Management of Common Side Effects of Apremilast.

J Cutan Med Surg. 2018 Jul/Aug;22(4):415-421

Authors: Langley A, Beecker J

Abstract
Apremilast is a relatively new therapy for the treatment of moderate to severe plaque psoriasis in adults. While this medication is considered safe with a very low risk of serious side effects, a few common (≥5% of patients) mild to moderate side effects have been reported, including diarrhea, nausea, headache, and nasopharyngitis. Not addressing these symptoms may lead to medication nonadherence and unnecessary discontinuation of therapy. These side effects are often easily managed with interventions available to the practicing dermatologist, and in only rare instances will these side effects require dose adjustment or discontinuation of therapy. The purpose of this article is to review common side effects of apremilast at its approved dose of 30 mg orally twice daily (BID) and to provide clear, simple recommendations for their management in dermatological practice.

PMID: 29290125 [PubMed - indexed for MEDLINE]

Fentanyl buccal tablet for breakthrough cancer pain in clinical practice: results of the non-interventional prospective study ErkentNIS.

Support Care Cancer. 2018 02;26(2):491-497

Authors: Masel EK, Landthaler R, Gneist M, Watzke HH

Abstract
PURPOSE: Several patients with advanced cancer suffer from breakthrough cancer pain (BTcP). BTcP is pain exacerbation despite opioid baseline therapy. Fentanyl buccal tablet (FBT) is a rapid-onset opioid for the treatment of BTcP. The aim of this study is to document the feasibility of FBT in patients with BTcP.
METHODS: The study was performed in 64 centers. Basic pain score was rated on a numeric rating scale (NRS) before and after treatment. BTcP episodes, baseline opioid therapy, and FBT dose were rated as well as individual dose titration, findings on tolerability, patient satisfaction, and safety of the drug.
RESULTS: Two hundred sixty-three patients were available for analysis. Patients rated a basic pain score of 6 (range 2-10) points on an NRS and described an average of 2 to 5 BTcP episodes per day. After titration of FBT, BTcP control was achieved within 5 min in 36%, within 10 min in 68%, and within 15 min in 95%. Basic pain score decreased to a mean NRS of 4 and BTcP episodes decreased to < 1 to 3 episodes per day. BTcP control, onset of action of FBT, potency of FBT, tolerability of FBT, and safety of FBT were rated as excellent or good by 89 to 99% of the patients. Adverse drug reactions were registered in 3%.
CONCLUSIONS: Treatment with FBT led to rapid pain relief and reductions in the number of BTcP episodes and patient satisfaction was rated as excellent or good.

PMID: 28849261 [PubMed - indexed for MEDLINE]

Tolerability of Opioid Analgesia for Chronic Pain: A Network Meta-Analysis.

Sci Rep. 2017 05 17;7(1):1995

Authors: Meng Z, Yu J, Acuff M, Luo C, Wang S, Yu L, Huang R

Abstract
Aim of this study was to study the tolerability of opioid analgesia by performing a network meta-analysis (NMA) of randomized-controlled trials (RCTs) which investigated effectiveness of opioids for the management of chronic pain. Research articles reporting outcomes of RCT/s comparing 2 or more opioid analgesics for the management of chronic pain were obtained by database search. Bayesian NMAs were performed to combine direct comparisons between treatments with that of indirect simulated evidence. Study endpoints were: incidence of adverse events, incidence of constipation, trial withdrawal rate, and patient satisfaction with treatment. Outcomes were also compared with conventional meta-analyses. Thirty-two studies investigating 10 opioid drugs fulfilled the eligibility criteria. Tapentadol treatment was top-ranking owing to lower incidence of overall adverse events, constipation, and least trial withdrawal rate. Tapentadol was followed by oxycodone-naloxone combination in providing better tolerability and less trial withdrawal rate. Patient satisfaction was found to be higher with oxycodone-naloxone followed by fentanyl and tapentadol. These results were in agreement with those achieved with conventional meta-analyses. Tapentadol and oxycodone-naloxone are found to exhibit better tolerability characteristics in comparison with other opioid drugs for the management of chronic pain and are associated with low trial withdrawal rate and better patient satisfaction.

PMID: 28515426 [PubMed - indexed for MEDLINE]

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A Computerized Scoring System to Improve Assessment of Heparin-induced Thrombocytopenia Risk.

