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Sample records for clinically significant drug

  1. Identification of clinically significant drug-drug interactions in cardiac ...

    African Journals Online (AJOL)

    Purpose: To identify clinically significant potential drug-drug interactions in cardiac intensive care units of two tertiary care ... hypertension, hyperlipidemia, diabetes or other diseases .... May result in digoxin toxicity (nausea, vomiting, cardiac.

  2. [Clinical significance of drug resistance-associated mutations in treatment of hepatitis C with direct-acting antiviral agents].

    Science.gov (United States)

    Li, Z; Chen, Z W; Ren, H; Hu, P

    2017-03-20

    Direct-acting antiviral agents (DAAs) achieve a high sustained virologic response rate in the treatment of chronic hepatitis C virus infection. However, drug resistance-associated mutations play an important role in treatment failure and have attracted more and more attention. This article elaborates on the clinical significance of drug resistance-associated mutations from the aspects of their definition, association with genotype, known drug resistance-associated mutations and their prevalence rates, the impact of drug resistance-associated mutations on treatment naive and treatment-experienced patients, and the role of clinical detection, in order to provide a reference for clinical regimens with DAAs and help to achieve higher sustained virologic response rates.

  3. Displacement of Drugs from Human Serum Albumin: From Molecular Interactions to Clinical Significance.

    Science.gov (United States)

    Rimac, Hrvoje; Debeljak, Željko; Bojić, Mirza; Miller, Larisa

    2017-01-01

    Human serum albumin (HSA) is the most abundant protein in human serum. It has numerous functions, one of which is transport of small hydrophobic molecules, including drugs, toxins, nutrients, hormones and metabolites. HSA has the ability to interact with a wide variety of structurally different compounds. This promiscuous, nonspecific affinity can lead to sudden changes in concentrations caused by displacement, when two or more compounds compete for binding to the same molecular site. It is important to consider drug combinations and their binding to HSA when defining dosing regimens, as this can directly influence drug's free, active concentration in blood. In present paper we review drug interactions with potential for displacement from HSA, situations in which they are likely to occur and their clinical significance. We also offer guidelines in designing drugs with decreased binding to HSA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. [Predictive factors of clinically significant drug-drug interactions among regimens based on protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir].

    Science.gov (United States)

    Cervero, Miguel; Torres, Rafael; Jusdado, Juan José; Pastor, Susana; Agud, Jose Luis

    2016-04-15

    To determine the prevalence and types of clinically significant drug-drug interactions (CSDI) in the drug regimens of HIV-infected patients receiving antiretroviral treatment. retrospective review of database. Centre: Hospital Universitario Severo Ochoa, Infectious Unit. one hundred and forty-two participants followed by one of the authors were selected from January 1985 to December 2014. from their outpatient medical records we reviewed information from the last available visit of the participants, in relation to HIV infection, comorbidities, demographics and the drugs that they were receiving; both antiretroviral drugs and drugs not related to HIV infection. We defined CSDI from the information sheet and/or database on antiretroviral drug interactions of the University of Liverpool (http://www.hiv-druginteractions.org) and we developed a diagnostic tool to predict the possibility of CSDI. By multivariate logistic regression analysis and by estimating the diagnostic performance curve obtained, we identified a quick tool to predict the existence of drug interactions. Of 142 patients, 39 (29.11%) had some type of CSDI and in 11.2% 2 or more interactions were detected. In only one patient the combination of drugs was contraindicated (this patient was receiving darunavir/r and quetiapine). In multivariate analyses, predictors of CSDI were regimen type (PI or NNRTI) and the use of 3 or more non-antiretroviral drugs (AUC 0.886, 95% CI 0.828 to 0.944; P=.0001). The risk was 18.55 times in those receiving NNRTI and 27,95 times in those receiving IP compared to those taking raltegravir. Drug interactions, including those defined as clinically significant, are common in HIV-infected patients treated with antiretroviral drugs, and the risk is greater in IP-based regimens. Raltegravir-based prescribing, especially in patients who receive at least 3 non-HIV drugs could avoid interactions. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  5. An Evidence-Based Assessment of the Clinical Significance of Drug-Drug Interactions Between Disease-Modifying Antirheumatic Drugs and Non-Antirheumatic Drugs According to Rheumatologists and Pharmacists

    NARCIS (Netherlands)

    van Roon, Eric N.; van den Bemt, Patricia M. L. A.; Jansen, Tim L. Th. A.; Houtman, Nella M.; van de Laar, Mart A. F. J.; Brouwers, Jacobus R. B. J.

    Background: Clinically relevant drug-drug interactions (DDIs) must be recognized in a timely manner and managed appropriately to prevent adverse drug reactions or therapeutic failure. Because the evidence for most DDIs is based on case reports or poorly documented clinical information, there is a

  6. Consensus-based evaluation of clinical significance and management of anticancer drug interactions

    NARCIS (Netherlands)

    Jansman, F.G.A.; Reyners, A.K.L.; van Roon, E.N.; Smorenburg, C.H.; Helgason, H.H.; le Comte, M.; Wensveen, B.M.; van den Tweel, A.M.A.; de Blois, M.; Kwee, W.; Kerremans, A.L.; Brouwers, J.R.B.J.

    Background: Anticancer drug interactions can affect the efficacy and toxicity of anticancer treatment and that of the interacting drugs. However, information on the significance, prevention, and management of these interactions is currently lacking. Objective: The purpose of this study was to assess

  7. Clinical relevance of cimetidine drug interactions.

    Science.gov (United States)

    Shinn, A F

    1992-01-01

    The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

  8. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs

    DEFF Research Database (Denmark)

    Prahl, Julie B; Johansen, Isik S; Cohen, Arieh S

    2014-01-01

    OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6......-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed...... failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid...

  9. Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

    Science.gov (United States)

    Bruun, Emmi; Virta, Lauri J; Kälviäinen, Reetta; Keränen, Tapani

    2017-08-01

    A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic

  10. Drug-induced psoriasis: clinical perspectives

    Directory of Open Access Journals (Sweden)

    Balak DMW

    2017-12-01

    Full Text Available Deepak MW Balak, Enes Hajdarbegovic Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands Abstract: Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxychloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of “classical” nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments

  11. Pharmacokinetics of Anti-Epileptic Drugs and their Clinical Significance

    Directory of Open Access Journals (Sweden)

    Svein I. Johannessen

    1990-01-01

    Full Text Available The serum concentration achieved and maintained following the administration of a fixed drug dosage is a direct consequence of the interactions of a wide variety of interrelated processes, including drug absorption, distribution, metabolism, and excretion, and the physiological status of the patient. These interrelationships are reviewed with specific reference to the major anti-epileptic drugs, phenobarbitone, phenytoin, sodium valproate, and carbamazepine, as well as a new first-line antiepileptic, oxcarbazepine. Both older drugs, such as phenobarbitone and phenytoin, and newer drugs, such as carbamazepine (CBZ and sodium valproate, have been studied extensively over the past years giving valuable information for drug treatment. An important feature of oxcarbazepine (OXC , which was developed through minimal changes in the structure of CBZ in order to improve on the tolerability of CBZ without sacrificing efficacy, is that its metabolites do not include the 11-epoxide which has been implicated in the side-effects of CBZ. In man, OXC is metabolized to a monohydroxy derivative which has independent anti-epileptic properties. OXC seems to lack several disadavantageous pharmacokinetic properties common to other major anti-epileptic drugs. OXC does not influence its own metabolism after repeated administration, in contrast to the auto-induction displayed by CBZ. The metabolism of OXC is not influenced by anti-epileptic co-medication and does not influence the kinetics of other anti-epileptic drugs – or if it does, then to a lesser extent than CBZ.

  12. Clinically significant drug–drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review

    Directory of Open Access Journals (Sweden)

    Kotlinska-Lemieszek A

    2015-09-01

    Full Text Available Aleksandra Kotlinska-Lemieszek,1 Pål Klepstad,2,3,6 Dagny Faksvåg Haugen2,4,5 1Palliative Medicine Chair and Department, University Hospital of the Lord’s Transfiguration, Karol Marcinkowski University of Medical Sciences, Poznan, Poland; 2European Palliative Care Research Centre, Faculty of Medicine, Norwegian University of Science and Technology,Trondheim, Norway; 3Department of Anaesthesiology and Intensive Care Medicine, St Olavs Hospital, Trondheim, Norway; 4Regional Centre of Excellence for Palliative Care, Haukeland University Hospital, Bergen, Norway; 5Department of Clinical Medicine K1, University of Bergen, Bergen, Norway; 6Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway Background: Opioids are the most frequently used drugs to treat pain in cancer patients. In some patients, however, opioids can cause adverse effects and drug–drug interactions. No advice concerning the combination of opioids and other drugs is given in the current European guidelines. Objective: To identify studies that report clinically significant drug–drug interactions involving opioids used for pain treatment in adult cancer patients. Design and data sources: Systematic review with searches in Embase, MEDLINE, and Cochrane Central Register of Controlled Trials from the start of the databases (Embase from 1980 through January 2014. In addition, reference lists of relevant full-text papers were hand-searched. Results: Of 901 retrieved papers, 112 were considered as potentially eligible. After full-text reading, 17 were included in the final analysis, together with 15 papers identified through hand-searching of reference lists. All of the 32 included publications were case reports or case series. Clinical manifestations of drug–drug interactions involving opioids were grouped as follows: 1 sedation and respiratory depression, 2 other central nervous system symptoms, 3 impairment of pain

  13. Significance and challenges of stereoselectivity assessing methods in drug metabolism

    Directory of Open Access Journals (Sweden)

    Zhuowei Shen

    2016-02-01

    Full Text Available Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug–drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs is expensive. As a detector of chromatographic methods, mass spectrometry (MS is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism.

  14. Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs: Review and Perspectives.

    Science.gov (United States)

    Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V; Mullangi, Ramesh; Srinivas, Nuggehally R

    2016-10-01

    Sucralfate, a complex of aluminium hydroxide with sulfated sucrose, forms a strong gastrointestinal tract (GIT) mucosal barrier with excellent anti-ulcer property. Because sucralfate does not undergo any significant oral absorption, sucralfate resides in the GIT for a considerable length of time. The unabsorbed sucralfate may alter the pharmacokinetics of the oral drugs by impeding its absorption and reducing the oral bioavailability. Because of the increased use of sucralfate, it was important to provide a reappraisal of the published clinical drug-drug interaction studies of sucralfate with scores of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along with study design, objectives and key remarks. While the loss of oral bioavailability was significant for the fluoroquinolone class, it generally varied for other classes of drugs, suggesting that impact of the co-administration of sucralfate is manageable in clinical situations. Given the technology advancement in formulation development, it may be in order feasible to develop appropriate formulation strategies to either avoid or minimize the absorption-related issues when co-administered with sucralfate. It is recommended that consideration of both in vitro and preclinical studies may be in order to gauge the level of interaction of a drug with sucralfate. Such data may aid in the development of appropriate strategies to navigate the co-administration of sucralfate with other drugs in this age of polypharmacy.

  15. Comparative analysis of three drug-drug interaction screening systems against probable clinically relevant drug-drug interactions: a prospective cohort study.

    Science.gov (United States)

    Muhič, Neža; Mrhar, Ales; Brvar, Miran

    2017-07-01

    Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs. A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated. Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems. DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.

  16. Delays in clinical development of neurological drugs in Japan.

    Science.gov (United States)

    Ikeda, Masayuki

    2017-06-28

    The delays in the approval and development of neurological drugs between Japan and other countries have been a major issue for patients with neurological diseases. The objective of this study was to analyze factors contributing to the delay in the launching of neurological drugs in Japan. We analyzed data from Japan and the US for the approval of 42 neurological drugs, all of which were approved earlier in the US than in Japan, and examined the potential factors that may cause the delay of their launch. Introductions of the 42 drugs in Japan occurred at a median of 87 months after introductions in the US. The mean review time of new drug applications for the 20 drugs introduced in Japan in January 2011 or later (15 months) was significantly shorter than that for the other 22 drugs introduced in Japan in December 2010 or earlier (24 months). The lag in the Japan's review time behind the US could not explain the approval delays. In the 31 of the 42 drugs, the application data package included overseas data. The mean review time of these 31 drugs (17 months) was significantly shorter than that of the other 11 drugs without overseas data (26 months). The mean approval lag behind the US of the 31 drugs (78 months) was also significantly shorter than that of the other 11 drugs (134 months). These results show that several important reforms in the Japanese drug development and approval system (e.g., inclusion of global clinical trial data) have reduced the delays in the clinical development of neurological drugs.

  17. Challenges and perspective of drug repurposing strategies in early phase clinical trials.

    Science.gov (United States)

    Kato, Shumei; Moulder, Stacy L; Ueno, Naoto T; Wheler, Jennifer J; Meric-Bernstam, Funda; Kurzrock, Razelle; Janku, Filip

    2015-01-01

    Despite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies.

  18. Big Data Mining and Adverse Event Pattern Analysis in Clinical Drug Trials.

    Science.gov (United States)

    Federer, Callie; Yoo, Minjae; Tan, Aik Choon

    2016-12-01

    Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov ( https://clinicaltrials.gov/ ), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov . Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs.

  19. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  20. Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.

    Science.gov (United States)

    Russo, Emilio; Scicchitano, Francesca; Whalley, Benjamin J; Mazzitello, Carmela; Ciriaco, Miriam; Esposito, Stefania; Patanè, Marinella; Upton, Roy; Pugliese, Michela; Chimirri, Serafina; Mammì, Maria; Palleria, Caterina; De Sarro, Giovambattista

    2014-05-01

    Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP. Copyright © 2013 John Wiley & Sons, Ltd.

  1. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  2. Comparison of 5 health care professionals’ratings of the clinical significance of drug related problems

    DEFF Research Database (Denmark)

    Villesen, Christine; Hojsted, Jette; Kjeldsen, Lene Juel

    2014-01-01

    to a mutual agreement on the level of clinical significance. However, to what degree does the panel agree?Purpose To compare the agreement between different health care professionals who have evaluated the clinical significance of DRPs.Materials and methods DRPs were identified in 30 comprehensive medicines...... reviews conducted by a clinical pharmacist. Two hospital pharmacists, a general practitioner and two specialists in pain management from hospital care (the Panel) evaluated each DRP considering the potential clinical outcome for the patient. The DRPs were rated either nil, low, minor, moderate or highly...... clinically significant. Agreement was analysed using Kappa statistics. A Kappa value of 0.8 to 1.0 indicated nearly perfect agreement between ratings of the Panel members.Results The Panel rated 45 percent of the total 162 DRPs as of moderate clinical significance. However, the overall kappa score was 0...

  3. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

    Science.gov (United States)

    Lammers, Twan; Kiessling, Fabian; Hennink, Wim E; Storm, Gert

    2012-07-20

    Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Classification and occurrence of clinically significant drug interactions with irinotecan and oxaliplatin in patients with metastatic colorectal cancer

    NARCIS (Netherlands)

    Jansman, FGA; Idzinga, FSF; Smit, WM; de Graaf, JC; Coenen, JLLM; Sleijfer, DT; Brouwers, JRBJ

    Background: Pharmacokinetic and pharmacodynamic drug interactions with cytotoxic drugs may significantly influence the efficacy and toxicity of chemotherapy. Objective: The purpose of this study was to identify drug interactions with irinotecan and oxaliplatin reported in the literature, to assess

  5. Toward a normalized clinical drug knowledge base in China-applying the RxNorm model to Chinese clinical drugs.

    Science.gov (United States)

    Wang, Li; Zhang, Yaoyun; Jiang, Min; Wang, Jingqi; Dong, Jiancheng; Liu, Yun; Tao, Cui; Jiang, Guoqian; Zhou, Yi; Xu, Hua

    2018-04-04

    In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Chinese drugs were collected from 4 major resources-China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia-for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems

  6. Risk of Clinically Relevant Pharmacokinetic-based Drug-drug Interactions with Drugs Approved by the U.S. Food and Drug Administration Between 2013 and 2016.

    Science.gov (United States)

    Yu, Jingjing; Zhou, Zhu; Tay-Sontheimer, Jessica; Levy, Rene H; Ragueneau-Majlessi, Isabelle

    2018-03-23

    A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database and the clinical relevance of these observations was characterized based on information from New Drug Application reviews. CYP3A was identified as a major contributor to clinical drug-drug interactions (DDIs), involved in approximately 2/3 of all interactions. Transporters (alone or with enzymes) were found to participate in about half of all interactions, although most of these were weak-to-moderate interactions. When considered as victims, eight new molecular entities (NMEs; cobimetinib, ibrutnib, isavuconazole, ivabradine, naloxegol, paritaprevir, simeprevir, and venetoclax) were identified as sensitive substrates of CYP3A, two NMEs (pirfenidone and tasimelteon) were sensitive substrates of CYP1A2, one NME (dasabuvir) was a sensitive substrate of CYP2C8, one NME (eliglustat) was a sensitive substrate of CYP2D6, and one NME (grazoprevir) was a sensitive substrate of OATP1B1/3 (with changes in exposure greater than 5-fold when co-administered with a strong inhibitor). Interestingly, approximately 75% of identified CYP3A substrates were also substrates of P-gp. As perpetrators, most clinical DDIs involved weak-to-moderate inhibition or induction, with only two drugs (Viekira Pak and idelalisib) showing strong inhibition of CYP3A, and one NME (lumacaftor) considered as a strong CYP3A inducer. Among drugs with large changes in exposure (≥ 5-fold), whether as victim or perpetrator, the most represented therapeutic classes were antivirals and oncology drugs, suggesting a significant risk of clinical DDIs in these patient populations. The American Society for Pharmacology and Experimental Therapeutics.

  7. IMPACT OF CLINICAL-TRIALS ON THE ADOPTION OF NEW DRUGS WITHIN A UNIVERSITY HOSPITAL

    NARCIS (Netherlands)

    DENIG, P; HAAIJER-RUSKAMP, FM; WESSELING, H

    1991-01-01

    To assess the influence that clinical trials may have on the introduction of new drugs into prescribing routines, the adoption of drugs has been studied in a university hospital in the Netherlands. A significant relation was found between the testing of semi-innovative drugs in clinical trials in

  8. Pharmacokinetic drug-drug interaction and their implication in clinical management

    OpenAIRE

    Palleria, Caterina; DI PAOLO, Antonello; Giofrè, Chiara; Caglioti, Chiara; Leuzzi, Giacomo; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2013-01-01

    Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In thi...

  9. Pharmacokinetic drug-drug interaction and their implication in clinical management.

    Science.gov (United States)

    Palleria, Caterina; Di Paolo, Antonello; Giofrè, Chiara; Caglioti, Chiara; Leuzzi, Giacomo; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2013-07-01

    Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.

  10. Challenges in the clinical development of new antiepileptic drugs.

    Science.gov (United States)

    Franco, Valentina; French, Jacqueline A; Perucca, Emilio

    2016-01-01

    Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Pharmacokinetic drug-drug interaction and their implication in clinical management

    Directory of Open Access Journals (Sweden)

    Palleria Caterina

    2013-01-01

    Full Text Available Drug-drug interactions (DDIs are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.

  12. Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

    DEFF Research Database (Denmark)

    Zielinski, Daniel C.; Filipp, F. V.; Bordbar, A.

    2015-01-01

    Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...

  13. 78 FR 20664 - Society of Clinical Research Associates-Food and Drug Administration: Food and Drug...

    Science.gov (United States)

    2013-04-05

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001] Society of Clinical Research Associates-Food and Drug Administration: Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good Clinical Practice AGENCY: Food and Drug...

  14. Clinical Management of HIV Drug Resistance

    Science.gov (United States)

    Cortez, Karoll J.; Maldarelli, Frank

    2011-01-01

    Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. PMID:21994737

  15. Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan?

    Science.gov (United States)

    Maeda, Hideki; Kurokawa, Tatsuo

    2015-12-01

    This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year.

  16. Pharmacometrics in early clinical drug development

    NARCIS (Netherlands)

    Keizer, R.J.

    2010-01-01

    Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and to reduce attrition rates on the route from drug discovery to approval. This field of drug research, which builds heavily on

  17. The target landscape of clinical kinase drugs.

    Science.gov (United States)

    Klaeger, Susan; Heinzlmeir, Stephanie; Wilhelm, Mathias; Polzer, Harald; Vick, Binje; Koenig, Paul-Albert; Reinecke, Maria; Ruprecht, Benjamin; Petzoldt, Svenja; Meng, Chen; Zecha, Jana; Reiter, Katrin; Qiao, Huichao; Helm, Dominic; Koch, Heiner; Schoof, Melanie; Canevari, Giulia; Casale, Elena; Depaolini, Stefania Re; Feuchtinger, Annette; Wu, Zhixiang; Schmidt, Tobias; Rueckert, Lars; Becker, Wilhelm; Huenges, Jan; Garz, Anne-Kathrin; Gohlke, Bjoern-Oliver; Zolg, Daniel Paul; Kayser, Gian; Vooder, Tonu; Preissner, Robert; Hahne, Hannes; Tõnisson, Neeme; Kramer, Karl; Götze, Katharina; Bassermann, Florian; Schlegl, Judith; Ehrlich, Hans-Christian; Aiche, Stephan; Walch, Axel; Greif, Philipp A; Schneider, Sabine; Felder, Eduard Rudolf; Ruland, Juergen; Médard, Guillaume; Jeremias, Irmela; Spiekermann, Karsten; Kuster, Bernhard

    2017-12-01

    Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  18. Improving clinical drug development regulatory procedures for anticonvulsants

    Directory of Open Access Journals (Sweden)

    Janković Slobodan

    2015-01-01

    Full Text Available Background: Clinical development of antiepileptic drugs is demanding due to complex character of the disorder and to diversity of its forms and etiologies. Objective: The aim of this review was to suggest improvements in regulatory procedures for clinical development of antiepileptic drugs. Methods: The following databases of scientific articles were searched: MEDLINE, SCOPUS and SCINDEKS. In total 558 publications were retrieved. The types of articles selected were reviews, reports on clinical trials and letters to the Editor. Results: There are several changes of regulatory documents necessary for improving process of clinical development of antiepileptic drugs: preference of parallel groups design for add-on trials should be explicit; the noninferiority design for monotherapy clinical trials should be acceptable; restrictive formulations when trials of antiepileptic drugs in children are in question should be avoided; requirements in regard to the efficacy measures should be harmonized among the regulatory bodies; proactive attitude towards discovery of adverse events; and precise requirements for clinical trials specifically designed to prove anti-epileptogenic effects should be made clear. Conclusion: Current regulatory documents are incomplete in many aspects; an international effort to improve and harmonize guidelines for clinical development of antiepileptic drugs is necessary for improvement of this process.

  19. Clinically relevant potential drug-drug interactions among outpatients: A nationwide database study.

    Science.gov (United States)

    Jazbar, Janja; Locatelli, Igor; Horvat, Nejc; Kos, Mitja

    2018-06-01

    Adverse drug events due to drug-drug interactions (DDIs) represent a considerable public health burden, also in Slovenia. A better understanding of the most frequently occurring potential DDIs may enable safer pharmacotherapy and minimize drug-related problems. The aim of this study was to evaluate the prevalence and predictors of potential DDIs among outpatients in Slovenia. An analysis of potential DDIs was performed using health claims data on prescription drugs from a nationwide database. The Lexi-Interact Module was used as the reference source of interactions. The influence of patient-specific predictors on the risk of potential clinically relevant DDIs was evaluated using logistic regression model. The study population included 1,179,803 outpatients who received 15,811,979 prescriptions. The total number of potential DDI cases identified was 3,974,994, of which 15.6% were potentially clinically relevant. Altogether, 9.3% (N = 191,213) of the total population in Slovenia is exposed to clinically relevant potential DDIs, and the proportion is higher among women and the elderly. After adjustment for cofactors, higher number of medications and older age are associated with higher odds of clinically relevant potential DDIs. The burden of DDIs is highest with drug combinations that increase risk of bleeding, enhance CNS depression or anticholinergic effects or cause cardiovascular complications. The current study revealed that 1 in 10 individuals in the total Slovenian population is exposed to clinically relevant potential DDIs yearly. Taking into account the literature based conservative estimate that approximately 1% of potential DDIs result in negative health outcomes, roughly 1800 individuals in Slovenia experience an adverse health outcome each year as a result of clinically relevant potential interactions alone. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Clinical toxicology of newer recreational drugs.

    Science.gov (United States)

    Hill, Simon L; Thomas, Simon H L

    2011-10-01

    Novel synthetic 'designer' drugs with stimulant, ecstasy-like (entactogenic) and/or hallucinogenic properties have become increasingly popular among recreational drug users in recent years. The substances used change frequently in response to market trends and legislative controls and it is an important challenge for poisons centres and clinical toxicologists to remain updated on the pharmacological and toxicological effects of these emerging agents. To review the available information on newer synthetic stimulant, entactogenic and hallucinogenic drugs, provide a framework for classification of these drugs based on chemical structure and describe their pharmacology and clinical toxicology. A comprehensive review of the published literature was performed using PUBMED and Medline databases, together with additional non-peer reviewed information sources, including books, media reports, government publications and internet resources, including drug user web forums. Novel synthetic stimulant, entactogenic or hallucinogenic designer drugs are increasingly available to users as demonstrated by user surveys, poisons centre calls, activity on internet drug forums, hospital attendance data and mortality data. Some population sub groups such as younger adults who attend dance music clubs are more likely to use these substances. The internet plays an important role in determining the awareness of and availability of these newer drugs of abuse. Most novel synthetic stimulant, entactogenic or hallucinogenic drugs of abuse can be classified according to chemical structure as piperazines (e.g. benzylpiperazine (BZP), trifluoromethylphenylpiperazine), phenethylamines (e.g. 2C or D-series of ring-substituted amfetamines, benzodifurans, cathinones, aminoindans), tryptamines (e.g. dimethyltryptamine, alpha-methyltryptamine, ethyltryptamine, 5-methoxy-alphamethyltryptamine) or piperidines and related substances (e.g. desoxypipradrol, diphenylprolinol). Alternatively classification may

  1. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort?

    Science.gov (United States)

    Mouly, Stéphane; Lloret-Linares, Célia; Sellier, Pierre-Olivier; Sene, Damien; Bergmann, J-F

    2017-04-01

    An interaction of drug with food, herbs, and dietary supplements is usually the consequence of a physical, chemical or physiologic relationship between a drug and a product consumed as food, nutritional supplement or over-the-counter medicinal plant. The current educational review aims at reminding to the prescribing physicians that the most clinically relevant drug-food interactions may not be strictly limited to those with grapefruit juice and with the Saint John's Wort herbal extract and may be responsible for changes in drug plasma concentrations, which in turn decrease efficacy or led to sometimes life-threatening toxicity. Common situations handled in clinical practice such as aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding may be at increased risk of drug-food or drug-herb interactions. Medications with narrow therapeutic index or potential life-threatening toxicity, e.g., the non-steroidal anti-inflammatory drugs, opioid analgesics, cardiovascular medications, warfarin, anticancer drugs and immunosuppressants may be at risk of significant drug-food interactions to occur. Despite the fact that considerable effort has been achieved to increase patient' and doctor's information and ability to anticipate their occurrence and consequences in clinical practice, a thorough and detailed health history and dietary recall are essential for identifying potential problems in order to optimize patient prescriptions and drug dosing on an individual basis as well as to increase the treatment risk/benefit ratio. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Clinically important drug interactions with zopiclone, zolpidem and zaleplon.

    Science.gov (United States)

    Hesse, Leah M; von Moltke, Lisa L; Greenblatt, David J

    2003-01-01

    Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The

  3. Mass Spectrometry in Clinical Laboratory: Applications in Therapeutic Drug Monitoring and Toxicology.

    Science.gov (United States)

    Garg, Uttam; Zhang, Yan Victoria

    2016-01-01

    Mass spectrometry (MS) has been used in research and specialized clinical laboratories for decades as a very powerful technology to identify and quantify compounds. In recent years, application of MS in routine clinical laboratories has increased significantly. This is mainly due to the ability of MS to provide very specific identification, high sensitivity, and simultaneous analysis of multiple analytes (>100). The coupling of tandem mass spectrometry with gas chromatography (GC) or liquid chromatography (LC) has enabled the rapid expansion of this technology. While applications of MS are used in many clinical areas, therapeutic drug monitoring, drugs of abuse, and clinical toxicology are still the primary focuses of the field. It is not uncommon to see mass spectrometry being used in routine clinical practices for those applications.

  4. Comparison of clinical features between primary and drug-induced sleep-related eating disorder

    Directory of Open Access Journals (Sweden)

    Komada Y

    2016-05-01

    Full Text Available Yoko Komada,1 Yoshikazu Takaesu,2 Kentaro Matsui,3 Masaki Nakamura,3 Shingo Nishida,3 Meri Kanno,3,† Akira Usui,3 Yuichi Inoue1,3 1Department of Somnology, 2Department of Psychiatry, Tokyo Medical University, 3Japan Somnology Center, Institute of Neuropsychiatry, Tokyo, Japan †Meri Kanno passed away on March 1, 2016 Purpose: The aim of this study was to ascertain the clinical characteristics of drug-induced sleep-related eating disorder (SRED. Patients and methods: We retrospectively reviewed the medical records of 30 patients with primary SRED (without any comorbid sleep disorders and who were not taking any possible causative medications, and ten patients with drug-induced SRED (occurrence of SRED episodes after starting nightly medication of sedative drugs, which completely resolved after dose reduction or discontinuation of the sedatives. Results: All patients with drug-induced SRED took multiple types of sedatives, such as benzodiazepines or benzodiazepine receptor agonists. Clinical features of drug-induced SRED compared with primary SRED were as follows: higher mean age of onset (40 years old in drug-induced SRED vs 26 years old in primary SRED, significantly higher rate of patients who had total amnesia during most of their SRED episodes (75.0% vs 31.8%, significantly lower rate of comorbidity of night eating syndrome (0% vs 63.3%, and significantly lower rate of history of sleepwalking (10.0% vs 46.7%. Increased doses of benzodiazepine receptor agonists may be responsible for drug-induced SRED. Conclusion: The clinical features of drug-induced SRED were different from those of primary SRED, possibly reflecting differences in the underlying mechanisms between these two categories of SREDs. Keywords: nocturnal eating syndrome, night eating, eating disorder, hypnotics, amnesia, sleepwalking, benzodiazepine

  5. Clinical pharmacokinetics of non-opiate abused drugs.

    Science.gov (United States)

    Busto, U; Bendayan, R; Sellers, E M

    1989-01-01

    The present review discusses the available data on the kinetic properties of non-opiate abused drugs including psychomotor stimulants, hallucinogens and CNS-depressants. Some of the drugs of abuse reviewed here are illicit drugs (e.g. cannabis, cocaine), while others are effective pharmacological agents but have the potential to be abused (e.g. benzodiazepines). Although some of the drugs mentioned in this review have been in use for centuries (e.g. caffeine, nicotine, cocaine, cannabis), knowledge of their kinetics and metabolism is very recent and in some cases still incomplete. This is partially due to the difficulties inherent in studying drugs of abuse in humans, and to the complex metabolism of some of these drugs (e.g. cannabis, caffeine) which has made it difficult to develop sensitive assays to determine biological pathways. Although drugs of abuse may have entirely different intrinsic pharmacological effects, the kinetic properties of such drugs are factors contributing to abuse and dependence. The pharmacokinetic properties that presumably contribute to self-administration and drug abuse include rapid delivery of the drug into the central nervous system and high free drug clearance. Kinetic characteristics also play an important role in the development of physical dependence and on the appearance of a withdrawal syndrome: the longer the half-life, the greater the likelihood of the development of physical dependence; the shorter the half-life, the earlier and more severe the withdrawal. The balance between these 2 factors, which has not yet been carefully studied, will also influence abuse patterns. The clinical significance of kinetic characteristics with respect to abuse is discussed where possible.

  6. [Targeting high-risk drugs to optimize clinical pharmacists' intervention].

    Science.gov (United States)

    Mouterde, Anne-Laure; Bourdelin, Magali; Maison, Ophélie; Coursier, Sandra; Bontemps, Hervé

    2016-12-01

    By the Order of 6 April 2011, the pharmacist must validate all the prescriptions containing "high-risk drugs" or those of "patients at risk". To optimize this clinical pharmacy activity, we identified high-risk drugs. A list of high-risk drugs has been established using literature, pharmacists' interventions (PI) performed in our hospital and a survey sent to hospital pharmacists. In a prospective study (analysis of 100 prescriptions for each high-risk drug selected), we have identified the most relevant to target. We obtained a statistically significant PI rate (P<0.05) for digoxin, oral anticoagulants direct, oral methotrexate and colchicine. This method of targeted pharmaceutical validation based on high-risk drugs is relevant to detect patients with high risk of medicine-related illness. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  7. [Significance of re-evaluation and development of Chinese herbal drugs].

    Science.gov (United States)

    Gao, Yue; Ma, Zengchun; Zhang, Boli

    2012-01-01

    The research of new herbal drugs involves in new herbal drugs development and renew the old drugs. It is necessary to research new herbal drugs based on the theory of traditional Chinese medicine (TCM). The current development of famous TCM focuses on the manufacture process, quality control standards, material basis and clinical research. But system management of security evaluation is deficient, the relevant system for the safety assessment TCM has not been established. The causes of security problems, security risks, target organ of toxicity, weak link of safety evaluation, and ideas of safety evaluation are discussed in this paper. The toxicology research of chinese herbal drugs is necessary based on standard of good laboratory practices (GLP), the characteristic of Chinese herbal drugs is necessary to be fully integrated into safety evaluation. The safety of new drug research is necessary to be integrated throughout the entire process. Famous Chinese medicine safety research must be paid more attention in the future.

  8. Prevalence of Potential and Clinically Relevant Statin-Drug Interactions in Frail and Robust Older Inpatients.

    Science.gov (United States)

    Thai, Michele; Hilmer, Sarah; Pearson, Sallie-Anne; Reeve, Emily; Gnjidic, Danijela

    2015-10-01

    A significant proportion of older people are prescribed statins and are also exposed to polypharmacy, placing them at increased risk of statin-drug interactions. To describe the prevalence rates of potential and clinically relevant statin-drug interactions in older inpatients according to frailty status. A cross-sectional study of patients aged ≥65 years who were prescribed a statin and were admitted to a teaching hospital between 30 July and 10 October 2014 in Sydney, Australia, was conducted. Data on socio-demographics, comorbidities and medications were collected using a standardized questionnaire. Potential statin-drug interactions were defined if listed in the Australian Medicines Handbook and three international drug information sources: the British National Formulary, Drug Interaction Facts and Drug-Reax(®). Clinically relevant statin-drug interactions were defined as interactions with the highest severity rating in at least two of the three international drug information sources. Frailty was assessed using the Reported Edmonton Frail Scale. A total of 180 participants were recruited (median age 78 years, interquartile range 14), 35.0% frail and 65.0% robust. Potential statin-drug interactions were identified in 10% of participants, 12.7% of frail participants and 8.5% of robust participants. Clinically relevant statin-drug interactions were identified in 7.8% of participants, 9.5% of frail participants and 6.8% of robust participants. Depending on the drug information source used, the prevalence rates of potential and clinically relevant statin-drug interactions ranged between 14.4 and 35.6% and between 14.4 and 20.6%, respectively. In our study of frail and robust older inpatients taking statins, the overall prevalence of potential statin-drug interactions was low and varied significantly according to the drug information source used.

  9. Drug Interactions in Clinical Practice | Ohaju-Obodo | Nigerian ...

    African Journals Online (AJOL)

    The existence of numerous drugs available today for clinical management of patients require consideration of their potential interactions - alteration of the effects of one drug by the concurrent or prior administration of one or more drugs (drug-drug interactions). There could also be alteration of the effects of a drug by food ...

  10. Functional alterations of astrocytes in mental disorders: pharmacological significance as a drug target

    Directory of Open Access Journals (Sweden)

    Yutaka eKoyama

    2015-07-01

    Full Text Available Astrocytes play an essential role in supporting brain functions in physiological and pathological states. Modulation of their pathophysiological responses have beneficial actions on nerve tissue injured by brain insults and neurodegenerative diseases, therefore astrocytes are recognized as promising targets for neuroprotective drugs. Recent investigations have identified several astrocytic mechanisms for modulating synaptic transmission and neural plasticity. These include altered expression of transporters for neurotransmitters, release of gliotransmitters and neurotrophic factors, and intercellular communication through gap junctions. Investigation of patients with mental disorders shows morphological and functional alterations in astrocytes. According to these observations, manipulation of astrocytic function by gene mutation and pharmacological tools reproduce mental disorder-like behavior in experimental animals. Some drugs clinically used for mental disorders affect astrocyte function. As experimental evidence shows their role in the pathogenesis of mental disorders, astrocytes have gained much attention as drug targets for mental disorders. In this article, I review functional alterations of astrocytes in several mental disorders including schizophrenia, mood disorder, drug dependence, and neurodevelopmental disorders. The pharmacological significance of astrocytes in mental disorders is also discussed.

  11. Asymptomatic proteinuria. Clinical significance.

    Science.gov (United States)

    Papper, S

    1977-09-01

    Patients with asymptomatic proteinuria have varied reasons for the proteinuria and travel diverse courses. In the individual with normal renal function and no systemic cause, ie, idiopathic asymptomatic proteinuria, the outlook is generally favorable. Microscopic hematuria probably raises some degree of question about prognosis. The kidney shows normal glomeruli, subtle changes, or an identifiable lesion. The initial approach includes a clinical and laboratory search for systemic disease, repeated urinalyses, quantitative measurements of proteinuria, determination of creatinine clearance, protein electrophoresis where indicated, and intravenous pyelography. The need for regularly scheduled follow-up evaluation is emphasized. Although the initial approach need not include renal biopsy, a decline in creatinine clearance, an increase in proteinuria, or both are indications for biopsy and consideration of drug therapy.

  12. Clinical risk management in Dutch community pharmacies: the case of drug-drug interactions.

    NARCIS (Netherlands)

    Buurma, H.; Smet, P.A.G.M. de; Egberts, A.C.G.

    2006-01-01

    BACKGROUND: The prevention of drug-drug interactions requires a systematic approach for which the concept of clinical risk management can be used. The objective of our study was to measure the frequency, nature and management of drug-drug interaction alerts as these occur in daily practice of Dutch

  13. Clinical and Drug Resistance Characteristics of New Pediatric Tuberculosis Cases in Northern China.

    Science.gov (United States)

    Wang, Ting; Dong, Fang; Li, Qin-Jing; Yin, Qing-Qin; Song, Wen-Qi; Mokrousov, Igor; Jiao, Wei-Wei; Shen, A-Dong

    2018-05-09

    The aim of this study was to evaluate the clinical features and characteristics of drug resistance in newly diagnosed pediatric tuberculosis (TB) patients in northern China. Mycobacterium tuberculosis isolates were collected from September 2010 to October 2016 at the Beijing Children's Hospital. Patients were divided into two groups (resistant to at least one drug and pan-susceptible) according to drug susceptibility testing (DST) results. A total of 132 new cases, mainly from northern China (87.9%), were included in the study. The median age was 1.9 years (1 month-15 years). Resistance to at least one drug was detected in Mycobacterium tuberculosis isolates from 33 (25%) cases. Eight cases of multidrug-resistant TB (MDR-TB) (6.1%) were detected. The two groups did not differ in clinical presentations (disease site, fever >2 weeks, and cough >2 weeks) or in chest imaging (lesion location, lymphadenitis [mediastinal], and pleural effusion). The rate of Mycobacterium tuberculosis drug resistance in new pediatric TB cases was as high as in the new adult patients surveyed in the national drug resistance survey conducted in 2007. No significant difference was observed in clinical features between patients infected with drug-resistant and drug-susceptible strains. Routine DST is important for prescribing effective antituberculosis treatment regimens.

  14. Comparison of three commercial knowledge bases for detection of drug-drug interactions in clinical decision support.

    Science.gov (United States)

    Fung, Kin Wah; Kapusnik-Uner, Joan; Cunningham, Jean; Higby-Baker, Stefanie; Bodenreider, Olivier

    2017-07-01

    To compare 3 commercial knowledge bases (KBs) used for detection and avoidance of potential drug-drug interactions (DDIs) in clinical practice. Drugs in the DDI tables from First DataBank (FDB), Micromedex, and Multum were mapped to RxNorm. The KBs were compared at the clinical drug, ingredient, and DDI rule levels. The KBs were evaluated against a reference list of highly significant DDIs from the Office of the National Coordinator for Health Information Technology (ONC). The KBs and the ONC list were applied to a prescription data set to simulate their use in clinical decision support. The KBs contained 1.6 million (FDB), 4.5 million (Micromedex), and 4.8 million (Multum) clinical drug pairs. Altogether, there were 8.6 million unique pairs, of which 79% were found only in 1 KB and 5% in all 3 KBs. However, there was generally more agreement than disagreement in the severity rankings, especially in the contraindicated category. The KBs covered 99.8-99.9% of the alerts of the ONC list and would have generated 25 (FDB), 145 (Micromedex), and 84 (Multum) alerts per 1000 prescriptions. The commercial KBs differ considerably in size and quantity of alerts generated. There is less variability in severity ranking of DDIs than suggested by previous studies. All KBs provide very good coverage of the ONC list. More work is needed to standardize the editorial policies and evidence for inclusion of DDIs to reduce variation among knowledge sources and improve relevance. Some DDIs considered contraindicated in all 3 KBs might be possible candidates to add to the ONC list. Published by Oxford University Press on behalf of the American Medical Informatics Association 2017. This work is written by US Government employees and is in the public domain in the United States.

  15. SIMulation of Medication Error induced by Clinical Trial drug labeling: the SIMME-CT study.

    Science.gov (United States)

    Dollinger, Cecile; Schwiertz, Vérane; Sarfati, Laura; Gourc-Berthod, Chloé; Guédat, Marie-Gabrielle; Alloux, Céline; Vantard, Nicolas; Gauthier, Noémie; He, Sophie; Kiouris, Elena; Caffin, Anne-Gaelle; Bernard, Delphine; Ranchon, Florence; Rioufol, Catherine

    2016-06-01

    To assess the impact of investigational drug labels on the risk of medication error in drug dispensing. A simulation-based learning program focusing on investigational drug dispensing was conducted. The study was undertaken in an Investigational Drugs Dispensing Unit of a University Hospital of Lyon, France. Sixty-three pharmacy workers (pharmacists, residents, technicians or students) were enrolled. Ten risk factors were selected concerning label information or the risk of confusion with another clinical trial. Each risk factor was scored independently out of 5: the higher the score, the greater the risk of error. From 400 labels analyzed, two groups were selected for the dispensing simulation: 27 labels with high risk (score ≥3) and 27 with low risk (score ≤2). Each question in the learning program was displayed as a simulated clinical trial prescription. Medication error was defined as at least one erroneous answer (i.e. error in drug dispensing). For each question, response times were collected. High-risk investigational drug labels correlated with medication error and slower response time. Error rates were significantly 5.5-fold higher for high-risk series. Error frequency was not significantly affected by occupational category or experience in clinical trials. SIMME-CT is the first simulation-based learning tool to focus on investigational drug labels as a risk factor for medication error. SIMME-CT was also used as a training tool for staff involved in clinical research, to develop medication error risk awareness and to validate competence in continuing medical education. © The Author 2016. Published by Oxford University Press in association with the International Society for Quality in Health Care; all rights reserved.

  16. Albumin-drug interaction and its clinical implication.

    Science.gov (United States)

    Yamasaki, Keishi; Chuang, Victor Tuan Giam; Maruyama, Toru; Otagiri, Masaki

    2013-12-01

    Human serum albumin acts as a reservoir and transport protein for endogenous (e.g. fatty acids or bilirubin) and exogenous compounds (e.g. drugs or nutrients) in the blood. The binding of a drug to albumin is a major determinant of its pharmacokinetic and pharmacodynamic profile. The present review discusses recent findings regarding the nature of drug binding sites, drug-albumin binding in certain diseased states or in the presence of coadministered drugs, and the potential of utilizing albumin-drug interactions in clinical applications. Drug-albumin interactions appear to predominantly occur at one or two specific binding sites. The nature of these drug binding sites has been fundamentally investigated as to location, size, charge, hydrophobicity or changes that can occur under conditions such as the content of the endogenous substances in question. Such findings can be useful tools for the analysis of drug-drug interactions or protein binding in diseased states. A change in protein binding is not always a problem in terms of drug therapy, but it can be used to enhance the efficacy of therapeutic agents or to enhance the accumulation of radiopharmaceuticals to targets for diagnostic purposes. Furthermore, several extracorporeal dialysis procedures using albumin-containing dialysates have proven to be an effective tool for removing endogenous toxins or overdosed drugs from patients. Recent findings related to albumin-drug interactions as described in this review are useful for providing safer and efficient therapies and diagnoses in clinical settings. This article is part of a Special Issue entitled Serum Albumin. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Clinical characteristics of Helicobacter pylori-negative drug-negative peptic ulcer bleeding.

    Science.gov (United States)

    Chung, Woo Chul; Jeon, Eun Jung; Kim, Dae Bum; Sung, Hea Jung; Kim, Yeon-Ji; Lim, Eun Sun; Kim, Min-Ah; Oh, Jung Hwan

    2015-07-28

    To investigate the clinical characteristics and outcomes of idiopathic Helicobacter pylori (H. pylori)-negative and drug-negative] peptic ulcer bleeding (PUB). A consecutive series of patients who experienced PUB between 2006 and 2012 was retrospectively analyzed. A total of 232 patients were enrolled in this study. The patients were divided into four groups according to the etiologies of PUB: idiopathic, H. pylori-associated, drug-induced and combined (H. pylori-associated and drug-induced) types. We compared the clinical characteristics and outcomes between the groups. When the silver stain or rapid urease tests were H. pylori-negative, we obtained an additional biopsy specimen by endoscopic re-examination and performed an H. pylori antibody test 6-8 wk after the initial endoscopic examination. For a diagnosis of idiopathic PUB, a negative result of an H. pylori antibody test was confirmed. In all cases, re-bleeding was confirmed by endoscopic examination. For the risk assessment, the Blatchford and the Rockall scores were calculated for all patients. For PUB, the frequency of H. pylori infection was 59.5% (138/232), whereas the frequency of idiopathic cases was 8.6% (20/232). When idiopathic PUB was compared to H. pylori-associated PUB, the idiopathic PUB group showed a higher rate of re-bleeding after initial hemostasis during the hospital stay (30% vs 7.4%, P = 0.02). When idiopathic PUB was compared to drug-induced PUB, the patients in the idiopathic PUB group showed a higher rate of re-bleeding after initial hemostasis upon admission (30% vs 2.7%, P ulcer (77% vs 49%, P < 0.01). However, the Blatchford and the Rockall scores were not significantly different between the two groups. Among the patients who experienced drug-induced PUB, no significant differences were found with respect to clinical characteristics, irrespective of H. pylori infection. Idiopathic PUB has unique clinical characteristics such as re-bleeding after initial hemostasis upon admission

  18. Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice.

    Science.gov (United States)

    Keller, Guillermo A; Alvarez, Paulino A; Ponte, Marcelo L; Belloso, Waldo H; Bagnes, Claudia; Sparanochia, Cecilia; Gonzalez, Claudio D; Villa Etchegoyen, M Cecilia; Diez, Roberto A; Di Girolamo, Guillermo

    2016-01-01

    The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.

  19. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Science.gov (United States)

    Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N

    2015-01-01

    Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  20. Drug-drug interactions among recently hospitalised patients--frequent but mostly clinically insignificant

    DEFF Research Database (Denmark)

    Glintborg, Bente; Andersen, Stig Ejdrup; Dalhoff, Kim

    2005-01-01

    OBJECTIVE: Patients use and store considerable amounts of drugs. The aim of the present study was to identify potential drug-drug interactions between drugs used by patients recently discharged from the hospital and, subsequently, to estimate the clinical implications of these interactions. METHODS......: Patients were visited within 1 week following their discharge from hospital and interviewed about their drug use. Stored products were inspected. We used a bibliography (Hansten and Horn; Wolters Kluwer Health, St. Louis, Mo., 2004) to identify and classify potential drug-drug interactions. RESULTS......: eight per patient; range: 1-24). With respect to those drugs used daily or on demand, 476 potential interactions were identified (126 patients); none were class 1 (always avoid drug combination) and 25 were class 2 (usually avoid combination; 24 patients). Eleven of the potential class 2 interactions...

  1. Drug repurposing: translational pharmacology, chemistry, computers and the clinic.

    Science.gov (United States)

    Issa, Naiem T; Byers, Stephen W; Dakshanamurthy, Sivanesan

    2013-01-01

    The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far-reaching geographic locations. More recently, de novo drug discovery has become a more rationalized process where drug-target-effect hypotheses are formulated on the basis of already known compounds/protein targets and their structures. Although this approach is hypothesis-driven, the actual success has been very low, contributing to the soaring costs of research and development as well as the diminished pharmaceutical pipeline in the United States. In this review, we discuss the evolution in computational pharmacology as the next generation of successful drug discovery and implementation in the clinic where high-performance computing (HPC) is used to generate and validate drug-target-effect hypotheses completely in silico. The use of HPC would decrease development time and errors while increasing productivity prior to in vitro, animal and human testing. We highlight approaches in chemoinformatics, bioinformatics as well as network biopharmacology to illustrate potential avenues from which to design clinically efficacious drugs. We further discuss the implications of combining these approaches into an integrative methodology for high-accuracy computational predictions within the context of drug repositioning for the efficient streamlining of currently approved drugs back into clinical trials for possible new indications.

  2. Measuring clinical trial transparency: an empirical analysis of newly approved drugs and large pharmaceutical companies.

    Science.gov (United States)

    Miller, Jennifer E; Wilenzick, Marc; Ritcey, Nolan; Ross, Joseph S; Mello, Michelle M

    2017-12-05

    To define a series of clinical trial transparency measures and apply them to large pharmaceutical and biotechnology companies and their 2014 FDA-approved drugs. Cross-sectional descriptive analysis of all clinical trials supporting 2014 Food and Drugs Administration (FDA)-approved new drug applications (NDAs) for novel drugs sponsored by large companies. Data from over 45 sources, including Drugs@FDA.gov, ClinicalTrials.gov, corporate and international registries; PubMed, Google Scholar, EMBASE, corporate press releases, Securities and Exchange Commission (SEC) filings and personal communications with drug manufacturers. Trial registration, results reporting, clinical study report (CSR) synopsis sharing, biomedical journal publication, and FDA Amendments Acts (FDAAA) compliance, analysed on the drug level. The FDA approved 19 novel new drugs, sponsored by 11 large companies, involving 553 trials, in 2014. We analysed 505 relevant trials. Per drug, a median of 100% (IQR 86%-100%) of trials in patients were registered, 71% (IQR 57%-100%) reported results or shared a CSR synopsis, 80% (70%-100%) were published and 96% (80%-100%) were publicly available in some form by 13 months after FDA approval. Disclosure rates were lower at FDA approval (65%) and improved significantly by 6 months post FDA approval. Per drug, a median of 100% (IQR 75%-100%) of FDAAA-applicable trials were compliant. Half of reviewed drugs had publicly disclosed results for all trials in patients in our sample. One trial was uniquely registered in a corporate registry, and not ClinicalTrials.gov; 0 trials were uniquely registered in international registries. Among large pharmaceutical companies and new drugs, clinical trial transparency is high based on several standards, although opportunities for improvement remain. Transparency is markedly higher for trials in patients than among all trials supporting drug approval, including trials in healthy volunteers. Ongoing efforts to publicly track

  3. Relationship between drug interactions and drug-related negative clinical outcomes in two community pharmacies

    Directory of Open Access Journals (Sweden)

    Gonzalo M

    2009-03-01

    Full Text Available Drug interactions may represent an iatrogenic risk that should be controlled in community pharmacies at the dispensing level. Aim: We analyzed the association between potential drug-drug interactions (DDIs and negative clinical outcomes.Methods: We used dispensing data from two community pharmacies: instances where drug dispensing was associated with a potential DDI and a comparison group of randomized dispensing operations with no potential DDI. In cases where potential DDIs were detected, we analyzed the underlying negative clinical outcomes. Age and gender data were included in the analysis.Results: During the study period, we registered 417 potential DDIs. The proportion of women and age were higher in the study group than in the comparison group. The average potential DDIs per patient was 1.31 (SD=0.72. The Consejo General de Colegios Oficiales de Farmacéuticos (CGCOF database did not produce an alert in 2.4% of the cases. Over-the-counter medication use was observed in 5% of the potential DDI cases. The drugs most frequently involved in potential DDIs were acenocoumarol, calcium salts, hydrochlorothiazide, and alendronic acid, whereas the most predominant potential DDIs were calcium salts and bisphosphonates, oral antidiabetics and thiazide diuretics, antidiabetics and glucose, and oral anticoagulant and paracetamol. The existence of a drug-related negative clinical outcome was observed only in 0.96% of the potential DDI cases (50% safety cases and 50% effectiveness cases. Conclusions: Only a small proportion of the detected potential DDIs lead to medication negative outcomes. Considering the drug-related negative clinical outcomes encountered, tighter control would be recommended in potential DDIs with NSAIDs or benzodiazepines.

  4. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens.

    Directory of Open Access Journals (Sweden)

    Shankar Thangamani

    Full Text Available Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90 were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated.

