International Journal of Toxicology最新文献_第4页

In Silico Human Cardiomyocyte Action Potential Modeling: Exploring Ion Channel Input Combinations. 硅学人类心肌细胞动作电位建模：探索离子通道输入组合

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-07-01 Epub Date: 2024-03-13 DOI: 10.1177/10915818241237988

Emmanuel Boulay, Eric Troncy, Vincent Jacquemet, Hai Huang, Michael K Pugsley, Anne-Marie Downey, Rafael Venegas Baca, Simon Authier

{"title":"In Silico Human Cardiomyocyte Action Potential Modeling: Exploring Ion Channel Input Combinations.","authors":"Emmanuel Boulay, Eric Troncy, Vincent Jacquemet, Hai Huang, Michael K Pugsley, Anne-Marie Downey, Rafael Venegas Baca, Simon Authier","doi":"10.1177/10915818241237988","DOIUrl":"10.1177/10915818241237988","url":null,"abstract":"In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model. Action potential values were calculated for epicardial, myocardial, and endocardial cells, with action potential curve modeling. This study assessed cardiac ion channel inhibition data combinations to consider when undertaking in silico modeling of proarrhythmic effects as stipulated in the Comprehensive in Vitro Proarrhythmia Assay (CiPA). As expected, our data highlight the importance of the delayed rectifier potassium channel (IKr) as the most impactful channel for APD prolongation. The impact of the transient outward potassium channel (Ito) inhibition on APD was minimal while the inward rectifier (IK1) and slow component of the delayed rectifier potassium channel (IKs) also had limited APD effects. In contrast, the contribution of fast sodium channel (INa) and/or L-type calcium channel (ICa) inhibition resulted in substantial APD alterations supporting the pharmacological relevance of in silico modeling using input from a limited number of cardiac ion channels including IKr, INa, and ICa, at least at an early stage of drug development.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

So…….You Want to be a Peer Reviewer? So.......You 想成为同行评审员吗？

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-07-01 Epub Date: 2024-05-20 DOI: 10.1177/10915818241254582

Mary Beth Genter

引用次数: 0

Isobutane, Isopentane, Butane, and Propane. 异丁烷、异戊烷、丁烷和丙烷。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-06-14 DOI: 10.1177/10915818241260280

Regina Tucker, Wilma F Bergfeld, Donald V Belsito, David E Cohen, Curtis D Klaassen, Allan E Rettie, David Ross, Thomas J Slaga, Paul W Snyder, Susan Tilton, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Triphenyl Phosphate as Used in Cosmetics. 化妆品中使用的磷酸三苯酯的安全性评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-06-14 DOI: 10.1177/10915818241259692

Christina L Burnett, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety and Pharmacokinetic Assessment of the FIC CLDN18.2/4-1BB Bispecific Antibody in Rhesus Monkeys. 恒河猴体内 FIC CLDN18.2/4-1BB 双特异性抗体的安全性和药代动力学评估

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-05-01 Epub Date: 2023-12-19 DOI: 10.1177/10915818231221282

Jing Wang, Tiantian Dong, Xinjiang Gong, Deli Li, Joanne Sun, Yi Luo, Huazhang Wu

{"title":"Safety and Pharmacokinetic Assessment of the FIC CLDN18.2/4-1BB Bispecific Antibody in Rhesus Monkeys.","authors":"Jing Wang, Tiantian Dong, Xinjiang Gong, Deli Li, Joanne Sun, Yi Luo, Huazhang Wu","doi":"10.1177/10915818231221282","DOIUrl":"10.1177/10915818231221282","url":null,"abstract":"Gastric cancer is one of the most common cancers worldwide, particularly in China, with over half a million new cases and over 400 thousand deaths in 2022. Zolbetuximab, a first-in-class investigational monoclonal antibody (mAb) targeting tumor-associated antigen CLDN18.2 which is highly expressed on gastric cancer cells, was recently reported to meet the primary endpoint in Phase III trial as first-line treatment in CLDN18.2 positive and HER2-negative gastric cancers. In the present study, we developed a humanized bispecific antibody (bsAb) CLDN18.2/4-1BB named PM1032. PM1032 activates immune cells via CLDN18.2 mediated crosslinking of 4-1BB, a potent stimulator of T/NK cells. It induced strong immunological memory in multiple tumor-bearing animal models, indicating significant potential as an effective treatment for CLDN18.2 positive cancers such as gastric cancer. Since liver and gastrointestinal (GI) related toxicities were reported in 4-1BB and CLDN18.2 targeting programs during the clinical development, respectively, extensive pharmacokinetics (PK) and safety profile characterization of PM1032 was performed in rhesus monkeys. PM1032 had a half-life comparable to a conventional IgG1 mAb, and serum drug concentration increased in a dose-dependent pattern. Furthermore, PM1032 was generally well tolerated, with no significant abnormalities observed in toxicity studies, including the liver and stomach. In summary, PM1032 demonstrated good PK and an exceptional safety profile in rhesus monkeys supporting further investigation in clinical studies.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138804302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Application of the Key Characteristics of Carcinogens to Bisphenol A. 将致癌物的关键特征应用于双酚 A。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-05-01 Epub Date: 2024-01-10 DOI: 10.1177/10915818231225161

