Review of the value of gacyclidine (GK-11) as adjuvant medication to conventional treatments of organophosphate poisoning: primate experiments mimicking various scenarios of military or terrorist attack by soman.
Today, organophosphorus nerve agents are still considered as potential threats in both military or terrorism situations. These agents act as potent irreversible inhibitors of acetylcholinesterase in both central and peripheral nervous systems. Conventional treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, numerous studies have demonstrated that the excitatory amino acid glutamate also plays a prominent role in the maintenance of organophosphate-induced seizures and in the subsequent neuropathology especially through an overactivation of the N-methyl-D-aspartate (NMDA) receptor subtype. Contrary to other non-competitive NMDA antagonists successfully tested in rodents exposed to organophosphate, gacyclidine is a novel antiNMDA compound which is in the process of approval for human use in France for neurotraumatology. This review summarizes the therapeutic value of gacyclidine as a complement to the available emergency treatment against severe organophosphate poisoning. Previous data obtained from experiments on primates in several scenarios mimicking military or terrorist attacks, using soman as the nerve agent, were used. Primates pretreated with pyridostigmine and receiving conventional emergency therapy at the first signs of poisoning survive. However, only gacyclidine is able to ensure complete management of nerve agent poisoning for rapid normalization of EEG activity, clinical recovery and neuroprotection. Gacyclidine also ensures optimal management of severe nerve agent poisoning in animals neither pretreated nor receiving emergency therapy likewise during an unexpected exposure. However, this beneficial effect is obtained provided that medical intervention is conducted rapidly after intoxication. Globally, the current lack of any other NMDA receptor antagonist suitable for human use reinforces the therapeutic value of gacyclidine as a central nervous system protective agent for the treatment of OP poisoning.
Lallement
G
G
Unité de Neuropharmacologie, Centre de Recherches du Service de Santé des Armées-La Tronche-France. 100437,201@compuserve.com
Baubichon
D
D
Clarençon
D
D
Galonnier
M
M
Peoc'h
M
M
Carpentier
P
P
D000818:Animals; D003510:Cyclohexanes / Q000627:therapeutic use*; D053138:Cyclohexenes; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D000882:Haplorhini; D006801:Humans; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010880:Piperidines / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control*; D012999:Soman / Q000633:toxicity*; D013997:Time Factors
D003510:Cyclohexanes; D053138:Cyclohexenes; D018691:Excitatory Amino Acid Antagonists; D009943:Organophosphorus Compounds; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C070707:gacyclidine; D012999:Soman