A Pharmacoepidemiology Database System for Monitoring Risk Due to the Use of Medicines by New Zealand Primary Care Patients.

Drug Saf. 2017 Dec;40(12):1259-1277

Authors: Tomlin AM, Reith DM, Woods DJ, Lloyd HS, Smith A, Fountain JS, Tilyard MW

Abstract
INTRODUCTION: The use of large record-linked healthcare databases for drug safety research and surveillance is now accepted practice. New Zealand's standardized national healthcare datasets provide the potential to automate the conduct of pharmacoepidemiological studies to provide rapid validation of medicine safety signals.
OBJECTIVES: Our objectives were to describe the methodology undertaken by a semi-automated computer system developed to rapidly assess risk due to drug exposure in New Zealand's population of primary care patients and to compare results from three studies with previously published findings.
METHODS: Data from three national databases were linked at the patient level in the automated studies. A retrospective nested case-control design was used to evaluate risk for upper gastrointestinal bleeding (UGIB), acute kidney failure (AKF), and serious arrhythmia associated with individual medicines, therapeutic classes of medicines, and concurrent use of medicines from multiple therapeutic classes.
RESULTS: The patient cohort available for each study included 5,194,256 patients registered between 2007 and 2014, with a total of 34,630,673 patient-years at risk. An increased risk for UGIB was associated with non-steroidal anti-inflammatory drugs (NSAIDs) (adjusted odds ratio [AOR] 4.16, 95% confidence interval [CI] 3.90-4.43, p < 0.001) and selective serotonin reuptake inhibitors (AOR 1.39, 95% CI 1.20-1.62, p < 0.001); an increased risk for AKF was associated with NSAIDs (AOR 1.78, 95% CI 1.73-1.83, p < 0.001) and proton pump inhibitors (AOR 1.78, 95% CI 1.72-1.83, p < 0.001); and an increased risk for serious arrhythmia was associated with fluoroquinolones (AOR 1.38, 95% CI 1.26-151, p < 0.001) and penicillins (AOR 1.69, 95% CI 1.61-1.77, p < 0.001).
CONCLUSIONS: Automated case-control studies using New Zealand's healthcare datasets can replicate associations of risk with drug exposure consistent with previous findings. Their speed of conduct enables systematic monitoring of risk for adverse events associated with a wide range of medicines.

PMID: 28766108 [PubMed - indexed for MEDLINE]

Neurological Adverse Effects Attributable to β-Lactam Antibiotics: A Literature Review.

Drug Saf. 2017 Dec;40(12):1171-1198

Authors: Deshayes S, Coquerel A, Verdon R

Abstract
β-lactam antibiotics are commonly prescribed antibiotic drugs. To describe the clinical characteristics, risk markers and outcomes of β-lactam antibiotic-induced neurological adverse effects, we performed a general literature review to provide updated clinical data about the most used β-lactam antibiotics. For selected drugs in each class available in France (ticarcillin, piperacillin, temocillin, ceftazidime, cefepime, cefpirome, ceftaroline, ceftobiprole, ceftolozane, ertapenem and aztreonam), a systematic literature review was performed up to April 2016 via an electronic search on PubMed. Articles that reported original data, written in French, Spanish, Portuguese or English, with available individual data for patients with neurological symptoms (such as seizure, disturbed vigilance, confusional state, myoclonia, localising signs, and/or hallucinations) after the introduction of a β-lactam antibiotic were included. The neurological adverse effects of piperacillin and ertapenem are often described as seizures and hallucinations (>50 and 25% of cases, respectively). Antibiotic treatment is often adapted to renal function (>70%), and underlying brain abnormalities are seen in one in four to one in three cases. By contrast, the neurological adverse drug reactions of ceftazidime and cefepime often include abnormal movements but few hallucinations and seizures. These reactions are associated with renal insufficiency (>80%) and doses are rarely adapted to renal function. Otherwise, it appears that monobactams do not have serious neurological adverse drug reactions and that valproic acid and carbapenem combinations should be avoided. The onset of disturbed vigilance, myoclonus, and/or seizure in a patient taking β-lactam antibiotics, especially if associated with renal insufficiency or underlying brain abnormalities, should lead physicians to suspect adverse drug reactions and to consider changes in antibacterial therapy.

