Sex Differences in Poisonings Among Older Adults: An Analysis of the Toxicology Investigators Consortium (ToxIC) Registry, 2010 to 2016.

Clin Ther. 2018 08;40(8):1366-1374.e8

Authors: Beauchamp GA, Carey JL, Adams T, Wier A, Colón MF, Cook M, Cannon R, Katz KD, Greenberg MR, Toxicology Investigators Consortium (ToxIC)

Abstract
PURPOSE: Adults aged >65 years are susceptible to intentional and unintentional poisoning, with contributing factors that include polypharmacy, comorbidity, susceptibility to medication error, and gaps in research. Although toxicologists are often tasked with managing and preventing poisoning among older adults, little is known about sex differences in these poisonings. The aim of this study was to review sex differences in poisonings among older adults managed at the bedside by medical toxicologists.
METHODS: All case subjects aged >65 years in the Toxicology Investigators Consortium (ToxIC) registry between January 2010 and December 2016 were reviewed. Data included reasons for exposure and consultation, exposure agents and routes, presenting clinical findings, and treatment provided. Cases missing age, sex, or primary reason for toxicology consultation data were excluded. We used χ2 tests to assess differences in distribution of study variables according to participant sex.
FINDINGS: Among 51,441 total registry cases, 542 (1.05%) were excluded because of missing data. Among the remaining 50,899 cases, 2930 (5.8%) were included for age >65 years; 52.3% of older adults were female. Race was missing or unknown for 49.2% of cases. Adverse drug reactions were more commonly encountered in female subjects than in their male counterparts (9.6% vs 6.4%; P = 0.001). No statistically significant sex differences were observed for total numbers of intentional, unintentional pharmaceutical, and nonpharmaceutical exposures. The most common medications involved were cardiovascular (16.8%) and analgesics/opioids (14.8%). Female subjects were more likely than male subjects to be evaluated by a toxicologist for cardiovascular medications (18.7% vs 14.7%; P = 0.004) and analgesics/opioids (17.6% vs 11.8%; P < 0.001). Male subjects were more likely than female subjects to be evaluated for ethanol toxicity (7.4% vs 1%; P < 0.001) and for envenomations (4.2% vs 1.8%; P < 0.001). The most common route of exposure was oral ingestion (81.3%). Signs/symptoms were noted in 54.8% of cases, with the most common abnormal vital sign being bradycardia (17.2%). Pharmacologic support was the most common intervention and was more common in male subjects than in female subjects (17.7% vs 12.3%; P < 0.001). Deaths were reported in 38 female subjects (2.45%) and 46 male subjects (3.34%); there was no statistically significant difference in death rate according to sex (P = 0.148).
IMPLICATIONS: Older female adults were more commonly evaluated by a medical toxicologist for an adverse drug reaction than older male adults. Female patients were more likely than male patients to be evaluated for poisoning related to analgesic/opioids and cardiovascular medications, and older male patients more frequently received pharmacologic support than older female patients. No significant sex differences were observed in numbers of toxicology consultations for intentional, unintentional pharmaceutical, and nonpharmaceutical exposures.

PMID: 30072041 [PubMed - indexed for MEDLINE]

Genetic Testing in Clinical Settings.

Am J Kidney Dis. 2018 10;72(4):569-581

Authors: Franceschini N, Frick A, Kopp JB

Abstract
Genetic testing is used for screening, diagnosis, and prognosis of diseases consistent with a genetic cause and to guide drug therapy to improve drug efficacy and avoid adverse effects (pharmacogenomics). This In Practice review aims to inform about DNA-related genetic test availability, interpretation, and recommended clinical actions based on results using evidence from clinical guidelines, when available. We discuss challenges that limit the widespread use of genetic information in the clinical care setting, including a small number of actionable genetic variants with strong evidence of clinical validity and utility, and the need for improving the health literacy of health care providers and the public, including for direct-to-consumer tests. Ethical, legal, and social issues and incidental findings also need to be addressed. Because our understanding of genetic factors associated with disease and drug response is rapidly increasing and new genetic tests are being developed that could be adopted by clinicians in the short term, we also provide extensive resources for information and education on genetic testing.

