International Journal of Toxicology最新文献

A Commentary: Looking Back and Looking Sideways.

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-04-09 DOI: 10.1177/10915818251328037

Anthony Dayan, Peter Pressman, Thomas Blackburn, Norbert Kaminski, Samuel Cohen, A Wallace Hayes

引用次数: 0

Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys.

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-04-01 DOI: 10.1177/10915818251327963

Alexis Ascah, Jean-Pierre Moreau, Simon Authier, David B Bharucha, Douglas Wight

{"title":"Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys.","authors":"Alexis Ascah, Jean-Pierre Moreau, Simon Authier, David B Bharucha, Douglas Wight","doi":"10.1177/10915818251327963","DOIUrl":"https://doi.org/10.1177/10915818251327963","url":null,"abstract":"Paroxysmal supraventricular tachycardia (PSVT) is a common cardiac arrhythmia associated with substantial health care burden. Etripamil, a fast-acting non-dihydropyridine calcium channel blocker developed for intranasal self-administration, is currently under investigation for acute treatment of PSVT episodes. A novel two-phase study design was used to test a series of five doses of intravenous etripamil (0, 0.025, 0.05, 0.15, and 0.3 mg/kg) in conscious cynomolgus monkeys. The cardiovascular effects (e.g., blood pressure and ECG recordings) were assessed during the first phase, and the pharmacokinetic profile was characterized during the second phase. Animals were dosed remotely to avoid the stress of intranasal dosing and minimize the impact of dose administration on measurements. Results were compared with findings from subsequent intranasal studies in cynomolgus monkeys and humans. Etripamil decreased systolic blood pressure and increased heart rate proportionately in a dose-dependent manner. Etripamil also induced dose-dependent increases in the PR interval. At a dose of 0.3 mg/kg (the highest dose), the mean highest PR prolongation from baseline during 20 minutes after dosing was 27.38%. Systemic exposure to etripamil increased in a dose-dependent manner. Mean area under the curve from administration to when drug was no longer present (AUC0-∞) values ranged from 179 to 2364 ng • min/mL, peak plasma concentration ranged from 13.2 to 176 ng/mL, and mean half-life ranged from 12.3 to 20.8 minutes (Figure 1). Results were consistent with data from subsequent intranasal preclinical and clinical studies. Intravenous etripamil demonstrated the desired targeted pharmacokinetic and pharmacodynamic profiles in conscious cynomolgus monkeys.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251327963"},"PeriodicalIF":1.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752711","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

A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin.

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-20 DOI: 10.1177/10915818251326466

Michael K Pugsley, Darren T Hwee, Brett R Winters, Jingying Wang, Eva R Chin, Bradley P Morgan, Fady I Malik

{"title":"A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin.","authors":"Michael K Pugsley, Darren T Hwee, Brett R Winters, Jingying Wang, Eva R Chin, Bradley P Morgan, Fady I Malik","doi":"10.1177/10915818251326466","DOIUrl":"https://doi.org/10.1177/10915818251326466","url":null,"abstract":"Aficamten (CK-3773274) is a cardiac myosin inhibitor in development for the treatment of hypertrophic cardiomyopathy (HCM), a commonly inherited heart condition often characterized as a disease of the sarcomere. Aficamten reduces pathologic cardiac hypercontractility by selectively binding to an allosteric site on cardiac myosin. To characterize the pharmacology and toxicology of aficamten, a series of nonclinical repeated dose studies were conducted. In a 10-day repeated dose pharmacology study in Sprague Dawley rats, aficamten produced dose-dependent reductions in left ventricular fractional shortening (FS) which were fully reversible within 24 h. Aficamten did not change the ratio of heart weight to tibia length (HW/TL) or left ventricular posterior wall (LVPW) thickness at any dose tested. At a supratherapeutic dose of 6 mg/kg/day, there was a significant increase in interventricular septum (IVS) thickness. Aficamten did not affect mRNA expression of the cardiac injury biomarkers BNP, β-MHC, or ANP. In repeated dose Good Laboratory Practice (GLP) regulatory toxicology studies in Sprague Dawley rats for up to 6 months and beagle dogs for up to 9 months, the primary adverse findings at supratherapeutic doses were consistent across all studies and observed in the heart consisting of atrial/ventricular dilatation that correlated with increased heart weights. These findings were largely reversible and consistent with excessive on-target pharmacology associated with cardiac myosin inhibition. The reversible nature of aficamten-associated adverse effects is supportive of its clinical safety as this property suggests that these findings, should they occur in humans, may also be reversible, limiting long-term human cardiac risk.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251326466"},"PeriodicalIF":1.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669782","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

An Industry Perspective on the Use of Novel Excipients in Lipid Nanoparticles-Nonclinical Considerations.

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-04 DOI: 10.1177/10915818251320631

Lorrene A Buckley, Jessica E Sutherland, Prachi Borude, Karine Broudic, Philippe Collin, Aimee Hillegas, Chris MacLauchlin, Amer F Saleh, Amy Sharma, Justina Thomas, Matthew O'Brien Laramy

