Immune Checkpoint Inhibitors and Immune-Related Adverse Events in Patients With Advanced Melanoma: A Systematic Review and Network Meta-analysis.

JAMA Netw Open. 2020 03 02;3(3):e201611

Authors: Chang CY, Park H, Malone DC, Wang CY, Wilson DL, Yeh YM, Van Boemmel-Wegmann S, Lo-Ciganic WH

Abstract
Importance: Since 2011, immune checkpoint inhibitors (ICIs) have been effective treatment options for advanced melanoma. Little is known about how risks of immune-related adverse events (irAEs) vary by ICIs.
Objective: To compare the risk of irAEs across different treatment regimens for advanced melanoma using network meta-analysis.
Data Sources: PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched for all randomized clinical trial (RCT) articles published from January 1, 2010, through June 30, 2019.
Study Selection: Studies included phases 2 and 3 RCTs in the treatment of advanced melanoma that compared ICIs (ipilimumab, nivolumab, and pembrolizumab) with chemotherapy drugs (eg, dacarbazine, carboplatin, and paclitaxel) or different ICI regimens.
Data Extraction and Synthesis: Different treatment regimens were compared using bayesian network meta-analysis with Markov chain Monte Carlo simulation with noninformative prior distribution and random-effects generalized linear models.
Main Outcomes and Measures: Primary outcomes were the cumulative incidence of any irAEs (regardless of severity) and severe irAEs (grades 3-5). Based on the pooled odds ratios (ORs) and 95% credible intervals (95% CrI), the probability of being associated with the lowest irAE risks was estimated for each treatment regimen.
Results: Nine RCTs with 8 different treatment regimens for advanced melanoma and involving a total of 5051 patients were included. Overall, the 3 ICI treatment regimens associated with the lowest risk of any or severe irAEs were pembrolizumab, 2 mg/kg, every 3 weeks; nivolumab, 3 mg/kg, every 2 weeks; and pembrolizumab, 10 mg/kg, every 3 weeks. Compared with ipilimumab, 10 mg/kg, every 3 weeks, only nivolumab, 3 mg/kg, every 2 weeks, was associated with a decreased risk for any irAEs (OR, 0.34; 95% CrI, 0.13-0.94). A decreased risk for severe irAEs was observed for ipilimumab, 3 mg/kg, every 3 weeks (OR, 0.35; 95% CrI, 0.14-0.74); pembrolizumab, 10 mg/kg, every 2 weeks (OR, 0.22; 95% CrI, 0.05-0.95) and 10 mg/kg every 3 weeks (OR, 0.20; 95% CrI, 0.06-0.68); and nivolumab, 3 mg/kg, every 2 weeks (OR, 0.20; 95% CrI, 0.07-0.48) compared with ipilimumab, 10 mg/kg, every 3 weeks. An increased risk for severe irAEs was associated with nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks compared with other ICI regimens (ORs ranging from 4.09 [95% CrI, 1.73-10.99] to 7.40 [95% CrI, 1.12-49.29]) except ipilimumab, 10 mg/kg, every 3 weeks.
Conclusions and Relevance: These findings suggest that for patients with advanced melanoma at high risk of irAEs, pembrolizumab, 2 mg/kg, every 3 weeks, nivolumab, 3 mg/kg, every 2 weeks, and pembrolizumab, 10 mg/kg, every 3 weeks may be the preferred treatment regimens (with respect to irAE risks) among the ICI regimens reported, whereas ipilimumab, 10 mg/kg, every 3 weeks alone and nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks should be used with caution. A network analysis may be valuable for clinical decision-making when evidence from head-to-head comparisons is lacking.

PMID: 32211869 [PubMed - indexed for MEDLINE]

The effect of asparaginase therapy on methotrexate toxicity and efficacy in children with acute lymphoblastic leukemia.