PMID: 29655499 [PubMed - indexed for MEDLINE]

Detecting Chemotherapeutic Skin Adverse Reactions in Social Health Networks Using Deep Learning.

JAMA Oncol. 2018 Apr 01;4(4):581-583

Authors: Ransohoff JD, Nikfarjam A, Jones E, Loew B, Kwong BY, Sarin KY, Shah NH

PMID: 29494731 [PubMed - indexed for MEDLINE]

Medications That Cause Dry Mouth As an Adverse Effect in Older People: A Systematic Review and Metaanalysis.

J Am Geriatr Soc. 2018 01;66(1):76-84

Authors: Tan ECK, Lexomboon D, Sandborgh-Englund G, Haasum Y, Johnell K

Abstract
OBJECTIVES: To assess and quantify the risk of drug-induced dry mouth as a side effect in older people.
DESIGN: Systematic review and metaanalysis.
SETTING: A search of the literature was undertaken using Medline, Embase, Cochrane, Web of Science, and PubMed from 1990 to 2016.
PARTICIPANTS: Older people (aged ≥60) who participated in intervention or observational studies investigating drug use as an exposure and xerostomia or salivary gland hypofunction as adverse drug outcomes.
MEASUREMENTS: Two pairs of authors screened titles and abstracts of studies for relevance. Two authors independently extracted data, including study characteristics, definitions of exposure and outcome, and methodological quality. For the metaanalyses, random-effects models were used for pooling the data and I2 statistics for exploring heterogeneity.
RESULTS: Of 1,544 potentially relevant studies, 52 were deemed eligible for inclusion in the final review and 26 in metaanalyses. The majority of studies were of moderate methodological quality. In the intervention studies, urological medications (odds ratio (OR) = 5.91, 95% confidence interval (CI) = 4.04-8.63; I2  = 62%), antidepressants (OR = 4.74, 95% CI = 2.69-8.32, I2  = 21%), and psycholeptics (OR = 2.59, 95% CI = 1.79-3.95, I2  = 0%) were significantly associated with dry mouth. In the observational studies, numbers of medications and several medication classes were significantly associated with xerostomia and salivary gland hypofunction.
CONCLUSION: Medication use was significantly associated with xerostomia and salivary gland hypofunction in older adults. The risk of dry mouth was greatest for drugs used for urinary incontinence. Future research should develop a risk score for medication-induced dry mouth to assist with prescribing and medication management.

PMID: 29071719 [PubMed - indexed for MEDLINE]

Impact of a New Consumer Form on Adverse Event Reporting to the United States Food and Drug Administration.

Pharmacotherapy. 2019 Sep 03;:

Authors: Muñoz MA, Delcher C, Dal Pan GJ, Kortepeter CM, Wu E, Jenny Wei YJ, Xiao H, Winterstein AG

Abstract
INTRODUCTION: Consumers and health care professionals (HCPs) can voluntarily report adverse experiences associated with drug products to the Food and Drug Administration Adverse Event Reporting System (FAERS). Consumers and HCPs used the same general voluntary reporting form (GVR) until mid-2013 when a consumer voluntary reporting form (ConVR) written in plain language was implemented.
OBJECTIVES: To examine the effect of the ConVR on the quality and quantity of consumer reports submitted directly to FAERS.
METHODS: We conducted a descriptive analysis of consumer and HCP reports received directly by the FDA from January 1, 2011 through December 31, 2015. Report quality was defined by the completeness of 15 individual data fields and via a structured tool measuring clinical documentation. An interrupted time-series design was used to evaluate the impact on the quantity of consumer reports.
RESULTS: Consumer reports submitted on the ConVR generally included more patient, product, and event data in the structured data fields than those submitted on the GVR. Fields with the greatest absolute percentage difference after the ConVR was introduced included race/ethnicity (+77.2%), product start and stop dates (+43%, +40.3%), dechallenge and rechallenge information (+19%, +29.4%), and medical history (+27%). Our structured assessment also classified more reports received on the ConVR as well documented (64.9 % vs 37.8%, p <0.01). The time-series model demonstrated an immediate increase of 499 consumer reports in the month following the ConVR's implementation (p<0.01).
CONCLUSIONS: Our findings suggest that the ConVR has contributed positively to both the quality and quantity of consumer reports. This article is protected by copyright. All rights reserved.

