray, L.; Glass, J.P.

1998-01-01

We compared high-dose (0.3 mmol/kg) and standard-dose (0.1 mmol/kg) gadolinium-enhanced MRI for diagnosis of meningeal metastases in 12 patients with suspected meningeal metastases. They were imaged with both standard-dose and high-dose gadolinium. All patients with abnormal meningeal enhancement underwent at least one lumbar puncture for cerebrospinal fluid (CSF) cytology, while patients with normal meningeal enhancement were followed clinically. All patients with negative CSF cytology also were followed clinically. A single observer reviewed all the images, with specific attention to the enhancement pattern of the meninges. Abnormal leptomeningeal enhancement was present in three cases, and abnormal pachymeningeal enhancement in three other patients. All of these patients had abnormal CSF analyses. In two of the three cases of abnormal leptomeningeal enhancement the disease was more evident on high-dose than on standard-dose imaging; in one case the abnormal enhancement was visible only on high-dose imaging. In one of the three cases with abnormal pachymeningeal enhancement, the disease was evident prospectively only with high-dose imaging. (orig.)

Investigation of polymer composite for high dose dosimetry

Energy Technology Data Exchange (ETDEWEB)

Pereira, E.L.M.; Batista, A.S.M., E-mail: adriananuclear@yahoo.com.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil); Ribeiro, F.A.S.; Santos, A.P.; Faria, L.O.; Oliveira, A.H. [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

2017-07-01

Introduction: This paper presents the efficacy evaluation of PVDF and nanocomposites of the PVDF films for high gamma dosimetry. Our scope in this first part of our studies is the selection of the most promising film for future dosimetry trials, where the proportionality of response of the selected material will be investigated over a large range of doses and dose rates. Methods: Was prepared nanocomposites made by mixing Poly(vinylidene fluoride) (PVDF), zirconium oxide (ZrO{sub 2}) and multi-walled carbon nanotubes (MWCNTs) aiming to find dosimetric properties for applications in high dose dosimetry. The samples were irradiated with a Co-60 source at constant dose rate (16.7 kGy/h), with doses ranging from 100 to 2750 kGy. The UV-Vis and FTIR spectrophotometry have been used to monitor the appearing of C=C conjugated bonds and radio-oxidation of carbon (C=O). Results: FTIR spectrometry has that the absorbance intensities at 1715 cm{sup -1} and 1730 cm{sup -1} can be used for high dosimetry purposes for gamma doses ranging from 400 to 2750 kGy. In this range, it is possible to observe a linear relationship between Abs & Dose. Fading of signal was evaluated for one month and reproducibility in 2000 kGy dose. Conclusion: FTIR spectroscopic data revealed two optical absorption bands at 1715 cm{sup -1} and 1730 cm{sup -1} whose intensities are unambiguously related to gamma delivered dose ranging from 400 kGy to 2750 kGy. (author)

Methodology of high dose research in medical radiodiagnostic

International Nuclear Information System (INIS)

Barboza, Adriana E.; Martins, Cintia P. de S.

2013-01-01

This work has as main purpose to study occupational exposure in diagnostic radiology in medical cases of high doses recorded in 2011 at the national level . These doses were recorded by monitoring individual of the occupationally exposed individuals (OEI's). This monitoring of the doses received by ionizing radiation has as main objective to ensure that the principle of dose limitation is respected. In this study it were evaluated doses of 372 OEI's radiology in different Brazilian states. Doses were extracted from the database of Sector Management Doses of the Institute for Radioprotection and Dosimetry - IRD/CNEN-RJ, Brazil. The information from the database provide reports of doses from several states, which allows to quantify statistically, showing those with the highest doses in four areas: dose greater than or equal to 20 mSv apron and chest and dose greater than or equal to 100 mSv apron and chest. The identification of these states allows the respective Sanitary Surveillance (VISA), be aware of the events and make plans to reduce them. This study clarified the required procedures when there is a record of high dose emphasizing the importance of using protective radiological equipment, dosimeter and provide a safety environment work by maintaining work equipment. Proposes the ongoing training of professionals, emphasizing the relevance of the concepts of radiation protection and the use of the questionnaire with their investigative systematic sequence, which will allow quickly and efficiently the success the investigations

High-dose preoperative radiation for cancer of the rectum: Impact of radiation dose on patterns of failure and survival

International Nuclear Information System (INIS)

Ahmad, N.R.; Mohiuddin, M.; Marks, G.

