Hepatotoxicity Modeling Using Counter-Propagation Artificial Neural Networks: Handling an Imbalanced Classification Problem.

Molecules. 2020 Jan 23;25(3):

Authors: Bajželj B, Drgan V

Abstract
Drug-induced liver injury is a major concern in the drug development process. Expensive and time-consuming in vitro and in vivo studies do not reflect the complexity of the phenomenon. Complementary to wet lab methods are in silico approaches, which present a cost-efficient method for toxicity prediction. The aim of our study was to explore the capabilities of counter-propagation artificial neural networks (CPANNs) for the classification of an imbalanced dataset related to idiosyncratic drug-induced liver injury and to develop a model for prediction of the hepatotoxic potential of drugs. Genetic algorithm optimization of CPANN models was used to build models for the classification of drugs into hepatotoxic and non-hepatotoxic class using molecular descriptors. For the classification of an imbalanced dataset, we modified the classical CPANN training algorithm by integrating random subsampling into the training procedure of CPANN to improve the classification ability of CPANN. According to the number of models accepted by internal validation and according to the prediction statistics on the external set, we concluded that using an imbalanced set with balanced subsampling in each learning epoch is a better approach compared to using a fixed balanced set in the case of the counter-propagation artificial neural network learning methodology.

PMID: 31979300 [PubMed - indexed for MEDLINE]

Medication-related harm in older adults following hospital discharge: development and validation of a prediction tool.

BMJ Qual Saf. 2020 02;29(2):142-153

Authors: Parekh N, Ali K, Davies JG, Stevenson JM, Banya W, Nyangoma S, Schiff R, van der Cammen T, Harchowal J, Rajkumar C

Abstract
OBJECTIVES: To develop and validate a tool to predict the risk of an older adult experiencing medication-related harm (MRH) requiring healthcare use following hospital discharge.
DESIGN, SETTING, PARTICIPANTS: Multicentre, prospective cohort study recruiting older adults (≥65 years) discharged from five UK teaching hospitals between 2013 and 2015.
PRIMARY OUTCOME MEASURE: Participants were followed up for 8 weeks in the community by senior pharmacists to identify MRH (adverse drug reactions, harm from non-adherence, harm from medication error). Three data sources provided MRH and healthcare use information: hospital readmissions, primary care use, participant telephone interview. Candidate variables for prognostic modelling were selected using two systematic reviews, the views of patients with MRH and an expert panel of clinicians. Multivariable logistic regression with backward elimination, based on the Akaike Information Criterion, was used to develop the PRIME tool. The tool was internally validated.
RESULTS: 1116 out of 1280 recruited participants completed follow-up (87%). Uncertain MRH cases ('possible' and 'probable') were excluded, leaving a tool derivation cohort of 818. 119 (15%) participants experienced 'definite' MRH requiring healthcare use and 699 participants did not. Modelling resulted in a prediction tool with eight variables measured at hospital discharge: age, gender, antiplatelet drug, sodium level, antidiabetic drug, past adverse drug reaction, number of medicines, living alone. The tool's discrimination C-statistic was 0.69 (0.66 after validation) and showed good calibration. Decision curve analysis demonstrated the potential value of the tool to guide clinical decision making compared with alternative approaches.
CONCLUSIONS: The PRIME tool could be used to identify older patients at high risk of MRH requiring healthcare use following hospital discharge. Prior to clinical use we recommend the tool's evaluation in other settings.

PMID: 31527053 [PubMed - indexed for MEDLINE]

Effectiveness and safety of toripalimab, camrelizumab, and sintilimab in a real-world cohort of hepatitis B virus associated hepatocellular carcinoma patients.

