Development of antidotes: problems and strategies.

Antidotes against chemical warfare agents are "orphan drugs" given that these poisonings are rare. Therefore, they are of limited interest to the pharmaceutical industry. For this reason, and recognizing the increasing threat of terrorist or asymmetrical use of chemical warfare agents, the responsibility for research into medical countermeasures against these weapons is of primary interest to armies. Accordingly, the research activities of the Bundeswehr Institute of Pharmacology and Toxicology are dedicated to improving diagnosis, prophylaxis and therapy of individuals who are exposed to a chemical agent. Here, antidote development and testing are a high priority in the research program, particularly with respect to organophosphorus (OP) nerve agents and sulphur mustard. The Institute has been coordinating research activities undertaken in house and in collaboration with external researchers. The research program aims to develop primarily in vitro models to minimize the sacrifice of animals, using strategies, which involve human material early in antidote testing. An animal model using isolated mouse diaphragm demonstrated the correlation between AChE activity and neuromuscular function. A similar relationship was found between erythrocyte AChE and neuromuscular function in patients with acute OP pesticide poisoning. In vitro rate constants of the various reactions that are involved in enzyme inhibition and reactivation using human material were used for prediction of what would happen in vivo. This prediction could be confirmed in a patient with acute OP pesticide poisoning. Finally, computer models are being established to estimate the therapeutic effect of an antidote in various human poisoning scenarios. This approach is necessary to compensate for the lack of human clinical pharmacodynamic studies that are usually required for drug regulatory approval, given the obvious ethical issues preventing human volunteer studies with these agents.