Pathology and pathophysiology of drug-induced arterial injury in laboratory animals and its implications on the evaluation of novel chemical entities for human clinical trials.
In toxicology studies, drug-induced arterial injury in laboratory animals continues to be a pressing issue of concern, particularly to those engaged in the discovery and development of novel therapies intended for human use. The concern is justifiably magnified because, currently, there is no unequivocal biochemical marker of arterial injury and/or toxicity in animals or man. Therefore, in laboratory animals used for toxicology studies a precise description of arterial lesions in terms of location, distribution and morphologic character is necessary so that a correlation can be drawn between structural damage and derangement of specific cardiovascular functions. The critical nature of the latter cannot be over-emphasized because this will provide a basis for understanding the mechanism of toxicity, the pathogenesis of the lesion and assessment of human risk. However, in the decision making process, utilization of pattern recognition must be supported by rigorous scientific investigations aimed at establishing a link, where possible, between the deranged cardiovascular function and alterations in cellular, biochemical and molecular events. Conceivably, engagement of the molecular pharmacology target initiates a series of interactive cascades among cellular and non-cellular arterial components that culminate in organ damage. Therefore, any investigative mechanistic studies aimed at understanding the initiation and development of arterial lesions in laboratory animals must make a conscientious attempt to identify and characterize the molecular target of toxicity.
Louden
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Department of Safety Assessment, SmithKline Beechman Pharmaceuticals, King of Prussia, PA 19403, USA. calvert.s.louden@dupontpharma.com
Morgan
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DG
D000818:Animals; D000830:Animals, Laboratory; D001158:Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D018570:Risk Assessment; D013045:Species Specificity; D015262:Xenobiotics / Q000633:toxicity*
D015415:Biomarkers; D015262:Xenobiotics