NDLI: Evaluation of subchronic toxicity of GRD081, a dual PI3K/mTOR inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and beagle dogs.

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Evaluation of subchronic toxicity of GRD081, a dual PI3K/mTOR inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and beagle dogs.

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Evaluation of subchronic toxicity of GRD081, a dual PI3K/mTOR inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and beagle dogs.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Xia, Zhenna Gao, Tingting Zong, Ying Zhang, Xiaofang Mao, Yu Yuan, Bojun Lu, Guocai
Description	Country affiliation: China Author Affiliation: Xia Z ( Center of Evaluation for Drug Safety, Second Military Medical University, Shanghai, China.)
Abstract	GRD081, a newly developed dual PI3K/mTOR inhibitor, is now being considered for evaluation in phase I clinical trial. In this work, the subchronic toxicity of GRD081 in Sprague-Dawley (SD) rats and beagle dogs has been characterized. Rats and dogs received GRD081 orally (2, 5, 10 and 1, 2, 4 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days following a 14 days of recovery period. The treatment resulted in unscheduled mortality in rats receiving 5 mg/kg/day and 10 mg/kg/day. The adverse effects of GRD081 on rats and dogs mainly included myelosuppression, immunosuppression, hematological toxicity, and moderate liver, pancreas and kidney toxicity. These observations are consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of PI3K/mTOR signaling inhibitors. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of GRD081 was 1mg/kg/day for beagle dogs and less than 2 mg/kg/day for SD rats.
File Format	HTM / HTML
ISSN	02786915
Volume Number	62
e-ISSN	18736351
Journal	Food and Chemical Toxicology
Language	English
Publisher	Elsevier
Publisher Date	2013-12-01
Publisher Place	Great Britain (UK)
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Toxicology__semicolon__nutritional Discipline Sciences Enzyme Inhibitors Pharmacology Tor Serine-threonine Kinases Antagonists & Inhibitors Toxicity Tests, Subchronic Methods Administration, Oral Animals Blood Glucose Analysis Dogs Dose-response Relationship, Drug Electrocardiography Female Immunosuppression Adverse Effects Kidney Drug Effects Pathology Liver Male No-observed-adverse-effect Level Pancreas Phosphatidylinositol 3-kinases Rats Rats, Sprague-dawley Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Medicine Toxicology Food Science

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