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Drug Safety
Journal Prestige (SJR): 1.447
Citation Impact (citeScore): 3
Number of Followers: 124  
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ISSN (Print) 0114-5916 - ISSN (Online) 1179-1942
Published by Adis Homepage  [21 journals]
  • Safety Profile of Benznidazole in the Treatment of Chronic Chagas Disease:
           Experience of a Referral Centre and Systematic Literature Review with
    • Abstract: Introduction Benznidazole is the preferred drug for treatment of Chagas disease. However, it is toxic and of limited value in chronic infection. Objective We aimed to estimate the rates of and factors related to adverse reactions (ARs) to benznidazole and treatment discontinuations (TDs). Methods A meta-analysis was performed using an electronic search of the published literature with no language restrictions until June 2017. Prospective studies were included of chronically infected patients in which at least one treatment arm included benznidazole. Data were added from a prospective cohort of patients with Chagas disease at our centre (January 2007–June 2017). Weighted rates of ARs and TDs were estimated, and potentially related factors were analysed. Results Some 413 studies were found, from which we chose 42 (nine clinical trials and 33 observational studies, including ours), comprising data for 7822 patients. The weighted rate of ARs to benznidazole was 44.1% (95% confidence interval [CI] 37.2–51.2). ARs were more frequent in adults than in children (51.6 vs. 24.5%), with the most common being skin reactions (34%), gastrointestinal complaints (12.6%) and neurological symptoms (11.5%). Grade 4 ARs were recorded in 3% of cases. The weighted rate of TDs was 11.4% (95% CI 8.5–14.5); TDs were more frequent in adults than in children (14.2 vs. 3.8%). In our cohort, only female sex was related to an increased rate of ARs but not to TDs. Conclusion Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women. Optimised dosing schedules and/or new drugs are urgently needed.
      PubDate: 2018-07-13
  • Changes in Outpatient Use of Antibiotics by Adults in the United States,
    • Abstract: Introduction Numerous initiatives over the past decade have targeted the problem of antibiotic overuse in the US; however, the cumulative impact of such initiatives upon recent patterns of use is not known. Objectives The aims of this study were to (1) describe general trends in outpatient antibiotic use among adults over the period 2006–2015; and (2) identify rapid shifts in use during this time period as potential indicators for key events. Methods This was an observational study set in the ambulatory setting. Patients ≥ 18 years of age were selected from the Optum Clinformatics Datamart™, a commercial insurance claims database. The outcome measures of interest were prescriptions filled/1000 enrolled individuals, by year or quarter. We used linear regression to identify trends in use over multiple years, and change-point regression to identify rapid shifts in use within individual years. Results From 2006 to 2015, antibiotic use declined significantly, decreasing by 12% for adults younger than 65 years of age (913–807 prescriptions/1000 individuals, p = 0.0001) and by 5% for adults ≥ 65 years of age (991–943 prescriptions/1000 individuals, p = 0.018). With change-point regression, we identified a number of rapid shifts in the use of specific antibiotic classes, such as downward shifts in the use of quinolones and macrolides during the second quarter of 2008 and 2013, respectively. Conclusions Over the period 2006–2015 outpatient use of antibiotics decreased substantially among adults. Rapid shifts in use occurring in 2008 and 2013 may reflect the presence of key drivers of change, such as abrupt changes in access to care or perceived antibiotic safety.
      PubDate: 2018-07-09
  • Sex Differences in Reported Adverse Drug Reactions of Selective Serotonin
           Reuptake Inhibitors
    • Abstract: Introduction Several studies have investigated sex as a risk factor for the occurrence of adverse drug reactions (ADRs) and found that women are more likely to experience ADRs than men. Objective The aim of this explorative study was to investigate whether differences exist in reported ADRs of selective serotonin reuptake inhibitors (SSRIs) for men and women in the database of the Netherlands Pharmacovigilance Centre Lareb. Methods A ratio of reports concerning women and men, corrected for the number of users, was calculated for all the ADRs reported on SSRIs. Results We found that 16 ADRs were statistically significantly more reported in women than men, and four ADRS were reported more in men than women. Conclusion ADRs more reported in women than men when using SSRIs were usually dose-related ADRs or commonly occurring ADRs. Differences in the pharmacokinetics of SSRIs between men and women may explain why these reports of dose-related ADRs when using SSRIs concern women more than men.
