Antipsychotic Use Among Adult Outpatients and Venous Thromboembolic Disease: A Retrospective Cohort Study.

J Clin Psychopharmacol. 2017 Jun 15;:

Authors: Ferraris A, Szmulewicz AG, Vazquez FJ, Vollmer WM, Angriman F

Abstract
BACKGROUND: Treatment with antipsychotic (AP) agents is associated with incident thromboembolic events. However, the underpinnings of this association remain unknown. We sought to evaluate the effect of AP agents-categorized by their metabolic/sedative and hyperprolactinemia adverse effect profile-on the risk of venous thromboembolic disease during long-term follow-up.
METHODS: A retrospective cohort study of adult patients initiating AP treatment for the first time was conducted. Primary outcome was defined as the time to venous thromboembolism (VTE) (either deep venous thrombosis or acute pulmonary embolism). Antipsychotic agents were categorized by their risk (high vs low) of either drug-induced (a) sedation/metabolic adverse event or (b) hyperprolactinemia. We used a propensity score-adjusted Cox proportional hazards model to control for confounding.
FINDINGS: One thousand eight patients (mean age, 72.4 y) were followed for a median of 36 months. Incident VTE occurred in 6.25% of patients, corresponding to an incidence rate of 184 cases per 10,000 person-years. We found no difference in the hazard of VTE during follow-up between high- and low-risk groups (hazard ratio, 1.23 [95% confidence interval, 0.74-2.04] for drug-induced sedation/metabolic adverse event risk categories, and hazard ratio 0.81 [95% confidence interval, 0.50-1.35] for high versus low hyperprolactinemia risk).
CONCLUSIONS: These results suggest that the risk of thromboembolic events in older adults who started AP treatment for the first time does not seem to be related to these drugs' risk of either sedation/metabolic adverse events or hyperprolactinemia. However, VTE remains a common problem in this subgroup of patients.

PMID: 28622161 [PubMed - as supplied by publisher]

Real-World Efficacy of Daclatasvir and Sofosbuvir, With and Without Ribavirin, in HIV/HCV Coinfected Patients With Advanced Liver Disease in a French Early Access Cohort.

J Acquir Immune Defic Syndr. 2017 May 01;75(1):97-107

Authors: Lacombe K, Fontaine H, Dhiver C, Metivier S, Rosenthal E, Antonini T, Valantin MA, Miailhes P, Harent S, Batisse D, Pageaux GP, Chas J, Aumaitre H, Dominguez S, Allegre T, Lafeuillade A, Billaud E, De Truchis P, Perre P, Leroy V, De Ledinghen V, Sogni P, Dabis F, Zhao Y, Filipovics A, Fedchuk L, Akremi R, Bennai Y, Salmon Ceron D

Abstract
BACKGROUND: Efficacious, well-tolerated, direct antiviral agents have drastically changed the prognosis of hepatitis C virus (HCV) disease, but real-world data for oral treatments are limited in key populations such as HIV/HCV coinfection with advanced liver disease. Daclatasvir (DCV) efficacy and safety was assessed in the French "Autorisation Temporaire d'Utilisation" (ATU) program, providing DCV ahead of market authorization to patients with advanced HCV disease without other treatment options.
METHODS: This was a subanalysis of HIV/HCV coinfected ATU patients treated with DCV plus sofosbuvir (SOF). Recommended duration was 24 weeks; addition of ribavirin (RBV) and/or shorter treatment was at the physician's discretion. The primary efficacy analysis was sustained virologic response at posttreatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting.
RESULTS: The efficacy population (N = 407) was mostly cirrhotic (72%, of whom 18% were decompensated), HCV treatment-experienced (82%), and infected with genotypes 1 (69%), 3 (12%), or 4 (19%). Median CD4 was 555 cells/mm; 95% had HIV RNA <50 copies/mL. Most (74%) were treated for 24 weeks; 14% received RBV. SVR12 was 92% overall (95% confidence interval: 88.6% to 94.0%); 90% (86.4% to 93.2%) in patients with cirrhosis; 95% (88.9% to 97.5%) in patients without cirrhosis. SVR12 was consistent across HCV genotypes and antiretroviral regimens. Among 617 patients with safety data, 7 discontinued for an adverse event and 10 died.
CONCLUSIONS: DCV+SOF±RBV achieved high SVR12 and was well tolerated in this large real-world cohort of HIV/HCV coinfected patients with advanced liver disease.

