GK-11 - PROMISING ADDITIONAL NEUROPROTECTIVE THERAPY FOR ORGANOPHOSPHATE POISONING

Recent experiments with primates have demonstrated that treatment with atropine/pralidoxime/diazepam, even if administered immediately after organophosphate exposure, does not totally prevent neuronal brain dam age. Using primates, we have studied, for the first time, the ability of GK-11 (gacyclidine), an antiglutamatergic drug in the process of ag reement for human use, given as an additional therapy, to counteract t he neuropathology due to organophosphate exposure that persists after classical treatment with oxime/atropine/benzodiazepine. We have also e xamined the recovery of the organophosphate-intoxicated primates. Male Cynomolgus monkeys were pretreated 1 hour before poisoning with pyrid ostigmine, then intoxicated with 8 LD50 of soman and immediately treat ed with the combination pralidoxime/atropine/diazepam. Some of the ani mals also received GK-11 at 0.07; 0.03 or 0.1 mg/kg (i.v). 10 minutes after soman challenge. Recovery of the primates (reflexes, movements, feeding) and the neuropathological changes that occured three weeks af ter intoxication (histological examinations and neuronal cell density measurement) were compared in GK-11-treated and control animals. At al l doses tested GK-11 prevented the neuronal rarefaction of the frontop arietal cortex that was observed in soman-intoxicated animals that rec eived only oxime/atropine/diazepam. Moreover, the 0.07 mg/kg dose of G K-11 improved the early recovery of intoxicated primates from 1 day af ter intoxication. In the view of the most effective management of orga nophosphate intoxication that is currently available, GK-11 thus appea rs to be a promising additional neuroprotective therapy. This drug is presently being evaluated in a human clinical trial for a different ne uroprotective indication. (C) 1997 Intox Press, Inc.