NERVE AGENT POISONING IN PRIMATES - ANTILETHAL, ANTIEPILEPTIC AND NEUROPROTECTIVE EFFECTS OF GK-11

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase re activator (an oxime), a muscarinic cholinergic receptor antagonist (at ropine) and a benzodiazepine anticonvulsant (diazepam). However, recen t experiments with primates have demonstrated that such treatment, eve n when administered immediately after organophosphate exposure, does n ot rapidly restore normal electroencephalographic (EEC) activity and f ails to totally prevent neuronal brain damage. The objective of this s tudy was to evaluate, in a realistic setting. the therapeutic benefit of administration of GK-II (gacyclidine), an antiglutamatergic compoun d, as a complement to the available emergency therapy against organoph osphate poisoning. GK-II was injected at a dose of 0.1 mg/kg (i.v) aft er a 45-min latency period to heavily intoxicated (8 LD50) primates. J ust after intoxication, man-equivalent doses of one autoinjector conta ining atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, reco very after challenge and central nervous system histology, The present data demonstrate that treatment with GK-11 prevents the mortality obs erved after early administration of classical emergency medication alo ne. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis w ithin the classical frequency bands (beta, theta, alpha, delta) demons trated that central activity was totally restored to normal after GK-I I treatment, but remained profoundly altered in animals receiving atro pine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clini cal recovery of soman-challenged primates, Lastly, this drug totally p revented the neuropathology observed 3 weeks after soman exposure in a nimals treated with classical emergency treatment alone. GK-11 represe nts a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoni ng in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.