International Journal of Toxicology最新文献_第9页

Mechanisms of Apoptosis and Pulmonary Fibrosis Resulting From Sulfur Mustard-Induced Acute Pulmonary Injury in Rats. 硫芥致大鼠急性肺损伤的细胞凋亡和肺纤维化机制。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-07-01 Epub Date: 2025-01-31 DOI: 10.1177/10915818251315907

Xiaoxuan Hu, Na Zhang, Yuxu Zhong, Tao Liu, Xiaoji Zhu

{"title":"Mechanisms of Apoptosis and Pulmonary Fibrosis Resulting From Sulfur Mustard-Induced Acute Pulmonary Injury in Rats.","authors":"Xiaoxuan Hu, Na Zhang, Yuxu Zhong, Tao Liu, Xiaoji Zhu","doi":"10.1177/10915818251315907","DOIUrl":"10.1177/10915818251315907","url":null,"abstract":"Sulfur mustard (SM) is a highly toxic bifunctional alkylating agent that inflicts severe damage on the respiratory tract. Although numerous studies have examined the mechanisms underlying SM-induced pulmonary injury, the exact pathways involved remain unclear. This study aims to investigate an acute pulmonary injury model, with SM administered as a single intraperitoneal injection (8 mg/kg) or single intratracheal instillation (2 mg/kg) at equal toxicity doses (1LD50). The results revealed that epithelial cells in the alveolar septa of the intraperitoneal SM group exhibited a significantly higher expression of apoptotic markers, including pro-apoptotic protein Bax, caspase-3, and caspase-9 proteins, than those in the tracheal SM group. Conversely, the expression of the anti-apoptotic protein Bcl-2 was significantly lower in the intraperitoneal SM group than in the tracheal SM group, as confirmed by TUNEL staining and immunohistochemical staining. The intraperitoneal SM group exhibited markedly higher expression of fibrosis-related proteins, including MMP-2, MMP-9, TIMP-1, TIMP-2, collagen type I, collagen type III, TGF-β1, and Smad7, than the tracheal SM group. These markers, detected through immunohistochemical immunolabeling, indicate a more significant fibrotic response in the intraperitoneal group. In summary, this study demonstrates that intraperitoneal exposure to SM results in increased apoptosis, elevated expression of pro-apoptotic proteins, and fibrosis-related proteins in the alveolar epithelial cells compared with intratracheal exposure, even at equivalent toxicity levels. Our findings highlight the suitability of the intraperitoneal route for further investigation and identify apoptotic and fibrosis-related proteins as potential targets for intervention in SM-induced pulmonary injury.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"314-327"},"PeriodicalIF":1.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070819","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

Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys. 静脉注射依曲帕米在有意识遥测食蟹猴体内的心血管和药代动力学特征。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-07-01 Epub 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":"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":"287-296"},"PeriodicalIF":1.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202829/pdf/","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":"OA","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. 心脏肌球蛋白可逆变构抑制剂Aficamten的非临床药理学和毒理学研究。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-01 Epub 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":"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":"211-234"},"PeriodicalIF":1.2,"publicationDate":"2025-05-01","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

I Wish I Had Known That! Impactful Guidance and Perspectives for a Fulfilling Career in Toxicology. 我要是知道就好了！毒理学职业生涯的有效指导和前景。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-01 Epub 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":"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":"235-244"},"PeriodicalIF":1.2,"publicationDate":"2025-05-01","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. AAV和慢病毒基因治疗的突变和致癌风险评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-01 Epub 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":"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":"183-195"},"PeriodicalIF":1.2,"publicationDate":"2025-05-01","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

An Industry Perspective on the Use of Novel Excipients in Lipid Nanoparticles-Nonclinical Considerations. 在脂质纳米颗粒中使用新型赋形剂的行业前景-非临床考虑。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-01 Epub 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":"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":"196-210"},"PeriodicalIF":1.2,"publicationDate":"2025-05-01","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

Review of the Hazards and Contraindications of Etomidate. 回顾依托咪酯的危害和禁忌症。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-01 Epub Date: 2024-11-06 DOI: 10.1177/10915818241297073

Gaolin Zheng, Yinyu Chen, Guangmei Wu, Tao Song, Xing Zou, Qianyun Nie, Peng Zhang

