Acute soman poisoning in primates neither pretreated nor receiving immediate therapy: value of gacyclidine (GK-11) in delayed medical support

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poison ing includes combined i.v. administration of a cholinesterase reactivator t an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a be nzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was inject ed (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivale nt doses after a 45- or 30-min latency period to intoxicated primates (2 LD 50). The effects of gacyclidine on the animals' survival, electroencephalog raphic (EEG) activity, signs of toxicity, recovery after challenge and cent ral nervous system histology were examined. The present data demonstrated t hat atropine/diazepam/pralidoxime alone or combined with gacyclidine did no t prevent signs of soman toxicity when treatment was delayed 45 min after p oisoning. Atropine/diazepam/pralidoxime also did not control seizures or pr event neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed taht additional treatment with gacyclidine wa s able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soma n exposure in animals treated with atropine/diazepam/pralidoxime alone. Ove rall, in the case of severe OF-poisoning, gacyclidine represents a promisin g adjuvant therapy to the currently available polymedication to ensure opti mal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective i ndication. However, it should always be kept in mind that. in the case of s evere OF-poisoning medical intervention must be conducted as early as possi ble.