PubMed1994
Treatment of the convulsive and neuropathologic actions of organophosphates comprise the major unsolved problem in defending against this class of chemical nerve agents. Understanding and preventing these central actions are important goals of chemical defense research. It is generally accepted that inhibition of acetylcholinesterase results in an accumulation of acetylcholine (ACh) which may be responsible for the acute toxic effects of nerve agents. Although atropine has long been used in the treatment of poisoning, it does not significantly reduce convulsions and seizures nor does it drastically alter the acute toxicity. Inasmuch as antimuscarinic agents do not provide sufficient antidotal activity, it follows that ACh may not be the only transmitter involved in the CNS actions of organophosphates. Benzodiazepines, the most potent of the clinically available anticonvulsants are potentially useful as antidote against nerve agent poisoning. However, significant disadvantages are associated with the im administration of benzodiazepines particularly diazepam the now anticonvulsant fielded drug. The present report was undertaken to compare the effectiveness of thienyl phencyclidine (TCP), a non-competitive antagonist at N-methyl-D-aspartate (NMDA) glutamate receptors, to diazepam both administered im for protection against soman toxicity (convulsions, seizures, incidence on death, brain damage). In a first set of experiments, male wistar rats were pretreated with diazepam (1 mg/kg) given im. Fifteen minutes later 1 x LD50 of soman was injected sc and the incidence of seizures and death were recorded for 24 hr. The therapeutic efficacy of a post-poisoning treatment of diazepam was also studied. In this case diazepam was administered 45 min after the onset of seizures. In a second set of experiments, guinea-pigs were pretreated with pyridostigmine (0.2 mg/kg, sc) in combination with atropine (5 mg/kg, im) 30 min before soman (62 micrograms/kg, sc) and the protective effect of TCP (2.5 mg/kg, im) evaluated when the drug was administered either before soman (15 or 30 min) or after the onset of EEG seizures (5, 30 or 60 min). Pretreatment with diazepam alone did reduce soman-induced seizures but did not reduce mortality of rats. Neuropathology was not observed in non-seizuring rats. When given 45 min after the onset of seizures, diazepam failed to protect against status epilepticus and neuropathology. Thus, diazepam was more effective when given before, rather than after, seizure initiation. Systemic injection of TCP blocked the seizures induced by 2 x LD50 of soman in guinea-pigs pretreated by pyridostigmine and atropine. The anticonvulsant potency of TCP was particularly obvious when the compound was administered curatively.(ABSTRACT TRUNCATED AT 400 WORDS)