J Thromb Haemost. 2018 Dec 14;:

Authors: Gallo T, Curry SC, Padilla-Jones A, Heise CW, Ramos KS, Woosley RL, Raschke RA

Abstract
BACKGROUND: Heparin induced thrombocytopenia (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The four T's (4Ts) score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation.
OBJECTIVES: Our main objective was to develop a HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified to be at risk for HIT.
METHODS: We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system to a clinically calculated 4Ts score. We took a 4Ts score ≥4 as the gold standard to determine if HIT diagnostic testing should be performed.
RESULTS: The best cutoff point of the HIT-CR score was a score of 3 which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% CI: 0.57 to 0.81). Ninety percent of patients with 4Ts score ≥4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT.
CONCLUSION: The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT. This article is protected by copyright. All rights reserved.

PMID: 30552743 [PubMed - as supplied by publisher]

Impact of medication therapy management on pharmacotherapy safety in an intensive care unit.

Int J Clin Pharm. 2018 Dec 15;:

Authors: Martins RR, Silva LT, Lopes FM

Abstract
Background Drug-related problems are mostly preventable or predictable circumstances that may impact on health outcomes. Clinical pharmacy activities such as medication therapy management can identify and solve these problems, with potential to improve medication safety and effectiveness. Objective To evaluate ability of medication therapy management service to detect drug-related problems and prevent adverse drug events. This study also aimed to assess the risk factors for drugrelated problem occurrence. Setting Medical intensive care unit of a public tertiary hospital in Brazil. Methods Patients were evaluated by a clinical pharmacist, who provided medication therapy management service. Detected drug-related problems were categorized according to the Pharmaceutical Care Network Europe methodology and analyzed in multinomial regression to identify risk factors. Main outcome measure Potential risk factors for drug-related problem occurrence. Results The proposed medication therapy management service allowed detection of 170 drug-related problems that had potential to reach patients causing harm and other 50 unavoidable adverse events. Drug-related problems identified were more often associated with antibacterial use, caused by improper combinations or inadequate drug dosage. These problems required interventions that were accepted by the multidisciplinary team, resulting in more than 85% adherence and total problem solving. Main risk factors identified were previous diagnosis of kidney injury (OR = 8.38), use of midazolam (OR = 7.96), furosemide (OR = 5.87) and vancomycin (OR = 4.82). Conclusion Medication therapy management proved to be an effective method not only for drug-related problem detection, but also for adverse drug event prevention, contributing to improve patient safety.

PMID: 30552623 [PubMed - as supplied by publisher]

Treatment of chronic hepatitis C virus infection in Rwanda with ledipasvir-sofosbuvir (SHARED): a single-arm trial.

Lancet Gastroenterol Hepatol. 2018 Dec 10;:

Authors: Gupta N, Mbituyumuremyi A, Kabahizi J, Ntaganda F, Muvunyi CM, Shumbusho F, Musabeyezu E, Mukabatsinda C, Ntirenganya C, Van Nuil JI, Kateera F, Camus G, Damascene MJ, Nsanzimana S, Mukherjee J, Grant PM