      PubDate: 2018-07-01
  • Glucocorticoids and the Risk of Peptic Ulcer Bleeding: Case–Control
           Analysis Based on Swiss Claims Data
    • Abstract: Introduction Controversy exists as to whether glucocorticoids (GC) are ulcerogenic per se and may thus cause peptic ulcer bleeding (PUB) independent of concomitantly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Objective To investigate the association between GC use and PUB with or without co-medication with NSAIDs. Methods We conducted a case–control study using administrative claims data from the Swiss health insurance company Helsana. We identified 1191 cases with incident PUB between 2012 and 2016 and matched up to 10 PUB-free controls to each case on age, sex, region and number of years insured with Helsana. We compared prior GC exposure between cases and controls using multivariate conditional logistic regression analyses controlling for several potential confounders. Patients with or without concomitant NSAID exposure were analysed separately. Results Patients with prior exposure to both GC and NSAIDs were five times more likely to experience PUB than patients who neither used GC nor NSAIDs (adjusted odds ratio [adj. OR] 4.80, 95% CI 3.55–6.71). Although the risk of PUB among patients who used NSAIDs without GC was increased threefold (adj. OR 3.20, 95% CI 2.59–3.95), we observed only a moderately increased risk among patients who used GC alone without NSAIDs (adj. OR 1.63, 95% CI 1.20–2.42). Conclusions The use of NSAIDs with or without GC was associated with a markedly higher risk of PUB compared with GC monotherapy. Use of GC alone was associated with a moderately increased risk of PUB, which might be causal or attributed to confounding by indication.
      PubDate: 2018-07-01
  • Interest in a Mobile App for Two-Way Risk Communication: A Survey Study
           Among European Healthcare Professionals and Patients
    • Abstract: Introduction Previously, an app has been developed for healthcare professionals (HCPs) and patients to report adverse drug reactions (ADRs) to national medicines agencies and to receive drug safety information. Objective This study aimed to assess (1) European HCPs’ and patients’ interest in an app for this two-way risk communication; (2) their preferences and perceptions towards specific app characteristics; and (3) which HCPs and patients are particularly interested in the app. In addition, these aspects were studied specifically for the countries where such an app was already available, i.e. Croatia, The Netherlands, and The UK. Methods European HCPs and patients were asked to complete a web-based survey developed in the context of the Web-Recognizing Adverse Drug Reactions (Web-RADR) project. Data on app interest and preferences and perceptions towards app characteristics were analysed descriptively. Logistic regression analyses were conducted to assess the association of HCP characteristics and patient characteristics on the level of interest in the app (i.e. very interested vs. not/somewhat interested). Results In total, 399 HCPs and 656 patients completed the survey. About half of the patients (48%; ranging from 38% from The Netherlands to 54% from The UK), and 61% of the HCPs (ranging from 42% from The Netherlands to 54% from The UK) were very interested in the app. A faster means of reporting ADRs and easier access to the reporting form were the main perceived benefits. HCPs and patients who already use a health app were particularly interested in the app (HCPs: odds ratio [OR] 3.52; 95% confidence interval [CI] 1.96–6.30, patients: OR 1.64; 95% CI 1.19–2.27). Conclusions An app is positively perceived by HCPs and patients for reporting ADRs quickly and for receiving drug safety information from national medicines agencies. In particular, HCPs and patients who already use other health apps were interested in the app.