PMID: 31479525 [PubMed - as supplied by publisher]

Expansion of EHR-Based Common Data Model (CDM).

Stud Health Technol Inform. 2019 Aug 21;264:1443-1444

Authors: Choi W, Ko SJ, Jung HJ, Kim TM, Choi I

Abstract
We expanded and constructed a Common Data Model (CDM) based on hospital EHR to enable analysis and comparison of Adverse Drug Reactions(ADRs) integrated with external organizations with different data structures. This is significant in that it is possible to conduct joint research, analysis, and comparisons among institutions with the same type of CDM constructed, and provide the basis for conducting the same research simultaneously on various data sources.

PMID: 31438172 [PubMed - indexed for MEDLINE]

American tegumentary leishmaniasis: severe side effects of pentavalent antimonial in a patient with chronic renal failure.

An Bras Dermatol. 2019 Jul 29;94(3):355-357

Authors: Marques SA, Merlotto MR, Ramos PM, Marques MEA

Abstract
Pentavalent antimonials are the first-line drug treatment for American tegumentary leishmaniasis. We report on a patient with chronic renal failure on hemodialysis who presented with cutaneous lesions of leishmaniasis for four months. The patient was treated with intravenous meglumine under strict nephrological surveillance, but cardiotoxicity, acute pancreatitis, pancytopenia, and cardiogenic shock developed rapidly. Deficient renal clearance of meglumine antimoniate can result in severe toxicity, as observed in this case. These side effects are related to cumulative plasma levels of the drug. Therefore, second-line drugs like amphotericin B are a better choice for patients on dialysis.

PMID: 31365669 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy following conversion to eslicarbazepine acetate monotherapy in adults with focal seizures.

Epilepsy Res. 2019 07;153:59-65

Authors: Chung S, Sinha SR, Shah A, Stern JM, Cheng H, Jung J, Grinnell T, Blum D

Abstract
OBJECTIVE: To assess the long-term safety and efficacy of eslicarbazepine acetate (ESL) monotherapy in adults with focal seizures (FS).
METHODS: Study 050 was a long-term, multicenter, open-label (OL) safety extension of two conversion-to-ESL monotherapy studies in adults with refractory FS. After participating in Study 045 or 046, patients started on ESL 1600 mg once daily (QD) (or 1200 mg if they previously had a dose reduction), and could adjust the dose 400 mg/week to a dose between 800-2400 mg QD. Patients could add up to two additional antiepileptic drugs (AEDs). This post-hoc analysis focuses on the actual monotherapy subgroup, which included patients in Studies 045/046/050 who did not add additional AEDs. Study endpoints included treatment retention time, time on ESL monotherapy, change in standardized seizure frequency (SSF), change in quality of life (QoL) in epilepsy (QOLIE-31) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs related to allergic reaction, hyponatremia and thyroid function were also evaluated.
RESULTS: There were 274 patients in the Study 050 full intent-to-treat (ITT) population and 140 patients in the actual monotherapy subgroup. Median treatment retention time and time on ESL monotherapy were both >5 years. Median reduction in SSF from baseline was 66.4% in the full ITT population and 78.3% in the actual monotherapy subgroup; responder (≥50% reduction in SSF) rates were 62.4% and 74.3%, respectively. QOLIE-31 scores increased from baseline in the full ITT population and the actual monotherapy subgroup (4.1- and 7.5-point increases, respectively). MADRS scores decreased from baseline in both the full ITT population and the actual monotherapy subgroup (0.7- and 2.9-point decreases, respectively). TEAEs occurred in 85.4% of patients in the full ITT population and 81.4% of patients in the actual monotherapy subgroup. Incidences of SAEs and TEAEs leading to discontinuation, as well as dizziness, depression, fall, partial seizures with secondary generalization, and complex partial seizures, were higher in the full ITT population than in the actual monotherapy subgroup. Allergic reactions, hyponatremia, and hypothyroidism were infrequent, particularly in the actual monotherapy subgroup.
CONCLUSIONS: The results of this post-hoc analysis suggest that long-term treatment with ESL was effective and well tolerated, both as a monotherapy and in combination with other AEDs for FS. QoL and tolerability appeared to be better, and incidence of depression lower, in the patient population taking ESL as a monotherapy, compared with the population that included patients taking ESL as an adjunctive therapy.

