Pathology and pathophysiology of drug-induced arterial injury in laboratory animals and its implications on the evaluation of novel chemical entitiesfor human clinical trials

In toxicology studies, drug-induced arterial injury in laboratory animals c ontinues to be a pressing issue of concern, particularly to those engaged i n the discovery and development of novel therapies intended for human use. The concern is justifiably magnified because, currently, there is no unequi vocal biochemical marker of arterial injury and/or toxicity in animals or m an. Therefore, in laboratory animals used for toxicology studies a precise description of arterial lesions in terms of location, distribution and morp hologic character is necessary so that a correlation can be drawn between s tructural damage and derangement of specific cardiovascular functions. The critical nature of the latter cannot be over-emphasized because this will p rovide a basis for understanding the mechanism of toxicity, the pathogenesi s of the lesion and assessment of human risk. However, in the decision maki ng process. utilization of pattern recognition must be supported by rigorou s scientific investigations aimed at establishing a link, where possible, b etween the deranged cardiovascular function and alterations in cellular, bi ochemical and molecular events. Conceivably, engagement of the molecular ph armacology target initiates a series of interactive cascades among cellular and non-cellular arterial components that culminate in organ damage. There fore, any investigative mechanistic studies aimed at understanding the init iation and development of arterial lesions in laboratory animals must make a conscientious attempt to identify and characterize the molecular target o f toxicity.