      PubDate: 2018-07-01
  • Safety Communication Tools and Healthcare Professionals’ Awareness of
           Specific Drug Safety Issues in Europe: A Survey Study
    • Abstract: Introduction National competent authorities (NCAs) use Direct Healthcare Professional Communications (DHPCs) to communicate new drug safety issues to healthcare professionals (HCPs). More knowledge is needed about the effectiveness of DHPCs and the extent to which they raise awareness of new safety issues among HCPs. Objective The objective was to assess and compare general practitioners’ (GPs’), cardiologists’, and pharmacists’ familiarity with DHPCs as communication tools, their awareness of specific drug safety issues, and the sources through which they had become aware of the specific issues. Methods GPs, cardiologists, and pharmacists from nine European countries (Croatia, Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the UK) completed a web-based survey. The survey was conducted in the context of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Respondents were asked about their familiarity with DHPCs in general and their awareness of safety issues that had recently been communicated and involved the following drugs: combined hormonal contraceptives, diclofenac, valproate, and ivabradine. Those HCPs who were aware of the specific safety issues were subsequently asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a Pearson χ2 test per country and post hoc Pearson χ2 tests in the case of statistically significant differences. Results Of the 3288 included respondents, 54% were GPs, 40% were pharmacists, and 7% were cardiologists. The number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with DHPCs, with one significant difference between the professions: pharmacists were more familiar than GPs in Italy (99 vs 90%, P = 0.004). GPs’ awareness ranged from 96% for the diclofenac issue to 70% for the ivabradine issue. A similar pattern was shown for pharmacists (91% aware of the diclofenac issue to 66% of the ivabradine issue). Cardiologists’ awareness ranged from 91% for the ivabradine issue to 34% for the valproate issue. Overall, DHPCs were a common source through which GPs (range: 45% of those aware of the contraceptives issue to 60% of those aware of the valproate issue), cardiologists (range: 33% for the contraceptives issue to 61% for the valproate issue), and pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the specific safety issues, followed by information on websites or in newsletters. Conclusions GPs, cardiologists, and pharmacists were to a similar extent (highly) familiar with DHPCs, but they differed in awareness levels of specific safety issues. Cardiologists were less aware of safety issues associated with non-cardiology drugs even if these had cardiovascular safety concerns. This implies that additional strategies may be needed to reach specialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their field of specialisation. DHPCs were an important source for the different professions to become aware of specific safety issues, but other sources were also often used. NCAs should consider the use of a range of sources when communicating important safety issues to HCPs.
      PubDate: 2018-07-01
  • Using the Symmetry Analysis Design to Screen for Adverse Effects of
           Non-vitamin K Antagonist Oral Anticoagulants
    • Abstract: Introduction Knowledge on adverse effects (AEs) related to non-vitamin K antagonist oral anticoagulants (NOACs) in real-world populations is sparse. Objective Our objective was to identify signals of potential AEs in patients with atrial fibrillation (AF) initiating NOAC treatment using a hypothesis-free screening approach. Methods Using the nationwide Danish registries, we identified patients with AF initiating dabigatran, rivaroxaban, or apixaban between 2011 and 2015 (n = 50,627). Applying a symmetry analysis design, we screened for AEs of NOAC, as reflected by new drug treatments, incident diagnoses, or procedures. For signals with the lowest number needed for one additional patient to be harmed (NNTH), we evaluated whether they likely represented genuine AEs or other types of associations. Signals assessed as potential AEs were grouped into five categories for analysis of effect modification according to patient and drug characteristics. Results Of the identified signals, 61 were classified as potential AEs. Most signals could be categorized as the following types of AEs: bleedings, non-bleeding gastrointestinal symptoms, mental disease, urinary tract disorders, and musculoskeletal symptoms. Older age and first-ever use of anticoagulants was associated with strengthening of all “NOAC-adverse effect” associations. Conversely, use of low-dose NOAC and apixaban led to attenuation of most associations. Conclusion Through a symmetry analysis-based hypothesis-free screening of large-scale healthcare databases, we were able to confirm well-established AEs of NOAC therapy in clinical practice as well as potential AEs that deserve further investigation.
