Institut für Toxikologie, der ETH und Universität Zürich, Zürich
Duration: 5 years End of the Project: 1993
Background and Aim
Standard toxicological studies in dogs using high doses of vasodilators and positive inotropic / vasodilating agents give rise to a species-specific cardiotoxicity. The reason may be the extreme sensitivity of the dog to the pharmacological effects of these drugs; exaggerated pharmacodynamic effects and prolonged disturbance of homeostasis mechanisms often are responsible for the observed organ lesions. An assessment of the toxicological relevance and the risk for patients taking the drugs at therapeutic doses cannot be made without taking into account their pathomechanisms and the pathophysiological basis of the exceptional reaction patterrns occurring in dogs.
Method and Results
A large series of vasodilating and positive inotropic agents are presented, their pharmacological properties are described, and toxicological effects in dogs are compared. In view of the poor correlation between the distinct cardiac lesions induced in dogs and a lack of comparable toxicity in humans, it appears desirable to reassess the adequacy of the standard toxicological approaches for these substances.
Zbinden G. (1991) Predictive value of animal studies in toxicology Regul. Tox. Pharm. 14, 167-177.
Dogterom P., Zbinden G., Reznik G.K. (1992) Cardiotoxicity of vasodilators and positive inotropic/vasodilating drugs in dogs: an overview. Crit. Rev. Toxicol. 22 (3-4): 203-41.
Zbinden G. (1993) The Concept of Multispecies Testing in Industrial Toxicology, Regul. Tox. Pharm. 17, 85-94.