Animal Studies — A Theoretical Basis for Treatment

Introduction Paracetamol* is a remarkably safe drug when used at therapeutic doses but it can induce in large overdoses centrilobular hepatic necrosis. The first cases of hepatotoxicity from overdose of paracetamol taken with suicidal intent were published by Davidson & Eastham (1966) and Thomson & Prescott (1966), and since these two first papers, many others have been published. A treatment for voluntary paracetamol intoxication had therefore to be found. Some physical techniques like haemodialysis (Farid et aI1972), charcoal column haemoperfusion (Wilson et al 1973) and forced diuresis (McLean et al 1968, Prescott & Wright 1973), have been suggested but their conditions of utilization were difficult and their efficacy was low when liver damage was severe. The discovery of an antidote was important, but obviously the initial research could not be done in man, and animal studies were necessary. The hepatotoxic effects of paracetamol overdose have been experimentally reproduced in different animal species (Boyd & Bereczky 1966, Dixon et al 1971, Jollow et a11973, Dixon et aI1975). In mice and rats very high dose levels of paracetamol induced a centrilobular hepatic necrosis and an increase in transaminase levels which were dose-related. The experimental study of the treatment of paracetamol overdosage was therefore possible on animals, and this is the subject of the experiments we are reporting. We have tried to use the most appropriate