International Journal of Toxicology最新文献_第3页

Validating and Using Cardiac NAMs for Toxicity Screening and Drug Development. 心脏名称在毒性筛选和药物开发中的验证和使用。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-09 DOI: 10.1177/10915818251375348

Jennifer Beck Pierson, Anthony Bahinski, Brian Berridge, Daniel Bramham, Todd Bourcier, Khuram W Chaudhary, Sandy Eldridge, Yasunari Kanda, William B Mattes, Jessica Oliphant, Li Pang, Alex Savtchenko, Jeffery Siegel, Natalie Simpson, Chengyi Tu, Ronald Wange, Joseph C Wu, Xi Yang

{"title":"Validating and Using Cardiac NAMs for Toxicity Screening and Drug Development.","authors":"Jennifer Beck Pierson, Anthony Bahinski, Brian Berridge, Daniel Bramham, Todd Bourcier, Khuram W Chaudhary, Sandy Eldridge, Yasunari Kanda, William B Mattes, Jessica Oliphant, Li Pang, Alex Savtchenko, Jeffery Siegel, Natalie Simpson, Chengyi Tu, Ronald Wange, Joseph C Wu, Xi Yang","doi":"10.1177/10915818251375348","DOIUrl":"10.1177/10915818251375348","url":null,"abstract":"Technological advances and the desire to reduce dependence on animal models have brought human-relevant models to the forefront of drug development. This paradigm shift is leveraging the advances in in vitro systems and new approach methodologies (NAMs), which was the focus of a workshop convened by the Health and Environmental Sciences Institute (HESI) in May 2024. Highlights included discussions on predicting cardiac failure modes and the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), microfluidic systems like BioFlux™, and engineered heart tissues in enhancing early-stage drug safety assessments. Regulatory perspectives underscored the challenges and potential for integrating NAMs into submissions, advocating for standardized reporting and validation protocols. Case studies where NAMs offered superior predictivity compared to traditional methods are emerging and offer insights into a roadmap forward. However, there remains a need for collaboration among academia, industry, and regulatory bodies to ensure robust validation and adoption. These efforts aim to refine cardiovascular drug discovery, reduce attrition rates, and accelerate the transition toward more ethical and efficient preclinical testing paradigms.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251375348"},"PeriodicalIF":1.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029755","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

Integrin αvβ3 Antagonist Ameliorates Atherosclerotic Progression by Reducing Platelet Hyperactivation. 整合素αvβ3拮抗剂通过降低血小板过度活化改善动脉粥样硬化进展。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-08 DOI: 10.1177/10915818251375887

Mengyun Xu, Xurui Zhang, Feng Qi, Jihong Zou, Cheng Xiao, Guangsheng Cai, Xiaojuan Pan

{"title":"Integrin αvβ3 Antagonist Ameliorates Atherosclerotic Progression by Reducing Platelet Hyperactivation.","authors":"Mengyun Xu, Xurui Zhang, Feng Qi, Jihong Zou, Cheng Xiao, Guangsheng Cai, Xiaojuan Pan","doi":"10.1177/10915818251375887","DOIUrl":"https://doi.org/10.1177/10915818251375887","url":null,"abstract":"Platelet hyperactivation represents a significant risk factor for atherosclerotic cardiovascular diseases. This study investigated the expression and functional roles of integrin αvβ3 and (Multimerin 1) MMRN1 in platelets from atherosclerotic conditions and evaluated the therapeutic potential of integrin αvβ3 antagonism in atherosclerotic progression. We examined the expression patterns of αvβ3 and MMRN1 in platelets from healthy controls, patients with coronary heart disease (CHD), and patients with acute myocardial infarction (AMI) using qRT-PCR and ELISA techniques. The correlation between αvβ3 and MMRN1 expression levels with platelet counts and aggregation was analyzed. Additionally, we established a mouse model of atherosclerosis to investigate the effects of an αvβ3 antagonist (SB273005) and MMRN1 knockdown on platelet activation and atherosclerosis progression. Our findings revealed positive correlations between MMRN1 and αvβ3 expression levels with both platelet counts and aggregation. Notably, elevated platelet counts and aggregation observed in CHD and AMI patient samples were effectively reduced by the αvβ3 antagonist treatment. Furthermore, both αvβ3 antagonist treatment and MMRN1 knockdown significantly ameliorated disease severity in the mouse atherosclerosis model. These results demonstrate that upregulation of αvβ3 integrin and MMRN1 contributes to platelet hyperactivation in atherosclerotic vascular diseases, and targeting the αvβ3/MMRN1 axis may serve as a promising intervention strategy for the clinical management of atherosclerotic vascular diseases.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251375887"},"PeriodicalIF":1.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023285","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