PMID: 28755095 [PubMed - indexed for MEDLINE]

Safety Profile of Eslicarbazepine Acetate as Add-On Therapy in Adults with Refractory Focal-Onset Seizures: From Clinical Studies to 6 Years of Post-Marketing Experience.

Drug Saf. 2017 Dec;40(12):1231-1240

Authors: Gama H, Vieira M, Costa R, Graça J, Magalhães LM, Soares-da-Silva P

Abstract
INTRODUCTION: Eslicarbazepine acetate was first approved in the European Union in 2009 as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.
OBJECTIVE: The objective of this study was to review the safety profile of eslicarbazepine acetate analyzing the data from several clinical studies to 6 years of post-marketing surveillance.
METHODS: We used a post-hoc pooled safety analysis of four phase III, double-blind, randomized, placebo-controlled studies (BIA-2093-301, -302, -303, -304) of eslicarbazepine acetate as add-on therapy in adults. Safety data of eslicarbazepine acetate in special populations of patients aged ≥65 years with partial-onset seizures (BIA-2093-401) and subjects with moderate hepatic impairment (BIA-2093-111) and renal impairment (BIA-2093-112) are also considered. The incidences of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and serious adverse events were analyzed. The global safety database of eslicarbazepine acetate was analyzed for all cases from post-marketing surveillance from 1 October, 2009 to 21 October, 2015.
RESULTS: From a pooled analysis of four phase III studies, it was concluded that the incidence of treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation, and adverse drug reactions were dose dependent. Dizziness, somnolence, headache, and nausea were the most common treatment-emergent adverse events (≥10% of patients) and the majority were of mild-to-moderate intensity. No dose-dependent trend was observed for serious adverse events and individual serious adverse events were reported in less than 1% of patients. Hyponatremia was classified as a possibly related treatment-emergent adverse event in phase III studies (1.2%); however, after 6 years of post-marketing surveillance it represents the most frequently (10.2%) reported adverse drug reaction, with more than half of these cases occurring with eslicarbazepine acetate at daily doses of 1200 mg. Other adverse drug reactions reported in post-marketing surveillance are seizure (5.8%), dizziness (4.1%), rash (2.6%), and fatigue (2.1%). The safety profile of eslicarbazepine acetate in renal and hepatic impairment subjects (phase I studies) and in elderly patients (phase III study) did not raise any specific concern.
CONCLUSION: After 6 years of post-marketing surveillance, eslicarbazepine acetate maintains a similar safety profile to that observed in pivotal clinical studies.

PMID: 28752473 [PubMed - indexed for MEDLINE]

Commercial Online Social Network Data and Statin Side-Effect Surveillance: A Pilot Observational Study of Aggregate Mentions on Facebook.

Drug Saf. 2017 Dec;40(12):1199-1204

Authors: Huesch MD

Abstract
INTRODUCTION: Surveillance of the safety of prescribed drugs after marketing approval has been secured remains fraught with complications. Formal ascertainment by providers and reporting to adverse-event registries, formal surveys by manufacturers, and mining of electronic medical records are all well-known approaches with varying degrees of difficulty, cost, and success. Novel approaches may be a useful adjunct, especially approaches that mine or sample internet-based methods such as online social networks.
METHODS: A novel commercial software-as-a-service data-mining product supplied by Sysomos from Datasift/Facebook was used to mine all mentions on Facebook of statins and stain-related side effects in the US in the 1-month period 9 January 2017 through 8 February 2017.
RESULTS: A total of 4.3% of all 25,700 mentions of statins also mentioned typical stain-related side effects. Multiple methodological weaknesses stymie interpretation of this percentage, which is however not inconsistent with estimates that 5-20% of patients taking statins will experience typical side effects at some time.
CONCLUSIONS: Future work on pharmacovigilance may be informed by this novel commercial tool, but the inability to mine the full text of a posting poses serious challenges to content categorization.

PMID: 28748367 [PubMed - indexed for MEDLINE]

Suspected Adverse Effects After Human Papillomavirus Vaccination: A Temporal Relationship Between Vaccine Administration and the Appearance of Symptoms in Japan.