Leuk Lymphoma. 2019 12;60(12):3002-3010

Authors: Kloos RQH, Pieters R, van den Bos C, van Eijkelenburg NKA, de Jonge R, van der Sluis IM

Abstract
Asparaginase and methotrexate (MTX), both essential for pediatric acute lymphoblastic leukemia therapy, are often used concomitantly. Depending on the sequence, in vitro, asparaginase inhibits MTX-polyglutamate (MTXPG) formation, and side effects overlap. MTX toxicity and efficacy, reflected by intracellular erythrocyte MTXPG's, were compared between children treated with and without asparaginase during high dose MTX (HD-MTX) courses of the DCOG ALL-11 protocol (NL50250.078.14). Seventy-three patients, of whom 23 received asparaginase during the HD-MTX courses, were included. Grade 3-4 leukopenia and neutropenia occurred more often (59% and 86% vs. 30% and 62%). The number of infections, grade 3-4 hepatotoxicity, nephrotoxicity, and neurotoxicity did not differ. Patients with asparaginase had lower MTXPG levels, although to a lesser extent than in vitro studies. Although patients with asparaginase during HD-MTX courses showed more myelosuppression, this had no (serious) clinical consequences. Regarding the MTX efficacy, the schedule-related antagonism seen in in vitro seems less important in vivo.

PMID: 31120351 [PubMed - indexed for MEDLINE]

Uterotonic drugs to prevent postpartum haemorrhage: a network meta-analysis.

Health Technol Assess. 2019 02;23(9):1-356

Authors: Gallos I, Williams H, Price M, Pickering K, Merriel A, Tobias A, Lissauer D, Gee H, Tunçalp Ö, Gyte G, Moorthy V, Roberts T, Deeks J, Hofmeyr J, Gülmezoglu M, Coomarasamy A