Evaluation of Plasma Polyethylene Glycol (PEG) Levels in a Healthy Adult Population. 健康成人血浆聚乙二醇（PEG）水平的评价

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-07 DOI: 10.1177/10915818251371966

Klaus Kubesch, Christian Lubich, Daniel Mascher, Srilatha Tangada, Peter L Turecek

{"title":"Evaluation of Plasma Polyethylene Glycol (PEG) Levels in a Healthy Adult Population.","authors":"Klaus Kubesch, Christian Lubich, Daniel Mascher, Srilatha Tangada, Peter L Turecek","doi":"10.1177/10915818251371966","DOIUrl":"https://doi.org/10.1177/10915818251371966","url":null,"abstract":"Polyethylene glycols (PEGs) are amphiphilic polymers that are used extensively in consumer products and PEGylated biotherapeutics. Although PEGs are considered biologically inert with a low toxicity, anti-PEG antibodies have been detected in patients receiving treatment with PEGylated biotherapeutics as well as in healthy individuals. Despite continual exposure in daily life, the prevalence of PEGs within the general population remains unclear. This study aimed to evaluate a healthy population for the presence of PEGs. A validated enzyme-linked immunosorbent assay (ELISA) platform was used to analyze 200 plasma samples from healthy adults for the presence of PEGs. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was also used to analyze the samples for the presence of four PEG analytes: PEG3350; PEG4000; PEG10000; and PEG2ru20K COOH, a 20 kDa PEG used to modify therapeutic proteins. The detection limit for PEG3350 calculated by extrapolation with linear regression was assumed to be 3.60 ng/mL. PEG levels above the lower limit of quantification (LLOQ) (21.6 ng/mL) were detected in 41 plasma samples, range 22.1-43.9 ng/mL, using the ELISA platform. None of the samples were found to contain detectable levels of PEG4000, PEG10000, or PEG2ru20K COOH. Following extrapolation, PEG3350 levels above the LLOQ (3.60 ng/mL) were detected in 154 plasma samples, range 3.69-46.0 ng/mL. Using an ELISA platform and HPLC-MS/MS analysis, PEGs were detected in the plasma of 77.4% of healthy adults. The findings are suggestive that expanding worldwide exposure to PEGs may have resulted in a much higher incidence of detectable plasma burdens of PEG than was previously realized.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251371966"},"PeriodicalIF":1.0,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015368","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

Nonclinical Safety Evaluation of 2-Deoxy-D-Glucose Following Twice-Daily Oral Administration for 28 Days in Beagle Dogs. Beagle犬每日两次口服2-脱氧- d -葡萄糖28天的非临床安全性评价。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-01 Epub Date: 2025-05-26 DOI: 10.1177/10915818251340393