  5. A commentary on transdermal drug delivery systems in clinical trials.

    Science.gov (United States)

    Watkinson, Adam C

    2013-09-01

    The number of drugs available as marketed transdermal products is limited to those that exhibit the correct physicochemical and pharmacokinetic properties that enable their effective delivery across the skin. In this respect, there are less than 20 drugs that are currently marketed in the US and EU as products that deliver systemic levels of their active ingredients. An analysis of clinical trials conducted in the transdermal sector shows a similar picture with only nine drugs accounting for approximately 80% of all transdermal clinical trials listed on ClinicalTrials.gov. Those drugs for which there are very few transdermal trials listed consist mostly of molecules that are inherently unsuitable for transdermal delivery and serve as a clear warning to drug developers that the science that governs transdermal drug delivery is well reflected by the successes and failures of drugs in development as well as those that make it to the market. Copyright © 2013 Wiley Periodicals, Inc.

  6. Use of biomarkers in ALS drug development and clinical trials.

    Science.gov (United States)

    Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert

    2015-05-14

    The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Advanced and controlled drug delivery systems in clinical disease management

    NARCIS (Netherlands)

    Brouwers, JRBJ

    1996-01-01

    Advanced and controlled drug delivery systems are important for clinical disease management. In this review the most important new systems which have reached clinical application are highlighted. Microbiologically controlled drug delivery is important for gastrointestinal diseases like ulcerative

  8. Three-dimensional (3D) culture in sarcoma research and the clinical significance.

    Science.gov (United States)

    Gao, Songtao; Shen, Jacson; Hornicek, Francis; Duan, Zhenfeng

    2017-08-03

    Sarcomas are rare malignant tumors that arise from transformed cells of mesenchymal origin. Despite the progress in diagnosis and treatment, sarcomas have a high mortality rate due to local recurrence, metastasis, and the development of drug resistance to chemotherapy. New models for sarcoma research are required to further understand the disease and to develop new therapies. In vitro sarcoma modeling is challenging because of significant genetic heterogeneities, diverse pathological, and overlapping clinical characteristics. Studies on the mechanisms of recurrence, metastasis, and drug resistance in sarcoma have resulted in the generation of novel three-dimensional (3D) culture models for sarcoma research. 3D culture models aim to recapitulate the tumor microenvironment that plays a critical role in the pathogenesis of sarcoma using biomaterial scaffolds of natural biological materials and artificial polymers. An ideal 3D culture model can properly mimic not only the microenvironment, oncogenesis, and maintenance of sarcoma cell growth, but also imitate the interactions between cells and to the extracellular matrix. More recently, 3D cell culture has been used to research the biological behavior and mechanism of chemotherapy and radiotherapy resistance in different sarcoma models. Ultimately, findings using 3D models that more accurately reflect human sarcoma biology are likely to translate into improved clinical outcomes. In this review, we discuss the most recent advances of 3D culture technologies in sarcoma research and emerging clinical applications.

  9. Optimizing clinical drug product performance

    DEFF Research Database (Denmark)

    Dickinson, Paul A.; Kesisoglou, Filippos; Flanagan, Talia

    2016-01-01

    The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical...... questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97). In BioRAM, risk is defined as not achieving the intended in vivo drug product performance, and success is assessed by time to decision-making and action. Emphasis on time to decision-making and time to action highlights the value of well....... Application of the BioRAM Scoring Grid is illustrated using published literature. Organizational considerations for implementing BioRAM strategy, including the interactions, function, and skillsets of the BioRAM group members, are also reviewed. As a creative and innovative systems approach, we believe...

  10. Clinical information in drug package inserts in India

    Directory of Open Access Journals (Sweden)

    Shivkar Y

    2009-01-01

    Full Text Available Background: It is widely recognized that accurate and reliable product information is essential for the safe and effective use of medications. Pharmaceutical companies are the primary source of most drug information, including package inserts. Package inserts are printed leaflets accompanying marketed drug products and contain information approved by the regulatory agencies. Studies on package inserts in India, in 1996, had shown that crucial information was often missing and they lacked uniformity. Aim: To assess the presentation and completeness of clinically important information provided in the currently available package inserts in India. Materials and Methods: Package inserts accompanying allopathic drug products marketed by pharmaceutical companies in India were collected. These package inserts were analyzed for the content of clinically important information in various sections. Statistical Analysis: The results were expressed as absolute numbers and percentages. Results: Preliminary analyses revealed that most package inserts did contain information under headings, such as, therapeutic indications, contraindications, undesirable effects, etc., listed in the Drugs and Cosmetics Rules 1945. The findings indicated considerable improvement in package inserts since 1996. However, on critical evaluation it was revealed that clinically important information was not well presented and was often incomplete. Information with regard to pediatric and geriatric use was present in only 44% and 13% of the package inserts, respectively. Only five of the inserts had information on the most frequent adverse drug reactions associated with the drug. Also, information on interactions and overdosage was often missing. Conclusion: Although the package inserts appear to have improved over the past decade there is still a definite need to further refine the clinical information contained, to minimize the risks to patients. This could be brought about by self

  11. Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

    Science.gov (United States)

    Prueksaritanont, T; Tatosian, D A; Chu, X; Railkar, R; Evers, R; Chavez-Eng, C; Lutz, R; Zeng, W; Yabut, J; Chan, G H; Cai, X; Latham, A H; Hehman, J; Stypinski, D; Brejda, J; Zhou, C; Thornton, B; Bateman, K P; Fraser, I; Stoch, S A

    2017-04-01

    A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  12. The biological significance and clinical applications of exosomes in ovarian cancer.

    Science.gov (United States)

    Dorayappan, Kalpana Deepa Priya; Wallbillich, John J; Cohn, David E; Selvendiran, Karuppaiyah

    2016-07-01

    Exosomes are nano-sized (20-100nm) vesicles released by a variety of cells and are generated within the endosomal system or at the plasma membrane. There is emerging evidence that exosomes play a key role in intercellular communication in ovarian and other cancers. The protein and microRNA content of exosomes has been implicated in various intracellular processes that mediate oncogenesis, tumor spread, and drug resistance. Exosomes may prime distant tissue sites for reception of future metastases and their release can be mediated by the tumor microenvironment (e.g., hypoxia). Ovarian cancer-derived exosomes have unique features that could be leveraged for use as biomarkers to facilitate improved detection and treatment of the disease. Further, exosomes have the potential to serve as targets and/or drug delivery vehicles in the treatment of ovarian cancer. In this review we discuss the biological and clinical significance of exosomes relevant to the progression, detection, and treatment of ovarian cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Prospective of clinical drugs for radioprotection

    International Nuclear Information System (INIS)

    Alok, Amit; Kumar, Sandeep; Kumar, Arun; Chaudhury, N.K.

    2014-01-01

    We are living in an era of nuclear power where power derived from nuclear reaction is used for power generation as well as for nuclear weapons. The terrorism and the threat of dirty bombs looms around the civilized population. Therefore, there is a need to develop radioprotector which could prevent against the harmful effect of radiation. The research on radioprotector started more than fifty years ago but still there is no approved radioprotector in the drug market. Hundreds of lead molecule have been screened and have shown varying amount of radioprotection either in vitro or in vivo or in both. Only one drug amifostine was approved by FDA but due to its toxicity in head and neck cancer, this drug is no more in use. Antioxidants too have proven to be a potential radioprotector but the dose required for radioprotection is too high for maintenance of homeostasis in physiological system. We have taken an alternative approach of using clinical drugs like diclofenac and tetracycline for development of approach for radioprotection and reported the radioprotective role of diclofenac. The advantage of using clinical drug is its wide availability in the market and the ease with which it could be channelized for radioprotection. Antiradical assays have demonstrated possible use of tetracycline for radioprotection. Tetracycline has also ability to reduce oxidative damages ex vivo. Studies related to comet assay as well as antioxidant assays in different organs are in progress for designing further work for efficacy and elucidation of mechanisms. (author)

  14. Free software to analyse the clinical relevance of drug interactions with antiretroviral agents (SIMARV®) in patients with HIV/AIDS.

    Science.gov (United States)

    Giraldo, N A; Amariles, P; Monsalve, M; Faus, M J

    Highly active antiretroviral therapy has extended the expected lifespan of patients with HIV/AIDS. However, the therapeutic benefits of some drugs used simultaneously with highly active antiretroviral therapy may be adversely affected by drug interactions. The goal was to design and develop a free software to facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. A comprehensive Medline/PubMed database search of drug interactions was performed. Articles that recognized any drug interactions in HIV disease were selected. The publications accessed were limited to human studies in English or Spanish, with full texts retrieved. Drug interactions were analyzed, assessed, and grouped into four levels of clinical relevance according to gravity and probability. Software to systematize the information regarding drug interactions and their clinical relevance was designed and developed. Overall, 952 different references were retrieved and 446 selected; in addition, 67 articles were selected from the citation lists of identified articles. A total of 2119 pairs of drug interactions were identified; of this group, 2006 (94.7%) were drug-drug interactions, 1982 (93.5%) had an identified pharmacokinetic mechanism, and 1409 (66.5%) were mediated by enzyme inhibition. In terms of clinical relevance, 1285 (60.6%) drug interactions were clinically significant in patients with HIV (levels 1 and 2). With this information, a software program that facilitates identification and assessment of the clinical relevance of antiretroviral drug interactions (SIMARV ® ) was developed. A free software package with information on 2119 pairs of antiretroviral drug interactions was designed and developed that could facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. [Exploration and demonstration study on drug combination from clinical real world].

    Science.gov (United States)

    Xie, Yan-ming; Wang, Lian-xin; Wang, Yong-yan

    2014-09-01

    Drug combination is extensive in the clinical real world,which is an important part and the inherent requirements of the post-marketing evaluation of traditional Chinese medicine (TCM). The key issues and technology include multi-domain and multi-disciplinary such as the rationality, efficacy and safety evaluation of combination drug starting from clinical real world, study on component in vivo and mechanism of combination drug, the risk/benefit assessment and cost-benefit evaluation of combination drug and so on. The topic has been studied as clinical demonstration on combination therapy of variety of diseases such as coronary heart disease, stroke, insomnia, depression, hepatitis, herpes zoster, psoriasis and ectopic pregnancy. Meanwhile, multi-disciplinary dynamic innovation alliance of clinical drug combination has been presented, which can promote the academic development and improving service ability and level of TCM.

  16. Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

    Science.gov (United States)

    Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

    2012-08-01

    Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

  17. Asymptomatic bacteriuria. Clinical significance and management.

    Science.gov (United States)

    Raz, Raul

    2003-10-01

    The clinical significance and management of asymptomatic bacteriuria (ASB) differs according to different groups of patients. ASB requires antibiotic treatment in pregnant women, children aged 5-6 years and prior to invasive genitourinary procedures. However, there is a consensus that ASB in the elderly, healthy school girls and young women, diabetic women and patients with indwelling catheters or intermittent catheterization has no clinical significance and antibiotic prescription is not indicated.

  18. Multiscale Modeling in the Clinic: Drug Design and Development

    Energy Technology Data Exchange (ETDEWEB)

    Clancy, Colleen E.; An, Gary; Cannon, William R.; Liu, Yaling; May, Elebeoba E.; Ortoleva, Peter; Popel, Aleksander S.; Sluka, James P.; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M.

    2016-02-17

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.

  19. Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

    Science.gov (United States)

    Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

    2018-01-01

    Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

  20. Fixed drug eruption at a dermatology clinic in Lagos, Nigeria

    Directory of Open Access Journals (Sweden)

    Olusola Olabisi Ayanlowo

    2015-01-01

    Full Text Available Background: Fixed drug eruption (FDE is common cutaneous drug eruption characterized by the development of one or more annular, oval, erythematous, and hyperpigmented patches as a result of systemic exposure to a drug. Drugs causing FDE vary with prevailing diseases and prescription pattern in different parts of the world. This study is aimed at reviewing cases of FDE seen at the dermatology outpatient clinic of Lagos University Teaching Hospital (LUTH over a 9-year period, highlighting the spectrum of drugs implicated and the clinical characteristics. Materials and Methods: Data were obtained from the clinic records and patients' case notes. These included the demographic details, duration of presentation, drugs implicated, and clinical characteristics. Results: FDE was diagnosed in 1.8% (295/16,160 of patients seen. There was a slight female preponderance. Antimalarials were the commonest group of medications implicated (51.0% followed by antibiotics (27.9%; analgesics (10.2%, herbal toothpaste (6.1%, and oral hypoglycemic agents (4.1%. Sulfonamides were the commonest group of drugs found in 78 patients (53.1% predominantly as sulfadoxine/pyrimethamine antimalarials and trimethoprim/sulfamethoxazole antibiotics (co-trimoxazole. Conclusion: Concerted efforts are needed to discourage over-the-counter sales and purchase of nonprescription sulfonamide-based medications. A change in prescription pattern from sulfonamides to other classes of antimalarials and antibiotics is desirable and/or recommended. Patients should inform their caregivers at any point of care about their reaction to drugs. It is advised that they have a list of common implicating drugs and they wear a medic alert or carry an ID card bearing this information.

  1. Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk.

    Science.gov (United States)

    Mignot, M A; Taisne, N; Legroux, I; Cortet, B; Paccou, J

    2017-12-01

    A cohort of 183 postmenopausal women, who had either discontinued or continued bisphosphonates (BPs) after first-line therapy, was used to investigate the relationships between "drug holiday" and clinical fracture. The risk of new clinical fractures was found to be 40% higher in women who had taken a BP "drug holiday." BPs are the most widely used treatment for postmenopausal osteoporosis. The optimal treatment duration, however, remains unclear. The purpose of this study was to evaluate the fracture risk in postmenopausal women with osteoporosis after discontinuing BP treatment (BP "drug holiday"). A retrospective analysis was performed at Lille University Hospital (LUH) on postmenopausal women with osteoporosis who had taken a "drug holiday" or continued treatment after first-line BP therapy (3 to 5 years). The occurrence of new clinical fractures during follow-up was also explored. Cox proportional hazards models were used to investigate the relationships between BP "drug holiday" and the occurrence of clinical fractures, while controlling for confounding factors. Survival without new clinical fractures was analyzed using Kaplan-Meier curves and log-rank tests. One hundred eighty-three women (mean age: 61.8 years; SD: 8.7) who had previously undergone BP treatment for 3 to 5 years were enrolled in our study. The patients had received alendronate (n = 81), risedronate (n = 73), zoledronic acid (n = 20), and ibandronate (n = 9). In 166 patients ("drug holiday" group: n = 31; continuous-treatment group: n = 135), follow-up ranged from 6 to 36 months (mean duration: 31.8 months; SD: 8.2). The incidences of new clinical fractures during follow-up were 16.1% (5/31) and 11.9% (16/135). After full adjustment, the hazard ratio of new clinical fractures among "drug holiday" patients was 1.40 (95% CI: 1.12-1.60; p = 0.0095). After first-line BP therapy in postmenopausal women with osteoporosis, the risk of new clinical fractures was 40% higher in

  2. [Current clinical significance of anaerobic bacteremia].

    Science.gov (United States)

    Jirsa, Roman; Marešová, Veronika; Brož, Zdeněk

    2010-10-01

    to estimate tje current clinical significance of anaerobic bacteremia in a group of Czech hospitals. this retrospective analysis comprised 8 444 anaerobic blood cultures in patients admitted to four Czech hospitals between 2004 and 2007. in 16 patients, blood cultures yielded significant anaerobic bacteria. Thus, anaerobic bacteremia accounted for less than 2 % of clinically significant bacteremia. Four patients (18 %) died but none of the deaths could be clearly attributable to anaerobic bacteria in the bloodstream. The most common comorbidities predisposing to anaerobic bacteremia and the most frequent sources of infection were similar to those reported by other authors. The majority of anaerobic bacteremia cases were due to gram-negative bacteria, followed by Clostridium perfringens and, surprisingly, Eubacterium spp. (particularly Eubacterium lentum). anaerobic bacteremia remains rare. The comparison of our data with those by other authors suggests that (despite the reported high mortality) the actual clinical significance of anaerobic bacteremia is rather controversial and that the anaerobic bacteremia might not correspond to more serious pathogenic role of the anaerobic bacteria as the source of infection.

  3. Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

    Science.gov (United States)

    Mauri, M C; Di Pace, C; Reggiori, A; Paletta, S; Colasanti, A

    2017-10-01

    The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Effectiveness of a Clinical Skills Workshop for drug-dosage calculation in a nursing program.

    Science.gov (United States)

    Grugnetti, Anna Maria; Bagnasco, Annamaria; Rosa, Francesca; Sasso, Loredana

    2014-04-01

    Mathematical and calculation skills are widely acknowledged as being key nursing competences if patients are to receive care that is both effective and safe. Indeed, weaknesses in mathematical competence may lead to the administration of miscalculated drug doses, which in turn may harm or endanger patients' lives. However, little attention has been given to identifying appropriate teaching and learning strategies that will effectively facilitate the development of these skills in nurses. One such approach may be simulation. To evaluate the effectiveness of a Clinical Skills Workshop on drug administration that focused on improving the drug-dosage calculation skills of second-year nursing students, with a view to promoting safety in drugs administration. A descriptive pre-post test design. Educational. Simulation center. The sample population included 77 nursing students from a Northern Italian University who attended a 30-hour Clinical Skills Workshop over a period of two weeks. The workshop covered integrated teaching strategies and innovative drug-calculation methodologies which have been described to improve psychomotor skills and build cognitive abilities through a greater understanding of mathematics linked to clinical practice. Study results showed a significant improvement between the pre- and the post-test phases, after the intervention. Pre-test scores ranged between 0 and 25 out of a maximum of 30 points, with a mean score of 15.96 (SD 4.85), and a median score of 17. Post-test scores ranged between 15 and 30 out of 30, with a mean score of 25.2 (SD 3.63) and a median score of 26 (pstudy shows that Clinical Skills Workshops may be tailored to include teaching techniques that encourage the development of drug-dosage calculation skills, and that training strategies implemented during a Clinical skills Workshop can enhance students' comprehension of mathematical calculations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Cost-effectiveness analysis of microdose clinical trials in drug development.

    Science.gov (United States)

    Yamane, Naoe; Igarashi, Ataru; Kusama, Makiko; Maeda, Kazuya; Ikeda, Toshihiko; Sugiyama, Yuichi

    2013-01-01

    Microdose (MD) clinical trials have been introduced to obtain human pharmacokinetic data early in drug development. Here we assessed the cost-effectiveness of microdose integrated drug development in a hypothetical model, as there was no such quantitative research that weighed the additional effectiveness against the additional time and/or cost. First, we calculated the cost and effectiveness (i.e., success rate) of 3 types of MD integrated drug development strategies: liquid chromatography-tandem mass spectrometry, accelerator mass spectrometry, and positron emission tomography. Then, we analyzed the cost-effectiveness of 9 hypothetical scenarios where 100 drug candidates entering into a non-clinical toxicity study were selected by different methods as the conventional scenario without MD. In the base-case, where 70 drug candidates were selected without MD and 30 selected evenly by one of the three MD methods, incremental cost-effectiveness ratio per one additional drug approved was JPY 12.7 billion (US$ 0.159 billion), whereas the average cost-effectiveness ratio of the conventional strategy was JPY 24.4 billion, which we set as a threshold. Integrating MD in the conventional drug development was cost-effective in this model. This quantitative analytical model which allows various modifications according to each company's conditions, would be helpful for guiding decisions early in clinical development.

  6. Patient compliance with drug therapy in schizophrenia. Economic and clinical issues.

    Science.gov (United States)

    Lindström, E; Bingefors, K

    2000-08-01

    The effectiveness of drug treatment in clinical practice is considerably lower than the efficacy shown in controlled studies. The lower effectiveness in practice presumably leads to lower cost effectiveness of drug treatment in real-life situations compared with that demonstrated by studies based on results from controlled trials. Improved cost effectiveness in routine clinical practice would be a significant advantage in the treatment of schizophrenia, one of the most costly diseases in society. The aetiology of schizophrenia is unknown, and there is no cure. The main aims of therapy with antipsychotic medication include the effective relief of symptoms without the introduction of adverse effects or serious adverse events, improved quality of life, cost effectiveness and a positive long term outcome. The older classical antipsychotic drugs do not always meet these requirements because of their well-known limitations, such as a lack of response in a subgroup of individuals with schizophrenia and intolerable adverse effects. There has long been a need for new antipsychotics that can ameliorate more symptoms and have no or few adverse effects. Some of the recently introduced antipsychotics have been shown to be more effective in certain clinical situations and to have a more favourable adverse effect profile than the classical antipsychotics. A major factor contributing to the lower effectiveness of drug treatment is noncompliance, which may be very high in schizophrenia. There are several factors influencing compliance, including drug type and formulation, patient, disease status, physician, health care system, community care and family. There have been very few studies of compliance improvement strategies in schizophrenia or, indeed, in medicine in general. Current methods are relatively complex and there are differing opinions on their effectiveness. There are several ways to increase compliance in schizophrenia--the evidence is strongest for psychoeducative

  7. Drug screening in clinical or forensic toxicology: are there differences?

    Science.gov (United States)

    Gerostamoulos, Dimitri; Beyer, Jochen

    2010-09-01

    Legal and medical practitioners need to remember that, with respect to drug analysis, there are two distinct disciplines in analytical toxicology concerned with human biological matrices, namely clinical and forensic toxicology. Both fields use similar analytical techniques designed to detect and quantify drugs, chemicals and poisons in fluids or tissues. In clinical toxicology, analytical results help to specify the appropriate treatment of a poisoned or intoxicated patient. In forensic toxicology, the results often play a vital role in determining the possible impairment or behavioural changes in an individual, or the contribution of drugs or poisons to death in a medico-legal investigation. This column provides an overview of the similarities and differences inherent in clinical and forensic toxicology.

  8. Transdermal drug delivery: approaches and significance

    OpenAIRE

    Murthy, SATHYANARAYANA

    2012-01-01

    S Narasimha MurthyDepartment of Pharmaceutics, The University of Mississippi, USATransdermal drug delivery systems deliver drugs through the skin as an alternative to oral, intravascular, subcutaneous, and transmucosal routes. Potential advantages of transdermal delivery include, but are not limited to, elimination of first-pass metabolism, steady delivery/blood levels, better patient compliance, reduced systemic drug interactions, possible dose intervention, avoidance of medically assisted d...

  9. Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov

    Directory of Open Access Journals (Sweden)

    Eric Wen Su

    2017-03-01

    Full Text Available Drug repositioning (i.e., drug repurposing is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics and PolyAnalyst (Megaputer were utilized. An I2E query extracts “Serious Adverse Events” (SAE data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer.

  10. Bioanalysis, metabolism & clinical pharmacology of antiretroviral drugs

    NARCIS (Netherlands)

    Heine, R. ter

    2009-01-01

    The aims of all studies described in this thesis were to develop new bioanalytical and more patient friendly methods for studying the clinical pharmacology of antiretroviral drugs and to ultimately improve antiretroviral treatment.

  11. The microculture-kinetic (MiCK) assay: the role of a drug-induced apoptosis assay in drug development and clinical care.

    Science.gov (United States)

    Bosserman, Linda; Prendergast, Franklyn; Herbst, Roy; Fleisher, Martin; Salom, Emery; Strickland, Steven; Raptis, Anastasios; Hallquist, Allan; Perree, Mathieu; Rajurkar, Swapnil; Karimi, Misagh; Rogers, Karl; Davidson, Dirk; Willis, Carl; Penalver, Manuel; Homesley, Howard; Burrell, Matthew; Garrett, Audrey; Rutledge, James; Chernick, Michael; Presant, Cary A

    2012-08-15

    A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development. ©2012 AACR.

  12. Perception of various stakeholders regarding clinical drug trial industry in India

    Directory of Open Access Journals (Sweden)

    Rakesh M Parikh

    2011-01-01

    Full Text Available Context: Though India has been thought to be an ideal destination for conduct of clinical drug trials, other smaller countries seem to be doing better. The pace of growth observed during 2005-2009 seems to be plateaued in 2010. Aims: There is an urgent need for introspection and corrective actions. Materials and Methods: An online survey was conducted among various stakeholders from clinical drug trial industry in India regarding their perception about clinical drug trial industry in India. Respondents were requested to rate training of investigator sites, industry, performance of regulatory, etc. Results: Majority of respondent felt that the clinical drug trial industry in India is growing, though India is not utilizing its full potential. Lack of trained investigators and delay in regulatory approvals came out as biggest hurdles. Conclusions: Urgent steps need to be taken in terms of proper training of all stakeholders. Regulatory bodies ought to bring about some radical changes in the system so as to match the other competing nations.

  13. A proposal for a pharmacokinetic interaction significance classification system (PISCS) based on predicted drug exposure changes and its potential application to alert classifications in product labelling.

    Science.gov (United States)

    Hisaka, Akihiro; Kusama, Makiko; Ohno, Yoshiyuki; Sugiyama, Yuichi; Suzuki, Hiroshi

    2009-01-01

    Pharmacokinetic drug-drug interactions (DDIs) are one of the major causes of adverse events in pharmacotherapy, and systematic prediction of the clinical relevance of DDIs is an issue of significant clinical importance. In a previous study, total exposure changes of many substrate drugs of cytochrome P450 (CYP) 3A4 caused by coadministration of inhibitor drugs were successfully predicted by using in vivo information. In order to exploit these predictions in daily pharmacotherapy, the clinical significance of the pharmacokinetic changes needs to be carefully evaluated. The aim of the present study was to construct a pharmacokinetic interaction significance classification system (PISCS) in which the clinical significance of DDIs was considered with pharmacokinetic changes in a systematic manner. Furthermore, the classifications proposed by PISCS were compared in a detailed manner with current alert classifications in the product labelling or the summary of product characteristics used in Japan, the US and the UK. A matrix table was composed by stratifying two basic parameters of the prediction: the contribution ratio of CYP3A4 to the oral clearance of substrates (CR), and the inhibition ratio of inhibitors (IR). The total exposure increase was estimated for each cell in the table by associating CR and IR values, and the cells were categorized into nine zones according to the magnitude of the exposure increase. Then, correspondences between the DDI significance and the zones were determined for each drug group considering the observed exposure changes and the current classification in the product labelling. Substrate drugs of CYP3A4 selected from three therapeutic groups, i.e. HMG-CoA reductase inhibitors (statins), calcium-channel antagonists/blockers (CCBs) and benzodiazepines (BZPs), were analysed as representative examples. The product labelling descriptions of drugs in Japan, US and UK were obtained from the websites of each regulatory body. Among 220

  14. [Relevance of drug use in clinical manifestations of schizophrenia].

    Science.gov (United States)

    Arias Horcajadas, F; Sánchez Romero, S; Padín Calo, J J

    2002-01-01

    To study the association between drugs use with schizophrenia clinical manifestations. The sample consists of 82 out-patients with schizophrenia, between 18 and 45 years old. They were evaluated with Addiction Severity Index (ASI) and with Positive and Negative Syndrome Scale (PANSS). A 6 months follow up was carried out. 37,8% patients had lifetime drug dependence (including alcohol and others drugs except for tobacco). The prevalence of dependence for the different drugs were: opioids 9,8%, cocaine 11%, alcohol 29,3%, cannabis 24,4%, tobacco 68,3%, caffeine 15,9%. Drug dependent had more family and legal problems. At the multiple regression analysis it was observed that cannabis and tobacco dependence was associated with a decrease in the PANSS negative symptoms subscale, and on the contrary, alcohol dependence produces a similar intensity increase at that scoring. We don't detect any clinical relevance effects over positive symptoms. Cannabis and tobacco may improve schizophrenia negative symptoms or neuroleptic secondary effects or patients with few negative symptoms may have more predisposition to the use, on the contrary alcohol use can impairment those symptoms.

  15. Drug side effect extraction from clinical narratives of psychiatry and psychology patients.

    Science.gov (United States)

    Sohn, Sunghwan; Kocher, Jean-Pierre A; Chute, Christopher G; Savova, Guergana K

    2011-12-01

    To extract physician-asserted drug side effects from electronic medical record clinical narratives. Pattern matching rules were manually developed through examining keywords and expression patterns of side effects to discover an individual side effect and causative drug relationship. A combination of machine learning (C4.5) using side effect keyword features and pattern matching rules was used to extract sentences that contain side effect and causative drug pairs, enabling the system to discover most side effect occurrences. Our system was implemented as a module within the clinical Text Analysis and Knowledge Extraction System. The system was tested in the domain of psychiatry and psychology. The rule-based system extracting side effects and causative drugs produced an F score of 0.80 (0.55 excluding allergy section). The hybrid system identifying side effect sentences had an F score of 0.75 (0.56 excluding allergy section) but covered more side effect and causative drug pairs than individual side effect extraction. The rule-based system was able to identify most side effects expressed by clear indication words. More sophisticated semantic processing is required to handle complex side effect descriptions in the narrative. We demonstrated that our system can be trained to identify sentences with complex side effect descriptions that can be submitted to a human expert for further abstraction. Our system was able to extract most physician-asserted drug side effects. It can be used in either an automated mode for side effect extraction or semi-automated mode to identify side effect sentences that can significantly simplify abstraction by a human expert.

  16. Imaging drugs with and without clinical analgesic efficacy.

    Science.gov (United States)

    Upadhyay, Jaymin; Anderson, Julie; Schwarz, Adam J; Coimbra, Alexandre; Baumgartner, Richard; Pendse, G; George, Edward; Nutile, Lauren; Wallin, Diana; Bishop, James; Neni, Saujanya; Maier, Gary; Iyengar, Smriti; Evelhoch, Jeffery L; Bleakman, David; Hargreaves, Richard; Becerra, Lino; Borsook, David

    2011-12-01

    The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

  17. PP22. PROGRESSING RADIOTHERAPY-DRUG COMBINATIONS TOWARDS EARLY PHASE CLINICAL TRIALS

    Science.gov (United States)

    Jones, Dr Hazel; Stock, Dr Julie; Chalmers, Prof Anthony

    2017-01-01

    Abstract The Radiotherapy-Drug Combinations consortium (RaDCom) works with UK-based investigators to design and deliver high quality preclinical projects evaluating specific radiotherapy-drug combinations. We have several collaborations with industry, from in vitro projects to understand the novel agent in the context of radiobiology, through to preclinical studies that will generate data to support the development of radiotherapy combination trials. RaDCom facilitates the coordination of industry interactions, triage new proposals, monitor active projects, and engages with the radiotherapy community to promote collaboration and networking (via a capability map). The CRUK New Agents Committee Preclinical Combination Grant scheme provides one of the funding options for these studies, with the potential to feed into early phase clinical trials via the ECMC Combinations Alliance. RaDCom also supports broader radiotherapy research initiatives, by working to improve preclinical quality assurance and identifying a route to registration for radiotherapy-drug treatments. These activities will place the UK at the forefront of radiotherapy-drug preclinical research and provide a significant incentive for pharmaceutical companies to invest in this area and utilise the RaDCom network. Further information can be found on our webpage: http://ctrad.ncri.org.uk/research-support/radiation-drug-combinations-radcom Successful projects from RaDCom can then move into early phase combinations trials within the Combinations Alliance. The Combinations Alliance supports early phase combination studies in the UK via the ECMC (Experimental Cancer Medicine Centres) network. It focuses on translational research, and enables clinical project teams to work with disease experts to set up investigator led trials. The CRUK Centre of Drug Development (CDD) supports these studies with further management and coordination ensuring more robust timelines and delivery. The Combinations Alliance framework

  18. Liposomal drug delivery system from laboratory to clinic

    Directory of Open Access Journals (Sweden)

    Kshirsagar N

    2005-01-01

    Full Text Available The main objective of drug delivery systems is to deliver a drug effectively, specifically to the site of action and to achieve greater efficacy and minimise the toxic effects compared to conventional drugs. Amongst various carrier systems, liposomes have generated a great interest because of their versatility. Liposomes are vesicular concentric bilayered structures, which are biocompatible, biodegradable and nonimmumnogenic. They can control the delivery of drugs by targeting the drug to the site of action or by site avoidance drug delivery or by prolonged circulation of drugs. Amphotericin B (Amp B remains the drug of choice in most systemic mycoses and also as a second line treatment for Kala azar. However, its toxic effects often limit its use. Although the liposome delivery system has been tried for several drugs, only a few have been used in patients due to the slow development of necessary large-scale pharmaceutical procedures. This paper reviews the development of the technique for liposomal Amphotericin B (L-Amp-LRC-1, FungisomeTM drug delivery system in our laboratory in collaboration with the department of Biochemistry, Delhi University in India and proving the safety and efficacy of this preparation in clinical practice. It also attempts to compare the efficacy and benefits of our product for Indian patients with those of similar products and it includes facts from the publications that flowed from our work. As compared to conventional Amp B, Fungisome is infused over a much shorter period requiring a smaller volume and no premedication. It was found to be safe in patients who had developed serious unacceptable toxicity with conventional Amp B. In renal transplant patients, Fungisome did not produce any nephrotoxicity. Fungisome is effective in fungal infections resistant to fluconazole, conventional Amp B and in virgin and resistant cases of visceral leishmaniasis. The cost of any drug is of great significance, especially in India

  19. Clinical significance of neonatal menstruation.

    Science.gov (United States)

    Brosens, Ivo; Benagiano, Giuseppe

    2016-01-01

    Past studies have clearly shown the existence of a spectrum of endometrial progesterone responses in neonatal endometrium, varying from proliferation to full decidualization with menstrual-like shedding. The bleedings represent, similar to what occurs in adult menstruation, a progesterone withdrawal bleeding. Today, the bleeding is completely neglected and considered an uneventful episode of no clinical significance. Yet clinical studies have linked the risk of bleeding to a series of events indicating fetal distress. The potential link between the progesterone response and major adolescent disorders requires to be investigated by prospective studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. [Clinical views from the forefront of immunosuppressive drugs].

    Science.gov (United States)

    Kobayashi, Eiji

    2005-11-01

    Recently, many immunosuppressants have been developed and some of them have already been introduced in clinical organ transplantation. With a new concept of immunoregulation, which focuses on prevention of rejection and over-immunosuppression, the latest protocol has been conducted. Chimeric or humanized antibodies targeting the lymphocyte surface molecule such as CD19, 20, 25, 40, and 52 are administrated in the induction phase, and calcineurin inhibitors (cyclosporin and tacrolimus) are used as key drugs. For tapering the doses of them, the combined application of anti-metabolic agents of azathioprine, mizoribine, or mycophenolate mofetil (MMF) has been proved effective. Lymphocyte forming drugs induce unique immunoregulation, targeting at sphingosine 1-phosphate (SlP) receptors. FTY720 is now in the procedure of clinical trial to compare with MMF. KRP203 is also a candidate for more specific SIP receptor agonist. In this issue, I reviewed the recent immunosuppressive strategy and focused on the advance of novel immunosuppressive drugs.

  1. 77 FR 49449 - Food and Drug Administration Clinical Trial Requirements, Compliance, and Good Clinical Practice...

    Science.gov (United States)

    2012-08-16

    ... investigator initiated research. Topics for discussion include the following: (1) What FDA Expects in a...] Food and Drug Administration Clinical Trial Requirements, Compliance, and Good Clinical Practice...-sponsorship with the Society of Clinical Research Associates (SoCRA) is announcing a public workshop. The...

  2. Phase II clinical development of new drugs

    CERN Document Server

    Ting, Naitee; Ho, Shuyen; Cappelleri, Joseph C

    2017-01-01

    This book focuses on how to appropriately plan and develop a Phase II program, and how to design Phase II clinical trials and analyze their data. It provides a comprehensive overview of the entire drug development process and highlights key questions that need to be addressed for the successful execution of Phase II, so as to increase its success in Phase III and for drug approval. Lastly it warns project team members of the common potential pitfalls and offers tips on how to avoid them.

  3. Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

    Science.gov (United States)

    Nyunt, Myat Htut; Han, Jin-Hee; Wang, Bo; Aye, Khin Myo; Aye, Kyin Hla; Lee, Seong-Kyun; Htut, Ye; Kyaw, Myat Phone; Han, Kay Thwe; Han, Eun-Taek

    2017-03-16

    One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance. While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria. To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, was conducted. A total of 906 from nine study sites were included in retrospective analysis and 208 from three study sites in prospective study. Uncomplicated vivax mono-infected patients were recruited and monitored with longitudinal follow-up until day 28 after treatment with chloroquine. Amplification and sequence analysis of molecular markers, such as mutations in pvcrt-O, pvmdr1, pvdhps and pvdhfr, were done in day-0 samples in prospective study. Clinical failure cases were found only in Kawthaung, southern Myanmar and western Myanmar sites within 2009-2016. Chloroquine resistance markers, pvcrt-O 'AAG' insertion and pvmdr1 mutation (Y976F) showed higher mutant rate in southern and central Myanmar than western site: 66.7, 72.7 vs 48.3% and 26.7, 17.0 vs 1.7%, respectively. A similar pattern of significantly higher mutant rate of antifolate resistance markers, pvdhps (S382A, K512M, A553G) and pvdhfr (F57L/I, S58R, T61M, S117T/N) were noted. Although clinical failure rate was low, widespread distribution of chloroquine and antifolate resistance molecular makers alert to the emergence and spread of drug resistance vivax malaria in Myanmar. Proper strategy and action plan to eliminate and contain the resistant strain strengthened together with clinical and molecular surveillance on drug resistance vivax is recommended.

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

    Directory of Open Access Journals (Sweden)

    José A G Agúndez

    2014-08-01

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

  5. Respiratory drugs prescribed off-label among children in the outpatient clinics of a hospital in Malaysia.

    Science.gov (United States)

    Mohamad, Nurul Fadilah; Mhd Ali, Adliah; Mohamed Shah, Noraida

    2015-02-01

    Prescribing medicines in an unlicensed and off-label manner for children is a widespread practice around the world. To determine the extent and predictors of off-label respiratory drug prescriptions for children in the outpatient clinics of a hospital in Malaysia. Outpatient clinics at the Universiti Kebangsaan Malaysia Medical Centre, a tertiary teaching hospital in Malaysia. The pharmacy-based computer system and medical records of the patients were utilized to collect data from 220 pediatric patients who were prescribed at least one respiratory drug from July 2011 to December 2011. Characteristics of the off-label respiratory drug prescriptions were measured. A total of 134 children (60.9 %) received at least one respiratory drug prescribed in an off-label manner. The most common reasons for the off-label prescribing of drugs were off-label use by indication (31.5 %), followed by higher than the recommended dose (24.9 %) and lower than the recommended frequency (17.1 %). Diphenhydramine was the most common respiratory drug prescribed off-label. The number of medications prescribed was the only significant predictor of off-label prescription of respiratory drugs. Pediatric patients receiving 4-6 medications were 7.8 times more likely to receive at least one off-label respiratory drug compared to pediatric patients that received 1-3 medications (OR 7.8, 95 % CI 1.74-37.44). There was substantial prescribing of respiratory drugs for children in an off-label manner at the outpatient clinics at the Universiti Kebangsaan Malaysia Medical Centre. This highlights the need for more research to be carried out on respiratory drugs in the pediatric population.

  6. Candiduria: A review of clinical significance and management

    International Nuclear Information System (INIS)

    Bukhary, Z.A.

    2008-01-01

    Candiduria is a common nosocomial infection afflicting the urinary tract. This review is aimed at providing an updated summary of the problem in hospitalized adult patients. A review of English Medline literature published between January 1970 until June 2007 was performed. Reviews, clinical trials and case-controlled studies in adult patients were included. Risk factors for candiduria included urinary indwelling catheters, use of antibiotics, elderly age, underlying genitourinary tract abnormality, previous surgery and presence of diabetes mellitus. Presence of candiduria may represent only colonization and there are no consistent diagnostic criteria to define significant infection. Candiduria may not be associated with candidemia and most cases are asymptomatic. Asymptomatic canididuria is usually benign, and does not require local or systemic antifungal therapy. Physicians need to confirm the infection by a second sterile urine sample, adopt non-pharmacologic interventions and modify risk factors. Mortality rate can be high particularly in debilitated patients and awareness to validate candiduria is necessary to stratify treatment according to patient status. Appropriate use of antifungal drugs, when indicated, should not replace correction of the underlying risk factors. Treatment of symptomatic candiduria is less controversial and easier. (author)

  7. Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

    Directory of Open Access Journals (Sweden)

    Ida Aka

    2017-11-01

    Full Text Available Cytochrome P450 (CYP enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug–CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC data and surveyed 10 years of electronic health records (EHR data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug–CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone. For these drugs, reports of the drug–CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole. For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

  8. Clinical significance of anismus in encopresis.

    Science.gov (United States)

    Catto-Smith, A G; Nolan, T M; Coffey, C M

    1998-09-01

    Treatments designed to relieve paradoxical contraction of the anal sphincters during defecation (anismus) have had limited success in children with encopresis. This has raised doubts as to the clinical relevance of this diagnosis in childhood as anorectal dysfunction. Our aim was to determine whether, in patients who had treatment-resistant encopresis, the presence of electromyographic anismus was associated with increased faecal retention. Sixty-eight children with soiling (mean age 8.7+/-2.06 years) were assessed by clinical examination, abdominal radiography and then with anorectal manometry. Patients with electromyographic anismus (n=32; 47%) had significantly increased radiographic rectal faecal retention and were significantly less likely to be able to defecate water-filled balloons. There were no significant differences in response to prior therapy, history of primary encopresis, behavioural adjustment or in sociodemographic data. Our results suggest that electromyographic anismus is associated with obstructed defecation and faecal retention.

  9. Drug-eluting stents: from bench-top to clinical research

    NARCIS (Netherlands)

    Basalus, Mounir Welson Zakhary

    2013-01-01

    The development of drug-eluting stents (DES) has improved the invasive treatment of obstructive coronary artery disease by reducing both, restenosis rate and need for reinterventions. This success resulted in a widespread utilization of DES in clinical practice and entailed many clinical research

  10. The thresholds for statistical and clinical significance

    DEFF Research Database (Denmark)

    Jakobsen, Janus Christian; Gluud, Christian; Winkel, Per

    2014-01-01

    BACKGROUND: Thresholds for statistical significance are insufficiently demonstrated by 95% confidence intervals or P-values when assessing results from randomised clinical trials. First, a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does...... not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore...... of the probability that a given trial result is compatible with a 'null' effect (corresponding to the P-value) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation; (3) adjust the confidence intervals and the statistical significance...

  11. Ethical and social significance of microdose clinical trial. Background of guidance draw-up

    International Nuclear Information System (INIS)

    Kurihara, Chieko

    2008-01-01

    Microdose clinical trial (MCT) aims to elucidate only the mass balance (pharmacokinetics, PK) in human of a new drug candidate compound before the first Phase I trial and is going to be approved by the authority MHLW in Japan. In MCT, the compound is administered in human in an extremely small amount (microdose) that is unexpected to exert its pharmacological effect ( 14 C) labeled compound is administered, LC/MS/MS with non-isotopic compound and positron emission tomography (PET) with compound labeled by positron emitter like 11 C, 13 N, etc. Under promotions by support and demand of related scientific societies and corporations in Japan as well as by ICH agreement, MHLW has defined MCT as one of clinical trials linked with GMP standard of drug candidate for clinical trials, with concept for assessment of internal radiation exposure, and with consistency with handling of radioisotopes, because of ethical consideration for volunteers to be enrolled. MCT can expectedly improve the cost- and time-effectiveness of new drug development, which ultimately leads to earlier supply of superior medicines. (R.T.)

  12. Therapeutic drug monitoring in epilepsy clinic: a multi-disciplinary approach

    Directory of Open Access Journals (Sweden)

    Sunee Lertsinudom

    2014-12-01

    Full Text Available Epilepsy is a common public health problem and needs multi-disciplinary treatment. Therapeutic drug monitoring (TDM is one of step of the multi-disciplinary treatment in epilepsy at Epilepsy clinic, Khon Kaen University (Thailand. The TDM service has been established since 2008. Here, we aimed to study the roles of TDM order and epilepsy control. This is a prospective descriptive study in which data collection was done from January 1 to December 31, 2010, the period when pharmacists took part in assessing the appropriateness in measurement and interpretation of TDM in order to provide suggestions for physicians. The 112 patients under study had an average age of 38.21±15.36 years; 254 samples were collected for therapeutic drug monitoring; phenytoin was submitted mostly for drug monitoring at 46.46%; 44.49% of sub-missions for drug level monitoring were made owing to a suspected sub-therapeutic level. Associations were found between reasons of sending samples for drug level monitoring and the measured drug levels, i.e., 66.67% of drug levels found was so low that they were undetectable in sample for patients’ compliance investigation and 38.94% of the drug levels were found to be sub-therapeutic as for the case where submission of samples was done because of suspected sub-therapeutic level, 40% of the cases were found to be in toxicity range in the cases with suspected over-therapeutic levels and monitoring levels, 58.25% were found to be within the therapeutic range. Pharmacists used the interpreted results in patients’ care by recommending physicians to monitor therapeutic drug closely, to adjust the dosage of drugs, and to recommend checking patients’ compliance in their use of drugs at 56.5, 38.9, and 4.3%, respectively. Physicians’ responses were found to be absolute follow, partial follow and not follow at 77.95, 11.03, and 7.48%, respectively. In conclusion, associations were found between reasons of TDM order and measured drug

  13. Deciphering the clinical effect of drugs through large-scale data integration

    DEFF Research Database (Denmark)

    Kjærulff, Sonny Kim

    . This work demonstrates the power of a strategy that uses clinical data mining in association with chemical biology in order to reduce the search space and aid identification of novel drug actions. The second article described in chapter 3 outlines a high confidence side-effect-drug interaction dataset. We...... demonstrates the importance of using high-confidence drug-side-effect data in deciphering the effect of small molecules in humans. In summary, this thesis presents computational systems chemical biology approaches that can help identify clinical effects of small molecules through large-scale data integration...

  14. Melatonin: a chemical photoperiodic signal with clinical significance in humans.

    Science.gov (United States)

    Pang, S F; Pang, C S; Poon, A M; Lee, P P; Liu, Z M; Shiu, S Y

    1998-03-01

    Secretion of pineal melatonin exhibits a diumal rhythm and a seasonal rhythm in humans. Night-time melatonin is high at 3-5 year-old and decreases with age. Many drugs and pathological conditions also change melatonin levels in the circulation. Melatonin has a mild sedative effect and has been used effectively in synchronizing the sleep-wake cycle of patients with sleep disorders. Immunoenhancing, anti-cancer, anti-aging and anti-oxidant effects of melatonin have been proposed. Recent studies suggest that melatonin receptors are present in central and peripheral tissues. The importance of melatonin receptors on the nervous, reproductive, immune and renal functions is implicated. Studies on the molecular biology, physiology and pathology of melatonin receptors in different tissues are progressing rapidly. The physiological and pathological changes in melatonin secretion, multifarious melatonin actions, and diverse melatonin receptors reported suggest that melatonin is a photoperiodic signal with clinical significance in humans.

  15. Prevalence of hypersensitivity to dental local anesthetic drugs in patients referred to Tehran Allergy clinic (2005-2007

    Directory of Open Access Journals (Sweden)

    Akhlaghi F.

    2009-03-01

    Full Text Available "nBackground and Aim: According to controversies in the prevalence of hypersensitivity to dental local anesthetic drugs and patients who claim hypersensitivity to these drugs, the aim of this study was to determine the prevalence of hypersensitivity to dental amide local anesthetic drugs in patients referred to Tehran Allergy Clinic in 2005-2007. "nMaterials and Methods: In this Study (Review of existing data, records of 130 patients who were referred to "Tehran allergy Clinic" (2005-2007 were studied. "nResults: The average age of patients was 29.5±18.8 years. 34% of cases showed positive skin reactions to at least one of the tested Lidocain concentrations and 10% of cases showed positive skin reactions to at least one of the tested Prilocain concentrations. There was a statistically significant difference in hypersensitivity to Lidocain 0.01 and 0.001 (p=0.017 and also between Lidocain 0.001 and 0.0001 (p<0.01. There was no statistically significant difference between other tested drug concentrations (p>0.05. "nConclusion: Many patients with history of hypersensitivity, show positive reaction to local dental anesthetic drugs. Prilocain hypersensitivity reactions are less than Lidocain. So application of Prilocain accompanies with less risk but its application should not be considered completely safe.

  16. Which drug or drug delivery system can change clinical practice for brain tumor therapy?

    OpenAIRE

    Siegal, Tali

    2013-01-01

    The prognosis and treatment outcome for primary brain tumors have remained unchanged despite advances in anticancer drug discovery and development. In clinical trials, the majority of promising experimental agents for brain tumors have had limited impact on survival or time to recurrence. These disappointing results are partially explained by the inadequacy of effective drug delivery to the CNS. The impediments posed by the various specialized physiological barriers and active efflux mechanis...

  17. Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism

    Directory of Open Access Journals (Sweden)

    Seung Ha Lee

    2017-01-01

    Full Text Available Objective Patients with drug-induced parkinsonism (DIP may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. Methods Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. Results Twenty-eight patients had normal (Group I and 13 patients had abnormal (Group II scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040. Three patients of Group I and six of Group II had hyposmia (p = 0.018. After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. Conclusion None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.

  18. Effect of a drug allergy educational program and antibiotic prescribing guideline on inpatient clinical providers' antibiotic prescribing knowledge.

    Science.gov (United States)

    Blumenthal, Kimberly G; Shenoy, Erica S; Hurwitz, Shelley; Varughese, Christy A; Hooper, David C; Banerji, Aleena

    2014-01-01

    Inpatient providers have varying levels of knowledge in managing patients with drug and/or penicillin (PCN) allergy. Our objectives were (1) to survey inpatient providers to ascertain their baseline drug allergy knowledge and preparedness in caring for patients with PCN allergy, and (2) to assess the impact of an educational program paired with the implementation of a hospital-based clinical guideline. We electronically surveyed 521 inpatient providers at a tertiary care medical center at baseline and again 6 weeks after an educational initiative paired with clinical guideline implementation. The guideline informed providers on drug allergy history taking and antibiotic prescribing for inpatients with PCN or cephalosporin allergy. Of 323 unique responders, 42% (95% CI, 37-48%) reported no prior education in drug allergy. When considering those who responded to both surveys (n = 213), we observed a significant increase in knowledge about PCN skin testing (35% vs 54%; P allergy over time (54% vs 80%; P allergy was severe significantly improved (77% vs 92%; P = .03). Other areas, including understanding absolute contraindications to receiving a drug again and PCN cross-reactivity with other antimicrobials, did not improve significantly. Inpatient providers have drug allergy knowledge deficits but are interested in tools to help them care for inpatients with drug allergies. Our educational initiative and hospital guideline implementation were associated with increased PCN allergy knowledge in several crucial areas. To improve care of inpatients with drug allergy, more research is needed to evaluate hospital policies and sustainable educational tools. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  19. Guanidino-containing drugs in cancer chemotherapy: biochemical and clinical pharmacology.

    Science.gov (United States)

    Ekelund, S; Nygren, P; Larsson, R

    2001-05-15

    The pharmacology and clinical application of three guanidino-containing compounds are reviewed in this commentary with special focus on a new member of this group of drugs, CHS 828 [N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N"-4-pyridylguanidine]. m-Iodobenzylguanidine (MIBG) and methylglyoxal bis(guanylhydrazone) (MGBG) have been extensively studied, preclinically as well as clinically, and have established use as anticancer agents. MIBG has structural similarities to the neurotransmitter, norepinephrine, and MGBG is a structural analog of the natural polyamine spermidine. CHS 828 is a pyridyl cyanoguanidine newly recognized as having cytotoxic effects when screening antihypertensive compounds. Apart from having the guanidino groups in common, there are many differences between these drugs in both structure and their mechanisms of action. However, they all inhibit mitochondrial function, a seemingly unique feature among chemotherapeutic drugs. In vitro in various cell lines and primary cultures of patient tumor cells and in vivo in various tumor models, CHS 828 has cytotoxic properties unlike any of the standard cytotoxic drugs with which it has been compared. Among these are non-cross-resistance to standard drugs and pronounced activity in tumor models acknowledged to be highly drug-resistant. Similar to MIBG, CHS 828 induces an early increase in extracellular acidification, due to stimulation of the glycolytic flux. Furthermore, ATP levels decrease, and the syntheses of DNA and protein are shut off after approximately 30 hr of exposure, indicating active cell death. CHS 828 is now in early clinical trials, the results of which are eagerly awaited.

  20. Clinical significance of the fabella

    International Nuclear Information System (INIS)

    Dodevski, A.; Lazarova-Tosovska, D.; Zhivadinovik, J.; Lazareska, M.

    2012-01-01

    Full text: Introduction: There is variable number of sesamoid bones in the human body; one of them is fabella, located in the tendon of the gastrocnemius muscle. Aim of this study was to investigate the frequency of occurrence of fabella in the Macedonian population and to discuss about clinical importance of this bone. Materials and methods: We retrospectively examined radiographs of 53 patients who had knee exams undertaken for a variety of clinical reasons, performed as a part of their medical treatment. Over a time span of six months, 53 patients (38 males and 15 females, age range 19-60 years, mean age of 36.7±12.3 years) were examined. Results: In seven (13.2%) patients of 53 analyzed reports, fabella was found in the lateral tendon of gastrocnemius muscle. We did not find a significant gender or side difference in the appearance of fabella. Conclusion: Although anatomic studies emphasized a lack of significance of the fabella, this bone has been associated with a spectrum of pathology affecting the knee as fabellar syndrome, perineal nerve injury and fracture. We should think of this sesamoid bone while performing diagnostic and surgical procedures

  1. Clinical significance of pneumatosis intestinalis - correlation of MDCT-findings with treatment and outcome

    Energy Technology Data Exchange (ETDEWEB)

    Treyaud, Marc-Olivier; Duran, Rafael; Knebel, Jean-Francois; Meuli, Reto A.; Schmidt, Sabine [Lausanne University Hospital, Department of Diagnostic and Interventional Radiology, Lausanne (Switzerland); Zins, Marc [Fondation Hopital St Joseph, Department of Radiology, Paris (France)

    2017-01-15

    To evaluate the clinical significance of pneumatosis intestinalis (PI) including the influence on treatment and outcome. Two radiologists jointly reviewed MDCT-examinations of 149 consecutive emergency patients (53 women, mean age 64, range 21-95) with PI of the stomach (n = 4), small (n = 68) and/or large bowel (n = 96). PI extension, distribution and possibly associated porto-mesenteric venous gas (PMVG) were correlated with other MDCT-findings, risk factors, clinical management, laboratory, histopathology, final diagnosis and outcome. The most frequent cause of PI was intestinal ischemia (n = 80,53.7 %), followed by infection (n = 18,12.1 %), obstructive (n = 12,8.1 %) and non-obstructive (n = 10,6.7 %) bowel dilatation, unknown aetiologies (n = 8,5.4 %), drugs (n = 8,5.4 %), inflammation (n = 7,4.7 %), and others (n = 6,4 %). Neither PI distribution nor extension significantly correlated with underlying ischemia. Overall mortality was 41.6 % (n = 62), mostly related to intestinal ischemia (p = 0.003). Associated PMVG significantly correlated with underlying ischemia (p = 0.009), as did the anatomical distribution of PMVG (p = 0.015). Decreased mural contrast-enhancement was the only other MDCT-feature significantly associated with ischemia (p p < 0.001). Elevated white blood count significantly correlated with ischemia (p = 0.03). In emergency patients, ischemia remains the most common aetiology of PI, showing the highest mortality. PI with associated PMVG is an alerting sign. PI together with decreased mural contrast-enhancement indicates underlying ischemia. (orig.)