      PubDate: 2018-07-01
  • Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac
           Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring
    • Abstract: Currently, there is a lack of international and national guidelines or consensus documents with specific recommendations for electrocardiogram (ECG) screening and monitoring during antidepressant treatment. To make a proper estimation of the risk of cardiac arrhythmias and sudden (cardiac) death during antidepressant use, both the drug and patient-specific factors should be taken into account; however, solid evidence on how this should be done in clinical practice is lacking. Available recommendations on the management of QT(c) prolongation (with antidepressant treatment) emphasize that special attention should be given to high-risk patients; however, clinicians are in need of more concrete suggestions about how to select patients for ECG screening and monitoring. Based on a review of the literature, a Dutch multidisciplinary expert panel aimed to formulate specific guidelines to identify patients at risk for cardiac arrhythmias and sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepressant use. These relative contributions of risk factors could not be determined since no systematic reviews or meta-analyses quantitatively addressed this topic. Because evidence was insufficient, additional expert opinion was used to formulate recommendations. This resulted in readily applicable recommendations for clinical practice for selection of high-risk patients for ECG screening and monitoring. ECG screening and monitoring is recommended before and following the start of QTc-prolonging antidepressants in the presence of vulnerability to QTc prolongation or two or more risk factors (age > 65 years, female sex, concomitant use of a QTc-prolonging drug or concomitant use of a drug that influences the metabolism of a QTc-prolonging drug, cardiac disease, excessive dosing and specific electrolyte disturbances).
      PubDate: 2018-07-01
  • Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid
           Arthritis: How Real is the Risk'
    • Abstract: Two different Janus kinase (JAK) inhibitors—baricitinib and tofacitinib—are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities.
      PubDate: 2018-07-01
  • EudraVigilance Medicines Safety Database: Publicly Accessible Data for
           Research and Public Health Protection
    • Abstract: The analysis of safety data from spontaneous reporting systems has a proven value for the detection and analysis of the risks of medicines following their placement on the market and use in medical practice. EudraVigilance is the pharmacovigilance database to manage the collection and analysis of suspected adverse reactions to medicines authorised in the European Economic Area. EudraVigilance first operated in December 2001, with access to the database being governed by the EudraVigilance access policy. We performed a literature search including data up to December 2016 to demonstrate how the data from EudraVigilance has been used in scientific publications. We describe the results, including by type of publication, research topics and drugs involved. In 50% of the publications, the data are used to describe safety issues, in 44% to analyse methodologies used in pharmacovigilance activities and in 6% to support clinical perspectives. We also outline a description of the use of the database by the European Union regulatory network. Driven by the full implementation of the 2010 pharmacovigilance legislation, EudraVigilance has undergone further enhancements together with a major revision of its access policy, taking into account the use of the new individual case safety report standard developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and the International Organization for Standardization. The aim of the broadened access is to facilitate more effective safety monitoring of authorised medicines, to make more data available for research and to provide better access to information on suspected adverse reactions for healthcare professionals and patients. In November 2017, the new full functionalities of EudraVigilance were launched, including the extensive web access to data on suspected adverse drug reactions and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research. The main objective of this article is to describe the new access to the database together with the opportunities that this new access can bring for research. It is intended to promote an appropriate use of the data to support the safe and effective use of medicines.