PMID: 30999260 [PubMed - indexed for MEDLINE]

Real-world treatment of over 1600 Japanese patients with EGFR mutation-positive non-small cell lung cancer with daily afatinib.

Int J Clin Oncol. 2019 Aug;24(8):917-926

Authors: Tamura K, Nukiwa T, Gemma A, Yamamoto N, Mizushima M, Ochai K, Ikeda R, Azuma H, Nakanishi Y

Abstract
BACKGROUND: This prospective, post-marketing observational study in Japanese patients aimed to evaluate the safety and effectiveness of daily afatinib use in general practice.
METHODS: This non-interventional study (NCT02131259) enrolled treatment-naïve and pre-treated patients with inoperable/recurrent EGFR mutation-positive NSCLC, eligible for afatinib treatment as per the afatinib label in Japan. Patients received afatinib at the approved dose (20, 30, 40, or 50 mg/day; physician decision), and were observed following treatment initiation for 52 weeks or until premature discontinuation. Primary endpoint was the incidence of adverse drug reactions (ADRs). Secondary endpoints included ADRs of special interest, and objective response rate (ORR). Post hoc Cox multivariate analyses were used to assess prognostic factors associated with the incidence of ADRs.
RESULTS: 1602 patients, at 374 sites (April 2014-March 2015), were included in the analysis; 307 (19%) were aged ≥ 75 years. The most frequently reported ADRs (all/grade 3-4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and nail effects (38%/4%). Serious ADRs resulting in death occurred in 18 patients (1%). 762 patients (48%) had ≥ 1 afatinib dose reduction and 366 (23%) discontinued due to ADRs; the most common reason for both was diarrhea (8.2% and 6.7%, respectively). ORR was 40.1%.
CONCLUSIONS: Real-world treatment of 1602 Japanese patients with afatinib was associated with a predictable ADR profile. Afatinib showed effectiveness in inoperable/recurrent EGFR mutation-positive NSCLC, especially as first-line treatment. As with other EGFR TKIs, prompt management of adverse events is needed in the Japanese population, to reduce serious events and outcomes, including interstitial lung disease.

PMID: 30953238 [PubMed - indexed for MEDLINE]

Adverse reactions of fluoroquinolones to central nervous system and rational drug use in nursing care.

Pak J Pharm Sci. 2019 Jan;32(1(Special)):427-432

Authors: Haiping L, Ziqiang J, Qina Z, Yuhua D

Abstract
.Fluoroquinolones are a kind of synthetic drugs commonly used in clinical treatment. They have good broad-spectrum antimicrobial properties. They are not only convenient to administer, but also have remarkable therapeutic effects. In this paper, we selected 70 patients with adverse reactions of central nervous system during the use of fluoroquinolones as the research object. We reviewed and analyzed the basic data, main manifestations and outcomes of adverse reactions, and summarized the influencing factors. The results showed that dizziness, irritability and insomnia were the main symptoms in 42 patients with mild adverse reactions. In 28 patients with moderate to severe adverse reactions, neuropsychiatric symptoms such as restlessness, depression, nervous excitation, phonism and hallucination were found. 54 patients were able to recover after stopping the medication. The remaining 16 patients were treated with drugs, and the effective rate was 87.5%. By analyzing the related factors, it can be seen that elderly patients over 60 years old, intravenous administration, combination of drugs and past history of neurological diseases are the main factors leading to adverse reactions of the central nervous system. In this survey, there were 7 kinds of adverse drug reactions, of which 31 cases (44.28%) were caused by levofloxacin. Therefore, fluoroquinolones have adverse effects on the central nervous system in the course of treatment, and the occurrence of adverse reactions is related to patients' age, route of administration, drug combination and past history of illness. It is important to grasp the above factors and make rational use of drugs.