  2. Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

    Science.gov (United States)

    Ogilvie, Brian W; Torres, Rosarelis; Dressman, Marlene A; Kramer, William G; Baroldi, Paolo

    2015-09-01

    Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. © 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

  3. Clinical neuropharmacology of drugs of abuse: a comparison of drug-discrimination and subject-report measures.

    Science.gov (United States)

    Kelly, Thomas H; Stoops, William W; Perry, Andrea S; Prendergast, Mark A; Rush, Craig R

    2003-12-01

    Advances in molecular pharmacology and behavioral science have helped elucidate the structure and function of the central nervous system and its relationship to behavior and has sparked the development of pharmacological agents that have increasingly selective and potent effects with fewer adverse side effects. The sensitivity and predictive validity of the two most commonly used methodologies for assessing the neuropharmacological effects of centrally active drugs, subject report of drug effects and drug discrimination, were examined. The sensitivity of the measures was comparable across stimulant, sedative, and opioid drugs. Results with drug-discrimination methodologies were generally consistent with hypothesized neuropharmacological mechanisms across all drug classes, whereas subject reports conformed under more limited testing conditions. Firm conclusions regarding the relative utility of drug-discrimination and subject-report measures for clinical studies of neuropharmacological mechanisms are limited by the small number of studies in which the two methodologies have been tested using identical pharmacological pretreatment manipulations.

  4. [Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

    Science.gov (United States)

    Martínez-Múgica, Cristina

    2015-12-01

    Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

  5. Clinical significance of dental root canal microflora.

    Science.gov (United States)

    Gomes, B P; Lilley, J D; Drucker, D B

    1996-01-01

    Previous work by this group has shown that a significant association exists between pain and the presence of either Prevotella or Peptostreptococcus spp. in dental root canals. The aim of this study was to examine a more extensive series of canals microbiologically, to determine whether any other particular endodontic symptoms or clinical signs showed specific associations with individual bacterial species. Seventy root canals were examined microbiologically and clinical data collected to investigate in detail such associations. Of the canals studied, 37 were associated with pain, 49 with tenderness to percussion, 23 with swelling, six with purulent exudate and 57 presented with wet root canals. Anaerobes were isolated from 70.3% of painful canals and from 29.7% of pain-free canals. Significant associations were found between (a) pain and either Prevotella spp. or peptostreptococci, both with P spp. (P Eubacterium spp. (P spp. or Pstr. micros, both with P spp. (each P Eubacterium, Peptostreptococcus, Prevotella or Propionibacterium (each P < 0.05). It was concluded that several different endodontic clinical signs and symptoms are significantly associated with specific bacterial species.

  6. Acrophialophora, a Poorly Known Fungus with Clinical Significance

    Science.gov (United States)

    Sandoval-Denis, Marcelo; Sutton, Deanna A.; Wiederhold, Nathan P.; Guarro, Josep

    2015-01-01

    Acrophialophora fusispora is an emerging opportunistic fungus capable of causing human infections. The taxonomy of the genus is not yet resolved and, in order to facilitate identification of clinical specimens, we have studied a set of clinical and environmental Acrophialophora isolates by morphological and molecular analyses. This set included the available type strains of Acrophialophora species and similar fungi, some of which were considered by various authors to be synonyms of A. fusispora. Sequence analysis of the large subunit (LSU) and internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and a fragment of the β-tubulin (Tub) gene revealed that Acrophialophora belongs in the family Chaetomiaceae and comprises three different species, i.e., A. fusispora, Acrophialophora levis, and Acrophialophora seudatica; the latter was previously included in the genus Ampullifera. The most prevalent species among clinical isolates was A. levis (72.7%), followed by A. fusispora (27.3%), both of which were isolated mostly from respiratory specimens (72.7%), as well as subcutaneous and corneal tissue samples. In general, of the eight antifungal drugs tested, voriconazole had the greatest in vitro activity, while all other agents showed poor in vitro activity against these fungi. PMID:25716450

  7. Randomized clinical trial on the use of antispasmodic drugs in barium enema: impact on radiological practice

    International Nuclear Information System (INIS)

    Goei, Reginald; Kessels, Alphons H.; Nix, Maarten; Knipschild, Paul G.

    2000-01-01

    Purpose: To assess the willingness of radiologists to change their practice when the results of a randomized clinical trial (RCT) on the use of antispasmodic drugs in barium enema are presented. Materials and Methods: During the years 1994 and 1995 two postal questionnaires were sent to 481 practicing radiologists who were all members of the Netherlands Society of Radiology. In the first questionnaire the respondents were asked to give the characteristics of their practices in performing daily barium enema. The data from this questionnaire was used as a reference. The second questionnaire was sent to the respondents together with an abstract on the randomized clinical trial supporting the use of antispasmodic drugs in barium enema. We also indicated a preference for Buscopan over Glucagon as the antispasmodic drug. The willingness to change prescription habits was measured by comparing the data of the two questionnaires. Results: Of 481 practicing radiologists, 312 responded to the first questionnaire and gave information of their prescription habits (response rate 64%). These 312 responders were sent an abstract of the RCT and were asked to fill out a second questionnaire to determine their willingness to change their practice. Two hundred and sixty-seven radiologists responded (response rate 86%). A significant number of 119 (51%) were willing to increase the use of antispasmodic drugs. A significant number of 128 (55%) chose to increase the use of Buscopan, while a significant number of 81 (32%) were willing to decrease the use of Glucagon. Conclusion: Direct exposure to the results of an RCT recommending the use of antispasmodic drugs in barium enema, especially Buscopan, is likely to increase its use by practicing radiologists

  8. Analysis of clinical drug-drug interaction data to predict uncharacterized interaction magnitudes between antiretroviral drugs and co-medications.

    Science.gov (United States)

    Stader, Felix; Kinvig, Hannah; Battegay, Manuel; Khoo, Saye; Owen, Andrew; Siccardi, Marco; Marzolini, Catia

    2018-04-23

    Despite their high potential for drug-drug-interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required.We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes such as CYP3A and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers and inhibitors of CYP3A, to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs.The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (n = 68) between ARVs and co-medications were successfully quantified meaning 53%, 85% and 98% of the predictions were within 1.25-fold (0.80 - 1.25), 1.5-fold (0.66 - 1.48) and 2-fold (0.66 - 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or conversely minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs.The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs being particularly relevant in a HIV-setting giving the treatments complexity, high DDI risk and limited guidance on the management of DDIs. Copyright © 2018 American Society for Microbiology.

  9. [Drug interactions in chronic prescription].

    Science.gov (United States)

    Comet, D; Casajuana, J; Bordas, J M; Fuentes, M A; Arnáiz, J A; Núñez, B; Pou, R

    1997-06-30

    Application of computerized program for detection of potential drug interactions (PDI) in chronic prescriptions in four primary care centers. To evaluate the clinical significance of PDI identified according to clinical criterions. An observational crossover study. Clutat Vella health district (City of Barcelona). Using information of Consejo General de Colegios Oficiales de Farmaceuticos databases and the chronic prescriptions database of the primary care centers, computerized drug-interaction system have been developed for detection of PDI in patients. A panel of primary care physicians and clinical pharmacists developed criteria that were used to evaluate the clinical significance of PDI. 9840 Cards of Authorized Prescription (CAP) were analyzed, 36108 medicaments and 42877 drugs. A total of 2140 patients were involved for a total of 3406 PDI, 21.75% of patients with CAP. Clinical signification for the panel was found in 40.07% of these 3406 PIF; 3.78% were suggest to avoid the association drugs. The incidence of PDI with clinical signification are lower than other studies of the literature; it suggest a appropriate knowledge of drug prescription. The application of computerized program make much more easy the detection of adverse drug interactions in chronic prescription.

  10. An Overview of Clinical and Commercial Impact of Drug Delivery Systems

    Science.gov (United States)

    Anselmo, Aaron C.; Mitragotri, Samir

    2014-01-01

    Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. The last few decades have seen a marked growth of the field fueled by increased number of researchers, research funding, venture capital and the number of start-ups. Collectively, the growth has led to novel systems that make use of micro/nano-particles, transdermal patches, inhalers, drug reservoir implants and antibody-drug conjugates. While the increased research activity is clearly an indication of proliferation of the field, clinical and commercial translation of early-stage research ideas is critically important for future growth and interest in the field. Here, we will highlight some of the examples of novel drug delivery systems that have undergone such translation. Specifically, we will discuss the developments, advantages, limitations and lessons learned from: (i) microparticle-based depot formulations, (ii) nanoparticle-based cancer drugs, (iii) transdermal systems, (iv) oral drug delivery systems, (v) pulmonary drug delivery, (vi) implants and (vii) antibody-drug conjugates. These systems have impacted treatment of many prevalent diseases including diabetes, cancer and cardiovascular diseases, among others. At the same time, these systems are integral and enabling components of products that collectively generate annual revenues exceeding US $100 billion. These examples provide strong evidence of the clinical and commercial impact of drug delivery systems. PMID:24747160

  11. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials

    Directory of Open Access Journals (Sweden)

    Gao XF

    2017-05-01

    Full Text Available Xiao-Fei Gao,1 Jun-Jie Zhang,1,2 Xiao-Min Jiang,1 Zhen Ge,1,2 Zhi-Mei Wang,1 Bing Li,1 Wen-Xing Mao,1 Shao-Liang Chen1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 2Department of Cardiology, Nanjing Heart Center, Nanjing, People’s Republic of China Background: Pulmonary arterial hypertension (PAH is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs, phosphodiesterase 5 inhibitors (PDE-5Is, and soluble guanylate cyclase stimulator (sGCS, have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH.Methods: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD.Results: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003 vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008 vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028 vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001 vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001 vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023 vs

  12. PROPOSAL OF GUIDELINE FOR CLINICAL TRIAL PROTOCOLS WITH HERBAL DRUGS

    Directory of Open Access Journals (Sweden)

    Migdacelys Arboláez Estrada.

    2007-04-01

    Full Text Available SUMMARYCuba has extensive experience about herbal drugs, however only a few products get to the clinical phase of drug development. Our objective was to design new guidelines for clinical trials with herbal drugs.A detailed bibliographic search about regulatory aspects about clinical trials in Cuba and the world was done for development of the guideline. The guideline's proposed format includes: 1 Index, including the classification of the content. 2 Summary, 3 Fifteen chapters, related to the clinical trials. The guideline also propose the inclusion of annexes.A new guideline containing 15 chapters allows for writing more clear and detailed clinical trial protocols. The guideline contains the information required to guide the research staff who is interested in the validation of herbal drugs pharmacological activations from the perspective of clinical trials. RESUMEN Cuba tiene experiencia extensa sobre plantas medicinales, aunque solo algunos productos llegan a una fase clínica del desarrollo. Nuestro objetivo fué diseñar una nueva guía para ensayos clínicos con plantas medicinales.Hemos realizado una detallada búsqueda bibliográfica sobre aspectos reguladores de ensayos clínicos en Cuba y el resto del mundo para el desarrollo de la guía. El formato propuesto de la guia incluye: 1 Índice, incluyendo la clasificación de los contenidos. 2 Resumen, 3 Quince capítulos, relacionados con los ensayos clínicos. La guía también propone la inclusión de anexos.La nueva guía que contiene 15 capítulos que orientan la redacción de protocolos de ensayos clínicos más claros y más detallados. La guía contiene la información requerida para orientar al personal investigador interesado en la validación de la actividad farmacológica de las plantas medicinales desde la perspectiva de los ensayos clínicos.

  13. Assessment of Sexual Desire for Clinical Trials of Women With Hypoactive Sexual Desire Disorder: Measures, Desire-Related Behavior, and Assessment of Clinical Significance.

    Science.gov (United States)

    Pyke, Robert E; Clayton, Anita H

    2018-01-19

    The Female Sexual Function Index-desire subscale is the standard measure for clinical trials of hypoactive sexual desire disorder (HSDD), but lacks items assessing sexually related behaviors and attitudes toward partner. Counting satisfying sexual events is criticized, but sexual behavior remains important. Mean treatment differences cannot define clinical significance; responder and remitter analyses help. We reviewed measures on sexual desire and sexual behavior relevant to HSDD, and how to assess clinical significance. We conducted a literature review of measures of sexual desire comparing expert-proposed criteria for dysfunctional desire, expert-developed scales, and scales from patient input. Commonly recognized symptoms of HSDD were identified. Results of HSDD trials and scale validation studies were evaluated to extract responder and remitter values. The utility of distribution-based measures of responders and remitters was assessed. Symptom relevance was evaluated as the proportion of symptom sets that included the item; responder and remitter cut points were determined by distribution-based methods. 12 Validated rating scales, 5 scales primarily derived from expert recommendations and 7 scales initially from patient input, and 5 sets of diagnostic criteria for conditions like HSDD were compared. Content varied highly between scales despite compliance with U.S. Food and Drug Administration recommendations for patient-reported outcomes. This disunity favors an expert-recommended scale such as the Elements of Desire Questionnaire with each of the common items, plus a measure of frequency of sexual activity, eg, item in the Patient Reported Outcomes Measurement Information System. Registrational drug trials, but not psychological treatment trials, usually give responder/remitter analyses, using dichotomized global impressions or anchor-based definitions. Distribution-based methods are more uniformly applicable to define responder and remitter status. The

  14. Random Forest Segregation of Drug Responses May define Regions of Biological Significance

    Directory of Open Access Journals (Sweden)

    Qasim eBukhari

    2016-03-01

    Full Text Available The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF method to detect differences in the pharmacological MRI (phMRI response in rats to treatment with an analgesic drug (buprenorphine as compared to control (saline. Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD and high dose (HD, and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow an unsupervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies.

  15. A significant association between BDNF promoter methylation and the risk of drug addiction.

    Science.gov (United States)

    Xu, Xuting; Ji, Huihui; Liu, Guili; Wang, Qinwen; Liu, Huifen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Zhou, Wenhua; Duan, Shiwei

    2016-06-10

    As a member of the neurotrophic factor family, brain derived neurotrophic factor (BDNF) plays an important role in the survival and differentiation of neurons. The aim of our work was to evaluate the role of BDNF promoter methylation in drug addiction. A total of 60 drug abusers (30 heroin and 30 methylamphetamine addicts) and 52 healthy age- and gender-matched controls were recruited for the current case control study. Bisulfite pyrosequencing technology was used to determine the methylation levels of five CpGs (CpG1-5) on the BDNF promoter. Among the five CpGs, CpG5 methylation was significantly lower in drug abusers than controls. Moreover, significant associations were found between CpG5 methylation and addictive phenotypes including tension-anxiety, anger-hostility, fatigue-inertia, and depression-dejection. In addition, luciferase assay showed that the DNA fragment of BDNF promoter played a key role in the regulation of gene expression. Our results suggest that BDNF promoter methylation is associated with drug addiction, although further studies are needed to understand the mechanisms by which BDNF promoter methylation contributes to the pathophysiology of drug addiction. Copyright © 2016. Published by Elsevier B.V.

  16. Clinical guidelines «Rational use of nonsteroidal anti-inflammatory drugs (NSAIDs in clinical practice»

    Directory of Open Access Journals (Sweden)

    A. E. Karateev

    2015-01-01

    Full Text Available The paper presents the new version of the clinical guidelines «Rational use of nonsteroidal anti-inflammatory drugs (NSAIDs in clinical practice » prepared by the Association of Rheumatologists of Russia, the Russian Pain Society, the Russian Gastroenterological Association, the Russian Society of Cardiology, the Association of Traumatologists and Orthopedists of Russia, the Association of Interdisciplinary Medicine, and the Russian Association of Palliative Medicine.In our country, NSAIDs are the most important and most popular class of analgesics. Unlike global practice, Russian physicians rather rarely recommend paracetamol as a first-line drug to relieve moderate or severe pain, by giving preference to NSAIDs; the use of opioid analgesics for noncancers is minimized because of tight legal restrictions.NSAIDs are effective and easy-to-use; however, they are far from safe; the administration of these medications may lead to serious gastrointestinal, cardiovascular, renal, and other complications in a number of cases. So the use of NSAIDs should be compulsorily monitored for adverse reactions and the choice of a specific drug for each clinical case should be based on the objective estimation of a ratio of its efficacy to safety.In recent years, there have been fresh data on the use of NSAIDs for different diseases and a few novel representatives of this drug group have appeared on the Russian pharmacological market.This all has necessitated a new version of the guidelines on the rational use of NSAIDs. These are based on the provisions that have high validity and have been confirmed by the results of well-organized clinical and large-scale population-based studies, as well as by their meta-analysis.The guidelines are intended for physicians of all specialties. 

  17. 'False-positive' and 'false-negative' test results in clinical urine drug testing.

    Science.gov (United States)

    Reisfield, Gary M; Goldberger, Bruce A; Bertholf, Roger L

    2009-08-01

    The terms 'false-positive' and 'false-negative' are widely used in discussions of urine drug test (UDT) results. These terms are inadequate because they are used in different ways by physicians and laboratory professionals and they are too narrow to encompass the larger universe of potentially misleading, inappropriate and unexpected drug test results. This larger universe, while not solely comprised of technically 'true' or 'false' positive or negative test results, presents comparable interpretive challenges with corresponding clinical implications. In this review, we propose the terms 'potentially inappropriate' positive or negative test results in reference to UDT results that are ambiguous or unexpected and subject to misinterpretation. Causes of potentially inappropriate positive UDT results include in vivo metabolic conversions of a drug, exposure to nonillicit sources of a drug and laboratory error. Causes of potentially inappropriate negative UDT results include limited assay specificity, absence of drug in the urine, presence of drug in the urine, but below established assay cutoff, specimen manipulation and laboratory error. Clinical UDT interpretation is a complicated task requiring knowledge of recent prescription, over-the-counter and herbal drug administration, drug metabolism and analytical sensitivities and specificities.

  18. Clinical Significance: a Therapeutic Approach Topsychological Assessment in Treatment Planning

    Directory of Open Access Journals (Sweden)

    Afolabi Olusegun Emmanuel

    2015-06-01

    Full Text Available Psychological assessment has long been reported as a key component of clinical psychology. This paper examines the complexities surrounding the clinical significance of therapeutic approach to treatment planning. To achieve this objective, the paper searched and used the PsycINFO and PubMed databases and the reference sections of chapters and journal articles to analysed, 1 a strong basis for the usage of therapeutic approach to psychological assessment in treatment plans, 2 explained the conceptual meaning of clinical significant change in therapeutic assessment, 3 answered some of the questions regarding practicability and the clinical significance of therapeutic approach to treatment plans, particularly during or before treatment, 4 linked therapeutic assessment to change in clients’ clinical impression, functioning and therapeutic needs 5 analysed the empirically documenting clinically significant change in therapeutic assessment. Finally, the study suggested that though therapeutic assessment is not sufficient for the systematic study of psychotherapy outcome and process, it is still consistent with both the layman and professional expectations regarding treatment outcome and also provides a precise method for classifying clients as ‘changed’ or ‘unchanged’ on the basis of clinical significance criteria.

  19. Antineoplastic Drugs

    Science.gov (United States)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  20. Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

    Science.gov (United States)

    Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra; Drabick, Joseph J; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

    2018-03-01

    Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1 H -pyrazolo[3,4- d ]pyrimidin-3(2 H )-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. Copyright © 2018 by The American

  1. Adverse effects of anticoagulation treatment: clinically significant upper gastrointestinal hemorrhage

    Directory of Open Access Journals (Sweden)

    Pavel Skok

    2006-12-01

    Full Text Available Background: Over the last years, the use of oral anticoagulant treatment has increased dramatically, principally for the prevention of venous thrombosis and thrombembolic events. This treatment is demanding, especially among the elderly with concommitant diseases and different medication. Aim of the study to evaluate the rate of serious complications, clinically significant hemorrhage from upper gastointestinal tract in patients treated with oral antiocoagulants in a prospective cohort study.Patients and methods: Included were patients admitted to our institution between January 1, 1994 and December 31, 2003 due to gastrointestinal hemorrhage. Emergency endoscopy and laboratory testing was performed in all patients.Results: 6416 patients were investigated: 2452 women (38.2 % and 3964 men (61.8 %, mean age 59.1 years, SD 17.2. Among our patients, 55 % were aged over 60 years. In 86.4 % of patients the source of bleeding was confirmed in the upper gastrointestinal tract. In the last week prior to bleeding, 20.4 % (1309/6416 of all patients were regularly taking nonsteroidal anti-inflammatory drugs, anticoagulant therapy or antiplatelet agents in single daily doses at least. 6.3 % of patients (82/1309 with abundant hemorrhage from upper gastrointestinal tract were using oral anticoagulant therapy and had INR > 5 at admission, 25.6 % of them had INR > 10. The mortality of patients using oral anticoagulants and INR > 5 was 17.1 %.Conclusions: Upper gastrointestinal hemorrhage is a serious complication of different medications, particularly in elderly patients. Safe use of anticoagulant therapy is based on careful selection of patients and correct intake of the prescribed drugs.

  2. pancreatic steatosis: diagnosis and clinical significance

    Directory of Open Access Journals (Sweden)

    Murat Daðdeviren

    2017-03-01

    Full Text Available Pancreatic steatosis (PS, with increased use of abdominal imaging in recent years generally appears as incidental. But it is a condition that is often overlooked. The reason for this is not yet fully demonstrated the clinical significance of PS while. However, in recent years, there are some studies conducted on the relationship with ps and other disease such as diabetes, metabolic syndrome, acute and chronic pancreatitis and pancreatic cancer. In this review, the etiology, diagnosis, treatment and clinical characteristics of ps were evaluated in the light of recent literature and current approaches. [J Contemp Med 2017; 7(1.000: 107-112

  3. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  4. Assessing clinical significance of treatment outcomes using the DASS-21.

    Science.gov (United States)

    Ronk, Fiona R; Korman, James R; Hooke, Geoffrey R; Page, Andrew C

    2013-12-01

    Standard clinical significance classifications are based on movement between the "dysfunctional" and "functional" distributions; however, this dichotomy ignores heterogeneity within the "dysfunctional" population. Based on the methodology described by Tingey, Lambert, Burlingame, and Hansen (1996), the present study sought to present a 3-distribution clinical significance model for the 21-item version of the Depression Anxiety Stress Scales (DASS-21; P. F. Lovibond & Lovibond, 1995) using data from a normative sample (n = 2,914), an outpatient sample (n = 1,000), and an inpatient sample (n = 3,964). DASS-21 scores were collected at pre- and post-treatment for both clinical samples, and patients were classified into 1 of 5 categories based on whether they had made a reliable change and whether they had moved into a different functional range. Evidence supported the validity of the 3-distribution model for the DASS-21, since inpatients who were classified as making a clinically significant change showed lower symptom severity, higher perceived quality of life, and higher clinician-rated functioning than those who did not make a clinically significant change. Importantly, results suggest that the new category of recovering is an intermediate point between recovered and making no clinically significant change. Inpatients and outpatients have different treatment goals and therefore use of the concept of clinical significance needs to acknowledge differences in what constitutes a meaningful change. (c) 2013 APA, all rights reserved.

  5. Antipsychotic drug treatment for patients with schizophrenia: theoretical background, clinical considerations and patients preferences

    DEFF Research Database (Denmark)

    Nielsen, René Ernst; Nielsen, Jimmi

    2009-01-01

      The cornerstone in treatment of psychosis is antipsychotic drugs. Treatment options have increased over the years; newer antipsychotic drugs with a proposed efficacy regarding negative and cognitive symptoms, but also a shift in side-effects from neurological side-effects to metabolic side......-effects have arisen as the new challenge. The basis of successful pharmacological treatment is a fundamental understanding of the mechanisms of action, the desired effects and side-effects of antipsychotic drugs, a good relationship with the patient and a thorough monitoring of the patient before and during...... treatment. The clinically relevant aspects of antipsychotic drug treatment are reviewed; mechanism of antipsychotic drug action, clinical considerations in treatment, switching antipsychotic drugs, polypharmacy, safety and patient preference.  ...

  6. Interplay between Mutations and Efflux in Drug Resistant Clinical Isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Miguel Viveiros

    2017-04-01

    Full Text Available Numerous studies show efflux as a universal bacterial mechanism contributing to antibiotic resistance and also that the activity of the antibiotics subject to efflux can be enhanced by the combined use of efflux inhibitors. Nevertheless, the contribution of efflux to the overall drug resistance levels of clinical isolates of Mycobacterium tuberculosis is poorly understood and still is ignored by many. Here, we evaluated the contribution of drug efflux plus target-gene mutations to the drug resistance levels in clinical isolates of M. tuberculosis. A panel of 17 M. tuberculosis clinical strains were characterized for drug resistance associated mutations and antibiotic profiles in the presence and absence of efflux inhibitors. The correlation between the effect of the efflux inhibitors and the resistance levels was assessed by quantitative drug susceptibility testing. The bacterial growth/survival vs. growth inhibition was analyzed through the comparison between the time of growth in the presence and absence of an inhibitor. For the same mutation conferring antibiotic resistance, different MICs were observed and the different resistance levels found could be reduced by efflux inhibitors. Although susceptibility was not restored, the results demonstrate the existence of a broad-spectrum synergistic interaction between antibiotics and efflux inhibitors. The existence of efflux activity was confirmed by real-time fluorometry. Moreover, the efflux pump genes mmr, mmpL7, Rv1258c, p55, and efpA were shown to be overexpressed in the presence of antibiotics, demonstrating the contribution of these efflux pumps to the overall resistance phenotype of the M. tuberculosis clinical isolates studied, independently of the genotype of the strains. These results showed that the drug resistance levels of multi- and extensively-drug resistant M. tuberculosis clinical strains are a combination between drug efflux and the presence of target-gene mutations, a reality

  7. Biological basis of sex differences in drug abuse: preclinical and clinical studies.

    Science.gov (United States)

    Lynch, Wendy J; Roth, Megan E; Carroll, Marilyn E

    2002-11-01

    The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific.

  8. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs.

    Science.gov (United States)

    Agrawal, Mukta; Saraf, Swarnlata; Saraf, Shailendra; Antimisiaris, Sophia G; Chougule, Mahavir Bhupal; Shoyele, Sunday A; Alexander, Amit

    2018-05-23

    According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found

  9. Editorial : Clinical drug interactions | Kokwaro | East African Medical ...

    African Journals Online (AJOL)

    Journal Home > Vol 78, No 10 (2001) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Editorial: Clinical drug interactions. G. O. Kokwaro. Abstract. (East African Medical Journal 2001 78 (10): 505-506). Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT

  10. The significance of sampling time in therapeutic drug monitoring of clozapine

    DEFF Research Database (Denmark)

    Jakobsen, M I; Larsen, J R; Svensson, C K

    2017-01-01

    OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite...... N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. METHOD: Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. RESULTS: Minor changes in median percentage values were...

  11. Expression and clinical significance of fibroblast growth factor 1 in gastric adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Liu NQ

    2015-03-01

    Full Text Available Naiqing Liu,1,2,* Jingyu Zhang,2,* Shuxiang Sun,2 Liguang Yang,2 Zhongjin Zhou,2 Qinli Sun,2 Jun Niu11Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Yishui Central Hospital, Linyi, People’s Republic of China*These authors contributed equally to this workBackground: The clinical significance of fibroblast growth factor 1 (FGF1 has been revealed in several cancers, including ovarian cancer, breast cancer, and bladder cancer. However, the clinical significance of FGF1 in gastric adenocarcinoma has not been explored.Patients and methods: In our experiments, we systematically evaluated FGF1 expression in 178 cases of gastric adenocarcinoma with immunohistochemistry, and subsequently analyzed the correlation between FGF1 expression and clinicopathologic features. Moreover, FGF1 expression in tumor tissue and corresponding adjacent tissue was detected and compared by real-time polymerase chain reaction. The Kaplan–Meier method and the Cox-regression model were used with univariate and multivariate analysis, respectively, to evaluate the prognostic value of FGF1 in gastric adenocarcinoma.Results: Higher FGF1 expression rate is 56.7% (101/178 in gastric adenocarcinoma. FGF1 expression in gastric adenocarcinoma was significantly higher than adjacent tissue (P<0.0001. Expression of FGF1 is significantly associated with lymph node invasion (P<0.001, distant metastasis (P=0.013, and differentiation (P=0.015. Moreover, FGF1 overexpression was closely related to unfavorable overall survival rate (P=0.021, and can be identified to be an independent unfavorable prognostic factor (P=0.004.Conclusion: FGF1 is an independent prognostic factor, indicating that FGF1 could be a potential molecular drug target in gastric adenocarcinoma.Keywords: fibroblast growth factor 1, gastric adenocarcinoma, prognosis, biomarker, lymph node, gene fusion

  12. Retrospective use of PBPK modelling to understand a clinical drug-drug interaction between dextromethorphan and GSK1034702.

    Science.gov (United States)

    Hobbs, Michael J; Bloomer, Jackie; Dear, Gordon

    2017-08-01

    1. In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702. PBPK models were populated with the in vitro parameters and DDI simulations conducted and compared to the observed data from a clinical study with DM and GSK1034702. 3. GSK1034702 was a potent direct and metabolism-dependent inhibitor of human CYP2D6, with inhibition parameters of: IC 50  =   1.6 μM, K inact  = 3.7 h -1 and K I  = 0.8 μM. Incorporating these data into PBPK models predicted a DDI after repeat, but not single, 5 mg doses of GSK1034702. 4. The DDI observed with repeat administration of GSK1034702 (5 mg) can be attributed to metabolism-dependent inhibition of CYP2D6. Further, in vitro data were generated and several potential mechanisms proposed to explain the interaction observed following a single dose of GSK1034702.

  13. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

    Science.gov (United States)

    Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

    2016-12-12

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

  14. Prevalence, characterization and clinical significance of Klebsiella pneumoniae carbapenemase (KPC producing Klebsiella pneumoniae

    Directory of Open Access Journals (Sweden)

    : Sarita Nayak, Suman Singh, Soeb Jankhwala, Riddhi Pradhan

    2014-11-01

    Full Text Available Klebsiella peumoniae, a capsulated gram negative bacillus is responsible for causing life threatening infections in humans. Carbapenems are the drug of choice for serious infection caused by multidrug resistant Klebsiella pneumoniae. The emergence of carbapenem resistance has made it extremely difficult to treat such infections resulting in significant morbidity and mortality. Aims: To study the prevalence of carbapenem resistance using ertapenem as a marker and to detect Klebsiella pneumoniae Carbapenemase (KPC producing Klebsiella pneumoniae as a mechanism of resistance. Material and Methods: The study included 102 patients from which Klebsiella pneumoniae isolated. Identification and antibiotic susceptibility testing of Klebsiella pneumoniae was performed on miniAPI (Analytical Profile Index, Semiautomated bacterial identification system according to Clinical and Laboratory Standards Institute (CLSI guidelines of 2011. The modified Hodge test was performed for detection of Carbapenemase production. Patient’s clinical and demographic details along with risk factors and co-morbid conditions, type of response to antimicrobial therapy and mortality were collected. Results: The prevalence of carbapenem resistance was found to be 30.41% with 16.6% KPC producing Klebsiella pneumoniae. The co-morbid conditions like immunocompromised state (p =0.042, prior antibiotics therapy (p=0.047, previous hospitalization (p =0.021, intensive care unit stay (p=0.047 and use of indwelling devices (p =0.013 were found to be significantly associated with carbapenem resistance. Adverse clinical outcomes (death or worsening among patients infected with ertapenem resistant patients was found to be statistically significant than ertapenem sensitive strains (p =0.008. Conclusions: A high degree of carbapenem resistance in present study is alarming and poses therapeutic dilemmas for clinicians. Initiating timely and appropriate infection control measures along with a

  15. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014

    Science.gov (United States)

    Schneider, Lon S.; Mangialasche, Francesca; Andreasen, Niels; Feldman, Howard; Giacobini, Ezio; Jones, Roy; Mantua, Valentina; Mecocci, Patrizia; Pani, Luca; Winblad, Bengt; Kivipelto, Miia

    2014-01-01

    The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities

  16. Prescribing patterns and perceptions of health care professionals about rational drug use in a specialist hospital clinic.

    Directory of Open Access Journals (Sweden)

    Moses A. Ojo

    2014-12-01

    Full Text Available Irrational drug use is associated with adverse consequences including drug resistance and avoidable adverse drug reactions. Studies of rational drug use in psychiatric facilities are scanty. This study evaluated prescription practices and perception of health care professionals regarding causes of irrational drug use. A retrospective study conducted at the outpatient clinic of Federal Neuro- psychiatric Hospital, Yaba, Lagos. Data on drug use indicators were analyzed. A cross-sectional assessment of perception of prescribers and dispensers regarding rational drug use was conducted. A total of 600 prescriptions were analyzed. Mean number of drugs per encounter was 3.5 and percentage generic prescribed was 58.5%. Poly-pharmacy (P=0.024, 95% CI=1.082-1.315 and non-generic prescribing (P=0.032, 95% CI=1.495-1.821 were significantly associated with young prescribers. Factors associated with irrational drug use include demand from patients, patients’ beliefs about injection drugs and influence of pharmaceutical sale representatives. Certain aspect of prescribers indicators are still poor in the hospital studied. Health care professionals identified possible associated factors for irrational drug use. Concerted efforts are required to ensure rational drug use especially in psychiatric facilities in Nigeria.

  17. Clinical meanings of determination of serum β-HCG levels in the management of drug abortion for family planning

    International Nuclear Information System (INIS)

    Wang Xianping; Zou Huifeng; Jiang Juping

    2005-01-01

    Objective: To study the clinical meanings of determination of serum β-HCG levels in the management of drug abortion for birth control. Methods: Serum β-HCG levels were determined with CLIA in 254 pregnant women asking for drug abortion and 102 women with ectopic gestation. Results: The serum β-HCG levels in women with normal pregnancy were significantly higher than those in women with ectopic gestation (P 0.05). Conclusion: For drug abortion in those pregnant women with amenorrhea over 45 days and serum β-HCG levels over 50000mlU/ml, a larger dose of misoprostol may be desirable. (authors)

  18. Clinical trials information in drug development and regulation : existing systems and standards

    NARCIS (Netherlands)

    Valkenhoef, Gert van; Tervonen, Tommi; Brock, Bert de; Hillege, Hans

    2012-01-01

    Clinical trials provide pivotal evidence on drug efficacy and safety. The evidence, information from clinical trials, is currently used by regulatory decision makers in marketing authorization decisions, but only in an implicit manner. For clinical trials information to be used in a transparent and

  19. Ethanol-drug absorption interaction: potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable formulations.

    Science.gov (United States)

    Lennernäs, Hans

    2009-01-01

    Generally, gastric emptying of a drug to the small intestine is controlled by gastric motor activity and is the main factor affecting the onset of absorption. Accordingly, the emptying rate from the stomach is mainly affected by the digestive state, the properties of the pharmaceutical formulation and the effect of drugs, posture and circadian rhythm. Variability in the gastric emptying of drugs is reflected in variability in the absorption rate and the shape of the plasma pharmacokinetic profile. When ethanol interacts with an oral controlled release product, such that the mechanism controlling drug release is impaired, the delivery of the dissolved dose into the small intestine and the consequent absorption may result in dangerously high plasma concentrations. For example, the maximal plasma concentration of hydromorphone has individually been shown to be increased as much as 16 times through in vivo testing as a result of this specific pharmacokinetic ethanol-drug formulation interaction. Thus, a pharmacokinetic ethanol-drug interaction is a very serious safety concern when substantially the entire dose from a controlled release product is rapidly emptied into the small intestine (dose dumping), having been largely dissolved in a strong alcoholic beverage in the stomach during a sufficient lag-time in gastric emptying. Based on the literature, a two hour time frame for screening the in vitro dissolution profile of a controlled release product in ethanol concentrations of up to 40% is strongly supported and may be considered as the absolute minimum standard. It is also evident that the dilution, absorption and metabolism of ethanol in the stomach are processes with a minor effect on the local ethanol concentration and that ethanol exposure will be highly dependent on the volume and ethanol concentration of the fluid ingested, together with the rate of intake and gastric emptying. When and in which patients a clinically significant dose dumping will happen is

  20. Evaluation of drug interaction microcomputer software: Dambro's Drug Interactions.

    Science.gov (United States)

    Poirier, T I; Giudici, R A

    1990-01-01

    Dambro's Drug Interactions was evaluated using general and specific criteria. The installation process, ease of learning and use were rated excellent. The user documentation and quality of the technical support were good. The scope of coverage, clinical documentation, frequency of updates, and overall clinical performance were fair. The primary advantages of the program are the quick searching and detection of drug interactions, and the attempt to provide useful interaction data, i.e., significance and reference. The disadvantages are the lack of current drug interaction information, outdated references, lack of evaluative drug interaction information, and the inability to save or print patient profiles. The program is not a good value for the pharmacist but has limited use as a quick screening tool.

  1. Sonographic ally Detected Architectural Distortion: Clinical Significance

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Shin Kee; Seo, Bo Kyoung; Yi, Ann; Cha, Sang Hoon; Kim, Baek Hyun; Cho, Kyu Ran; Kim, Young Sik; Son, Gil Soo; Kim, Young Soo; Kim, Hee Young [Korea University Ansan Hospital, Ansan (Korea, Republic of)

    2008-12-15

    Architectural distortion is a suspicious abnormality for the diagnosis of breast cancer. The aim of this study was to investigate the clinical significance of sonographic ally detected architectural distortion. From January 2006 to June 2008, 20 patients were identified who had sonographic ally detected architectural distortions without a history of trauma or surgery and abnormal mammographic findings related to an architectural distortion. All of the lesions were pathologically verified. We evaluated the clinical and pathological findings and then assessed the clinical significance of the sonographic ally detected architectural distortions. Based on the clinical findings, one (5%) of the 20 patients had a palpable lump and the remaining 19 patients had no symptoms. No patient had a family history of breast cancer. Based on the pathological findings, three (15%) patients had malignancies. The malignant lesions included invasive ductal carcinomas (n = 2) and ductal carcinoma in situ (n = 1). Four (20%) patients had high-risk lesions: atypical ductal hyperplasia (n = 3) and lobular carcinoma in situ (n = 1). The remaining 13 (65%) patients had benign lesions, however, seven (35%) out of 13 patients had mild-risk lesions (three intraductal papillomas, three moderate or florid epithelial hyperplasia and one sclerosing adenosis). Of the sonographic ally detected architectural distortions, 35% were breast cancers or high-risk lesions and 35% were mild-risk lesions. Thus, a biopsy might be needed for an architectural distortion without an associated mass as depicted on breast ultrasound, even though the mammographic findings are normal

  2. Sonographic ally Detected Architectural Distortion: Clinical Significance

    International Nuclear Information System (INIS)

    Kim, Shin Kee; Seo, Bo Kyoung; Yi, Ann; Cha, Sang Hoon; Kim, Baek Hyun; Cho, Kyu Ran; Kim, Young Sik; Son, Gil Soo; Kim, Young Soo; Kim, Hee Young

    2008-01-01

    Architectural distortion is a suspicious abnormality for the diagnosis of breast cancer. The aim of this study was to investigate the clinical significance of sonographic ally detected architectural distortion. From January 2006 to June 2008, 20 patients were identified who had sonographic ally detected architectural distortions without a history of trauma or surgery and abnormal mammographic findings related to an architectural distortion. All of the lesions were pathologically verified. We evaluated the clinical and pathological findings and then assessed the clinical significance of the sonographic ally detected architectural distortions. Based on the clinical findings, one (5%) of the 20 patients had a palpable lump and the remaining 19 patients had no symptoms. No patient had a family history of breast cancer. Based on the pathological findings, three (15%) patients had malignancies. The malignant lesions included invasive ductal carcinomas (n = 2) and ductal carcinoma in situ (n = 1). Four (20%) patients had high-risk lesions: atypical ductal hyperplasia (n = 3) and lobular carcinoma in situ (n = 1). The remaining 13 (65%) patients had benign lesions, however, seven (35%) out of 13 patients had mild-risk lesions (three intraductal papillomas, three moderate or florid epithelial hyperplasia and one sclerosing adenosis). Of the sonographic ally detected architectural distortions, 35% were breast cancers or high-risk lesions and 35% were mild-risk lesions. Thus, a biopsy might be needed for an architectural distortion without an associated mass as depicted on breast ultrasound, even though the mammographic findings are normal

  3. Clinical significance of monitoring of serum TRAb in pregnant women with graves' disease treated by propylthiouracil

    International Nuclear Information System (INIS)

    Zou Jinhai; Li Xue; Wang Yansheng; Zhang Qingfeng; Wang Jianchun

    2011-01-01

    Objective: To discuss the change of serum TRAb and changeable regularity of thyroid function and clinical significance of pregnant women with Graves' diease treated by propylthiouracil. Methods: Detecting the serum TRAb, FT 3 , FT 4 , TSH levels of pregnant women with Graves' disease treated by propylthiouracil using radioreceptor assay and electro chemiluminescence. Results: The serum TRAb level of the pregnant women with Graves' disease in early gestation treated by propylthiouracil descended much more than that in the initial diagnosis (P<0.01). The positive rates of TRAb in the women before treated by propylthiouracil and treated 3 months, 6 months, 8 months were 90.2%, 82.9%, 68.2% and 21.9% separately. The activity of TRAb descended slightly 3 months latter after treated. The activity of TRAb descend obviously and the positive rates changed largely 8 months after treated. Conclusion: There is very important clinical significance of monitoring of serum TRAb in pregnant women with Graves' disease in diagnosis and differential diagnosis and observation of therapeutic effects. Also, a favourable prognosis judgement. Meanwhile, provides significant reference index of pathogenetic condition judgement and drug discontinuance whether or not for the clinician. (authors)

  4. [Clinical audit on drug prescriptions for elderly patients hospitalized in a unit of psychiatry].

    Science.gov (United States)

    Humaraut, C; Caron, J; Bayonne, L; Moalic, Y

    2016-02-01

    The elderly are particularly vulnerable to the iatrogenic effects of drugs that are a major public health problem. In a geriatric care unit of a psychiatric hospital, the pharmacist, in close cooperation with the various health professionals, takes part in the optimization of drug therapy of these patients during cross-professional consultation meetings. From 2009 to 2011, an evaluation of professional practices was run through a targeted clinical audit on the theme of "prescription drugs at the age of 75 and over". The main objective of this study is to measure the differences between the practices and the guidelines for prescription drugs concerning the elderly, and then to analyze and amend these differences. The secondary objective is to gather data on the prescription drugs for the elderly in the particular context of a psychiatric unit. The evaluation was performed using two standards: the evaluation chart of prescriptions of the Professional College of French Geriatrics (CPGF) and the French National Authority for Health and the list of Laroche et al. In the first round, after analyzing the prescriptions of 105 patients, the gap between practice and accepted standards led to the definition of three areas of improvement on the associations of neuroleptics, on the use of anticholinergic drugs and on the prescription of benzodiazepines, the latter being subject of another communication. After reassessment, the prescriptions of 101 patients were thereafter analyzed in relation to the identified areas of improvement. Patient samples of both phases were statistically homogeneous. Between the two evaluations, the percentage of prescriptions with at least two neuroleptics remained stable, the decline was not significant (18.1% to 13.9%, P≥0.05). However, it was observed that the second suggested a "conditional" decline with dosages less than or equal to those recommended for the elderly dosages. The proportion of patients who did not take anticholinergic drugs

  5. A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data.

    Science.gov (United States)

    Liu, Wei; Ding, Jinhui

    2018-04-01

    The application of the principle of the intention-to-treat (ITT) to the analysis of clinical trials is challenged in the presence of missing outcome data. The consequences of stopping an assigned treatment in a withdrawn subject are unknown. It is difficult to make a single assumption about missing mechanisms for all clinical trials because there are complicated reactions in the human body to drugs due to the presence of complex biological networks, leading to data missing randomly or non-randomly. Currently there is no statistical method that can tell whether a difference between two treatments in the ITT population of a randomized clinical trial with missing data is significant at a pre-specified level. Making no assumptions about the missing mechanisms, we propose a generalized complete-case (GCC) analysis based on the data of completers. An evaluation of the impact of missing data on the ITT analysis reveals that a statistically significant GCC result implies a significant treatment effect in the ITT population at a pre-specified significance level unless, relative to the comparator, the test drug is poisonous to the non-completers as documented in their medical records. Applications of the GCC analysis are illustrated using literature data, and its properties and limits are discussed.

  6. Impact of drug awareness and treatment camps on attendance at a community outreach de-addiction clinic

    Directory of Open Access Journals (Sweden)

    Om Prakash Giri

    2015-01-01

    Full Text Available Background: Substance misuse is an increasing problem in urban and rural India. The utility of community-based interventions and preventive strategies are increasingly emphasized in this context. The drug de-addiction and treatment center, Department of Psychiatry, Postgraduate Institute of Medical Education and Research, has been running a drug de-addiction and treatment clinic at Kharar Civil Hospital, Kharar, District Mohali, Punjab, since 1998. As part of an effort to enhance this community outreach program, community-based drug awareness and treatment camps have been organized since March 2004 in villages in and around Tehsil Kharar of Mohali. Aim: To study the impact of the drug awareness and treatment camps on the attendance of patients at the community outreach drug de-addiction and treatment clinic at Kharar Civil Hospital. Methods: Sociodemographic and clinical variables, including treatment outcome-related variables, of patients attending the clinic at Kharar Civil Hospital, before and after the camps were compared. Discussion and Conclusion: The study showed a positive impact on drug awareness and treatment camps held in the community on outpatient attendance at a community outreach clinic, with attendance increasing more than 1.8 times.

  7. Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs

    DEFF Research Database (Denmark)

    Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V

    2016-01-01

    of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along...

  8. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Francesco Panza

    2016-01-01

    Full Text Available The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI is methylthioninium (MT, a drug existing in equilibrium between a reduced (leuco-methylthioninium and oxidized form (MT+. MT chloride (methylene blue was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

  9. CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.

    Science.gov (United States)

    Ma, Leyuan; Boucher, Jeffrey I; Paulsen, Janet; Matuszewski, Sebastian; Eide, Christopher A; Ou, Jianhong; Eickelberg, Garrett; Press, Richard D; Zhu, Lihua Julie; Druker, Brian J; Branford, Susan; Wolfe, Scot A; Jensen, Jeffrey D; Schiffer, Celia A; Green, Michael R; Bolon, Daniel N

    2017-10-31

    Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9-based saturated mutagenesis approach to generate comprehensive libraries of point mutations at a defined genomic location and systematically study their effect on cell growth. As proof of concept, we mutagenized a selected region within the leukemic oncogene BCR-ABL1 Using bulk competitions with a deep-sequencing readout, we analyzed hundreds of mutations under multiple drug conditions and found that the effects of mutations on growth in the presence or absence of drug were critical for predicting clinically relevant resistant mutations, many of which were cancer adaptive in the absence of drug pressure. Using this approach, we identified all clinically isolated BCR-ABL1 mutations and achieved a prediction score that correlated highly with their clinical prevalence. The strategy described here can be broadly applied to a variety of oncogenes to predict patient mutations and evaluate resistance susceptibility in the development of new therapeutics. Published under the PNAS license.

  10. [The incidence, etiology and clinical significance of visceral mycoses in patients with AIDS].

    Science.gov (United States)

    Manfredi, R; Nanetti, A; Mazzoni, A; Mastroianni, A; Chiodo, F

    1993-01-01

    The incidence, aetiology and clinical significance of visceral mycoses in HIV-infected subjects were evaluated by a retrospective survey of the clinical and microbiological records of 237 consecutive AIDS patients followed-up since 1984. Seventy-four patients out of 237 (31.2%) (56 males, 18 females; 55 IV drug abusers, 7 heterosexuals, 6 homobisexuals, 3 blood recipients and 3 children with congenitally-acquired HIV infection) presented 77 different episodes of visceral fungal infection as a whole, represented by candidiasis in 56 cases (oesophageal 45, pulmonary 5, sepsis 2, eye involvement 2, endocarditis and invasive oropharyngeal infection in the remaining 2 patients), cryptococcosis in 17 cases (meningoencephalitis in all subjects, with disseminated infection in 11 of them), and aspergillosis in 4 cases (pulmonary 2, cerebral and cranio-facial in the remaining 2 patients). In 57 out of 74 patients (77%), visceral mycoses were diagnostic or concurrent with the diagnosis of AIDS. Fungal diseases, as a whole, showed a significantly higher incidence (p drug abusers, whereas homobisexual men presented a significantly lower frequency (p test) than AIDS patients with other risk factors for HIV infection. The onset of cryptococcosis was significantly associated with the male sex (p test). All subjects suffering from a visceral mycosis were severely immunosuppressed, with a higher rate of neutropenia in patients developing Candida and Aspergillus spp. infection (23 out of 56 patients with visceral candidiasis and 3 out of 4 cases of aspergillosis had an absolute neutrophil count lower than 1500 cells/mm3), while a severe reduction in CD4+ lymphocyte count was more evident among patients with cryptococcosis (13 out of 17 patients had a CD4+ cell count lower than 50/mm3). After remission of the primary episode of fungal infection (obtained in 80.5% of cases), the incidence of relapse observed in a long follow-up period (mean time 57.6 +/- 39.2 weeks) was elevated both

  11. Clinical trials using a radiopharmaceutical investigational drug: What legal environment and what authorizations required?

    International Nuclear Information System (INIS)

    El-Deeb, G.; Nguon, B.; Tibi, A.; Rizzo-Padoin, N.

    2009-01-01

    Recent revision of the legal environment for clinical research in France provided an opportunity to review what a hospital needs to carry out clinical trials using a radiopharmaceutical investigational drug. Legal measures concerning radiopharmaceutical investigational drugs are indeed more complex than those of classical clinical trials because of the additional legal provisions governing the use of ionizing radiation. Thus, requirements by the concerned staff (sponsor, pharmacist, person in charge of the nuclear activity) are described here. (authors) [fr

  12. Prescription practice of anti-tuberculosis drugs in Yunnan, China: A clinical audit.

    Directory of Open Access Journals (Sweden)

    Lin Xu

    Full Text Available China has a high burden of drug-resistant tuberculosis (TB. As irrational use and inadequate dosing of anti-TB drugs may contribute to the epidemic of drug-resistant TB, we assessed the drug types and dosages prescribed in the treatment of TB cases in a representative sample of health care facilities in Yunnan.We applied multistage cluster sampling using probability proportion to size to select 28 counties in Yunnan. Consecutive pulmonary TB patients were enrolled from either the TB centers of Yunnan Center of Disease Control or designated TB hospitals. Outcomes of interest included the regimen used in the treatment of new and retreatment TB patients; and the proportion of patients treated with adequate dosing of anti-TB drugs. Furthermore, we assess whether there has been reduction in the use of fluoroquinolone and second line injectables in Tuberculosis Clinical Centre (TCC after the training activity in late 2012.Of 2390 TB patients enrolled, 582 (24.4% were prescribed second line anti-TB drugs (18.0% in new cases and 60.9% in retreatment cases; 363(15.2% prescribed a fluoroquinolone. General hospitals (adjusted odds ratio (adjOR 1.97, 95% confidence interval (CI 1.47-2.66, retreatment TB cases (adjOR 4.75, 95% CI 3.59-6.27, smear positive cases (adjOR 1.69, 95% CI 1.22-2.33, and extrapulmonary TB (adjOR 2.59, 95% CI 1.66-4.03 were significantly associated with the use of fluoroquinolones. The proportion of patients treated with fluoroquinolones decreased from 41.4% before 2013 to 13.5% after 2013 (adjOR 0.19, 95% CI 0.12-0.28 in TCC. The proportion of patients with correct, under and over dosages of isoniazid was 88.2%, 1.5%, and 10.4%, respectively; of rifampicin was 50.2%, 46.8%, and 2.9%; of pyrazinamide was 67.6%, 31.7% and 0.7%; and of ethambutol was 41.4%, 57.5%, and 1.0%.The prescribing practice of anti-TB drugs was not standardized, findings with significant programmatic implication.

  13. Clinical Effects of Synthetic Cannabinoid Receptor Agonists Compared with Marijuana in Emergency Department Patients with Acute Drug Overdose.