Drug Saf. 2017 Dec;40(12):1219-1229

Authors: Ozawa K, Hineno A, Kinoshita T, Ishihara S, Ikeda SI

Abstract
INTRODUCTION: In Japan, after receiving human papillomavirus vaccination, a significant number of adolescent girls experienced various symptoms, the vast majority of which have been ascribed to chronic regional pain syndrome, orthostatic intolerance, and/or cognitive dysfunction. However, a causal link has not been established between human papillomavirus vaccination and the development of these symptoms.
OBJECTIVE: The aim of this study was to clarify the temporal relationship between human papillomavirus vaccination and the appearance of post-vaccination symptoms.
METHODS: Between June 2013 and December 2016, we examined symptoms and objective findings in 163 female patients who had received human papillomavirus vaccination. We used newly defined diagnostic criteria for accurate inclusion of patients who experienced adverse symptoms after human papillomavirus vaccination; these diagnostic criteria were created for this study, and thus their validity and reliability have not been established.
RESULTS: Overall, 43 female patients were excluded. Among the remaining 120 patients, 30 were diagnosed as having definite vaccine-related symptoms, and 42 were diagnosed as probable. Among these 72 patients, the age at initial vaccination ranged from 11 to 19 years (average 13.6 ± 1.6 years), and the age at appearance of symptoms ranged from 12 to 20 years (average 14.4 ± 1.7 years). The patients received the initial human papillomavirus vaccine injection between May 2010 and April 2013. The first affected girl developed symptoms in October 2010, and the last two affected girls developed symptoms in October 2015. The time to onset after the first vaccine dose ranged from 1 to 1532 days (average 319.7 ± 349.3 days).
CONCLUSIONS: The period of human papillomavirus vaccination considerably overlapped with that of unique post-vaccination symptom development. Based on these sequential events, it is suggested that human papillomavirus vaccination is related to the transiently high prevalence of the previously mentioned symptoms including chronic regional pain syndrome and autonomic and cognitive dysfunctions in the vaccinated patients.

PMID: 28744844 [PubMed - indexed for MEDLINE]

Analysis of safety-related regulatory actions by Japan's pharmaceutical regulatory agency.

Pharmacoepidemiol Drug Saf. 2017 Nov;26(11):1314-1320

Authors: Ishiguro C, Misu T, Iwasa E, Izawa T

Abstract
PURPOSE: To evaluate the safety-related regulatory actions implemented by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in 2012.
METHODS: We analyzed serious safety issues appended to drug package inserts (PIs) in Japan in 2012. The issues were characterized according to drug class, adverse event, years since drug approval, initiator of regulatory actions, revised section of PI, and evidence source. We also quantified the durations from signal detection to tentative decision and from tentative decision to regulatory action.
RESULTS: We identified 144 serious safety issues during the study period, and the majority of evidence originated from spontaneous reports (83.5%). The PMDA initiated regulatory actions for half of all safety issues, and the median duration from drug approval to regulatory action was 8 years (interquartile range [IQR], 3-26.5 years). The median duration was 49 days (IQR, 0-362 days) from signal detection to tentative decision and 84 days (IQR, 63-136 days) from tentative decision to regulatory action. Several safety issues involving older drugs and multiple products had protracted decision-making durations.
CONCLUSIONS: Most safety issues led to prompt regulatory actions predominantly based on spontaneous reports. Some safety issues that were not easily detected by the spontaneous reporting system were identified years after approval. In addition, several safety issues required assessments of multiple drug products, which prolonged the decision-making process.

PMID: 28722235 [PubMed - indexed for MEDLINE]

Postmarketing withdrawal of human medicinal products because of adverse reactions in animals: a systematic review and analysis.