Ann Transl Med. 2020 Sep;8(18):1187

Authors: Chen J, Hu X, Li Q, Dai W, Cheng X, Huang W, Yu W, Chen M, Guo Y, Yuan G

Abstract
Background: The clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is understudied. We thus aimed to evaluate the safety and efficacy of PD-1 inhibitors with toripalimab, camrelizumab or sintilimab for Chinese hepatocellular carcinoma (HCC) patients in a real-life cohort.
Methods: We analysed hepatitis B virus (HBV)-associated HCC patients treated with toripalimab, camrelizumab, or sintilimab in a retrospective single-center cohort from November 2018 to June 2020. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Safety data were also recorded.
Results: Seventy patients were finally included in the analysis: 23 were treated with toripalimab, 33 with camrelizumab, and 14 with sintilimab. The mean duration of follow-up was 44.7 (95% CI: 39.9-49.6) weeks and the mean cycles of PD-1 at cutoff were 8.3±8.0 for all patients. The ORR and DCR for the whole cohort were 30% and 72.9%, respectively. Overall, 25 (35.7%) patients had radiological disease progression and 10 (14.3%) patients died during follow-up. Median PFS, median TTP, and median OS had not yet been reached. Most frequent drug-related adverse events (AEs) were rash (27.1%), hypertension (18.6%), fatigue (17.1%), diarrhea (17.1%), paresthesia (15.7%), and nausea (15.7%).
Conclusions: Our findings suggest that (I) PD-1 targeted immunotherapy with toripalimab, camrelizumab, or sintilimab yielded a promising outcome in Chinese HBV patients with HCC and that (II) immunotherapy was well tolerated generally and had manageable side effects. This approach thus warrants further popularization and application in clinical practice.

PMID: 33241036 [PubMed]

Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes.

Ther Adv Chronic Dis. 2020;11:2040622320964152

Authors: Potmešil P, Szotkowská R

Abstract
Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient's medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.

PMID: 33240477 [PubMed]

Non-pharmacological interventions to reduce agitation in dementia.

Drug Ther Bull. 2020 Nov 25;:

Authors:

Abstract
Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID: 33239329 [PubMed - as supplied by publisher]

Prescribing practices of lopinavir/ritonavir, hydroxychloroquine and azithromycin during the COVID-19 epidemic crisis and pharmaceutical interventions in a French teaching hospital.

Eur J Hosp Pharm. 2020 Nov 25;:

Authors: Gourieux B, Reisz F, Belmas AS, Danion F, Fourtage M, Nai T, Reiter-Schatz A, Ruch Y, Walther J, Nivoix Y, Michel B

Abstract
OBJECTIVE: The aims of this study were to describe prescribing practices of lopinavir/ritonavir, hydroxychloroquine and azithromycin during the COVID-19 epidemic crisis (primary endpoint), then to characterise pharmaceutical interventions (PIs) targeted to these medications and evaluate the impact of these PIs on prescribers' practices (secondary end-points).
METHODS: This retrospective observational study was carried out at the University Hospital of Strasbourg (France) from March to April 2020. The analysed population excluded patients from intensive care units but included all other adult patients with COVID-19 who received at least one dose of lopinavir/ritonavir combination, hydroxychloroquine or azithromycin, while inpatients. Analyses were performed by using data extracted from electronic medical records.
RESULT: During the study period, 278 patients were included. A rapid decrease in lopinavir/ritonavir prescriptions was observed. This was accompanied by an increase in hydroxychloroquine and azithromycin prescriptions until the end of March, followed by a decrease leading to the disappearance of these two medications in April. The pharmaceutical analysis of the prescriptions resulted in 59 PIs of which 21 were associated with lopinavir/ritonavir, 32 with hydroxychloroquine and 6 with azithromycin. Regarding the medication-related problems, the most frequent ones were incorrect treatment durations (n=32 (54.2%)), drug interactions with potential torsadogenic reactions (n=14 (23.7%)) and incorrect dosing (n=6 (10.2%)). From the 59 PIs, 48 (81.4%) were accepted and physicians adjusted the medication regimens in a timely manner.
CONCLUSION: This study demonstrated the value-even more meaningful in a crisis situation-of a strong synergy between physicians and pharmacists for patient-safety focused practices.

