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Multifaceted interventions for improving spontaneous reporting of adverse drug reactions in a general hospital in China.

BMC Pharmacol Toxicol. 2017 Jun 26;18(1):49

Authors: Fang H, Lin X, Zhang J, Hong Z, Sugiyama K, Nozaki T, Sameshima T, Kobayashi S, Namba H, Asakawa T

Abstract
BACKGROUND: The present study investigates changes in spontaneous reporting (SR) compliance and ADR patterns following adoption of a new hospital SR system, and multiple interventions designed for its improvement use under modified drug administration guidelines.
METHODS: In total, 1389 ADR cases were reviewed. Cases were divided into two groups, cases from period 1 (n = 557, from January 2006 to June 2011) under the old SR system and cases in period 2 (n = 832, from July 2011 to December 2016) under the new SR system with multiple interventions to improve physician SR compliance. General information, drug information, and clinical manifestations were investigated and compared between periods.
RESULTS: Interventions for improved clinician training, education on knowledge, attitudes, and practices (KAP), and economic incentives substantially improved SR adherence. We also found that changing drug usage patterns (based on the new drug administration guidelines) greatly influenced ADR occurrence and type.
CONCLUSIONS: We found the SR compliance can be improved by multifaceted interventions. Drug usage patterns also influence ADR occurrence, so programs tailored for rational use are essential. These results could lead to further improvements in the SR system for ADRs in China, and provide guidance for establishing better methods of pharmacovigilance.

PMID: 28651624 [PubMed - indexed for MEDLINE]

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How do smoking cessation medicines compare with respect to their neuropsychiatric safety? A protocol for a systematic review, network meta-analysis and cost-effectiveness analysis.

BMJ Open. 2017 Jun 17;7(6):e015414

Authors: Thomas KH, Caldwell D, Dalili MN, Gunnell D, Munafò MR, Stevenson M, Welton NJ

Abstract
INTRODUCTION: Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis.
METHODS AND ANALYSIS: We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (τ2). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model.
ETHICS AND DISSEMINATION: Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost-effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers.
PROSPERO REGISTRATION NUMBER: CRD42016041302.

PMID: 28624760 [PubMed - indexed for MEDLINE]

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

BMC Pharmacol Toxicol. 2017 Jun 08;18(1):44

Authors: Liu R, AbdulHameed MDM, Kumar K, Yu X, Wallqvist A, Reifman J

Abstract
BACKGROUND: The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects.
METHOD: We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles.
RESULTS: We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs 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.
CONCLUSION: 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.

PMID: 28595649 [PubMed - indexed for MEDLINE]

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Repeated "Day 1" FOB testing in ICH S7A safety assessment protocols: The influence of within- and between-session learning.

J Pharmacol Toxicol Methods. 2017 May - Jun;85:61-72

Authors: Gauvin DV, Zimmermann ZJ, Dalton JA, Baird TJ

Abstract
A large number of CNS safety assessment studies using the standard Functional Observational Battery (FOB) are conducted each year at Contract Research Organizations throughout the globe. Study design characteristics are as varied as the Sponsors for whom they are contracted. Gender inclusion, sample sizes, and timing of the FOBs are generally negotiated during protocol development. The ICH S7A guidelines describe a dose-effect study design for CNS safety assessment to be conducted prior to the first dose administration in man. Additionally, some Sponsors attempt to use the CNS safety FOB to establish both time- and dose-related acute behavioral effects of their compound in this single critical safety study. In this review, we highlight the confounding influences of multiple postdose FOBs (Day 1) versus the more standard, single FOB scheduled near systemic Cmax of the compound. Within- and between-session learning, combined with changes in vigilance/alertness/fatigue in both the animals and raters, can limit the generalizability of the FOB to accurately assess CNS effects under the current guidelines. Rationale is provided as to the tenuous nature of conducting simultaneous time- and dose-effect behavioral assessments as part of the core safety pharmacology programs.

PMID: 28216425 [PubMed - indexed for MEDLINE]

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Trigger factors of cutaneous lupus erythematosus: a review of current literature.