Pharmacoepidemiol Drug Saf. 2017 Nov;26(11):1328-1337

Authors: Onakpoya IJ, Heneghan CJ, Aronson JK

Abstract
PURPOSE: We have identified human medicinal products for which animal data were used as evidence for withdrawal, determined whether the adverse reactions were reported in humans, established whether confirmatory human studies were conducted, and explored the withdrawal patterns over time.
METHODS: We searched the World Health Organization's Consolidated List of [Medicinal] Products, drug regulatory authorities' websites, PubMed, Google Scholar, and selected textbooks to identify medicinal products withdrawn from 1950 to June 2016. We included medicinal products for which animal data were specifically reported as a reason for withdrawal. We used a checklist adapted from the International Agency for Research on Cancer criteria to rate the evidence.
RESULTS: In 37 cases, evidence from animals was the reason given for withdrawal between 1963 and 2000. Evidence of carcinogenicity was cited in 23 cases (62%). Limited evidence for harms occasioned withdrawal in over 80% of cases. In 11 cases (30%), the adverse drug reactions were subsequently reported in humans. In 5 instances (14%), formal studies were conducted in humans. The median interval to withdrawal following reports of adverse reactions was 2 years (IQR = 1-9 y).
CONCLUSIONS: Regulatory authorities and drug manufacturers are likely to withdraw medicinal products quickly from the market when animal experiments suggest increased risks of cancers or congenital malformations. Human studies are seldom conducted when harms are suspected in animals. Future research should explore better methods of extrapolating harms data from animal research to humans.

PMID: 28691251 [PubMed - indexed for MEDLINE]

Drug-induced obesity and its metabolic consequences: a review with a focus on mechanisms and possible therapeutic options.

J Endocrinol Invest. 2017 Nov;40(11):1165-1174

Authors: Verhaegen AA, Van Gaal LF

Abstract
Weight gain is a common side effect of many widely used drugs. Weight gain of a few kilograms to an increase of 10% or more of initial body weight has been described. Not only the weight gain as such puts a burden on the health risks of the involved patients, the accompanying increase in the incidence of the metabolic syndrome, type 2 diabetes mellitus, and cardiovascular risk factors urges the caregiver to identify and to closely monitor the patients at risk. In this review, the different classes of drugs with significant weight gaining properties and the metabolic consequences are described. Specific attention is given to pathogenetic mechanisms underlying the metabolic effects and to potential therapeutic measures to prevent them.

PMID: 28660606 [PubMed - indexed for MEDLINE]

Effect of integrated yoga on anti-psychotic induced side effects and cognitive functions in patients suffering from schizophrenia.

J Complement Integr Med. 2018 Jun 26;:

Authors: Verma M, Bhargav H, Varambally S, Raghuram N, Bn G

Abstract
Background Twenty one (12 females) subjects, diagnosed with schizophrenia by a psychiatrist using ICD-10, in the ages 52.87 + 9.5 years and suffering since 24.0 ± 3.05 years were recruited into the study from a schizophrenia rehabilitation center in Bengaluru. Methods All subjects were taking anti-psychotic medications and were in stable state for more than a month. Psychiatric medications were kept constant during the study period. Assessments were done at three points of time: (1) baseline, (2) after one month of usual routine (pre) and (3) after five months of validated Integrated Yoga (IY) intervention (post). Validated 1 h Yoga module (consisting of asanas, pranayama, relaxation techniques and chantings) was practiced for 5 months, five sessions per week. Antipsychotic-induced side effects were assessed using Simpson Angus Scale (SAS) and Udvalg for Kliniske Undersogelser (UKU) side effect rating scale. Cognitive functions (using Trail making Test A and B), clinical symptoms and anthropometry were assessed as secondary variables. Comparisons between "pre" and "post" data was done using paired samples t-tests after subtracting baseline scores from them respectively. Results At the end of five months, significant reduction in drug-induced Parkinsonian symptoms (SAS score; p=0.001) and 38 items of UKU scale was observed along with significant improvement in processing speed, executive functions and negative symptoms of schizophrenia patients. No side effects of Yoga were reported. Conclusions The present study provides preliminary evidence for usefulness of Integrated Yoga intervention in managing anti-psychotic-induced side effects.

PMID: 29944467 [PubMed - as supplied by publisher]

Incidence of and Predictors for Early Discontinuation of Biological Therapies in Veteran Patients with Inflammatory Bowel Disease.