PMID: 33239282 [PubMed - as supplied by publisher]

Ursodeoxycholic acid and bezafibrate were useful for steroid-refractory, immune-related hepatitis: a case report.

J Med Case Rep. 2020 Nov 26;14(1):230

Authors: Onishi S, Tajika M, Bando H, Matsubara Y, Hosoda W, Muro K, Niwa Y

Abstract
BACKGROUND: Immune checkpoint inhibitors have shown clinically significant antitumor efficacy and have been approved for the treatment of various kinds of advanced malignancies. On the other hand, these immunotherapies show unique adverse events, termed "immune-related adverse events," which are distinctly associated with conventional cytotoxic chemotherapy. Hepatotoxicity is recognized as an immune-related adverse event; prompt treatment with corticosteroids is recommended. However, some cases are refractory to steroids. Here, we report the first case (to our knowledge) of steroid-refractory immune-related hepatitis that was successfully treated with ursodeoxycholic acid and bezafibrate.
CASE PRESENTATION: A 68-year-old Asian man, came to our hospital for the treatment of malignant melanoma involving the gingiva and presenting with multiple lymph node and bone metastases was administered nivolumab as a first-line treatment. Two months into treatment, the patient developed diarrhea as a result of immune-related colitis; the colitis was treated successfully with prednisolone 60 mg/ day, resulting in improvement in the patient's symptoms. However, when steroids were being tapered, acute elevation of liver enzymes was observed. Autoimmune hepatitis was suspected as an immune-related adverse event, and treatment with intravenous prednisolone 60 mg/ day was reinitiated. However, restoration of the steroid treatment failed to improve the patient's liver enzymes. On the basis of histological findings from liver biopsy and exclusion of other etiologies such as viral infection and other drug-induced hepatitis, steroid-refractory hepatic immune-related adverse event was deemed the most likely cause of the patient's acute hepatitis. In general, mycophenolate mofetil or tacrolimus is known to provide benefits in cases of steroid-refractory hepatitis. We therefore decided to add oral ursodeoxycholic acid and bezafibrate in consideration of the patient's background of repeated aspiration pneumonia. Administration of this regimen resulted in an improvement in liver function, which remained normal even after tapering of prednisolone.
CONCLUSIONS: Ursodeoxycholic acid and bezafibrate may be useful for treatment of steroid-refractory immune-related adverse event hepatitis.

PMID: 33239098 [PubMed - in process]

Comparisons of exacerbations and mortality among LAMA/LABA combinations in stable chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis.

Respir Res. 2020 Nov 25;21(1):310

Authors: Lee HW, Park J, Jang EJ, Lee CH

Abstract
BACKGROUND: Only few randomized controlled trials (RCTs) for head-to-head comparison have been conducted between various combinations of long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs). Our study was conducted to compare acute exacerbation and all-cause mortality among different LAMA/LABA regimens using Bayesian network meta-analysis (NMA).
METHODS: We searched Medline, EMBASE, and the Cochrane library (search date: July 1, 2019). We included parallel-group RCTs comparing LAMA/LABA combinations with other inhaled drugs in the stable COPD for ≥ 48 weeks. Two different network geometries were used. The geometry of network (A) had nodes of individual drugs or their combination, while that of network (B) combined all other treatments except LAMA/LABA into each drug class. This study was prospectively registered in PROSPERO; CRD42019126753.
RESULTS: We included 16 RCTs involving a total of 39,065 patients with stable COPD. Six combinations of LAMA/LABA were identified: tiotropium/salmeterol, glycopyrrolate/indacaterol, umeclidinium/vilanterol, tiotropium/olodaterol, aclidinium/formoterol, and glycopyrrolate/formoterol. We found that umeclidinium/vilanterol was associated with a lower risk of total exacerbations than other LAMA/LABAs in the NMA using network (A) (level of evidence: low or moderate). However, the significant differences were not present in the NMA of network (B). There were no significant differences among the LAMA/LABA combinations in terms of the number of moderate to severe exacerbations, all-cause mortality, major adverse cardiovascular events, or pneumonia.
CONCLUSIONS: The present NMA including all available RCTs provided that there is no strong evidence suggesting different benefits among LAMA/LABAs in patients with stable COPD who have been followed up for 48 weeks or more.
TRIAL REGISTRATION: This study was prospectively registered in PROSPERO; CRD42019126753.