Rahul M Nandre, Pramod S Joshi, Thomas P Sutula, Pramod S Terse

{"title":"Nonclinical Safety Evaluation of 2-Deoxy-D-Glucose Following Twice-Daily Oral Administration for 28 Days in Beagle Dogs.","authors":"Rahul M Nandre, Pramod S Joshi, Thomas P Sutula, Pramod S Terse","doi":"10.1177/10915818251340393","DOIUrl":"10.1177/10915818251340393","url":null,"abstract":"2-Deoxy-D-Glucose (2-DG) has anticonvulsant and antiseizure effects in rodent models and is in the development phase for novel antiseizure treatment. To evaluate potential toxicity, Beagle dogs (five/sex/group) were orally gavaged with either vehicle (deionized water) or 2-DG (5, 30, and 90 mg/kg BID) for 28 days followed by a 14-day recovery period. The safety endpoints evaluated were mortality, clinical observations, body temperature, respiratory assessment, body weights, food consumption, ophthalmic examinations, electrocardiograph (ECG), blood pressure, cardiac biomarker (NT-proBNP), and pathology. Toxicokinetic analysis was conducted after the first dose on days 1 and 28. The dose formulation analysis confirmed that 2-DG concentrations were within 93%-107% of the target concentrations. There were no 2-DG associated effects observed in mortality, clinical signs, body temperature, respiratory parameters, body weights, food consumption, ophthalmic examination, ECG, blood pressure, and NT-proBNP. There was an increase (∼1.7X) in aspartate transaminase on day 29, while histopathological evaluation revealed hepatic cytoplasmic alterations in 2 of 6 dogs on day 29 and only in 1 of 4 dogs on day 43 at 90 mg/kg BID. These changes were considered non-adverse because of minimal severity, reversibility trend after recovery period and no correlative increase in alanine transaminase. Toxicokinetic evaluation revealed dose dependent increases in Cmax of ∼7.8, 39.5, and 114 μg/mL, and AUCs of 12.2, 70.8, and 202 h*μg/mL at 5, 30, and 90 mg/kg, respectively with Tmax of ∼0.5-0.9 h and T1/2 of ∼3.8-5.4 h. In conclusion, 90 mg/kg BID of 2-DG was considered as the No Observed Adverse Effect Level following 28-day administration in dogs.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"407-414"},"PeriodicalIF":1.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150476","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 Comparison of Spontaneous Tumor Incidence in Charles River Sprague Dawley Rats and Wistar Hannover Rats. Charles River Sprague Dawley大鼠与Wistar Hannover大鼠自发性肿瘤发生率的比较。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-01 Epub Date: 2025-05-26 DOI: 10.1177/10915818251342565

Mark A Morse, Christopher N Papagiannis, Donald G Stump, Bevin Zimmerman, Steven J Bulera

{"title":"A Comparison of Spontaneous Tumor Incidence in Charles River Sprague Dawley Rats and Wistar Hannover Rats.","authors":"Mark A Morse, Christopher N Papagiannis, Donald G Stump, Bevin Zimmerman, Steven J Bulera","doi":"10.1177/10915818251342565","DOIUrl":"10.1177/10915818251342565","url":null,"abstract":"The Crl:CD(SD) Sprague Dawley rat and the Crl:WI(Han) Wistar Hannover (Wistar Han) rat are two outbred rat models commonly used in 2-year carcinogenicity testing. In this presentation, the spontaneous incidences of common, rare, and fatal neoplasms in the two models in 2-year carcinogenicity studies were compared from 51 Sprague Dawley rat studies and 31 Wistar Han rat studies that were completed from 2016 to 2023. All Wistar Han rat studies completed the intended 104 weeks of dosing, whereas 47 of the 51 Sprague Dawley rat studies were terminated early in both sexes or terminated early in one sex. The incidence of total spontaneous neoplasms was greater in Sprague Dawley rats when compared to Wistar Han rats of either sex, with the greatest incidence found in female Sprague Dawley rats (95.93%). Of palpable masses that corresponded to neoplasms, approximately 85-90% of masses were mammary tumors in females of either strain, while a similar percentage of masses corresponded to skin tumors in male rats of either strain. Common fatal tumors included pituitary adenoma of the pars distalis, carcinoma of the pars distalis, mammary adenocarcinoma, and mammary fibroadenoma, and were found at a lower incidence in Wistar Han rats; where calculable, the onset of these neoplasms was earlier in Sprague Dawley rats.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"355-394"},"PeriodicalIF":1.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150475","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

Evaluation of In Vitro Toxicity of OrPhyllo™, a New Vehicle to Produce Orodispersible Films. 制备多孔分散膜的新载体OrPhyllo™体外毒性评价