    Science.gov (United States)

    Zaurova, Milana; Hoffman, Robert S; Vlahov, David; Manini, Alex F

    2016-12-01

    Synthetic cannabinoid receptor agonists (SCRAs) are heterogeneous compounds originally intended as probes of the endogenous cannabinoid system or as potential therapeutic agents. We assessed the clinical toxicity associated with recent SCRA use in a large cohort of drug overdose patients. This subgroup analysis of a large (n = 3739) drug overdose cohort study involved consecutive ED patients at two urban teaching hospitals collected between 2009 and 2013. Clinical characteristics of patients with the exposure to SCRAs (SRCA subgroup) were compared with those from patients who smoked traditional cannabinoids (marijuana subgroup). Data included demographics, exposure details, vital signs, mental status, and basic chemistries gathered as part of routine clinical care. Study outcomes included altered mental status and cardiotoxicity. Eighty-seven patients reported exposure to any cannabinoid, of whom 17 reported SCRAs (17 cases, 70 controls, mean age 38.9 years, 77 % males, 31 % Hispanic). There were no significant differences between SRCA and marijuana with respect to demographics (age, gender, and race/ethnicity), exposure history (suicidality, misuse, and intent), vital signs, or serum chemistries. Mental status varied between SRCA and marijuana, with agitation significantly more likely in SCRA subgroup (OR = 3.8, CI = 1.2-11.9). Cardiotoxicity was more pronounced in the SCRA subgroup with dysrhythmia significantly more likely (OR = 9.2, CI = 1.0-108). In the first clinical study comparing the adverse effects of SCRA overdose vs. marijuana controls in an ED population, we found that SCRA overdoses had significantly pronounced neurotoxicity and cardiotoxicity compared with marijuana.

  14. Clinical benefits of drug-eluting stent implantation in septuagenarians with coronary artery disease

    International Nuclear Information System (INIS)

    Fang Yuehua; Shen Weifeng; Zhang Ruiyan; Zhang Jiansheng; Hu Jian; Zhang Xian; Zheng Aifang

    2005-01-01

    Objective: This study evaluated the safety and long-term outcomes of drug-eluting stents in septuagenarians with coronary artery disease. Methods: Two hundred and thirty-nine consecutive patients with coronary artery disease underwent drug-eluting stenting, including 88 patients aged ≥70 years (group A) and 151 aged <70 years (group B). Baseline clinical characteristics, procedural success rate, occurrence of cardiac events during follow-up were recorded and compared between the two groups. Results: Procedural success rate and complications were similar for the two groups. During follow-up, group A had higher recurrence rate of chest pain than group B (23.9% vs. 7.3%, P<0.001), and occurrence of cardiac events was higher in group A than in group B (5.7% vs. 2.7%, P<0.296). There was no significant difference in the frequency of restenosis between the two groups. Conclusions: Drug-eluting stent implantation for septuagenarians with coronary artery disease is safe but may have more recurrence of angina than younger ones during long-term follow-up. (authors)

  15. Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

    Directory of Open Access Journals (Sweden)

    Maarten Janssen

    2014-03-01

    Full Text Available Osteoarthritis (OA is a big burden of disease worldwide and one of the most common causes of disability in the adult population. Currently applied therapies consist of physical therapy, oral medication, intra-articular injections, and surgical interventions, with the main goal being to reduce pain and improve function and quality of life. Intra-articular (IA administration of drugs has potential benefits in OA treatment because it minimizes systemic bioavailability and side effects associated with oral administration of drugs without compromising the therapeutic effect in the joint. However, IA drug residence time is short and there is a clinical need for a vehicle that is able to provide a sustained release long enough for IA therapy to fulfill its promise. This review summarizes the use of different polymeric systems and the incorporated drugs for IA drug delivery in the osteoarthritic joint with a primary focus on clinical needs and opportunities.

  16. Use of Immunomodulatory Drugs at a Uveitis Clinic.

    Science.gov (United States)

    Millán-Longo, Claudia; Peiteado, Diana; Schlincker, Armelle; Hidalgo, Ventura; Pieren, Amara; Balsa, Alejandro; de Miguel, Eugenio

    2017-11-10

    The treatment of noninfectious uveitis includes steroids and immunomodulatory drugs, the use of which has increased in the last few years, and the options have been enriched with the development of new treatments. However, clear therapeutic guidelines and protocols have not been developed. The purpose is to analyze the response to the drugs used and the characteristics of the patients treated at a multidisciplinary uveitis clinic. Observational and retrospective study of the patients attended to from January 2012 to December 2015. Infectious, posttraumatic and postoperative uveitis, as well as masquerade syndrome, were excluded. Two hundred six patients were included. Overall, 58.80% had uveitis without association of systemic disease, mostly idiopathic uveitis, and 35.65% had uveitis with systemic involvement, mainly related to spondyloarthritis. Uveitis without systemic association and anterior uveitis achieved disease control with local treatment more frequently than others (p=.002 and p treatment. Among those treated with immunomodulators, 53.26% needed a second drug and 31.52% needed a third drug. Women required immunomodulators more often than men (P=.042). Methotrexate was the most widely used immunomodulator. Posterior uveitis responded less favorably to the second immunomodulator than anterior uveitis (p=.006). Almost half of the patients needed an immunomodulatory drug and some of them required successive drug changes. Intermediate uveitis was the most treatment-refractory uveitis. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  17. Whole genome sequencing of clinical strains of Mycobacterium tuberculosis from Mumbai, India: A potential tool for determining drug-resistance and strain lineage.

    Science.gov (United States)

    Chatterjee, Anirvan; Nilgiriwala, Kayzad; Saranath, Dhananjaya; Rodrigues, Camilla; Mistry, Nerges

    2017-12-01

    Amplification of drug resistance in Mycobacterium tuberculosis (M.tb) and its transmission are significant barriers in controlling tuberculosis (TB) globally. Diagnostic inaccuracies and delays impede appropriate drug administration, which exacerbates primary and secondary drug resistance. Increasing affordability of whole genome sequencing (WGS) and exhaustive cataloguing of drug resistance mutations is poised to revolutionise TB diagnostics and facilitate personalized drug therapy. However, application of WGS for diagnostics in high endemic areas is yet to be demonstrated. We report WGS of 74 clinical TB isolates from Mumbai, India, characterising genotypic drug resistance to first- and second-line anti-TB drugs. A concordance analysis between phenotypic and genotypic drug susceptibility of a subset of 29 isolates and the sensitivity of resistance prediction to the 4 drugs was calculated, viz. isoniazid-100%, rifampicin-100%, ethambutol-100% and streptomycin-85%. The whole genome based phylogeny showed almost equal proportion of East Asian (27/74) and Central Asian (25/74) strains. Interestingly we also found a clonal group of 9 isolates, of which 7 patients were found to be from the same geographical location and accessed the same health post. This provides the first evidence of epidemiological linkage for tracking TB transmission in India, an approach which has the potential to significantly improve chances of End-TB goals. Finally, the use of Mykrobe Predictor, as a standalone drug resistance and strain typing tool, requiring just few minutes to analyse raw WGS data into tabulated results, implies the rapid clinical applicability of WGS based TB diagnosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. New developments in the clinical use of drug-coated balloon catheters in peripheral arterial disease

    Directory of Open Access Journals (Sweden)

    Naghi J

    2016-06-01

    Full Text Available Jesse Naghi, Ethan A Yalvac, Ali Pourdjabbar, Lawrence Ang, John Bahadorani, Ryan R Reeves, Ehtisham Mahmud, Mitul Patel Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California, San Diego, CA, USA Abstract: Peripheral arterial disease (PAD involving the lower extremity is a major source of morbidity and mortality. Clinical manifestations of PAD span the spectrum from lifestyle limiting claudication to ulceration and gangrene leading to amputation. Advancements including balloon angioplasty, self-expanding stents, drug-eluting stents, and atherectomy have resulted in high technical success rates for endovascular therapy in patients with PAD. However, these advances have been limited by somewhat high rates of clinical restenosis and clinically driven target lesion revascularization. The recent introduction of drug-coated balloon technology shows promise in limiting neointimal hyperplasia induced by vascular injury after endovascular therapies. This review summarizes the contemporary clinical data in the emerging area of drug-coated balloons. Keywords: drug-coated balloons, endovascular, percutaneous transluminal angioplasty, paclitaxel, peripheral arterial disease

  19. Prevalence of recreational drug use reported by men who have sex with men attending sexual health clinics in Manchester, UK.

    Science.gov (United States)

    Tomkins, A; Ahmad, S; Cannon, L; Higgins, S P; Kliner, M; Kolyva, A; Ward, C; Vivancos, R

    2018-03-01

    Recreational drug use (RDU) has been reported to be disproportionately higher in men who have sex with men (MSM) when compared to their heterosexual counterparts. To identify RDU, links to risky sexual practices and infections for MSM attending three sexual health clinics across Manchester, United Kingdom, a retrospective case note review was conducted using a random powered sample of service users attending three sites during 2014. Three hundred and fifty-seven case notes were reviewed across three sites. Eighteen per cent of service users reported any type of RDU. Use of at least one of the three drugs associated with chemsex (crystal methamphetamine, mephedrone, gamma hydroxybutyrate/gamma butyrolactone) was reported by 3.6%. A statistically significant difference was identified between non-drug users and any-drug users reporting: group sex (odds ratio [OR] 5.88, p = 0.013), condomless receptive anal intercourse (CRAI) (OR 2.77, p = 0.003) and condomless oral intercourse (OR 2.52, p = 0.016). A statistically significant difference was identified between chemsex-related drug user and non-drug user groups reporting: group sex (OR 13.05, p = 0.023), CRAI (OR 3.69, p = 0.029) and condomless insertive anal intercourse (OR 1.27, p = 0.039). There was also a statistically higher incidence of gonorrhoea infection in chemsex-related drug use compared with those not using drugs (p = 0.002, OR 6.88). This study identifies that substance use is common in MSM attending sexual health clinics in Manchester. High-risk sexual practices and certain sexually transmitted infections are more common in MSM reporting RDU.

  20. Physician adherence to hypertension treatment guidelines and drug acquisition costs of antihypertensive drugs at the cardiac clinic: a pilot study

    Directory of Open Access Journals (Sweden)

    Abdulameer SA

    2012-01-01

    Full Text Available Shaymaa Abdalwahed Abdulameer1, Mohanad Naji Sahib1, Noorizan Abd Aziz1,2, Yahaya Hassan1,2, Hadeer Akram Abdul AlRazzaq1, Omar Ismail31School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia; 2Faculty of Pharmacy, Universiti Teknologi MARA (UiTM, 42300 Puncak Alam, Selangor, Malaysia; 3Hospital Pulau Pinang, 10900, Penang, MalaysiaAbstract: Prescribing pattern surveys are one of the pharmacoepidemiological techniques that provide an unbiased picture of prescribing habits. Prescription surveys permit the identification of suboptimal prescribing patterns for further evaluation. The aims of this study were to determine the prescribing trend, adherence of the prescribers to the guideline, and the impact of drug expenditure on drug utilization at the cardiac clinic of Penang Hospital, Malaysia. This was a cross-sectional study. Demographic data of the patients, diagnoses and the drugs prescribed were recorded. The average drug acquisition costs (ADAC were calculated for each antihypertensive drug class on a daily and annual basis. Adherence to the guideline was calculated as a percentage of the total number of patients. A total of 313 individuals fulfilled the inclusion criteria. The average age of the study population was 59.30 ± 10.35 years. The mean number of drugs per prescription in the study was 2.09 ± 0.78. There were no significant differences in the demographic data. Antihypertensive drugs were used in monotherapy and polytherapy in 20.8% and 79.2% of the patients, respectively. Adherence to the guideline regarding prescription occurred in 85.30% of the patients. The lowest priced drug class was diuretics and the highest was angiotensin-receptor blockers. In conclusion, the total adherence to the guideline was good; the adherence percentage only slightly decreased with a co-existing comorbidity (such as diabetes mellitus. The use of thiazide diuretics was encouraged because they are well tolerated and

  1. The clinical implication of drug dependency in children and adults with inflammatory bowel disease: a review

    DEFF Research Database (Denmark)

    Duricova, Dana; Pedersen, Natalia; Lenicek, Martin

    2011-01-01

    Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug...... corticosteroid dependency. Infliximab dependency was described in 42-66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients...... was suggested to postpone if not avoid the need of surgery. Lastly, mesalazine dependency was identified in 23% of adults with Crohn's disease. These patients were characterized by mild disease course and lower surgical risk compared to non-responders to mesalazine (32 vs. 61%). Identification of drug...

  2. Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin.

    Science.gov (United States)

    Macy, Eric; Ngor, Eunis W

    2013-01-01

    Penicillin skin testing is rarely used to undiagnose penicillin "allergy" in the United States, partially because of concern that commercially available materials are inadequate. We determined whether skin testing with only commercially available penicilloyl-poly-lysine and penicillin followed by an oral amoxicillin challenge, if skin test-negative, can safely identify clinically significant penicillin allergy. Five hundred sequential persons with positive history of penicillin "allergy" were evaluated by skin testing with penicilloyl-poly-lysine and penicillin between June 8, 2010, and March 29, 2012. All persons with negative skin tests were given an oral amoxicillin challenge and observed for 1 hour. Persons undergoing penicillin allergy testing were representative of all health plan members with penicillin allergy. Only 4 persons (0.8%; 95% CI, 0.32%-2.03%) had a positive skin test result. Only 4 persons (0.8%; 95% CI, 0.32%-2.03%) had an acute objective oral amoxicillin challenge reaction. Fifteen persons (3.0%; 95% CI, 1.83%-4.98%) had subjective oral challenge reactions, either acute transient itching or dizziness. All were women and 11 (73.3%) had multiple drug intolerance syndrome. None had severe reactions or objective signs. These were not considered to be positive challenge reactions. Sixty-eight subjects (13.6%) who were negative on testing were exposed to 88 courses of penicillins during 90 days of follow-up. New reactions were reported after 4 courses (4.5%), 3 (75%) occurring in subjects with multiple drug intolerance syndrome. Penicillin skin testing, using only penicilloyl-poly-lysine and penicillin, followed by oral amoxicillin challenge, if negative, can safely identify clinically significant IgE-mediated penicillin allergy in patients who use health care in the United States at this time. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  3. Identifying Adult Dengue Patients at Low Risk for Clinically Significant Bleeding.

    Directory of Open Access Journals (Sweden)

    Joshua G X Wong

    Full Text Available Clinically significant bleeding is important for subsequent optimal case management in dengue patients, but most studies have focused on dengue severity as an outcome. Our study objective was to identify differences in admission parameters between patients who developed clinically significant bleeding and those that did not. We sought to develop a model for discriminating between these patients.We conducted a retrospective study of 4,383 adults aged >18 years who were hospitalized with dengue infection at Tan Tock Seng Hospital, Singapore from 2005 to 2008. Patients were divided into those with clinically significant bleeding (n = 188, and those without (n = 4,195. Demographic, clinical, and laboratory variables on admission were compared between groups to determine factors associated with clinically significant bleeding during hospitalization.On admission, female gender (p38°C (p38°C (aOR 1.81; 95% CI: 1.27-2.61, nausea/vomiting (aOR 1.39; 95% CI: 0.94-2.12, ANC (aOR 1.3; 95% CI: 1.15-1.46, ALC (aOR 0.4; 95% CI: 0.25-0.64, hematocrit percentage (aOR 0.96; 95% CI: 0.92-1.002 and platelet count (aOR 0.993; 95% CI: 0.988-0.998. At the cutoff of -3.919, the model achieved an AUC of 0.758 (sensitivity:0.87, specificity: 0.38, PPV: 0.06, NPV: 0.98.Clinical risk factors associated with clinically significant bleeding were identified. This model may be useful to complement clinical judgement in triaging adult dengue patients given the dynamic nature of acute dengue, particularly in pre-identifying those less likely to develop clinically significant bleeding.

  4. General Beliefs and Stigma Regarding Illicit Drug Use: Perspectives of Family Members and Significant Others of Drug Users in an Inner City in Brazil.

    Science.gov (United States)

    Ventura, Carla Aparecida Arena; Carrara, Bruna Sordi; Bobbili, Sireesha; Vedana, Kelly Graziani Giacchero; Khenti, Akwatu; Hayashida, Miyeko; Ferreira, Paulo Sergio

    2017-09-01

    People who use drugs are continuously subjected to harsh stigmatization through a process of relational and social degradation, which limits their possibility for recovery. This quantitative study explores the perspectives of family members or significant others of illicit drug users, regarding general beliefs about illicit drug use and their stigma. Respondents agree that most people do not trust people who use drugs, disregard individuals who have been hospitalized due to drug problems and do not think people who use drugs are as intelligent as the general population. These findings reveal a high level of public stigma regarding illicit drug use.

  5. Drug release, preclinical and clinical pharmacokinetics relationships of alginate pellets prepared by melt technology.

    Science.gov (United States)

    Bose, Anirbandeep; Harjoh, Nurulaini; Pal, Tapan Kumar; Dan, Shubhasis; Wong, Tin Wui

    2016-01-01

    Alginate pellets prepared by the aqueous agglomeration technique experience fast drug dissolution due to the porous pre-formed calcium alginate microstructure. This study investigated in vitro drug release, preclinical and clinical pharmacokinetics relationships of intestinal-specific calcium acetate-alginate pellets against calcium-free and calcium carbonate-alginate pellets. Alginate pellets were prepared by solvent-free melt pelletization instead of aqueous agglomeration technique using chlorpheniramine maleate as model drug. A fast in situ calcium acetate dissolution in pellets resulted in rapid pellet breakup, soluble Ca(2+) crosslinking of alginate fragments and drug dissolution retardation at pH 1.2, which were not found in other pellet types. The preclinical drug absorption rate was lower with calcium acetate loaded than calcium-free alginate pellets. In human subjects, however, the extent and the rate of drug absorption were higher from calcium acetate-loaded pellets than calcium-free alginate pellets. The fine, dispersible and weakly gastric mucoadhesive calcium alginate pellets underwent fast human gastrointestinal transit. They released the drug at a greater rate than calcium-free pellets in the intestine, thereby promoting drug bioavailability. Calcium acetate was required as a disintegrant more than as a crosslinking agent clinically to promote pellet fragmentation, fast gastrointestinal transit and drug release in intestinal medium, and intestinal-specific drug bioavailability.

  6. Evidence behind FDA alerts for drugs with adverse cardiovascular effects: implications for clinical practice.

    Science.gov (United States)

    Rackham, Daniel M; C Herink, Megan; Stevens, Ian G; Cardoza, Natalie M; Singh, Harleen

    2014-01-01

    The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications. © 2013 Pharmacotherapy Publications, Inc.

  7. The antiplatelet effects of nitrates: is it of clinical significance in patients with cardiovascular disease?

    Science.gov (United States)

    Zhou, Rui-Hai; Frishman, William H

    2010-01-01

    Organic nitrates have been used for over a century in cardiovascular therapy and are still widely used in the treatment of acute coronary syndromes, chronic angina pectoris, and congestive heart failure. Nitrates, together with sodium nitroprusside, generally referred to as nitrovasodilators, exert their biologic effects via the release of nitric oxide. They are also known as nitric oxide donors. The mechanism of action of these drugs is traditionally believed to lie in their arterial vasodilation and venodilation effects, resulting in an improvement of coronary artery blood supply and/or reduction of cardiac workload in the treatment of coronary artery disease and congestive heart failure. Recently it has been recognized that these drugs also have intrinsic antiplatelet and antithrombotic effects, demonstrated both in vitro and in vivo, which would add further rationale for the use of these drugs in atherothrombotic diseases. Research has shown that nitrovasodilators can nonselectively inhibit platelet aggregation induced by multiple stimuli. However, clinical trials have yielded conflicting results regarding clinical outcome, especially with long-term nitrate use. The potentially beneficial effects of nitrates could be negated by the development of tolerance and the generation of deleterious oxidative stress causing endothelial dysfunction during continuous nitrate administration. Much progress has been made in the development of new nitric oxide donors devoid of oxidant-generating properties. Novel combination therapies with nitrovasodilators plus antioxidants or agents with antioxidant properties have shown promise in reducing or reversing tolerance, potentiating antiplatelet effects, and improving clinical outcome. It is expected that clinical introduction of novel nitrovasodilator regimens will provide a new approach to the prevention and treatment of atherothrombotic diseases. Large-scale clinical trials will ultimately provide the evidence-based answers.

  8. Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet.

    Directory of Open Access Journals (Sweden)

    Tracey J Weiland

    Full Text Available Fatigue contributes a significant burden of disease for people with multiple sclerosis (PwMS. Modifiable lifestyle factors have been recognized as having a role in a range of morbidity outcomes in PwMS. There is significant potential to prevent and treat fatigue in PwMS by addressing modifiable risk factors.To explore the associations between clinically significant fatigue and demographic factors, clinical factors (health-related quality of life, disability and relapse rate and modifiable lifestyle, disease-modifying drugs (DMD and supplement use in a large international sample of PwMS.PwMS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic, lifestyle and clinical characteristics, including health-related quality of life, disability, and relapse rate.Of 2469 participants with confirmed MS, 2138 (86.6% completed a validated measure of clinically significant fatigue, the Fatigue Severity Scale. Participants were predominantly female from English speaking countries, with relatively high levels of education, and due to recruitment methods may have been highly pro-active about engaging in lifestyle management and self-help. Approximately two thirds of our sample (1402/2138; 65.6% (95% CI 63.7-67.7 screened positive for clinically significant fatigue. Bivariate associations were present between clinically significant fatigue and several demographic, clinical, lifestyle, and medication variables. After controlling for level of disability and a range of stable socio-demographic variables, we found increased odds of fatigue associated with obesity, DMD use, poor diet, and reduced odds of fatigue with exercise, fish consumption, moderate alcohol use, and supplementation with vitamin D and flaxseed oil.This study supports strong and significant associations between clinically significant fatigue and modifiable lifestyle factors. Longitudinal follow-up of this sample may help clarify the contribution

  9. Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

    Science.gov (United States)

    Kosa, Rachel E; Lazzaro, Sarah; Bi, Yi-An; Tierney, Brendan; Gates, Dana; Modi, Sweta; Costales, Chester; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena V

    2018-06-07

    We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP) and talinolol (P-gp) were obtained in cynomolgus monkey - alone or in combination with transporter inhibitors. Single dose rifampicin (30 mg/kg) significantly (pdrugs, with a marked effect on pitavastatin and rosuvastatin (AUC ratio ~21-39). Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (pdrug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions. The American Society for Pharmacology and Experimental Therapeutics.

  10. 76 FR 51040 - Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good...

    Science.gov (United States)

    2011-08-17

    ... requirements, and investigator initiated research. Topics for discussion include the following: (1) What FDA...] Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good Clinical... Clinical Research Associates (SoCRA) is announcing a public workshop. The public workshop on FDA's clinical...

  11. Phase II drugs under clinical investigation for the treatment of chronic constipation.

    Science.gov (United States)

    Mozaffari, Shilan; Didari, Tina; Nikfar, Shekoufeh; Abdollahi, Mohammad

    2014-11-01

    Chronic constipation (CC) is a common gastrointestinal (GI) motility disorder that significantly impairs the quality of life in affected subjects. As almost half of the patients suffering from CC are not satisfied with currently available medicines, there is a need to develop new molecules with better effectiveness and tolerability. The authors include all experimental and clinical trials (up to Phase II) about new investigational drugs for the treatment of CC. The article identifies nine new agents: mitemcinal, TD-8954, YKP10811, itopride, RM-131, KWA-0711, elobixibat, velusetrag, and naronapride. All nine agents have shown prokinetic effects in different stages of the development. The mechanisms of new developing drugs include: the activation of 5-hydroxytryptamine type-4 (5-HT4), ghrelin and motilin receptors, antagonizing dopamine type-2 (D2) receptors, inhibition of ileal bile acid reabsorption and acetylcholine esterase, as well as water absorption from the GI tract. At this current point in time, new generations of 5-HT4 receptor agonists (velusetrag, noranopride and YKP10811) are hoped to progress, further in the future, due to better efficiency and safety. However, it is not possible to make a concise conclusion at this current time due to a lack of evidence. Further clinical trials with a longer duration and a larger sample size are warranted.

  12. Associating Drugs, Targets and Clinical Outcomes into an Integrated Network Affords a New Platform for Computer-Aided Drug Repurposing

    DEFF Research Database (Denmark)

    Oprea, Tudor; Nielsen, Sonny Kim; Ursu, Oleg

    2011-01-01

    benefit from an integrated, semantic-web compliant computer-aided drug repurposing (CADR) effort, one that would enable deep data mining of associations between approved drugs (D), targets (T), clinical outcomes (CO) and SE. We report preliminary results from text mining and multivariate statistics, based...... on 7684 approved drug labels, ADL (Dailymed) via text mining. From the ADL corresponding to 988 unique drugs, the "adverse reactions" section was mapped onto 174 SE, then clustered via principal component analysis into a 5 x 5 self-organizing map that was integrated into a Cytoscape network of SE......Finding new uses for old drugs is a strategy embraced by the pharmaceutical industry, with increasing participation from the academic sector. Drug repurposing efforts focus on identifying novel modes of action, but not in a systematic manner. With intensive data mining and curation, we aim to apply...

  13. Characterization of drug-related problems identified by clinical pharmacy staff at Danish hospitals

    DEFF Research Database (Denmark)

    Kjeldsen, Lene Juel; Birkholm, Trine; Fischer, Hanne

    2014-01-01

    Background In 2010, a database of drug related problems (DRPs) was implemented to assist clinical pharmacy staff in documenting clinical pharmacy activities locally. A study of quality, reliability and generalisability showed that national analyses of the data could be conducted. Analyses...... at the national level may help identify and prevent DRPs by performing national interventions. Objective The aim of the study was to explore the DRP characteristics as documented by clinical pharmacy staff at hospital pharmacies in the Danish DRP-database during a 3-year period. Setting Danish hospital pharmacies....... Method Data documented in the DRP-database during the initial 3 years after implementation were analyzed retrospectively. The DRP-database contains DRPs reported at hospitals by clinical pharmacy staff. The analyses focused on DRP categories, implementation rates and drugs associated with the DRPs. Main...

  14. Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review.

    Science.gov (United States)

    Van Herwaarden, Noortje; Van Den Bemt, Bart J F; Wientjes, Maike H M; Kramers, Cornelis; Den Broeder, Alfons A

    2017-08-01

    Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient. Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity. Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.

  15. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis.

    Science.gov (United States)

    Kesselheim, Aaron S; Misono, Alexander S; Lee, Joy L; Stedman, Margaret R; Brookhart, M Alan; Choudhry, Niteesh K; Shrank, William H

    2008-12-03

    Use of generic drugs, which are bioequivalent to brand-name drugs, can help contain prescription drug spending. However, there is concern among patients and physicians that brand-name drugs may be clinically superior to generic drugs. To summarize clinical evidence comparing generic and brand-name drugs used in cardiovascular disease and to assess the perspectives of editorialists on this issue. Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1984 to August 2008. Studies compared generic and brand-name cardiovascular drugs using clinical efficacy and safety end points. We separately identified editorials addressing generic substitution. We extracted variables related to the study design, setting, participants, clinical end points, and funding. Methodological quality of the trials was assessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed to determine an aggregate effect size. For editorials, we categorized authors' positions on generic substitution as negative, positive, or neutral. We identified 47 articles covering 9 subclasses of cardiovascular medications, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equivalence was noted in 7 of 7 RCTs (100%) of beta-blockers, 10 of 11 RCTs (91%) of diuretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1 of 1 RCT (100%) of alpha-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n = 837) was -0.03 (95% confidence interval, -0.15 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution. Whereas evidence does not

  16. Multi-regional clinical trials and global drug development

    Directory of Open Access Journals (Sweden)

    Premnath Shenoy

    2016-01-01

    Full Text Available Drug development has been globalized, and multi-regional clinical trial (MRCT for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and improve patient access to new and innovative treatments. Sponsors are facing several challenges while conducting multiregional clinical trials. Challenges under the heads statistics, clinical, regulatory operational, and ethics have been discussed. Regulators in different countries such as USA, EU-Japan, and China have issued guidance documents in respect of MRCT's. Lack of harmonization in the design and planning of MRCT is perceived to create a difficult situation to sponsors adversely affecting progressing MRCT in more and more discoveries. International conference on hormonisation (ICH has initiated the process for having a harmonized guidance document on MRCT. This document is likely to be issued in early 2017.

  17. 76 FR 78933 - Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good...

    Science.gov (United States)

    2011-12-20

    ..., electronic record requirements, and investigator initiated research. Topics for discussion include the...] Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good Clinical... Clinical Research Associates (SoCRA), is announcing a public workshop. The public workshop on FDA's...

  18. Drug therapy problems identification by clinical pharmacists in a private hospital in Kuwait.

    Science.gov (United States)

    Bayoud, T; Waheedi, M; Lemay, J; Awad, A

    2018-05-01

    To report the types and frequency of drug therapy problems (DTPs) identified and the physician acceptance of the clinical pharmacist interventions in a private hospital in Kuwait. A retrospective cross-sectional study was conducted on 3500 patients admitted to the hospital between December 2010 and April 2013. A structured approach was used to identify DTPs and recommend interventions. Data were analyzed using MAXQDA version 11. A total of 670 DTPs were identified and recommendations were proposed to treating physicians for each DTP. Overdosage was the most frequently identified drug therapy problem (30.8%), followed by low dosage (17.6%), unnecessary drug therapy (17.3%), need for additional drug therapy (11.6%), and need for different drug product (11.6%). The drug classes most frequently involved were anti-infectives (36.9%), analgesics (25.2%), and gastrointestinal agents (15.5%). More than two-third of the interventions (67.5%) were accepted and implemented by physicians. The most frequently accepted interventions were related to nonadherence, adverse drug reaction, monitoring parameters, inappropriate dosage, and need for additional drug therapy. The current findings expand the existing body of data by reporting on pharmacist recommendations of identified DTPs and importantly, their high rate of acceptance and implementation by the treating physician. These results could serve as a springboard to support further development and implementation of clinical pharmacy services in other healthcare settings in Kuwait. Copyright © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

  19. Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review.

    Science.gov (United States)

    Yu, Jingjing; Ritchie, Tasha K; Mulgaonkar, Aditi; Ragueneau-Majlessi, Isabelle

    2014-12-01

    The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Chiral drug analysis using mass spectrometric detection relevant to research and practice in clinical and forensic toxicology.

    Science.gov (United States)

    Schwaninger, Andrea E; Meyer, Markus R; Maurer, Hans H

    2012-12-21

    This paper reviews analytical approaches published in 2002-2012 for chiral drug analysis and their relevance in research and practice in the field of clinical and forensic toxicology. Separation systems such as gas chromatography, high performance liquid chromatography, capillary electromigration, and supercritical fluid chromatography, all coupled to mass spectrometry, are discussed. Typical applications are reviewed for relevant chiral analytes such as amphetamines and amphetamine-derived designer drugs, methadone, tramadol, psychotropic and other CNS acting drugs, anticoagulants, cardiovascular drugs, and some other drugs. Usefulness of chiral drug analysis in the interpretation of analytical results in clinical and forensic toxicology is discussed as well. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. 75 FR 14448 - Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good...

    Science.gov (United States)

    2010-03-25

    ... requirements, and investigator initiated research. Topics for discussion include the following: (1) What FDA...] Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good Clinical... Society of Clinical Research Associates, Inc. (SoCRA) is announcing a public workshop entitled ``FDA...

  2. 77 FR 8886 - Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good...

    Science.gov (United States)

    2012-02-15

    ..., electronic record requirements, and investigator initiated research. Topics for discussion include the...] Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good Clinical... Research Associates (SoCRA) is announcing a public workshop. The public workshop on FDA's clinical trial...

  3. A clinical perspective on mucoadhesive buccal drug delivery systems

    Science.gov (United States)

    Gilhotra, Ritu M; Ikram, Mohd; Srivastava, Sunny; Gilhotra, Neeraj

    2014-01-01

    Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Among the various transmucosal routes, buccal mucosa has excellent accessibility and relatively immobile mucosa, hence suitable for administration of retentive dosage form. The objective of this paper is to review the works done so far in the field of mucoadhesive buccal drug delivery systems (MBDDS), with a clinical perspective. Starting with a brief introduction of the mucoadhesive drug delivery systems, oral mucosa, and the theories of mucoadhesion, this article then proceeds to cover the works done so far in the field of MBDDS, categorizing them on the basis of ailments they are meant to cure. Additionally, we focus on the various patents, recent advancements, and challenges as well as the future prospects for mucoadhesive buccal drug delivery systems. PMID:24683406

  4. How to ascertain drug related deaths during clinical trials ?

    Science.gov (United States)

    Lele, R D

    2013-10-01

    Recent guidelines by the Drug Controller General of India require extra care by Investigators & Sponsors of Clinical Trials in India. The author, an eminent member & Chairman of various Independent Ethics Committees in Mumbai, proposes various concrete solutions for adherence to these guidelines. Insurance cover to the subjects, use of Internet databanks for drug interactions, active involvement by the pharmacologists in Ethics Committee, review of data from animal studies, being amongst them. In case of death due to trial, autopsies, or at least verbal autopsies, are essential in the interest of Science and Law. More importantly Anticipation and prevention of ADEs can be done by exclusion of subjects from trials by using newer technologies like cDNA in microarrays to determine several polygenic quantitative trait loci (QTLs) and tests for Single Nucleotide Polymorphisms (SNPs). Drug manufacturers must provide prototypes of Affymetrix chips to clinicians and bear the cost in their own enlightened self-interest.

  5. Significant inhibitory impact of dibenzyl trisulfide and extracts of Petiveria alliacea on the activities of major drug-metabolizing enzymes in vitro: An assessment of the potential for medicinal plant-drug interactions.

    Science.gov (United States)

    Murray, J; Picking, D; Lamm, A; McKenzie, J; Hartley, S; Watson, C; Williams, L; Lowe, H; Delgoda, R

    2016-06-01

    Dibenzyl trisulfide (DTS) is the major active ingredient expressed in Petiveria alliacea L., a shrub widely used for a range of conditions, such as, arthritis, asthma and cancer. Given its use alone and concomitantly with prescription medicines, we undertook to investigate its impact on the activities of important drug metabolizing enzymes, the cytochromes P450 (CYP), a key family of enzymes involved in many adverse drug reactions. DTS and seven standardized extracts from the plant were assessed for their impact on the activities of CYPs 1A2, 2C19, 2C9, 2D6 and 3A4 on a fluorometric assay. DTS revealed significant impact against the activities of CYPs 1A2, 2C19 and 3A4 with IC50 values of 1.9, 4.0 and 3.2μM, respectively, which are equivalent to known standard inhibitors of these enzymes (furafylline, and tranylcypromine), and the most potent interaction with CYP1A2 displayed irreversible enzyme kinetics. The root extract, drawn with 96% ethanol (containing 2.4% DTS), displayed IC50 values of 5.6, 3.9 and 4.2μg/mL respectively, against the same isoforms, CYPs 1A2, 2C19 and 3A4. These investigations identify DTS as a valuable CYP inhibitor and P. alliacea as a candidate plant worthy of clinical trials to confirm the conclusions that extracts yielding high DTS may lead to clinically relevant drug interactions, whilst extracts yielding low levels of DTS, such as aqueous extracts, are unlikely to cause adverse herb-drug interactions. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Defibrotide: properties and clinical use of an old/new drug.

    Science.gov (United States)

    Pescador, R; Capuzzi, L; Mantovani, M; Fulgenzi, A; Ferrero, M E

    2013-01-01

    The drug named defibrotide (DFT) has been studied for many years. It has been shown to possess many activities: profibrinolytic, antithrombotic-thrombolytic, antiischemic (heart, liver, kidney, skin, brain), antishock, antiatherosclerotic, antirejection and anti-angiogenic. The previously displayed activities, as antithrombotic, profibrinolytic and anti-inflammatory, suggested its use in vascular disorders, as in the treatment of peripheral obliterative arterial disease and in thrombophlebitis. Some years after, the use of DFT in hepatic veno-occlusive disease has been also proposed. Even if DFT was considered for long time a multi-target drug, now it could be considered on the whole as a drug able to protect endothelium against activation. The present work reviews the more important experimental and clinical studies performed to detect DFT effects. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Systematic evaluation of drug-disease relationships to identify leads for novel drug uses.

    Science.gov (United States)

    Chiang, A P; Butte, A J

    2009-11-01

    Drug repositioning refers to the discovery of alternative uses for drugs--uses that are different from that for which the drugs were originally intended. One challenge in this effort lies in choosing the indication for which a drug of interest could be prospectively tested. We systematically evaluated a drug treatment-based view of diseases in order to address this challenge. Suggestions for novel drug uses were generated using a "guilt by association" approach. When compared with a control group of drug uses, the suggested novel drug uses generated by this approach were significantly enriched with respect to previous and ongoing clinical trials.

  8. Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru.

    Science.gov (United States)

    Magee, M J; Bloss, E; Shin, S S; Contreras, C; Huaman, H Arbanil; Ticona, J Calderon; Bayona, J; Bonilla, C; Yagui, M; Jave, O; Cegielski, J P

    2013-06-01

    Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan-Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5 kg/m(2) (pdiabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  9. Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Tadahiro Shinozawa

    2017-02-01

    Full Text Available To predict drug-induced serious adverse events (SAE in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox-induced QT prolongation. Different Mox-induced field potential duration (FPD prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66 in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

  10. Primary care physicians' adoption of new drugs is not associated with their clinical interests: A pharmacoepidemiologic study

    DEFF Research Database (Denmark)

    Dybdahl, Torben; Søndergaard, Jens; Kragstrup, Jakob

    2011-01-01

    Abstract Objectives. Increasing drug expenditures call for better understanding of the reasons behind individual general practitioners' (GPs') prescribing decisions. The aim was to analyse associations between GPs' clinical interests and their preference for new drugs. Design. Historical cohort...... association between GPs' self-rated clinical interest and their prescribing of new drugs was found.......-II antagonists) were analysed. The preference was defined as the percentage of patients receiving a new drug among first-time users of either the new drug or an older alternative. The GPs' preference proportion was modelled using linear regression analysis. Data from a questionnaire on GPs' interest...

  11. Identification of drug-related problems by a clinical pharmacist in addition to computerized alerts

    NARCIS (Netherlands)

    Zaal, R.J.; Jansen, M.; Duisenberg-van Essenberg, M.; C.C., Tijssen; Roukema, J.A.; van den Bemt, P.M.

    2013-01-01

    Background Both clinical pharmacists and computerized physician order entry systems with clinical decision support (CPOE/CDSS) can reduce drug-related problems (DRPs). However, the contribution of a clinical pharmacist in addition to CPOE/CDSS has not been established in a prospective study.

  12. Identification of drug-related problems by a clinical pharmacist in addition to computerized alerts

    NARCIS (Netherlands)

    R.J. Zaal (Rianne); M.M.P.M. Jansen (Mark M. P.); M. Duisenberg-Van Essenberg (Marjolijn); C.C. Tijssen (Cees); J.A. Roukema; P.M.L.A. van den Bemt (Patricia)

    2013-01-01

    textabstractBackground Both clinical pharmacists and computerized physician order entry systems with clinical decision support (CPOE/CDSS) can reduce drug-related problems (DRPs). However, the contribution of a clinical pharmacist in addition to CPOE/CDSS has not been established in a prospective

  13. Some uses of predictive probability of success in clinical drug development

    Directory of Open Access Journals (Sweden)

    Mauro Gasparini

    2013-03-01

    Full Text Available Predictive probability of success is a (subjective Bayesian evaluation of the prob- ability of a future successful event in a given state of information. In the context of pharmaceutical clinical drug development, successful events relate to the accrual of positive evidence on the therapy which is being developed, like demonstration of su- perior efficacy or ascertainment of safety. Positive evidence will usually be obtained via standard frequentist tools, according to the regulations imposed in the world of pharmaceutical development.Within a single trial, predictive probability of success can be identified with expected power, i.e. the evaluation of the success probability of the trial. Success means, for example, obtaining a significant result of a standard superiority test.Across trials, predictive probability of success can be the probability of a successful completion of an entire part of clinical development, for example a successful phase III development in the presence of phase II data.Calculations of predictive probability of success in the presence of normal data with known variance will be illustrated, both for within-trial and across-trial predictions.

  14. Data-driven prediction of adverse drug reactions induced by drug-drug interactions.

    Science.gov (United States)

    Liu, Ruifeng; AbdulHameed, Mohamed Diwan M; Kumar, Kamal; Yu, Xueping; Wallqvist, Anders; Reifman, Jaques

    2017-06-08

    via DDIs. This allowed us to identify potential DDI-induced ADRs not yet clinically reported. The ability of the models to quantify adverse effects between drug classes also suggests that we may be able to select drug combinations that minimize the risk of ADRs. Almost all information on DDI-induced ADRs is generated after drug approval. This situation poses significant health risks for vulnerable patient populations with comorbidities. To help mitigate the risks, we developed a robust probabilistic approach to prospectively predict DDI-induced ADRs. Based on this approach, we developed prediction models for 1,096 ADRs and used them to predict the propensity of all pairwise combinations of nearly 800 drugs to be associated with these ADRs via DDIs. We made the predictions publicly available via internet access.

  15. [Morphological signs of inflammatory activity in different clinical forms of drug-resistant pulmonary tuberculosis].

    Science.gov (United States)

    Elipashev, A A; Nikolsky, V O; Shprykov, A S

    to determine whether the activity of tuberculous inflammation is associated with different clinical forms of drug-resistant pulmonary tuberculosis. The material taken from 310 patients operated on in 2010-2015 were retrospectively examined. The patients underwent economical lung resections of limited extent (typical and atypical ones of up to 3 segments) for circumscribed forms of tuberculosis with bacterial excretion. A study group consisted of 161 (51.9%) patients with drug-resistant variants of pulmonary tuberculosis. A control group included 149 (48.1%) patients with preserved susceptibility of Mycobacterium tuberculosis to anti-TB drugs. The activity of specific changes in tuberculosis was morphologically evaluated in accordance with the classification proposed by B.M. Ariel in 1998. The highest activity of fourth-to-fifth degree specific inflammation, including that outside the primary involvement focus, was obtained in the drug-resistant pulmonary tuberculosis group due to the predominance of patients with cavernous and fibrous-cavernous tuberculosis versus those in whom the susceptibility to chemotherapeutic agents was preserved. A macroscopic study showed that the primary lesion focus had a median size in one-half of the all the examinees; but large tuberculomas, caverns, and fibrous caverns over 4 cm in diameter were multiple and detected in the drug-resistant pulmonary tuberculosis group. Multidrug resistance was observed in more than 60% of the patients with fibrous-cavernous pulmonary tuberculosis, extensive drug resistance was seen in those with cavernous tuberculosis, which is an aggravating factor. The data obtained from the morphological study of the intraoperative material can specify the clinical form of tuberculosis and evaluate the efficiency of preoperative specific therapy. The highest activity of specific inflammation was observed in patients with multiple drug-resistant pulmonary tuberculosis, the prevalence of third-to-fourth degree

  16. Adverse Drug Reactions Related to Drug Administration in Hospitalized Patients.

    Science.gov (United States)

    Gallelli, Luca; Siniscalchi, Antonio; Palleria, Caterina; Mumoli, Laura; Staltari, Orietta; Squillace, Aida; Maida, Francesca; Russo, Emilio; Gratteri, Santo; De Sarro, Giovambattista

    2017-01-01

    Drug treatment may be related to the development of adverse drug reactions (ADRs). In this paper, we evaluated the ADRs in patients admitted to Catanzaro Hospital. After we obtained the approval by local Ethical Committee, we performed a retrospective study on clinical records from March 01, 2013 to April 30, 2015. The association between drug and ADR or between drug and drug-drug-interactions (DDIs) was evaluated using the Naranjo's probability scale and Drug Interaction Probability Scale (DIPS), respectively. During the study period, we analyzed 2870 clinical records containing a total of 11,138 prescriptions, and we documented the development of 770 ADRs. The time of hospitalization was significantly higher (P<0.05) in women with ADRs (12.6 ± 1.2 days) with respect to men (11.8± 0.83 days). Using the Naranjo score, we documented a probable association in 78% of these reactions, while DIPS revealed that about 22% of ADRs were related to DDIs. Patients with ADRs received 3052 prescriptions on 11,138 (27.4%) having a mean of 6.1±0.29 drugs that was significantly higher (P<0.01) with respect to patients not experiencing ADRs (mean of 3.4±0.13 drugs). About 19% of ADRs were not diagnosed and were treated as new diseases. Our results indicate that drug administration induces the development of ADRs also during the hospitalization, particularly in elderly women. Moreover, we also documented that ADRs in some patients are under-diagnosed, therefore, it is important to motivate healthcare to report the ADRs in order to optimize the patients' safety. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. On-site management of investigational products and drug delivery systems in conformity with Good Clinical Practices (GCPs).

    Science.gov (United States)

    Méthot, Julie; Brisson, Diane; Gaudet, Daniel

    2012-04-01

    Investigators and research teams participating in clinical trials have to deal with complex investigational products, study designs, and research environments. The emergence of new drug delivery systems and investigational products combining more than one drug and the development of biodrugs such as monoclonal antibodies, peptides, siRNA, and gene therapy to treat orphan or common diseases constitute a new challenge for investigators and clinical sites. We describe the requirements and challenges of drug management in conformity with Good Clinical Practices (GCPs) for investigators and sites participating in clinical trials. Review At all sites participating in clinical trials, standard operating procedures (SOPs) covering the critical path of drug and drug delivery systems management are required. All steps should be auditable, including reception, validation, storage, access, preparation, distribution, techniques of administration, use, return, and destruction of research products. Biodrugs require traceability and specific SOPs on the management of potential immune reactions. Investigational products must be stored under standard auditable conditions. The traceability of storage conditions (including temperature) requires these conditions to be monitored on a continuous basis. A dedicated space with restricted access limited to authorized qualified personnel facilitates the monitoring. The development of standardized, auditable settings and the application of dedicated, site-specific SOPs for the management of investigational products and drug delivery systems contribute to guarantee the compliance to GCP requirements.

  18. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    International Nuclear Information System (INIS)

    Chintamani; Singhal, Vinay; Singh, JP; Lyall, Ashima; Saxena, Sunita; Bansal, Anju

    2004-01-01

    Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins) brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio). Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide) were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was assessed using chi-square test and coefficient

  19. Nanotechnology-based drug delivery systems for Alzheimer's disease management: Technical, industrial, and clinical challenges.

    Science.gov (United States)

    Wen, Ming Ming; El-Salamouni, Noha S; El-Refaie, Wessam M; Hazzah, Heba A; Ali, Mai M; Tosi, Giovanni; Farid, Ragwa M; Blanco-Prieto, Maria J; Billa, Nashiru; Hanafy, Amira S

    2017-01-10

    Alzheimer's disease (AD) is a neurodegenerative disease with high prevalence in the rapidly growing elderly population in the developing world. The currently FDA approved drugs for the management of symptomatology of AD are marketed mainly as conventional oral medications. Due to their gastrointestinal side effects and lack of brain targeting, these drugs and dosage regiments hinder patient compliance and lead to treatment discontinuation. Nanotechnology-based drug delivery systems (NTDDS) administered by different routes can be considered as promising tools to improve patient compliance and achieve better therapeutic outcomes. Despite extensive research, literature screening revealed that clinical activities involving NTDDS application in research for AD are lagging compared to NTDDS for other diseases such as cancers. The industrial perspectives, processability, and cost/benefit ratio of using NTDDS for AD treatment are usually overlooked. Moreover, active and passive immunization against AD are by far the mostly studied alternative AD therapies because conventional oral drug therapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this research from 'paper to clinic' and raise hope for AD sufferers and their caretakers. This review summarizes the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability. Additionally, it highlights the ongoing clinical trials for AD management. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions.

    Science.gov (United States)

    Adiwidjaja, Jeffry; McLachlan, Andrew J; Boddy, Alan V

    2017-09-01

    Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

  1. Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs

    Directory of Open Access Journals (Sweden)

    Devesh Tewari

    2018-02-01

    Full Text Available Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer's disease (AD, Huntington's disease (HD, and Parkinson's disease (PD. Although there are well-established (semi-synthetic drugs currently used for the management of AD and AD-associated dementia, most of them have several adverse effects. Thus, traditional medicine provides various plant-derived lead molecules that may be useful for further medical research. Herein we review the worldwide use of ethnomedicinal plants in dementia treatment. We have explored a number of recognized databases by using keywords and phrases such as “dementia”, “Alzheimer's,” “traditional medicine,” “ethnopharmacology,” “ethnobotany,” “herbs,” “medicinal plants” or other relevant terms, and summarized 90 medicinal plants that are traditionally used to treat dementia. Moreover, we highlight five medicinal plants or plant genera of prime importance and discuss the physiological effects, as well as the mechanism of action of their major bioactive compounds. Furthermore, the link between mitochondrial dysfunction and dementia is also discussed. We conclude that several drugs of plant origin may serve as promising therapeutics for the treatment of dementia, however, pivotal evidence for their therapeutic efficacy in advanced clinical studies is still lacking.

  2. Quantifying the Clinical Significance of Cannabis Withdrawal

    Science.gov (United States)

    Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

    2012-01-01

    Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

  3. Quantifying the clinical significance of cannabis withdrawal.

    Directory of Open Access Journals (Sweden)

    David J Allsop

    Full Text Available Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV. This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p=0.0001. Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p=0.03. Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p=0.001.Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes.

  4. USE OF DRUGS AND PATIENT’S QUALITY OF LIFE IN HEART FAILURE CLINIC

    Directory of Open Access Journals (Sweden)

    Mitja Lainščak

    2003-05-01

    Full Text Available Background. Heart failure is associated with poor quality of life and frequent hospitalizations. Implementation of the clinical trials results, especially prescription of adequate daily doses, is regarded as insufficient. In Slovenia there is no data on quality of life in patients treated in heart failure clinic.Aim. This study assessed the effects of heart failure clinic on patients pharmacological treatment, number of hospitalisations and quality of life.Methods. Patients with established heart failure were enrolled on a basis of the European Society of Cardiology guidelines.Results. During seven months 48 patients (28 men and 20 women, aged 68.4 ± 11.9 years were included. Half of the patients referred after heart failure hospitalisation. After mean of 3.8 ± 1.5 visits in mean time of 2.9 ± 2.6 months more patients received angiotenzin converting enzyme inhibitors and beta adrenergic blockers (90 vs. 100%, p < 0.05 and 42% vs. 88%, p < 0.001, respectively. There was also an increase in mean daily dose of both drugs: from 60% to 86% for angiotenzin converting enzyme inhibitors and from 26% to 44% for beta adrenergic blockers (p < 0.001 for both. Hospital admissions were reduced by 79%. Quality of life, health, MLHFQ result and NYHA class all significantly improved (p < 0.001.Conclusions. Heart failure clinic can significantly improve patient’s quality of life and pharmacological treatment as well as reduce number of admissions due to heart failure.

  5. Clinical effectiveness of multiple-drug injection treatment in unruptured ectopic pregnancies: a retrospective study.

    Science.gov (United States)

    Dai, Quan; Wang, Lu-Lu; Shao, Xiao-Hui; Wang, Si-Ming; Dong, Xiao-Qiu

    2012-10-01

    To study the effect of local interventional treatment of unruptured ectopic pregnancies with multiple-drug injection guided by color Doppler sonography. In this retrospective analysis, 49 patients with an unruptured ectopic pregnancy were treated with two different local injection methods administered under sonographic guidance. The patients were divided into single-drug (n = 23) and multiple-drug (n = 26) injection groups, and they received a locally administered injection of methotrexate alone or a combination including methotrexate, hemocoagulase, antibiotics, and anti-inflammatory drugs, respectively. Overall, local injection treatment was successful in 44 patients. The 5 patients with failed treatment underwent laparotomy about 1 week after single-drug injection. Serum β-human chorionic gonadotropin (β-hCG ) levels, ectopic pregnancy mass sizes, blood flow at various points after treatment, the incidence of pelvic bleeding, and the time for serum β-hCG levels to return to normal and the mass to resolve were analyzed in the remaining 44 patients. Single-drug treatment was successful in 18 patients; 10 of 23 had low to moderate pelvic bleeding after treatment, and 5 were referred for surgery. All 26 patients were successfully treated by multiple-drug injection. Only 2 patients had a small amount of pelvic bleeding. Differences between groups were statistically significant (P injection under color Doppler guidance is a new, safe, and effective method for treating unruptured ectopic pregnancies. It accelerates the serum β-hCG decline and facilitates mass resolution. This regimen is associated with a very low rate of pelvic bleeding, improves the success rate of conservative treatment, and, therefore, has value as an important clinical application.

  6. The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.

    Science.gov (United States)

    Denny, Joshua C; Van Driest, Sara L; Wei, Wei-Qi; Roden, Dan M

    2018-03-01

    Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  7. Clopidogrel-Proton Pump Inhibitor Drug-Drug Interaction and Risk of Adverse Clinical Outcomes Among PCI-Treated ACS Patients: A Meta-analysis.