PMID: 33238986 [PubMed - in process]

Does Older Age have an Impact on Rituximab Efficacy and Safety? Results from the NOR-DMARD Register.

Drugs Aging. 2020 08;37(8):617-626

Authors: Mielnik P, Sexton J, Lie E, Bakland G, Loli LP, Kristianslund EK, Rødevand E, Lexberg ÅS, Kvien TK

Abstract
OBJECTIVE: The objective of this study was to compare the efficacy and safety of rituximab in older vs younger patients with rheumatoid arthritis.
METHODS: Data on 367 patients with rheumatoid arthritis treated with rituximab in the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) register were analysed, comparing patients aged ≥ 65 years (n = 91) with patients aged < 65 years (n = 276). Drug survival was compared using a Kaplan-Meier analysis and Cox proportional hazard models. Disease activity, as assessed by the Disease Activity Score based on 28 joints and erythrocyte sedimentation rate (DAS28-ESR) and the Simplified Disease Activity Index, was analysed with linear mixed models. The occurrence of adverse events was analysed by quasi-Poisson regression models.
RESULTS: Drug survival was similar in the two age groups. The proportion of patients who remained taking rituximab over 2 years was 72% in those under aged 65 years vs 74% in those aged ≥ 65 years. No statistically significant association with age was found for drug survival in either the unadjusted (hazard ratio 1.13, p = 0.65) or adjusted Cox proportional hazard analyses for the model with DAS28-ESR as a confounder (effect size 1.11, p = 0.73). Models including the Simplified Disease Activity Index instead of DAS28-ESR yielded similar results. Age was furthermore not significantly associated with disease activity over time, although there was a tendency towards a poorer response in older patients. In the older age group, there was a higher incidence of pneumonia (107 vs 51 per 1000 patient-years) and other serious infections (142 vs 66 per 1000 patient-years).
CONCLUSIONS: Rituximab is a reasonable therapeutic option for older patients with rheumatoid arthritis although vigilance is needed with regard to the infection profile.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01581294.

PMID: 32648248 [PubMed - indexed for MEDLINE]

Thalidomide use in the management of oromucosal disease: A 10-year review of safety and efficacy in 12 patients.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2020 Oct;130(4):398-401

Authors: Harte MC, Saunsbury TA, Hodgson TA

Abstract
OBJECTIVE: Thalidomide is an effective systemic agent in the management of ulcerative oromucosal conditions. However, its clinical use is limited because of its known adverse effect profile, including teratogenicity, peripheral neuropathy, and thromboembolic risk. The aim of this study was to review the efficacy and safety of thalidomide over a 10-year period in an Oral Medicine specialty clinic.
STUDY DESIGN: Clinical records of the Oral Medicine Department at the Royal National ENT and Eastman Dental Hospitals (London, UK) were retrospectively reviewed for patients prescribed thalidomide between 2009 and 2019 for the management of oromucosal ulceration. Twelve eligible patients were identified. Data on patient response to treatment and major/minor adverse events were obtained from their clinical and electrophysiologic records.
RESULTS: A complete remission rate was noted in 50% (6 of 12) patients treated for recurrent aphthous stomatitis, HIV-related ulceration and oral Crohn disease. A thalidomide-induced neuropathy rate of 41.7% (5 of 12) was detected by electrophysiology testing, however clinical symptoms of neuropathy were only described by 3 subjects. No other major adverse effects were reported.
CONCLUSIONS: Thalidomide demonstrates a good efficacy-to-safety ratio in the management of oromucosal ulceration over a prolonged treatment period. Interval electrophysiologic testing is essential to monitor for thalidomide-induced neuropathy. In this cohort, neuropathy does not appear to be a dose-dependent outcome.