Lupus. 2017 Jul;26(8):791-807

Authors: Szczęch J, Samotij D, Werth VP, Reich A

Abstract
It is currently believed that autoimmune conditions are triggered and aggravated by a variety of environmental factors such as cigarette smoking, infections, ultraviolet light or chemicals, as well as certain medications and vaccines in genetically susceptible individuals. Recent scientific data have suggested a relevant role of these factors not only in systemic lupus erythematosus, but also in cutaneous lupus erythematosus (CLE). A variety of environmental factors have been proposed as initiators and exacerbators of this disease. In this review we focused on those with the most convincing evidence, emphasizing the role of drugs in CLE. Using a combined search strategy of the MEDLINE and CINAHL databases the following trigger factors and/or exacerbators of CLE have been identified and described: drugs, smoking, neoplasms, ultraviolet radiation and radiotherapy. In order to give a practical insight we emphasized the role of drugs from various groups and classes in CLE. We also aimed to present a short clinical profile of patients with lesions induced by various drug classes.

PMID: 28173739 [PubMed - indexed for MEDLINE]

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Efficacy of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting: a meta-analysis.

Br J Clin Pharmacol. 2017 Jul;83(7):1369-1379

Authors: Yang T, Liu Q, Lu M, Ma L, Zhou Y, Cui Y

Abstract
AIM: The aim of the present study was to evaluate the efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV).
METHODS: The literature was searched for randomized controlled trials (RCTs) evaluating the efficacy of olanzapine for the prophylaxis of CINV using PubMed, Embase, Central, as well as clinicaltrials.gov for unpublished studies. The endpoints of the study were the number of patients who achieved a complete response (CR; no emesis and no rescue) and no nausea in the acute, delayed and overall phases. Two authors independently selected studies, assessed the risk of bias and extracted data. The included RCTs were analysed using RevMan 5.3 provided by the Cochrane Collaboration.
RESULTS: Ten RCTs were identified for the meta-analysis. Compared with other antiemetic agents, olanzapine significantly improved the CR in the delayed and overall phases, but did not enhance the CR in the acute phase. For the control of CINV, olanzapine was better than and comparable with aprepitant in the acute phase and delayed phase, respectively. Compared with placebo, treatment with 5 mg and 10 mg olanzapine exhibited similar efficacy in terms of the CR in the delayed and overall phases.
CONCLUSIONS: Olanzapine is an excellent alternative for the prophylaxis of CINV. Olanzapine 5 mg per day should be recommended as the initial dose because of equivalent efficacy to a 10 mg dose but a lower potential risk of side effects. Further studies are needed to explore the optimal combination of medicines.

PMID: 28112422 [PubMed - indexed for MEDLINE]

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The northeast regional SPS meeting update: Safety pharmacology innovations and applications.

J Pharmacol Toxicol Methods. 2017 May - Jun;85:82-86

Authors: Pannirselvam M, Brabham T, Botchway AW, Hodges DB, Traebert M, Pugsley MK

Abstract
The Safety Pharmacology Society (SPS) held a Northeast (NE) regional meeting in Boston, MA on May 13, 2016 at the Vertex Pharmaceuticals Incorporated site. There were 103 attendees from the pharmaceutical industry, contract research organizations (CROs), academia, and global regulatory agencies. An assortment of scientific topics were presented by 7 speakers that included broad topics in the cardiovascular (organ on chip, statistical power and translation of rat cardiovascular telemetry data and dual inhibition of IKr and IKs on QT interval prolongation) and central nervous system (in vitro platform for neurotoxicity, an integrated risk assessment of suicidal ideation and behavior, and EEG advances in safety pharmacology) and a novel topic discussing preclinical challenges faced in the development of a novel gene therapy. A highlight of the meeting was an in-depth discussion on the fatty acid acyl hydrolase (FAAH) inhibitor BIA 10-2474 which involved a comprehensive overview of the biology and pharmacology of FAAH followed by a presentation from the Biotrial (Rennes, France) team that conducted the clinical trial. An additional poster session was held that included 13 fascinating posters on cutting edge safety pharmacology topics.

PMID: 27913272 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-CA-18-021 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites revision applications from investigators with active NCI R01 research grants. These revision applications are expected to focus on research related to one of the 12 of the NCI's Provocative Questions (PQs) published for new applications in RFA-CA-18-019 (R01) and RFA-CA-18-020 (R21) . This FOA encourages research that directly addresses PQs, including research that helps validate PQ research outcomes or adopt and disseminate PQ research results that impact cancer research and clinical care. Studies proposed in the revision applications must correspond to additional specific aims, expanding the scope of individual, already funded projects of the parent R01 award.