PMID: 28272163 [PubMed - indexed for MEDLINE]

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

J Acquir Immune Defic Syndr. 2017 May 01;75(1):61-66

Authors: Gallant JE, Thompson M, DeJesus E, Voskuhl GW, Wei X, Zhang H, White K, Cheng A, Quirk E, Martin H

Abstract
OBJECTIVE: To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI).
DESIGN: Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study.
METHODS: HIV-infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted average change from baseline to day 11 (DAVG11) for plasma HIV-1 RNA. HIV-1 RNA, adverse events (AEs), and laboratory assessments were evaluated through day 17.
RESULTS: Twenty participants were enrolled (n = 4/group). Mean DAVG11 ranged from -0.92 to -1.61 across BIC doses versus -0.01 for placebo. Significant reductions in plasma HIV-1 RNA from baseline at day 11 were observed for all BIC doses compared with placebo (P < 0.001); mean decreases were 1.45-2.43 log10 copies/mL. Increased BIC exposures correlated with increased reduction in plasma HIV-1 RNA from baseline on day 11. Three participants on BIC (50 or 100 mg) achieved plasma HIV-1 RNA <50 copies/mL by end of study. Median Tmax ranged from 1.0 to 1.8 hours (day 1, postdose) and 1.3-2.7 hours (day 10), with median t1/2 ranging from 15.9 to 20.9 hours. No participant developed primary INSTI-R substitution through day 17. BIC was well tolerated, with no discontinuations because of adverse events.
CONCLUSIONS: BIC is a novel, potent, unboosted INSTI that demonstrated rapid, dose-dependent declines in HIV-1 RNA after 10 days of monotherapy. BIC was well tolerated, and displayed rapid absorption and a half-life supportive of once-daily therapy in HIV-infected subjects.

PMID: 28196003 [PubMed - indexed for MEDLINE]

Adverse Reactions to Contrast Material: A Canadian Update.

Can Assoc Radiol J. 2017 May;68(2):187-193

Authors: Morzycki A, Bhatia A, Murphy KJ

Abstract
Imaging techniques frequently employ contrast agents to improve image resolution and enhance pathology detection. These gadolinium- and iodine-based media, although generally considered safe, are associated with a number of adverse effects ranging from mild to severe. Reactions are classified as either anaphylactoid ("anaphylaxis-like") or nonanaphylactoid, depending on a number of elements that will be reviewed. Herein, we have summarized predisposing risk factors for adverse events resulting from the use of contrast, their associated pathophysiological mechanisms as well as known prophylaxis for the antitreatment of high-risk patients. In the unlikely event that a serious adverse reaction does occur, we have provided a comprehensive summary of treatment protocols. Our goal was to thoroughly evaluate the current literature regarding adverse reactions to radiocontrast agents and provide an up to date review for the health care provider.

PMID: 27745988 [PubMed - indexed for MEDLINE]

Implementation of a module to promote competency in adverse drug reaction reporting in undergraduate medical students.

Indian J Pharmacol. 2016 Oct;48(Suppl 1):S69-S73

Authors: Tripathi RK, Jalgaonkar SV, Sarkate PV, Rege NN

Abstract
OBJECTIVES: Underreporting and poor quality of adverse drug reaction (ADR) reports pose a challenge for the Pharmacovigilance Program of India. A module to impart knowledge and skills of ADR reporting to MBBS students was developed and evaluated.
MATERIALS AND METHODS: The module consisted of (a) e-mailing an ADR narrative and online filling of the "suspected ADR reporting form" (SARF) and (b) a week later, practical on ADR reporting was conducted followed by online filling of SARF postpractical at 1 and 6 months. SARF was an 18-item form with a total score of 36. The module was implemented in the year 2012-2013. Feedback from students and faculty was taken using 15-item prevalidated feedback questionnaires. The module was modified based on the feedback and implemented for the subsequent batch in the year 2013-2014. The evaluation consisted of recording the number of students responding and the scores achieved.
RESULTS: A total of 171 students in 2012-2013 batch and 179 in 2013-2014 batch participated. In the 2012-2013 batch, the number of students filling the SARF decreased from basal: 171; 1 month: 122; 6 months: 17. The average scores showed improvement from basal 16.2 (45%) to 26.4 (73%) at 1 month and to 27.3 (76%) at 6 months. For the 2013-2014 batch, the number (n = 179) remained constant throughout and the average score progressively increased from basal 10.5 (30%) to 27.8 (77%) at 1 month and 30.3 (84%) at 6 months.
CONCLUSION: This module improved the accuracy of filling SARF by students and this subsequently will led to better ADR reporting. Hence, this module can be used to inculcate better ADR reporting practices in budding physicians.