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-01 Epub Date: 2025-05-06 DOI: 10.1177/10915818251340384

Hudson Polonini, Bruna Marianni, Emanuel da Silva Rovai, Maria Aparecida Neves Jardini, Camilla Magnoni Moretto Nunes, Carlos Rocha Oliveira

{"title":"Evaluation of In Vitro Toxicity of OrPhyllo™, a New Vehicle to Produce Orodispersible Films.","authors":"Hudson Polonini, Bruna Marianni, Emanuel da Silva Rovai, Maria Aparecida Neves Jardini, Camilla Magnoni Moretto Nunes, Carlos Rocha Oliveira","doi":"10.1177/10915818251340384","DOIUrl":"10.1177/10915818251340384","url":null,"abstract":"Orodispersible films (ODFs) are advanced drug delivery systems that consist of thin, mechanically robust polymeric films designed to dissolve or disintegrate quickly in the oral cavity, facilitating local and systemic drug administration. Orphyllo™ is a novel ODF vehicle developed to enhance the stability and delivery efficiency of active pharmaceutical ingredients. This study aimed to assess the safety profile of Orphyllo™ through a comprehensive evaluation of its cytotoxicity and genotoxicity on human oral mucosa cell lines. The cytotoxicity was evaluated using (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) MTT, Neutral Red Uptake (NR), and Lactate Dehydrogenase (LDH) assays, which tested the impact of Orphyllo™ at concentrations of 5.0% and 10.0% over 24, 48, and 72 hours. Results indicated no significant reduction in cell viability (P > 0.05), demonstrating the formulation's biocompatibility. To evaluate genotoxicity, the micronucleus test was performed, showing no significant increase in the frequency of micronuclei compared to the control group, thus indicating no DNA damage. Additionally, the Annexin/7-AAD assay was employed to assess apoptosis and necrosis, revealing no significant induction of cell death at the tested concentrations (P > 0.05). These findings highlight that Orphyllo™ presents, even at an early stage, the potential to become a promising vehicle for oral drug administration applications, with potential benefits in several therapeutic areas, especially for populations that require ease of administration.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"415-423"},"PeriodicalIF":1.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990289","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

Predictive Modeling of Pharmacokinetic Drug-Drug and Herb-Drug Interactions in Oncology: Insights From PBPK Studies. 肿瘤药物动力学-药物和草药-药物相互作用的预测模型：来自PBPK研究的见解。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-01 Epub Date: 2025-06-11 DOI: 10.1177/10915818251345116

Enes Emre Taş, Kutlu O Ulgen

{"title":"Predictive Modeling of Pharmacokinetic Drug-Drug and Herb-Drug Interactions in Oncology: Insights From PBPK Studies.","authors":"Enes Emre Taş, Kutlu O Ulgen","doi":"10.1177/10915818251345116","DOIUrl":"10.1177/10915818251345116","url":null,"abstract":"Physiologically based pharmacokinetic (PBPK) modeling is increasingly used to anticipate, quantify, and strategically manage drug-drug (DDI) and herb-drug (HDI) interactions that can alter the exposure of chemotherapy agents together with co-administered phytochemicals or nutraceuticals. To evaluate current knowledge, we performed a comprehensive Google Scholar search (2003-2024) and selected studies that employed PBPK platforms, reported quantitative validation, and focused on chemotherapy-related interactions. From these reports, key modeling parameters, validation metrics, and clinically relevant outcomes were extracted, and then the information was synthesized to identify common trends. Collectively, the evidence indicates that unintended changes in drug exposure-most often mediated by CYP3A4 inhibition or induction-may modify efficacy, toxicity, and overall anticancer response; nevertheless, PBPK models reproduce these effects with high accuracy, and emerging AI-enhanced approaches promise even finer precision. Accordingly, our synthesis underscores how PBPK modeling can help clinicians forecast interaction risk, individualize dosing, and avert therapeutic failure, especially in polypharmacy settings. Integrating these models into routine oncology practice therefore offers a proactive path toward safer, more personalized chemotherapy and, ultimately, better patient outcomes within an increasingly complex therapeutic landscape.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"424-440"},"PeriodicalIF":1.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274861","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 and Toxicological Evaluation of Subunit Keyhole Limpet Hemocyanin-Loaded Lipid-PLGA Hybrid Nanoparticles (sKLH-hNPs) as a Nanocarrier for an Opioid Use Disorder Vaccine. 亚基锁孔帽贝血青素负载脂质-聚乳酸杂化纳米颗粒（sKLH-hNPs）作为阿片类药物使用障碍疫苗纳米载体的安全性和毒理学评价