Inflamm Bowel Dis. 2017 Aug;23(8):1434-1439

Authors: Feagins LA, Waljee A, Hou JK, Gu P, Kanjo S, Rudrapatna V, Cipher DJ, Govani S, Gaidos J

Abstract
BACKGROUND: Biological therapies are effective for inducing and maintaining remission in inflammatory bowel disease (IBD), but patients often require changes in biological agents over the course of their illness. We sought to evaluate the rate of and reasons for discontinuing biological agents and to identify risk factors for their discontinuation.
METHODS: We performed a retrospective cohort study across 4 VA hospital systems (Dallas, TX; Houston, TX; Ann Arbor, MI; Richmond, VA). Patients with IBD who were started on biological therapy between 1998 and 2015 were identified, and their medical records were reviewed to confirm the diagnosis of IBD and to collect study data.
RESULTS: Of 1969 patients with IBD; 256 were treated with 346 courses of therapy. By 6 months after initiation of therapy, 82 (24%) had stopped the biological agent. Among patients starting their first biological agent, 21.5% had stopped by 6 months. Patients taking a concomitant thiopurine and those with ileocolonic disease or a nonpenetrating, nonstricturing phenotype were less likely to discontinue biological therapy, whereas those taking 5-ASA concomitantly were more likely to discontinue biological therapy. The most common reasons for discontinuation were primary nonresponse (40%) and adverse drug reactions (29%).
CONCLUSIONS: In conclusion, in a large multicenter VA cohort, we found that 24% of patients who are prescribed a biological stop their treatment early, most commonly for primary nonresponse or for an adverse drug reaction. Consideration should be given to treating patients with a concomitant thiopurine if at all possible, as this reduces the likelihood of early discontinuation.

PMID: 28570429 [PubMed - indexed for MEDLINE]

Effect of Opioids and Benzodiazepines on Clinical Outcomes in Patients Receiving Palliative Care: An Exploratory Analysis.

J Palliat Med. 2017 Nov;20(11):1274-1279

Authors: Boland JW, Allgar V, Boland EG, Oviasu O, Agar M, Currow DC, Johnson MJ

Abstract
BACKGROUND: Medications for symptom management in palliative care have associated, but poorly understood, harms. Drug-related harms have important clinical implications, may impact on patients' compliance and contribute to symptoms.
OBJECTIVE: To explore the longitudinal relationship between oral morphine equivalent daily dose (MEDD) and oral diazepam equivalent daily dose (DEDD) with functional, cognitive, and symptom outcomes in patients receiving palliative care.
DESIGN: Secondary longitudinal analysis of cancer decedents (n = 235) was carried out from a palliative care randomized controlled trial with multiple outcome measures. At each time point, MEDD and DEDD were calculated. Multilevel modeling was used to investigate independent associations between MEDD and DEDD, and cognitive and gastrointestinal symptoms, quality of life (QoL), performance status, and survival.
SETTING/SUBJECTS: Participants were recruited from a specialist palliative care program in southern Adelaide, were expected to live ≥48 hours, had pain in the previous 3 months, and a baseline Folstein Mini-Mental Status Examination score ≥25.
RESULTS: Cognitive and gastrointestinal symptoms, performance status, and QoL worsened over time. In the adjusted multilevel analysis, statistically significant relationships remained between MEDD/DEDD and worsening performance status (p = 0.001), DEDD and gastrointestinal effects (p < 0.001), MEDD and QoL (p < 0.022).
CONCLUSIONS: Commonly used palliative medications were associated with deteriorating performance status. The lack of association between MEDD with gastrointestinal or cognitive symptoms underlines that these associations are not inevitable with close attention. This analysis highlights the importance of including other medications as confounders when exploring medication-related harms. An understanding of the risk-benefit balance of medications is needed to maximize net benefits for patients.

PMID: 28570119 [PubMed - indexed for MEDLINE]

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Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach.

Toxicol Lett. 2018 Jun 21;:

Authors: Ruan LY, Fan JT, Hong W, Zhao H, Li MH, Jiang L, Fu YH, Xing YX, Chen C, Wang JS

Abstract
Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

PMID: 29936297 [PubMed - as supplied by publisher]

Anti-PCSK9 treatment: Is ultra-low LDL always good?

