Mechanisms of Drug Toxicity [antikvár]

Helena RaskovA The tremendous progress in the field of modern drug therapy also brings shadows with the benefits. These shadows, in the form of side-effects in man with possible fatal outcome, not only raise a new point of fundamental medical ethics for the physician to always plot the necessity of a given drug medication against its risk, but has profound aspects on how to prevent risk for man. Of course, this is not only for drugs. Pesticides, industrial materials, food additives — wherever we look in our world of civilization, man-made disease or at least the man-made danger of disease appears. To safeguard man against ill effects of drugs, elaborate studies have to be performed on laboratory animals. Since the thalidomide disaster more and more emphasis has been put by national health authorities, as well as by international organizations like the World Health Organization, on how to proceed to increase maximally the safety of drugs. As soon as research began to focus on the toxicity of drugs, it became almost instantly apparent that much of the conventional toxicology work was rather empirical and that the predictability from animal to man, even using a number of different species, was not possible. Therefore, symposia like this are in my opinion very useful in showing various aspects of basic research necessary for practical progress in the future. The external and internal factors which have to be studied are numerous. Seasonal influences can be of first-rate importance, as we can show by our experience with an antimetabolite 6-azacytidine. This anti- metabolite interrupts pregnancy in mice very easily after a single dose of 200 mg per kilo in winter, while in summer a higher dose and repeated administration is necessary.(1) The metabolism of drugs must be thoroughly studied, otherwise the wrong species can be easily chosen, as was again demonstrated in our group for 6-azacytidine. This drug is deaminated by mice, guinea pigs, dogs, cats, rabbits and man, but not by rats.(2) And as only the deaminated product 6-azauridine is active, important errors in evaluation could arise, if only this species would be used.<3) Several generations in the horizontal and vertical evaluation of drugs are necessary to safeguard humans from teratogenicity. t