PMID: 28031613 [PubMed - indexed for MEDLINE]

The need for a comprehensive medication safety module in medical education.

Indian J Pharmacol. 2016 Oct;48(Suppl 1):S57-S60

Authors: Chandy SJ

Abstract
OBJECTIVE: A rising number of medicines and minimal emphasis on rational prescribing in the medical curriculum may compromise medication safety. There is no focused module in the curriculum dealing with factors affecting safety such as quality, medicines management, rational use, and approach to adverse effects. Creating awareness of these issues would hopefully plant a seed of safe prescribing and encourage pharmacovigilance. A study was therefore done to determine the need for such a module.
METHOD: A quasi-experimental pre-post module study. Medical students (n = 88) completing pharmacology term were recruited after informed consent. A questionnaire containing 20 questions on various themes was administered and scored. Subsequently a module was developed and relevant safety themes taught to the students. After one month, the questionnaire was re-administered.
RESULTS: The pre module score was 9.52/20. Knowledge about the various themes, adverse effects, medication management, quality issues and rational use were similar though poor knowledge was evident in specific areas such as clinical trials, look alike-sound alike medicines (LASA) and medicine storage. The post module score was 12.24/20. The improvement of score was statistically significant suggesting the effectiveness of the module.
CONCLUSION: The relatively poor knowledge and improvement with a specific educational module emphasizes the need of such a module within the medical curriculum to encourage safe use of medicines by Indian Medical Graduates (IMG). It is hoped that the policy makers in medical education will introduce such a module within the medical curriculum.

PMID: 28031610 [PubMed - indexed for MEDLINE]

Prediction of Hospitalization due to Adverse Drug Reactions in Elderly Community-Dwelling Patients (The PADR-EC Score).

PLoS One. 2016;11(10):e0165757

Authors: Parameswaran Nair N, Chalmers L, Connolly M, Bereznicki BJ, Peterson GM, Curtain C, Castelino RL, Bereznicki LR

Abstract
BACKGROUND: Adverse drug reactions (ADRs) are the major cause of medication-related hospital admissions in older patients living in the community. This study aimed to develop and validate a score to predict ADR-related hospitalization in people aged ≥65 years.
METHODS: ADR-related hospitalization and its risk factors were determined using a prospective, cross-sectional study in patients aged ≥65 years admitted to two hospitals. A predictive model was developed in the derivation cohort (n = 768) and the model was applied in the validation cohort (n = 240). ADR-related hospital admission was determined through expert consensus from comprehensive reviews of medical records and patient interviews. The causality and preventability of the ADR were assessed based on the Naranjo algorithm and modified Schumock and Thornton criteria, respectively.
RESULTS: In the derivation sample (mean [±SD] age, 80.1±7.7 years), 115 (15%) patients were admitted due to a definite or probable ADR; 92.2% of these admissions were deemed preventable. The number of antihypertensives was the strongest predictor of an ADR followed by presence of dementia, renal failure, drug changes in the preceding 3 months and use of anticholinergic medications; these variables were used to derive the ADR prediction score. The predictive ability of the score, assessed from calculation of the area under the receiver operator characteristic (ROC) curve, was 0.70 (95% confidence interval (CI) 0.65-0.75). In the validation sample (mean [±SD] age, 79.6±7.6 years), 30 (12.5%) patients' admissions were related to definite or probable ADRs; 80% of these admissions were deemed preventable. The area under the ROC curve in this sample was 0.67 (95% CI 0.56-0.78).
CONCLUSIONS: This study proposes a practical and simple tool to identify elderly patients who are at an increased risk of preventable ADR-related hospital admission. Further refinement and testing of this tool is necessary to implement the score in clinical practice.

PMID: 27798708 [PubMed - indexed for MEDLINE]

Sensitising effects of genetically modified enzymes used in flavour, fragrance, detergence and pharmaceutical production: cross-sectional study.