Abstract
BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can reduce blood loss and are routinely recommended. There are several uterotonic drugs for preventing PPH, but it is still debatable which drug or combination of drugs is the most effective.
OBJECTIVES: To identify the most effective and cost-effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile.
METHODS: The Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO)'s International Clinical Trials Registry Platform (ICTRP) were searched for unpublished trial reports (30 June 2015). In addition, reference lists of retrieved studies (updated October 2017) were searched for randomised trials evaluating uterotonic drugs for preventing PPH. The study estimated relative effects and rankings for preventing PPH, defined as blood loss of ≥ 500 ml and ≥ 1000 ml. Pairwise meta-analyses and network meta-analysis were performed to determine the relative effects and rankings of all available drugs and combinations thereof [ergometrine, misoprostol (Cytotec®; Pfizer Inc., New York, NY, USA), misoprostol plus oxytocin (Syntocinon®; Novartis International AG, Basel, Switzerland), carbetocin (Pabal®; Ferring Pharmaceuticals, Saint-Prex, Switzerland), ergometrine plus oxytocin (Syntometrine®; Alliance Pharma plc, Chippenham, UK), oxytocin, and a placebo or no treatment]. Primary outcomes were stratified according to the mode of birth, prior risk of PPH, health-care setting, drug dosage, regimen and route of drug administration. Sensitivity analyses were performed according to study quality and funding source, among others. A model-based economic evaluation compared the relative cost-effectiveness separately for vaginal births and caesareans with or without including side effects.
RESULTS: From 137 randomised trials and 87,466 women, ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin were found to reduce the risk of PPH blood loss of ≥ 500 ml compared with the standard drug, oxytocin [ergometrine plus oxytocin: risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83; carbetocin: RR 0.72, 95% CI 0.52 to 1.00; misoprostol plus oxytocin: RR 0.73, 95% CI 0.6 to 0.9]. Each of these three strategies had 100% cumulative probability of being ranked first, second or third most effective. Oxytocin was ranked fourth, with an almost 0% cumulative probability of being ranked in the top three. Similar rankings were noted for the reduction of PPH blood loss of ≥ 1000 ml (ergometrine plus oxytocin: RR 0.77, 95% CI 0.61 to 0.95; carbetocin: RR 0.70, 95% CI 0.38 to 1.28; misoprostol plus oxytocin: RR 0.90, 95% CI 0.72 to 1.14), and most secondary outcomes. Ergometrine plus oxytocin and misoprostol plus oxytocin had the poorest ranking for side effects. Carbetocin had a favourable side-effect profile, which was similar to oxytocin. However, the analysis was restricted to high-quality studies, carbetocin lost its ranking and was comparable to oxytocin. The relative cost-effectiveness of the alternative strategies is inconclusive, and the results are affected by both the uncertainty and inconsistency in the data reported on adverse events. For vaginal delivery, when assuming no adverse events, ergometrine plus oxytocin is less costly and more effective than all strategies except carbetocin. The strategy of carbetocin is both more effective and more costly than all other strategies. When taking adverse events into consideration, all prevention strategies, except oxytocin, are more costly and less effective than carbetocin. For delivery by caesarean section, with and without adverse events, the relative cost-effectiveness is different, again because of the uncertainty in the available data.
LIMITATIONS: There was considerable uncertainty in findings within the planned subgroup analyses, and subgroup effects cannot be ruled out.
CONCLUSIONS: Ergometrine plus oxytocin, carbetocin and misoprostol plus oxytocin are more effective uterotonic drug strategies for preventing PPH than the current standard, oxytocin. Ergometrine plus oxytocin and misoprostol plus oxytocin cause significant side effects. Carbetocin has a favourable side-effect profile, which was similar to oxytocin. However, most carbetocin trials are small and of poor quality. There is a need for a large high-quality trial comparing carbetocin with oxytocin; such a trial is currently being conducted by the WHO. The relative cost-effectiveness is inconclusive, and results are affected by uncertainty and inconsistency in adverse events data.
STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020005; Cochrane Pregnancy and Childbirth Group (substudy) reference number 0871; PROSPERO-Cochrane (substudy) reference number CRD42015026568; and sponsor reference number ERN_13-1414 (University of Birmingham, Birmingham, UK).
FUNDING: Funding for this study was provided by the National Institute for Health Research Health Technology Assessment programme in a research award to the University of Birmingham and supported by the UK charity Ammalife (UK-registered charity 1120236). The funders of the study had no role in study design, data collection, data synthesis, interpretation or writing of the report.

PMID: 30821683 [PubMed - indexed for MEDLINE]

Comparative effectiveness study of single high-dose cisplatin with fractionated doses cisplatin in first-line therapy for treatment-naive Chinese patients with advanced non-small-cell lung cancer.

Curr Probl Cancer. 2019 12;43(6):100466

Authors: Li X, Zhao X, Abbas M, Wang L, Li C, Liu S, Feng J, Shi M

Abstract
BACKGROUND: Cisplatin is one of the most effective chemotherapeutic drugs for patients with advanced non-small-cell lung cancer (NSCLC). Single high-dose cisplatin is a commonly used chemotherapy regimen in the world. At present, fractionated doses cisplatin is used in most hospitals in China. Although many doctors have begun to try a single dose of cisplatin, there are still few studies on the comparison of the 2 regimens. This study describes the efficacy and side effects of cisplatin single-dose administration and fractionated doses regimen in the treatment of advanced NSCLC.
METHODS: A retrospective study was conducted on 219 patients with advanced NSCLC who received chemotherapy with DDP were divided into 2 groups according to the single dose of cisplatin from January 2014 to December 2017. For experimental group, 108 patients were enrolled and received DDP at a dose of 75 mg/m2 on day 1. A total of 111 patients were enrolled in the control group, and DDP was administrated at 25 mg/m2 on days 1-3. The efficacy, toxicity, and progression-free survival of the 2 groups were observed and analyzed.
RESULTS: In the experimental group, the numbers of patients who received PR, SD, and PD were 66, 34, and 8 respectively. In the control group, the numbers of patients who received PR, SD, and PD were 18, 77, and 16 respectively. The percentages of patients with a objective response rate response in the experimental group were significantly higher than that in the control group (61.11% vs 16.22%, P < 0.0001). The incidence of III-IV vomiting in the experimental group was lower than that in the control group (11.11% vs 26.13%). The incidence of I-II hiccups in the experimental group was higher than that in the control group (15.74% vs 10.81%). None of the patients had III-IV degree nephrotoxicity. Myelosuppression mainly manifested as leukopenia. In the experimental group, the incidence of I-II degree of leukopenia was 71.30%, and the III-IV degree was 7.41%, which was 74.77% and 11.71 respectively in the control group. A small number of patients have a decrease in mild platelets and hemoglobin.
CONCLUSION: For patients with advanced NSCLC who require chemotherapy with DDP regimen, the short-term effect of single-dose administration of DDP is better than that of fractional small-dose administration. Toxicity can be tolerated and it is worth promoting clinically.

