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- Evaluation of Repeat Dose Toxicity and Embryo-Fetal Developmental Toxicity
of Novel Glucokinase Activator ZYGK1 in Wistar Rats-
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Authors: Kalpesh Patani; Sudhir Patel, Amit Joharapurkar, Rajesh Sundar, Mukul Jain1Division of Biological Sciences, Ahmedabad University, Ahmedabad, India2Zydus Research Centre, Ahmedabad, India
Abstract: International Journal of Toxicology, Ahead of Print.
ZYGK1 is a novel small molecule glucokinase (GK) activator. The purpose of this study was to assess the repeated dose toxicity of ZYGK1 in male and female Wistar rats and its effect on pregnancy and embryo-fetal development in pregnant female Wistar rats. ...
Citation: International Journal of Toxicology
PubDate: 2025-06-27T07:11:09Z
DOI: 10.1177/10915818251353718
- Predictive Modeling of Pharmacokinetic Drug–Drug and Herb–Drug
Interactions in Oncology: Insights From PBPK Studies-
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Authors: Enes Emre Taş; Kutlu O. Ulgen1Department of Chemical Engineering, 52949Boğaziçi University, İstanbul, Turkey
Abstract: International Journal of Toxicology, Ahead of Print.
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 ...
Citation: International Journal of Toxicology
PubDate: 2025-06-11T09:08:53Z
DOI: 10.1177/10915818251345116
- A Comparison of Spontaneous Tumor Incidence in Charles River Sprague
Dawley Rats and Wistar Hannover Rats-
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Authors: Mark A. Morse; Christopher N. Papagiannis, Donald G. Stump, Bevin Zimmerman, Steven J. Bulera1728285Charles River Laboratories, Spencerville, OH, USA2728285Charles River Laboratories, Mattawan, MI, USA3728285Charles River Laboratories, Ashland, OH, USA4728285Charles River Laboratories, Reno, NV, USA
Abstract: International Journal of Toxicology, Ahead of Print.
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 ...
Citation: International Journal of Toxicology
PubDate: 2025-05-27T05:36:14Z
DOI: 10.1177/10915818251342565
- Nonclinical Safety Evaluation of 2-Deoxy-D-Glucose Following Twice-Daily
Oral Administration for 28 Days in Beagle Dogs-
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Authors: Rahul M. Nandre; Pramod S. Joshi, Thomas P. Sutula, Pramod S. Terse1390834National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA2144153University of Wisconsin, Madison, WI, USA
Abstract: International Journal of Toxicology, Ahead of Print.
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 (...
Citation: International Journal of Toxicology
PubDate: 2025-05-27T04:43:48Z
DOI: 10.1177/10915818251340393
- Effects of Solvent Dimethyl Sulfoxide Invites a Rethink of Its Application
in Amyloid Beta Cytotoxicity-
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Authors: Yanhong Fu; Jiafa Zhang, Canhong Yang, Yuanyuan Wang, Yunzhu Yang, Pingming Qiu, Weibing Xie, Shufen Zhang, Tianming Lǚ1Department of Neurology, The Third Affiliated Hospital, 572489Southern Medical University, Guangzhou, China2Center for Cognition Mental Diseases, Guangxi Academy of Medical Sciences, Nanning, China3School of Forensic Medicine, 70570Southern Medical University, Guangzhou, China4Internal Medicine Department, The Second People’s Hospital of Guangzhou Nansha, Guangzhou, China
Abstract: International Journal of Toxicology, Ahead of Print.
Dimethyl sulfoxide (DMSO) is commonly used as a solvent for preparing amyloid-beta (Aβ) peptides implicated in Alzheimer’s disease. While considered relatively non-toxic at low concentrations, DMSO itself may exert biological effects that could confound ...
Citation: International Journal of Toxicology
PubDate: 2025-05-15T07:12:22Z
DOI: 10.1177/10915818251338235
- Safety Evaluation of N-trans-caffeoyltyramine Derived From a Strain of
Yarrowia lipolytica Through Precision Fermentation-
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Authors: Sungwon Lee; Srinivas Seekallu, Suresh Babu Venkataramaiah, Chandrashekar Mataguru Doreswamy, Mohan Cheluru Umesh, Sandeep Malleshappa, Sajeev Justin Dev, Ganadhal Puttaramaiah Chethankumara, Nagaraju Lohith, Gajanan Rajpal Deshmukh, Brian Premkumar, Brinda Mahadevan1585850Brightseed Inc, South San Francisco, CA, USA2294519Anthem Biosciences Limited, Bengaluru, Karnataka, India35211Maastricht University, Maastricht, Netherlands4Brincor Associates, LLC, Corvallis, OR, USA
Abstract: International Journal of Toxicology, Ahead of Print.