PMID: 32622799 [PubMed - indexed for MEDLINE]

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Chronic Hepatotoxicity in Patients with Metastatic Neuroendocrine Tumor: Transarterial Chemoembolization versus Transarterial Radioembolization.

J Vasc Interv Radiol. 2020 Oct;31(10):1627-1635

Authors: Currie BM, Nadolski G, Mondschein J, Dagli M, Sudheendra D, Stavropoulos SW, Soulen MC

Abstract
PURPOSE: To compare the manifestations of chronic liver injury following transarterial chemoembolization with those of transarterial radioembolization (TARE) in patients with neuroendocrine tumor (NET).
MATERIALS AND METHODS: This study consisted of an Institutional Review Board-approved single-institution retrospective analysis of NET patients who received transarterial chemoembolization from 2006 to 2016 and TARE from 2005 to 2014 and survived at least 1 year from the initial treatment. Patients receiving only transarterial chemoembolization (n = 63) or TARE (n = 28) were evaluated for the presence or absence of durable hepatic toxicities occurring at least 6 months after initial treatment. The definitions and grades of liver injury were adapted from Common Terminology Criteria for Adverse Events version 4.0 and were characterized by the presence of laboratory or clinical toxicities of Grade 3 or above.
RESULTS: Chronic hepatic toxicity occurred in 14 of 63 transarterial chemoembolization patients (22%) with a total of 26 Grade 3-4 events, in whom elevation of bilirubin was the most common toxicity, compared to 8 of 28 TARE patients (29%) with a total of 16 Grade 3-4 and 2 Grade 5 events, in whom ascites were the most frequent toxicity. There were more laboratory toxicities in the transarterial chemoembolization group (65% vs 38%, P = .11) and fewer Grade 4-5 injuries (6% vs 27% of patients, P = .06). There was also a significantly higher number of patients who experienced intrahepatic progression of disease in the transarterial chemoembolization cohort than in the TARE patients (75% vs 43%, respectively; P = .005).
CONCLUSIONS: Delayed hepatotoxicity from transarterial chemoembolization and TARE occurred in 22% and 29% of patients, respectively, from 6 months to several years following treatment. Transarterial chemoembolization-related toxicities on average were less severe and manifested primarily as laboratory derangements, compared to TARE toxicities which consisted of clinical hepatic decompensation.

PMID: 33004146 [PubMed - indexed for MEDLINE]

Development of the Adverse Analgesic Drug Event Measure.

Nurs Res. 2020 Jul/Aug;69(4):299-306

Authors: McDonald DD, Ward C, Zhang Y

Abstract
BACKGROUND: Little is known about how people respond to an analgesic adverse drug event despite the significant incidence of deaths and hospitalizations associated with analgesic adverse drug events.
OBJECTIVE: The purpose of this two-phase instrument development study was to test the validity and reliability of the Analgesic Adverse Drug Event Measure (AADEM).
METHODS: Content validity was established during Phase I. Six experts rated the 58-item measure developed from a pilot survey of adults who had experienced an analgesic adverse drug event. Experts' ratings supported a 17-item AADEM with a scale content validity index of .86. Phase II consisted of online administration of the AADEM to a national Qualtrics panel who reported an adverse drug event from a self-administered analgesic. Exploratory factor analysis was conducted using principal axis factoring and oblique rotation including Direct Oblimin and Promax rotations with Kaiser normalization.
RESULTS: Four factors emerged from the analysis: sought care, consulted provider, discontinued or continued analgesic, and attributed adverse drug event with a total explained variance of 55.4%. Scale content validity index for the 13-item AADEM was .88. Internal consistency for the four subscales was acceptable, but low for the full 13-item AADEM.
DISCUSSION: Results establish preliminary evidence for the validity and reliability of the 13-item AADEM to measure response to an analgesic adverse drug event. Next steps involve confirmatory factor analysis in a different sample to examine the underlying construct of the AADEM. The AADEM might help identify people at risk for serious analgesic adverse drug events.

