Organophosphorus (OP)
nerve agents are still used as warfare and terrorism compounds. Classical
delayed treatment of victims of
organophosphate poisoning includes combined i.v. administration of a
cholinesterase reactivator (an
oxime), a
muscarinic cholinergic receptor antagonist (
atropine) and a
benzodiazepine 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 injected (i.v.) in combination with
atropine/
diazepam/
pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of
gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that
atropine/
diazepam/
pralidoxime alone or combined with
gacyclidine did not prevent signs of
soman toxicity when treatment was delayed 45 min after
poisoning.
Atropine/
diazepam/
pralidoxime also did not control
seizures or prevent neuropathology in primates exhibiting severe signs of
poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with
gacyclidine was able to stop
soman-induced
seizures and restore normal EEG activity. This
drug also totally prevented the neuropathology observed 5 weeks after
soman exposure in animals treated with
atropine/
diazepam/
pralidoxime alone. Overall, in the case of severe OP-
poisoning,
gacyclidine represents a promising adjuvant
therapy to the currently available
polymedication to ensure optimal management of
organophosphate poisoning in man. This
drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-
poisoning, medical intervention must be conducted as early as possible.