PMID: 30777344 [PubMed - indexed for MEDLINE]

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Cervical cancer in pregnancy.

Klin Onkol. 2020;33(4):268-273

Authors: Nocarová L, Ondruš D

Abstract
BACKGROUND: Cervical cancer is one of the most frequent cancers in pregnant women, despite this combination being a rare condition. More than 70% of cases are dia-gnosed in early stages and its treatment can be postponed after the delivery. Invasive cancer dia-gnosis in pregnancy is difficult for a patient, her family and doctors. A multidisciplinary team should take care of the patient and foetus and patients wishes are respected regarding her treatment and pregnancy. Radiotherapy in pregnancy is contraindicated. Neoadjuvant or adjuvant chemotherapy is therefore a main treatment method in patients with high risk disease either during pregnancy, or after the delivery. Neoadjuvant chemotherapy choice, delivery timing and definitive treatment are keys to mothers and childs health. Palliative treatment during pregnancy is extremely rare and the prognosis is poor. Bevacizumab and pembrolizumab are promising in the palliative treatment of non-pregnant patients. Neither bio-logical therapy by bevacizumab, nor immunotherapy by pembrolizumab can be administered to pregnant patient due to their mechanisms of action.
PURPOSE: This overviews aim is to analyse data of cervical cancer treatment for pregnant women, focusing on dia-gnostics, therapy and delivery timing and treatment modalities choice according to the stage of the disease and gestational age. Individual approach is always necessary; our aim is, however, to emphasise current evidence-based recommendations in pregnancy. 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.

PMID: 32894955 [PubMed - in process]

Toxicity profile of thiopurines in inflammatory bowel disease: a retrospective cohort analysis.

Tunis Med. 2020 May;98(5):404-412

Authors: Labidi A, Hafi M, Ben Mustapha N, Serghini M, Fekih M, Boubaker J

Abstract
BACKGROUND: Thiopurines have proven efficacy in inflammatory bowel disease. However, their use is limited by adverse effects in a subset of patients.
AIMS: The present study aimed to evaluate toxicity profile and identify clinical predictive factors of thiopurine adverse effects in inflammatory bowel disease patients.
METHODS: A retrospective longitudinal study was conducted among inflammatory bowel disease patients treated with thiopurines. Multiple logistic regression was used to identify risk factors for thiopurine adverse effects.
RESULTS: A total of  210 patients were enrolled in the study. Mean age at disease onset was 29.8±11.4 years.  One hundred sixty-nine (169) patients had Crohn's disease, 29 had ulcerative colitis and 12 had indeterminate colitis. During a median follow-up of 28.5 ± 20 months, 56 patients (26.6%) had thiopurine-related adverse effects including digestive intolerance (n=14; 6.6%), immunoallergic reactions (n=8; 3.8%), myelotoxicity (n=25; 11.9%) and hepatotoxicity (n=8; 3.8%). Treatment withdrawal was reported in 19 patients (9%).  The only independent predictive factor for thiopurine adverse effects found in this study was steroid-dependence (OR= 3.96; 95% CI: 1.07- 14.53; p= 0.038).
CONCLUSIONS: Almost a quarter of inflammatory bowel disease patients treated with thiopurines developed adverse effects. These adverse effects lead to drug withdrawal in almost 9% of patients either as monotherapy or as in combination with biologic therapies.  Steroid-dependent patients were significantly at higher risk for thiopurine-related toxicity.

