Wetherell_2006_Neurotoxicol_27_485

This study forms part of a larger programme of work aimed at developing improved medical countermeasures for nerve agent poisoning with less reliance on pretreatment. Therapy with N(6)-cyclopentyladenosine (CPA), physostigmine, hyoscine and HI-6 protected guinea-pigs against the incapacitating and lethal effects of a supralethal challenge of soman (135 microg/kg) when given 1 min after poisoning. CPA, however has well-recognised side effects that are likely to preclude it being licensed for use in humans so further refinements were made to the doses of the other therapy components to improve efficacy in the absence of CPA. An immediate therapy comprising physostigmine (0.2 mg/kg), hyoscine (4 mg/kg) and HI-6 (93.6 mg/kg), when given 1 min after nerve agent, provided good protection against the lethal effects of GA, GB, GD, GF and VX poisoning and reduced the duration of the signs of incapacitation and hypothermia. In the case of GA and GB poisoning some animals exhibited a short period of substantial incapacitation. Most animals continued to gain weight over the following 6 days without the need for further medical intervention. In the case of GA poisoning further medical intervention would be needed to ensure the longer term survival of all animals and it is likely that in the battlefield situation further medical treatment would be available within 2-4 h. The drug combination described in this paper protects against supralethal doses of a range of nerve agents, with minimal incapacitation in the absence of any pretreatment. Further modification and refinement of this therapy is required for human use and it may provide a way forward for development of medical countermeasures for the treatment of organophosphate poisoning in the wider community should there be a need.