Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11 |
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Authors: | G Lallement Didier Clarençon Catherine Masqueliez Dominique Baubichon Monique Galonnier Marie-France Burckhart Michel Peoc’h Jean Claude Mestries |
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Affiliation: | (1) Unité de Neurotoxicologie, CRSSA, BP. 87 F-38702, La Tronche Cedex, France, FR;(2) Unité de Radioprotection, CRSSA, BP. 87 F-38702, La Tronche Cedex, France, FR;(3) Service de Microscopie et d’Imagerie, CRSSA, BP. 87 F-38702, La Tronche Cedex, France, FR;(4) Service d’Anatomopathologie, CHU Grenoble, France, FR;(5) Unité de Radiopathologie, CRSSA, BP. 87 F-38702, La Tronche Cedex, France, FR |
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Abstract: | Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency 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, recent experiments with
primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not
rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. 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 available emergency therapy against organophosphate poisoning. GK-11 was
injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were
administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and
central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after
early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that
GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta,
alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly
altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged
primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated
with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency
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.
Received: 16 June 1997 / Accepted: 23 September 1997 |
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Keywords: | Organophosphate poisoning Seizures Neuropathology Gacyclidine Primates |
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