1993-01-01

A variety of dose-time schedules are currently used for preoperative radiation therapy of rectal cancer. An analysis of patients treated with high-dose preoperative radiation therapy was undertaken to determine the influence of radiation dose on the patterns of failure, survival, and complications. Two hundred seventy-five patients with localized rectal cancer were treated with high-dose preoperative radiation therapy. One hundred fifty-six patients received 45 Gy (low-dose group). Since 1985, 119 patients with clinically unfavorable cancers were given a higher dose, 55 Gy using a shrinking field technique (high-dose group). All patients underwent curative resection. Median follow-up was 66 months in the low-dose group and 28 months in the high-dose group. Patterns of failure, survival, and complications were analyzed as a function of radiation dose. Fourteen percent of the total group developed a local recurrence; 20% in the low-dose group as compared with 6% in the high-dose group. The actuarial local recurrence rate at 5 years was 20% for the low-dose group and 8% for the high-dose group, and approached statistical significance with p = .057. For tethered/fixed tumors the actuarial local recurrence rates at 5 years were 28% and 9%, respectively, with p = .05. Similarly, for low-lying tumors (less than 6 cm from the anorectal junction) the rates were 24% and 9%, respectively, with p = .04. The actuarial rate of distant metastasis was 28% in the low-dose group and 20% in the high-dose group and was not significantly different. Overall actuarial 5-year survival for the total group of patients was 66%. No significant difference in survival was observed between the two groups, despite the higher proportion of unfavorable cancers in the high-dose group. The incidence of complications was 2%, equally distributed between the two groups. High-dose preoperative radiation therapy for rectal cancer results in excellent local control rates. 27 refs., 2 figs., 8 tabs

High-dose therapy and autologous transplantation for lymphoma: the Peter MacCallum Cancer institute experience

International Nuclear Information System (INIS)

Dowling, A.J.; Prince, H.M.; Wolf, M.; Januszewicz, H.; Seymour, J.F.; Gates, P.; Wirth, A.; Juneja, S.; Smith, J.G.

2001-01-01

High-dose therapy (HDT) with autologous bone marrow or blood cell transplantation for the treatment of lymphoma commenced at Peter MacCallum Cancer Institute in 1986. To examine the patient characteristics and outcomes of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) treated with HDT and autologous transplantation at our Institute in the first 10 years of the service (1986-95). A retrospective analysis was performed examining patient characteristics, prior chemotherapy regimens, pretransplant disease status, HDT regimen, source of stem cells, time for haematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and progression-free survival (PFS). Sixty-seven patients with NHL were treated with an estimated 5-year OS rate of 44% (95% confidence interval (CI) 32-56%) and PFS rate of 34% (95% CI 21-44%). Factors independently predictive of an unfavourable PFS on multivariate analyses were presence of constitutional symptoms at transplant (P < 0.002) and chemotherapy-resistant disease at transplant (P= 0.02). Twenty-three patients with HD were treated with a 5-year predicted OS rate of 74% (95% CI 56-92%) and PFS rate of 57% (95% CI 36-77%).There was no difference in PFS for HD patients who relapsed either within 12 months of completion of front-line therapy or after this time (P =0.5). The transplant-related mortality for the entire cohort was 17%, with a progressive decrease over time. HDT with autologous transplantation achieves durable PFS and OS in patients with lymphoma. Improved patient selection, therapy modifications according to prognostic factors and ongoing improvements in supportive care should improve outcomes further

Acute renal failure in high dose carboplatin chemotherapy

NARCIS (Netherlands)

Frenkel, J.; Kool, G.; de Kraker, J.