{"title":"Review of the Hazards and Contraindications of Etomidate.","authors":"Gaolin Zheng, Yinyu Chen, Guangmei Wu, Tao Song, Xing Zou, Qianyun Nie, Peng Zhang","doi":"10.1177/10915818241297073","DOIUrl":"10.1177/10915818241297073","url":null,"abstract":"Etomidate, an ultrashort-acting non-barbiturate sedative derived from imidazole, exerts potent inhibitory effects on the central nervous system. It is commonly employed for the induction of intravenous general anaesthesia or assisted anaesthesia. Recently, etomidate has emerged as an alternative to narcotics and novel psychoactive substances, leading to an increasing trend of abuse. Chronic overdose of etomidate can result in irreversible brain damage and various mental disorders. Severe cases may manifest as mental disturbances, behavioural disorders, self-mutilation and even death. The toxicological mechanisms of etomidate remain poorly understood. Additionally, there is limited information on the clinical symptoms and histopathological changes associated with etomidate poisoning and standardized detection methods for etomidate in blood, urine and hair are lacking. Consequently, further research on toxicological pathology and the development of reliable testing methods is crucial. This study reviews the metabolism, distribution, adverse reactions, poisoning manifestations, toxicology mechanisms and testing methods of etomidate.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"245-253"},"PeriodicalIF":1.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583211","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

Four-Week GLP Immunotoxicity Assessment of Lactoferrin Alpha Produced by Komagataella phaffii in Sprague-Dawley Rats. 在 Sprague-Dawley 大鼠体内对 Komagataella phaffii 产生的 Alpha 乳铁蛋白进行为期四周的 GLP 免疫毒性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-01 Epub Date: 2024-11-13 DOI: 10.1177/10915818241299344

Ross Peterson, Robert B Crawford, Lance K Blevins, Norbert E Kaminski, Anthony J Clark, Carrie-Anne Malinczak

{"title":"Four-Week GLP Immunotoxicity Assessment of Lactoferrin Alpha Produced by Komagataella phaffii in Sprague-Dawley Rats.","authors":"Ross Peterson, Robert B Crawford, Lance K Blevins, Norbert E Kaminski, Anthony J Clark, Carrie-Anne Malinczak","doi":"10.1177/10915818241299344","DOIUrl":"10.1177/10915818241299344","url":null,"abstract":"Oral toxicity and toxicokinetic properties of human lactoferrin (LF) alpha produced in Komagataella phaffii (effera™) were investigated in adult Sprague-Dawley rats over a 28-day period under good laboratory practice conditions. Main study dosing used groups of 10 rats/sex/dose, and a secondary study evaluating toxicokinetic parameters used 6 rats/sex/dose. The vehicle control group received sodium citrate buffer, test groups received daily doses of 200, 600, and 2000 mg of effera™ per kg body weight, and the comparative control group received 2000 mg bovine LF (bLF)/kg body weight per day. T-cell-dependent antibody response against keyhole limpet hemocyanin and immunophenotyping of the spleen were performed as measures of immunotoxicity. Clinical observations, body weight, hematology, coagulation, clinical chemistry, urinalysis, immunotoxicity, gross necropsy, and histopathology were assessed. Toxicokinetic parameters were analyzed as an indication of LF bioavailability, and anti-LF antibody assays were conducted to detect antibodies produced against LF to measure immunogenicity. No treatment related toxicologically significant changes were observed. Based on the absence of toxicologically relevant changes, effera™ is well tolerated in rats at doses up to 2000 mg rhLF/kg/day, an amount ∼400 times that of the estimated daily intake at the 90th percentile proposed for human adult use.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"125-140"},"PeriodicalIF":1.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620664","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

The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD. 新型抗ceacam5抗体Exatecan偶联物的非临床安全性评估预测间质性肺疾病（ILD）患者的低风险- ILD背后的推测机制

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-01 Epub Date: 2025-01-04 DOI: 10.1177/10915818241306039

Willem N Sloot, Elisa Bertotti, Manuela Onidi, Andrea Paoletti, Ilse De Salve, Patrizia Tavano, Enrico Vigna, Gundi Mueller