N-trans-caffeoyltyramine (NCT) is a phenolic hydroxycinnamic acid amide naturally present in many plant crop species and is associated with immune response and many development processes. Little research has been done on the potential safety of NCT for ...
Citation: International Journal of Toxicology
PubDate: 2025-05-07T08:00:24Z
DOI: 10.1177/10915818251338788
- Evaluation of In Vitro Toxicity of OrPhyllo™, a New Vehicle to
Produce Orodispersible Films-
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Authors: Hudson Polonini; Bruna Marianni, Emanuel da Silva Rovai, Maria Aparecida Neves Jardini, Camilla Magnoni Moretto Nunes, Carlos Rocha Oliveira1Global Innovation Department, Fagron BV, Rotterdam, The Netherlands2Department of Diagnosis Technology, 28105Federal University of Sao Paulo (UNIFESP), São José dos Campos, Brazil5Biotechnology Laboratory, Gap Biotech, São José dos Campos, Brazil
Abstract: International Journal of Toxicology, Ahead of Print.
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 ...
Citation: International Journal of Toxicology
PubDate: 2025-05-07T02:44:36Z
DOI: 10.1177/10915818251340384
- Comparative Analyses of the Influences of Vehicles on Selected Biological
Parameters Following Single-Dose Oral Administration in Sprague-Dawley
Rats-
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Authors: Tae-Woo Kim, Tae-Kyung Kim, Hye-Joon Park, Mu-Jin Lee, Sung-Jin Park, Laehong Jo, Yong-Hoon Lee, Yong-Seok Kim, Byeongwoo Ahn1Laboratory of Veterinary Pathology, College of Veterinary Medicine, 34933Chungbuk National University, Cheongju, Korea2ABSolution Co. Ltd; Toxicopathology Team, Hwaseong, Korea
Abstract: International Journal of Toxicology, Ahead of Print.
Various types of vehicles are used in non-clinical studies to administer treatment substances to experimental animals. It is recognized that these vehicle substances can influence animal physiology to some extent. Studies are designed to minimize the ...
Citation: International Journal of Toxicology
PubDate: 2025-04-22T09:30:36Z
DOI: 10.1177/10915818251330516
- A Commentary: Looking Back and Looking Sideways
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Authors: Anthony Dayan; Peter Pressman, Thomas Blackburn, Norbert Kaminski, Samuel Cohen, A. Wallace Hayes1Hounsfield Lodge, London, UK26251The University of Maine, Orono, ME, USA3TPBioventures LLC/Ltd, Hoboken, NJ, USA4Department of Pharmacology & Toxicology, Center for Research on Ingredient Safety, Institute for Integrative Toxicology, 3078Michigan State University, East Lansing, MI, USA5Department of Pathology, Microbiology, the Buffett Cancer Center, 12284University of Nebraska Medical Center, Omaha, NE, USA6College of Public Health, 7831University of South Florida, Tampa, FL, USA7Institute for Integrative Toxicology, 3078Michigan State University, East Lansing, MI, USA
Abstract: International Journal of Toxicology, Ahead of Print.
It has been said that “too much confidence cannot be placed on the lessons of history.” We suggest that this declaration is particularly salient for the dynamic field of toxicology. The intersection of historical trends and technological developments ...
Citation: International Journal of Toxicology
PubDate: 2025-04-09T12:49:52Z
DOI: 10.1177/10915818251328037
- Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in
Conscious Telemetered Cynomolgus Monkeys-
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Authors: Alexis Ascah; Jean-Pierre Moreau, Simon Authier, David B. Bharucha, Douglas Wight1Charles River, Laval, QC, Canada2Recherche Continuum Research, Rigaud, QC, Canada3556975Milestone Pharmaceuticals Inc, Charlotte, NC, USA4556974Milestone Pharmaceuticals Inc, Montreal, QC, Canada
Abstract: International Journal of Toxicology, Ahead of Print.
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 ...
Citation: International Journal of Toxicology
PubDate: 2025-04-01T10:04:39Z
DOI: 10.1177/10915818251327963
- A Characterization of the Nonclinical Pharmacology and Toxicology of
Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin-
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Authors: Michael K. Pugsley, Darren T. Hwee, Brett R. Winters, Jingying Wang, Eva R. Chin, Bradley P. Morgan, Fady I. Malik1Research & Nonclinical Development, 7016Cytokinetics, Inc; South San Francisco, CA, USA2Research & Development, 7016Cytokinetics, Inc, South San Francisco, CA, USA
Abstract: International Journal of Toxicology, Ahead of Print.