Cardiovasc Res. 2018 Jun 20;:

Authors: Noto D, Giammanco A, Barbagallo CM, Cefalù AB, Averna MR

Abstract
Anti-pcsk9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (Mab) are novel, potent lipid-lowering drugs. They demonstrated to improve the lipid profile in high cardiovascular risk patients. Anti-pcsk9 Mab inhibit the targeted LDL-receptor degradation induced by pcsk9 protein and are able to reduce LDL cholesterol (LDL-C) levels on top of conventional lipid-lowering therapy.Though these drugs proved to be very safe in the short term, little is known about the possible long term effects, due to the short period of their marketing. The genetic low-cholesterol syndromes (LCS) represent the natural models of the lipid-lowering anti-PCSK9 therapy, and a valuable opportunity to predict the long term effects of these drugs. By looking at the clinical features of such models we could be able to foresee possible drug-induced side effects. In the present review the correspondences and discordances between the side effects of anti-pcsk9 therapy and the corresponding LCS models will be examined in the attempt to forecast possible long term consequences of these novel lipid lowering agents.

PMID: 29931148 [PubMed - as supplied by publisher]

The safety, tolerability, and pharmacokinetic profile of GSK2838232, a novel 2nd generation HIV maturation inhibitor, as assessed in healthy subjects.

Pharmacol Res Perspect. 2018 Jul;6(4):e00408

Authors: Johnson M, Jewell RC, Peppercorn A, Gould E, Xu J, Lou Y, Davies M, Baldwin S, Tenorio AR, Burke M, Jeffrey J, Johns BA

Abstract
This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose-escalation studies in healthy subjects which assessed single oral doses (5-250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug-related AEs. GSK2838232 tested fasted was quickly absorbed with a tmax of 2-3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and Cmax. Overall, following single doses GSK2838232 AUC and Cmax generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20-200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and Cmax by 10- and 3-fold, respectively. Half-life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat-dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once-daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.

PMID: 29930812 [PubMed - in process]

Stevens-Johnsons syndrome or drug-induced lupus - a clinical dilemma: A case report and review of the literature.

Biomed Rep. 2018 Jul;9(1):37-41

Authors: Bojinca VC, Bojinca M, Gheorghe M, Birceanu A, Iosif CI, Balanescu SM, Balanescu AR

Abstract
Tumor necrosis factor inhibitors are the first biological agents used in the treatment of rheumatoid arthritis (RA) to have yielded satisfactory results in terms of clinical improvement and radiologic progression, but they are also associated with the possibility of occurrence of a number of autoimmune systemic events [drug-induced lupus (DIL), vasculitis, sarcoidosis] and localized adverse events [uveitis, psoriasis, interstitial lung disease, erythema multiforme including the major form Stevens-Johnson syndrome (SJS)]. During treatment with TNF inhibitors, many patients develop positivity for antinuclear, antihistone and anti-double stranded DNA antibodies, though only a minority of patients will develop clinical manifestations and approximately less than 1% will fulfill the classification criteria for systemic lupus erythematosus. Mucocutaneous manifestations are the most frequent manifestations of DIL following treatment with TNF inhibitors, and can be severe and occasionally difficult to differentiate from erythema multiforme/SJS. Stopping the causative drug (the TNF inhibitor) and general supportive measures are usually sufficient in mild forms, but in moderate to severe forms, systemic glucocorticoids and sometimes immunosuppressive drugs are required. The present report presents the case of a patient with rheumatoid arthritis who developed severe recurrent cutaneous reactions and positive autoantibodies during TNF inhibitor treatment, with difficulties in differential diagnosis and treatment. A review of the literature is also presented.

PMID: 29930803 [PubMed]

Management of Subfoveal Perfluorocarbon Liquid: A Review.