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-09-01 Epub Date: 2025-07-05 DOI: 10.1177/10915818251355948

Debra Walter, Qiaoqiao Ci, He Hu, Riley DeHority, Jonathan Hinckley, Yuanzhi Bian, Priscila B S Serpa, Teresa Southard, Stephen R Werre, Marco Pravetoni, Marion Ehrich, Chenming Zhang

{"title":"Safety and Toxicological Evaluation of Subunit Keyhole Limpet Hemocyanin-Loaded Lipid-PLGA Hybrid Nanoparticles (sKLH-hNPs) as a Nanocarrier for an Opioid Use Disorder Vaccine.","authors":"Debra Walter, Qiaoqiao Ci, He Hu, Riley DeHority, Jonathan Hinckley, Yuanzhi Bian, Priscila B S Serpa, Teresa Southard, Stephen R Werre, Marco Pravetoni, Marion Ehrich, Chenming Zhang","doi":"10.1177/10915818251355948","DOIUrl":"10.1177/10915818251355948","url":null,"abstract":"A nanoparticle-based immunization strategy offers a promising treatment for opioid use disorder (OUD). This study tested the in vivo safety of subunit keyhole limpet hemocyanin-loaded lipid-PLGA hybrid nanoparticles (sKLH-hNPs) as a nanocarrier for OUD vaccine in adult male BALB/c mice by subcutaneous administration at an effective low dose (60 μg) and a dose 5-fold higher (300 μg), with cohorts of animals (n = 10/group, including controls) observed and evaluated for behavioral changes. At 3, 14, 28, and 56 days after dosing, mice (n = 3/dose) were sacrificed, and serum was collected for evaluation of electrolytes, minerals, proteins, liver function, renal function, and energy metabolism. Histological examination included all critical organs, gastrocnemius muscle, and skin from the site of injection. For behavioral evaluation, home cage, open field, and reflex observations were compared among the groups. Results demonstrated no statistical differences among the groups, with the exception of respirations observed in the home cage (O-RESP) on Day 3 (P = 0.03). There was no evidence of any effect of the test product on energy (glucose, cholesterol, triglycerides) or mineral metabolism (phosphorus, calcium) and hepatic function (urea nitrogen, albumin, total bilirubin), and no indication that the test agent caused liver injury, cholestasis, muscle damage, or acid-base imbalance. Histological analysis in control and treated mice generally revealed no significant findings, although small areas of hemorrhage, lymphocyte infiltration, and thick areas in the subcutis were noted in a subset of samples from both control and treated animals. These experiments suggest that the nanoparticle-based product would be safe for vaccines treating OUD.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"395-406"},"PeriodicalIF":1.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567367","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 1-Month Exploratory Combination Safety and Toxicity Study of Co-Administration of Sitagliptin and Telmisartan in Male Wistar Han Rats. 西格列汀与替米沙坦在雄性Wistar Han大鼠1个月联合用药安全性及毒性的探索性研究。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-08-30 DOI: 10.1177/10915818251374566

Chitrang R Shah, Sandip B Patel, Vishal J Patel, Hardikkumar H Savsani, Amit A Joharapurkar, Urvit P Patel, Jitendra H Patel, Ramchandra K Ranvir, Rajesh Sundar, Mukul R Jain