PMID: 32548844 [PubMed - indexed for MEDLINE]

EHRs could clarify drug safety in pregnant people.

Nat Med. 2020 06;26(6):820-821

Authors: Challa AP, Lavieri RR, Lippmann ES, Goldstein JA, Bastarache L, Pulley JM, Aronoff DM

PMID: 32457445 [PubMed - indexed for MEDLINE]

Liver toxicity of macrolide antibiotics in zebrafish.

Toxicology. 2020 08;441:152501

Authors: Zhang MQ, Chen B, Zhang JP, Chen N, Liu CZ, Hu CQ

Abstract
Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections, but macrolides also expose people to the risk of adverse events include hepatotoxicity. Here, we report the liver toxicity of macrolides with different structures in zebrafish. The absorption, distribution, metabolism, excretion and toxicology (ADMET) parameters of macrolide compounds were predicted and contrasted by utilizing in silico analysis. Fluorescence imaging and Oil Red O stain assays showed all the tested macrolide drugs induced liver degeneration, changed liver size and liver steatosis in larval zebrafish. Through RNA-seq analysis, we found seven co-regulated differentially expressed genes (co-DEGs) associated with metabolism, apoptosis and immune system biological processes, and two co-regulated significant pathways including amino sugar and nucleotide sugar metabolism and apoptosis signaling pathway. We found that only fosab of seven co-DEGs was in the two co-regulated significant pathways. fosab encoded proto-oncogene c-Fos, which was closely associated with liver diseases. The whole-mount in situ hybridization showed high transcription of c-Fos induced by macrolide compounds mainly in the liver region of zebrafish larvae. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) leakage assays revealed that macrolides exerts significant cytotoxic effects on L02 cells. qRT-PCR and western blot analysis demonstrated macrolides also promoted human c-Fos expression in L02 cells. The c-Fos overexpression significantly reduced cell viability by using CCK-8 assay. These data indicate that hepatotoxicity induced by macrolides may be correlated with c-Fos expression activated by these compounds. This study may provide a biomarker for the further investigations on the mechanism of hepatotoxicity induced by macrolide drugs with different structures, and extend our understanding for improving rational clinical application of macrolides.

PMID: 32454074 [PubMed - indexed for MEDLINE]

[Pregnancy & glaucoma: SFO-SFG recommendations].

J Fr Ophtalmol. 2020 Jan;43(1):63-66

Authors: Blumen-Ohana E, Sellem E

PMID: 31813552 [PubMed - indexed for MEDLINE]

Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: Results of a multicenter naturalistic study (ETAPE).

Eur Neuropsychopharmacol. 2019 12;29(12):1397-1407

Authors: Menard ML, Thümmler S, Giannitelli M, Cruzel C, Bonnot O, Cohen D, Askenazy F, ETAPE Study Group

Abstract
The main objective of ETAPE study was to determine the incidence of adverse events (AEs) potentially related to antipsychotic (AP) during a 12-months observational study of naturalistic treatment. ETAPE is a naturalistic prospective multicenter study conducted between April 2013 and May 2016. 200 patients were included. The mean age was 12 ± 3 years, with 73.6% being males. Patients presented a significant clinical improvement over time. At baseline, 92% of patients received a second generation AP, 74% AP monotherapy and 79.5% off-label AP prescriptions. Clinical diagnoses were heterogeneous including psychosis, anxiety, mood and neurodevelopmental disorders. The overall AE incidence rate was 11.52 AEs per person-years. Among AEs potentially attributable to AP, 15.4% were neuromotor, 14.8% gastroenterological, 12.2% metabolic and 11.8% general symptoms. Weight and body mass index increased significantly. More than half of AE appeared during the first 3 months, but onset of AE was noted all over follow-up. The presence of AEs was stable over time. ETAPE study highlights a high incidence rate of AE in children treated with AP. A careful and continuous clinical and biological monitoring is required to adapt treatment decisions based on benefice-risk-analysis. Moreover, additional research is warranted, also in regard of high proportion of off-label prescriptions.