      PubDate: 2018-07-01
  • Authors’ Response to Silverman and Colleagues’ Comment on “Review of
           Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone
           for Opioid Dependence”
    • PubDate: 2018-06-28
  • Comment on “Review of Case Narratives from Fatal Overdoses Associated
           with Injectable Naltrexone for Opioid Dependence”
    • PubDate: 2018-06-28
  • Gabapentin and Pregabalin and Risk of Atrial Fibrillation in the Elderly:
           A Population-Based Cohort Study in an Electronic Prescription Database
    • Abstract: Introduction Gabapentin and pregabalin are widely prescribed to elderly people, but data on their pharmacokinetics, safety, and efficacy in this population are scarce. Neurological adverse effects are common. Atrial fibrillation (AF) associated with their use has been described in several case reports and case series, but the incidence is unknown. Objective The aim of this study was to assess the association between exposure to gabapentin or pregabalin and AF in the elderly. Methods Patients ≥ 65 years of age starting treatment with either gabapentin or pregabalin between January 1 and March 31, 2015, free of cardiovascular disease, and who did not receive the alternate study medications were studied. They were compared with patients who initiated treatment with an analgesic opiate or with alprazolam or diazepam. The two primary outcome variables were a first claim of an oral anticoagulant plus an antiarrhythmic drug (OAC + AA), or of an oral anticoagulant or an antiplatelet agent plus an antiarrhythmic drug (OAC/APA + AA), in the 3 months after treatment initiation. Results Compared with opiate analgesics, both gabapentin and pregabalin were associated with an increased risk of initiating OAC/APA + AA. The incidence was 6 of 668 (9.0 per 1000 patients) with gabapentin, versus 12 of 3889 (3.1 per 1000) with opiates, relative risk (RR) 2.91 (95% confidence interval [CI] 1.10–7.73), and for pregabalin it was 6 of 698 (8.6 per 1000) RR 2.79 (95% CI 1.05–7.40). The comparison with alprazolam/diazepam gave similar results. The risks did not vary by age, sex, or co-treatment with NSAIDs, and they increased with dose. Conclusion In elderly patients free of cardiovascular disease, an association between new exposure to gabapentin or pregabalin and initiating treatment for AF was found. These results should be confirmed in other studies.
      PubDate: 2018-06-28
  • Role of Serotonin Transporter in Antidepressant-Induced Diabetes Mellitus:
           A Pharmacoepidemiological–Pharmacodynamic Study in VigiBase ®
    • Abstract: Background The association between antidepressant exposure and type 2 diabetes mellitus is still debated. Moreover, the pharmacological mechanisms remain unknown. Objective The objective of this study was to investigate this putative relationship with the role of antidepressant pharmacological targets using the ‘pharmacoepidemiological–pharmacodynamic’ method. Methods First, we performed case/non-case analyses in VigiBase® (the World Health Organization international database of suspected adverse drug reactions) to examine a signal of increased type 2 diabetes reporting (expressed as the reporting odds ratio and its 95% confidence interval) for antidepressants in general; examine and rank type 2 diabetes signals between the different pharmacological classes of antidepressants and the different antidepressants (58 in total). Second, we performed linear regression analyses to explore the association between the type 2 diabetes signal ranked between antidepressants and their binding affinities for nine targets (serotonin, norepinephrine, dopamine transporters, 5-HT2C serotonin, D2 dopamine, α1, α2 adrenergic, M3 muscarinic and H1 histamine receptors). Results A significant type 2 diabetes signal was found for antidepressants in general, three classes of antidepressants (tricyclic antidepressants, serotonin reuptake inhibitors and “other” antidepressants) and 15 individual antidepressants in particular. Among the antidepressants, three serotonin reuptake inhibitors [escitalopram (adjusted reporting odds ratio 1.15 [1.07–1.25]), paroxetine (1.15 [1.07–1.23]), sertraline (1.23 [1.17–1.31])] and three “other” antidepressants [duloxetine (1.15 [1.07–1.23]), trazodone (1.20 [1.09–1.32]), venlafaxine (1.15 [1.08–1.23])] were the antidepressants most frequently reported with type 2 diabetes. We found a significant correlation between the type 2 diabetes signal and serotonin transporter affinity (slope = 0.14 [0.06–0.23], p = 0.003, R2 = 0.43) but not the other targets. Conclusion The present study suggests a potential role for serotonin transporter in antidepressant-induced type 2 diabetes.