Occup Environ Med. 2017 Jan;74(1):39-45

Authors: Budnik LT, Scheer E, Burge PS, Baur X

Abstract
OBJECTIVES: The use of genetically engineered enzymes in the synthesis of flavourings, fragrances and other applications has increased tremendously. There is, however, a paucity of data on sensitisation and/or allergy to the finished products. We aimed to review the use of genetically modified enzymes and the enormous challenges in human biomonitoring studies with suitable assays of specific IgE to a variety of modified enzyme proteins in occupational settings and measure specific IgE to modified enzymes in exposed workers.
METHODS: Specific IgE antibodies against workplace-specific individual enzymes were measured by the specific fluorescence enzyme-labelled immunoassay in 813 exposed workers seen in cross-sectional surveys.
RESULTS: Twenty-three per cent of all exposed workers showed type I sensitisation with IgE antibodies directed against respective workplace-specific enzymes. The highest sensitisation frequencies observed were for workers exposed enzymes derived from α-amylase (44%), followed by stainzyme (41%), pancreatinin (35%), savinase (31%), papain (31%), ovozyme (28%), phytase (16%), trypsin (15%) and lipase (4%). The highest individual antibody levels (up to 110 kU/L) were detected in workers exposed to phytase, xylanase and glucanase. In a subgroup comprising 134 workers, detailed clinical diagnostics confirmed work-related symptoms. There was a strong correlation (r=0.75, p<0.0001) between the symptoms and antibody levels. Workers with work-related respiratory symptoms showed a higher prevalence for the presence of specific IgE antibodies against workplace-specific enzymes than asymptomatic exposed workers (likelihood ratio 2.32, sensitivity 0.92, specificity 0.6).
CONCLUSIONS: Our data confirm the previous findings showing that genetically engineered enzymes are potent allergens eliciting immediate-type sensitisation. Owing to lack of commercial diagnostic tests, few of those exposed receive regular surveillance including biomonitoring with relevant specific IgE assays.

PMID: 27655774 [PubMed - indexed for MEDLINE]

Variation in Preventive Care in Children Receiving Chronic Glucocorticoid Therapy.

J Pediatr. 2016 Dec;179:226-232

Authors: Basiaga ML, Burrows EK, Denburg MR, Meyers KE, Grossman AB, Mamula P, Grundmeier RW, Burnham JM

Abstract
OBJECTIVE: To assess preventive care measure prescribing in children exposed to glucocorticoids and identify prescribing variation according to subspecialty and patient characteristics.
STUDY DESIGN: Retrospective cohort study of children initiating chronic glucocorticoids in the gastroenterology, nephrology, and rheumatology divisions at a pediatric tertiary care center. Outcomes included 25-hydroxyvitamin D (25OHD) and lipid testing, pneumococcal polysaccharide (PPV) and influenza vaccination, and stress dose hydrocortisone prescriptions.
RESULTS: A total of 701 children were followed for a median of 589 days. 25OHD testing was performed in 73%, lipid screening in 29%, and PPV and influenza vaccination in 16% and 78%, respectively. Hydrocortisone was prescribed in 2%. Across specialties, 25OHD, lipid screening, and PPV prescribing varied significantly (all P < .001). Using logistic regression adjusting for specialty, 25OHD testing was associated with older age, female sex, non-Hispanic ethnicity, and lower baseline height and body mass index z-scores (all P < .03). Lipid screening was associated with older age, higher baseline body mass index z-score, and lower baseline height z-score (all P < .01). Vaccinations were associated with lower age (P < .02), and PPV completion was associated with non-White race (P = .04).
CONCLUSIONS: Among children chronically exposed to glucocorticoids, 25OHD testing and influenza vaccination were common, but lipid screening, pneumococcal vaccination, and stress dose hydrocortisone prescribing were infrequent. Except for influenza vaccination, preventive care measure use varied significantly across specialties. Quality improvement efforts are needed to optimize preventive care in this high-risk population.

PMID: 27622698 [PubMed - indexed for MEDLINE]

Are proton pump inhibitors really so dangerous?

