Patterns of drug-induced cardiovascular pathology in the beagle dog: relevance for humans.
In toxicity studies, the examination of tissue sections for pathological changes is the principle method for the identification of organ toxicity and characterisation of the hazard of novel drugs for humans. Study of the patterns of pathological alterations also represents an important means of developing an understanding of the mechanism of toxicity. However as pathological change frequently represents a final common expression of diverse processes, additional functional information is often required for a clear understanding of the mechanisms of toxicity. This is exemplified in the evaluation of the effects of drugs on the beagle dog cardiovascular system where an understanding of mechanisms 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, assessment based on the interpretation of patterns of cardiovascular pathology alone may be misleading. Quite different changes in cardiac and vascular function or direct cellular toxicity may also be manifest by pathological features in common. Therefore, a clear understanding of mechanism frequently requires additional in vivo or in vitro physiological, pharmacological, biochemical or other mechanistic information. The beagle dog remains an important model for the study of cardiovascular toxicity because in this species, haemodynamic changes and pathological alterations can be related in a way that provides the basis for the safe study in humans of novel drugs with cardiovascular activity.
Greaves
P
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Safety of Medicines Group, ZENECA Pharmaceuticals, Macclesfield, Cheshire, UK.
D000818:Animals; D002317:Cardiovascular Agents / Q000633:toxicity*; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000473:pathology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology; D006351:Heart Valves / Q000187:drug effects / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000139:chemically induced / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D013045:Species Specificity
D002317:Cardiovascular Agents