PMID: 31699516 [PubMed - indexed for MEDLINE]

Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy.

Clin Cancer Res. 2019 11 01;25(21):6295-6301

Authors: Hu S, Huang KM, Adams EJ, Loprinzi CL, Lustberg MB

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity, negatively affecting both quality of life and disease outcomes. To date, there is no proven preventative strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.

PMID: 31123053 [PubMed - indexed for MEDLINE]

Cytoprotective Agents to Avoid Chemotherapy Induced Sideeffects on Normal Cells: A Review.

Curr Cancer Drug Targets. 2019;19(10):765-781

Authors: Rohilla S, Dureja H, Chawla V

Abstract
Anticancer agents play a vital role in the cure of patients suffering from malignancy. Though, the chemotherapeutic agents are associated with various adverse effects which produce significant toxic symptoms in the patients. But this therapy affects both the malignant and normal cells and leads to constricted therapeutic index of antimalignant drugs which adversely impacts the quality of patients' life. Due to these adversities, sufficient dose of drug is not delivered to patients leading to delay in treatment or improper treatment. Chemoprotective agents have been developed either to minimize or to mitigate the toxicity allied with chemotherapeutic agents. Without any concession in the therapeutic efficacy of anticancer drugs, they provide organ specific guard to normal tissues.

PMID: 30914026 [PubMed - indexed for MEDLINE]

Deprescribing in Advanced Illness: Aligning Patient, Clinician, and Health Plan Goals.

J Gen Intern Med. 2019 04;34(4):631-633

Authors: Parekh N, Schenker Y, Good CB, Neilson L, Shrank WH

Abstract
Polypharmacy has been linked to adverse outcomes including increased risk of hospitalization, falls, and death and contributes to unnecessary healthcare spending. Deprescribing efforts aim to reduce medication burden while improving or maintaining patients' quality of life. While the practice of deprescribing is gaining momentum, quality measurement and provider reimbursement are barriers that must be addressed for deprescribing to achieve widespread adoption. Because many quality measures are focused on medication use and adherence, deprescribing efforts may negatively impact primary care provider and health plan quality ratings and value-based reimbursement. In addressing this conflict, there are opportunities to proactively align the priorities and incentives of patients, providers, and plans to promote deprescribing. In this report, we propose several actionable steps to address quality and reimbursement-based barriers such as facilitating the exclusion of those engaged in deprescribing efforts from quality measures and the development of deprescribing-based quality measures.

PMID: 30719644 [PubMed - indexed for MEDLINE]

Adverse Drug Events in the Oral Cavity.

Dermatol Clin. 2020 Oct;38(4):523-533

Authors: Yuan A, Woo SB

Abstract
Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely hyposalivation, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, reactive keratosis, dysesthesia, osteonecrosis, infection, angioedema, and malignancy.

PMID: 32892860 [PubMed - in process]

[AI-based QSAR Modeling for Prediction of Active Compounds in MIE/AOP].

