International Journal of Toxicology最新文献_第5页

Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia. 对犬科猕猴（Macaca fascicularis）进行依曲帕米鼻腔喷雾剂的临床前安全性评价，以评估其对阵发性室上性心动过速患者的安全性。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-07-22 DOI: 10.1177/10915818241263068

Johanne Pion, Carlos Lopez Mendez, Jean-Pierre Moreau, Veronique Boulanger, Douglas Wight

{"title":"Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia.","authors":"Johanne Pion, Carlos Lopez Mendez, Jean-Pierre Moreau, Veronique Boulanger, Douglas Wight","doi":"10.1177/10915818241263068","DOIUrl":"10.1177/10915818241263068","url":null,"abstract":"Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"503-510"},"PeriodicalIF":1.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734065","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

Safety Assessment of Polysilicone-11 as Used in Cosmetics. 化妆品中使用的聚硅氧烷-11 的安全性评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-12 DOI: 10.1177/10915818241237789

Priya Cherian, Wilma F Bergfeld, Donald V Belsito, David E Cohen, Curtis D Klaassen, Daniel C Liebler, James G Marks, Lisa A Peterson, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Capryloyl Salicylic Acid as Used in Cosmetics. 化妆品中使用的辛酰水杨酸的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-11 DOI: 10.1177/10915818241237794

Wilbur Johnson, Wilma F Bergfeld, Donald V Belsito, Curtis D Klaassen, Daniel C Liebler, James G Marks, Lisa A Peterson, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Basic Red 76 as Used in Cosmetics. 化妆品中使用的碱性红 76 的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-12 DOI: 10.1177/10915818241237795

Priya Cherian, 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 Assessment of Hydroxyethyl Urea as Used in Cosmetics. 化妆品中使用的羟乙基尿素的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-11 DOI: 10.1177/10915818241237791

Alice Akinsulie, 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 Assessment of Hydrogen Peroxide as Used in Cosmetics. 化妆品中使用的过氧化氢的安全评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-12 DOI: 10.1177/10915818241237790

Lillian C Becker, Priya A Cherian, 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 Assessment of Palm-Derived Ingredients as Used in Cosmetics. 化妆品中使用的棕榈提取物成分的安全评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-14 DOI: 10.1177/10915818241237797

Wilbur Johnson, Wilma F Bergfeld, Donald V Belsito, Curtis D Klaassen, Daniel C Liebler, James G Marks, Lisa A Peterson, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate. 绒猴感染甲型肝炎病毒影响候选药物的安全性评估

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-07-01 Epub Date: 2024-03-19 DOI: 10.1177/10915818241237992

Chris J Powell, John C Kapeghian, John C Bernal, John R Foster

{"title":"Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate.","authors":"Chris J Powell, John C Kapeghian, John C Bernal, John R Foster","doi":"10.1177/10915818241237992","DOIUrl":"10.1177/10915818241237992","url":null,"abstract":"In a 3-month toxicity study in cynomolgus monkeys at a European contract laboratory, animals were infected with HAV, initially resulting in hepatic injury being incorrectly attributed to the test compound. Elevated serum ALT/AST/GLDH (5- to 10-fold) were noted in individual animals from all groups including controls, with no apparent dose, exposure, or time-related relationship. Liver histopathology revealed minimal to slight inflammatory cell accumulation in periportal zones of most animals, and minimal to slight hepatocyte degeneration/necrosis in 10/42 animals from all groups. As these findings were more pronounced in 6 drug-treated animals, including 2/6 in the low dose group, the draft report concluded: \"treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL.\" However, the unusual pattern of hepatotoxicity suggested a factor other than drug exposure might have caused the hepatic effects. Therefore, snap-frozen liver samples were tested for hepatitis viruses using a PCR method. Tests for hepatitis B, C, and E virus were negative; however, 20/42 samples were positive for hepatitis A virus (HAV). Infection was strongly associated with increased serum ALT/GLDH, and/or hepatocyte degeneration/necrosis. Re-evaluation of the study in light of these data concluded that the hepatic injury was not drug-related. A subsequent 6-month toxicology study in HAV-vaccinated cynomolgus monkeys confirmed the absence of hepatotoxicity. Identification of HAV infection supported progression of the drug candidate into later clinical trials. Although rarely investigated, subclinical HAV infection has occasionally been reported in laboratory primates, including those used for toxicology studies and it may be more prevalent than the literature indicates.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"368-376"},"PeriodicalIF":2.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158138","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

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":" ","pages":"357-367"},"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

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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