{"title":"A 1-Month Exploratory Combination Safety and Toxicity Study of Co-Administration of Sitagliptin and Telmisartan in Male Wistar Han Rats.","authors":"Chitrang R Shah, Sandip B Patel, Vishal J Patel, Hardikkumar H Savsani, Amit A Joharapurkar, Urvit P Patel, Jitendra H Patel, Ramchandra K Ranvir, Rajesh Sundar, Mukul R Jain","doi":"10.1177/10915818251374566","DOIUrl":"10.1177/10915818251374566","url":null,"abstract":"Diabetes and hypertension often coexist and need complex pharmacological management. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used for glycemic control, and telmisartan, an angiotensin II receptor blocker, is the preferred treatment for hypertension. Thus, we have conducted a 1-month exploratory combination safety and toxicity study in male Wistar Han rats. Animals were administered 100 mg/kg/day of sitagliptin or telmisartan individually, or in combination by oral gavage. We have evaluated effects on body weight, feed intake, clinical chemistry, and hematology parameters, and microscopic examination of liver, kidney, adrenal glands, heart, lungs, lymphatic organs, and gastrointestinal tract. The combination showed a decrease in body weight gain, feed intake, hematocrit, reticulocytes, WBCs, serum triglycerides, AST, total protein, globulin, and heart weight, and increased serum levels of urea, phosphorous, magnesium, potassium, and kidney weight. Co-administration showed an additive effect on decrease in WBC counts, potentiating the effects on decreased serum triglycerides and increased phosphorous levels and kidney weights, and a synergistic effect on serum AST levels. Sitagliptin attenuated the changes caused by telmisartan on reticulocyte counts, serum creatinine levels, and liver and thymus weights. Administration of the individual compounds caused a reduction in spleen weight, though the combination had no effect. Sitagliptin, telmisartan, or combination dosing showed no significant organ toxicity upon histopathological examination. It appears that co-administration of telmisartan and sitagliptin is well tolerated in rats. Three-month toxicity studies, in both genders, with full toxicokinetic profiling and thorough tissue examination, will be necessary to support the combination's toxicity profile.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251374566"},"PeriodicalIF":1.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954187","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 Comprehensive Toxicological Safety Evaluation of Anaerostipes caccae. 厌氧菌疫苗的毒理学安全性综合评价。

IF 1 4区医学

International Journal of Toxicology Pub Date : 2025-08-29 DOI: 10.1177/10915818251367353

Vickie Modica, Róbert Glávits, Amy Clewell, John R Endres, Gábor Hirka, Adél Vértesi, Erzsébet Béres, Ilona Pasics Szakonyiné

{"title":"A Comprehensive Toxicological Safety Evaluation of Anaerostipes caccae.","authors":"Vickie Modica, Róbert Glávits, Amy Clewell, John R Endres, Gábor Hirka, Adél Vértesi, Erzsébet Béres, Ilona Pasics Szakonyiné","doi":"10.1177/10915818251367353","DOIUrl":"https://doi.org/10.1177/10915818251367353","url":null,"abstract":"Anaerostipes caccae CLB101 (CLB101) is an obligate, anaerobic bacteria that was isolated from the stool of a healthy infant. Due to its ability to produce butyrate and its potential promotion of microbiome health through multiple homeostatic interactions there is interest in its consumption by humans. No toxicity data are publicly available for any strain of A. caccae. Therefore, its genotoxic and toxicological potential was investigated in the current study. Due to its anaerobic nature, a genotoxicity evaluation was performed using the in vivo comet assay and the in vivo mammalian micronucleus assay, which found no evidence of clastogenicity or aneugenicity. General toxicity and potential target organs were assessed in a 90-day, repeated-dose, oral toxicity study using 0, 250, 500, and 1000 mg/kg bw/day in Wistar rats. CLB101 exposure did not result in adverse effects in male or female rats when evaluated for clinical signs, body weight, food consumption, clinical pathology, organ weight, and histopathology after administration, at any dose. Therefore, a NOAEL of 1000 mg/kg bw/day, equivalent to 1.9 × 1011 CFU/kg bw/day for all cells and, based on ∼32% cell viability in the buffer used (Mitsuoka), ∼6.1 × 1010 CFU/kg bw/d for living cells.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251367353"},"PeriodicalIF":1.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954223","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