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 ...
Citation: International Journal of Toxicology
PubDate: 2025-03-21T12:05:29Z
DOI: 10.1177/10915818251326466
- An Industry Perspective on the Use of Novel Excipients in Lipid
Nanoparticles—Nonclinical Considerations-
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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; Jessica E. Sutherland, Prachi Borude, Karine Broudic, Philippe Collin, Aimee Hillegas, Chris MacLauchlin, Amer F. Saleh, Amy Sharma, Justina Thomas, Matthew O’Brien Laramy1Lilly Research Laboratories, Eli Lilly & Co., Inc., Indianapolis, IN, USA210774Early Development, Alnylam Pharmaceuticals, Inc., Cambridge, MA, USA33663Sanofi, Research & Development, Paris, France4Clinical Pharmacology Early Development, 7412Genentech, Inc., South San Francisco, CA, USA
Abstract: International Journal of Toxicology, Ahead of Print.
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.
Citation: International Journal of Toxicology
PubDate: 2025-03-05T06:10:57Z
DOI: 10.1177/10915818251320631
- I Wish I Had Known That! Impactful Guidance and Perspectives for a
Fulfilling Career in Toxicology-
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Authors: Jessica C. Graham, Joel Bercu, Marie C. Fortin, Andy Kiorpes, Sunjay Sethi, Robert Roy; Joel Bercu, Marie C. Fortin, Andy Kiorpes, Sunjay Sethi, Robert Roy17412Translational Safety, Genentech, Inc., South San Francisco, CA, USA22158Nonclinical Safety Pathobiology, Gilead Sciences, Foster City, CA, USA32793Nonclinical Drug Safety, Merck Co., West Point, PA, USA4River Bluff Associates LLC, Bloomington, MN, USA5485557Toxicology, IDEAYA Biosciences, Inc., South San Francisco, CA, USA6Northland Toxicology Consultants LLC, Chanhassen, MN, USA
Abstract: International Journal of Toxicology, Ahead of Print.
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.
Citation: International Journal of Toxicology
PubDate: 2025-02-14T08:52:46Z
DOI: 10.1177/10915818251319250
- Mutagenesis and Carcinogenesis Risk Evaluation for AAV and Lentiviral Gene
Therapies-
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Authors: Toufan Parman, Daniella M. Pizzurro, Jacquelynn Lucas, Zhechu Peng; Inc, Boston, MA, USA3ModeX Therapeutics, Weston, MA, USA46893Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
Abstract: International Journal of Toxicology, Ahead of Print.
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.
Citation: International Journal of Toxicology
PubDate: 2025-02-12T07:27:48Z
DOI: 10.1177/10915818251318248
- Mechanisms of Apoptosis and Pulmonary Fibrosis Resulting From Sulfur
Mustard-Induced Acute Pulmonary Injury in Rats-
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Authors: Xiaoxuan Hu, Na Zhang, Yuxu Zhong, Tao Liu, Xiaoji Zhu; Na Zhang, Yuxu Zhong, Tao Liu, Xiaoji Zhu1Weifang No. 2 People’s Hospital, Weifang Respiratory Disease Hospital, Weifang, China2State Key Laboratory of Antitoxic Drugs Pharmacology, 71040Academy of Military Medical Sciences, Beijing, China3Department of Respiration, The 80th Group Army Hospital of People’s Liberation Army, Weifang, China4Department of Respiration, Jiaozhou Branch of Shanghai East Hospital, Tongji University, Qingdao, China
Abstract: International Journal of Toxicology, Ahead of Print.
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.
Citation: International Journal of Toxicology
PubDate: 2025-01-31T06:17:46Z
DOI: 10.1177/10915818251315907
- Review of the Hazards and Contraindications of Etomidate
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Authors: Gaolin Zheng, Yinyu Chen, Guangmei Wu, Tao Song, Xing Zou, Qianyun Nie, Peng Zhang; Yinyu Chen, Guangmei Wu, Tao Song, Xing Zou, Qianyun Nie, Peng Zhang1Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Forensic Medicine, Hainan Provincial Tropical Forensic Engineering Research Center, 12455Hainan Medical University, Haikou, China2Department of Pathology, School of Basic Medicine Life Sciences, 12455Hainan Medical University, Haikou, China3Department of Pathology, 12455The First Affiliated Hospital of Hainan Medical University, Haikou, China
Abstract: International Journal of Toxicology, Ahead of Print.
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.
Citation: International Journal of Toxicology
PubDate: 2024-11-06T09:13:56Z
DOI: 10.1177/10915818241297073
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