PMID: 30852480 [PubMed - indexed for MEDLINE]

Prospective Validation of Clinical Criteria to Identify Emergency Department Patients at High Risk for Adverse Drug Events.

Acad Emerg Med. 2018 09;25(9):1015-1026

Authors: Hohl CM, Badke K, Zhao A, Wickham ME, Woo SA, Sivilotti MLA, Perry JJ

Abstract
OBJECTIVES: Adverse drug events (ADEs) cause or contribute to one in nine emergency department (ED) presentations in North America and are often misdiagnosed. EDs have insufficient clinical pharmacists to complete medication reviews in all incoming patients, even though pharmacist-led medications reviews have been associated with improved health outcomes. Our objective was to validate clinical decision rules to identify patients presenting with ADEs so they could be prioritized for pharmacist-led medication review.
METHODS: This multicenter, prospective study was conducted in two tertiary and one community hospital in Canada. We enrolled 1,529 adults presenting to EDs over 12 months. We applied two clinical decision rules and collected baseline variables prior to assessments by clinical pharmacists and physicians. We compared the physician and pharmacist diagnoses with the decision rule results. The primary outcome was a moderate or severe ADE, defined as an unintended and harmful event related to medication use or misuse, which required a change in medical therapy, diagnostic testing, consultation, or admission. An independent committee adjudicated uncertain and discordant cases. We calculated the diagnostic accuracy of both rules.
RESULTS: Among 1,529 patients, 184 (12.0%) were diagnosed with an ADE. Rule 1 contained the variables 1) having a preexisting medical condition or having taken antibiotics within 1 week and 2) age > 80 years or having a medication change within 28 days. They had a sensitivity of 91.3% (95% confidence interval [CI] = 86.3%-95.0%) and a specificity of 37.9% (95% CI = 35.3%-40.6%) for ADEs.
CONCLUSIONS: Our study validated clinical decision rules that can be applied by clinical pharmacists to limit the number of patients requiring medication review, while identifying the majority of patients presenting with clinically significant ADEs.

PMID: 29517818 [PubMed - indexed for MEDLINE]

Echinocandins vs. amphotericin B against invasive candidiasis in children and neonates: A meta-analysis of randomized controlled trials.

Int J Antimicrob Agents. 2019 Jun;53(6):789-794

Authors: Chen YH, Cheng IL, Lai CC, Tang HJ

Abstract
OBJECTIVE: The aim of this meta-analysis was to assess the efficacy and safety of treatment with echinocandins compared with amphotericin B in paediatric patients with invasive candidiasis.
METHODS: PubMed, Embase and Cochrane databases were searched up to August 2018. Only randomized controlled trials (RCTs) evaluating echinocandins and amphotericin B in the treatment of paediatric patients with invasive candidiasis were included. The outcomes were clinical responses and adverse effects.
RESULTS: Five RCTs of 354 patients (191 patients in the echinocandins group and 163 patients in the amphotericin B group) were included in this study. Overall, no significant differences in clinical response were found between echinocandins and amphotericin B (odds ratio [OR], 1.38; 95% confidence interval [CI], 0.68-2.80; I2 = 39%). Similar results were also observed in the high-risk group (OR, 3.10; 95% CI, 0.10-97.23; I2 = 76%), the low-risk group (OR, 1.29; 95% CI, 0.36-4.62; I2 = 21%) and the neutropenia group (OR, 1.56; 95% CI, 0.75-3.26; I2 = 0%). The risk of discontinuing treatment because of adverse effects was significantly lower in the echinocandins group than in the amphotericin B group (OR, 0.30, 95% CI, 0.12-0.76; I2 = 0%).
CONCLUSIONS: There were no differences in efficacy between the echinocandins group and the amphotericin B group in the treatment of invasive candidiasis in paediatric patients. However, the echinocandins group had a significantly lower risk of discontinuing treatment than the amphotericin B group.