{"title":"The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD.","authors":"Willem N Sloot, Elisa Bertotti, Manuela Onidi, Andrea Paoletti, Ilse De Salve, Patrizia Tavano, Enrico Vigna, Gundi Mueller","doi":"10.1177/10915818241306039","DOIUrl":"10.1177/10915818241306039","url":null,"abstract":"The therapeutic window of antibody drug-conjugates (ADC) remains challenging due to safety issues such as interstitial lung disease (ILD) observed with specific deruxtecan-based ADCs. To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic β-glucuronide linker to exatecan and our anti-CEACAM5 (CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 5) specific antibody. Following repeated iv-infusion at 3 to 30 mg/kg of M9140 every 3 weeks, the pathological findings obtained in cynomolgus monkeys were confined to gastrointestinal and hematolymphoid tissues and resembled the toxicity of exatecan. At 24 mg/kg or higher, transient reductions in neutrophil and reticulocyte counts were observed with each dosing event along with reversible anemia throughout the study. The no observed adverse effect level was 24 mg/kg and the maximum tolerated dose was 30 mg/kg. The difference in toxicity by this small dose increment was correlated with a 2.5-fold difference in plasma exatecan exposure indicating antigen-independent toxicity. As anticipated, no lung toxicity was found with M9140 in these studies that were similar in study design to those used to confirm ILD with trastuzumab-deruxtecan in monkeys. Since the non-human primate model is regarded as predictive for the ILD risk in humans, this result indicates a low risk for ILD when applying M9140 to patients. The current M9140 safety data are discussed with special focus on the absence or presence of ILD with other antibody camptothecin-conjugates, for which a hypothetical pathogenic mechanism is postulated here. The favorable nonclinical profile of M9140 warrants further investigation in patients with CEACAM5-overexpressing tumors.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"153-169"},"PeriodicalIF":1.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926988","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

DEHP and Its Metabolite MEHP Alter the Insr and Glut4 Gene Expression by Blunting the Interaction of Transcription Factors in L6 Myotubes. DEHP及其代谢产物MEHP通过减弱L6肌管中转录因子的相互作用来改变Insr和Glut4基因的表达。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-01 Epub Date: 2024-12-10 DOI: 10.1177/10915818241305090

Mangala Priya Viswanathan, Vigneswari Mullainadhan, Balasubramanian Karundevi

{"title":"DEHP and Its Metabolite MEHP Alter the Insr and Glut4 Gene Expression by Blunting the Interaction of Transcription Factors in L6 Myotubes.","authors":"Mangala Priya Viswanathan, Vigneswari Mullainadhan, Balasubramanian Karundevi","doi":"10.1177/10915818241305090","DOIUrl":"10.1177/10915818241305090","url":null,"abstract":"Endocrine-disrupting chemicals (EDCs) play an important role in the incidence of type-2 diabetes. Di-2-ethyl hexyl Phthalate (DEHP) is one of the endocrine-disrupting chemicals used as a plasticizer to impart flexibility and softness to plastic-containing materials. Mono-2-ethylhexyl Phthalate (MEHP), a DEHP's primary metabolite, is preferentially absorbed once metabolized. A previous study from our laboratory showed that DEHP and MEHP altered the key proteins such as insulin receptor (INSR) and glucose transporter-4 (GLUT4) in L6 myotubes. In a sequel to the previous study, the present study hypothesized that DEHP and its metabolite MEHP may alter the Insr and Glut4 gene expression in L6 myotubes. Therefore, to find out the molecular mechanism behind the decreased INSR and GLUT4 protein levels in the previous study, the direct effect of DEHP and its metabolite MEHP in regulating Insr and Glut4 gene transcription in L6 myotubes was studied. The L6 myotubes were exposed to 50 and 100 μM DEHP and MEHP for 24 h, followed by insulin stimulation for 20 min. We observed decreased Insr and Glut4 mRNA levels in DEHP and MEHP-treated groups. Western blot data showed decreased protein levels of MEF2A and MyoD in treated groups. ChIP assay detected a decreased association of MEF2A and MyoD to the Glut4 gene promoter and HMGA1 to the Insr gene promoter. The study revealed that DEHP and MEHP diminished the Insr and Glut4 gene expression through weakened interaction of their transcription factors on the respective promoter.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"170-180"},"PeriodicalIF":1.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800583","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