Funding Opportunity RFA-CA-18-022 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites revision applications from investigators with active NCI U01 research grants. These revision applications are expected to focus on research related to one of the 12 of the NCI's Provocative Questions (PQs) published for new applications in RFA-CA-18-019 (R01) and RFA-CA-18-020 (R21) . This FOA encourages research that directly addresses PQs, including research that helps validate PQ research outcomes or adopt and disseminate PQ research results that impact cancer research and clinical care. Studies proposed in the revision applications must correspond to additional specific aims, expanding the scope of individual, already funded projects of the parent U01 award.

Funding Opportunity RFA-CA-18-024 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites revision applications from investigators with active NCI P50 research grants. These revision applications are expected to focus on research related to one of the 12 of the NCI's Provocative Questions (PQs) published for new applications in RFA-CA-18-019 (R01) and RFA-CA-18-020 (R21) . This FOA encourages research that directly addresses PQs, including research that helps validate PQ research outcomes or adopt and disseminate PQ research results that impact cancer research and clinical care. Studies proposed in the revision applications must correspond to additional specific aims, expanding the scope of individual, already funded projects of the parent P50 award.

Funding Opportunity RFA-CA-18-023 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites revision applications from investigators with active NCI P01 research grants. These revision applications are expected to focus on research related to one of the 12 of the NCI's Provocative Questions (PQs) published for new applications in RFA-CA-18-019 (R01) and RFA-CA-18-020 (R21) . This FOA encourages research that directly addresses PQs, including research that helps validate PQ research outcomes or adopt and disseminate PQ research results that impact cancer research and clinical care. Studies proposed in the revision applications must correspond to additional specific aims, expanding the scope of individual, already funded projects of the parent P01 award.

Notice NOT-CA-18-060 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-742 from the NIH Guide for Grants and Contracts. The purpose of this initiative is to encourage research that investigates the role of molecular epigenetic or non-coding RNA regulatory pathways in the development or maintenance of chronic pain. Ultimately research in the area will provide foundational knowledge that can be exploited to develop novel and non-addictive pain medications.

Funding Opportunity PA-18-741 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages R21 applications that propose to conduct secondary analyses of existing data sets relevant to diabetes and selected endocrine and metabolic diseases including thyroid, parathyroid and Cushings diseases and acromegaly; and genetic metabolic disease including cystic fibrosis, lysosomal storage diseases, and disorders of the urea cycle, amino acid metabolism and metal transport where the focus is on peripheral metabolism or organ function; obesity, liver diseases, alimentary GI tract diseases and nutrition; kidney, urologic, and hematologic diseases. The goal of this program is to facilitate research that explores innovative hypotheses through the use of existing data sets or data, for which the primary goal is data analysis and not preparation/presentation of data.

Funding Opportunity RFA-RM-18-011 from the NIH Guide for Grants and Contracts. The overarching goal of this FOA is to add informatics capabilities to the Common Fund program, Illuminating the Druggable Genome (IDG; https://commonfund.nih.gov/idg/index). The IDG consortium's purpose is to facilitate the unveiling of the functions of selected understudied proteins in the Druggable Genome using experimental and informatics approaches. Currently, this research consortium is composed of multiple Data and Resource Generation Centers (DRGCs), a Knowledge Management Center (KMC), and a Resource Dissemination and Outreach Center (RDOC). The purpose of this specific FOA is to solicit applications to build a set of Cutting Edge Informatics Tools (CEITs) that will augment the capability of the KMC as well as the broader IDG Consortium in two ways: (1) by deploying tools to enhance the communitys ability to process, analyze, visualize data, to prioritize new data resources and methods to be incorporated into Pharos that will strengthen predictions about physiological and disease associations around the understudied proteins and (2) to prioritize physiological and disease relevant cellular and animal models for further study of the understudied proteins (non-olfactory GPCRs, protein kinases, and ion channels) both within the IDG program and by the larger community.

Funding Opportunity PAR-18-740 from the NIH Guide for Grants and Contracts. This FOA encourages applications for the Lasker Clinical Research Scholars Program for the purpose of supporting the research activities during the early stage careers of independent clinical researchers. The program offers the opportunity for a unique bridge between the NIH intramural and extramural research communities and contains two phases. In the first phase, Lasker scholars will receive appointments for up to 5-7 years as tenure-track investigators within the NIH Intramural Research Program with independent research budgets. In the second phase, successful scholars will receive up to 3 years of NIH support for their research at an extramural research facility; or, the scholar can be considered to remain as an investigator within the intramural program

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