PATTERNS OF DRUG-INDUCED CARDIOVASCULAR PATHOLOGY IN THE BEAGLE DOG -RELEVANCE FOR HUMANS

In toxicity studies, the examination of tissue sections for pathologic al changes is the principle method for the identification of organ tox icity and characterisation of the hazard of novel drugs for humans. St udy of the patterns of pathological alterations also represents an imp ortant means of developing an understanding of the mechanism of toxici ty. However as pathological change frequently represents a final commo n expression of diverse processes, additional functional information i s often required for a clear understanding of the mechanisms of toxici ty. This is exemplified in the evaluation of the effects of drugs on t he beagle dog cardiovascular system where an understanding of mechanis ms is crucial in the assessment of human risk. Particular patterns of drug-induced structural change in the myocardium or blood vessels are frequently linked to specific mechanisms of toxicity. However, assessm ent based on the interpretation of patterns of cardiovascular patholog y alone may be misleading. Quite different changes in cardiac and vasc ular function or direct cellular toxicity may also be manifest by path ological features in common. Therefore, a clear understanding of mecha nism frequently requires additional in vivo or in vitro physiological, pharmacological, biochemical or other mechanistic information. The be agle dog remains an important model for the study of cardiovascular to xicity because in this species, haemodynamic changes and pathological alterations can be related in a way that provides the basis for the sa fe study in humans of novel drugs with cardiovascular activity.