Abstract
BACKGROUND: Limited treatment data are available for hepatitis C virus (HCV) in sub-Saharan Africa, especially for genotype 4. Our objective was to establish the safety and efficacy of ledipasvir-sofosbuvir for chronic HCV genotype 1 or 4 infection in adults in Rwanda.
METHODS: We did a single-arm trial to evaluate the safety and efficacy of ledipasvir-sofosbuvir in Rwandan adults with chronic HCV infection at a single study site (Rwanda Military Hospital, Kigali, Rwanda). We enrolled individuals aged 18 years or older with HCV genotype 1 or 4 infection and a plasma HCV RNA concentration of more than 1000 IU/mL at screening. All participants were given ledipasvir (90 mg) and sofosbuvir (400 mg) in a single combination tablet once daily for 12 weeks. We established HCV genotype using an Abbott platform, and HCV subtype with PCR amplification. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after therapy (SVR12). All patients enrolled in the study were included in the primary endpoint analyses. This study is registered with ClinicalTrials.gov, number NCT02964091.
FINDINGS: 300 participants were enrolled between Feb 6, 2017, and Sept 18, 2017, and the follow-up period was completed on March 1, 2018. On genotyping, 248 (83%) participants were reported as having genotype 4, four (1%) genotype 1, and 48 (16%) both genotype 1 and genotype 4. Subsequent viral sequencing showed all participants actually had genotype 4 infection with subtype 4k (134 [45%]), subtype 4r (48 [16%]), subtype 4q (42 [14%]), and subtype 4v (24 [8%]) predominating. Overall, 261 (87%, 95% CI 83-91) participants achieved SVR12. In participants with genotype 4r, SVR12 was observed in 27 (56%, 95% CI 41-71) participants versus 234 (93%, 90-96) individuals with other subtypes. There were no drug-related treatment discontinuations due to ledipasvir-sofosbuvir. The most common adverse events were hypertension (97 [32%]), headache (78 [26%]), dizziness (61 [20%]), and fatigue (56 [19%]). There were six serious adverse events; none were assessed to be due to the study drug. 296 participants had data for pill counts at week 4 and 8; 271 (92%) had 100% adherence and only one (<1%) had an adherence of less than 90%.
INTERPRETATION: This is the first large-scale prospective study reporting direct-acting antiviral outcomes in sub-Saharan Africa. The high adherence and treatment success without intensive support measures or highly specialised clinical providers, and lack of treatment discontinuations due to adverse events support the feasibility of HCV treatment decentralisation and scale-up in sub-Saharan Africa. Genotype 4r is uniquely expressed in this region and associated with high rates of treatment failure, suggesting a need for rigorous test-of-cure in clinical practice and consideration of the use of newer pangenotypic direct-acting antiviral regimens in this region.
FUNDING: Gilead Sciences.

PMID: 30552056 [PubMed - as supplied by publisher]

Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy.

Int J Rheum Dis. 2018 Nov 22;:

Authors: Liew DFL, Leung JLY, Liu B, Cebon J, Frauman AG, Buchanan RRC

Abstract
AIM: To investigate whether any patient or treatment characteristics are associated with the development of rheumatic immune-related adverse events (irAEs) following programmed cell death protein 1 (PD-1) inhibitor therapy for cancer.
METHOD: This was a retrospective chart review of all patients who were dispensed nivolumab or pembrolizumab at a single center before 1 January, 2017, with follow-up until 1 July, 2017. Patients with any diagnosis of a non-cutaneous irAE were identified, regardless of severity, and rheumatic irAEs were characterized.
RESULTS: Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic irAEs were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64).
CONCLUSION: Rheumatic irAEs are relatively common with PD-1 inhibitor therapy, and appear to be associated with a good oncological response to therapy. Many rheumatic irAEs were not referred to rheumatological services. Prospective systematic investigation would be of benefit to explore these characteristics.

PMID: 30549256 [PubMed - as supplied by publisher]

Comment on "Assessment of the Utility of Social Media for Broad-Ranging Statistical Signal Detection in Pharmacovigilance: Results from the WEB-RADR Project".

Drug Saf. 2018 12;41(12):1371-1373

Authors: Bousquet C, Audeh B, Bellet F, Lillo-Le Louët A

Abstract

PMID: 30341678 [PubMed - indexed for MEDLINE]

Dose-dependent transcriptomic responses of zebrafish eleutheroembryos to Bisphenol A.

Environ Pollut. 2018 Dec;243(Pt B):988-997

Authors: Martínez R, Esteve-Codina A, Herrero-Nogareda L, Ortiz-Villanueva E, Barata C, Tauler R, Raldúa D, Piña B, Navarro-Martín L

Abstract
Despite the abundant literature on the adverse effects of Bisphenol A (BPA) as endocrine disruptor, its toxicity mechanisms are still poorly understood. We present here a study of its effects on the zebrafish eleutheroembryo transcriptome at concentrations ranging from 0.1 to 4 mg L-1, this latter representing the lowest observed effect concentration (LOEC) found in our study at three different macroscopical endpoints (survival, hatching and swim bladder inflation). Multivariate data analysis methods identified both monotonic and bi-phasic patterns of dose-dependent responses. Functional analyses of genes affected by BPA exposure suggest an interaction of BPA with different signaling pathways, being the estrogenic and retinoid receptors two likely targets. In addition, we identified an apparently unrelated inhibitory effect on, among others, visual function genes. We interpret our data as the result of a sum of underlying, independent molecular mechanisms occurring simultaneously at the exposed animals, well below the macroscopic LOEC, but related to at least some of the observed morphological alterations, particularly in eye size and yolk sac resorption. Our data supports the idea that the physiological effects of BPA cannot be only explained by its rather weak interaction with the estrogen receptor, and that multivariate analyses are required to analyze the effects of toxicants like BPA, which interact with different cellular targets producing complex phenotypes.

