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 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.
Lallement
G
G
Unité de Neurotoxicologie, Centre de Recherches du Service de Santé des Armées-La Tronche, France.
Mestries
J C
JC
Privat
A
A
Brochier
G
G
Baubichon
D
D
Carpentier
P
P
Kamenka
J M
JM
Sentenac-Roumanou
H
H
Burckhart
M F
MF
Peoc'h
M
M
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology*; D053138:Cyclohexenes; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008251:Macaca; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology*
D003510:Cyclohexanes; D053138:Cyclohexenes; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D010880:Piperidines; C070707:gacyclidine