Karin Ricker, Vanessa Cheng, Chingyi Jennifer Hsieh, Feng C Tsai, Gwendolyn Osborne, Kate Li, Meltem Yilmazer-Musa, Martha S Sandy, Vincent J Cogliano, Rose Schmitz, Meng Sun

{"title":"Application of the Key Characteristics of Carcinogens to Bisphenol A.","authors":"Karin Ricker, Vanessa Cheng, Chingyi Jennifer Hsieh, Feng C Tsai, Gwendolyn Osborne, Kate Li, Meltem Yilmazer-Musa, Martha S Sandy, Vincent J Cogliano, Rose Schmitz, Meng Sun","doi":"10.1177/10915818231225161","DOIUrl":"10.1177/10915818231225161","url":null,"abstract":"The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139417071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Electrophysiological Changes in the Rabbit Ventricular Wedge and Human-Induced Pluripotent Stem-Cell Derived (IPSC) Cardiomyocytes Translate to Severe Arrhythmia Observed in a Canine Toxicology Study, Not Predicted by Standard In Vitro Ion Channel Assays. 兔室楔和人类诱导多能干细胞衍生（IPSC）心肌细胞的电生理学变化转化为犬毒理学研究中观察到的严重心律失常，而标准体外离子通道测定无法预测这种变化。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-05-01 Epub Date: 2024-02-08 DOI: 10.1177/10915818241230900

Alan P Brown, Gregory S Friedrichs, Hai-Ming Tang, Martin Traebert, Valerie Weber, Nancy Yao, Gan-Xin Yan

{"title":"Electrophysiological Changes in the Rabbit Ventricular Wedge and Human-Induced Pluripotent Stem-Cell Derived (IPSC) Cardiomyocytes Translate to Severe Arrhythmia Observed in a Canine Toxicology Study, Not Predicted by Standard In Vitro Ion Channel Assays.","authors":"Alan P Brown, Gregory S Friedrichs, Hai-Ming Tang, Martin Traebert, Valerie Weber, Nancy Yao, Gan-Xin Yan","doi":"10.1177/10915818241230900","DOIUrl":"10.1177/10915818241230900","url":null,"abstract":"During drug discovery, small molecules are typically assayed in vitro for secondary pharmacology effects, which include ion channels relevant to cardiac electrophysiology. Compound A was an irreversible inhibitor of myeloperoxidase investigated for the treatment of peripheral artery disease. Oral doses in dogs at ≥5 mg/kg resulted in cardiac arrhythmias in a dose-dependent manner (at Cmax, free ≥1.53 μM) that progressed in severity with time. Nevertheless, a panel of 13 different cardiac ion channel (K, Na, and Ca) assays, including hERG, failed to identify pharmacologic risks of the molecule. Compound A and a related Compound B were evaluated for electrophysiological effects in the isolated rabbit ventricular wedge assay. Compounds A and B prolonged QT and Tp-e intervals at ≥1 and ≥.3 μM, respectively, and both prolonged QRS at ≥5 μM. Compound A produced early after depolarizations and premature ventricular complexes at ≥5 μM. These data indicate both compounds may be modulating hERG (Ikr) and Nav1.5 ion channels. In human IPSC cardiomyocytes, Compounds A and B prolonged field potential duration at ≥3 μM and induced cellular dysrhythmia at ≥10 and ≥3 μM, respectively. In a rat toxicology study, heart tissue: plasma concentration ratios for Compound A were ≥19X at 24 hours post-dose, indicating significant tissue distribution. In conclusion, in vitro ion channel assays may not always identify cardiovascular electrophysiological risks observed in vivo, which can be affected by tissue drug distribution. Risk for arrhythmia may increase with a \"trappable\" ion channel inhibitor, particularly if cardiac tissue drug levels achieve a critical threshold for pharmacologic effects.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review. 死藤水和二甲基色胺的不良事件和毒性分析：系统性专题回顾。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-05-01 Epub Date: 2024-02-16 DOI: 10.1177/10915818241230916