1995-01-01

Carboplatin has been reported to cause acute renal failure when administered in high doses to adult patients. We report a 4 1/2-year-old girl who was treated with high-dose carboplatin for metastatic parameningeal embryonal rhabdomyosarcoma. Acute renal failure developed followed by a slow partial

Dose intercomparison studies for standardization of high-dose dosimetry in Viet Nam

International Nuclear Information System (INIS)

Mai Hoang Hoa; Duong Nguyen Dinh; Kojima, T.

1999-01-01

The Irradiation Center of the Vietnam Atomic Energy Commission (IC-VAEC) is planning to establish a traceability system for high-dose dosimetry and to provide high-dose standards as a secondary standard dosimetry laboratory (SSDL) level in Vietnam. For countries which do not have a standard dosimetry laboratory, the participation in the International Dose Assurance Service (IDAS) operated by the International Atomic Energy Agency (IAEA) is the most common means to verify own dosimetry performance with a certain uncertainty. This is, however, only one-direction dose intercomparison with evaluation by IAEA including unknown parameter at participant laboratories. The SSDL level laboratory should have traceability as well as compatibility, ability to evaluate uncertainties of its own dosimetry performance by itself In the present paper, we reviewed our dosimetry performance through two-way dose intercomparison studies and self-evaluation of uncertainty in our dosimetry procedure. The performance of silver dichromate dosimeter as reference transfer dosimeter in IC-VAEC was studied through two-way blind dose intercomparison experiments between the IC-VAEC and JAERI. As another channel of dose intercomparison with IAEA, alanine dosimeters issued by IDAS were simultaneously irradiated with the IC-VAEC dichromate dosimeters at IC-VAEC and analyzed by IAEA. Dose intercomparison between IC-VAEC and JAERI results into a good agreement (better than ±2.5%), and IDAS results also show similar agreement within ±3.0%. The uncertainty was self-estimated on the basis of the JAERI alanine dosimetry, and a preliminary value of about 1.86% at a 68% confidence level is established. The results from these intercomparisons and our estimation of the uncertainty are consistent. We hope that our experience is valuable to other countries which do not have dosimetry standard laboratories and/or are planning to establish them. (author)

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification.

Science.gov (United States)

Moj, Daniel; Britz, Hannah; Burhenne, Jürgen; Stewart, Clinton F; Egerer, Gerlinde; Haefeli, Walter E; Lehr, Thorsten

2017-11-01

This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach. A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration-time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi. The PBPK/PD model suggests dosages of 80 and 230 mg/m 2 for children of 0-1 and 1-17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%. Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.

SINGLE-DOSE VERSUS 3-DAY PROPHYLAXIS WITH CIPROFLOXACIN IN TRANSURETHRAL SURGERY - A CLINICAL-TRIAL

NARCIS (Netherlands)

BIJL, W; JANKNEGT, RA

1993-01-01

in 235 patients who underwent transurethral surgery, perioperative oral ciprofloxacin prophylaxis was given as a single dose 500 mg versus a 3-day regimen. Out of 180 evaluable patients, 84 received a single dose and 96 received a 3-day course. In the single dose prophylaxis group there were 5

Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality.

Directory of Open Access Journals (Sweden)

Carole D Mitnick

Full Text Available A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.This study assessed the impact of an aggressive regimen-one containing at least five likely effective drugs, including a fluoroquinolone and injectable-on treatment outcomes in a large MDR-TB patient cohort.This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7 drugs. Cure or completion was achieved in 66.1% (442 of patients; death occurred in 20.8% (139. Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89, compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93.The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.

Differences in Lipid Measurements by Antiretroviral Regimen Exposure in Cohorts from Asia and Australia