PMID: 30831231 [PubMed - indexed for MEDLINE]

Fluoroquinolone-based versus β-lactam-based regimens for complicated intra-abdominal infections: a meta-analysis of randomised controlled trials.

Int J Antimicrob Agents. 2019 Jun;53(6):746-754

Authors: Mavros MN, Theochari NA, Kyriakidou M, Economopoulos KP, Sava JA, Falagas ME

Abstract
Complicated intra-abdominal infections (cIAIs) are common and confer significant morbidity, mortality and costs. In this era of evolving antimicrobial resistance, selection of appropriate empirical antimicrobials is paramount. This systematic review and meta-analysis of randomised controlled trials compared the effectiveness and safety of fluoroquinolone (FQ)-based versus β-lactam (BL)-based regimens for the treatment of patients with cIAIs. Primary outcomes were treatment success in the clinically evaluable (CE) population and all-cause mortality in the intention-to-treat (ITT) population. Subgroup analyses were performed based on specific antimicrobials, infection source and isolated pathogens. Seven trials (4125 patients) were included. FQ-based regimens included moxifloxacin (four studies) or ciprofloxacin/metronidazole (three studies); BL-based regimens were ceftriaxone/metronidazole (three studies), carbapenems (two studies) or piperacillin/tazobactam (two studies). There was no difference in effectiveness in the CE (2883 patients; RR = 1.00, 95% CI 0.95-1.04) or ITT populations (3055 patients; RR = 0.97, 95% CI 0.94-1.01). Mortality (3614 patients; RR = 1.04, 95% CI 0.75-1.43) and treatment-related adverse events (2801 patients; RR = 0.97, 95% CI 0.70-1.33) were also similar. On subset analysis, moxifloxacin was slightly less effective than BLs in the CE (1934 patients; RR = 0.96, 95% CI 0.93-0.99) and ITT populations (1743 patients; RR = 0.94, 95% CI 0.91-0.98). Although FQ- and BL-based regimens appear equally effective and safe for the treatment of cIAIs, limited data suggest slightly inferior results with moxifloxacin. Selection of empirical coverage should be based on local bacterial epidemiology and patterns of resistance as well as antimicrobial stewardship protocols.

PMID: 30639629 [PubMed - indexed for MEDLINE]

Hepatitis C virus therapy: No one will be left behind.

Int J Antimicrob Agents. 2019 Jun;53(6):755-760

Authors: Bourlière M, Pietri O

Abstract
The advent of oral direct-acting antiviral agents (DAAs) has dramatically improved the hepatitis C treatment landscape in the last 4 years, providing cure rates over 95% with shorter duration of treatment and a very good safety profile. This gave access to treatment to almost all Hepatitis C virus (HCV)-infected patients. The launch of two pangenotypic fixed-dose combinations (FDCs) in 2017 was a step forward in hepatitis C treatment, by slightly increasing efficacy and more importantly allowing the treatment of patients without HCV genotyping, and in some cases without fibrosis assessment. New triple regimens have solved the issue of retreatment of the few patients who present failure to DAAs therapy. In the present review we describe the current HCV landscape that allows almost all HCV-infected patients to be cured.

PMID: 30605721 [PubMed - indexed for MEDLINE]

Chemical-Induced Phenotypes at CTD Help Inform the Predisease State and Construct Adverse Outcome Pathways.

Toxicol Sci. 2018 09 01;165(1):145-156

Authors: Davis AP, Wiegers TC, Wiegers J, Johnson RJ, Sciaky D, Grondin CJ, Mattingly CJ