{"title":"An Industry Perspective on the Use of Novel Excipients in Lipid Nanoparticles-Nonclinical Considerations.","authors":"Lorrene A Buckley, Jessica E Sutherland, Prachi Borude, Karine Broudic, Philippe Collin, Aimee Hillegas, Chris MacLauchlin, Amer F Saleh, Amy Sharma, Justina Thomas, Matthew O'Brien Laramy","doi":"10.1177/10915818251320631","DOIUrl":"https://doi.org/10.1177/10915818251320631","url":null,"abstract":"Nucleic acid drug delivery with lipid nanoparticle (LNP) formulations has enabled the development of novel therapeutics and vaccines. LNP formulations are composed of both naturally occurring and synthetic lipid excipients. This perspective shares current practices in the nonclinical safety assessment of novel lipid excipients contained in LNP formulations and identifies gaps in current regulatory guidance on this topic. There is no globally harmonized regulatory guidance for the nonclinical safety assessment of novel excipients or guidance specific to safety testing of novel excipients in LNPs. Given the complexity of these LNP formulations, most nonclinical safety studies to support development are conducted with the drug product or with a LNP that contains non-active cargo. Three case studies (Onpattro®, Comirnaty®, and SpikeVax®) highlight that specific assessments may differ depending on the encapsulated modality, the intended use (e.g., therapeutic versus preventative vaccine), dose, and frequency of dosing. These case studies also suggest that regulatory agencies are open to scientific rationale to justify why certain tests should or should not be performed. As more products are approved, it will be important to understand how precedents set for approved products can be leveraged and what additional unique strategies may be applied to ensure nonclinical safety assessments are predictive, relevant, and meaningful for human safety. Proactive alignment with regulatory authorities will be critical in this context, especially as new approaches are proposed. Guidance documents may need to be revised or created as more experience is acquired to reflect the unique considerations for these novel excipients.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251320631"},"PeriodicalIF":1.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557014","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

I Wish I Had Known That! Impactful Guidance and Perspectives for a Fulfilling Career in Toxicology.

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-02-14 DOI: 10.1177/10915818251319250

Jessica C Graham, Joel Bercu, Marie C Fortin, Andy Kiorpes, Sunjay Sethi, Robert Roy

{"title":"I Wish I Had Known That! Impactful Guidance and Perspectives for a Fulfilling Career in Toxicology.","authors":"Jessica C Graham, Joel Bercu, Marie C Fortin, Andy Kiorpes, Sunjay Sethi, Robert Roy","doi":"10.1177/10915818251319250","DOIUrl":"https://doi.org/10.1177/10915818251319250","url":null,"abstract":"Have you ever reflected on your career or other experiences and thought, if I knew 10 or 20 years ago, what I know now, it would have enabled me to do this or that better-or I would have had a different attitude or perhaps even taken a different path? This article presents the proceedings from the symposium entitled \"I Wish I Had Known That! Impactful Guidance and Perspectives for a Fulfilling Career in Toxicology\" held at the 2023 annual meeting of the American College of Toxicology. In this session, toxicology professionals reflected on the highlights of their careers, the most impactful advice/mentoring they received or wish they had received, and the characteristics that have been key components of their success. This session consisted of didactic talks from a diverse panel representing various career stages and backgrounds, followed by a panel discussion and the opportunity for the audience to ask questions. Using a structured approach, speakers actively engaged the audience, providing insights gained through their professional journeys. This article offers experiential-based insights to help guide individuals in achieving successful and fulfilling careers in toxicology, considering both professional aspirations and the integration of personal values with life goals.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251319250"},"PeriodicalIF":1.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416776","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

Mutagenesis and Carcinogenesis Risk Evaluation for AAV and Lentiviral Gene Therapies.

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-02-11 DOI: 10.1177/10915818251318248

Toufan Parman, Daniella M Pizzurro, Jacquelynn Lucas, Zhechu Peng

{"title":"Mutagenesis and Carcinogenesis Risk Evaluation for AAV and Lentiviral Gene Therapies.","authors":"Toufan Parman, Daniella M Pizzurro, Jacquelynn Lucas, Zhechu Peng","doi":"10.1177/10915818251318248","DOIUrl":"https://doi.org/10.1177/10915818251318248","url":null,"abstract":"Fueled by the identification and invention of novel gene delivery vectors, gene therapy efforts now hold promise for treating a wide range of diseases and are seen as a crucial part of growth for the biopharmaceutical industry. Currently, recombinant adeno-associated virus vectors (rAAVs) and lentiviral vectors (LVs) are the main vectors used in gene therapies that are approved or tested in human clinical trials. Meanwhile, ongoing research continuously reveals unprecedented knowledge of viral vectors on the host genome, which may subsequently affect the mutagenic and carcinogenic potential of these therapies. This article summarizes the content and addresses the commentary from the scientific symposium entitled \"Mutagenesis and Carcinogenesis Risk Evaluation for AAV and Lentiviral Gene Therapies,\" conducted at the 43rd Annual Meeting of the American College of Toxicology, November 2022 in Denver, CO. The objective is to summarize the current understanding of rAAV and LV related mutagenicity/carcinogenicity risk, describe the methods and interpretation of results to guide risk assessments, as well as the current regulatory landscape on the carcinogenicity and mutagenicity assessment of rAAV and LV gene therapy products.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251318248"},"PeriodicalIF":1.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399131","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

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 : 2025-02-01 Epub 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 Mannitol, Sorbitol, and Xylitol as Used in Cosmetics. 化妆品中使用的甘露醇、山梨醇和木糖醇的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-02-01 Epub Date: 2024-11-18 DOI: 10.1177/10915818241297097

Priya Cherian, 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 Ascorbyl Glucoside and Sodium Ascorbyl Glucoside as Used in Cosmetics. 化妆品中使用的抗坏血酸葡萄糖苷和抗坏血酸葡萄糖苷钠的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-02-01 Epub Date: 2024-11-08 DOI: 10.1177/10915818241297075

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 Wheat-Derived Ingredients as Used in Cosmetics. 化妆品中使用的小麦提取成分的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-02-01 Epub Date: 2024-11-08 DOI: 10.1177/10915818241294063

Christina L Burnett, 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