PMID: 30248606 [PubMed - indexed for MEDLINE]

Side effects of corticosteroids in patients with advanced cancer: a systematic review.

Support Care Cancer. 2018 Dec;26(12):3979-3983

Authors: Hatano Y, Matsuoka H, Lam L, Currow DC

Abstract
PURPOSE: Corticosteroids are commonly used in palliative care settings, but are associated with several side effects. Although adverse events (AEs) are highly distressing for patients, few data are available from prospective studies to look at incidence or predictors of such harms. The aim of this study is to identify AE reporting among studies of patients with advanced cancer receiving corticosteroids for any reason.
METHODS: A systematic review was conducted using the following data sources: PubMed, Medline, SCOPUS, Cochrane reviews, and CINAHL. Randomized controlled trials (RCTs) with patients with advanced cancer assessing the effect of corticosteroids were included. Consecutive cohort observational studies of corticosteroid toxicities in cancer patients were also included.
RESULTS: Twenty-seven RCTs and 12 consecutive cohort observational studies were identified. The most frequently reported primary outcome of RCTs was nausea and vomiting (8/27). Dexamethasone was prescribed in almost half of RCTs (13/27). In consecutive cohort studies, the primary outcomes were a wide variety of symptoms. Dexamethasone was also the most common glucocorticoid used (7/12). In terms of quality of AE reporting, two RCTs and one consecutive cohort study used a validated AE assessment tool in their studies.
CONCLUSIONS: Side effects of corticosteroids in advanced cancer patients were poorly reported with few data using validated tools. Researchers should be aware of the guideline of AE reporting to provide the best evidence of risk-benefit balance. Developing specific consensus guidelines about AE reporting in studies of glucocorticoids in studies of people with advanced cancer would be useful.

PMID: 29980905 [PubMed - indexed for MEDLINE]

Prognostic significance of tumor budding in cutaneous squamous cell carcinoma.

J Am Acad Dermatol. 2018 07;79(1):e5

Authors: Kanitakis J, Karayannopoulou G

PMID: 29908823 [PubMed - indexed for MEDLINE]

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

J Pharmacol Toxicol Methods. 2018 Nov - Dec;94(Pt 1):50-63

Authors: Gauvin DV, Zimmermann ZJ, Yoder J, Harter M, Holdsworth D, Kilgus Q, May J, Dalton J, Baird TJ

Abstract
Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards.
PREFATORY NOTE: For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions.

PMID: 29751085 [PubMed - indexed for MEDLINE]

Anesthesia Case of the Month.

J Am Vet Med Assoc. 2017 06 01;250(11):1246-1249

Authors: Wendt-Hornickle E, Goudie-DeAngelis E, Baldo C

PMID: 28509637 [PubMed - indexed for MEDLINE]

Assessment of Incidence and Character of Neurologic/ Neuropsychiatric Complications in a Group of Patients with Malignant Melanoma Treated with Adjuvant High Dose Interferon.

Klin Onkol. 2018;31(5):361-365

Authors: Jarmila P, Jiří G, Jindřich K, Peter P, Iva P, Petronela T, Věra J, Adam P, Šárka L, Filip