Dig Liver Dis. 2016 Aug;48(8):851-9

Authors: Savarino V, Dulbecco P, Savarino E

Abstract
For decades, millions of patients with acid-related disorders have had their acid inhibited effectively and safely first with H2-receptor antagonists (H2RAs) and then with proton pump inhibitors (PPI). As with any pharmacological agent, PPIs have been reported to be associated with some adverse events, but several recent large-scale observational studies have evidenced new and serious abnormalities generally linked to their chronic use. However, these studies have often important limitations for their frequent retrospective design and other methodological drawbacks, such as selection biases of the analyzed populations and the presence of various confounding factors. Overall, although the conclusions of these pharmacovigilant investigations must be taken into account and can generate important hypotheses for future research, they do not have to create panic among patients and alarmism among physicians. On considering the weakness of these studies, we suggest physicians should not refrain from continuing to use PPIs, if these drugs are given for medical indications clearly established in the literature and, more importantly, they should not be induced to shift to H2RAs, a class of antisecretory agents that are much less effective than PPIs. A return to the past is potentially dangerous for the patients, taking into account the well-known success of PPIs in the wide spectrum of all acid-related conditions.

PMID: 27321544 [PubMed - indexed for MEDLINE]

Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study.

Respir Med. 2017 Jul;128:50-56

Authors: Halank M, Hoeper MM, Ghofrani HA, Meyer FJ, Stähler G, Behr J, Ewert R, Fletcher M, Colorado P, Nikkho S, Grimminger F

Abstract
BACKGROUND: Riociguat was well tolerated and improved exercise and functional capacity in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) in a 12-week Phase II trial. We present final data from the long-term extension phase of this study.
METHODS: During this multicenter, open-label, uncontrolled long-term extension study, riociguat dose could be changed at the physician's discretion (range 0.5-2.5 mg three times daily). The primary outcome was long-term safety and tolerability of riociguat; secondary outcomes included 6-minute walking distance, World Health Organization functional class, survival, and clinical worsening-free survival.
RESULTS: Sixty-eight patients (inoperable CTEPH, n = 41; PAH, n = 27) entered the long-term extension. Median treatment duration at the final data cut-off was 77 months. The most common adverse events were nasopharyngitis (57%) and peripheral edema (37%). Three patients (4%) experienced serious adverse events of hemoptysis: two moderate, one severe, none fatal or considered drug-related. At Month 48, 6-minute walking distance increased from baseline by 69 ± 105 m, and World Health Organization functional class improved/stabilized/worsened versus baseline in 50/45/5% of patients. Three-year survival and clinical worsening-free survival were 91% and 49%, respectively (with patients censored if they withdrew without experiencing an event). Starting a new PAH treatment was the most frequent clinical worsening event.
CONCLUSIONS: Improvements in exercise and functional capacity were maintained at 4 years in patients remaining on treatment, with no new safety signals identified. These data support riociguat as a long-term treatment option for PAH and inoperable CTEPH.
TRIAL REGISTERED AT: ClinicalTrials.gov.
REGISTRATION NUMBER: NCT00454558.

PMID: 28610669 [PubMed - in process]

Using electronic medical record data to report laboratory adverse events.

Br J Haematol. 2017 Apr;177(2):283-286

Authors: Miller TP, Li Y, Getz KD, Dudley J, Burrows E, Pennington J, Ibrahimova A, Fisher BT, Bagatell R, Seif AE, Grundmeier R, Aplenc R

Abstract
Despite the importance of adverse event (AE) reporting, AEs are under-reported on clinical trials. We hypothesized that electronic medical record (EMR) data can ascertain laboratory-based AEs more accurately than those ascertained manually. EMR data on 12 AEs for patients enrolled on two Children's Oncology Group (COG) trials at one institution were extracted, processed and graded. When compared to gold standard chart data, COG AE report sensitivity and positive predictive values (PPV) were 0-21·1% and 20-100%, respectively. EMR sensitivity and PPV were >98·2% for all AEs. These results demonstrate that EMR-based AE ascertainment and grading substantially improves laboratory AE reporting accuracy.

PMID: 28146330 [PubMed - indexed for MEDLINE]

A Critical Asthma Standardized Clinical and Management Plan Reduces Duration of Critical Asthma Therapy.