Ophthalmologica. 2018;240(1):1-7

Authors: Liu W, Gao M, Liang X

Abstract
Perfluorocarbon liquid (PFCL) has been widely used in vitreoretinal surgeries, especially in retinal detachment treatment. A prominent complication of intraoperative PFCL application is inadvertent subretinal PFCL retention. Subfoveal PFCL, even in small amounts, receives much attention due to its potential side effect on the macular structure and function. Whether to observe with follow-up or to deal with surgery is often an intractable problem in the management of subfoveal PFCL. Safety and necessity are the 2 key issues in considering surgical treatment, that is, can we avoid surgically induced macular injury and will surgery be beneficial for the recovery of vision? Herein, the authors review sub-foveal PFCL retention with its risk factors, morphological manifestations, pathological studies, clinical natural consequences, and different surgical methods with their outcomes. Analysis of the existing literature shows that visual acuity improved significantly after subfoveal PFCL removal or displacement and was positively correlated with visual acuity before the operation.

PMID: 29669355 [PubMed - indexed for MEDLINE]

A hierarchical anatomical classification schema for prediction of phenotypic side effects.

PLoS One. 2018;13(3):e0193959

Authors: Wadhwa S, Gupta A, Dokania S, Kanji R, Bagler G

Abstract
Prediction of adverse drug reactions is an important problem in drug discovery endeavors which can be addressed with data-driven strategies. SIDER is one of the most reliable and frequently used datasets for identification of key features as well as building machine learning models for side effects prediction. The inherently unbalanced nature of this data presents with a difficult multi-label multi-class problem towards prediction of drug side effects. We highlight the intrinsic issue with SIDER data and methodological flaws in relying on performance measures such as AUC while attempting to predict side effects.We argue for the use of metrics that are robust to class imbalance for evaluation of classifiers. Importantly, we present a 'hierarchical anatomical classification schema' which aggregates side effects into organs, sub-systems, and systems. With the help of a weighted performance measure, using 5-fold cross-validation we show that this strategy facilitates biologically meaningful side effects prediction at different levels of anatomical hierarchy. By implementing various machine learning classifiers we show that Random Forest model yields best classification accuracy at each level of coarse-graining. The manually curated, hierarchical schema for side effects can also serve as the basis of future studies towards prediction of adverse reactions and identification of key features linked to specific organ systems. Our study provides a strategy for hierarchical classification of side effects rooted in the anatomy and can pave the way for calibrated expert systems for multi-level prediction of side effects.

PMID: 29494708 [PubMed - indexed for MEDLINE]

Sofosbuvir Adverse Events Profile in a Subset of Pakistani Population.

J Coll Physicians Surg Pak. 2018 Feb;28(2):146-149

Authors: Iqbal S, Yousuf MH, Raza A, Yousaf MI

Abstract
OBJECTIVE: To determine frequency and pattern of adverse events reporting in a subset of Pakistani population being treated for chronic hepatitis C with sofosbuvir combination therapy.
STUDY DESIGN: Descriptive study.
PLACE AND DURATION OF STUDY: Department of Medicine, Gastroenterology Division, Shalamar Hospital, Lahore, from September 2015 to May 2016.
METHODOLOGY: Patients who were offered sofosbuvir therapy for treatment of chronic hepatitis C were randomly enrolled. The study subset included both treatment nave as well as retreatment groups. Patients were screened for subjective as well as objective evidence of adverse events at regular intervals. Frequency was determined.
RESULTS: Among 196 patients with chronic hepatitis C, 192 patients received dual therapy consisting of ribavirin and sofosbuvir. The most frequent complaints in these subjects were fatigue, fever, myalgias and nausea accounting for 55%, 42%, 44.2% and 50%, respectively. Twenty-seven percent of patients reported with drop in hemoglobin of >2g/dl, while absolute neutropenia and moderate to severe thrombocytopenia was observed in 3% and 5% of patients, respectively. One patient died as a result of severe pancytopenia. Later derangements were all observed in patients with decompensated disease.
CONCLUSION: Sofosbuvir showed less severe adverse effects in terms of symptomatology and less frequent neutropenia and thrombocytopenia as compared to previous regimens. Careful monitoring is required, especially in those with decompensated liver disease.

PMID: 29394975 [PubMed - indexed for MEDLINE]

[Role of Pharmacy in the Promotion of Drug Safety in Pharmacotherapy].

Yakugaku Zasshi. 2018;138(2):149-150

Authors: Satoh M

PMID: 29386428 [PubMed - indexed for MEDLINE]