Abstract
BACKGROUND: Authors describe the incidence and character of neurologic and neuropsychiatric complications - particularly depression and parkinsonism - during adjuvant treatment of malignant melanoma (MM) with high dose interferon (HDI). Among the most frequently observed side effects are fatigue, hematotoxicity, and hepatotoxicity. Most research has been directed at depression and parkinsonism because of the lack of literature concerning these complications. Interferon induced parkinsonism has only been described rarely and only in case reports.
PATIENTS AND METHODS: Twenty-nine patients with MM, treated from January 2010 to January 2014 with adjuvant high dose interferon alfa-2b intravenous (HDI 20MIU/sqm for 5 days per week during the first 4 weeks, and then maintenance subcutaneous 10MIU/sqm up to a total time of 1 year) were retrospectively evaluated and the incidence and character of neurologic and neuropsychiatric complications were determined.
RESULTS: Significant neurologic and neuropsychiatric complications were observed in 3 of the 29 patients. Dose modifications were required in 2 cases. One case developed parkinsonism and treatment had to be stopped after 10 applications of intravenous interferon.
CONCLUSION: High dose interferon can cause depression and parkinsonism. Prophylaxis with antidepressant medication can keep the incidence of depression as low as 10% or lower. Development of parkinsonism during HDI is rare. According to available reports, this is the first description of parkinsonism development related to HDI in MM. Key words malignant melanoma - high dose interferon - neurologic and neuropsychiatric complication - drug-induced depression - drug-induced  parkinsonism The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 7. 4. 2018 Accepted: 16. 8. 2018.

PMID: 30541322 [PubMed - in process]

Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.

Lancet Oncol. 2018 Dec 03;:

Authors: Lombardi G, De Salvo GL, Brandes AA, Eoli M, Rudà R, Faedi M, Lolli I, Pace A, Daniele B, Pasqualetti F, Rizzato S, Bellu L, Pambuku A, Farina M, Magni G, Indraccolo S, Gardiman MP, Soffietti R, Zagonel V

Abstract
BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.
METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.
FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related.
INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.
FUNDING: Veneto Institute of Oncology and Bayer Italy.

PMID: 30522967 [PubMed - as supplied by publisher]

Clozapine-Induced Myocarditis: The Heartfelt Silent Assassin.

Prim Care Companion CNS Disord. 2018 10 11;20(5):

Authors: Deardorff OG, Conklin TM, Hopkins TM, Hall LR, Trout MG, Cafer J

PMID: 30326189 [PubMed - indexed for MEDLINE]

Toxic liver injury after high-dose methylprednisolone in people with multiple sclerosis.

Mult Scler Relat Disord. 2018 Oct;25:43-45

Authors: Adamec I, Pavlović I, Pavičić T, Ruška B, Habek M

Abstract
The standard therapy of multiple sclerosis (MS) relapse is high-dose pulse corticosteroid therapy. Although commonly applied and usually well tolerated it may as well carry certain risks for people with MS, the more severe of them being hepatotoxicity. This report describes three cases of acute liver injury following pulse corticosteroid therapy with reference to other possible causative factors. Caution should be exercised when applying high-dose methylprednisolone given the potential liver related adverse events it may cause.

PMID: 30032042 [PubMed - indexed for MEDLINE]

Factors associated with congenital anomalies in Addis Ababa and the Amhara Region, Ethiopia: a case-control study.

BMC Pediatr. 2018 04 25;18(1):142

Authors: Taye M, Afework M, Fantaye W, Diro E, Worku A

Abstract
BACKGROUND: The early stage of embryo development is extremely vulnerable to various teratogenic factors, leading to congenital anomalies. In Ethiopia, a significant number of babies are born with congenital anomalies, but the risk factors for the anomalies have never been studied. Understanding the specific risk factors for congenital anomalies is very essential to provide health education that aims at creating awareness and establishing preventive strategic plan/s. The main objective of this study was to assess the risk factors associated with congenital anomalies in Addis Ababa and the Amhara Region, Ethiopia.
METHODS: A case-control study was conducted from January 1- June 30, 2015. The participants were recruited at the purposively selected hospitals in Addis Ababa and the Amhara Region. A total of 207 cases and 207 controls were included in the study. Cases were neonates, infants, and children 0-11 months of age with external and internal major congenital anomalies diagnosed by pediatricians. Controls were neonates, infants, and children 0-11 months of age without external and internal anomalies. Data on sociodemographic characteristics, exposure to risk factors, and reproductive history were collected by face to face interviews with children's mothers/caregivers using a structured questionnaire. Binary logistic regression was employed to explore risk factors associated with the occurrence of the problems.
RESULTS: About 87.4% of the children were below 6 months, and 12.6% were between 6 and 11 months. The majority (59.9%) of the children were male, with the M: F sex ratio of 1.49. The mean age of the mothers was 26 years (16-45 years). Unidentified medication use during early pregnancy (AOR = 4.595; 95% CI: 1.868-11.301, P-value = 0.001), maternal alcohol drinking (AOR = 2.394; 95% CI: 1.212-4.726, P-value = 0.012), and exposure to chemicals (AOR = 9.964; 95% CI = 1.238-80.193, P-value = 0.031) were significantly associated with the occurrence of congenital anomalies. Iron folate use (AOR = 0.051; 95% CI: 0.010-0.260, P-value = < 0.001) before and during early pregnancy had a protective effect on congenital anomaly.
CONCLUSION: Unidentified medication use, alcohol drinking during early pregnancy, and exposure to chemicals had a significant association with the occurrence of congenital anomalies, whereas iron folate use before and during early pregnancy had a protective effect from congenital anomalies.