      PubDate: 2018-06-28
  • What Future Healthcare Professionals Need to Know About Pharmacovigilance:
           Introduction of the WHO PV Core Curriculum for University Teaching with
           Focus on Clinical Aspects
    • Abstract: Adverse drug reactions (ADRs) can cause serious health problems, as shown in studies about drug-related hospitalizations. To build knowledge of and raise awareness about ADRs among healthcare professionals, more education in the field of ADRs and pharmacovigilance (PV) is needed. No standard exists for teaching PV at universities for medical, pharmacy, dentistry and nursing students, so a core curriculum needs to be developed to teach important aspects of PV to students. In September 2016, a stakeholders’ meeting was initiated on behalf of the World Health Organization (WHO) and organized by the Netherlands Pharmacovigilance Centre Lareb. This meeting addressed and agreed on the PV competencies students need to develop and what key aspects of the subject should be taught. Five key aspects were identified: understanding the importance of PV in the context of pharmacotherapy, and preventing, recognizing, managing and reporting ADRs. Since time and resources for PV education are limited, elements of the WHO PV core curriculum for university teaching were designed to be integrated into existing courses but can be used as a stand-alone programme. The basis of and outline for the WHO PV core curriculum for university teaching are addressed in this paper. It is expected that PV competencies for students are vital for their contribution to safe use of medicines in the future. In addition, this article aims to stimulate discussion on this subject and promote collaboration between universities, national PV centres and other stakeholders to integrate key aspects of PV in their educational programmes.
      PubDate: 2018-06-13
  • MOdified NARanjo Causality Scale for ICSRs (MONARCSi): A Decision Support
           Tool for Safety Scientists
    • Abstract: Introduction Within the field of Pharmacovigilance, the most common approaches for assessing causality between a report of a drug and a corresponding adverse event are clinical judgment, probabilistic methods and algorithms. Although multiple methods using these three approaches have been proposed, there is currently no universally accepted method for assessing drug-event causality in ICSRs and variability in drug-event causality assessments is well documented. Objective This study describes the development and validation of an Individual Case Safety Report (ICSR) Causality Decision Support Tool to assist Safety Professionals (SPs) performing causality assessments. Methods Roche developed this model with nine drug-event pair features capturing important aspects of Naranjo’s scoring system, selected Bradford–Hill criteria, and internal Roche safety practices. Each of the features was weighted based on individual safety professional (n = 65) assessments of the importance of that feature when assessing causality, using an ordinal weighting scale (0 = no importance, 4 = very high importance). The mean and associated standard deviation for each feature weight was calculated and were used as inputs to a fitted logistic equation, which calculated the probability of a causal relationship between the drug and adverse event. Model training, validation, and testing were conducted by comparing MONARCSi causality classifications to previous company causality assessments for 978 randomly selected, clinical trial drug-event pairs based on their respective features and weights. Results The final model test, a two-by-two comparison of the results, showed substantial agreement (Gwet Kappa = 0.77) between MONARCSi and Roche safety professionals’ assessments of causality, using global introspection. The model exhibited moderate sensitivity (65%) and high specificity (93%), high positive and negative predictive values (79 and 88%, respectively), and an F1 score of 71%. Conclusion Analysis suggests that the MONARCSi model could potentially be a useful decision support tool to assist pharmacovigilance safety professionals when evaluating drug-event causality in a consistent and documentable manner.