    Science.gov (United States)

    Serbin, Michael A; Guzauskas, Gregory F; Veenstra, David L

    2016-08-01

    Uncertainty regarding clopidogrel effectiveness attenuation because of a drug-drug interaction with proton pump inhibitors (PPI) has led to conflicting guidelines on concomitant therapy. In particular, the effect of this interaction in patients who undergo a percutaneous coronary intervention (PCI), a population known to have increased risk of adverse cardiovascular events, has not been systematically evaluated. To synthesize the evidence of the effect of clopidogrel-PPI drug interaction on adverse cardiovascular outcomes in a PCI patient population. We conducted a systematic literature review for studies reporting clinical outcomes in patients who underwent a PCI and were initiated on clopidogrel with or without a PPI. Studies were included in the analysis if they reported at least 1 of the clinical outcomes of interest (major adverse cardiovascular event [MACE], cardiovascular death, all-cause death, myocardial infarction, stroke, stent thrombosis, and bleed events). We excluded studies that were not exclusive to PCI patients or had no PCI subgroup analysis and/or did not report at least a 6-month follow-up. Statistical and clinical heterogeneity were evaluated and HRs and 95% CIs for adverse clinical events were pooled using the DerSimonian and Laird random-effects meta-analysis method. We identified 12 studies comprising 50,277 PCI patients that met our inclusion and exclusion criteria. Our analysis included retrospective analyses of randomized controlled trials (2), health registries (3), claims databases (2), and institutional records (5); no prospective studies of PCI patients were identified. On average, patients were in their mid-60s, male, and had an array of comorbidities, including hyperlipidemia, diabetes, hypertension, and smoking history. Concomitant therapy following PCI resulted in statistically significant increases in composite MACE (HR = 1.28; 95% CI = 1.24-1.32), myocardial infarction (HR = 1.51; 95% CI = 1.40-1.62), and stroke (HR = 1.46; 95

  8. Drug-Drug/Drug-Excipient Compatibility Studies on Curcumin using Non-Thermal Methods

    Directory of Open Access Journals (Sweden)

    Moorthi Chidambaram

    2014-05-01

    Full Text Available Purpose: Curcumin is a hydrophobic polyphenol isolated from dried rhizome of turmeric. Clinical usefulness of curcumin in the treatment of cancer is limited due to poor aqueous solubility, hydrolytic degradation, metabolism, and poor oral bioavailability. To overcome these limitations, we proposed to fabricate curcumin-piperine, curcumin-quercetin and curcumin-silibinin loaded polymeric nanoformulation. However, unfavourable combinations of drug-drug and drug-excipient may result in interaction and rises the safety concern. Hence, the present study was aimed to assess the interaction of curcumin with excipients used in nanoformulations. Methods: Isothermal stress testing method was used to assess the compatibility of drug-drug/drug-excipient. Results: The combination of curcumin-piperine, curcumin-quercetin, curcumin-silibinin and the combination of other excipients with curcumin, piperine, quercetin and silibinin have not shown any significant physical and chemical instability. Conclusion: The study concludes that the curcumin, piperine, quercetin and silibinin is compatible with each other and with other excipients.

  9. Doing the right things and doing things right : inpatient drug surveillance assisted by clinical decision support

    NARCIS (Netherlands)

    Helmons, Pieter J.; Suijkerbuijk, Bas O.; Nannan Panday, Prashant V.; Kosterink, Jos G. W.

    Increased budget constraints and a continuous focus on improved quality require an efficient inpatient drug surveillance process. We describe a hospital-wide drug surveillance strategy consisting of a multidisciplinary evaluation of drug surveillance activities and using clinical decision support to

  10. C-A4-01: Computerized Clinical Decision Support During Drug Ordering for Long-term Care Residents With Renal Insufficiency

    Science.gov (United States)

    Field, Terry S; Rochon, Paula; Lee, Monica; Gavendo, Linda; Baril, Joann L; Gurwitz, Jerry H

    2010-01-01

    Objective: To determine whether a computerized clinical decision support system (CDSS) providing patient specific recommendations in real- time improves the quality of prescribing for long-term care residents with renal insufficiency. Design: A randomized trial within the long-stay units of a large long-term care facility. Randomization was within blocks by unit type. Alerts related to medication prescribing for residents with renal insufficiency were displayed to prescribers in the intervention units and hidden but tracked in control units. Measurement: The proportions of final drug orders that were appropriate were compared between intervention and control units within alert categories: recommended medication doses; recommended administration frequencies; recommendations to avoid the drug; 4) warnings of missing information. Results: The rates of alerts were nearly equal in the intervention and control units: 2.5 per 1000 resident days in the intervention units and 2.4 in the control units. The proportions of dose alerts for which the final drug orders were appropriate were similar between the intervention and control units (relative risk 0.95, 95% confidence interval 0.83, 1.1). For the remaining alert categories significantly higher proportions of final drug orders were appropriate in the intervention units: relative risk 2.4 for maximum frequency (1.4, 4.4); 2.6 for drugs that should be avoided (1.4, 5.0); and 1.8 for alerts to acquire missing information (1.1, 3.4). Overall, final drug orders were appropriate significantly more often than a relative risk 1.2 (1.0, 1.4). By tracking personnel time and expenditures, we estimated the cost of developing the CDSS as $48,668.57. Drug costs saved during the 12 months of the trial are estimated at $2,137. Conclusion: Clinical decision support for physicians prescribing medications for long-term care residents with renal insufficiency can improve the quality of prescribing decisions. However, patient well-being and

  11. A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice.

    Science.gov (United States)

    Tagliamonte, Maria; Petrizzo, Annacarmen; Napolitano, Maria; Luciano, Antonio; Rea, Domenica; Barbieri, Antonio; Arra, Claudio; Maiolino, Piera; Tornesello, Marialina; Ciliberto, Gennaro; Buonaguro, Franco M; Buonaguro, Luigi

    2016-02-24

    The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response. In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious. Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA. The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.

  12. Disentangling the Correlates of Drug Use in a Clinic and Community Sample: A Regression Analysis of the Associations between Drug Use, Years-of-School, Impulsivity, IQ, Working Memory, and Psychiatric Symptoms.

    Science.gov (United States)

    Heyman, Gene M; Dunn, Brian J; Mignone, Jason

    2014-01-01

    Years-of-school is negatively correlated with illicit drug use. However, educational attainment is positively correlated with IQ and negatively correlated with impulsivity, two traits that are also correlated with drug use. Thus, the negative correlation between education and drug use may reflect the correlates of schooling, not schooling itself. To help disentangle these relations we obtained measures of working memory, simple memory, IQ, disposition (impulsivity and psychiatric status), years-of-school and frequency of illicit and licit drug use in methadone clinic and community drug users. We found strong zero-order correlations between all measures, including IQ, impulsivity, years-of-school, psychiatric symptoms, and drug use. However, multiple regression analyses revealed a different picture. The significant predictors of illicit drug use were gender, involvement in a methadone clinic, and years-of-school. That is, psychiatric symptoms, impulsivity, cognition, and IQ no longer predicted illicit drug use in the multiple regression analyses. Moreover, high risk subjects (low IQ and/or high impulsivity) who spent 14 or more years in school used stimulants and opiates less than did low risk subjects who had spent IQ and years-of-school predicted whether someone ever became a smoker, whereas impulsivity predicted the frequency of drinking bouts, but years-of-school did not. Many subjects reported no use of one or more drugs, resulting in a large number of "zeroes" in the data sets. Cragg's Double-Hurdle regression method proved the best approach for dealing with this problem. To our knowledge, this is the first report to show that years-of-school predicts lower levels of illicit drug use after controlling for IQ and impulsivity. This paper also highlights the advantages of Double-Hurdle regression methods for analyzing the correlates of drug use in community samples.

  13. Online drug databases: a new method to assess and compare inclusion of clinically relevant information.

    Science.gov (United States)

    Silva, Cristina; Fresco, Paula; Monteiro, Joaquim; Rama, Ana Cristina Ribeiro

    2013-08-01

    Evidence-Based Practice requires health care decisions to be based on the best available evidence. The model "Information Mastery" proposes that clinicians should use sources of information that have previously evaluated relevance and validity, provided at the point of care. Drug databases (DB) allow easy and fast access to information and have the benefit of more frequent content updates. Relevant information, in the context of drug therapy, is that which supports safe and effective use of medicines. Accordingly, the European Guideline on the Summary of Product Characteristics (EG-SmPC) was used as a standard to evaluate the inclusion of relevant information contents in DB. To develop and test a method to evaluate relevancy of DB contents, by assessing the inclusion of information items deemed relevant for effective and safe drug use. Hierarchical organisation and selection of the principles defined in the EGSmPC; definition of criteria to assess inclusion of selected information items; creation of a categorisation and quantification system that allows score calculation; calculation of relative differences (RD) of scores for comparison with an "ideal" database, defined as the one that achieves the best quantification possible for each of the information items; pilot test on a sample of 9 drug databases, using 10 drugs frequently associated in literature with morbidity-mortality and also being widely consumed in Portugal. Main outcome measure Calculate individual and global scores for clinically relevant information items of drug monographs in databases, using the categorisation and quantification system created. A--Method development: selection of sections, subsections, relevant information items and corresponding requisites; system to categorise and quantify their inclusion; score and RD calculation procedure. B--Pilot test: calculated scores for the 9 databases; globally, all databases evaluated significantly differed from the "ideal" database; some DB performed

  14. FDA drug safety communications: a narrative review and clinical considerations for older adults.

    Science.gov (United States)

    Marcum, Zachary A; Vande Griend, Joseph P; Linnebur, Sunny A

    2012-08-01

    The US Food and Drug Administration (FDA) has new regulatory authorities intended to enhance drug safety monitoring in the postmarketing period. This has resulted in an increase in communication from the FDA in recent years about the safety profile of certain drugs. It is important to stay abreast of the current literature on drug risks to effectively communicate these risks to patients, other health care providers, and the general public. To summarize 4 new FDA drug safety communications by describing the evidence supporting the risks and the clinical implications for older adults. The FDA Web site was reviewed for new drug safety communications from May 2011 to April 2012 that would be relevant to older adults. Approved labeling for each drug or class was obtained from the manufacturer, and PubMed was searched for primary literature that supported the drug safety concern. FDA drug safety communications for 4 drugs were chosen because of the potential clinical importance in older adults. A warning for citalopram was made because of potential problems with QT prolongation in patients taking less than 40 mg per day. The evidence suggests minor changes in QT interval. Given the flat dose-response curve in treating depression with citalopram, the new 20-mg/d maximum dose in older adults is sensible. Another warning was made for proton pump inhibitors (PPIs) and an increased risk of Clostridium difficile infection. A dose-response relationship was found for this drug risk. With C. difficile infections on the rise in older adults, along with other safety risks of PPI therapy, PPIs should only be used in older adults indicated for therapy for the shortest duration possible. In addition, a warning about dabigatran was made. There is strong evidence from a large clinical trial, as well as case reports, of increased bleeding risk in older adults taking dabigatran, especially in older adults with decreased renal function. This medication should be used with caution in older

  15. Clinical evaluation of domestic biodegradable drug-eluting stents in the treatment of coronary heart disease

    International Nuclear Information System (INIS)

    Yu Hongying; Suo Chuantao; Shang Ruiping

    2009-01-01

    Objective: To evaluate the safety and efficacy of domestic biodegradable drug-eluting stent, EXCEL, in clinical treatment of coronary heart disease. Methods: During the period of Jan. 2008-Oct. 2008, 100 patients with coronary heart disease who consented to PCI and postoperative coronary angiography were selected and enrolled in the study. The patients were divided into EXCEL group (n = 58) and Cypher group (n = 42). The immediate successful rate of interventional therapy and the complications occurred during hospitalization were observed. Postoperative follow-up and checkup coronary angiography were conducted. Results: No significant difference in the relevant clinical data, in the number and type of diseased coronary branch and in the mean length of implanted stents existed between two groups. Also, no statistically significant difference in the occurrence of major adverse cardiac event (MACE), in-stent restenosis and thrombosis was present between two groups. Conclusion: Compared with Cypher stenting, EXCEL stenting carries similar, i.e. rather low, occurrence of MACE and in-stent restenosis. (authors)

  16. Clinical Decision Support to Implement CYP2D6 Drug-Gene Interaction.

    Science.gov (United States)

    Caraballo, Pedro J; Parkulo, Mark; Blair, David; Elliott, Michelle; Schultz, Cloann; Sutton, Joseph; Rao, Padma; Bruflat, Jamie; Bleimeyer, Robert; Crooks, John; Gabrielson, Donald; Nicholson, Wayne; Rohrer Vitek, Carolyn; Wix, Kelly; Bielinski, Suzette J; Pathak, Jyotishman; Kullo, Iftikhar

    2015-01-01

    The level of CYP2D6 metabolic activity can be predicted by pharmacogenomic testing, and concomitant use of clinical decision support has the potential to prevent adverse effects from those drugs metabolized by this enzyme. Our initial findings after implementation of clinical decision support alerts integrated in the electronic health records suggest high feasibility, but also identify important challenges.

  17. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

    Science.gov (United States)

    Passini, Elisa; Britton, Oliver J; Lu, Hua Rong; Rohrbacher, Jutta; Hermans, An N; Gallacher, David J; Greig, Robert J H; Bueno-Orovio, Alfonso; Rodriguez, Blanca

    2017-01-01

    Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC 50 /Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca 2+ -transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca 2+ /late Na + currents and Na + /Ca 2+ -exchanger, reduced Na + /K + -pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density

  18. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity

    Directory of Open Access Journals (Sweden)

    Elisa Passini

    2017-09-01

    Full Text Available Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient. Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs. Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density

  19. Out-patient drug policy by clinical assessment rather than financial constraints? The gate-keeping function of the out-patient drug reimbursement system in The Netherlands

    NARCIS (Netherlands)

    Pronk, Marja H.; Bonsel, Gouke J.

    2004-01-01

    Since 1991, the Dutch Price Reference System (DPRS) has aimed at a growth reduction of out-patient drug costs without loss of medical quality. New drugs are excluded unless they pass legally anchored clinical criteria, i.e. substitutability with accepted drugs (DPRS-list 1a, implies a reimbursement

  20. SMART drug delivery systems: Back to the future vs. clinical reality

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria

    2013-01-01

    Recent advances in nanotechnology and material science have re-ignited interest in drug delivery research. Arguably, however, hardly any of the systems developed and strategies proposed are really relevant for shaping the future (clinical) face of the nanomedicine field. Consequently, as outlined in

  1. Confidence intervals for effect sizes: compliance and clinical significance in the Journal of Consulting and clinical Psychology.

    Science.gov (United States)

    Odgaard, Eric C; Fowler, Robert L

    2010-06-01

    In 2005, the Journal of Consulting and Clinical Psychology (JCCP) became the first American Psychological Association (APA) journal to require statistical measures of clinical significance, plus effect sizes (ESs) and associated confidence intervals (CIs), for primary outcomes (La Greca, 2005). As this represents the single largest editorial effort to improve statistical reporting practices in any APA journal in at least a decade, in this article we investigate the efficacy of that change. All intervention studies published in JCCP in 2003, 2004, 2007, and 2008 were reviewed. Each article was coded for method of clinical significance, type of ES, and type of associated CI, broken down by statistical test (F, t, chi-square, r/R(2), and multivariate modeling). By 2008, clinical significance compliance was 75% (up from 31%), with 94% of studies reporting some measure of ES (reporting improved for individual statistical tests ranging from eta(2) = .05 to .17, with reasonable CIs). Reporting of CIs for ESs also improved, although only to 40%. Also, the vast majority of reported CIs used approximations, which become progressively less accurate for smaller sample sizes and larger ESs (cf. Algina & Kessleman, 2003). Changes are near asymptote for ESs and clinical significance, but CIs lag behind. As CIs for ESs are required for primary outcomes, we show how to compute CIs for the vast majority of ESs reported in JCCP, with an example of how to use CIs for ESs as a method to assess clinical significance.

  2. Food-drug interactions

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    Interactions between food and drugs may inadvertently reduce or increase the drug effect. The majority of clinically relevant food-drug interactions are caused by food-induced changes in the bioavailability of the drug. Since the bioavailability and clinical effect of most drugs are correlated......, the bioavailability is an important pharmacokinetic effect parameter. However, in order to evaluate the clinical relevance of a food-drug interaction, the impact of food intake on the clinical effect of the drug has to be quantified as well. As a result of quality review in healthcare systems, healthcare providers...... are increasingly required to develop methods for identifying and preventing adverse food-drug interactions. In this review of original literature, we have tried to provide both pharmacokinetic and clinical effect parameters of clinically relevant food-drug interactions. The most important interactions are those...

  3. Clinical significance of metabolic superscan in patients with hyperthyroidism

    International Nuclear Information System (INIS)

    Kotb, M.; Khalafallah, K.; Omar, W.; El-Maghraby, T.; Grace, G.

    2007-01-01

    Hyperthyroid patients commonly complain of generalized bony aches, which are frequently overlooked due to the more prominent symptoms of cardiovascular and nervous disturbances. Hyperthyroid patients are expected to have abnormal bone metabolism as part of the generalized hypermetabolic status. The aim of this study is to verify the presence of metabolic bone superscan in association with the hypermetabolic stats in various groups of hyperthyroidism. Secondly, to correlate these superscan features with the various laboratory results in hyperthyroid patients. Forty-five hyperthyroid patients confirmed by clinical and laboratory results were enrolled in this work. In all patients, a 99 m T c-pertechnetate thyroid uptake scan was acquired. On a different day, total body bone scan was acquired three hours post IV injection of 555-925 MBq of 99 m T c-MDP. Serum FT3, FT4, TSH, Ca ++ , alkaline phosphatase (AP) and parathyroid hormone (PTH) were monitored in all patients as markers of thyroid and bone metabolism. Ten cases with no thyroid diseases were included as a control group. Patients with thyroiditis or long history of antithyroid drugs for more than one year were excluded from the study. The patients were subdivided into three groups: Graves' disease (GD) (n = 30), toxic nodular goiter (TNG) (n = 10) and autonomous toxic adenoma (AT) (n = 5). The TSH for the whole group was significantly suppressed compared to the control group with higher suppression in the Graves' disease group than in the TNG or AT groups. 99m Tc-pertechnetate uptake values in the Graves' disease group were significantly higher than the TNG and AT groups (p + , AP and PTH between the Graves' and non-Graves' groups (p ≥ 0.05). Disturbances in bone metabolism are more prevalent in Graves' disease than in other types of hyperthyroidism. The addition of the bone scan to the diagnostic work up of patients with Graves' disease is a sensitive indicator for metabolic bone changes and could help in the

  4. Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development.

    Science.gov (United States)

    Smelick, Gillian S; Heffron, Timothy P; Chu, Laura; Dean, Brian; West, David A; Duvall, Scott L; Lum, Bert L; Budha, Nageshwar; Holden, Scott N; Benet, Leslie Z; Frymoyer, Adam; Dresser, Mark J; Ware, Joseph A

    2013-11-04

    Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered

  5. Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

    Energy Technology Data Exchange (ETDEWEB)

    Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

    2016-12-01

    Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

  6. Transmitted drug resistance in the CFAR network of integrated clinical systems cohort: prevalence and effects on pre-therapy CD4 and viral load.

    Directory of Open Access Journals (Sweden)

    Art F Y Poon

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL and CD4+ cell count (CD4 at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184 were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (-1.7 log₁₀pVL and D67N/G (-2.1[³√CD4] and 0.4 log₁₀pVL were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1

  7. The prevalence and clinical significance of maxillary sinus mucous retention cysts in a general clinic population.

    Science.gov (United States)

    Rhodus, N L

    1990-02-01

    Previous studies have documented the occurrence and potential clinical significance of MSMR cysts. Studies also have alluded to a relationship between the MSMR cyst and certain signs or symptoms of disease. We determined the prevalence of MSMR cysts in a general clinic population and identified some important correlations with clinical signs and symptoms.

  8. The Importance of Prolonged Provocation in Drug Allergy - Results From a Danish Allergy Clinic.

    Science.gov (United States)

    Fransson, Sara; Mosbech, Holger; Kappel, Mogens; Hjortlund, Janni; Poulsen, Lars K; Kvisselgaard, Ask D; Garvey, Lene H

    Drug provocation is the "Gold Standard" in drug allergy investigation. Recent studies suggest that a negative drug provocation on first dose should be followed by a prolonged provocation over several days. To evaluate drug allergy investigations on the basis of drug provocation, including prolonged provocation. Data from adult patients investigated for drug allergy in a Danish Allergy Clinic during the period 2010 to 2014 were entered into a database. Data included clinical details and results of provocations with suspected culprit drug (for penicillins performed only in specific IgE-negative patients). If provocation was negative on first dose, treatment was continued for 3 to 10 days. A total of 1,913 provocations were done in 1,659 patients, median age 46 years, of whom 1,237 (74.6%) were females. Drugs investigated were antibiotics, 1,776 (92.8%), of which 1,590 (89.5%) were penicillins; analgesics, 59 (3.1%); local anesthetics, 33 (1.7%); and other drugs, 45 (2.4%). In total, 211 of 1,913 (11.0%) provocations were positive. Causes were antibiotics, 198 (93.8%), of which 167 (84.3%) were penicillins; analgesics, 7 (3.3%); local anesthetics, 0; and other drugs, 6 (2.8%). Only 43 (20.4%) provocations were positive on first dose, whereas 95 (45.0%) turned positive more than 3 days later. Only 11.0% of the provocations were positive. Importantly, only 1 of 5 patients tested positive on the first dose, indicating that prolonged exposure should always be considered when drug provocation is included in allergy investigations. Most provocations were with penicillins, reflecting the pattern of antibiotic use in Denmark, which differs from that in other countries, especially outside Northern Europe. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Investigational drugs in early development for treating dengue infection.

    Science.gov (United States)

    Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam

    2016-09-01

    Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development. This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization's International Clinical Trials Registry Platform web portal using the search term 'dengue' on December 31(st), 2015. None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict 'high-risk' patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.

  10. Integrity, standards, and QC-related issues with big data in pre-clinical drug discovery.

    Science.gov (United States)

    Brothers, John F; Ung, Matthew; Escalante-Chong, Renan; Ross, Jermaine; Zhang, Jenny; Cha, Yoonjeong; Lysaght, Andrew; Funt, Jason; Kusko, Rebecca

    2018-06-01

    The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development. We describe standardized approaches for maximizing the utility of publicly available or privately generated biological data and address some of the common pitfalls. We also discuss the increasing interest to integrate and interpret cross-platform data. Principles outlined here should serve as a useful broad guide for existing analytical practices and pipelines and as a tool for developing additional insights into therapeutics using big data. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. Adult-onset photosensitivity: clinical significance and epilepsy syndromes including idiopathic (possibly genetic) photosensitive occipital epilepsy.

    Science.gov (United States)

    Koutroumanidis, Michalis; Tsirka, Vasiliki; Panayiotopoulos, Chrysostomos

    2015-09-01

    To evaluate the clinical associations of adult-onset photosensitivity, we studied the clinical and EEG data of patients who were referred due to a possible first seizure and who had a photoparoxysmal response on their EEG. Patients with clinical evidence of photosensitivity before the age of 20 were excluded. Of a total of 30 patients, four had acute symptomatic seizures, two had vasovagal syncope, and 24 were diagnosed with epilepsy. Nine of the 24 patients had idiopathic (genetic) generalized epilepsies and predominantly generalized photoparoxysmal response, but also rare photically-induced seizures, while 15 had exclusively, or almost exclusively, reflex photically-induced occipital seizures with frequent secondary generalization and posterior photoparoxysmal response. Other important differences included a significantly older age at seizure onset and paucity of spontaneous interictal epileptic discharges in patients with photically-induced occipital seizures; only a quarter of these had occasional occipital spikes, in contrast to the idiopathic (genetic) generalized epilepsy patients with typically generalized epileptic discharges. On the other hand, both groups shared a positive family history of epilepsy, common seizure threshold modulators (such as tiredness and sleep deprivation), normal neurological examination and MRI, a generally benign course, and good response to valproic acid. We demonstrated that photosensitivity can first occur in adult life and manifest, either as idiopathic (possibly genetic) photosensitive occipital epilepsy with secondary generalization or as an EEG, and less often, a clinical/EEG feature of idiopathic (genetic) generalized epilepsies. Identification of idiopathic photosensitive occipital epilepsy fills a diagnostic gap in adult first-seizure epileptology and is clinically important because of its good response to antiepileptic drug treatment and fair prognosis.

  12. A Bayesian approach for incorporating economic factors in sample size design for clinical trials of individual drugs and portfolios of drugs.

    Science.gov (United States)

    Patel, Nitin R; Ankolekar, Suresh

    2007-11-30

    Classical approaches to clinical trial design ignore economic factors that determine economic viability of a new drug. We address the choice of sample size in Phase III trials as a decision theory problem using a hybrid approach that takes a Bayesian view from the perspective of a drug company and a classical Neyman-Pearson view from the perspective of regulatory authorities. We incorporate relevant economic factors in the analysis to determine the optimal sample size to maximize the expected profit for the company. We extend the analysis to account for risk by using a 'satisficing' objective function that maximizes the chance of meeting a management-specified target level of profit. We extend the models for single drugs to a portfolio of clinical trials and optimize the sample sizes to maximize the expected profit subject to budget constraints. Further, we address the portfolio risk and optimize the sample sizes to maximize the probability of achieving a given target of expected profit.

  13. Assessing the clinical significance of tumor markers in common neoplasms.

    Science.gov (United States)

    Beketic-Oreskovic, Lidija; Maric, Petra; Ozretic, Petar; Oreskovic, Darko; Ajdukovic, Mia; Levanat, Sonja

    2012-06-01

    The term tumor markers include a spectrum of molecules and substances with widely divergent characteristics whose presence in the significant amount can be related to the malignant disease. An ideal tumor marker should have high specificity and sensitivity, which would allow its use in early diagnosis and prognosis of malignant disease, as well as in prediction of therapeutic response and follow-up of the patients. Numerous biochemical entities have emerged as potentially valuable tumor markers so far, but only few markers showed to be of considerable clinical reliability and have been accepted into standard clinical practice. Recent development of genomics and proteomics has enabled the examination of many new potential tumor markers. Scientific studies on discovery, development, and application of tumor markers have been proceeding quite rapidly providing great opportunities for improving the management of cancer patients. This review is focusing on the clinical usefulness of various tumor markers already in clinical practice as well as certain potential markers, giving a brief description of their prognostic and predictive significance in most common malignancies.

  14. Clinically significant anti M antibodies--a report of two cases.

    Science.gov (United States)

    Kaur, Gagandeep; Basu, Sabita; Kaur, Paramjit; Kaur, Ravneet

    2012-12-01

    Most anti-M antibodies are not active at 37°C and are thus of no clinical significance. Occasionally these antibodies have a wide thermal range and can lead to hemolytic transfusion reactions or hemolytic disease of the new born. We describe two cases of anti-M antibodies, both of which were clinically significant. The first case was detected due to crossmatch incompatibility and the second presented as a blood group discrepancy. When the antibody is active at 37°C, M antigen negative red cell units should be issued. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

    Science.gov (United States)

    Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

    2017-11-01

    Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

  16. Information needs for making clinical recommendations about potential drug-drug interactions: a synthesis of literature review and interviews.

    Science.gov (United States)

    Romagnoli, Katrina M; Nelson, Scott D; Hines, Lisa; Empey, Philip; Boyce, Richard D; Hochheiser, Harry

    2017-02-22

    Drug information compendia and drug-drug interaction information databases are critical resources for clinicians and pharmacists working to avoid adverse events due to exposure to potential drug-drug interactions (PDDIs). Our goal is to develop information models, annotated data, and search tools that will facilitate the interpretation of PDDI information. To better understand the information needs and work practices of specialists who search and synthesize PDDI evidence for drug information resources, we conducted an inquiry that combined a thematic analysis of published literature with unstructured interviews. Starting from an initial set of relevant articles, we developed search terms and conducted a literature search. Two reviewers conducted a thematic analysis of included articles. Unstructured interviews with drug information experts were conducted and similarly coded. Information needs, work processes, and indicators of potential strengths and weaknesses of information systems were identified. Review of 92 papers and 10 interviews identified 56 categories of information needs related to the interpretation of PDDI information including drug and interaction information; study design; evidence including clinical details, quality and content of reports, and consequences; and potential recommendations. We also identified strengths/weaknesses of PDDI information systems. We identified the kinds of information that might be most effective for summarizing PDDIs. The drug information experts we interviewed had differing goals, suggesting a need for detailed information models and flexible presentations. Several information needs not discussed in previous work were identified, including temporal overlaps in drug administration, biological plausibility of interactions, and assessment of the quality and content of reports. Richly structured depictions of PDDI information may help drug information experts more effectively interpret data and develop recommendations

  17. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    Directory of Open Access Journals (Sweden)

    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  18. «Dallas Buyers Club (2013» clinical research with drugs for the AIDS epidemic 80

    Directory of Open Access Journals (Sweden)

    Marian de HAAN-BOSCH

    2015-07-01

    Full Text Available Dallas Buyers Club (2013, inspired by true events, tells the story of Ron Woodroof, a middle?aged elec? trician from Dallas (Texas, who is diagnosed with AIDS in 1985. With few treatment options, he estab? lishes the Dallas Buyers Club in order to provide unapproved drugs to the AIDS community. This results in constant business travels, disputes with the FDA and problems with the law and the IRS. The article analyzes the buyers’ clubs phenomenon in the US, the drugs cited in the film and the clinical trial with zidovudine shown in the movie. The film could be useful as a teaching tool providing an introduction to the AIDS epidemic, clinical research and drug development, bioethics of human research and the agen? cies that regulate drug approval and their availability. Finally, the article presents a possible guideline for the use of the film in a teaching environment.

  19. Effect of radioimmunoassay procedures on therapeutic drug monitoring

    International Nuclear Information System (INIS)

    Kampa, I.S.

    1985-01-01

    Methods for the measurement of therapeutic drugs have covered every aspect of analysis from extraction to derivatization. In general, published methods were modified to shorten drug extractions and overall analysis time. The use of different standards, as well as the frequent omission of internal standards, often produced large and clinically unacceptable analytical variations. As a result, physicians would adjust drug dosages according to the physiological response to a standard dose. The introduction of radioimmunoassay techniques for the quantitation of therapeutic drugs have made a significant impact on the clinical chemistry laboratory. The similarities of the various assay methods and the technologists' familiarity with the assay protocols have produced clinically relevant results. Clinical laboratories are now able to frequently analyze a large number of samples with acceptable accuracy and precision. The esoteric test once performed infrequently is today a routine analytical assay often performed STAT. Therapeutic drug monitoring has become a major activity in many clinical laboratories

  20. Clinical Relevance and Predictive Value of Damage Biomarkers of Drug-Induced Kidney Injury.

    Science.gov (United States)

    Kane-Gill, Sandra L; Smithburger, Pamela L; Kashani, Kianoush; Kellum, John A; Frazee, Erin

    2017-11-01

    Nephrotoxin exposure accounts for up to one-fourth of acute kidney injury episodes in hospitalized patients, and the associated consequences are as severe as acute kidney injury due to other etiologies. As the use of nephrotoxic agents represents one of the few modifiable risk factors for acute kidney injury, clinicians must be able to identify patients at high risk for drug-induced kidney injury rapidly. Recently, significant advancements have been made in the field of biomarker utilization for the prediction and detection of acute kidney injury. Such biomarkers may have a role both for detection of drug-induced kidney disease and implementation of preventative and therapeutic strategies designed to mitigate injury. In this article, basic principles of renal biomarker use in practice are summarized, and the existing evidence for six markers specifically used to detect drug-induced kidney injury are outlined, including liver-type fatty acid binding protein, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 times insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]), kidney injury molecule-1 and N-acetyl-β-D-glucosaminidase. The results of the literature search for these six kidney damage biomarkers identified 29 unique articles with none detected for liver-type fatty acid binding protein and [TIMP-2]·[IGFBP7]. For three biomarkers, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-β-D-glucosaminidase, the majority of the studies suggest utility in clinical practice. While many questions need to be answered to clearly articulate the use of biomarkers to predict drug-induced kidney disease, current data are promising.

  1. Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens.

    Science.gov (United States)

    Karuppiah, Ponmurugan; Rajaram, Shyamkumar

    2012-08-01

    To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary.

  2. Clinical significance of anaplasia in childhood rhabdomyosarcoma

    International Nuclear Information System (INIS)

    Sidhom, I.; El Nadi, E.; Taha, H.; Elkinaai, N.; Zaghloul, M.S.; Younes, A.; Labib, R.; Sabry, M.

    2015-01-01

    Background: The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma. Aim: Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome. Patients and Methods: Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children’s Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010. Results: Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age P 10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8 ± 10.6% and 53.4 ± 5.8%, respectively (p = 0.014) and the 3-year overall survival rates were 35.3 ± 11.6% and 61 ± 6%, respectively (p = 0.019). Conclusions: The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome

  3. Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis

    Science.gov (United States)

    Keefer, Laurie; Taft, Tiffany H; Kiebles, Jennifer L; Martinovich, Zoran; Barrett, Terrence A; Palsson, Olafur S

    2013-01-01

    Summary Background Psychotherapy is not routinely recommended for in ulcerative colitis (UC). Gut-directed hypnotherapy (HYP) has been linked to improved function in the gastrointestinal tract and may operate through immune-mediated pathways in chronic diseases. Aims To determine the feasibility and acceptability of hypnotherapy and estimate the impact of hypnotherapy on clinical remission status over a 1 year period in patients with an historical flare rate of 1.3 times per year. Methods 54 patients were randomized at a single site to 7 sessions of gut-directed hypnotherapy (N = 26) or attention control (CON; N = 29) and followed for 1 year. The primary outcome was the proportion of participants in each condition that had remained clinically asymptomatic (clinical remission) through 52 weeks post-treatment. Results One-way ANOVA comparing hypnotherapy and control subjects on number of days to clinical relapse favored the hypnotherapy condition [F = 4.8 (1, 48), p = .03] by 78 days. Chi square analysis comparing the groups on proportion maintaining remission at 1 year was also significant [X2(1) = 3.9, p = .04], with 68% of hypnotherapy and 40% of control patients maintaining remission for 1 year. There were no significant differences between groups over time in quality of life, medication adherence, perceived stress or psychological factors. Conclusions This is the first prospective study that has demonstrated a significant effect of a psychological intervention on prolonging clinical remission in patients with quiescent UC. Clinical Trial # NCT00798642 PMID:23957526

  4. European recommendations for the clinical use of HIV drug resistance testing: 2011 update

    DEFF Research Database (Denmark)

    Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca

    2011-01-01

    , and other drug targets (integrase and envelope) if such drugs were part of the failing regimen; (iii) consider testing for CCR5 tropism at virologic failure or when a change of therapy has to be made in absence of detectable viral load, and in the latter case test DNA or last detectable plasma RNA; (iv...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure...... is needed after treatment failure. The Panel recommends genotyping in most situations, using updated and clinically evaluated interpretation systems. It is mandatory that laboratories performing HIV resistance tests take part regularly in external quality assurance programs, and that they consider storing...

  5. Significant role of cationic polymers in drug delivery systems.

    Science.gov (United States)

    Farshbaf, Masoud; Davaran, Soodabeh; Zarebkohan, Amir; Annabi, Nasim; Akbarzadeh, Abolfazl; Salehi, Roya

    2017-11-06

    Cationic polymers are characterized as the macromolecules that possess positive charges, which can be either inherently in the polymer side chains and/or its backbone. Based on their origins, cationic polymers are divided in two category including natural and synthetic, in which the possessed positive charges are as result of primary, secondary or tertiary amine functional groups that could be protonated in particular situations. Cationic polymers have been employed commonly as drug delivery agents due to their superior encapsulation efficacy, enhanced bioavailability, low toxicity and improved release profile. In this paper, we focus on the most prominent examples of cationic polymers which have been revealed to be applicable in drug delivery systems and we also discuss their general synthesis and surface modification methods as well as their controlled release profile in drug delivery.

  6. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    International Nuclear Information System (INIS)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y.

    2014-01-01

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  7. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

    2014-09-15

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  8. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    Science.gov (United States)

    Wilby, J; Kainth, A; Hawkins, N; Epstein, D; McIntosh, H; McDaid, C; Mason, A; Golder, S; O'Meara, S; Sculpher, M; Drummond, M; Forbes, C

    2005-04-01

    To examine the clinical effectiveness, tolerability and cost-effectiveness of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TGB), topiramate (TPM) and vigabatrin (VGB) for epilepsy in adults. Electronic databases. Internet resources. Pharmaceutical company submissions. Selected studies were screened and quality assessed. Separate analyses assessed clinical effectiveness, serious, rare and long-term adverse events and cost-effectiveness. An integrated economic analysis incorporating information on costs and effects of newer and older antiepileptic drugs (AEDs) was performed to give direct comparisons of long-term costs and benefits. A total of 212 studies were included in the review. All included systematic reviews were Cochrane reviews and of good quality. The quality of randomised controlled trials (RCTs) was variable. Assessment was hampered by poor reporting of methods of randomisation, allocation concealment and blinding. Few of the non-randomised studies were of good quality. The main weakness of the economic evaluations was inappropriate use of the cost-minimisation design. The included systematic reviews reported that newer AEDs were effective as adjunctive therapy compared to placebo. For newer versus older drugs, data were available for all three monotherapy AEDs, although data for OXC and TPM were limited. There was limited, poor-quality evidence of a significant improvement in cognitive function with LTG and OXC compared with older AEDs. However, there were no consistent statistically significant differences in other clinical outcomes, including proportion of seizure-free patients. No studies assessed effectiveness of AEDs in people with intellectual disabilities or in pregnant women. There was very little evidence to assess the effectiveness of AEDs in the elderly; no significant differences were found between LTG and carbamazepine monotherapy. Sixty-seven RCTs compared adjunctive therapy with placebo, older

  9. 3-Year Clinical Follow-Up of the RIBS IV Clinical Trial: A Prospective Randomized Study of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis in Coronary Arteries Previously Treated With Drug-Eluting Stents.

    Science.gov (United States)

    Alfonso, Fernando; Pérez-Vizcayno, María José; Cuesta, Javier; García Del Blanco, Bruno; García-Touchard, Arturo; López-Mínguez, José Ramón; Masotti, Mónica; Zueco, Javier; Cequier, Angel; Velázquez, Maite; Moreno, Raúl; Mainar, Vicente; Domínguez, Antonio; Moris, Cesar; Molina, Eduardo; Rivero, Fernando; Jiménez-Quevedo, Pilar; Gonzalo, Nieves; Fernández-Pérez, Cristina

    2018-05-28

    This study sought to compare the long-term safety and efficacy of drug-eluting balloons (DEB) and everolimus-eluting stents (EES) in patients with in-stent restenosis (ISR) of drug-eluting stents (DES). Treatment of patients with DES-ISR remains a challenge. The RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents) trial is a prospective multicenter randomized clinical trial comparing DEB and EES in patients with DES-ISR. The pre-specified comparison of the 3-year clinical outcomes obtained with these interventions is the main objective of the present study. A total of 309 patients with DES-ISR were randomized to DEB (n = 154) or EES (n = 155). At angiographic follow-up, the in-segment minimal lumen diameter was larger in the EES arm (2.03 ± 0.7 mm vs. 1.80 ± 0.6 mm; p 1 year) target lesion revascularization (2.6% vs. 4%) and target vessel revascularization (4% vs. 6.6%) was similar in the 2 arms. Rates of cardiac death (3.9% vs. 3.2%), myocardial infarction (2.6% vs. 4.5%), and stent thrombosis (1.3% vs. 2.6%) at 3 years were also similar in both arms. The 3-year clinical follow-up of this randomized clinical trial demonstrates that in patients with DES-ISR, EES reduce the need for repeat interventions compared with DEB. (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents [RIBS IV]; NCT01239940). Published by Elsevier Inc.

  10. Multimodal system designed to reduce errors in recording and administration of drugs in anaesthesia: prospective randomised clinical evaluation.

    Science.gov (United States)

    Merry, Alan F; Webster, Craig S; Hannam, Jacqueline; Mitchell, Simon J; Henderson, Robert; Reid, Papaarangi; Edwards, Kylie-Ellen; Jardim, Anisoara; Pak, Nick; Cooper, Jeremy; Hopley, Lara; Frampton, Chris; Short, Timothy G

    2011-09-22

    in nine administrations) (P = 0.045 for difference). Most were recording errors, and, though fewer drug administration errors occurred with the new system, the comparison with conventional methods did not reach significance. Rates of errors in drug administration were lower when anaesthetists consistently applied two key principles of the new system (scanning the drug barcode before administering each drug and keeping the voice prompt active) than when they did not: mean 6.0 (3.1 to 8.8) errors per 100 administrations v 9.7 (8.4 to 11.1) respectively (P = 0.004). Lapses in the vigilance latency task occurred in 12% (58/471) of cases with the new system and 9% (40/473) with conventional methods (P = 0.052). The records generated by the new system were more legible, and anaesthetists preferred the new system, particularly in relation to long, complex, and emergency cases. There were no differences between new and conventional systems in respect of outcomes in patients or anaesthetists' workload. The new system was associated with a reduction in errors in the recording and administration of drugs in anaesthesia, attributable mainly to a reduction in recording errors. Automatic compilation of the anaesthetic record increased legibility but also increased lapses in a vigilance latency task and decreased time spent watching monitors. Trial registration Australian New Zealand Clinical Trials Registry No 12608000068369.

  11. Cutaneous adverse drug reactions: clinical pattern and causative agents--a 6 year series from Chandigarh, India.

    Directory of Open Access Journals (Sweden)

    Sharma V

    2001-04-01

    Full Text Available AIM: To study the different clinical spectrum of cutaneous adverse drug reactions (ADR and to determine the causative drugs. MATERIALS & METHODS: A prospective, hospital based study was carried out over a period of 6 years recording various cutaneous ADR. RESULTS: A total of 500 patients with cutaneous ADR were enrolled in the study. The most common types of cutaneous ADR patterns were maculopapular rash (34.6%, fixed drug eruption (FDE (30% and urticaria (14%. The drugs most often incriminated for the various cutaneous ADR were antimicrobials (42.6%, anticonvulsants (22.2% and NSAIDs (18%. Anticonvulsants were implicated in 41.6% of maculopapular rashes. Sulfonamides accounted for 43.3% and NSAIDs for 30.7% of FDE. Urticaria was caused mainly by NSAIDs(24.3% and penicillins(20%. Anticonvulsants were responsible for 43.8% of life-threatening toxic epidermal necrolysis and Stevens Johnson syndrome. CONCLUSIONS: The clinical pattern and drugs causing cutaneous ADR are similar to those observed in other countries except for minor variations. Cutaneous ADR patterns and the drugs causing various reactions are changing every year, which may be due to the emergence of newer molecules and changing trends in the use of drugs.

  12. [Direct costs and clinical aspects of adverse drug reactions in patients admitted to a level 3 hospital internal medicine ward].

    Science.gov (United States)

    Tribiño, Gabriel; Maldonado, Carlos; Segura, Omar; Díaz, Jorge

    2006-03-01

    Adverse drug reactions (ADRs) occur frequently in hospitals and increase costs of health care; however, few studies have quantified the clinical and economic impact of ADRs in Colombia. These impacts were evaluated by calculating costs associated with ADRs in patients hospitalized in the internal medicine ward of a Level 3 hospital located in Bogotá, Colombia. In addition, salient clinical features of ADRs were identified and characterized. Intensive follow-ups for a cohort of patients were conducted for a five month period in order to detect ADRs; different ways to classify them, according to literature, were considered as well. Information was collected using the INVIMA reporting format, and causal probability was evaluated with the Naranjo algorithm. Direct costs were calculated from the perspective of payer, based on the following costs: additional hospital stay, medications, paraclinical tests, additional procedures, patient displacement to intermediate or intensive care units, and other costs. Of 836 patients admitted to the service, 268 adverse drug reactions were detected in 208 patients (incidence proportion 25.1%, occurence rate 0.32). About the ADRs found, 74.3% were classified as probable, 92.5% were type A, and 81.3% were moderate. The body system most often affected was the circulatory system (33.9%). Drugs acting on the blood were most frequently those ones associated with adverse reactions (37.6%). The costs resulting from medical care of adverse drug reactions varied from COL dollar 93,633,422 (USD dollar 35,014.92) to COL dollar 122,155,406 (USD dollar 45,680.94), according to insurance type, during the study period. Adverse drug reactions have a significant negative health and financial impact on patient welfare. Because of the substantial resources required for their medical care and the significant proportion of preventable adverse reactions, active programs of institutional pharmacovigilance are highly recommended.

  13. Clinical developments of chemotherapeutic nanomedicines: Polymers and liposomes for delivery of camptothecins and platinum (II) drugs

    KAUST Repository

    Kieler-Ferguson, Heidi M.

    2013-01-17

    For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting. Although a number of macromolecular-drug conjugates have progressed to clinical trials, tuning drug release to maintain efficacy in conjunction with controlling drug toxicity has prevented the clinical adoption of many vehicles. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery. WIREs Nanomed Nanobiotechnol 2013, 5:130-138. doi: 10.1002/wnan.1209 For further resources related to this article, please visit the WIREs website. Conflict of interest: Drs Kieler-Ferguson and Fréchet declare no conflicts of interest. Dr Szoka is the founder of a liposome drug delivery company that is not working on any of the compounds mentioned in this article. © 2013 Wiley Periodicals, Inc.

  14. Drug interactions between common illicit drugs and prescription therapies.

    Science.gov (United States)

    Lindsey, Wesley T; Stewart, David; Childress, Darrell

    2012-07-01

    The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug-drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

  15. Types, frequencies, and burden of nonspecific adverse events of drugs: analysis of randomized placebo-controlled clinical trials.

    Science.gov (United States)

    Mahr, Alfred; Golmard, Clara; Pham, Emilie; Iordache, Laura; Deville, Laure; Faure, Pierre

    2017-07-01

    Scarce studies analyzing adverse event (AE) data from randomized placebo-controlled clinical trials (RPCCTs) of selected illnesses suggested that a substantial proportion of collected AEs are unrelated to the drug taken. This study analyzed the nonspecific AEs occurring with active-drug exposure in RPCCTs for a large range of medical conditions. Randomized placebo-controlled clinical trials published in five prominent medical journals during 2006-2012 were searched. Only trials that evaluated orally or parenterally administered active drugs versus placebo in a head-to-head setting were selected. For AEs reported from ≥10 RPCCTs, Pearson's correlation coefficients (r) were calculated to determine the relationship between AE rates in placebo and active-drug recipients. Random-effects meta-analyses were used to compute proportions of nonspecific AEs, which were truncated at a maximum of 100%, in active-drug recipients. We included 231 trials addressing various medical domains or healthy participants. For the 88 analyzed AE variables, AE rates for placebo and active-drug recipients were in general strongly correlated (r > 0.50) or very strongly correlated (r > 0.80). The pooled proportions of nonspecific AEs for the active-drug recipients were 96.8% (95%CI: 95.5-98.1) for any AEs, 100% (97.9-100) for serious AEs, and 77.7% (72.7-83.2) for drug-related AEs. Results were similar for individual medical domains and healthy participants. The pooled proportion of nonspecificity of 82 system organ class and individual AE types ranged from 38% to 100%. The large proportion of nonspecific AEs reported in active-drug recipients of RPCCTs, including serious and drug-related AEs, highlights the limitations of clinical trial data to determine the tolerability of drugs. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  16. The toxicological significance of post-mortem drug concentrations in bile.

    Science.gov (United States)

    Ferner, Robin E; Aronson, Jeffrey K

    2018-01-01

    Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value. To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature. We made a systematic search of EMBASE 1980-2016 using the search terms ("bile/" OR "exp drug bile level/concentration/") AND "drug blood level/concentration/", PubMed 1975-2017 for ("bile[tw]" OR "biliary[tw]") AND ("concentration[tw]" OR "concentrations[tw]" OR "level[tw]" OR "levels[tw]") AND "post-mortem[tw]" and also MEDLINE 1990-2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs. Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058-0.32) for dextromoramide to 520 (range 0.62-43,000) for buprenorphine. Median bile

  17. Drug metabolism and ageing.

    Science.gov (United States)

    Wynne, Hilary

    2005-06-01

    Older people are major consumers of drugs and because of this, as well as co-morbidity and age-related changes in pharmacokinetics and pharmacodynamics, are at risk of associated adverse drug reactions. While age does not alter drug absorption in a clinically significant way, and age-related changes in volume of drug distribution and protein binding are not of concern in chronic therapy, reduction in hepatic drug clearance is clinically important. Liver blood flow falls by about 35% between young adulthood and old age, and liver size by about 24-35% over the same period. First-pass metabolism of oral drugs avidly cleared by the liver and clearance of capacity-limited hepatically metabolized drugs fall in parallel with the fall in liver size, and clearance of drugs with a high hepatic extraction ratio falls in parallel with the fall in hepatic blood flow. In normal ageing, in general, activity of the cytochrome P450 enzymes is preserved, although a decline in frail older people has been noted, as well as in association with liver disease, cancer, trauma, sepsis, critical illness and renal failure. As the contribution of age, co-morbidity and concurrent drug therapy to altered drug clearance is impossible to predict in an individual older patient, it is wise to start any drug at a low dose and increase this slowly, monitoring carefully for beneficial and adverse effects.

  18. Monoscopic versus stereoscopic photography in screening for clinically significant macular edema.

    Science.gov (United States)

    Welty, Christopher J; Agarwal, Anita; Merin, Lawrence M; Chomsky, Amy

    2006-01-01

    The purpose of the study was to determine whether monoscopic photography could serve as an accurate tool when used to screen for clinically significant macular edema. In a masked randomized fashion, two readers evaluated monoscopic and stereoscopic retinal photographs of 100 eyes. The photographs were evaluated first individually for probable clinically significant macular edema based on the Early Treatment Diabetic Retinopathy Study criteria and then as stereoscopic pairs. Graders were evaluated for sensitivity and specificity individually and in combination. Individually, reader one had a sensitivity of 0.93 and a specificity of 0.77, and reader two had a sensitivity of 0.88 and a specificity of 0.94. In combination, the readers had a sensitivity of 0.91 and a specificity of 0.86. They correlated on 0.76 of the stereoscopic readings and 0.92 of the monoscopic readings. These results indicate that the use of monoscopic retinal photography may be an accurate screening tool for clinically significant macular edema.

  19. 78 FR 13070 - Guidance for Clinical Investigators, Industry, and Food and Drug Administration Staff: Financial...

    Science.gov (United States)

    2013-02-26

    ... marketing applications, (2) what is meant by ``due diligence'' in obtaining financial disclosures from...: Financial Disclosure by Clinical Investigators; Availability AGENCY: Food and Drug Administration, HHS... guidance entitled ``Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by...

  20. Rational drug therapy education in clinical phase carried out by task-based learning

    Science.gov (United States)

    Bilge, S. Sırrı; Akyüz, Bahar; Ağrı, Arzu Erdal; Özlem, Mıdık

    2017-01-01

    Objectives: Irrational drug use results in drug interactions, treatment noncompliance, and drug resistance. Rational pharmacotherapy education is being implemented in many faculties of medicine. Our aim is to introduce rational pharmacotherapy education by clinicians and to evaluate task-based rational drug therapy education in the clinical context. Methods: The Kirkpatrick's evaluation model was used for the evaluation of the program. The participants evaluated the program in terms of constituents of the program, utilization, and contribution to learning. Voluntary participants responded to the evaluation forms after the educational program. Data are evaluated using both quantitative and qualitative tools. SPSS (version 21) used for quantitative data for determining mean and standard deviation values. Descriptive qualitative analysis approach is used for the analysis of open-ended questions. Results: It was revealed that the program and its components have been favorable. A total 95.9% of the students consider the education to be beneficial. Simulated patients practice and personal drug choice/problem-based learning sessions were appreciated by the students in particular. 93.9% of the students stated that all students of medicine should undergo this educational program. Among the five presentations contained in the program, “The Principles of Prescribing” received the highest points (9 ± 1.00) from participating students in general evaluation of the educational program. Conclusion: This study was carried out to improve task-based rational drug therapy education. According to feedback from the students concerning content, method, resource, assessment, and program design; some important changes, especially in number of facilitators and indications, are made in rational pharmacotherapy education in clinical task-based learning program. PMID:28458432

  1. The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients.

    Science.gov (United States)

    Lepeytre, Fanny; Cardinal, Héloise; Fradette, Lorraine; Verhave, Jacobien; Dorais, Marc; LeLorier, Jacques; Pichette, Vincent; Madore, François

    2017-06-01

    Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications.

  2. Gender differences in clinical manifestations before AIDS diagnosis among injecting drug users

    NARCIS (Netherlands)

    Spijkerman, I. J.; Langendam, M. W.; van Ameijden, E. J.; Coutinho, R. A.; van den Hoek, A.

    1998-01-01

    We compared incidence rates of self-reported HIV-related symptoms and illnesses, verified clinical manifestations and findings on physical examination between female and male injecting drug users (IDU) stratified by HIV serostatus in the Amsterdam cohort study on the natural history of HIV

  3. Clinical significance of anaplasia in childhood rhabdomyosarcoma.

    Science.gov (United States)

    Sidhom, Iman; El Nadi, Enas; Taha, Hala; Elkinaai, Naglaa; Zaghloul, Mohamed S; Younes, Alaa; Labib, Rania; Sabry, Mohamed

    2015-06-01

    The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma. Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome. Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children's Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010. Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age⩾10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8±10.6% and 53.4±5.8%, respectively (p=0.014) and the 3-year overall survival rates were 35.3±11.6% and 61±6%, respectively (p=0.019). The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  4. Prevalence and clinical significance of cathepsin G antibodies in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    M. Favaro

    2011-09-01

    Full Text Available Objectives: To evaluate the prevalence and clinical significance of cathepsin G antibodies in patients affected with systemic sclerosis (SSc, scleroderma. Methods: 115 patients affected by SSc, 55 (47,8% with diffuse scleroderma (dSSc and 60 (52,2% with limited scleroderma (lSSc, were tested for cathepsin G antibodies by ELISA method. Moreover these sera were evaluated by indirect immunofluorescence (IIF on ethanol and formalin fixed human neutrophils. Results: By means of the ELISA method 16 (13,9% patients were found to be sera positive for anti-cathepsin G, 2 (12.5% of which showed a perinuclear fluorescence pattern (P-ANCA and 4 (25% an atypical ANCA staining, while 10 (62,5% were negative on IIF. The IIF on scleroderma sera revealed 5 (4,3% P-ANCA and 18 (15,7% atypical ANCA patterns. The anti-cathepsin G antibodies significantly prevailed in scleroderma sera (p=0.02 when their frequency was compared with that of healthy controls; while they were not significantly associated to any clinical or serological features of SSc patients. Conclusions: The anti-cathepsin G antibodies were significantly frequent in scleroderma sera; however, no clinical correlations were found. Thus, the significance of their presence in SSc still needs to be clarified.