Hosp Pediatr. 2017 02;7(2):79-87

Authors: Wong J, Agus MS, Graham DA, Melendez E

Abstract
BACKGROUND AND OBJECTIVE: Reduction of critical asthma management time can reduce intensive care utilization. The goal of this study was to determine whether a Critical Asthma Standardized Clinical Assessment and Management Plan (SCAMP) can decrease length of critical asthma management time.
METHODS: This retrospective study compared critical asthma management times in children managed before and after implementation of a Critical Asthma SCAMP. The SCAMP used an asthma severity score management scheme to guide stepwise escalation and weaning of therapies. The SCAMP guided therapy until continuous albuterol nebulization (CAN) was weaned to intermittent albuterol every 2 hours (q2h). Because the SCAMP was part of a quality improvement initiative in which all patients received a standardized therapy, informed consent was waived. The study was conducted in Medicine ICU and Intermediate Care Units in a tertiary care freestanding children's hospital. Children ≥2 years of age who had CAN initiated in the emergency department and were admitted to the Division of Medicine Critical Care with status asthmaticus were included. The time to q2h dosing from initiation of CAN was compared between the baseline and SCAMP cohorts. Adverse events were compared. The Mann-Whitney test was used for analysis; P values <.05 were considered statistically significant.
RESULTS: There were 150 baseline and 123 SCAMP patients eligible for analysis. There was a decrease in median time to q2h dosing after the SCAMP (baseline, 21.6 hours [interquartile range, 3.2-32.3 hours]; SCAMP, 14.2 hours [interquartile range, 9.0-23.1 hours]; P < .01). There were no differences in adverse events or readmissions.
CONCLUSIONS: A Critical Asthma SCAMP was effective in decreasing time on continuous albuterol.

PMID: 28096296 [PubMed - indexed for MEDLINE]

Changing perceptions and efficacy of generic medicines: An intervention study.

Health Psychol. 2016 Nov;35(11):1246-1253

Authors: Colgan SL, Faasse K, Pereira JA, Grey A, Petrie KJ

Abstract
OBJECTIVE: Generic medicines provide a safe and economical medical treatment and are used routinely throughout the world. However, a significant proportion of individuals view generic medicines as less safe, less effective and of lower quality compared with their equivalent branded medicines. This study aimed to investigate the effect of an educational intervention on improving perceptions and perceived efficacy of generic medicines.
METHOD: Seventy participants who experienced frequent tension headaches were randomized to receive an educational video about generic medicines or a control video. Participants then alternatively took branded and generic ibuprofen to treat their next two consecutive headaches. Changes in perceptions of generic medicines, pain relief and side effects were measured.
RESULTS: The intervention was effective in modifying and improving perceptions of generic medicines in the areas of understanding (p < .05), preference for a generic medicine to treat a serious illness (p < .05), and overall preference for generic medicines (p < .01). However, contrary to predictions, participants in the intervention group reported significantly less pain relief (p = .03) and more symptoms (p = .04) after taking generic ibuprofen compared with branded ibuprofen.
CONCLUSION: This study identified that an educational intervention is effective in modifying and improving perceptions of generic medicines but produced paradoxical effects on drug efficacy and side effects. These findings suggest that complex mechanisms are involved in the relationship between perceptions and drug efficacy and contradict the assumption that improving attitudes toward generic medicines will have a flow-on effect to improving health outcomes. (PsycINFO Database Record

PMID: 27505191 [PubMed - indexed for MEDLINE]

Post-Marketing Surveillance of Human Rabies Diploid Cell Vaccine (Imovax) in the Vaccine Adverse Event Reporting System (VAERS) in the United States, 1990‒2015.

PLoS Negl Trop Dis. 2016 Jul;10(7):e0004846

Authors: Moro PL, Woo EJ, Paul W, Lewis P, Petersen BW, Cano M

Abstract
BACKGROUND: In 1980, human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur), was licensed for use in the United States.
OBJECTIVE: To assess adverse events (AEs) after HDCV reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system.
METHODS: We searched VAERS for US reports after HDCV among persons vaccinated from January 1, 1990-July 31, 2015. Medical records were requested for reports classified as serious (death, hospitalization, prolonged hospitalization, disability, life-threatening-illness), and those suggesting anaphylaxis and Guillain-Barré syndrome (GBS). Physicians reviewed available information and assigned a primary clinical category to each report using MedDRA system organ classes. Empirical Bayesian (EB) data mining was used to identify disproportional AE reporting after HDCV.
RESULTS: VAERS received 1,611 reports after HDCV; 93 (5.8%) were serious. Among all reports, the three most common AEs included pyrexia (18.2%), headache (17.9%), and nausea (16.5%). Among serious reports, four deaths appeared to be unrelated to vaccination.
CONCLUSIONS: This 25-year review of VAERS did not identify new or unexpected AEs after HDCV. The vast majority of AEs were non-serious. Injection site reactions, hypersensitivity reactions, and non-specific constitutional symptoms were most frequently reported, similar to findings in pre-licensure studies.