Abstract
The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a public resource that manually curates the scientific literature to provide content that illuminates the molecular mechanisms by which environmental exposures affect human health. We introduce our new chemical-phenotype module that describes how chemicals can affect molecular, cellular, and physiological phenotypes. At CTD, we operationally distinguish between phenotypes and diseases, wherein a phenotype refers to a nondisease biological event: eg, decreased cell cycle arrest (phenotype) versus liver cancer (disease), increased fat cell proliferation (phenotype) versus morbid obesity (disease), etc. Chemical-phenotype interactions are expressed in a formal structured notation using controlled terms for chemicals, phenotypes, taxon, and anatomical descriptors. Combining this information with CTD's chemical-disease module allows inferences to be made between phenotypes and diseases, yielding potential insight into the predisease state. Integration of all 4 CTD modules furnishes unique opportunities for toxicologists to generate computationally predictive adverse outcome pathways, linking chemical-gene molecular initiating events with phenotypic key events, adverse diseases, and population-level health outcomes. As examples, we present 3 diverse case studies discerning the effect of vehicle emissions on altered leukocyte migration, the role of cadmium in influencing phenotypes preceding Alzheimer disease, and the connection of arsenic-induced glucose metabolic phenotypes with diabetes. To date, CTD contains over 165 000 interactions that connect more than 6400 chemicals to 3900 phenotypes for 760 anatomical terms in 215 species, from over 19 000 scientific articles. To our knowledge, this is the first comprehensive set of manually curated, literature-based, contextualized, chemical-induced, nondisease phenotype data provided to the public.

PMID: 29846728 [PubMed - indexed for MEDLINE]

When potion becomes poison! A case report of flecainide toxicity.

J Postgrad Med. 2017 Oct-Dec;63(4):265-267

Authors: Bajaj S, Tullu MS, Khan Z, Agrawal M

Abstract
We report a 48-day-old female infant, who developed cardiac conduction abnormalities and seizures secondary to supratherapeutic doses of oral flecainide. Flecainide was started in this infant for treatment of supraventricular tachycardia. The drug was withdrawn with successful normalization of the QRS complex and no further recurrence of seizures. The Naranjo probability score for adverse drug reaction was 8, making the causality "probable." The case restates an important message that physicians should be aware of the side effects of the drugs that they prescribe, especially of those drugs which have a narrow therapeutic window.

PMID: 28272074 [PubMed - indexed for MEDLINE]

Extended likelihood ratio test-based methods for signal detection in a drug class with application to FDA's adverse event reporting system database.

Stat Methods Med Res. 2018 03;27(3):876-890

Authors: Zhao Y, Yi M, Tiwari RC

Abstract
A likelihood ratio test, recently developed for the detection of signals of adverse events for a drug of interest in the FDA Adverse Events Reporting System database, is extended to detect signals of adverse events simultaneously for all the drugs in a drug class. The extended likelihood ratio test methods, based on Poisson model (Ext-LRT) and zero-inflated Poisson model (Ext-ZIP-LRT), are discussed and are analytically shown, like the likelihood ratio test method, to control the type-I error and false discovery rate. Simulation studies are performed to evaluate the performance characteristics of Ext-LRT and Ext-ZIP-LRT. The proposed methods are applied to the Gadolinium drug class in FAERS database. An in-house likelihood ratio test tool, incorporating the Ext-LRT methodology, is being developed in the Food and Drug Administration.

PMID: 27142982 [PubMed - indexed for MEDLINE]

Class-imbalanced subsampling lasso algorithm for discovering adverse drug reactions.

Stat Methods Med Res. 2018 03;27(3):785-797

Authors: Ahmed I, Pariente A, Tubert-Bitter P

Abstract
Background All methods routinely used to generate safety signals from pharmacovigilance databases rely on disproportionality analyses of counts aggregating patients' spontaneous reports. Recently, it was proposed to analyze individual spontaneous reports directly using Bayesian lasso logistic regressions. Nevertheless, this raises the issue of choosing an adequate regularization parameter in a variable selection framework while accounting for computational constraints due to the high dimension of the data. Purpose Our main objective is to propose a method, which exploits the subsampling idea from Stability Selection, a variable selection procedure combining subsampling with a high-dimensional selection algorithm, and adapts it to the specificities of the spontaneous reporting data, the latter being characterized by their large size, their binary nature and their sparsity. Materials and method Given the large imbalance existing between the presence and absence of a given adverse event, we propose an alternative subsampling scheme to that of Stability Selection resulting in an over-representation of the minority class and a drastic reduction in the number of observations in each subsample. Simulations are used to help define the detection threshold as regards the average proportion of false signals. They are also used to compare the performances of the proposed sampling scheme with that originally proposed for Stability Selection. Finally, we compare the proposed method to the gamma Poisson shrinker, a disproportionality method, and to a lasso logistic regression approach through an empirical study conducted on the French national pharmacovigilance database and two sets of reference signals. Results Simulations show that the proposed sampling strategy performs better in terms of false discoveries and is faster than the equiprobable sampling of Stability Selection. The empirical evaluation illustrates the better performances of the proposed method compared with gamma Poisson shrinker and the lasso in terms of number of reference signals retrieved.