  5. Immunosuppressive Drug Discontinuation in Noninfectious Uveitis From Real-Life Clinical Practice: A Survival Analysis.

    Science.gov (United States)

    Abásolo, Lydia; Rosales, Zulema; Díaz-Valle, David; Gómez-Gómez, Alejandro; Peña-Blanco, Rayma C; Prieto-García, Ángela; Benítez-Del-Castillo, José Manuel; Pato, Esperanza; García-Feijoo, Julián; Fernández-Gutiérrez, Benjamín; Rodriguez-Rodriguez, Luis

    2016-09-01

    To assess in uveitis patients the rate of immunosuppressive drug (ISD) discontinuation in real-life clinical practice, comparing this rate among ISDs. Longitudinal retrospective cohort study. We included uveitis patients attending a tertiary eye referral center from Madrid (Spain) between 1989 and 2015, prescribed any ISDs (cyclosporine, methotrexate, azathioprine, anti-TNF drugs, or others). Our main outcome was discontinuation of all ISDs owing to clinical efficacy, inefficacy, adverse drug reaction (ADR), and other medical causes. Discontinuation rates (DRs) per 100 patient-years were estimated. Variables associated with specific-cause discontinuations were analyzed using Cox bivariate and multivariate models. We analyzed 110 patients with 263 treatment courses and 665.2 patient-years of observation. Cyclosporine (66.4%), methotrexate (47.3%), azathioprine (30.9%), and anti-TNFs (30.9%) were the most frequently used ISDs. Treatment was suspended in 136 cases (mostly owing to clinical efficacy [38.2%], inefficacy [26.5%], and ADRs [22.8%]). All-cause DR with 95% confidence interval was 20.4 [17.3-24.2]. Retention rates at 1 and 10 years were 74% and 16%, respectively. In the multivariate analysis, combined treatment exhibited higher DRs owing to clinical efficacy than other ISDs in monotherapy. Conversely, nonbiologic combination therapy with azathioprine exhibited the highest DR owing to ADRs. Clinical efficacy was the most frequent cause for ISD discontinuation, followed by inefficacy and ADRs. DR owing to efficacy was higher for combination therapy. Furthermore, nonbiologic combination therapy with azathioprine was associated with a higher DR owing to ADRs. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer.

    Science.gov (United States)

    Berstein, Lev M

    2005-06-28

    Factors predisposing hormone-dependent tissues to the development of tumors coincide, at least partly, with hormonal-metabolic promoters (like insulin resistance, glucose intolerance, visceral obesity, etc.) of other main non-communicable diseases. This important knowledge poses the question of whether the same approach which is applied for prevention/treatment of a metabolic syndrome and the associated endocrine disorders might also be used in preventive and therapeutic oncology. Whereas an answer to this question remains controversial and is based mainly on experimental evidence, there is accumulating clinical data suggesting a practical significance of such a strategy, even though it is not to be considered as directly cytostatic. Among the many drugs under discussion, three groups of medicines (statins, antidiabetic biguanides, and thiazolidinediones) are the most attractive. The concept of metabolic rehabilitation is proposed and used practically in an adjuvant setting for the correction of the above-mentioned endocrine-metabolic disorders commonly found in cancer patients. The current use and aim of this approach is to improve the survival of patients and limit cancer progression. Nonetheless, it also appears potentially useful as a neoadjuvant therapy as well as a prophylactic treatment earlier in life for specific groups of people with hormone-associated enhanced oncological risk. It seems possible that certain hypolipidemic and antidiabetic medicines with pleiotropic effects might be combined with traditional antisteroid prevention/therapeutic approaches in routine clinical situations as well as for overcoming resistance to standard cancer hormonal therapies including receptor-negative cases. Characteristic at the end of the 20th and at the beginning of the 21st century is an epidemic of diabetes and obesity, which might further increase the incidence of certain cancers. This makes it timely to apply hypolipidemic and antidiabetic drugs (in combination

  7. 76 FR 12742 - Guidance for Industry and Food and Drug Administration Staff; Clinical Investigations of Devices...

    Science.gov (United States)

    2011-03-08

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2008-D-0457] Guidance for Industry and Food and Drug Administration Staff; Clinical Investigations of Devices Indicated... other electrical continence devices; protective garment for incontinence; surgical mesh; electrosurgical...

  8. Meta-Analysis of Randomized Clinical Trials Comparing Biodegradable Polymer Drug-Eluting Stent to Second-Generation Durable Polymer Drug-Eluting Stents.

    Science.gov (United States)

    El-Hayek, Georges; Bangalore, Sripal; Casso Dominguez, Abel; Devireddy, Chandan; Jaber, Wissam; Kumar, Gautam; Mavromatis, Kreton; Tamis-Holland, Jacqueline; Samady, Habib

    2017-03-13

    The authors sought to perform a meta-analysis of randomized clinical trials (RCTs) comparing the safety and efficacy of biodegradable polymer drug-eluting stents (BP-DES) to second-generation durable polymer drug-eluting stents (DP-DES). Prior meta-analyses have established the superiority of BP-DES over bare-metal stents and first-generation DP-DES; however, their advantage compared with second-generation DP-DES remains controversial. The authors searched PubMed and Scopus databases for RCTs comparing BP-DES to the second-generation DP-DES. Outcomes included target vessel revascularization (TVR) as efficacy outcome and cardiac death, myocardial infarction (MI), and definite or probable stent thrombosis (ST) as safety outcomes. In addition, we performed landmark analysis for endpoints beyond 1 year of follow-up and a subgroup analysis based on the stent characteristics. The authors included 16 RCTs comprising 19,886 patients in the meta-analysis. At the longest available follow-up (mean duration 26 months), we observed no significant differences in TVR (p = 0.62), cardiac death (p = 0.46), MI (p = 0.98), or ST (risk ratio: 0.83, 95% confidence interval: 0.64 to 1.09; p = 0.19). Our landmark analysis showed that BP-DES were not associated with a reduction in the risk of very late ST (risk ratio: 0.87, 95% confidence interval: 0.49 to 1.53; p = 0.62). Similar outcomes were seen regardless of the eluting drug (biolimus vs. sirolimus), the stent platform (stainless steel vs. alloy), the kinetics of polymer degradation or drug release (6 months), the strut thickness of the BP-DES (thin 100 μm), or the DAPT duration (≥6 months vs. ≥12 months). BP-DES have similar safety and efficacy profiles to second-generation DP-DES. Published by Elsevier Inc.

  9. Drug-Drug and Herb-Drug Interaction-A Comment | Esimone ...

    African Journals Online (AJOL)

    Clinically relevant drug-drug interactions may be pharmacodynamic or pharmacokinetic. And herbal medicinal products are becoming increasingly popular. Drug interactions can be in vivo or in vitro. Pharmacodynamic outcomes take such forms as Additive, Synergistic, Antagonistic or Indifferent. The paper reviews and ...

  10. Clinical Significance and Characteristic Clinical Differences of Cytolytic Vaginosis in Recurrent Vulvovaginitis.

    Science.gov (United States)

    Yang, Shuhua; Zhang, Yuexiang; Liu, Ying; Wang, Jianhong; Chen, Shuqin; Li, Shuxia

    2017-01-01

    The study aimed to evaluate whether cytolytic vaginosis (CV) has important clinical implications for recurrent vulvovaginitis and to identify clinical differences between CV and vulvovaginal candidosis (VVC). Medical histories, physical examinations and laboratory findings were used to diagnose and assess the prevalence rates of various vulvovaginal infections among 536 women with recurrent vulvovaginitis. Chi-square and Fisher exact tests were used to compare age, menstrual cycle phase at episode onset, symptoms/signs of infection and discharge characteristics between CV and VVC with single infection. Among the 484 women with a single-infection recurrent vulvovaginitis, the prevalence of CV (n = 143; 26.7%) was second only to VVC (n = 196; 36.6%). CV symptoms occurred predominantly during the ovulatory and luteal phases. Meanwhile, VVC episodes were not concentrated premenstrually, but rather occurred throughout the menstrual cycle. Significant differences were found in the vaginal pH, discharge characteristics and frequency of inflammatory symptoms between the 2 groups. CV is clinically important, because it is a common cause of recurrent vulvovaginitis. To distinguish CV from VVC, gynecologists should consider the patient's medical history, physical and laboratory findings, vaginal pH and vaginal discharge characteristics. © 2016 S. Karger AG, Basel.

  11. A guided interview process to improve student pharmacists' identification of drug therapy problems.

    Science.gov (United States)

    Rovers, John; Miller, Michael J; Koenigsfeld, Carrie; Haack, Sally; Hegge, Karly; McCleeary, Erin

    2011-02-10

    To measure agreement between advanced pharmacy practice experience students using a guided interview process and experienced clinical pharmacists using standard practices to identify drug therapy problems. Student pharmacists enrolled in an advanced pharmacy practice experience (APPE) and clinical pharmacists conducted medication therapy management interviews to identify drug therapy problems in elderly patients recruited from the community. Student pharmacists used a guided interview tool, while clinical pharmacists' interviews were conducted using their usual and customary practices. Student pharmacists also were surveyed to determine their perceptions of the interview tool. Fair to moderate agreement was observed on student and clinical pharmacists' identification of 4 of 7 drug therapy problems. Of those, agreement was significantly higher than chance for 3 drug therapy problems (adverse drug reaction, dosage too high, and needs additional drug therapy) and not significant for 1 (unnecessary drug therapy). Students strongly agreed that the interview tool was useful but agreed less strongly on recommending its use in practice. The guided interview process served as a useful teaching aid to assist student pharmacists to identify drug therapy problems.

  12. An epidemiological and clinical analysis of cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia

    Directory of Open Access Journals (Sweden)

    Siew-Eng Choon

    2012-01-01

    Full Text Available Background: The prevalence, clinical patterns, and causative drugs of cutaneous adverse drug reactions (cADR vary among the different populations previously studied. Aim: To determine the prevalence, the clinical patterns of drug eruptions, and the common drugs implicated, particularly in severe cADR such as Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN and drug rash with eosinophilia and systemic symptoms (DRESS in our population. Methods: We analyzed the database established for all cADR seen by the department of Dermatology from January 2001 till December 2010. Results: A total of 362 cADR were seen among 42 170 new clinic attendees, yielding an incidence rate of 0.86%. The most common reaction pattern seen was maculopapular eruption (153 cases followed by SJS/TEN (110 cases and DRESS (34 cases. Antibiotics was the most commonly implicated drug group (146 cases followed by anticonvulsants (81 cases and antigout drugs (50 cases. The most frequently implicated drug was allopurinol (50 cases. Carbamazepine, allopurinol, and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 21.8%, 20.9%, and 12.7%, respectively, of the 110 cases seen, whereas DRESS was mainly caused by allopurinol (15 cases. Mortality rates for TEN, SJS, and DRESS were 28.6%, 2.2%, and 5.9%, respectively Conclusions: The low rate of cADR with a high proportion of severe reactions observed in this study was probably due to referral bias. Otherwise, the reaction patterns and drugs causing cADR in our population were similar to those seen in other countries. Carbamazepine, allopurinol, and cotrimoxazole were the three main causative drugs of SJS/TEN in our population.

  13. An epidemiological and clinical analysis of cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia.

    Science.gov (United States)

    Choon, Siew-Eng; Lai, Nai-Ming

    2012-01-01

    The prevalence, clinical patterns, and causative drugs of cutaneous adverse drug reactions (cADR) vary among the different populations previously studied. To determine the prevalence, the clinical patterns of drug eruptions, and the common drugs implicated, particularly in severe cADR such as Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms (DRESS) in our population. We analyzed the database established for all cADR seen by the department of Dermatology from January 2001 till December 2010. A total of 362 cADR were seen among 42 170 new clinic attendees, yielding an incidence rate of 0.86%. The most common reaction pattern seen was maculopapular eruption (153 cases) followed by SJS/TEN (110 cases) and DRESS (34 cases). Antibiotics was the most commonly implicated drug group (146 cases) followed by anticonvulsants (81 cases) and antigout drugs (50 cases). The most frequently implicated drug was allopurinol (50 cases). Carbamazepine, allopurinol, and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 21.8%, 20.9%, and 12.7%, respectively, of the 110 cases seen, whereas DRESS was mainly caused by allopurinol (15 cases). Mortality rates for TEN, SJS, and DRESS were 28.6%, 2.2%, and 5.9%, respectively. The low rate of cADR with a high proportion of severe reactions observed in this study was probably due to referral bias. Otherwise, the reaction patterns and drugs causing cADR in our population were similar to those seen in other countries. Carbamazepine, allopurinol, and cotrimoxazole were the three main causative drugs of SJS/TEN in our population.

  14. Clinical Significance of CK19 Negative Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fujisue, Mamiko, E-mail: nishimura.reiki@cityhosp-kumamoto.jp; Nishimura, Reiki; Okumura, Yasuhiro [Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan); Tashima, Rumiko [Department of Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan); Nishiyama, Yasuyuki; Osako, Tomofumi [Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan); Toyozumi, Yasuo; Arima, Nobuyuki [Department of Pathology, Kumamoto City Hospital, 1-1-60 Kotoh, Kumamoto City, Kumamoto 862-8505 (Japan)

    2012-12-21

    Analysis of sentinel lymph nodes (SLNs) by means of One-Step Nucleic Acid Amplification (OSNA) is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19) which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis.

  15. Clinical Significance of CK19 Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nobuyuki Arima

    2012-12-01

    Full Text Available Analysis of sentinel lymph nodes (SLNs by means of One-Step Nucleic Acid Amplification (OSNA is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19 which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis.

  16. Clinical Significance of CK19 Negative Breast Cancer

    International Nuclear Information System (INIS)

    Fujisue, Mamiko; Nishimura, Reiki; Okumura, Yasuhiro; Tashima, Rumiko; Nishiyama, Yasuyuki; Osako, Tomofumi; Toyozumi, Yasuo; Arima, Nobuyuki

    2012-01-01

    Analysis of sentinel lymph nodes (SLNs) by means of One-Step Nucleic Acid Amplification (OSNA) is gaining widespread use as a quick and accurate method. This assay detects the expression level of cytokeratin 19 (CK19) which is present in some but not all breast tumors. In this study, the clinical significance of negative CK19 was investigated in 219 cases of primary breast cancer. In 179 patients with clinically negative nodes, OSNA and imprint smear cytology of SLN were performed simultaneously. The OSNA revealed a node-positive rate of 24.6%. Negative CK19 correlated significantly with negative ER/PgR and higher Ki-67 values, and marginally with higher nuclear grade and p53 overexpression. The triple negative subtype showed lower CK19 expression. OSNA revealed that one of the negative CK19 cases was actually a false negative but this was corrected with the use of the imprint smear cytology. In conclusion, CK19 negativity reflected the aggressiveness of primary breast cancer. OSNA assay used to analyze SLN was useful, but there is a possibility that it will mistakenly detect false negatives in CK19 negative tumors. Therefore, in tumors with negative CK19, the imprint smear cytology may be more useful in cases with macrometastasis

  17. The effect of combined drugs therapy on the course of clinical rabies infection in a murine model.

    Science.gov (United States)

    Smreczak, Marcin; Orłowska, Anna; Marzec, Anna; Trębas, Paweł; Kycko, Anna; Reichert, Michał; Koraka, Penelope; Osterhaus, Albert D M E; Żmudziński, Jan Franciszek

    2018-04-09

    Rabies is a fatal disease of all mammals causing almost 60,000 human deaths every year. To date, there is no effective treatment of clinical rabies once the symptoms appear. Here, we describe the promising effect of combination therapy composed of molecules that target replication of the rabies virus (RV) at different stages of life cycle and molecules that inhibit some pathways of the innate host immune response accompanied by a blood-brain barrier opener on the outcome of RV infection. The study reports statistically significant extension of survival of mice treated with the drug cocktail containing T-705, ribavirin, interferon α/β, caspase-1 inhibitor, TNF-α inhibitor, MAPKs inhibitor and HRIG compared to the survival of mice in the virus control group (p = 0.0312). Furthermore, the study points to the significant impact of interferon α/β on the survival of RV-infected mice. We have shown a significant down regulation of pro-inflammatory molecules (caspase-1 and TNF-a) in the CNS in RV-infected mice treated with a combination of drugs including interferon α/β. Copyright © 2018. Published by Elsevier Ltd.

  18. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy.

    Science.gov (United States)

    Pasipanodya, Jotam G; Srivastava, Shashikant; Gumbo, Tawanda

    2012-07-01

    Using hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators. Thirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI, .9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or small-study effects were observed for the outcomes evaluated. Pharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.

  19. Speciation and Biofilm Production of Coagulase Negative Staphylococcal Isolates from Clinically Significant Specimens and their Antibiogram

    Directory of Open Access Journals (Sweden)

    S. S. Vijayasri Badampudi

    2016-04-01

    Full Text Available Background: Coagulase Negative Staphylococci (CONS are increasingly recognized as significant nosocomial pathogens. Their ability of biofilm formation and multiple drug resistance are causing serious human infections. Aim and Objectives: To isolate, identify, speciate clinically significant CONS from various specimens, to study antibiotic resistance pattern and biofilm production. Material and Methods: Specimens were collected aseptically, processed and identified upto the species level by a simple scheme of tests urease, novobiocin resistance, mannose and mannitol fermentation, ornithine decarboxylase. Antibiotic sensitivity was done with special reference to methicillin resistance. Biofilm formation was detected by Congo Red Agar (CRA method and Tube Method (TM. Results: Study groupOf 100 isolates majority were pus (40, followed by urine (28, blood (16, CSF (5, body fluids (4 and catheter tips and implants (7. The most common species isolated was S. epidermidis (40% followed by S. haemolyticus (26%, S. saprophyticus (15%, S. schleiferi (13%, S. simulans (2%, S. cohnii (2% and S. warneri and S. capitis each 1%. Resistance to penicillin was 91% followed by ampicillin (79%, cotrimoxazole (67%. Methicillin resistance was 72%. Biofilm producers were 69% by CRAmethod and 33% by TM with majority species S. epidermidis (82.5%- CRA and 55%-TM. Biofilm production was significantly associated with MRCONS (p value 0.0036. Control group-Of 30 isolates were S. epidermidis 66.6% followed by S. haemolyticus (16.66%. Biofilm producers were 53.33% by CRA method and 26.65% by TM with majority species S. epidermidis (65%-CRA and 30%-TM.Methicillin resistance was 26.6%. Conclusion: Clinical significance of CONS is increasing day by day, so there is a need for accurate identification to species level and their antibiogram to avoid multidrug resistance. Biofilm producing CONS species pose a risk and CRA method for screening biofilm can be used in all conventional

  20. [Change in drug resistance of Staphylococcus aureus].

    Science.gov (United States)

    Lin, Yan; Liu, Yan; Luo, Yan-Ping; Liu, Chang-Ting

    2013-11-01

    To analyze the change in drug resistance of Staphylococcus aureus (SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards (NCCLS) guidelines. SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillin-resistant Staphylococcus aureus (MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive Staphylococcus aureus (MSSA) (P resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.

  1. Drug utilization pattern in a pain clinic of a tertiary care teaching hospital in Eastern India

    Directory of Open Access Journals (Sweden)

    Debjyoti Dutta

    2013-01-01

    Full Text Available Background: Patients attend the Pain Clinic with varieties of complains of pain, like low back pain, knee pain, shoulder pain, headache, facial pain, different neuralgias and other neuropathic pain states. They receive a multimodal treatment for their pain, Multimodal pain therapy is an integrated multidisciplinary treatment in small groups with a closely coordinated therapeutic approach. Drugs that are prescribed for treatment are not only NSAIDS or Opioids, but also various groups of adjuvant pain medications like anti-epileptics, antidepressants etc. Aim: To find out the drug utilization pattern in the Pain Clinic of a tertiary care medical college hospital in Eastern India. Materials and Methods: A cross sectional; unicentric study was conducted in the Pain Clinic during April 2013 to June 2013. New patients who were willing to participate in the study were enrolled as per selection criteria. A copy of prescriptions were collected from the patients. The drugs prescription patterns were analyzed. Result: 319 patients were included in this study in three months period and their prescriptions were analyzed. Female patients (222 were more in number than male (97. As single prescription and also as combination therapy, paracetamol was found to be the most frequently prescribed drug. Frequently used adjuvant pain medications were found to be pregabalin (21.63% and amitriptyline (16.92%.. Antacid was commonly prescribed as gastroprotective agent. Among drug combinations paracetamol (325 mg + tramadol (37.5 mg combination was used most frequently. (55.17%. Conclusion: In this uncentric study we found that patacetamol, tramadol, pregabalin and amitriptyline are the commonly used medications in a pain clinic. We need more multi-centric and comparative Indian studies.

  2. A comparison of patients with major depressive disorder recruited through newspaper advertising versus consultation referrals for clinical drug trials.

    Science.gov (United States)

    Miller, C A; Hooper, C L; Bakish, D

    1997-01-01

    Difficulties in recruiting patients for clinical trials have plagued investigators for many years. One concern is the generalizability of clinical trial results to community practice, that is, whether volunteers recruited through advertising are homogeneous with those seeking treatment in a clinical setting. This article retrospectively compares the baseline characteristics of patients recruited through newspaper advertisements with those recruited through consultation referrals by reviewing the charts of 54 patients enrolled in two clinical trials for major depressive disorder (MDD). We examined demographic data, background information, clinical histories, and baseline status. Results indicated homogeneity for most variables. The consultation group was significantly more likely to have had previous treatment for the current episode of depression. These results suggest that, although the advertisement and consultation groups were very similar, the drug naivety of the advertisement group may make them a preferred source in terms of generalizability to community practice.

  3. Efflux Pump-mediated Drug Resistance in Burkholderia

    Directory of Open Access Journals (Sweden)

    Nicole L Podnecky

    2015-04-01

    Full Text Available Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in B. cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance.

  4. Biomarkers of adverse drug reactions.

    Science.gov (United States)

    Carr, Daniel F; Pirmohamed, Munir

    2018-02-01

    Adverse drug reactions can be caused by a wide range of therapeutics. Adverse drug reactions affect many bodily organ systems and vary widely in severity. Milder adverse drug reactions often resolve quickly following withdrawal of the casual drug or sometimes after dose reduction. Some adverse drug reactions are severe and lead to significant organ/tissue injury which can be fatal. Adverse drug reactions also represent a financial burden to both healthcare providers and the pharmaceutical industry. Thus, a number of stakeholders would benefit from development of new, robust biomarkers for the prediction, diagnosis, and prognostication of adverse drug reactions. There has been significant recent progress in identifying predictive genomic biomarkers with the potential to be used in clinical settings to reduce the burden of adverse drug reactions. These have included biomarkers that can be used to alter drug dose (for example, Thiopurine methyltransferase (TPMT) and azathioprine dose) and drug choice. The latter have in particular included human leukocyte antigen (HLA) biomarkers which identify susceptibility to immune-mediated injuries to major organs such as skin, liver, and bone marrow from a variety of drugs. This review covers both the current state of the art with regard to genomic adverse drug reaction biomarkers. We also review circulating biomarkers that have the potential to be used for both diagnosis and prognosis, and have the added advantage of providing mechanistic information. In the future, we will not be relying on single biomarkers (genomic/non-genomic), but on multiple biomarker panels, integrated through the application of different omics technologies, which will provide information on predisposition, early diagnosis, prognosis, and mechanisms. Impact statement • Genetic and circulating biomarkers present significant opportunities to personalize patient therapy to minimize the risk of adverse drug reactions. ADRs are a significant heath issue

  5. Rapid Globalization of Medical Device Clinical Development Programs in Japan - The Case of Drug-Eluting Stents.

    Science.gov (United States)

    Murakami, Madoka; Suzuki, Yuka; Tominaga, Toshiyoshi

    2018-02-23

    Delays in the introduction to the Japanese market of drug-eluting stents (DES) developed overseas (i.e., "device lag") decreased sharply between 2004 and 2012. The reduction accompanied a shift in clinical development from a succession pattern (initial product development and approval overseas followed by eventual entrance into the Japanese market) to parallel development (employing multiregional clinical trials (MRCTs)). Although resource-intensive in the short-term, MRCTs are proving to be an effective tool in simultaneous global product development. Creative study designs and the absence of significant ethnic differences in Japanese subjects regarding DES safety and efficacy and the pharmacokinetic behavior of their coating drugs propel this process. More general factors such as medical need and industry incentivization also encourage this shift. Physicians' preference for DES over other percutaneous coronary interventions, the expanding global DES market, and streamlined development and approval prospects each motivate industry to continue investing in DES product development. The efforts of various stakeholders were also integral to overcoming practical obstacles, and contributions by 'Harmonization by Doing' and a premarket collaboration initiative between the USA and Japan were particularly effective. Today, USA/Japan regulatory cooperation is routine, and Japan is now integrated into global medical device development. MRCTs including Japanese subjects, sites, and investigators are now commonplace.

  6. Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions.

    Science.gov (United States)

    Ono, Chiho; Kikkawa, Hironori; Suzuki, Akiyuki; Suzuki, Misaki; Yamamoto, Yuichi; Ichikawa, Katsuomi; Fukae, Masato; Ieiri, Ichiro

    2013-11-01

    Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.

  7. Efficacy Coefficients Determined Using Nail Permeability and Antifungal Activity in Keratin-Containing Media Are Useful for Predicting Clinical Efficacies of Topical Drugs for Onychomycosis.

    Directory of Open Access Journals (Sweden)

    Yoshiki Matsuda

    Full Text Available Onychomycosis is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. In order to obtain an in vitro index that is relevant to the clinical efficacy of topical anti-onychomycosis drugs, we profiled five topical drugs: amorolfine, ciclopirox, efinaconazole, luliconazole, and terbinafine, for their nail permeabilities, keratin affinities, and anti-dermatophytic activities in the presence of keratin. Efinaconazole and ciclopirox permeated full-thickness human nails more deeply than luliconazole. Amorolfine and terbinafine did not show any detectable permeation. The free-drug concentration of efinaconazole in a 5% human nail keratin suspension was 24.9%, which was significantly higher than those of the other drugs (1.1-3.9%. Additionally, efinaconazole was released from human nail keratin at a greater proportion than the other drugs. The MICs of the five drugs for Trichophyton rubrum were determined at various concentrations of keratin (0-20% in RPMI 1640 medium. The MICs of ciclopirox were not affected by keratin, whereas those of efinaconazole were slightly increased and those of luliconazole and terbinafine were markedly increased in the presence of 20% keratin. Efficacy coefficients were calculated using the nail permeation flux and MIC in media without or with keratin. Efinaconazole showed the highest efficacy coefficient, which was determined using MIC in media with keratin. The order of efficacy coefficients determined using MIC in keratin-containing media rather than keratin-free media was consistent with that of complete cure rates in previously reported clinical trials. The present study revealed that efficacy coefficients determined using MIC in keratin-containing media are useful for predicting the clinical efficacies of topical drugs. In order to be more effective, topical drugs have to possess higher efficacy coefficients.

  8. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2)

    Science.gov (United States)

    Wanwimolruk, Sompon; Phopin, Kamonrat; Prachayasittikul, Virapong

    2014-01-01

    To date, a number of significant herbal drug interactions have their origins in the alteration of cytochrome P450 (CYP) activity by various phytochemicals. Among the most noteworthy are those involving St. John's wort and drugs metabolized by human CYP3A4 enzyme. This review article is the continued work from our previous article (Part 1) published in this journal (Wanwimolruk and Prachayasittikul, 2014[ref:133]). This article extends the scope of the review to six more herbs and updates information on herbal drug interactions. These include black cohosh, ginseng, grape seed extract, green tea, kava, saw palmetto and some important Chinese medicines are also presented. Even though there have been many studies to determine the effects of herbs and herbal medicines on the activity of CYP, most of them were in vitro and in animal studies. Therefore, the studies are limited in predicting the clinical relevance of herbal drug interactions. It appeared that the majority of the herbal medicines have no clear effects on most of the CYPs examined. For example, the existing clinical trial data imply that black cohosh, ginseng and saw palmetto are unlikely to affect the pharmacokinetics of conventional drugs metabolized by human CYPs. For grape seed extract and green tea, adverse herbal drug interactions are unlikely when they are concomitantly taken with prescription drugs that are CYP substrates. Although there were few clinical studies on potential CYP-mediated interactions produced by kava, present data suggest that kava supplements have the ability to inhibit CYP1A2 and CYP2E1 significantly. Therefore, caution should be taken when patients take kava with CYP1A2 or CYP2E1 substrate drugs as it may enhance their therapeutic and adverse effects. Despite the long use of traditional Chinese herbal medicines, little is known about the potential drug interactions with these herbs. Many popularly used Chinese medicines have been shown in vitro to significantly change the

  9. Thermodynamic study of three pharmacologically significant drugs: Density, viscosity, and refractive index measurements at different temperatures

    International Nuclear Information System (INIS)

    Iqbal, Muhammad Javed; Chaudhry, Mansoora Ahmed

    2009-01-01

    Measurements of density, viscosity, and refractive index of three pharmacologically significant drugs, i.e. diclofenac sodium, cetrizine, and doxycycline have been carried in aqueous medium at T = (293.15 to 313.15) K. An automated vibrating-tube densimeter, viscometer, and refractometer are used in a concentration range from (7.5) . 10 -3 to 25 . 10 -3 ) mol . kg -1 . The precise density results are used to evaluate the apparent molar volume, partial molar volume, thermal expansion coefficient, partial molar expansivity, and the Hepler's constant. Viscosity results are used to calculate the Jones-Dole viscosity B-coefficient, free energy of activation of the solute and solvent, activation enthalpy, and activation entropy. The molar refractive indices of the drug solutions can be employed to calculate molar refraction. It is inferred from these results that the above mentioned drugs act as structure-making compounds due to hydrophobic hydration of the molecules in the drugs

  10. Adverse drug reactions induced by cardiovascular drugs in outpatients.

    Science.gov (United States)

    Gholami, Kheirollah; Ziaie, Shadi; Shalviri, Gloria

    2008-01-01

    Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions (ADRs) induced by this class of medicinal products seems necessary. To determine the rate and seriousness of adverse reactions induced by cardiovascular drugs in outpatients. To compare sex and different age groups in developing ADRs with cardiovascular agents. To assess the relationship between frequencies of ADRs and the number of drugs used. This cross-sectional study was done in cardiovascular clinic at a teaching hospital. All patients during an eight months period were evaluated for cardiovascular drugs induced ADRs. Patient and reaction factors were analyzed in detected ADRs. Patients with or without ADRs were compared in sex and age by using chi-square test. Assessing the relationship between frequencies of ADRs and the number of drugs used was done by using Pearson analysis. The total number of 518 patients was visited at the clinic. ADRs were detected in 105 (20.3%) patients. The most frequent ADRs were occurred in the age group of 51-60. The highest rate of ADRs was recorded to be induced by Diltiazem (23.5%) and the lowest rate with Atenolol (3%). Headache was the most frequent detected ADR (23%). Assessing the severity and preventability of ADRs revealed that 1.1% of ADRs were detected as severe and 1.9% as preventable reactions. Women significantly developed more ADRs in this study (chi square = 3.978, PPearson=0.259, P<0.05). Monitoring ADRs in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and underlying diseases.

  11. Transdermal drug delivery

    Science.gov (United States)

    Prausnitz, Mark R.; Langer, Robert

    2009-01-01

    Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine. PMID:18997767

  12. Prevalence and clinical significance of extravascular incidental findings in patients undergoing CT cervico-cerebral angiography

    International Nuclear Information System (INIS)

    Crockett, Matthew Thomas; Murphy, Blathnaid; Smith, Jennifer; Kavanagh, Eoin Carl

    2015-01-01

    Highlights: • CT cervico-cerebral angiography (CTCCA) is a commonly performed study for assessment of vascular pathologies of head and neck. • This study assessed the prevalence, clinical significance and management of extravascular incidental findings detected on CTCCA. • This study demonstrated the presence of clinically significant incidental findings in 14% of patients undergoing CTCCA with 8% of these findings deemed to be highly significant. 19% of patients with highly clinically significant findings did not receive appropriate follow up. • A standardised method of reporting incidental findings, such as that used in this paper is suggested to aid radiologists and referring physicians in recording and communicating these findings. - Abstract: Introduction: CT cervico-cerebral angiography (CTCCA) is now the first line diagnostic imaging modality for the majority of vascular pathologies of the head and neck with diagnostic value comparable to or better than traditional angiographic techniques. The aim of this study was to assess the prevalence, clinical significance and management of extravascular incidental findings detected on CTCCA. Materials and methods: A retrospective review of the CTCCA reports of 302 consecutive patients from 2009 to 2013 was undertaken. Extravascular incidental findings were classified, according to an adaptation of the CT colonography data and reporting system (CRADS), as EV1–EV4. EV1 = no incidental findings, EV2 = clinically insignificant incidental finding, EV3 = incidental finding of intermediate clinical significance, EV4 = highly clinically significant finding. Follow up of the electronic medical records of patients with EV3 or EV4 findings was undertaken to determine subsequent management. Results: Potentially clinically significant findings were demonstrated in 14.2% of patients with 8.6% of patients having a highly clinically significant finding. 4 incidental findings were confirmed to be malignant lesions and 5

  13. Clinical features and 123I-FP-CIT SPECT imaging in drug-induced parkinsonism and Parkinson's disease

    International Nuclear Information System (INIS)

    Diaz-Corrales, Francisco J.; Escobar-Delgado, Teresa; Sanz-Viedma, Salome; Garcia-Solis, David; Mir, Pablo

    2010-01-01

    To determine clinical predictors and accuracy of 123 I-FP-CIT SPECT imaging in the differentiation of drug-induced parkinsonism (DIP) and Parkinson's disease (PD). Several clinical features and 123 I-FP-CIT SPECT images in 32 patients with DIP, 25 patients with PD unmasked by antidopaminergic drugs (PDu) and 22 patients with PD without a previous history of antidopaminergic treatment (PDc) were retrospectively evaluated. DIP and PD shared all clinical features except symmetry of parkinsonian signs which was more frequently observed in patients with DIP (46.9%) than in patients with PDu (16.0%, p 123 I-FP-CIT SPECT images were normal in 29 patients with DIP (90.6%) and abnormal in all patients with PD, and this imaging technique showed high levels of accuracy. DIP and PD are difficult to differentiate based on clinical signs. The precision of clinical diagnosis could be reliably enhanced by 123 I-FP-CIT SPECT imaging. (orig.)

  14. Choosing the right laboratory: a review of clinical and forensic toxicology services for urine drug testing in pain management.

    Science.gov (United States)

    Reisfield, Gary M; Goldberger, Bruce A; Bertholf, Roger L

    2015-01-01

    Urine drug testing (UDT) services are provided by a variety of clinical, forensic, and reference/specialty laboratories. These UDT services differ based on the principal activity of the laboratory. Clinical laboratories provide testing primarily focused on medical care (eg, emergency care, inpatients, and outpatient clinics), whereas forensic laboratories perform toxicology tests related to postmortem and criminal investigations, and drug-free workplace programs. Some laboratories now provide UDT specifically designed for monitoring patients on chronic opioid therapy. Accreditation programs for clinical laboratories have existed for nearly half a century, and a federal certification program for drug-testing laboratories was established in the 1980s. Standards of practice for forensic toxicology services other than workplace drug testing have been established in recent years. However, no accreditation program currently exists for UDT in pain management, and this review considers several aspects of laboratory accreditation and certification relevant to toxicology services, with the intention to provide guidance to clinicians in their selection of the appropriate laboratory for UDT surveillance of their patients on opioid therapy.

  15. Confidence Intervals for Effect Sizes: Compliance and Clinical Significance in the "Journal of Consulting and Clinical Psychology"

    Science.gov (United States)

    Odgaard, Eric C.; Fowler, Robert L.

    2010-01-01

    Objective: In 2005, the "Journal of Consulting and Clinical Psychology" ("JCCP") became the first American Psychological Association (APA) journal to require statistical measures of clinical significance, plus effect sizes (ESs) and associated confidence intervals (CIs), for primary outcomes (La Greca, 2005). As this represents the single largest…

  16. Colchicine in Pericardial Disease: from the Underlying Biology and Clinical Benefits to the Drug-Drug Interactions in Cardiovascular Medicine.

    Science.gov (United States)

    Schenone, Aldo L; Menon, Venu

    2018-06-14

    This is an in-depth review on the mechanism of action, clinical utility, and drug-drug interactions of colchicine in the management of pericardial disease. Recent evidence about therapeutic targets on pericarditis has demonstrated that NALP3 inflammasome blockade is the cornerstone in the clinical benefits of colchicine. Such benefits extend from acute and recurrent pericarditis to transient constriction and post-pericardiotomy syndrome. Despite the increased utilization of colchicine in cardiovascular medicine, safety concerns remains unsolved regarding the long-term use of colchicine in the cardiac patient. Moreover, recent evidence has demonstrated that numerous cardiovascular medications, ranging from antihypertensive medication to antiarrhythmics, are known to interact with the CYP3A4 and/or P-gp system increasing the toxicity potential of colchicine. The use of adjunctive colchicine in the management of inflammatory pericardial diseases is standard of care in current practice. It is advised that a careful medication reconciliation with emphasis on pharmacokinetic is completed before prescribing colchicine in order to avoid harmful interaction by finding an alternative regimen or adjusting colchicine dosing.

  17. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.

    Science.gov (United States)

    Malykh, Andrei G; Sadaie, M Reza

    2010-02-12

    There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various

  18. Computational Approach to Annotating Variants of Unknown Significance in Clinical Next Generation Sequencing.

    Science.gov (United States)

    Schulz, Wade L; Tormey, Christopher A; Torres, Richard

    2015-01-01

    Next generation sequencing (NGS) has become a common technology in the clinical laboratory, particularly for the analysis of malignant neoplasms. However, most mutations identified by NGS are variants of unknown clinical significance (VOUS). Although the approach to define these variants differs by institution, software algorithms that predict variant effect on protein function may be used. However, these algorithms commonly generate conflicting results, potentially adding uncertainty to interpretation. In this review, we examine several computational tools used to predict whether a variant has clinical significance. In addition to describing the role of these tools in clinical diagnostics, we assess their efficacy in analyzing known pathogenic and benign variants in hematologic malignancies. Copyright© by the American Society for Clinical Pathology (ASCP).

  19. A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

    Science.gov (United States)

    Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, Mc.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

    2017-04-01

    There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

  20. Extensively and Pre-Extensively Drug Resistant Tuberculosis in Clinical Isolates of Multi-Drug Resistant Tuberculosis Using Classical Second Line Drugs (Levofloxacin and Amikacin)

    International Nuclear Information System (INIS)

    Mirza, I. A.; Khan, F. A.; Khan, K. A.; Satti, L.; Ghafoor, T.; Fayyaz, M.

    2015-01-01

    Objective:To find out the frequency of Extensively Drug Resistant (XDR) and pre-XDR tuberculosis in clinical isolates of Multi-Drug Resistant (MDR) Tuberculosis (TB) by determining the susceptibilities against Levofloxacin and Amikacin (classical second line antituberculosis drugs). Study Design: A descriptive cross-sectional study. Place and Duration of Study: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. Methodology: Amikacin (AK) and Levofloxacin (LEVO) were obtained in chemically pure form from Sigma (Taufkirchen, Germany). The breakpoint concentration used for AK was 1.0 micro g/ml and for LEVO 2.0 micro g/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. Results: A total of 3 MDR-TB isolates (3 percentage) turned out to be XDR-TB based upon simultaneous resistance to injectable second line antituberculosis drug AK and one of the fluoro-quinolones (LEVO). A total of 24 MDR-TB isolates (24 percentage) were found to be pre-XDR based upon resistance to LEVO alone. Treatment status record of patients with XDR and pre-XDRTB isolates revealed that majority of patients had received fluoroquinolones (FQs) during the course of treatment. Conclusion: XDR-TB has started to emerge in MDR-TB isolates in our set up. The worrying sign is the high frequency of pre-XDR tuberculosis. Urgent steps need to be taken to stem the tide of pre-XDR-TB in our population. It is thus recommended to develop facilities to carry out drug susceptibility testing to monitor the status of pre-XDR and XDR-TB in our population. (author)

  1. Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance.

    Directory of Open Access Journals (Sweden)

    Anirvan Chatterjee

    Full Text Available The identification of multidrug resistant (MDR, extensively and totally drug resistant Mycobacterium tuberculosis (Mtb, in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB, cell wall biosynthesis (emb genes, protein synthesis (rpl and additional central metabolic pathways (ppdK, pknH, pfkB were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with

  2. Anticholinergic drugs and negative outcomes in the older population: from biological plausibility to clinical evidence.

    Science.gov (United States)

    Collamati, Agnese; Martone, Anna Maria; Poscia, Andrea; Brandi, Vincenzo; Celi, Michela; Marzetti, Emanuele; Cherubini, Antonio; Landi, Francesco

    2016-02-01

    The use of medication with anticholinergic properties is widespread among older subjects. Many drugs of common use such as antispasmodics, bronchodilators, antiarrhythmics, antihistamines, anti-hypertensive drugs, antiparkinson agents, skeletal muscle relaxants, and psychotropic drugs have been demonstrated to have an anticholinergic activity. The most frequent adverse effects are dry mouth, nausea, vomiting, constipation, abdominal pain, urinary retention, blurred vision, tachycardia and neurologic impairment such as confusion, agitation and coma. A growing evidence from experimental studies and clinical observations suggests that drugs with anticholinergic properties can cause physical and mental impairment in the elderly population. However, the morbidity and management issues associated with unwanted anticholinergic activity are underestimated and frequently overlooked. Moreover, their possible relation with specific negative outcome in the elderly population is still not firmly established. The aim of the present review was to evaluate the relationship between the use of drugs with anticholinergic activity and negative outcomes in older persons. We searched PubMed and Cochrane combining the search terms "anticholinergic", "delirium", "cognitive impairment", "falls", "mortality" and "discontinuation". Medicines with anticholinergic properties may increase the risks of functional and cognitive decline, morbidity, institutionalization and mortality in older people. However, such evidences are still not conclusive probably due to possible confounding factors. In particular, more studies are needed to investigate the effects of discontinuation of drug with anticholinergic properties. Overall, minimizing anticholinergic burden should always be encouraged in clinical practice to improve short-term memory, confusion and delirium, quality of life and daily functioning.

  3. Development of novel drug delivery systems using phage display technology for clinical application of protein drugs.

    Science.gov (United States)

    Nagano, Kazuya; Tsutsumi, Yasuo

    2016-01-01

    Attempts are being made to develop therapeutic proteins for cancer, hepatitis, and autoimmune conditions, but their clinical applications are limited, except in the cases of drugs based on erythropoietin, granulocyte colony-stimulating factor, interferon-alpha, and antibodies, owing to problems with fundamental technologies for protein drug discovery. It is difficult to identify proteins useful as therapeutic seeds or targets. Another problem in using bioactive proteins is pleiotropic actions through receptors, making it hard to elicit desired effects without side effects. Additionally, bioactive proteins have poor therapeutic effects owing to degradation by proteases and rapid excretion from the circulatory system. Therefore, it is essential to establish a series of novel drug delivery systems (DDS) to overcome these problems. Here, we review original technologies in DDS. First, we introduce antibody proteomics technology for effective selection of proteins useful as therapeutic seeds or targets and identification of various kinds of proteins, such as cancer-specific proteins, cancer metastasis-related proteins, and a cisplatin resistance-related protein. Especially Ephrin receptor A10 is expressed in breast tumor tissues but not in normal tissues and is a promising drug target potentially useful for breast cancer treatment. Moreover, we have developed a system for rapidly creating functional mutant proteins to optimize the seeds for therapeutic applications and used this system to generate various kinds of functional cytokine muteins. Among them, R1antTNF is a TNFR1-selective antagonistic mutant of TNF and is the first mutein converted from agonist to antagonist. We also review a novel polymer-conjugation system to improve the in vivo stability of bioactive proteins. Site-specific PEGylated R1antTNF is uniform at the molecular level, and its bioactivity is similar to that of unmodified R1antTNF. In the future, we hope that many innovative protein drugs will be

  4. Effects of a clinical pharmacist service on health-related quality of life and prescribing of drugs: a randomised controlled trial.

    Science.gov (United States)

    Bladh, Lina; Ottosson, Ellinor; Karlsson, John; Klintberg, Lars; Wallerstedt, Susanna M

    2011-09-01

    OBJECTIVE To evaluate the effects of a clinical pharmacist service on health-related quality of life (HRQL) and prescribing of drugs. METHODS A randomised controlled study was performed in two internal medicine wards. The intervention consisted of medication reviews with feedback to the physicians, drug treatment discussion with patients at discharge and medication reports. HRQL was evaluated at inclusion and after six months by self-rated global health (1: very poor; 5: very good) and by the EuroQol 5-dimension questionnaire (EQ-5D). Prescribing of drugs was analysed regarding three established drug-specific quality indicators (intervention and control patients) and potential drug-related problems (DRPs) during in-hospital care (intervention patients). RESULTS 345 patients (61% female; median age: 82) were analysed, 204 of whom (59%) completed the six-month HRQL follow-up. A total of 87 patients (53% of the intervention patients) received all parts of the intervention. Intention-to-treat analysis revealed no significant findings for any of the HRQL measures. Per-protocol analysis revealed significantly better HRQL in the intervention group at six-month follow-up as measured by global health (mean: 3.14 (SD: 0.87) vs 2.77 (0.94), p=0.020), but not as measured by summarised EQ-5D index (0.48 (0.36) vs 0.43 (0.37), p=0.57). The number of potentially inappropriate prescribings per patient according to the quality indicators (admission vs discharge) was 0.35 (0.73) versus 0.38 (0.72), p=0.47 (control patients), and 0.39 (0.83) versus 0.26 (0.56), p=0.039 (intervention patients who received the intervention). In the intervention group, 133 relevant potential DRPs were identified in 81 patients, 55 of which (41%) were acted upon by the attending physician. CONCLUSION A clinical pharmacist service during inpatient care may improve quality of prescribing and patients' HRQL. Trial registration clinicaltrials.gov Identifier: NCT01016301.

  5. The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14.

    Science.gov (United States)

    Levit, Anat; Nowak, Stefanie; Peters, Maximilian; Wiener, Ayana; Meyerhof, Wolfgang; Behrens, Maik; Niv, Masha Y

    2014-03-01

    Bitter taste receptors (TAS2Rs) mediate aversive response to toxic food, which is often bitter. These G-protein-coupled receptors are also expressed in extraoral tissues, and emerge as novel targets for therapeutic indications such as asthma and infection. Our goal was to identify ligands of the broadly tuned TAS2R14 among clinical drugs. Molecular properties of known human bitter taste receptor TAS2R14 agonists were incorporated into pharmacophore- and shape-based models and used to computationally predict additional ligands. Predictions were tested by calcium imaging of TAS2R14-transfected HEK293 cells. In vitro testing of the virtual screening predictions resulted in 30-80% success rates, and 15 clinical drugs were found to activate the TAS2R14. hERG potassium channel, which is predominantly expressed in the heart, emerged as a common off-target of bitter drugs. Despite immense chemical diversity of known TAS2R14 ligands, novel ligands and previously unknown polypharmacology of drugs were unraveled by in vitro screening of computational predictions. This enables rational repurposing of traditional and standard drugs for bitter taste signaling modulation for therapeutic indications.

  6. Intravenous Antiepileptic Drugs in Russia

    Directory of Open Access Journals (Sweden)

    P. N. Vlasov

    2014-01-01

    Full Text Available Launching four intravenous antiepileptic drugs: valproate (Depakene and Convulex, lacosamide (Vimpat, and levetiracetam (Keppra – into the Russian market has significantly broadened the possibilities of rendering care to patients in seizure emergency situations. The chemi- cal structure, mechanisms of action, indications/contraindications, clinical effectiveness and tolerability, advantages/disadvantages, and adverse events of using these drugs in urgent and elective neurology are discussed. 

  7. Thermodynamic study of three pharmacologically significant drugs: Density, viscosity, and refractive index measurements at different temperatures

    Energy Technology Data Exchange (ETDEWEB)

    Iqbal, Muhammad Javed [Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan)], E-mail: mjiqauchem@yahoo.com; Chaudhry, Mansoora Ahmed [Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan)

    2009-02-15

    Measurements of density, viscosity, and refractive index of three pharmacologically significant drugs, i.e. diclofenac sodium, cetrizine, and doxycycline have been carried in aqueous medium at T = (293.15 to 313.15) K. An automated vibrating-tube densimeter, viscometer, and refractometer are used in a concentration range from (7.5) . 10{sup -3} to 25 . 10{sup -3}) mol . kg{sup -1}. The precise density results are used to evaluate the apparent molar volume, partial molar volume, thermal expansion coefficient, partial molar expansivity, and the Hepler's constant. Viscosity results are used to calculate the Jones-Dole viscosity B-coefficient, free energy of activation of the solute and solvent, activation enthalpy, and activation entropy. The molar refractive indices of the drug solutions can be employed to calculate molar refraction. It is inferred from these results that the above mentioned drugs act as structure-making compounds due to hydrophobic hydration of the molecules in the drugs.

  8. Drug addicts seeking treatment after the Iranian Revolution: a clinic-based study.

    Science.gov (United States)

    Dalvand, S; Agahi, C; Spencer, C

    1984-09-01

    A sample survey of 200 addicts attending the Rehabilitation Centre at Shiraz was conducted after the 1979 Iranian Revolution had disrupted both drug supply and addict treatment programmes. The study showed that clinics were, after the revolution, seeing a broader social range of addicts than before; and that action by the authorities was bringing many recently-addicted individuals to clinics. Heroin use predominated among those who were urban residents, whilst villagers were more likely to be opium users. The survey also sought the addicts' perceptions of the reasons for their initiation and addiction.

  9. Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012

    Science.gov (United States)

    Miller, Jennifer E; Korn, David; Ross, Joseph S

    2015-01-01

    Objective To evaluate clinical trial registration, reporting and publication rates for new drugs by: (1) legal requirements and (2) the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge. Design Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies. Data sources Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications. Main outcome measures Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts (FDAAA), analysed on the drug level. Results The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99 599 research participants. Per drug, a median of 57% (IQR 32–83%) of trials were registered, 20% (IQR 12–28%) reported results in ClinicalTrials.gov, 56% (IQR 41–83%) were published, and 65% (IQR 41–83%) were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% (IQR 8–20%) of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% (IQR 0–100%) were FDAAA-compliant. 68% of research participants (67 629 of 99 599) participated in FDAAA-subject trials, with 51% (33 405 of 67 629) enrolled in non-compliant trials. Transparency varied widely among companies. Conclusions Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve

  10. Feature Issue Introduction: Bio-Optics in Clinical Applications, Nanotechnology, and Drug Discovery

    OpenAIRE

    Nordstrom, Robert J.; Almutairi, Adah; Hillman, Elizabeth M.C.

    2010-01-01

    The editors introduce the Biomedical Optics Express feature issue, “Bio-Optics in Clinical Applications, Nanotechnology, and Drug Discovery,” which combines three technical areas from the 2010 Optical Society of America (OSA), Biomedical Optics (BIOMED) Topical Meeting held on 11–14 April in Miami, FL and includes contributions from conference attendees.

  11. Significance of mammographic signs in clinically occult disease

    Energy Technology Data Exchange (ETDEWEB)

    Waal, J.C. de; Steil, B.; Baltzer, J.; Vaillant, W.; Zander, J.

    1987-10-01

    The significance of various radiographic signs in 183 patients with clinically occult breast disease is described. 30.6% hat a carcinoma of the breast or a carcinoma in situ. The radiological features have varying predictive values and there is variation in the incidence of lymph node metastases. It is considered useful to classify the radiological appearances under the headings of round foci, star-shaped opacities, diffuse opacities, opacities with calcification and groups of micro-calcification. Despite the early diagnosis, 24% of patients already had lymph node metastases.

  12. Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries

    Directory of Open Access Journals (Sweden)

    Hartmann Markus

    2012-04-01

    Full Text Available Abstract Background Shifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials. Methods Rates of Clinical Trial Applications (CTA for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies. Results Since 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth. For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (P Conclusions The EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to

  13. Integrative approach to pre-operative determination of clinically significant prostate cancer

    Directory of Open Access Journals (Sweden)

    Shatylko T.V.

    2015-09-01

    Full Text Available Aim: improvement of early diagnostics of prostate cancer by developing a technique, which makes possible to predict its clinical significance in outpatient setting before initiation of invasive procedures. Material and Methods. Clinical data of 398 patients who underwent transrectal prostate biopsy in 2012-2014 in SSMU S. R. Mirotvortsev Clinical Hospital, was used to build an artificial neural network, while its output allowed to determine whether the tumour corresponds to Epstein criteria and which D'Amico risk group it belongs to. Internal validation was performed on 80 patients, who underwent prostate biopsy in September 2014 — December 2014. Sensitivity, specificity, positive and negative predictive value of artificial neural network were calculated. Results. Accuracy of predicting adenocarcinoma presence in biopsy specimen was 93,75%; accuracy of predicting whether the cancer meets active surveillance criteria was 90%. Accuracy of predicting T stage (T1c, T2a, T2b, T2cwas 57,1%. Prediction of D'Amico risk group was accurate in 70% of cases; for low-risk cancer accuracy was 81,2%. Conclusion. Artificial neural networks may be responsible for prostate cancer risk stratification and determination of its clinical significance prior to biopsy.