Yakugaku Zasshi. 2020;140(4):499-505

Authors: Uesawa Y

Abstract
Toxicity testing is critical for new drug and chemical development process. A clinical study, experimental animal models, and in vitro study are performed to evaluate the safety of a new drug. The limitations of these methods include extensive time for toxicity testing, an ethical problem, and high costs of experimentation. Therefore computational methods are considered useful for estimating chemical toxicity. In silico toxicity prediction is one of the toxicity assessments that uses computational methods to predict and stimulate the toxicity of chemicals. In silico study aims to contribute to effective development of new drug and chemical design. In this study, quantitative structure-activity relationship (QSAR) models will be used to predict toxicities based on chemical structural parameters. Because toxicities are complicated physiological phenomena, a similar toxicity expression might cause a different pathway. Also, since many drugs with unknown mechanisms of actions are available, the application of artificial intelligence (AI)-which uses sophisticated algorithms- is increasingly used to predict toxicities. Recently, the QSAR model was applied to determine complex relations between chemical structures and toxicities. However, accuracy of QSAR for toxicity prediction remains an important issue. International competitions funded by public institutions can address this issue. Two important toxicity challenges were organized in the past decade; this article presents issues of toxicity based on these challenges.

PMID: 32238631 [PubMed - indexed for MEDLINE]

[Molecular Pathway and AOP Development Using Gene Network Analysis].

Yakugaku Zasshi. 2020;140(4):485-489

Authors: Tanabe S, Hirose A, Whelan M, Yamada T

Abstract
The Organisation for Economic Co-operation and Development (OECD) has initiated the adverse outcome pathway (AOP) Development Program in which the concept of AOP is applied to evaluate the safety of molecules such as chemicals. This program aims to assist regulatory needs and construct a knowledge base by accumulating AOP case studies. AOP consists of a molecular initiating event (MIE) as the initiating event of the pathway; key events (KEs) as the events themselves, such as cellular-molecular interactions; and adverse outcome (AO), such as signaling transduction-induced toxicity, as adverse events. KEs are extracted as important events at various levels, such as the molecular, cellular, tissue, organ, individual, and species levels; measurement of KEs and key event relationships (KERs), including mechanisms, plausibility, species differences, and empirical support information, are gathered. The development status of the AOP relating to histone deacetylase inhibition-induced testicular toxicity, currently being reviewed by the OECD, has been introduced. The AOP describing malignancies by Wnt ligand stimulation and Wnt signaling activation using gene expression network analysis-based mechanisms in molecular pathway elucidation has been suggested.

PMID: 32238629 [PubMed - indexed for MEDLINE]

[Challenge for Adverse Outcome Pathway (AOP)-based Chemical Safety Assessment].

Yakugaku Zasshi. 2020;140(4):481-484

Authors: Yamada T, Ashikaga T, Kojima H, Hirose A

Abstract
The latest chemical management policies require toxicological evaluation of marketed but untested chemicals. Furthermore, in Europe, for animal welfare reasons sales of cosmetics and raw materials for which animal experiments were conducted were totally banned, in 2013. Responding to these regulatory trends, a strong demand exists to develop new in vitro test methods and to improve in silico prediction models for safety assessments. In recent years, the development of adverse outcome pathways (AOPs) has been actively promoted in the Organisation for Economic Co-operation and Development (OECD). Since it is difficult to replace a particular in vivo animal test with a single in vitro test method or in silico prediction model, integrated approaches to testing and assessment (IATA) have been studied based on AOP information. With regard to skin sensitization, several in vitro test methods that measure key events of AOP have been established, and integrated strategies using in vitro tests have been examined using AOP. Currently, numerous AOPs are under development for a wide range of complex toxicity endpoints in the OECD AOP program. The AOPs are expected to contribute to the development of many accurate in vitro test methods and to establish IATA as well as to evaluate safety in humans of many substances, including household chemicals, food-related chemicals, cosmetics, and pharmaceuticals.

PMID: 32238628 [PubMed - indexed for MEDLINE]

Evaluation of 3 Months of Once-Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection.