PMID: 32084103 [PubMed - indexed for MEDLINE]

Potential Psychotropic Drug Interactions among Drug-dependent People.

J Psychoactive Drugs. 2020 Nov 22;:1-9

Authors: Zapelini do Nascimento D, Marques GM, Schuelter-Trevisol F

Abstract
Using psychiatric drugs to treat drug dependence and its comorbidities is very common. The objective of this study was to analyze the interactions between prescribed drugs for patients treated at a specialized mental health-care center for persons who use drugs, located in the state of Santa Catarina, Brazil. A cross-sectional study was conducted on secondary data collected from 2010 to 2018. We reviewed the medical records of patients aged 18 years or older who took psychotropic drugs and had any type of substance dependence. The analysis of psychotropic drug interactions was conducted in three databases: Medscape, Drug Interactions Checker, and Micromedex. We included 1,022 of the 2,322 patients attending the care center during the study period. Psychotropic drug interactions were found in 779 (76.4%) study participants, and they presented 2,292 (100%) interactions, out of which 136 (6.0%) had minor clinical risk, 537 (23.4%) had moderate risk, and 1,619 (70.6%) had major risk for the patient, totaling 172 incompatible combinations between two psychotropic drugs. Of the total number of interactions, 128 were pharmacokinetic and 44 were pharmacodynamic. The high number of psychotropic drug interactions is a serious public health issue. Psychopharmacological treatment should be carefully addressed to be safe for the patient.

PMID: 33225871 [PubMed - as supplied by publisher]

A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of 5-HT1A Antagonist GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation.

J Sex Med. 2020 Nov 19;:

Authors: Migliorini F, Tafuri A, Bettica P, Ziviani L, Lund J, Poggesi I, Marcer A, Cacciamani GE, Lorenzo-Gomez MF, Porcaro AB, Antonelli A, Milleri S

Abstract
BACKGROUND: Premature ejaculation (PE) is a common male neurobiological sexual disorder, related to a disturbance in central serotonin (5-hydroxytryptamine or 5-HT) neurotransmission.
AIM: To assess the efficacy of a single oral dose of 5HT1A receptor antagonist GSK958108 on ejaculation latency time (ELT) in male subjects suffering from PE.
METHODS: A total of 35 male subjects were enrolled in a Phase 1 double-blind, placebo-controlled, parallel group masturbation-model study. All subjects completed the study. No subject was withdrawn from the study. There were no major protocol deviations reported during the study.
OUTCOMES: The primary outcome of the study was to evaluate the effect of a single oral dose of 5HT1A receptor antagonist GSK958108 on ELT as measured in the masturbation model; additionally, we investigated drug's safety and tolerability.
RESULTS: In the 3 mg GSK958108 treatment group, the ELT was estimated to be 16% longer (1.542 vs 1.328, 95% CI: -16% to +61%) than if the subjects had taken placebo. In the 7 mg GSK958108 treatment group, the ELT was estimated to be 77% longer (2.346 vs 1.328, 95% CI: +28% to +144%) than in the placebo group. The systemic exposure to GSK958108 increased with dosage between 3 mg and 7 mg. A significant trend toward an increase of ELT was observed with increasing plasma concentrations of GSK958108. A total of 4 patients all treated with 7 mg dose experienced minor drug related adverse events (5 adverse events in 4 patients): somnolence (n = 3), headache (n = 1), tinnitus (n = 1).
CLINICAL IMPLICATIONS: In the current double-blind, placebo-controlled parallel group study the 5HT1A receptor antagonist GSK958108 was tested in 3 mg and 7 mg doses for PE treatment in humans. It was shown that GSK958108 significantly delayed ejaculation showing a new and safe alternative in PE treatment.
STRENGTHS & LIMITATIONS: The present study showed innovative results suggesting an important role of 5HT1A receptor antagonist in the PE treatment. However, the use of masturbation model and the small population are the main limitations of this investigation.
CONCLUSION: 5HT1A receptor antagonist GSK958108 3 mg per day and 7 mg per day was found to be well-tolerated, safe and effective for the treatment of PE subjects and demonstrated a strong association between 5HT1A receptors and ejaculation control in humans (NCT00861484). Migliorini F, Tafuri A, Bettica P, et al. A Double-Blind, Placebo-Controlled Parallel Group Study to Evaluate the Effect of a Single Oral Dose of 5-HT1A Antagonist GSK958108 on Ejaculation Latency Time in Male Patients Suffering From Premature Ejaculation. J Sex Med 2020;XX:XXX-XXX.