  14. Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

    International Nuclear Information System (INIS)

    Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

    2008-01-01

    Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

  15. Expression and clinical significance of Pax6 gene in retinoblastoma

    Directory of Open Access Journals (Sweden)

    Hai-Dong Huang

    2013-07-01

    Full Text Available AIM: To discuss the expression and clinical significance of Pax6 gene in retinoblastoma(Rb. METHODS: Totally 15 cases of fresh Rb organizations were selected as observation group and 15 normal retinal organizations as control group. Western-Blot and reverse transcriptase polymerase chain reaction(RT-PCRmethods were used to detect Pax6 protein and Pax6 mRNA expressions of the normal retina organizations and Rb organizations. At the same time, Western Blot method was used to detect the Pax6 gene downstream MATH5 and BRN3b differentiation gene protein level expression. After the comparison between two groups, the expression and clinical significance of Pax6 gene in Rb were discussed. RESULTS: In the observation group, average value of mRNA expression of Pax6 gene was 0.99±0.03; average value of Pax6 gene protein expression was 2.07±0.15; average value of BRN3b protein expression was 0.195±0.016; average value of MATH5 protein expression was 0.190±0.031. They were significantly higher than the control group, and the differences were statistically significant(PCONCLUSION: Abnormal expression of Pax6 gene is likely to accelerate the occurrence of Rb.

  16. Prognostic significance of clinical seizures after cardiac arrest and target temperature management

    DEFF Research Database (Denmark)

    Lybeck, Anna; Friberg, Hans; Aneman, Anders

    2017-01-01

    AIM: Clinical seizures are common after cardiac arrest and predictive of a poor neurological outcome. Seizures may be myoclonic, tonic-clonic or a combination of seizure types. This study reports the incidence and prognostic significance of clinical seizures in the target temperature management (...

  17. Drug development in neuropsychopharmacology.

    Science.gov (United States)

    Fritze, Jürgen

    2008-03-01

    Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

  18. Microdose clinical trial by use of radioisotope and perspective of its possible utilization in drug development

    International Nuclear Information System (INIS)

    Yano, Tsuneo; Watanabe, Yasuyoshi

    2009-01-01

    Many promising PET tracers have been developed by the progress of molecular imaging research, and new era could be opened by clinical trials using investigational products labeled by RI. Guidance for microdose clinical trial issued by MHLW in June, 2008, is the regulatory basis to develop PET tracer under clinical trial by the pharmaceutical affairs law. In this review, the discussion from the aspect of regulatory science is highlighted, particularly, on the topics of guidance for microdose and exploratory IND study including sub-therapeutic dose (type II) and therapeutic dose (type III), the revised GMP for investigational product including RI-labeled product, and to ward guidance for microdose clinical trial for biological product. Finally, the US FDA guidance developing medical imaging drug including biological product is introduced, and then perspective of possible utilization of in vivo radiopharmaceutical agents in drug development is discussed. (author)

  19. Clinical outcomes of the inclusion of the therapeutic drug monitoring report in the electronic clinical record

    Directory of Open Access Journals (Sweden)

    Marina Sáez Belló

    2016-12-01

    Full Text Available Objectives: To assess the inclusion of the Therapeutic Drug Monitoring Report (TDMR in the Electronic Clinical Record (ECR. Method: An observational ambispective cohort study with a duration of 149 days: PRE (retrospective, 49 days with the TDMR printed in paper, and POST (prospective, 100 days with the TDMR included in the ECR. Exclusion criteria: Patients not hospitalized, applications for Therapeutic Drug Monitoring by Critical Care and Neonatal Units, as well as monitoring with an objective other than dose adjustment. Variables: Number of TDMRs prepared, number of patients admitted with TDMR, time of delay for treatment adjustment, defined as the number of adjustments made to the treatment within over or under 24 hours from the time of TDMR preparation, and medication errors (MEs associated with said delay, as well as the degree of acceptance of the TDMR. Results: 690 TDMRs were conducted in 391 patients, 339 in PRE (n = 206 and 351 in POST (n = 185. The number of treatment modifications made in under 24 hours increased from 73.9% in PRE to 87.3% in POST [RR = 1.2 (CI95% = 0.97-1.43. We identified 35 patients with ME, 9.7% of them in PRE and 8.1% in POST (RR = 0.84 (CI95% = 0.44-1.58]. The degree of acceptance of the pharmacist recommendation increased from 53.3% in PRE to 68.3% in POST [RR = 1.3 (CI95% = 1.02- 1.62]. Conclusions: The inclusion of the Therapeutic Drug Monitoring Report (TDMR in the Electronic Clinical Record increases the degree of acceptance of recommendations, and may reduce the delay in treatment modifications, reducing MEs and improving the process quality in terms of efficacy and safety

  20. Clinically significant change in stroke volume in pulmonary hypertension.

    Science.gov (United States)

    van Wolferen, Serge A; van de Veerdonk, Marielle C; Mauritz, Gert-Jan; Jacobs, Wouter; Marcus, J Tim; Marques, Koen M J; Bronzwaer, Jean G F; Heymans, Martijn W; Boonstra, Anco; Postmus, Pieter E; Westerhof, Nico; Vonk Noordegraaf, Anton

    2011-05-01

    Stroke volume is probably the best hemodynamic parameter because it reflects therapeutic changes and contains prognostic information in pulmonary hypertension (PH). Stroke volume directly reflects right ventricular function in response to its load, without the correction of compensatory increased heart rate as is the case for cardiac output. For this reason, stroke volume, which can be measured noninvasively, is an important hemodynamic parameter to monitor during treatment. However, the extent of change in stroke volume that constitutes a clinically significant change is unknown. The aim of this study was to determine the minimal important difference (MID) in stroke volume in PH. One hundred eleven patients were evaluated at baseline and after 1 year of follow-up with a 6-min walk test (6MWT) and cardiac MRI. Using the anchor-based method with 6MWT as the anchor, and the distribution-based method, the MID of stroke volume change could be determined. After 1 year of treatment, there was, on average, a significant increase in stroke volume and 6MWT. The change in stroke volume was related to the change in 6MWT. Using the anchor-based method, an MID of 10 mL in stroke volume was calculated. The distribution-based method resulted in an MID of 8 to 12 mL. Both methods showed that a 10-mL change in stroke volume during follow-up should be considered as clinically relevant. This value can be used to interpret changes in stroke volume during clinical follow-up in PH.

  1. Methodological characteristics of academic clinical drug trials--a retrospective cohort study of applications to the Danish Medicines Agency 1993-2005

    DEFF Research Database (Denmark)

    Berendt, Louise; Håkansson, Cecilia; Bach, Karin F

    2010-01-01

    The aim of this study was to investigate the temporal trends in characteristics of academic clinical drug trials. We here report characteristics on trial methodology.......The aim of this study was to investigate the temporal trends in characteristics of academic clinical drug trials. We here report characteristics on trial methodology....

  2. Will clinical trial data disclosure reduce incentives to develop new uses of drugs?

    DEFF Research Database (Denmark)

    Price II, William Nicholson; Minssen, Timo

    2015-01-01

    public trust in drugs and industry and the possibility of facilitating large cross-border clinical trials for, inter alia, rare diseases5. Despite these benefits, the costs and concerns associated with opening up trial data are also substantial—for patients (patient privacy), for research (related...

  3. 75 FR 8968 - Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability

    Science.gov (United States)

    2010-02-26

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0090] Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability... familiar and less familiar approaches. As more experience is obtained with the less familiar designs...

  4. Inhaled antibiotics in the treatment of non-cystic fibrosis bronchiectasis: clinical and drug delivery perspectives.

    Science.gov (United States)

    Sugianto, Tiffanie Daisy; Chan, Hak-Kim

    2016-01-01

    Non-cystic fibrosis bronchiectasis (NCFB) is a chronic, progressive, suppurative lung disease characterized by permanent dilatation of bronchial subdivisions, which further causes accumulation of sputum and bacterial infections. The advent of inhaled antibiotics over the past two decades has been expected to effectively attenuate the problem of chronic bacterial infections in CF and NCFB subjects with higher, local drug concentrations and minimal systemic side effects. This review summarizes and evaluates current clinical evidence of efficacy and adverse effects of inhaled antibiotics in NCFB, as well as ongoing preclinical and clinical studies, followed by a discussion of issues and challenges in clinical practice and drug delivery strategies, together with future research directions. The evidence base of the clinical efficacy of inhaled antibiotics in NCFB is limited and the degrees of reported clinical benefits have been modest and conflicting. Challenges surrounding inhaled antibiotics application and development include the lack of knowledge of disease factors and optimum management strategies, unreceptive lung pathophysiology and the lack of factors that support compliance and tolerability. Nonetheless, research continues to give birth to new clinical findings and novel formulations such as combination antibiotics and sustained-release formulations, which add great value to the development of efficacious, safe and convenient inhalable antibiotics of the future.

  5. Inpatient Treatment for Adolescents with Anorexia Nervosa: Clinical Significance and Predictors of Treatment Outcome.

    Science.gov (United States)

    Schlegl, Sandra; Diedrich, Alice; Neumayr, Christina; Fumi, Markus; Naab, Silke; Voderholzer, Ulrich

    2016-05-01

    This study evaluated the clinical significance as well as predictors of outcome for adolescents with severe anorexia nervosa (AN) treated in an inpatient setting. Body mass index (BMI), eating disorder (ED) symptoms [Eating Disorder Inventory-2 (EDI-2)], general psychopathology and depression were assessed in 238 patients at admission and discharge. BMI increased from 14.8 + 1.2 to 17.3 + 1.4 kg/m(2). Almost a fourth (23.6%) of the patients showed reliable changes, and 44.7% showed clinically significant changes (EDI-2). BMI change did not significantly differ between those with reliable or clinically significant change or no reliable change in EDI-2. Length of stay, depression and body dissatisfaction were negative predictors of a clinically significant change. Inpatient treatment is effective in about two thirds of adolescents with AN and should be considered when outpatient treatment fails. About one third of patients showed significant weight gain, but did not improve regarding overall ED symptomatology. Future studies should focus on treatment strategies for non-responders. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

  6. Trends in oral drug bioavailability following bariatric surgery: examining the variable extent of impact on exposure of different drug classes.

    Science.gov (United States)

    Darwich, Adam S; Henderson, Kathryn; Burgin, Angela; Ward, Nicola; Whittam, Janet; Ammori, Basil J; Ashcroft, Darren M; Rostami-Hodjegan, Amin

    2012-11-01

    Changes to oral drug bioavailability have been observed post bariatric surgery. However, the magnitude and the direction of changes have not been assessed systematically to provide insights into the parameters governing the observed trends. Understanding these can help with dose adjustments. Analysis of drug characteristics based on a biopharmaceutical classification system is not adequate to explain observed trends in altered oral drug bioavailability following bariatric surgery, although the findings suggest solubility to play an important role. To identify the most commonly prescribed drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral drug bioavailability post bariatric surgery. A retrospective audit was undertaken to document commonly prescribed drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for drug administration following bariatric surgery. The available literature was examined for trends relating to drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination. No significant difference in the 'post/pre surgery oral drug exposure ratio' (ppR) was apparent between BCS class I to IV drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as 'solubility limited' displayed an overall reduction as compared with 'freely soluble' compounds, as well as an unaltered and increased ppR. Clinical studies establishing guidelines for commonly prescribed drugs, and the monitoring of drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral drug exposure and in developing practical clinical guidance. © 2012 The Authors

  7. [Clinical Significance of HBV Detection in NHL Patients].

    Science.gov (United States)

    Zhang, Tian-Ling; Zhang, Juan; Lv, Cheng-Xiu; Hu, Tian-Yu; Li, Qing

    2018-04-01

    To analyze the relation of HBV infection with clinical characteristics and prognosis in NHL patients, so as to explore the significance of HBV detection. Sixty-eight NHL patients from December 2013 to December 2016 were enrolled in NHL group and 136 patients with other malignancies were chosen in control group, the detectable rate of HBV was compared between 2 groups. The correlation of HBV infection with sex, age, stage, cell origin, expression of P53 and BCL-2 in NHL patients was analyzed. The prognosis-related factors in NHL patients were also analyzed. The infection rate of HBV in NHL group was 51.47%(35/68), that in control group was 15.44% (21/136), and the difference was statistically significant(χ 2 =27.768,PHBV infection correlated with cell origins and expression of BCL-2 in NHL patients(PHBV infection (P>0.05), while the prognosis was significantly related with stage, expression of P53 and BCL-2(PHBV infection correlates with BCL-2 expression level of NHL patients, and shows influence on the prognosis of patients.

  8. Antifungal therapy: drug-drug interactions at your fingertips

    NARCIS (Netherlands)

    Lempers, V.J.; Bruggemann, R.J.

    2016-01-01

    The Information Age has revolutionized the ability of healthcare professionals (HCPs) to oversee a substantial body of clinically relevant information literally at one's fingertips. In the field of clinical pharmacology, this may be particularly useful for managing drug-drug interactions (DDIs). A

  9. Clinical significance of circumportal pancreas, a rare congenital anomaly, in pancreatectomy.

    Science.gov (United States)

    Ohtsuka, Takao; Mori, Yasuhisa; Ishigami, Kousei; Fujimoto, Takaaki; Miyasaka, Yoshihiro; Nakata, Kohei; Ohuchida, Kenoki; Nagai, Eishi; Oda, Yoshinao; Shimizu, Shuji; Nakamura, Masafumi

    2017-08-01

    Circumportal pancreas is a rare congenital pancreatic anomaly. The aim of this study was to clarify the clinical characteristics of patients with circumportal pancreases undergoing pancreatectomy. The medical records of 508 patients who underwent pancreatectomy were retrospectively reviewed. The prevalence of circumportal pancreas and related anatomical variations were assessed. Surgical procedures and postoperative outcomes were compared in patients with and without circumportal pancreas. Circumportal pancreas was observed in 9 of the 508 patients (1.7%). In all nine patients, the portal vein was completely encircled by the pancreatic parenchyma above the level of the splenoportal junction, and the main pancreatic duct ran dorsal to the portal vein. The rate of variant hepatic artery did not differ significantly in patients with and without circumportal pancreas. Pancreatic fistula developed more frequently in patients with than without circumportal pancreas (44% vs. 14%, p = 0.03), but other clinical parameters did not differ significantly in these two groups. Despite being rare, circumportal pancreas may increase the risk of postoperative pancreatic fistula in patients undergoing pancreatectomy. However, a prospective, large-cohort study is necessary to determine the real incidence of relevant anatomical variations and the definitive clinical significance of this rare anomaly. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Clinical significance of Phosphatidyl Inositol Synthase overexpression in oral cancer

    International Nuclear Information System (INIS)

    Kaur, Jatinder; Sawhney, Meenakshi; DattaGupta, Siddartha; Shukla, Nootan K; Srivastava, Anurag; Ralhan, Ranju

    2010-01-01

    We reported increased levels of Phosphatidyl Inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display. This study determined the clinical significance of PI synthase overexpression in oral squamous cell carcinoma (OSCC) and premalignant lesions (leukoplakia), and identified the downstream signaling proteins in PI synthase pathway that are perturbed by smokeless tobacco (ST) exposure. Tissue microarray (TMA) Immunohistochemistry, Western blotting, Confocal laser scan microscopy, RT-PCR were performed to define the expression of PI synthase in clinical samples and in oral cell culture systems. Significant increase in PI synthase immunoreactivity was observed in premalignant lesions and OSCCs as compared to oral normal tissues (p = 0.000). Further, PI synthase expression was significantly associated with de-differentiation of OSCCs, (p = 0.005) and tobacco consumption (p = 0.03, OR = 9.0). Exposure of oral cell systems to smokeless tobacco (ST) in vitro confirmed increase in PI synthase, Phosphatidylinositol 3-kinase (PI3K) and cyclin D1 levels. Collectively, increased PI synthase expression was found to be an early event in oral cancer and a target for smokeless tobacco

  11. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  12. Prolongevity medicine: Antagonic-Stress drug in distress, geriatrics, and related diseases. II. Clinical review--2003.

    Science.gov (United States)

    Riga, S; Riga, D; Schneider, F

    2004-06-01

    Distress and senescence, their reciprocal aggravating-quickening connections, and their related pathologies have a large worldwide impact on healthcare systems in this new millennium. For this reason, Antagonic-Stress (AS)--an advanced integrative therapy, with specific synergistic composition, and patented internationally--represents a significant strategy in health, aging, and longevity. Clinical research with AS proves the drug's efficacy in the management of distress (neurotic, stress-related, and affective disorders; behavioral syndromes associated with physiological disturbances and physical factors; mental and behavioral disorders due to psychoactive substance uses) and psychogeriatrics [organic, including symptomatic, mental disorders (OMD)]. Specific multiaxial psychopathological instruments and psychometric tests in multiple assessments used for gerontopsychiatry demonstrated strong improvements after AS administration in early-moderate stages of Alzheimer or vascular dementia, as well as in other OMD. In addition, comparative clinical studies evinced the superiority of AS (synergistic multitherapy) versus monotherapy [meclofenoxate (MF), piracetam (PA), pyritinol (PT), and nicergoline (NE), respectively]. These comparative clinical trials agreed closely with comparative preclinical research and confirmed AS synergistic homeostatic, adaptogenic, antioxidative, cerebrovascular, neurometabolic, and nootropic actions. Also, the AS protective actions against oxidative stress recommend this orthomolecular therapy in stress, aging, and free radical pathology.

  13. 75 FR 37818 - Issues in the Design and Conduct of Clinical Trials for Antibacterial Drug Development; Public...

    Science.gov (United States)

    2010-06-30

    ... public workshop will help in developing topics for further discussion. Date and Time: The public workshop... Moser or Lori Benner, Center for Drug Evaluation and Research, Food and Drug Administration, Office of... of efficacy endpoints. Challenges in the conduct of clinical trials will be discussed, including good...

  14. Clinical significance of gamma camera renography in chronic renal insufficiency

    International Nuclear Information System (INIS)

    Dudczak, R.; Frischauf, H.; Kletter, K.

    1980-01-01

    Gamma camera renography allows, together with renal imaging, an evaluation of individual renal function. For these examinations, I 123 orthoiodohippurate is preferred and most widely used. The results on patients with chronic renal insufficiency, including urologic and posttransplantation patients, are reported. Whereas the method is of clinical significance in evaluating posttransplantation complications and in assessing individual kidney function preoperatively in urology, as well as in monitoring therapeutic effects in the early period of renal disease, it is of limited diagnostic value in chronic renal insufficiency. In this latter regard, clinical and laboratory examinations are of primary importance. (author)

  15. Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

    Science.gov (United States)

    2017-10-01

    US Food and Drug Administration Perspective.” Both manuscripts have been attached to annual report submitted to Department of Defenses in November...follow-up, conduct weekly telephone meetings with site data managers , and conduct monthly telephone meetings with site PIs (Months 23-75) Completed...Measurement in Cancer Clinical Trials: The US Food and Drug Administration Perspective. Cancer, 2014 Mar 1;120(5):761-7. doi: 10.1002/cncr.28470

  16. Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

    NARCIS (Netherlands)

    Kip, Anke E; Schellens, Jan H M; Beijnen, Jos H; Dorlo, Thomas P C

    This review describes the pharmacokinetic properties of the systemically administered antileishmanial drugs pentavalent antimony, paromomycin, pentamidine, miltefosine and amphotericin B (AMB), including their absorption, distribution, metabolism and excretion and potential drug-drug interactions.

  17. Is statistical significance clinically important?--A guide to judge the clinical relevance of study findings

    NARCIS (Netherlands)

    Sierevelt, Inger N.; van Oldenrijk, Jakob; Poolman, Rudolf W.

    2007-01-01

    In this paper we describe several issues that influence the reporting of statistical significance in relation to clinical importance, since misinterpretation of p values is a common issue in orthopaedic literature. Orthopaedic research is tormented by the risks of false-positive (type I error) and

  18. Analysis of Potential Drug-Drug Interactions and Its Clinical Manifestation of Pediatric Prescription on 2 Pharmacies in Bandung

    Directory of Open Access Journals (Sweden)

    Melisa I. Barliana

    2013-09-01

    Full Text Available The potential of Drug-Drug Interactions (DDI in prescription have high incidence around the world, including Indonesia. However, scientific evidence regarding DDI in Indonesia is not available. Therefore, in this study we have conducted survey in 2 pharmacies in Bandung against pediatric prescription given by pediatrician. These prescriptions then analyzed the potential for DDI contained in the prescription and clinical manifestation. The analysis showed that in pharmacy A, there are 33 prescriptions (from a total of 155 prescriptions that have potential DDI, or approximately 21.19% (2 prescriptions have the potential DDI major categories, 23 prescriptions categorized as moderate, and 8 prescriptions as minor. In Pharmacy B, there are 6 prescriptions (from a total of 40 prescriptions or 15% of potential DDI (4 prescriptions categorized as moderate and 2 prescriptions as minor. This result showed that potential DDI happened less than 50% in pediatric prescription from both pharmacies. However, this should get attention because DDI should not happen in a prescription considering its clinical manifestations caused by DDI. Moreover, current pharmaceutical care refers to patient oriented than product oriented. In addition, further study for the pediatric prescription on DDI incidence in large scale need to be investigated.

  19. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  20. Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

    Science.gov (United States)

    Braggio, Simone; Montanari, Dino; Rossi, Tino; Ratti, Emiliangelo

    2010-07-01

    As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

  1. Investigating drug repositioning opportunities in FDA drug labels through topic modeling.

    Science.gov (United States)

    Bisgin, Halil; Liu, Zhichao; Kelly, Reagan; Fang, Hong; Xu, Xiaowei; Tong, Weida

    2012-01-01

    Drug repositioning offers an opportunity to revitalize the slowing drug discovery pipeline by finding new uses for currently existing drugs. Our hypothesis is that drugs sharing similar side effect profiles are likely to be effective for the same disease, and thus repositioning opportunities can be identified by finding drug pairs with similar side effects documented in U.S. Food and Drug Administration (FDA) approved drug labels. The safety information in the drug labels is usually obtained in the clinical trial and augmented with the observations in the post-market use of the drug. Therefore, our drug repositioning approach can take the advantage of more comprehensive safety information comparing with conventional de novo approach. A probabilistic topic model was constructed based on the terms in the Medical Dictionary for Regulatory Activities (MedDRA) that appeared in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of the labels of 870 drugs. Fifty-two unique topics, each containing a set of terms, were identified by using topic modeling. The resulting probabilistic topic associations were used to measure the distance (similarity) between drugs. The success of the proposed model was evaluated by comparing a drug and its nearest neighbor (i.e., a drug pair) for common indications found in the Indications and Usage Section of the drug labels. Given a drug with more than three indications, the model yielded a 75% recall, meaning 75% of drug pairs shared one or more common indications. This is significantly higher than the 22% recall rate achieved by random selection. Additionally, the recall rate grows rapidly as the number of drug indications increases and reaches 84% for drugs with 11 indications. The analysis also demonstrated that 65 drugs with a Boxed Warning, which indicates significant risk of serious and possibly life-threatening adverse effects, might be replaced with safer alternatives that do not have a Boxed Warning. In

  2. Drugs and personality: comparison of drug users, nonusers, and other clinical groups on the 16PF.

    Science.gov (United States)

    Spotts, J V; Shontz, F C

    1991-10-01

    This article reviews published 16PF research on drug users. It also compares the 16PF scores of a new sample of nonusers with scores of matched groups of heavy, chronic users of cocaine, amphetamine, opiates, and barbiturates/sedative hypnotics, as well as combined groups of stimulant users, depressant users, and a combined group of users of all substances. No significant differences were found among drug user groups, but the profile of the nonuser group was distinctive. K-Means Cluster Analyses, as well as Cattell's Similarity and Pearson Product Moment Correlation Coefficients, were used to compare profiles of these new samples with the 19 groups described in an earlier meta-analysis of published 16PF studies. Data from the new samples did not cluster with data from other published research, although certain specific similarities appeared in more detailed correlational analyses. Methodological problems are discussed, and it is recommended that in future studies drug user groups be more carefully selected and defined, sample descriptions be more thorough and complete, complete profile information be routinely provided, and efforts be made to explore the utility of the Cattell CAQ in studies of drug users/misusers.

  3. Comparative studies on drug binding to the purified and pharmaceutical-grade human serum albumins: Bridging between basic research and clinical applications of albumin.

    Science.gov (United States)

    Ashrafi-Kooshk, Mohammad Reza; Ebrahimi, Farangis; Ranjbar, Samira; Ghobadi, Sirous; Moradi, Nastaran; Khodarahmi, Reza

    2015-09-01

    Human serum albumin (HSA), the most abundant protein in blood plasma, is a monomeric multidomain protein that possesses an extraordinary capacity for binding, so that serves as a circulating depot for endogenous and exogenous compounds. During the heat sterilization process, the structure of pharmaceutical-grade HSA may change and some of its activities may be lost. In this study, to provide deeper insight on this issue, we investigated drug-binding and some physicochemical properties of purified albumin (PA) and pharmaceutical-grade albumin (PGA) using two known drugs (indomethacin and ibuprofen). PGA displayed significantly lower drug binding capacity compared to PA. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between the drugs and the proteins are different from each other. Surface hydrophobicity as well as the stability of PGA decreased compared to PA, also surface hydrophobicity of PA and PGA increased upon drugs binding. Also, kinetic analysis of pseudo-esterase activities indicated that Km and Vmax parameters for PGA enzymatic activity are more and less than those of PA, respectively. This in vitro study demonstrates that the specific drug binding of PGA is significantly reduced. Such studies can act as connecting bridge between basic research discoveries and clinical applications. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  4. AIDSinfo Drug Database

    Science.gov (United States)

    ... AIDS Drugs Clinical Trials Apps skip to content Drugs Home Drugs Find information on FDA-approved HIV/ ... infection drugs and investigational HIV/AIDS drugs. Search Drugs Search drug Search Icon What's this? Close Popup ...

  5. The patient's safety and access to experimental drugs after the termination of clinical trials: regulations and trends.

    Science.gov (United States)

    da Silva, Ricardo Eccard; Amato, Angélica Amorim; Sousa, Thiago do Rego; de Carvalho, Marta Rodrigues; Novaes, Maria Rita Carvalho Garbi

    2018-05-12

    Participants' rights and safety must be guaranteed not only while a clinical trial is being conducted but also when a clinical trial finishes. The criteria for post-trial access to experimental drugs, however, are unclear in various countries. The objectives of this study were (i) to ascertain if there were regulations or guidelines related to patients' access to drugs after the end of clinical trials in the countries selected in the study and (ii) to analyze trends in post-trial access in countries classified by their level of economic development. This study is a retrospective review. The data are from the records of clinical trials from 2014 registered in the World Health Organization's International Clinical Trials Registry Platform (ICTRP) database. Among the countries selected, provision of drugs post-trial is mandatory only in Argentina, Brazil, Chile, Finland, and Peru. The plans for post-trial access tend to be more present in low- and middle-income and upper middle-income countries, in comparison with high-income countries. Studies involving vulnerable populations are 2.53 times more likely to have plans for post-trial access than studies which do not. The guaranteeing of post-trial access remains mandatory in few countries. Considering that individuals seen as vulnerable have been included in clinical trials without plans for post-trial access, stakeholders must discuss the need to develop regulations mandating the guaranteeing of post-trial access in specified situations.

  6. [Prescribed drug use for bipolar disorder type I and II in clinical practice].

    Science.gov (United States)

    Persson, Charlotte; Kardell, Mathias; Karanti, Alina; Isgren, Anniella; Annerbrink, Kristina; Landen, Mikael

    2017-01-10

    Prescribed drug use for bipolar disorder type I and II in clinical practice Practice guidelines based on available evidence and clinical consensus are available for the treatment of bipolar disorder. We surveyed to which extent those guidelines are implemented in clinical practice in Sweden. We analysed pharmacological treatment in patients with bipolar disorder in 2015 using the national quality register for bipolar disorder (BipoläR). We compared bipolar disorder type I (BDI) with type bipolar disorder type II (BDII). The vast majority of patients were prescribed a mood stabilizer either as monotherapy or as a part of combination therapy (BDI 87%, BDII 83%, pbipolar disorder.

  7. Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development.

    Science.gov (United States)

    Thelin, Eric Peter; Carpenter, Keri L H; Hutchinson, Peter J; Helmy, Adel

    2017-03-01

    Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

  8. Subclassification of autoimmune pancreatitis: a histologic classification with clinical significance.

    Science.gov (United States)

    Deshpande, Vikram; Gupta, Rajib; Sainani, Nisha; Sahani, Dushyant V; Virk, Renu; Ferrone, Cristina; Khosroshahi, Arezou; Stone, John H; Lauwers, Gregory Y

    2011-01-01

    Autoimmune pancreatitis (AIP) is a chronic inflammatory disease of the pancreas. Examination of pancreatic resection specimens from patients with AIP has shown that there are 2 subclasses of this disease. However, there is no widely accepted pathologic classification scheme and the clinical significance of such a classification remains to be established. In this study, we revisited the subclassification of AIP and examine whether this provides clinically and prognostically meaningful information. We evaluated 29 pancreatic resection specimens from patients with AIP. Demographic, clinical, and imaging data were recorded, as was evidence of extrapancreatic manifestations. In addition to a detailed and semiquantitative histologic evaluation, immunohistochemistry for IgG4 was performed on pancreatic and extrapancreatic tissues. We also evaluated 48 consecutive cases of chronic pancreatitis, not otherwise specified. The resected specimens could readily be subclassified into 2 subtypes: type 1 (n=11) and type 2 (n=18). In comparison with patients with type 2 disease, patients with type 1 disease were significantly more likely to be males (P=0.09), older (P=0.02), and present with jaundice (P=0.01), and less likely to be associated with abdominal pain (P=0.04). On imaging, the pancreatic tail cut-off sign was exclusively seen in patients with type 2 disease (4 of 10 cases). Hypercellular inflamed interlobular stroma was unique to type 1 pattern (91%), whereas significant ductal injury in the form of microabscesses and ductal ulceration was almost exclusively seen in type 2 pattern (78%). Eight of 10 patients with a type 1 pattern had evidence of a systemic disease. Three patients with type 2 disease had recurrent episodes of pancreatitis after their pancreatic resection. In comparison with the cohort of chronic pancreatitis, not otherwise specified, type 2 AIP cases were less likely to be associated with a history of alcohol abuse, and showed significantly more foci of

  9. Yoga & Cancer Interventions: A Review of the Clinical Significance of Patient Reported Outcomes for Cancer Survivors

    Directory of Open Access Journals (Sweden)

    S. Nicole Culos-Reed

    2012-01-01

    Full Text Available Limited research suggests yoga may be a viable gentle physical activity option with a variety of health-related quality of life, psychosocial and symptom management benefits. The purpose of this review was to determine the clinical significance of patient-reported outcomes from yoga interventions conducted with cancer survivors. A total of 25 published yoga intervention studies for cancer survivors from 2004–2011 had patient-reported outcomes, including quality of life, psychosocial or symptom measures. Thirteen of these studies met the necessary criteria to assess clinical significance. Clinical significance for each of the outcomes of interest was examined based on 1 standard error of the measurement, 0.5 standard deviation, and relative comparative effect sizes and their respective confidence intervals. This review describes in detail these patient-reported outcomes, how they were obtained, their relative clinical significance and implications for both clinical and research settings. Overall, clinically significant changes in patient-reported outcomes suggest that yoga interventions hold promise for improving cancer survivors' well-being. This research overview provides new directions for examining how clinical significance can provide a unique context for describing changes in patient-reported outcomes from yoga interventions. Researchers are encouraged to employ indices of clinical significance in the interpretation and discussion of results from yoga studies.

  10. Dual cusped protostylid: Case report and clinical significance

    Directory of Open Access Journals (Sweden)

    Preeti Bhattacharya

    2016-01-01

    Full Text Available Protostylids are superstructures on maxillary or mandibular molars, which have rarely been reported in literature, and the significance of their presence has also been underestimated. The dental practitioners may easily misdiagnose a tooth, with such conical tubercles as malformed tooth. Interestingly, this is neither a malformation nor an anomaly but rather an important morphological trait of an individual. Once in a while, one may come across such a distinct morphological trait without being able to diagnose. To the authors' best knowledge, only one similar case has been reported previously, and the second such case internationally. Bearing all such facts in mind, the authors attempt to educate the readers towards the existence of such a trait so that it can be identified and studied in larger numbers. Hence, it is the authors' endeavor to report an unusual case of dual cusped maxillary protostylid along with its clinical significance.

  11. Assessing Clinical Significance: Does it Matter which Method we Use?

    Science.gov (United States)

    Atkins, David C.; Bedics, Jamie D.; Mcglinchey, Joseph B.; Beauchaine, Theodore P.

    2005-01-01

    Measures of clinical significance are frequently used to evaluate client change during therapy. Several alternatives to the original method devised by N. S. Jacobson, W. C. Follette, & D. Revenstorf (1984) have been proposed, each purporting to increase accuracy. However, researchers have had little systematic guidance in choosing among…

  12. Evaluation of new drugs in daily clinical practice: anti-TNF alpha in rheumatoid arthritis patients.

    OpenAIRE

    Kievit, W.

    2008-01-01

    The objective of this thesis was to explore the value and the validity of data collected in daily clinical practice for drug evaluation and cost-effectiveness studies, using data collected on TNFa blocking agents in rheumatoid arthritis. First, the need for and value of information from daily clinical practice was researched. Together, the results of Chapters 3, 4 and 5 illustrated that treatment of RA patients with anti-TNFa blocking agents in daily clinical practice was different from what ...

  13. Intensive inpatient treatment for bulimia nervosa: Statistical and clinical significance of symptom changes.

    Science.gov (United States)

    Diedrich, Alice; Schlegl, Sandra; Greetfeld, Martin; Fumi, Markus; Voderholzer, Ulrich

    2018-03-01

    This study examines the statistical and clinical significance of symptom changes during an intensive inpatient treatment program with a strong psychotherapeutic focus for individuals with severe bulimia nervosa. 295 consecutively admitted bulimic patients were administered the Structured Interview for Anorexic and Bulimic Syndromes-Self-Rating (SIAB-S), the Eating Disorder Inventory-2 (EDI-2), the Brief Symptom Inventory (BSI), and the Beck Depression Inventory-II (BDI-II) at treatment intake and discharge. Results indicated statistically significant symptom reductions with large effect sizes regarding severity of binge eating and compensatory behavior (SIAB-S), overall eating disorder symptom severity (EDI-2), overall psychopathology (BSI), and depressive symptom severity (BDI-II) even when controlling for antidepressant medication. The majority of patients showed either reliable (EDI-2: 33.7%, BSI: 34.8%, BDI-II: 18.1%) or even clinically significant symptom changes (EDI-2: 43.2%, BSI: 33.9%, BDI-II: 56.9%). Patients with clinically significant improvement were less distressed at intake and less likely to suffer from a comorbid borderline personality disorder when compared with those who did not improve to a clinically significant extent. Findings indicate that intensive psychotherapeutic inpatient treatment may be effective in about 75% of severely affected bulimic patients. For the remaining non-responding patients, inpatient treatment might be improved through an even stronger focus on the reduction of comorbid borderline personality traits.

  14. Clinical observations on the use of new anti-VEGF drug, conbercept, in age-related macular degeneration therapy: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Cui C

    2017-12-01

    Full Text Available Chunmei Cui, Hong Lu Department of Ophthalmology, Beijing Chao-Yang Hospital, Beijing, China Purpose: Conbercept is a new anti-vascular endothelial growth factor (VEGF drug approved for the treatment of age-related macular degeneration (AMD. Although this novel drug has been widely used in clinic, unlike other anti-VEGF drugs, validation and consensus on its method of clinical application and clinical safety have not yet been achieved.Methods: Relevant literature was searched on PubMed, Web of Science, China National Knowledge Internet, and Wanfang Data. Stata 12.0 was used for data analysis. Random- and fixed-effect models were employed to evaluate heterogeneity. Best-corrected visual acuity (BCVA and central retinal thickness (CRT were utilized to measure the improvement of AMD patients.Results: In this study, we analyzed conbercept administration and compared its application with other control clinical methods for AMD treatment. Ranibizumab, triamcinolone, and traditional transpupillary thermotherapy (TTT were administered in the control group. No differences were found in the BCVA and CRT improvement between the groups treated with conbercept and ranibizumab. However, the conbercept group had a lower serum VEGF level. After 3 months of treatment, conbercept led to a more significant BCVA and CRT improvement than triamcinolone. A more considerable BCVA improvement was observed in the group treated with conbercept than in the group treated with TTT. Moreover, even 6 months after the treatment, the effect of conbercept on CRT improvement was still more pronounced than that of TTT.Conclusion: In AMD patients, conbercept exerts considerably more positive effects on the long-term BCVA and CRT improvement than triamcinolone and TTT. The serum VEGF level in the conbercept group was lower than that in the ranibizumab group. Keywords: AMD, VEGF, conbercept, BCVA, CRT

  15. Drug Repurposing from an Academic Perspective.

    Science.gov (United States)

    Oprea, Tudor I; Bauman, Julie E; Bologa, Cristian G; Buranda, Tione; Chigaev, Alexandre; Edwards, Bruce S; Jarvik, Jonathan W; Gresham, Hattie D; Haynes, Mark K; Hjelle, Brian; Hromas, Robert; Hudson, Laurie; Mackenzie, Debra A; Muller, Carolyn Y; Reed, John C; Simons, Peter C; Smagley, Yelena; Strouse, Juan; Surviladze, Zurab; Thompson, Todd; Ursu, Oleg; Waller, Anna; Wandinger-Ness, Angela; Winter, Stuart S; Wu, Yang; Young, Susan M; Larson, Richard S; Willman, Cheryl; Sklar, Larry A

    2011-01-01

    Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences.

  16. Body Dysmorphic Disorder and Other Clinically Significant Body Image Concerns in Adolescent Psychiatric Inpatients: Prevalence and Clinical Characteristics

    Science.gov (United States)

    Dyl, Jennifer; Kittler, Jennifer; Phillips, Katharine A.; Hunt, Jeffrey I.

    2006-01-01

    Background: This study assessed prevalence and clinical correlates of body dysmorphic disorder (BDD), eating disorders (ED), and other clinically significant body image concerns in 208 consecutively admitted adolescent inpatients. It was hypothesized that adolescents with BDD would have higher levels of depression, anxiety, and suicidality.…

  17. Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

    Science.gov (United States)

    Chan, Lingtak-Neander; Anderson, Gail D

    2014-12-01

    Ethanol (alcohol) is one of the most widely used legal drugs in the world. Ethanol is metabolized by alcohol dehydrogenase (ADH) and the cytochrome P450 (CYP) 2E1 drug-metabolizing enzyme that is also responsible for the biotransformation of xenobiotics and fatty acids. Drugs that inhibit ADH or CYP2E1 are the most likely theoretical compounds that would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs. Acute ethanol primarily alters the pharmacokinetics of other drugs by changing the rate and extent of absorption, with more limited effects on clearance. Both acute and chronic ethanol use can cause transient changes to many physiologic responses in different organ systems such as hypotension and impairment of motor and cognitive functions, resulting in both pharmacokinetic and pharmacodynamic interactions. Evaluating drug interactions with long-term use of ethanol is uniquely challenging. Specifically, it is difficult to distinguish between the effects of long-term ethanol use on liver pathology and chronic malnutrition. Ethanol-induced liver disease results in decreased activity of hepatic metabolic enzymes and changes in protein binding. Clinical studies that include patients with chronic alcohol use may be evaluating the effects of mild cirrhosis on liver metabolism, and not just ethanol itself. The definition of chronic alcohol use is very inconsistent, which greatly affects the quality of the data and clinical application of the results. Our study of the literature has shown that a significantly higher volume of clinical studies have focused on the pharmacokinetic interactions of ethanol and other drugs. The data on pharmacodynamic interactions are more limited and future research addressing pharmacodynamic interactions with ethanol, especially regarding the non-central nervous system effects, is much needed.

  18. Accelerant-related burns and drug abuse: Challenging combination.

    Science.gov (United States)

    Leung, Leslie T F; Papp, Anthony

    2018-05-01

    Accelerants are flammable substances that may cause explosion when added to existing fires. The relationships between drug abuse and accelerant-related burns are not well elucidated in the literature. Of these burns, a portion is related to drug manufacturing, which have been shown to be associated with increased burn complications. 1) To evaluate the demographics and clinical outcomes of accelerant-related burns in a Provincial Burn Centre. 2) To compare the clinical outcomes with a control group of non-accelerant related burns. 3) To analyze a subgroup of patients with history of drug abuse and drug manufacturing. Retrospective case control study. Patient data associated with accelerant-related burns from 2009 to 2014 were obtained from the British Columbia Burn Registry. These patients were compared with a control group of non-accelerant related burns. Clinical outcomes that were evaluated include inhalational injury, ICU length of stay, ventilator support, surgeries needed, and burn complications. Chi-square test was used to evaluate categorical data and Student's t-test was used to evaluate mean quantitative data with the p value set at 0.05. A logistic regression model was used to evaluate factors affecting burn complications. Accelerant-related burns represented 28.2% of all burn admissions (N=532) from 2009 to 2014. The accelerant group had higher percentage of patients with history of drug abuse and was associated with higher TBSA burns, ventilator support, ICU stay and pneumonia rates compared to the non-accelerant group. Within the accelerant group, there was no difference in clinical outcomes amongst people with or without history of drug abuse. Four cases were associated with methamphetamine manufacturing, all of which underwent ICU stay and ventilator support. Accelerant-related burns cause significant burden to the burn center. A significant proportion of these patients have history of drug abuse. Copyright © 2017 Elsevier Ltd and ISBI. All rights

  19. In Vitro Drug Transfer Due to Drug Retention in Human Epidermis Pretreated with Application of Marketed Estradiol Transdermal Systems.

    Science.gov (United States)

    Krishnaiah, Yellela S R; Pavurala, Naresh; Yang, Yang; Manda, Prashanth; Katragadda, Usha; Yang, Yongsheng; Shah, Rakhi; Fang, Guodong; Khan, Mansoor A

    2017-08-01

    Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P  0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug-retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined.

  20. Drugs indicated for use during pregnancy.

    Science.gov (United States)

    Lalonde, André B

    2011-01-01

    The Society of Obstetricians and Gynaecologists of Canada (SOGC) advocates that drugs used during pregnancy be tested exclusively in women. The SOGC holds the opinion that drugs to be used exclusively in men or in women should not be tested in a small number of men and women. The SOGC, always cautious with the choice of pharmacological treatments recommended for use during pregnancy, welcomes the increased options resulting from the introduction of generic formulations of drugs shown to be bioequivalent to currently available brand name products. These formulations provide less expensive options to Canadian women in need of drug therapy. However, the Society does not believe that drugs should be substituted without the patient and the physician both agreeing to such a change. Generic substitutions of some products may mean a potentially clinically significant difference in drug dose, possibly resulting in a changed patient effect. Furthermore, substituting a product on the basis of price alone is not acceptable.The SOGC, as an organization with the role of advising its members on clinical practice, calls on Health Canada to review its guideline on testing of drugs for vulnerable populations, especially pregnant women.

  1. Clinical practice - Drug desensitization in children

    NARCIS (Netherlands)

    de Groot, H.; Mulder, W.M.C.

    2010-01-01

    Immediate type allergic reactions to medication are potentially life threatening and can hamper drug therapy of several medical conditions. Exact incidence and prevalence data for these reactions in children are lacking. If no alternative drug treatment is available, a desensitization procedure may

  2. Current good manufacturing practice and investigational new drugs intended for use in clinical trials. Final rule.

    Science.gov (United States)

    2008-07-15

    The Food and Drug Administration (FDA) is amending the current good manufacturing practice (CGMP) regulations for human drugs, including biological products, to exempt most phase 1 investigational drugs from complying with the regulatory CGMP requirements. FDA will continue to exercise oversight of the manufacture of these drugs under FDA's general statutory CGMP authority and through review of the investigational new drug applications (IND). In addition, elsewhere in this issue of the Federal Register, FDA is announcing the availability of a guidance document entitled "Guidance for Industry: CGMP for Phase 1 Investigational Drugs" dated November 2007 (the companion guidance). This guidance document sets forth recommendations on approaches to compliance with statutory CGMP for the exempted phase 1 investigational drugs. FDA is taking this action to focus a manufacturer's effort on applying CGMP that is appropriate and meaningful for the manufacture of the earliest stage investigational drug products intended for use in phase 1 clinical trials while ensuring safety and quality. This action will also streamline and promote the drug development process.

  3. Accurate coding in sepsis: clinical significance and financial implications.

    Science.gov (United States)

    Chin, Y T; Scattergood, N; Thornber, M; Thomas, S

    2016-09-01

    Sepsis is a major healthcare problem and leading cause of death worldwide. UK hospital mortality statistics and payments for patient episodes of care are calculated on clinical coding data. The accuracy of these data depends on the quality of coding. This study aimed to investigate whether patients with significant bacteraemia are coded for sepsis and to estimate the financial costs of miscoding. Of 54 patients over a one-month period with a significant bacteraemia, only 19% had been coded for sepsis. This is likely to lead to falsely high calculated hospital mortality. Furthermore, this resulted in an underpayment of £21,000 for one month alone. Copyright © 2016 The Healthcare Infection Society. All rights reserved.

  4. Identification of multi-drug resistant Pseudomonas aeruginosa clinical isolates that are highly disruptive to the intestinal epithelial barrier

    Directory of Open Access Journals (Sweden)

    Shevchenko Olga

    2006-06-01

    Full Text Available Abstract Background Multi-drug resistant Pseudomonas aeruginosa nosocomial infections are increasingly recognized worldwide. In this study, we focused on the virulence of multi-drug resistant clinical strains P. aeruginosa against the intestinal epithelial barrier, since P. aeruginosa can cause lethal sepsis from within the intestinal tract of critically ill and immuno-compromised patients via mechanisms involving disruption of epithelial barrier function. Methods We screened consecutively isolated multi-drug resistant P. aeruginosa clinical strains for their ability to disrupt the integrity of human cultured intestinal epithelial cells (Caco-2 and correlated these finding to related virulence phenotypes such as adhesiveness, motility, biofilm formation, and cytotoxicity. Results Results demonstrated that the majority of the multi-drug resistant P. aeruginosa clinical strains were attenuated in their ability to disrupt the barrier function of cultured intestinal epithelial cells. Three distinct genotypes were found that displayed an extreme epithelial barrier-disrupting phenotype. These strains were characterized and found to harbor the exoU gene and to display high swimming motility and adhesiveness. Conclusion These data suggest that detailed phenotypic analysis of the behavior of multi-drug resistant P. aeruginosa against the intestinal epithelium has the potential to identify strains most likely to place patients at risk for lethal gut-derived sepsis. Surveillance of colonizing strains of P. aeruginosa in critically ill patients beyond antibiotic sensitivity is warranted.

  5. Using Clinical Data, Hypothesis Generation Tools and PubMed Trends to Discover the Association between Diabetic Retinopathy and Antihypertensive Drugs

    Energy Technology Data Exchange (ETDEWEB)

    Senter, Katherine G [ORNL; Sukumar, Sreenivas R [ORNL; Patton, Robert M [ORNL; Chaum, Ed [University of Tennessee, Knoxville (UTK)

    2015-01-01

    Diabetic retinopathy (DR) is a leading cause of blindness and common complication of diabetes. Many diabetic patients take antihypertensive drugs to prevent cardiovascular problems, but these drugs may have unintended consequences on eyesight. Six common classes of antihypertensive drug are angiotensin converting enzyme (ACE) inhibitors, alpha blockers, angiotensin receptor blockers (ARBs), -blockers, calcium channel blockers, and diuretics. Analysis of medical history data might indicate which of these drugs provide safe blood pressure control, and a literature review is often used to guide such analyses. Beyond manual reading of relevant publications, we sought to identify quantitative trends in literature from the biomedical database PubMed to compare with quantitative trends in the clinical data. By recording and analyzing PubMed search results, we found wide variation in the prevalence of each antihypertensive drug in DR literature. Drug classes developed more recently such as ACE inhibitors and ARBs were most prevalent. We also identified instances of change-over-time in publication patterns. We then compared these literature trends to a dataset of 500 diabetic patients from the UT Hamilton Eye Institute. Data for each patient included class of antihypertensive drug, presence and severity of DR. Graphical comparison revealed that older drug classes such as diuretics, calcium channel blockers, and -blockers were much more prevalent in the clinical data than in the DR and antihypertensive literature. Finally, quantitative analysis of the dataset revealed that patients taking -blockers were statistically more likely to have DR than patients taking other medications, controlling for presence of hypertension and year of diabetes onset. This finding was concerning given the prevalence of -blockers in the clinical data. We determined that clinical use of -blockers should be minimized in diabetic patients to prevent retinal damage.

  6. Use of analgesic and sedative drugs in the NICU: integrating clinical trials and laboratory data.

    Science.gov (United States)

    Durrmeyer, Xavier; Vutskits, Laszlo; Anand, Kanwaljeet J S; Rimensberger, Peter C

    2010-02-01

    Recent advances in neonatal intensive care include and are partly attributable to growing attention for comfort and pain control in the term and preterm infant requiring intensive care.Limitation of painful procedures is certainly possible, but most critically ill infants require unavoidable painful or stressful procedures such as intubation, mechanical ventilation, or catheterization.Many analgesics (opioids and nonsteroidal anti-inflammatory drugs)and sedatives (benzodiazepines and other anesthetic agents) are available but their use varies considerably among units. This review summarizes current experimental knowledge on the effects of sedative and analgesic drugs on brain development and reviews clinical evidence that speaks for or against the use of common analgesic and sedative drugs in the NICU but avoids any discussion of anesthesia during surgery. Risk/benefit ratios of intermittent boluses or continuous infusions for the commonly used sedative and analgesic agents are discussed in the light of clinical and experimental studies. The limitations of extrapolating experimental results from animals to humans must be considered while making practical recommendations based on the currently available evidence.

  7. Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism.

    Science.gov (United States)

    Kashif, Muhammad; Andersson, Claes; Mansoori, Sharmineh; Larsson, Rolf; Nygren, Peter; Gustafsson, Mats G

    2017-11-28

    We analyzed survival effects for 15 different pairs of clinically relevant anti-cancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy™ II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.

  8. Clinical relevance of drug binding to plasma proteins

    Science.gov (United States)

    Ascenzi, Paolo; Fanali, Gabriella; Fasano, Mauro; Pallottini, Valentina; Trezza, Viviana

    2014-12-01

    Binding to plasma proteins highly influences drug efficacy, distribution, and disposition. Serum albumin, the most abundant protein in plasma, is a monomeric multi-domain macromolecule that displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds, such as fatty acids and most acidic drugs. α-1-Acid glycoprotein, the second main plasma protein, is a glycoprotein physiologically involved in the acute phase reaction and is the main carrier for basic and neutral drugs. High- and low-density lipoproteins play a limited role in drug binding and are natural drug delivery system only for few lipophilic drugs or lipid-based formulations. Several factors influence drug binding to plasma proteins, such as pathological conditions, concurrent administration of drugs, sex, and age. Any of these factors, in turn, influences drug efficacy and toxicity. Here, biochemical, biomedical, and biotechnological aspects of drug binding to plasma proteins are reviewed.

  9. Clinical pharmacology of novel anticancer drug formulations

    NARCIS (Netherlands)

    Stuurman, F.E.

    2013-01-01

    Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The

  10. Frequency and clinical significance of transient hyperechoic renal medulla in neonates

    International Nuclear Information System (INIS)

    Cho, Sung Shick; Kim, Jung Hoon; Hong, Hyun Sook; Shin, Ji Hoon; Hwang, Jung Hwa; Goo, Dong Erk; Kwon, Kui Hyang; Choi, Deuk Lin

    2001-01-01

    To evaluate the clinical significance of transient hyperechogenicity of the renal medulla in neonates by comparing the clinical features, urinalysis and follow-up ultrasonographic examination of the control group. One hundred ten neonates were divided into 2 groups, hyperechoic and normal renal medulla groups, and all of them underwent abdominal ultrasound with a 7.5 MHz linear transducer (Sonoace 8800MT, Medicine, Korea) from November 1999 to January 2000. Whether there was any difference in clinical features including birth weight, body surface area, gestational age, sex, date of examination and mode of delivery between two groups was evaluated. In addition, any difference in their urinary osmolarity, albumin, uric acid and calcium in 41 neonates who underwent urinalysis was evaluated. In ten neonates with hyperechoic renal medulla underwent follow-up study, the follow-up ultrasonographic findings were compared with the initial study. In 67 of 110 (61%) neonates, ultrasonography demonstrated hyperechoic renal medulla. There was no difference in clinical features between the hyperechoic renal medullary group and normal group. In 41 neonates, there was no significant difference in urinalysis between two groups. (Osmolarity=146.46 ± 68.4 mOsml/KgH 2 O in the hyperechoic renal medullary group vs. 149.8 ± 77.7 mOsml/KgH 2 O in the normal group; albumin=13.9 ± 10.2 mg/ml vs. 17.6 ± 13.6 mg/dl; uric acid=50.0 ± 23.3 mg/dl vs. 44.9 ± 34.1 mg/dl; calcium=1.38 ± 3.0 mg/ dl vs. 0.44 ± 0.07 mg/dl.) Ten neonates who underwent follow-up ultrasonography within 20 days after the initial study showed the normal medullary echogenicity. There were no significant difference between the hyperechoic renal medullary group and the normal echogenic group in their clinical features and urinalysis. Therefore, the hyperechoic renal medullar in neonate is considered as an usual and transient finding which disappears on follow-up study.