Ann Pharmacother. 2020 05;54(5):457-463

Authors: Walker RE, Bass S, Srinivas P, Miranda C, Johnson L, Pallotta AM

Abstract
Background: Centers for Disease Control and Prevention recommends 3 months of once-weekly rifapentine/isoniazid (3HP) for latent tuberculosis infection (LTBI) treatment given by directly observed therapy (DOT) or self-administered therapy (SAT) in patients ≥2 years old. 3HP has been associated with increased incidence of hepatic, gastrointestinal, flu-like, and cutaneous adverse drug reactions (ADRs) compared with isoniazid monotherapy. Objective: This study evaluated 3HP completion rates and tolerability for LTBI treatment in a real-world setting. Methods: A single-center retrospective cohort with a nested case-control study, comparing patients experiencing ADRs with those who did not, evaluated patients ≥18 years old receiving 3HP by DOT or SAT for LTBI at Cleveland Clinic from October 2011 through July 2018. Information on baseline characteristics, 3HP administrations, and ADRs were collected. Results: Of 199 patients screened, 144 were included (111 DOT, 33 SAT). 3HP completion rates were high at 82.6% and similar between DOT and SAT groups. During treatment, 92/144 (63.9%) patients experienced any ADR. The most common ADR included flu-like symptoms (38.2%) and gastrointestinal (31.9%) and hepatic (2.1%) reactions. Despite high rate of overall ADRs, rates of significant ADRs (grade 2 or higher) were 4.2%. Overall, 9% of patients discontinued 3HP because of ADRs. After adjusting for other factors associated with ADRs at baseline, SAT was not associated with increased incidence of ADRs, but female sex was a significant predictor (odds ratio = 2.61 [95% CI, 1.23 to 5.56]). Conclusion and Relevance: This study observed high 3HP treatment completion rates, low incidence of significant ADRs, and low discontinuation rates resulting from ADRs.

PMID: 31729245 [PubMed - indexed for MEDLINE]

Safety of High-Intensity Statins in the Veteran Population: Atorvastatin 40 to 80 mg Compared With Rosuvastatin 20 to 40 mg.

Ann Pharmacother. 2020 05;54(5):405-413

Authors: Stein B, Ward T, Hale G, Lyver E

Abstract
Background: High-intensity statin therapy is recommended in patients with clinical atherosclerotic cardiovascular disease (ASCVD) or at high risk of ASCVD. Current evidence demonstrates efficacy of high-intensity statin therapy in reducing major adverse cardiovascular events; yet the comparative safety profile between high-intensity statin agents remains unknown. In 2011, when atorvastatin became generic, the Veteran's Health Administration made the formulary switch from rosuvastatin to atorvastatin. Currently, rosuvastatin is generic; however, at the time of this study, it was still under patent. Objective: The primary objective was to determine if high-intensity atorvastatin compared with rosuvastatin is associated with an increased incidence of adverse drug reactions (ADRs) in the veteran population. Methods: A retrospective cohort study at James A. Haley Veterans' Hospital compared patients receiving rosuvastatin 20 to 40mg from January 2009 to November 2011 (n = 4,165) and atorvastatin 40 to 80mg from May 2012 to June 2016 (n = 5,852). Patients were excluded if they were nonadherent to statin therapy or had a documented ADR to atorvastatin prior to formulary switch. Results: A difference in overall ADR rates was found between atorvastatin and rosuvastatin groups (4.59% vs 2.91%; odds ratio [OR], 1.61; 95% CI, 1.29 to 2.00; P < 0.05). Statistically significant differences in abnormal liver transaminases (3.99% vs 1.39%; OR, 2.95; 95% CI, 2.21 to 3.94; P < 0.05) and statin-associated muscle symptoms (1.14% vs 0.5%; OR, 2.29; 95% CI, 1.39 to 3.74; P < 0.05) were identified between groups. Patients receiving rosuvastatin were on therapy 2.5 times longer before developing an ADR. Conclusion and Relevance: High-intensity atorvastatin compared with rosuvastatin is associated with an increased incidence of ADRs.

PMID: 31718234 [PubMed - indexed for MEDLINE]