PMID: 27114328 [PubMed - indexed for MEDLINE]

[The general practitioner's knowledge and attitude towards proton pump inhibitors adverse effects].

Therapie. 2019 Aug 01;:

Authors: Rudelle K, Laroche ML

Abstract
INTRODUCTION: Proton pump inhibitors (PPIs) are frequently prescribed by general practitioners (GPs) who consider these drugs to be safe. However, more and more adverse drug reactions (ADRs) associated with PPIs are described.
OBJECTIVE: To determine the level of knowledge and attitude of GPs with respect to the ADRs of PPIs in adults.
METHOD: The GPs of the Nouvelle-Aquitaine region and the chief residents or former chief residents of the 35 French university departments of general medicine were questioned online using a list of 12 ADRs based on a semi-systematic literature review (neutropenia, thrombocytopenia, anemia, hypomagnesemia, increased liver enzymes, renal failure, pneumonitis, skin reactions, fracture, gastric polyps, microscopic colitis, Clostridium difficile colitis) and their attitude towards these ADRs.
RESULT: Out of the 232 (7.5%) GPs who participated, 38.4% had come across PPI ADRs (mainly digestive) in the last 6 months. These ADRs had been reported to pharmacovigilance in only 2.3% of the cases. No ADR at all was known by more than 70% of the GPs. The attitude of the GPs who had identified them was, in the majority, to stop PPI treatement. No difference in knowledge was found between university supervisors and non-supervisors. Finally, 74.7% of GPs declared that they required more information on IPP ADRs and 80.4% were willing to "deprescribe" these drugs.
CONCLUSION: Aside from digestive ADRs, GPs have a poor knowledge of IPP-related ADRs. Those who do know them have an appropriate attitude and interrupt IPP treatment. The information requested by the GPs about the risks of PPIs is pertinent, particularly in a PPI-adapted prescription procedure, which also involves knowing how to "deprescribe".

PMID: 31471066 [PubMed - as supplied by publisher]

Pharmacovigilance Assessment of Drug-Induced Acute Pancreatitis Using a Spontaneous Reporting Database.

Int J Toxicol. 2019 Aug 30;:1091581819870717

Authors: Niinomi I, Hosohata K, Oyama S, Inada A, Wakabayashi T, Iwanaga K

Abstract
BACKGROUND: Acute pancreatitis (AP) is associated with risks of morbidity and mortality. The incidence of AP recently increased compared to that traditionally reported in the literature.
OBJECTIVE: The purpose of this study was to evaluate the possible association between AP and drugs using the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database of adverse drug events.
METHODS: Adverse event reports submitted to the JADER database between 2004 and 2017 were analyzed. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence intervals for signal detection.
RESULTS: A total of 3,443 reports (0.17% of all adverse events) were identified as drug-induced AP, in which 431 different drugs were involved. Acute pancreatitis was frequently reported in men (58.5%) in their 60s (19.1%); 40.6% developed AP within 4 weeks after the treatment. Among the most frequently reported drugs, signals were detected for prednisolone, ribavirin, sitagliptin, mesalazine, tacrolimus, and l-asparaginase, which are well-known causes of AP. Telaprevir, donepezil, and ustekinumab also generated signals. As for drugs with high RORs, l-asparaginase and alogliptin were noteworthy.
CONCLUSION: Most of the identified drugs were already known to induce AP, but the likelihood of the reporting of AP varied among the drugs. Our results should raise physicians' awareness of drugs associated with AP, but further investigation of these medications is warranted.

PMID: 31470743 [PubMed - as supplied by publisher]