  11. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    LENUS (Irish Health Repository)

    Toomey, David

    2009-01-01

    BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins\\/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and\\/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY\\/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS\\/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under \\'change-of-application\\' patents.

  12. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    Directory of Open Access Journals (Sweden)

    David Toomey

    Full Text Available BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i homologous to previously crystallized proteins or (ii targets of known drugs, but are (iii not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under 'change-of-application' patents.

  13. Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls.

    Science.gov (United States)

    Cremers, Serge; Garnero, Patrick

    2006-01-01

    Biochemical markers of bone turnover are used increasingly during the clinical development of drugs for the treatment of metabolic bone diseases such as Paget's disease, osteoporosis and cancer that has metastasised to the bone. However, assessing the optimal value of these markers is often complicated, and such an assessment is an obvious prerequisite for rational use of the markers and, consequently, potential improvement of clinical drug development. Biochemical markers of bone turnover are substances in the blood or urine that are produced or released during bone remodelling. They provide semiquantitative information on bone remodelling, and are often the most adequate tool to describe the pharmacodynamics of the drug. Their use has increased considerably because of dose-effect relationships that have been seen with certain drugs, but also because they have proven relationships with clinical outcomes in several metabolic bone diseases. However, there is a lack of information on the kinetics of these markers, and the immunoassays that are frequently used in their monitoring often measure a mixture of fragments rather than a single molecular entity. For drug development it should also be realised that different markers, but also different assays for the same marker, may provide different results, considerably limiting the ability to compare results. In postmenopausal osteoporosis, relationships have been shown between several biochemical markers of bone turnover, and either fracture risk and/or the antifracture efficacy of drugs. Such relationships can be used for the development of drugs with similar mechanisms of action, but also for the development of these drugs for closely related indications, such as corticosteroid-induced osteoporosis. In both of these instances, data on effects on biochemical markers of bone turnover are usually employed in combination with information about effects on bone mineral density. However, the relationships of these parameters

  14. Adverse drug reactions induced by cardiovascular drugs in outpatients

    Directory of Open Access Journals (Sweden)

    Gholami K

    2008-03-01

    Full Text Available Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions (ADRs induced by this class of medicinal products seems necessary.Objectives: To determine the rate and seriousness of adverse reactions induced by cardiovascular drugs in outpatients. To compare sex and different age groups in developing ADRs with cardiovascular agents. To assess the relationship between frequencies of ADRs and the number of drugs used. Methods: This cross-sectional study was done in cardiovascular clinic at a teaching hospital. All patients during an eight months period were evaluated for cardiovascular drugs induced ADRs. Patient and reaction factors were analyzed in detected ADRs. Patients with or without ADRs were compared in sex and age by using chi-square test. Assessing the relationship between frequencies of ADRs and the number of drugs used was done by using Pearson analysis. Results: The total number of 518 patients was visited at the clinic. ADRs were detected in 105 (20.3% patients. The most frequent ADRs were occurred in the age group of 51-60. The highest rate of ADRs was recorded to be induced by Diltiazem (23.5% and the lowest rate with Atenolol (3%. Headache was the most frequent detected ADR (23%. Assessing the severity and preventability of ADRs revealed that 1.1% of ADRs were detected as severe and 1.9% as preventable reactions. Women significantly developed more ADRs in this study (chi square = 3.978, P<0.05. ADRs more frequently occurred with increasing age in this study (chi square = 15.871, P<0.05. With increasing the number of drugs used, the frequency of ADRs increased (Pearson=0.259, P<0.05. Conclusion: Monitoring ADRs in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and underlying diseases.

  15. The clinical significance of detection of serum Pre-S1 antigen

    International Nuclear Information System (INIS)

    Jiang Xuehua; Huang Zhuqing; Han Yi; Gong Shoujun

    2003-01-01

    To study the clinical significance of detection of serum Pre-S 1 Ag, the serum Pre-S 1 Ag, HBV-marks and HBV-DNA were detected in 338 patients with hepatitis B. The positive rate and the relationship between them were analyzed and compared. In 338 patients, the positive rate of serum Pre-S 1 Ag, HBeAg, HBV-DNA was 63.02%, 48.52%, 68.05% respectively, and the co-positive rate of Pre-S 1 Ag with HBV-DNA, HBeAg was 78.56%, 81.17% respectively. There was a significant correlation between Pre-S 1 Ag, HBeAg and HBV-DNA (P 1 Ag could well reflect the reproductive status of hepatitis B virus, and so it could be used as the clinical marker of the reproductive status of hepatitis B virus

  16. Psychopharmacologic treatment of children prenatally exposed to drugs of abuse.

    Science.gov (United States)

    Hulvershorn, Leslie A; Schroeder, Kristen M; Wink, Logan K; Erickson, Craig A; McDougle, Christopher J

    2015-05-01

    This pilot study compared the pharmacologic treatment history and clinical outcomes observed in pediatric outpatients with psychiatric disorders exposed to drugs of abuse in utero to those of an age-matched, sex-matched and psychiatric disorder-matched, non-drug-exposed group. In this matched cohort study, medical records of children treated at an academic, child and adolescent psychiatry outpatient clinic were reviewed. Children with caregiver-reported history of prenatal drug exposure were compared with a non-drug-exposed control group being cared for by the same providers. Patients were rated with the Clinical Global Impressions-Severity scale (CGI-S) throughout treatment. The changes in pre-treatment and post-treatment CGI-S scores and the total number of medication trials were determined between groups. The drug-exposed group (n = 30) had a higher total number of lifetime medication trials compared with the non-drug-exposed group (n = 28) and were taking significantly more total medications, at their final assessment. Unlike the non-drug-exposed group, the drug-exposed group demonstrated a lack of clinical improvement. These results suggest that in utero drug-exposed children may be more treatment-refractory to or experience greater side effects from the pharmacologic treatment of psychiatric disorders than controls, although we cannot determine if early environment or drugs exposure drives these findings. Copyright © 2015 John Wiley & Sons, Ltd.

  17. [How to adapt to the requirements of "clinical value-oriented drug innovation" for pharmaceutical research in application process of new traditional Chinese medicine].

    Science.gov (United States)

    Jin, Fang

    2017-05-01

    On August 9, 2015, the State Council promulgated the "Opinions of the State Council on the reform of drug and medical device review and approval system" (Guofa 2015 No. 44), and established the "clinical value-oriented drug innovation" model to encourage the research and development of new drugs. Following that, China Food and Drug Administration (CFDA) promulgated the "Notice on several policies for drug registration review and approval" (2015 No. 230 ) on November 11, 2015, clearly specifying that CFDA would "implement one-time approval for clinical trials application of the new drugs, and no longer take a phased declaration, review and approval system; for the new drugs that apply for clinical trials, mainly review the scientific natureof the clinical protocols and the risk control of the new drugs to guarantee the safety of subjects". Accordingly, the evaluation ideas and forms of new drug registration have also been adjusted greatly. For example, issues like the rationality of the drug manufacturing process, whether the scale can reflect the stability of the process, whether the preparation process is sufficient, and whether the choice of dosage form is reasonable are no longer the focus of evaluation before clinical trials. Issues regarding whether the preparation process design is reasonable, whether the effective components can be transferred to the preparation to a maximum extent, whether the process parameters determined in small and middle pilot trials can adapt to the requirements of mass production, no longer act as the reasons for refusing the clinical trials. The corresponding risks shall be borne by the applicant as the subject of liability. The focus in registration evaluation is mainly transferred to how to ensure the consistence of quality between clinical trial samples and the samples already available on market by guaranteeing stable sources of drug raw materials and stable quality of medicines as well as control of the whole preparation

  18. Fragment-based drug discovery and molecular docking in drug design.

    Science.gov (United States)

    Wang, Tao; Wu, Mian-Bin; Chen, Zheng-Jie; Chen, Hua; Lin, Jian-Ping; Yang, Li-Rong

    2015-01-01

    Fragment-based drug discovery (FBDD) has caused a revolution in the process of drug discovery and design, with many FBDD leads being developed into clinical trials or approved in the past few years. Compared with traditional high-throughput screening, it displays obvious advantages such as efficiently covering chemical space, achieving higher hit rates, and so forth. In this review, we focus on the most recent developments of FBDD for improving drug discovery, illustrating the process and the importance of FBDD. In particular, the computational strategies applied in the process of FBDD and molecular-docking programs are highlighted elaborately. In most cases, docking is used for predicting the ligand-receptor interaction modes and hit identification by structurebased virtual screening. The successful cases of typical significance and the hits identified most recently are discussed.

  19. Significance and clinical value of the transitional zone volume (TZV ...

    African Journals Online (AJOL)

    M. El Ghoneimy

    2017-01-12

    Jan 12, 2017 ... Objective: The aim of this work was to evaluate the significance and clinical value of the TZI, which has been a point of ... Conclusion: Estimating the transition zone volume during TRUS is a reasonable way to obtain the required ... Besides the IPSS score, a complete medical and surgical history was also.

  20. 76 FR 39883 - Design of Clinical Trials for Systemic Antibacterial Drugs for the Treatment of Acute Otitis...

    Science.gov (United States)

    2011-07-07

    ...] Design of Clinical Trials for Systemic Antibacterial Drugs for the Treatment of Acute Otitis Media... Clinical Trials for Systemic Antibacterial Agents for the Treatment of Acute Otitis Media. This public... the treatment of acute otitis media (middle ear infection). Discussions will focus on [[Page 39884...

  1. Clinical Features and Correlates of Outcomes for High-Risk, Marginalized Mothers and Newborn Infants Engaged with a Specialist Perinatal and Family Drug Health Service

    Directory of Open Access Journals (Sweden)

    Lee Taylor

    2012-01-01

    Full Text Available Background. There is a paucity of research in Australia on the characteristics of women in treatment for illicit substance use in pregnancy and the health outcomes of their neonates. Aims. To determine the clinical features and outcomes of high-risk, marginalized women seeking treatment for illicit substance use in pregnancy and their neonates. Methods. 139 women with a history of substance abuse/dependence engaged with a perinatal drug health service in Sydney, Australia. Maternal (demographic, drug use, psychological, physical, obstetric, and antenatal care and neonatal characteristics (delivery, early health outcomes were examined. Results. Compared to national figures, pregnant women attending a specialist perinatal and family drug health service were more likely to report being Australian born, Aboriginal or Torres Strait Islander, younger, unemployed, and multiparous. Opiates were the primary drug of concern (81.3%. Pregnancy complications were common (61.9%. Neonates were more likely to be preterm, have low birth weight, and be admitted to special care nursery. NAS was the most prevalent birth complication (69.8% and almost half required pharmacotherapy. Conclusion. Mother-infant dyads affected by substance use in pregnancy are at significant risk. There is a need to review clinical models of care and examine the longer-term impacts on infant development.

  2. Positron emission tomography in drug development

    International Nuclear Information System (INIS)

    Rubin, R. H.; Fischman, A. J.

    1997-01-01

    There are four kinds of measurements that can be carried out with positron emission tomography (PET) that can contribute significantly to the process of drug development: pharmacodynamic measurement of tissue metabolism influenced by a given drug; precise measurements of tissue blood flow; tissue pharmacokinetics of a given drug following administration of a particular dose; and the temporal course of ligand-receptor interaction. One or more of these measurements can greatly improve the decision making involved in determining the appropriate dose of a drug, the clinical situations in which a drug might be useful, and the linkage of pharmacokinetics with pharmacodynamics, which is at the heart of effective drug development. The greater the potential of a particular compound as a therapeutic agent, the greater the potential for PET to contribute to the drug development process

  3. Indolealkylamines: biotransformations and potential drug-drug interactions.

    Science.gov (United States)

    Yu, Ai-Ming

    2008-06-01

    Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug-drug interactions (DDIs). A stable, principal metabolite of an IAA drug of abuse could serve as a useful biomarker in assessing intoxication of the IAA substance. Studies on the metabolism of IAA drugs of abuse including lysergic acid amides, tryptamine derivatives and beta-carbolines are therefore emerging. An important role for polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of IAA drugs of abuse has been revealed by recent studies, suggesting that variations in IAA metabolism, pharmaco- or toxicokinetics and dynamics can arise from distinct CYP2D6 status, and CYP2D6 polymorphism may represent an additional risk factor in the use of these IAA drugs. Furthermore, DDIs with IAA agents could occur additively at the pharmaco/toxicokinetic and dynamic levels, leading to severe or even fatal serotonin toxicity. In this review, the metabolism and potential DDIs of these therapeutic and abused IAA drugs are described.

  4. Expanding the National Drug Abuse Treatment Clinical Trials Network to address the management of substance use disorders in general medical settings

    Directory of Open Access Journals (Sweden)

    Tai B

    2014-07-01

    Full Text Available Betty Tai, Steven Sparenborg, Udi E Ghitza, David Liu Center for the Clinical Trials Network, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA Abstract: The Patient Protection and Affordable Care Act (2010 and the Mental Health Parity and Addiction Equity Act (2008 expand substance use disorder (SUD care services in the USA into general medical settings. Care offered in these settings will engage substance-using patients in an integrated and patient-centered environment that addresses physical and mental health comorbidities and follows a chronic care model. This expansion of SUD services presents a great need for evidence-based practices useful in general medical settings, and reveals several research gaps to be addressed. The National Drug Abuse Treatment Clinical Trials Network of the National Institute on Drug Abuse can serve an important role in this endeavor. High-priority research gaps are highlighted in this commentary. A discussion follows on how the National Drug Abuse Treatment Clinical Trials Network can transform to address changing patterns in SUD care to efficiently generate evidence to guide SUD treatment practice within the context of recent US health care legislation. Keywords: Patient Protection and Affordable Care Act, National Drug Abuse Treatment Clinical Trials Network, substance use disorders, practice-based research network, electronic health records

  5. Clinical significance of inadequate endometrial biopsies prior to hysterectomy.

    Science.gov (United States)

    Turney, Emily H; Farghaly, Hanan; Eskew, Ashley M; Parker, Lynn P; Milam, Michael R

    2012-01-01

    To evaluate preoperative clinical risk factors associated with significant uterine histopathologic abnormalities in final hysterectomy specimens in patients with inadequate preoperative endometrial biopsies. This is an institutional review board-approved, retrospective cohort analysis of 469 consecutive patients who underwent preoperative endometrial biopsies with subsequent hysterectomy from January 1, 2005, to December 31, 2009, at the University of Louisville Medical Center. We analyzed risk factors for inadequate biopsy and for final diagnosis of endometrial pathology (defined as endometrial hyperplasia or uterine cancer). Of the 469 preoperative endometrial biopsies reviewed, 26.2% (123/469) were inadequate (IBx) and 73.8% (346/469) were adequate and benign. IBx on endometrial biopsies was associated with a greater risk of having significant uterine histopathologic abnormalities on final hysterectomy specimens (6.5% vs. 2.3%, RR 2.8 [95% CI 1.1-7.3], p = 0.04). Although inadequate endometrial biopsies are a common finding, they can be associated with significant uterine histopathologic abnormalities on final hysterectomy specimens.

  6. Clinical perspectives on the influence of drug formulation on patient tolerability and use of commonly prescribed antidepressants in major depressive disorder

    Directory of Open Access Journals (Sweden)

    Matthew A Fuller

    2013-01-01

    Full Text Available The purpose of this review is to summarize the formulation options for currently available antidepressants, and discuss examples of the influence that formulation may have on the pharmacologic and clinical profiles of the medications. A review of current literature suggests that differences in drug-delivery technologies can lead to variations in the pharmacokinetic and pharmacodynamic profiles of generic and branded drugs, despite generic drugs being required to meet bioequivalence standards compared with their branded counterparts. These differences may influence the effectiveness and tolerability of treatment. Recent reports have highlighted the need for individualized treatment regimens and careful assessment of tolerability and efficacy when switching patients from brand to generic formulations. There is a growing body of evidence indicating that differences in formulation can substantially impact drug pharmacokinetics and pharmacodynamics, which in turn, can affect drug effects. The clinical impact of these differences remains unclear. Further research is needed to clarify the influence of antidepressant formulations on treatment adherence, patient preference, and quality of life, and how this impacts clinical practice with regard to brand versus generic treatment selection.

  7. Molecularly targeted drugs for metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Cheng YD

    2013-11-01

    Full Text Available Ying-dong Cheng, Hua Yang, Guo-qing Chen, Zhi-cao Zhang Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China Abstract: The survival rate of patients with metastatic colorectal cancer (mCRC has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin–fluorouracil–irinotecan (FOLFIRI chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin–fluorouracil–oxaliplatin (FOLFOX or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs. Keywords: metastatic colorectal cancer (mCRC, antiangiogenic drug, bevacizumab, aflibercept, regorafenib, cetuximab, panitumumab, clinical trial, molecularly targeted therapy

  8. Capillary Electrophoresis Hyphenated with Mass Spectrometry for Determination of Inflammatory Bowel Disease Drugs in Clinical Urine Samples

    Directory of Open Access Journals (Sweden)

    Katarína Maráková

    2017-11-01

    Full Text Available Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a separation method based on the capillary electrophoresis (CE hyphenated with tandem mass spectrometry (MS/MS for the simultaneous determination of azathioprine and its selected metabolites (6-thioguanine, 6-mercaptopurine, and 6-methylmercaptopurine as well as other co-medicated drugs (mesalazine, prednisone, and allopurinol. The optimized CE-MS/MS conditions provided a very efficient and stable system for the separation and sensitive detection of these drugs in human urine matrices. The developed method was successfully applied for the assay of the targeted drugs and their selected metabolites in urine samples collected from patients suffering from inflammatory bowel disease (IBD and receiving azathioprine therapy. The developed CE-MS/MS method, due to its reliability, short analysis time, production of complex clinical profiles, and favorable performance parameters, evaluated according to FDA guidelines for bioanalytical method validation, is proposed for routine clinical laboratories to optimize thiopurine therapy, estimate enzymatic activity, and control patient compliance with medication and co-medication.

  9. Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

    Science.gov (United States)

    Vainionpää, Mari H; Raekallio, Marja R; Pakkanen, Soile A E; Ranta-Panula, Ville; Rinne, Valtteri M; Scheinin, Mika; Vainio, Outi M

    2013-05-01

    To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. Experimental randomized blinded crossover study. Six healthy horses. Detomidine (10 μg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 μg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses. © 2013 The Authors. Veterinary Anaesthesia and Analgesia © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  10. Food-Drug Interactions

    Directory of Open Access Journals (Sweden)

    Arshad Yar Khan

    2011-03-01

    Full Text Available The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction, food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction or another disease the person has (drug-disease interaction. A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least fooddrug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient.

  11. Rectal drug administration: clinical pharmacokinetic considerations.

    Science.gov (United States)

    de Boer, A G; Moolenaar, F; de Leede, L G; Breimer, D D

    1982-01-01

    The human rectum represents a body cavity in which drugs can be easily introduced and retained and from which absorption is well possible. There are important therapeutic reasons why it is sometimes preferable to give a drug rectally rather than orally, e.g. in cases of nausea and vomiting. Drawbacks of rectal drug administration include the interruption of absorption by defaecation and lack of patient acceptability. The mechanism of drug absorption from the rectum is probably no different to that in the upper part of the gastrointestinal tract, despite the fact that the physiological circumstances (e.g. pH, fluid content) differ substantially, Absorption from aqueous and alcoholic solutions may occur very rapidly, which has proved to be of considerable therapeutic value in the rapid suppression of acute convulsive attacks by diazepam (e.g. in children), but absorption from suppositories is generally slower and very much dependent on the nature of the suppository base, the use of surfactants or other additives, particle size of the active ingredient, etc. There is some evidence that hepatic first-pass elimination of high clearance drugs is partially avoided after rectal administration, e.g. lignocaine. This can be explained by the rectal venous blood supply: the upper part is connected with the portal system, whereas the lower part is directly connected with the systemic circulation. Plasma concentration data following rectal administration of representatives of several classes of drugs are reviewed: anticonvulsants, non-narcotic analgesics and non-steroidal anti-inflammatory agents, hypnosedatives and anaesthetics, strong analgesics, theophylline and derivatives, corticosteroids, antibacterial agents, thiazinamium, promethazine, hyoscine-N-butyl-bromide, streptokinase, progesterone, ergotamine tartrate and levodopa. Only limited number of cases has it been adequately shown that the rectal route of administration gives plasma concentrations which are comparable to

  12. Liposomal Formulations in Clinical Use: An Updated Review

    Directory of Open Access Journals (Sweden)

    Upendra Bulbake

    2017-03-01

    Full Text Available Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil®, Ambisome®, DepoDur™, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoam™ Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes.

  13. CLINICAL AND PHARMACOLOGICAL APPROACHES TO OPTIMIZE THE DOSING REGIMEN OF ANTIBACTERIAL DRUGS IN PEDIATRICS

    Directory of Open Access Journals (Sweden)

    Natal’ya B. Lazareva

    2018-01-01

    Full Text Available The rational use of antibacterial drugs in children implies an adequate choice of the necessary medication, its dosing regimen, and the duration of treatment in order to achieve maximum efficacy and minimize toxic effects. The knowledge of pharmacokinetic and pharmacodynamic profiles of the antibacterial drug plays a crucial role for optimizing the dosing regimen. The strategy of individual choice of the dosing regimen, taking into account the principles of pharmacokinetics and pharmacodynamics, can be especially effective in patients with the expectedly changed parameters of pharmacokinetics and in infections caused by bacteria strains with low sensitivity to antibiotics. The review presents a contemporary view of pharmacokinetic and pharmacodynamic profiles of antibacterial drugs most commonly used in pediatrics and their relationship to the clinical efficacy of the administered therapy.

  14. Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016.

    Directory of Open Access Journals (Sweden)

    Arif Khan

    Full Text Available Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension.For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms. Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures.Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018 and effect size (R2 = 0.013, p = 0.187 drug-placebo difference (R2 = 0.013, p = 0.182 and success rate (134/142, 94.4% have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, p<0.001. Treatment arms are likely overpowered with sample sizes increasing over time (R2 = 0.387, p<0.0001 and stable, large effect sizes (0.78 ±0.37. The exploratory analysis of sample size, trial duration, baseline blood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877, antihypertensive-placebo differences (p = 0.752, or p-values (p = 0.963 but was correlated with antihypertensive response

  15. Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016

    Science.gov (United States)

    Fahl Mar, Kaysee; Schilling, Joshua; Brown, Walter A.

    2018-01-01

    Background Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension. Method For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms). Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures. Results Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018) and effect size (R2 = 0.013, p = 0.187) drug-placebo difference (R2 = 0.013, p = 0.182) and success rate (134/142, 94.4%) have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, parms are likely overpowered with sample sizes increasing over time (R2 = 0.387, pblood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877), antihypertensive-placebo differences (p = 0.752), or p-values (p = 0.963) but was correlated with antihypertensive response (R2 = 0.347, p<0.0001). Conclusions As hypothesized, this study shows that placebo response is increasing in clinical

  16. Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions

    Directory of Open Access Journals (Sweden)

    Saab YB

    2015-09-01

    Full Text Available Yolande B Saab,1 Rony Zeenny,2 Wijdan H Ramadan2 1School of Pharmacy, Pharmaceutical Sciences Department, 2School of Pharmacy, Pharmacy Practice Department, Lebanese American University, Byblos, Lebanon Purpose: Response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced function of the gene variant of the CYP2C19 has been associated with lower drug metabolite levels, and hence diminished platelet inhibition. Drugs that alter CYP2C19 activity may also mimic genetic variants. The aim of the study is to investigate the cumulative effect of CYP2C19 gene polymorphisms and drug interactions that affects clopidogrel dosing, and apply it into a new clinical-pharmacogenetic algorithm that can be used by clinicians in optimizing clopidogrel-based treatment. Method: Clopidogrel dose optimization was analyzed based on two main parameters that affect clopidogrel metabolite area under the curve: different CYP2C19 genotypes and concomitant drug intake. Clopidogrel adjusted dose was computed based on area under the curve ratios for different CYP2C19 genotypes when a drug interacting with CYP2C19 is added to clopidogrel treatment. A clinical-pharmacogenetic algorithm was developed based on whether clopidogrel shows 1 expected effect as per indication, 2 little or no effect, or 3 clinical features that patients experience and fit with clopidogrel adverse drug reactions. Results: The study results show that all patients under clopidogrel treatment, whose genotypes are different from *1*1, and concomitantly taking other drugs metabolized by CYP2C19 require clopidogrel dose adjustment. To get a therapeutic effect and avoid adverse drug reactions, therapeutic dose of 75 mg clopidogrel, for example, should be lowered to 6 mg or increased to 215 mg in patients with different genotypes. Conclusion: The implementation of clopidogrel new algorithm has the potential to maximize the benefit of clopidogrel pharmacological therapy

  17. Drug-specific characteristics of thrombocytopenia caused by non-cytotoxic drugs

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Andersen, M; Hansen, P B

    1999-01-01

    OBJECTIVE: To analyse drug-specific clinical characteristics and to investigate the possible influence of epidemiological and other factors on thrombocytopenia induced by selected non-cytotoxic drugs. METHODS: A retrospective analysis of drug-induced thrombocytopenia reported to the Danish...... determined by the drug itself and also by its usage pattern. No specific patient-related factor responsible for the heterogeneity of the clinical appearance of the adverse reaction was identified. Factors related to the physician, such as monitoring recommendations or level of attention towards the adverse...

  18. Macrolides versus azalides: a drug interaction update.

    Science.gov (United States)

    Amsden, G W

    1995-09-01

    To describe the current drug interaction profiles for all approved and investigational macrolide and azalide antimicrobials, and to comment on the clinical impact of these interactions when appropriate. MEDLINE was searched to identify all pertinent studies, review articles, and case reports from 1975 to 1995. When appropriate information was not available in the literature, data were obtained from the product manufacturers. All available data were reviewed to give an unbiased account of possible drug interactions. Data for some of the interactions were not available from the literature, but were available from abstracts or from company-supplied materials. Although the data were not always entirely explicative, the best attempt was made to deliver the pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. Since the introduction of erythromycin into clinical practice, there have been several clinically significant drug interactions identified throughout the literature associated with this drug. These interactions have been caused mostly by inhibition of the CYP3A subclass of hepatic enzymes, thereby decreasing the metabolism of any other agent given concurrently that is also cleared through this mechanism. With the development and marketing of several new macrolides, it was hoped that the drug interaction profile associated with this class would improve. This has been met with variable success. Although some of the extensions of the 14-membered ring macrolides have shown an incidence of interactions equal to that of erythromycin, others have shown improved profiles. In contrast, the 16-membered ring macrolides have demonstrated a much improved, though not absent, interaction profile. The most success in avoiding drug interactions through structure modification has been accomplished

  19. Success rates for product development strategies in new drug development.

    Science.gov (United States)

    Dahlin, E; Nelson, G M; Haynes, M; Sargeant, F

    2016-04-01

    While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008

  20. Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians

    NARCIS (Netherlands)

    Sijmons, Rolf H.; Greenblatt, Marc S.; Genuardi, Maurizio

    Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance

  1. Clinical trials for vaccine development in registry of Korea Food and Drug Administration.

    Science.gov (United States)

    Kang, Seog-Youn

    2013-01-01

    Based on the action plan "Ensuring a stable supply of National Immunization Program vaccines and sovereignty of biopharmaceutical products," Korea Food and Drug Administration (KFDA) has made efforts to develop vaccines in the context of self reliance and to protect public health. Along with the recognized infrastructures for clinical trials, clinical trials for vaccines have also gradually been conducted at multinational sites as well as at local sites. KFDA will support to expand six to eleven kinds of vaccines by 2017. In accordance with integrated regulatory system, KFDA has promoted clinical trials, established national lot release procedure, and strengthened good manufacturing practices inspection and post marketing surveillance. Against this backdrop, KFDA will support the vaccine development and promote excellent public health protection.

  2. Clinical significance of nerve root enhancement in contrast-enhanced MR imaging of the postoperative lumbar spine

    International Nuclear Information System (INIS)

    Lee, Yeon Soo; Lee, Eun Ja; Kang, Si Won; Choi, Eun Seok; Song, Chang June; Kim, Jong Chul

    2001-01-01

    To determine the significance of nerve root contrast enhancement in patients with residual or recurrent symptomatic postoperative lumbar spine. Eighty-eight patients with 116 postoperative lumbar disc lesions causing radiating back pain underwent enhanced MR imaging. Intradural nerve root enhancement was quantified by pixel measurement, and affected nerve roots were compared before and after contrast administration. Extradural nerve root enhancement was assessed visually, and nerve root enhancement and clinical symptoms were correlated. Associated lesions such as recurrent disc herniation, scar tissue, nerve root thickening and nerve root displacement were also evaluated. Of 26 cases (22.4%) involving intradural nerve root enhancement, 22 (84.6%) showed significant clinical symptoms (p=0.002). and of 59 (50.9%) demonstrating extradural enhancement, clinical symptoms showed significant correlation in 47 (79.7%) (p=0.001). Nerve root enhancement, including eleven cases where this was both intra-and extradural, showed highly significant association with clinical symptoms in 74 of the 116 cases (63.8%) (p=0.000). Among 33 cases (28.4%) of recurrent disc herniation, nerve root enhancement was observed in 28 (84.8%) and in 24 of these 28 (85.7%), significant correlation with clinical symptoms was observed (p=0.000). Where epidural fibrosis was present, correlation between nerve root enhancement and clinical symptoms was not significant (p>0.05). Nerve root thickening and displaced nerve root were, however, significantly associated with symptoms (87.2% and 88.6%, respectively). In patients with postoperative lumbar spine, the association between nerve root enhancement revealed by MRI and clinical symptoms was highly significant

  3. Assessment of clinical risk factors for drug-resistant epilepsy in children and teenagers

    Directory of Open Access Journals (Sweden)

    Marta Kasprzyk

    2014-09-01

    Full Text Available Introduction: Epilepsy is one of the most common neurological illnesses occurring in children. In approximately 20–30% of cases it is drug-resistant. Aim of the research: To assess the already-known risk factors, analyse the rarely described ones, and find new causes of epilepsy drug resistance in children, taking into account the level of impact of each factor. Material and methods : The study comprised 152 of all 383 children hospitalised in 2012 at the Neurology Department of the Polish Mother’s Memorial Hospital in Lodz due to epilepsy. Based on medical documentation, neurological examination, and our own questionnaire, we divided patients into two groups: drug-resistant epilepsy or drug-sensitive epilepsy. We compared the type, level of influence, and prevalence of different factors. For statistical analysis, the 2 test was used. Statistical significance was set at p < 0.05. Results: Drug-resistant epilepsy was found in 64 patients (42.1%, and drug-sensitive epilepsy was found in 88 patients (57.9%. Factors that were most probable to cause drug resistance included: high prevalence of seizures (Cramer’s V = 0.66, type of epileptic syndrome (V = 0.62, psychomotor developmental delay (V = 0.62, and occurrence of status epilepticus (V = 0.6. Factors such as infections of CNS in early childhood, repeated severe infections of airways in childhood, and mother’s infectious diseases with high fever during pregnancy were rare or non occurring (Cramer’s V = 0.41, 0.32, and 0.31, respectively. Conclusions : The study confirmed the previously known causes of drug resistance and indicated the significance of underestimated inflammatory and infectious factors involving pyrexia, in children and also in mothers during pregnancy.

  4. The effect of hypnotic drug type on anesthetic depth and amnesia: a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Amiri HR

    2009-06-01

    .001 in two groups were significant, respectively. No delay in recovery was observed."n"nConclusion: Although the Modified Ramsey Sedation Score and clinical sedation indices were the same, but BIS in patients varied in a wide range. Hypnotic drug was a main determinant of BIS score and amnesia.

  5. Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug.

    Science.gov (United States)

    Carlyle, Wenda C; McClain, James B; Tzafriri, Abraham R; Bailey, Lynn; Zani, Brett G; Markham, Peter M; Stanley, James R L; Edelman, Elazer R

    2012-09-28

    Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-powder electrostatic process. The AC-SES demonstrated enhanced drug stability under simulated use conditions and consistent drug delivery balanced with coating erosion in a porcine coronary implant model. The initial drug burst was eliminated and drug release was sustained after implantation. The coating was absorbed within 90 days. Following implantation into porcine coronary arteries the AC-SES coating is distributed in the surrounding intimal tissue over the course of several weeks. Computational modeling of drug delivery characteristics demonstrates how distributed coating optimizes the load of drug immediately around each stent strut and extends drug delivery between stent struts. The result was a highly efficient arterial uptake of drug with superior performance to a clinical bare metal stent (BMS). Neointimal thickness (0.17±0.07 mm vs. 0.28±0.11 mm) and area percent stenosis (22±9% vs. 35±12%) were significantly reduced (pstent implantation in an overlap configuration in porcine coronary arteries. Inflammation was significantly reduced in the AC-SES compared to the BMS at both 30 and 90 days after implantation. Biocompatible, rapidly absorbable stent coatings enable the matching of drug release with coating erosion and provide for the controlled migration of coating material into tissue to reduce vicissitudes in drug tissue levels, optimizing efficacy and reducing potential toxicity. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Childhood extracranial neoplasms: the role of imaging in drug development and clinical trials

    International Nuclear Information System (INIS)

    Fowkes, Lucy A.; Koh, Dow-Mu; MacVicar, David; Collins, David J.; Jerome, Neil P.; Chua, Sue C.; Pearson, Andrew D.J.

    2015-01-01

    Cancer is the leading cause of death in children older than 1 year of age and new drugs are necessary to improve outcomes. Imaging is crucial to the drug development process and assessment of therapeutic response. In adults, tumours are often assessed with CT using size criteria. Unfortunately, techniques established in adults are not necessarily applicable in children due to differing pathophysiology, ability to cooperate and increased susceptibility to ionising radiation. MRI, in particular quantitative MRI, has to date not been fully utilised in children with extracranial neoplasms. The specific challenges of imaging in children, the potential for functional imaging techniques to inform upon and their inclusion in clinical trials are discussed. (orig.)

  7. Childhood extracranial neoplasms: the role of imaging in drug development and clinical trials

    Energy Technology Data Exchange (ETDEWEB)

    Fowkes, Lucy A.; Koh, Dow-Mu; MacVicar, David [Royal Marsden NHS Foundation Trust, Department of Radiology, Sutton, Surrey (United Kingdom); Collins, David J.; Jerome, Neil P. [Institute of Cancer Research, Cancer Research UK and EPSRC Cancer Imaging Centre, Sutton, Surrey (United Kingdom); Chua, Sue C. [Royal Marsden NHS Foundation Trust, Nuclear Medicine and PET Department, Sutton, Surrey (United Kingdom); Pearson, Andrew D.J. [Royal Marsden NHS Foundation Trust, Paediatric Drug Development Unit, Children and Young People' s Unit, Sutton, Surrey (United Kingdom)

    2015-10-15

    Cancer is the leading cause of death in children older than 1 year of age and new drugs are necessary to improve outcomes. Imaging is crucial to the drug development process and assessment of therapeutic response. In adults, tumours are often assessed with CT using size criteria. Unfortunately, techniques established in adults are not necessarily applicable in children due to differing pathophysiology, ability to cooperate and increased susceptibility to ionising radiation. MRI, in particular quantitative MRI, has to date not been fully utilised in children with extracranial neoplasms. The specific challenges of imaging in children, the potential for functional imaging techniques to inform upon and their inclusion in clinical trials are discussed. (orig.)

  8. Gender bias in clinical research, pharmaceutical marketing, and the prescription of drugs

    Directory of Open Access Journals (Sweden)

    Elisa Chilet-Rosell

    2014-12-01

    Full Text Available This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are inaccuracies in medical practice, in addition to a lack of rigour and transparency. It worked with the distinction between the concepts of sex and gender and between the concepts of sex-related differences and gender inequalities, in terms of applying a gender perspective in the study design and the subsequent analysis. This PhD review presents the research process conducted in Spain, which can provide an example for future research. Study I described a review of 58 clinical trials (CTs of etoricoxib to assess its compliance with the Recommendations of Evaluation of Gender Differences in the Clinical Evaluation of Drugs. In Study II, key informants from professions related to different areas in drug development and pharmacovigilance held a working meeting to reach a consensus document on recommendations for the study and evaluation of gender differences in CTs in Spain. In Study III, the websites of the eight best-selling hormone replacement therapy drugs in Spain on Google first page of results were analysed. In Study IV, a logistic regression analysis was performed to compare analgesic prescription by sex in regions with a higher or lower Gender Development Index (GDI than the Spanish average. Gender biases identified in this thesis limited the legitimacy of medicine, which is not based on the best possible evidence. The results also demonstrate the existence of inequalities between men and women that are not due merely to biological differences, but are gender inequalities stemming from the social differences that exist between both sexes.

  9. Gender bias in clinical research, pharmaceutical marketing, and the prescription of drugs.

    Science.gov (United States)

    Chilet-Rosell, Elisa

    2014-01-01

    This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are inaccuracies in medical practice, in addition to a lack of rigour and transparency. It worked with the distinction between the concepts of sex and gender and between the concepts of sex-related differences and gender inequalities, in terms of applying a gender perspective in the study design and the subsequent analysis. This PhD review presents the research process conducted in Spain, which can provide an example for future research. Study I described a review of 58 clinical trials (CTs) of etoricoxib to assess its compliance with the Recommendations of Evaluation of Gender Differences in the Clinical Evaluation of Drugs. In Study II, key informants from professions related to different areas in drug development and pharmacovigilance held a working meeting to reach a consensus document on recommendations for the study and evaluation of gender differences in CTs in Spain. In Study III, the websites of the eight best-selling hormone replacement therapy drugs in Spain on Google first page of results were analysed. In Study IV, a logistic regression analysis was performed to compare analgesic prescription by sex in regions with a higher or lower Gender Development Index (GDI) than the Spanish average. Gender biases identified in this thesis limited the legitimacy of medicine, which is not based on the best possible evidence. The results also demonstrate the existence of inequalities between men and women that are not due merely to biological differences, but are gender inequalities stemming from the social differences that exist between both sexes.

  10. Clinical significance of the corpus callosum in cerebral palsy

    International Nuclear Information System (INIS)

    Lee, Eun Ja; Kim, Ji Chang; Kim, Jong Chul; And Others

    2000-01-01

    To evaluate, using magnetic resonance (MR) imaging, the clinal significance of the corpus callosum by measuring the size of various portions of the corpus callosum in children with cerebral palsy, and in paired controls. Fifty-two children (30 boys and 22 girls aged between six and 96 (median, 19) months) in whom cerebral palsy was clinically diagnosed underwent MR imaging. There were 23 term patients and 29 preterm, and the control group was selected by age and sex matching. Clinal subtypes of cerebral palsy were classified as hemiplegia (n=14), spastic diplegia (n=22), or spastic quadriplegia (n=16), and according to the severity of motor palsy, the condition was also classified as mild (n=26), moderate (n=13), or severe (n=13). In addition to the length and height of the corpus callosum, the thickness of its genu, body, transitional zone and splenium, as seen on midsagittal T1-weighted MR images, were also measured. Differences in the measured values of the two groups were statistically analysed and differences in the size of the corpus callosum according to the clinical severity and subtypes of cerebral palsy, and gestational age, were also assessed. Except for height, the measured values of the corpus callosum in patients with cerebral palsy were significantly less than those of the control group (p less than 0.05). Its size decreased according to the severity of motor palsy. Compared with term patients, the corpus callosum in preterm patients was considerably smaller (p less than 0.05). There was statistically significant correlation between the severity of motor palsy and the size of the corpus callosum. Quantitative evaluation of the corpus callosum might be a good indicator of neurologic prognosis, and a sensitive marker for assessing the extent of brain injury

  11. Clinical significance of the corpus callosum in cerebral palsy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eun Ja; Kim, Ji Chang [The Catholic University of Korea, Seoul (Korea, Republic of); Kim, Jong Chul [School of Medicine, Chungnam National University, Taejon (Korea, Republic of); And Others

    2000-10-01

    To evaluate, using magnetic resonance (MR) imaging, the clinal significance of the corpus callosum by measuring the size of various portions of the corpus callosum in children with cerebral palsy, and in paired controls. Fifty-two children (30 boys and 22 girls aged between six and 96 (median, 19) months) in whom cerebral palsy was clinically diagnosed underwent MR imaging. There were 23 term patients and 29 preterm, and the control group was selected by age and sex matching. Clinal subtypes of cerebral palsy were classified as hemiplegia (n=14), spastic diplegia (n=22), or spastic quadriplegia (n=16), and according to the severity of motor palsy, the condition was also classified as mild (n=26), moderate (n=13), or severe (n=13). In addition to the length and height of the corpus callosum, the thickness of its genu, body, transitional zone and splenium, as seen on midsagittal T1-weighted MR images, were also measured. Differences in the measured values of the two groups were statistically analysed and differences in the size of the corpus callosum according to the clinical severity and subtypes of cerebral palsy, and gestational age, were also assessed. Except for height, the measured values of the corpus callosum in patients with cerebral palsy were significantly less than those of the control group (p less than 0.05). Its size decreased according to the severity of motor palsy. Compared with term patients, the corpus callosum in preterm patients was considerably smaller (p less than 0.05). There was statistically significant correlation between the severity of motor palsy and the size of the corpus callosum. Quantitative evaluation of the corpus callosum might be a good indicator of neurologic prognosis, and a sensitive marker for assessing the extent of brain injury.

  12. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

    Directory of Open Access Journals (Sweden)

    Alison E. M. Vickers

    2017-03-01

    Full Text Available Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM, diclofenac (DCF, 1 mM and etomoxir (ETM, 100 μM. Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM and cyclosporin A (CSA, 10 μM, while GSH was affected more than ATP by methimazole (MMI, 500 μM, terbinafine (TBF, 100 μM, and carbamazepine (CBZ 100 μM. Oxidative stress genes were affected by TBF (18%, CBZ, APAP, and ETM (12%–11%, and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%. Apoptosis genes were affected by DCF (14%, while apoptosis plus necrosis were altered by APAP and ETM (15%. Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%, ETM (66%, DCF, TBF, MMI (61%–60%, APAP, CBZ (57%–56%, and DTL (48%. Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%, CBZ and ETM (44%–43%, APAP and DCF (40%–38%, MMI, TBF and CSA (37%–35%. This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  13. Translating data on antihypertensive drugs into clinical practice.

    Science.gov (United States)

    Weber, M A

    1998-06-01

    Two problems in the treatment of hypertension continue to be largely unsolved. The first, and more simple, is our inability to adequately control blood pressure in the majority of hypertensive patients. This not only reflects the difficulty of retaining patients in effective treatment programs, but also of convincing physicians to strive for optimal blood pressure levels. There is a continuing need for new antihypertensive drugs and combinations to help accomplish these goals. The second major problem is that the major clinical endpoints, including coronary events and renal failure, have not been adequately reduced by traditional therapies. Standard regimens, particularly those including diuretics, have protected against strokes and heart failure. Our improved understanding of vascular biology in hypertension has directed interest to the mechanisms in hypertensive patients that might accelerate atherosclerosis and vascular events in these individuals. This involves addressing the concomitant metabolic risk factors that comprise the "Hypertension Syndrome," and, perhaps of equal importance, finding therapies that directly inhibit unwanted types of growth and proliferative activities within the walls of critical arteries. Many substances within the endothelium and the vascular wall may participate as initiators or mediators of pathology, but most information thus far has focused on the renin-angiotensin system. Angiotensin converting enzyme inhibitors (and potentially angiotensin receptor blockers) have provided coronary and renal protection in various cardiovascular conditions, though not yet in formal hypertension trials. Calcium channel blockers have also shown promise, including recent stroke and cardiovascular benefits in patients with isolated systolic hypertension, but, again, definitive coronary data in hypertension are awaited. Unless concomitant conditions mandate the selection of a particular antihypertensive drug class, physicians currently have a dilemma

  14. Species distribution and drug susceptibility of candida in clinical isolates from a tertiary care centre at Indore

    Directory of Open Access Journals (Sweden)

    N Pahwa

    2014-01-01

    Full Text Available Background: The incidence of fungal infections has increased significantly, contributing to morbidity and mortality. This is caused by an alarming increase in infections with multi-drug resistant bacteria leading to overuse of broad-spectrum antimicrobials, which lead to overgrowth of Candida, thus enhancing its opportunity to cause disease. Candida are major human fungal pathogens that cause both mucosal and deep tissue infections. Objective : The aim of our study was to identify the distribution of Candida species among clinical isolates and their sensitivity pattern for common antifungal drugs. Materials and Methods : Two hundred and thirty-seven different clinical isolates of Candida were collected from patients visiting to a tertiary care centre of Indore from 2010 to 2012. Identification of Candida species as well as antifungal sensitivity testing was performed with Vitek2 Compact (Biomerieux France using vitek 2 cards for identification of yeast and yeast like organisms (ID-YST cards. Antifungal susceptibility testing was performed with Vitek2 "Fungal Susceptibility Card (AST YS01 kits respectively. Results : We found that the non-albicans Candida were more prevalent than Candida albicans in paediatric (60 year patients than other age group (4-18, 19-60 years patients and also in intensive care unit (ICU patients as compared to out patient department (OPD patients. Resistance rates for amphotericin B, fluconazole, flucytosine, itraconazole, and voriconazole were 2.9%, 5.9%, 0.0%, 4.2% and 2.5%%, respectively. All the strains of C. krusei were found resistant to fluconazole with intermediate sensitivity to flucytosine. Conclusion: Species-level identification of Candida and their antifungal sensitivity testing should be performed to achieve better clinical results.

  15. Macrolide drug interactions: an update.

    Science.gov (United States)

    Pai, M P; Graci, D M; Amsden, G W

    2000-04-01

    To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions. A MEDLINE search (1975-1998) was performed to identify all pertinent studies, review articles, and case reports. When appropriate information was not available in the literature, data were obtained from the product manufacturers. All available data were reviewed to provide an unbiased account of possible drug interactions. Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials. Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. Several clinically significant drug interactions have been identified since the approval of erythromycin. These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs. The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events. The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class. However, this has produced variable success. Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have improved profiles. The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the

  16. The worldwide trend of using botanical drugs and strategies for developing global drugs.

    Science.gov (United States)

    Ahn, Kyungseop

    2017-03-01

    Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with healthenhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development. [BMB Reports 2017; 50(3): 111-116].

  17. Clinical Significance of A Waves in Acute Inflammatory Demyelinating Polyradiculoneuropathy.

    Science.gov (United States)

    Lakshminarasimhan, Sindhuja; Venkatraman, Chandramouleeswaran; Vellaichamy, Kannan; Ranganathan, Lakshminarasimhan

    2018-05-25

    A wave is a late response recognized during recording of F waves. Though they might be seen in healthy subjects, their presence assumes significance in a patient presenting with polyradiculoneuropathy. In this prospective study, 75 patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) were enrolled. They were divided into two groups based on the presence or absence of A waves. Clinical features, electrophysiological parameters and extent of clinical recovery in short-term follow-up were analyzed. A waves were present in 49 out of 75 patients (65%). Most common pattern observed was multiple A waves. Prevalence of A waves was more in lower limb nerves than upper limb nerves. Occurrence of A waves correlated with the presence of conduction block. Patients with A waves had higher Hughes grade (P = 0.003) and lower Medical Research Council sum score at 6 weeks of follow-up (P = 0.04) as compared to patients without A waves. A waves are common in acute inflammatory demyelinating polyradiculoneuropathy form of Guillain Barre syndrome and are considered as a marker of demyelination. Long-term follow-up studies are required to ascertain their significance in prognostication and assessing recovery.

  18. Clinical significance of pretreatment FDG PET/CT IN MOBG-avid pediatric neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Seo Young; Kim, Yong Il; Cheon, Gi Jeong; Kang, Keon Wook; Chung, June Key; Lee, Dong Soo; Kang, Hyoung Jin; Shin, Hee Young [Seoul National University Hospital, Seoul (Korea, Republic of); Kim, E. Edmund [Seoul National University, Seoul (Korea, Republic of); Rahim, Muhammad Kashif [Nishtar Medical College and Hospital, Multan (Pakistan)

    2017-06-15

    {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is well known to have clinical significance in the initial staging and response evaluation of the many kinds of neoplasms. However, its role in the pediatric neuroblastoma is not clearly defined. In the present study, the clinical significance of FDG-PET/computed tomography (CT) in 123I- or 131I-metaiodobenzylguanidine (MIBG)-avid pediatric neuroblastoma was investigated. Twenty patients with neuroblastoma who undertook pretreatment FDG PET/CT at our institute between 2008 and 2015 and showed MIBG avidity were retrospectively enrolled in the present study. Clinical information—including histopathology, and serum markers—and several PET parameters—including SUVmax of the primary lesion (Psuv), target-to-background ratio (TBR), metabolic tumor volume (MTV), and coefficient of variation (CV)—were analyzed. The prognostic effect of PET parameters was evaluated in terms of progression-free survival (PFS). Total 20 patients (4.5 ± 3.5 years) were divided as two groups by disease progression. Six patients (30.0 %) experienced disease progression and one patient (5.0 %) died during follow-up period. There were not statistically significant in age, stage, MYCN status, primary tumor size, serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE), and ferritin level between two groups with progression or no progression. However, Psuv (p = 0.017), TBR (p = 0.09), MTV (p = 0.02), and CV (p = 0.036) showed significant differences between two groups. In univariate analysis, PFS was significantly associated with Psuv (p = 0.021) and TBR (p = 0.023). FDG-PET parameters were significantly related with progression of neuroblastoma. FDG-PET/CT may have the potential as a valuable modality for evaluating prognosis in the patients with MIBG-avid pediatric neuroblastoma.

  19. Effect of European Clinical Trials Directive on academic drug trials in Denmark: retrospective study of applications to the Danish Medicines Agency 1993-2006

    DEFF Research Database (Denmark)

    Berendt, Louise; Hakansson, Cecilia; Bach, Karin Ursula Friis

    2008-01-01

    To determine the impact of the European Union's Clinical Trials Directive on the number of academic drug trials carried out in Denmark.......To determine the impact of the European Union's Clinical Trials Directive on the number of academic drug trials carried out in Denmark....

  20. Prediction of clinical response to drugs in ovarian cancer using the chemotherapy resistance test (CTR-test).

    Science.gov (United States)

    Kischkel, Frank Christian; Meyer, Carina; Eich, Julia; Nassir, Mani; Mentze, Monika; Braicu, Ioana; Kopp-Schneider, Annette; Sehouli, Jalid

    2017-10-27

    In order to validate if the test result of the Chemotherapy Resistance Test (CTR-Test) is able to predict the resistances or sensitivities of tumors in ovarian cancer patients to drugs, the CTR-Test result and the corresponding clinical response of individual patients were correlated retrospectively. Results were compared to previous recorded correlations. The CTR-Test was performed on tumor samples from 52 ovarian cancer patients for specific chemotherapeutic drugs. Patients were treated with monotherapies or drug combinations. Resistances were classified as extreme (ER), medium (MR) or slight (SR) resistance in the CTR-Test. Combination treatment resistances were transformed by a scoring system into these classifications. Accurate sensitivity prediction was accomplished in 79% of the cases and accurate prediction of resistance in 100% of the cases in the total data set. The data set of single agent treatment and drug combination treatment were analyzed individually. Single agent treatment lead to an accurate sensitivity in 44% of the cases and the drug combination to 95% accuracy. The detection of resistances was in both cases to 100% correct. ROC curve analysis indicates that the CTR-Test result correlates with the clinical response, at least for the combination chemotherapy. Those values are similar or better than the values from a publication from 1990. Chemotherapy resistance testing in vitro via the CTR-Test is able to accurately detect resistances in ovarian cancer patients. These numbers confirm and even exceed results published in 1990. Better sensitivity detection might be caused by a higher percentage of drug combinations tested in 2012 compared to 1990. Our study confirms the functionality of the CTR-Test to plan an efficient chemotherapeutic treatment for ovarian cancer patients.

  1. Impact of Drug Metabolism/Pharmacokinetics and Their Relevance upon Taxus-based Drug Development.

    Science.gov (United States)

    Hao, Da-Cheng; Ge, Guang-Bo; Wang, Ping; Yang, Ling

    2018-05-22

    Drug metabolism and pharmacokinetic (DMPK) studies of Taxus natural products, their semi-synthetic derivatives and analogs are indispensable in the optimization of lead compounds and clinical therapy. These studies can lead to development of new drug entities with improved absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiles. To date, there have been no comprehensive reviews of the DMPK features of Taxus derived medicinal compounds.Natural and semi-synthetic taxanes may cause and could be affected by drug-drug interaction (DDI). Hence ADME/T studies of various taxane-containing formulations are important; to date these studies indicate that the role of cytochrome p450s and drug transporters is more prominent than phase II drug metabolizing enzymes. Mechanisms of taxane DMPK mediated by nuclear receptors, microRNAs, and single nucleotide polymorphisms are being revealed. Herein we review the latest knowledge on these topics, as well as the gaps in knowledge of the DMPK issues of Taxus compounds. DDIs significantly impact the PK/pharmacodynamics performance of taxanes and co-administered chemicals, which may inspire researchers to develop novel formula. While the ADME/T profiles of some taxanes are well defined, DMPK studies should be extended to more Taxus compounds, species, and Taxus -involved formulations, which would be streamlined by versatile omics platforms and computational analyses. Further biopharmaceutical investigations will be beneficial tothe translation of bench findings to the clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy

    OpenAIRE

    Pasipanodya, Jotam G.; Srivastava, Shashikant; Gumbo, Tawanda

    2012-01-01

    Laboratory studies have questioned nonadherence as a cause of antituberculosis drug failure and propose that between-patient pharmacokinetic variability may be the cause. This meta-analysis provides clinical evidence that pharmacokinetic variability of isoniazid alone leads to worse microbiological failure, relapse, and acquired drug resistance.