PMID: 29699508 [PubMed - indexed for MEDLINE]

Human abuse potential of brivaracetam in healthy recreational central nervous system depressant users.

Epilepsy Behav. 2018 01;78:194-201

Authors: Schoedel KA, Stockis A, Sellers EM

Abstract
BACKGROUND: Brivaracetam is a new antiepileptic drug indicated for adjunctive treatment of focal seizures in adults at a dose of 50-200mg/day taken in two equal doses. The objective of this study was to evaluate the abuse potential of brivaracetam compared with alprazolam (positive control), placebo, and levetiracetam.
METHODS: This was a randomized, double-blind, triple-dummy, crossover study in healthy male and female recreational central nervous system (CNS) depressant users aged 18-55years, who could distinguish between the subjective effects of alprazolam 2mg and placebo. All participants received single doses of brivaracetam (50 [therapeutic dose], 200, 1000mg [supratherapeutic doses]), alprazolam (1.5, 3mg), placebo, and levetiracetam (4000mg) in random order each separated by 7-10days. Subjective Visual Analogue Scales (VAS) and Addiction Research Center Inventory (ARCI) scales were completed at intervals up to 24h postdose. Primary endpoints were Drug Liking (at this moment) VAS, Overall Drug Liking VAS, Feeling High VAS, and ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG, sedation) maximum effect (Emax). Maximum effect values on each scale were analyzed using a mixed-effect model (per protocol population, N=44).
RESULTS: The maximum effect for both alprazolam doses was significantly greater versus placebo for six designated endpoints, confirming study validity. Drug Liking (at this moment) VAS Emax was significantly lower for brivaracetam 50mg than alprazolam (both doses); there were no significant differences between brivaracetam 200mg and alprazolam (both doses), and brivaracetam 1000mg and alprazolam 1.5mg. Brivaracetam 1000mg (supratherapeutic single dose) had significantly higher Drug Liking (at this moment) VAS Emax than alprazolam 3mg. Overall, Drug Liking VAS Emax for brivaracetam 50 and 200mg was not significantly different from alprazolam (both doses). Brivaracetam 1000mg had significantly higher Overall Drug Liking VAS Emax than alprazolam 1.5mg, but was not significantly different from alprazolam 3mg. Feeling High VAS Emax was lower versus alprazolam with brivaracetam 50 and 200mg, while brivaracetam 1000mg was comparable with alprazolam (both doses). Addiction Research Center Inventory PCAG Emax for brivaracetam (all doses) was significantly lower than alprazolam (both doses). On the secondary/supportive endpoints, compared with alprazolam, brivaracetam had fewer positive effects (ARCI Morphine Benzedrine Group [euphoria]; Good Drug Effects VAS [50mg]) and fewer negative effects (Bad Drug Effects VAS; ARCI Lysergic Acid Diethylamide [dysphoria]). Brivaracetam was not significantly different from alprazolam for Take Drug Again VAS (50, 200mg). For most endpoints, brivaracetam (50-200mg) was not significantly different from levetiracetam (4000mg).
CONCLUSION: This study in healthy recreational CNS depressant users showed that single doses of brivaracetam 50mg (therapeutic single dose) had lower sedative, positive, and negative drug effects than alprazolam, while brivaracetam 200 and 1000mg (supratherapeutic single doses) were more similar to alprazolam. The subjective profile of brivaracetam appeared to be similar to that of levetiracetam, but further evaluation using a range of levetiracetam doses would be needed to confirm similar abuse potential.

PMID: 29153631 [PubMed - indexed for MEDLINE]