PMID: 27410239 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes.

Diabetes Obes Metab. 2017 Jun 13;:

Authors: Kadowaki T, Inagaki N, Kondo K, Nishimura K, Kaneko G, Maruyama N, Nakanishi N, Watanabe Y, Gouda M, Iijima H

Abstract
AIM: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy.
METHODS: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included the changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to week 52 (with last observation carried forward).
RESULTS: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence of AEs and drug-related AEs was 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean (95% confidence interval) changes in HbA1c, FPG, and body weight were -0.99% (-1.12% to -0.85%), -38.6 mg/dL (-43.4 to -33.9 mg/dL), and -3.92% (-4.53% to -3.31%), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52.
CONCLUSIONS: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG, and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese T2DM patients with inadequate glycaemic control on teneligliptin alone.

PMID: 28608617 [PubMed - as supplied by publisher]

Risk factors for adverse drug reactions in pediatric inpatients: a systematic review.

Ther Adv Drug Saf. 2017 Jun;8(6):199-210

Authors: Andrade PHS, Santos ADS, Souza CAS, Lobo IMF, da Silva WB

Abstract
BACKGROUND: The main objective of the present systematic review is to identify potential risk factors for adverse drug reactions (ADRs) through prospective cohort studies in pediatric inpatients.
METHODS: The data search was done in the following electronic databases PubMed/MEDLINE; Scopus; LILACS and Web of Science from the earliest record until 31 May 2015. Two reviewers independently screened each study and one of them assessed the methodological quality according to the Newcastle-Ottawa scale for cohort studies. The data extraction was conducted according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative for cohort studies.
RESULTS: The only risk factor observed in all studies was the increase in the number of prescription drugs. However, other factors were identified, such as the increase in the length of stay or the number of low- or high-risk drugs prescribed, use of general anesthesia and oncological diagnosis. The cumulative incidence of ADR was 16.4% (95% confidence interval: 15.6 to 17.2). The main professional responsible for ADR identification was the pharmacist and the dominant category among the ADRs were gastrointestinal disorders. In addition, analgesics, antibacterial agents and corticosteroids were the drug classes commonly associated with ADRs. The methodology used in this study was tried to homogenize the data extracted; however, this was not sufficient to correct the discrepancies so it was not possible to perform a meta-analysis.
CONCLUSIONS: The increase in the number of prescription drugs was the main risk factor in this population. However, additional studies are required to identify the risk factors for ADRs in pediatric inpatients.

PMID: 28607669 [PubMed - in process]

Identification of enzymes responsible for nitrazepam metabolism and toxicity in human.

Biochem Pharmacol. 2017 Jun 09;:

Authors: Konishi K, Fukami T, Gotoh S, Nakajima M

Abstract
Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N(1)-methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-L-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.

PMID: 28606603 [PubMed - as supplied by publisher]

Inferring Genes and Biological Functions That Are Sensitive to the Severity of Toxicity Symptoms.

Int J Mol Sci. 2017 Apr 02;18(4):

Authors: Kim J, Shin M

Abstract
The effective development of new drugs relies on the identification of genes that are related to the symptoms of toxicity. Although many researchers have inferred toxicity markers, most have focused on discovering toxicity occurrence markers rather than toxicity severity markers. In this study, we aimed to identify gene markers that are relevant to both the occurrence and severity of toxicity symptoms. To identify gene markers for each of four targeted liver toxicity symptoms, we used microarray expression profiles and pathology data from 14,143 in vivo rat samples. The gene markers were found using sparse linear discriminant analysis (sLDA) in which symptom severity is used as a class label. To evaluate the inferred gene markers, we constructed regression models that predicted the severity of toxicity symptoms from gene expression profiles. Our cross-validated results revealed that our approach was more successful at finding gene markers sensitive to the aggravation of toxicity symptoms than conventional methods. Moreover, these markers were closely involved in some of the biological functions significantly related to toxicity severity in the four targeted symptoms.

PMID: 28368331 [PubMed - indexed for MEDLINE]

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.

Gastroenterology. 2017 Apr;152(5):1078-1089

Authors: Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernández N, Ibáñez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK, International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium

Abstract
BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.
METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs.
RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10(-9)). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10(-9)). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10(-9)). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224.
CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.

PMID: 28043905 [PubMed - indexed for MEDLINE]