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 damage. Using primates, we have studied, for the first time, the ability of
GK-11 (
gacyclidine), an antiglutamatergic
drug in the process of agreement for human use, given as an additional
therapy, to counteract the neuropathology due to
organophosphate exposure that persists after classical treatment with
oxime/
atropine/
benzodiazepine. We have also examined the recovery of the
organophosphate-intoxicated primates. Male Cynomolgus monkeys were pretreated 1 hour before
poisoning with
pyridostigmine, then intoxicated with 8 LD50 of
soman and immediately treated with the combination
pralidoxime/
atropine/
diazepam. Some of the animals also received
GK-11 at 0.01; 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 occurred three weeks after intoxication (histological examinations and neuronal cell density measurement) were compared in GK-11-treated and control animals. At all doses tested,
GK-11 prevented the neuronal rarefaction of the frontoparietal cortex that was observed in
soman-intoxicated animals that received only
oxime/
atropine/
diazepam. Moreover, the 0.01 mg/kg dose of
GK-11 improved the early recovery of intoxicated primates from 1 day after intoxication. In the view of the most effective management of
organophosphate intoxication that is currently available,
GK-11 thus appears to be a promising additional neuroprotective
therapy. This
drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.