PMID: 33223426 [PubMed - as supplied by publisher]

Pharmacogenomic Studies in Intellectual Disabilities and Autism Spectrum Disorder: A Systematic Review: Études Pharmacogénomiques en Déficiences Intellectuelles et Trouble du Spectre de L'autisme: Une Revue Systématique.

Can J Psychiatry. 2020 Nov 23;:706743720971950

Authors: Yoshida K, Koyama E, Zai CC, Beitchman JH, Kennedy JL, Lunsky Y, Desarkar P, Müller DJ

Abstract
BACKGROUND: Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID.
METHODS: We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects).
RESULTS: A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The DRD3 Ser9Gly (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the SLC6A4 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of CYP2D6 and DRD2 Taq1A polymorphisms, respectively, yielding mostly negative study findings.
CONCLUSIONS: There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.

PMID: 33222504 [PubMed - as supplied by publisher]

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis.

Aliment Pharmacol Ther. 2020 06;51(12):1286-1304

Authors: Czaja AJ

Abstract
BACKGROUND: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.
AIMS: To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.
METHODS: English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed.
RESULTS: Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.
CONCLUSIONS: The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

PMID: 32363674 [PubMed - indexed for MEDLINE]

Limited added value of laboratory monitoring in thiopurine maintenance monotherapy in inflammatory bowel disease patients.

Aliment Pharmacol Ther. 2020 06;51(12):1353-1364

Authors: Kreijne JE, de Vries AC, de Veer RC, Bouma G, Dijkstra G, Voskuil MD, West R, van Moorsel SAW, de Jong DJ, de Boer NK, van der Woude CJ, initiative on Crohn and Colitis (ICC)

Abstract
BACKGROUND: To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low.
AIM: To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment.
METHODS: Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed.
RESULTS: In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring.
CONCLUSION: Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.

PMID: 32342997 [PubMed - indexed for MEDLINE]

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.

J Gastroenterol Hepatol. 2020 Oct;35(10):1782-1788

Authors: Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Umemura M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Ohnishi S, Komatsu Y, Hata H, Takeuchi S, Abe T, Sakakibara-Konishi J, Teshima T, Homma A, Sakamoto N

Abstract
BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified.
METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data.
RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.
CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

PMID: 32187734 [PubMed - indexed for MEDLINE]

Chez les sujets avec insuffisance cardiaque à fraction d’éjection diminuée avec ou sans diabète de type 2, est-ce que la dapagliflozine, un inhibiteur des SGLT2, est efficace pour prévenir l’insuffisance cardiaque décompensée ou la mortalité cardiovasculaire tout en étant sécuritaire ?

Rev Med Interne. 2020 Feb;41(2):143-144

Authors: Lanthier L, Dussault C, Huard G, Plourde MÉ, Cauchon M

PMID: 31928796 [PubMed - indexed for MEDLINE]