Eleanor White, Tom Kennedy, Simon Ruffell, Daniel Perkins, Jerome Sarris

{"title":"Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review.","authors":"Eleanor White, Tom Kennedy, Simon Ruffell, Daniel Perkins, Jerome Sarris","doi":"10.1177/10915818241230916","DOIUrl":"10.1177/10915818241230916","url":null,"abstract":"The objective of this paper is to conduct a systematic thematic review of adverse events, safety, and toxicity of traditional ayahuasca plant preparations and its main psychoactive alkaloids (dimethyltryptamine [DMT], harmine, harmaline, and tetrahydroharmine), including discussing clinical considerations (within clinical trials or approved settings). A systematic literature search of preclinical, clinical, epidemiological, and pharmacovigilance data (as well as pertinent reviews and case studies) was conducted for articles using the electronic databases of PubMed and Web of Science (to 6 July 2023) and PsycINFO, ClinicalTrials.gov, and Embase (to 21 September 2022) and included articles in English in peer-reviewed journals. Additionally, reference lists were searched. Due to the breadth of the area covered, we presented the relevant data in a thematic format. Our searches revealed 78 relevant articles. Data showed that ayahuasca or DMT is generally safe; however, some adverse human events have been reported. Animal models using higher doses of ayahuasca have shown abortifacient and teratogenic effects. Isolated harmala alkaloid studies have also revealed evidence of potential toxicity at higher doses, which may increase with co-administration with certain medications. Harmaline revealed the most issues in preclinical models. Nevertheless, animal models involving higher-dose synthetic isolates may not necessarily be able to be extrapolated to human use of therapeutic doses of plant-based extracts. Serious adverse effects are rarely reported within healthy populations, indicating an acceptable safety profile for the traditional use of ayahuasca and DMT in controlled settings. Further randomized, controlled trials with judicious blinding, larger samples, and longer duration are needed.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to "Eleventh Triennial Toxicology Salary Survey". 第十一次三年期毒理学薪酬调查 "更正。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-05-01 Epub Date: 2023-12-23 DOI: 10.1177/10915818231218209

引用次数: 0

Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats. OECD TG 422重复给药和汉族Wistar大鼠生殖/发育毒性筛选试验中高级烯烃的毒理学评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-05-01 Epub Date: 2023-11-07 DOI: 10.1177/10915818231210856

Quan Shi, Juan-Carlos Carrillo, Michael G Penman, Hua Shen, Colin M North, Sophie Jia, Tilly Borsboom-Patel, Yuan Tian, Fabienne Hubert, Jason C Manton, Peter J Boogaard

{"title":"Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats.","authors":"Quan Shi, Juan-Carlos Carrillo, Michael G Penman, Hua Shen, Colin M North, Sophie Jia, Tilly Borsboom-Patel, Yuan Tian, Fabienne Hubert, Jason C Manton, Peter J Boogaard","doi":"10.1177/10915818231210856","DOIUrl":"10.1177/10915818231210856","url":null,"abstract":"Higher olefins (HO) are used primarily as intermediates in the production of other chemicals, such as polymers, fatty acids, plasticizer alcohols, surfactants, lubricants, amine oxides, and detergent alcohols. The potential toxicity of five HO (i.e., 1-Octene, Nonene, Decene, Hexadecene, and 1-Octadecene) with carbon ranging from C8 to C18 was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD TG 422). These five HO were administered to Han Wistar rats by gavage at 0 (controls), 100, 300, and 1000 mg/kg bw/day. As a group of substances, adaptive changes in the liver (liver weight increase without pathological evidence), as well as increased kidney weight in male rats, were observed in HO with carbon numbers from C8 to C10. The overall systemic no observed adverse effect level (NOAEL) for all HO was determined at 1000 mg/kg bw/day. In the reproductive/developmental toxicity assessment, offspring viability, size, and weights were reduced in litters from females treated with Nonene at 1000 mg/kg bw/day. The overall no observed effects level (NOEL) for reproductive toxicity was considered to be 300 mg/kg bw/day for Nonene and 1000 mg/kg bw/day for the other four HO, respectively. These data significantly enrich the database on the toxicity of linear and branched HO, allowing comparison with similar data published on a range of linear and branched HO. Comparisons between structural class and study outcome provide further supportive data in order to validate the read-across hypothesis as part of an overall holistic testing strategy.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71481530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0