      PubDate: 2018-06-06
  • Predicting Adverse Drug Effects from Literature- and Database-Mined
    • Abstract: Introduction Given that adverse drug effects (ADEs) have led to post-market patient harm and subsequent drug withdrawal, failure of candidate agents in the drug development process, and other negative outcomes, it is essential to attempt to forecast ADEs and other relevant drug–target–effect relationships as early as possible. Current pharmacologic data sources, providing multiple complementary perspectives on the drug–target–effect paradigm, can be integrated to facilitate the inference of relationships between these entities. Objective This study aims to identify both existing and unknown relationships between chemicals (C), protein targets (T), and ADEs (E) based on evidence in the literature. Materials and Methods Cheminformatics and data mining approaches were employed to integrate and analyze publicly available clinical pharmacology data and literature assertions interrelating drugs, targets, and ADEs. Based on these assertions, a C–T–E relationship knowledge base was developed. Known pairwise relationships between chemicals, targets, and ADEs were collected from several pharmacological and biomedical data sources. These relationships were curated and integrated according to Swanson’s paradigm to form C–T–E triangles. Missing C–E edges were then inferred as C–E relationships. Results Unreported associations between drugs, targets, and ADEs were inferred, and inferences were prioritized as testable hypotheses. Several C–E inferences, including testosterone → myocardial infarction, were identified using inferences based on the literature sources published prior to confirmatory case reports. Timestamping approaches confirmed the predictive ability of this inference strategy on a larger scale. Conclusions The presented workflow, based on free-access databases and an association-based inference scheme, provided novel C–E relationships that have been validated post hoc in case reports. With refinement of prioritization schemes for the generated C–E inferences, this workflow may provide an effective computational method for the early detection of potential drug candidate ADEs that can be followed by targeted experimental investigations.
      PubDate: 2018-06-06
  • Authors’ Reply to: Tomoyuki Kawada’s Comment on: “All-Cause and
           Drug-Related Medical Events Associated with Overuse of Gabapentin and/or
           Opioid Medications: A Retrospective Cohort Analysis of a Commercially
           Insured US Population’’
    • PubDate: 2018-06-01
  • Gastrointestinal Perforations with Biologics in Patients with Rheumatoid
           Arthritis: Implications for Clinicians
    • Abstract: Gastrointestinal (GI) perforations are rare events in rheumatoid arthritis (RA) patients, but cause significant morbidity and mortality. Several studies indicate that RA patients may be at higher risk of GI perforation. Traditional RA treatments such as glucocorticoids and non-steroidal anti-inflammatory drugs increase the risk of perforation. In the past two decades, a new class of therapeutic agents called biologics has been added to the RA treatment armamentarium. Biologics are effective in controlling disease activity and are generally well tolerated; however, reports of GI perforations in association with biologics have arisen. In particular, drugs that inhibit the interleukin (IL)-6 cytokine receptor have demonstrated a higher risk of perforation compared with other therapies. Recent reports also suggest that janus kinase inhibitors may increase the risk of perforation, perhaps via downstream effects on IL-6 signaling. In this review, we discuss current data on the risk of GI perforations among RA patients receiving targeted therapies and its clinical relevance.
      PubDate: 2018-06-01
  • Evidence-Based Recommendations to Improve the Safe Use of Drugs in
           Patients with Liver Cirrhosis
    • Abstract: Introduction The presence of liver cirrhosis can have a major impact on pharmacodynamics and pharmacokinetics, but guidance for prescribing is lacking. Objective The aim of this study is to provide an overview of evidence-based recommendations developed for the safe use of drugs in liver cirrhosis. Methods Recommendations were based on a systematic literature search combined with expert opinion from a panel of 10 experts. The safety of each drug was classified as safe, no additional risks known, additional risks known, unsafe, unknown or the safety class was dependent on the severity of liver cirrhosis (Child–Pugh classification). If applicable, drug-specific dosing advice was provided. All recommendations were implemented in clinical decision support systems and on a website. Results We formulated 218 recommendations for a total of 209 drugs. For nine drugs, two recommendations were formulated for different administration routes or indications. Drugs were classified as ‘safe’ in 29 recommendations (13.3%), ‘no additional risks known’ in 60 (27.5%), ‘additional risks known’ in 3 (1.4%), and ‘unsafe’ in 30 (13.8%). In 57 (26.1%) of the recommendations, safety depended on the severity of liver cirrhosis and was ‘unknown’ in 39 (17.9%) recommendations. Large alterations in pharmacodynamics were the main reason for classifying a drug as ‘unsafe’. For 67 drugs (31%), a dose adjustment was needed. Conclusions Over 200 recommendations were developed for the safe use of drugs in patients with liver cirrhosis. Implementing these recommendations into clinical practice can possibly enhance medication safety in this vulnerable patient group.
      PubDate: 2018-06-01
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