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Anticonvulsant effects of diazepam and MK-801 in soman poisoning
1Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Abstract:
An animal model was developed to evaluate the anticonvulsant effects of diazepam and MK-801 in soman poisoning and to examine the possible mechanism of soman-induced convulsions. The oxime HI-6 (125 mg/kg, i.p.) was given to male rats, to increase survival, 30 min prior to 180 micrograms/kg, s.c. (equivalent to 1.6 x LD50) of soman, which produced 100% occurrence of convulsions. Initially, diazepam was studied with or without the concomitant administration of various doses of atropine sulfate 30 min prior to soman challenge. Diazepam (1.25-10.0 mg/kg, i.m.) alone did not prevent soman-induced convulsions. In the presence of 2, 4, 8, and 16 mg/kg of atropine, the anticonvulsant ED50 doses of diazepam were 0.490, 0.257, 0.132 and 0.136 mg/kg, respectively. Atropine sulfate at a dose of 16 mg/kg prevented the soman-induced hypersecretion, showed some anticonvulsant activity and provided a good motor recovery. MK-801 by itself, at or above 1 mg/kg, prevented convulsions, but markedly potentiated the lethal effects produced by soman. With atropine (16 mg/kg), the anticonvulsant ED50 for MK-801 was 0.037 mg/kg, which indicated that MK-801 was about 4 times as potent as diazepam, and the lethal interactions between MK-801 and soman were suppressed. The findings indicate that, in soman poisoning, diazepam and MK-801 are effective anticonvulsants in the presence of the anticholinergic atropine sulfate. The possible sequence of events and neuropharmacological mechanism of soman-induced convulsions are discussed.
Insights
This study shows that atropine sulfate enhances the anticonvulsant effects of diazepam and MK-801 against soman poisoning in rats. These findings suggest a potential treatment strategy for nerve agent exposure.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Soman poisoning can cause severe convulsions and death.
- Anticonvulsant medications are crucial for managing nerve agent toxicity.
- Understanding the mechanisms of soman-induced seizures is vital for developing effective countermeasures.
Purpose of the Study:
- To evaluate the anticonvulsant efficacy of diazepam and MK-801 in a rat model of soman poisoning.
- To investigate the role of atropine sulfate in modulating the effects of these anticonvulsants against soman.
- To explore the neuropharmacological mechanisms underlying soman-induced convulsions.
Main Methods:
- Development of a rat model for soman poisoning, utilizing HI-6 for survival enhancement.
- Administration of diazepam and MK-801, with and without varying doses of atropine sulfate, prior to soman challenge.
- Assessment of anticonvulsant activity, lethality, and physiological effects (e.g., hypersecretion, motor recovery).
Main Results:
- Diazepam alone did not prevent soman-induced convulsions; however, its efficacy increased significantly with atropine sulfate.
- MK-801 prevented convulsions but potentiated soman's lethal effects; this potentiation was suppressed by atropine sulfate.
- Atropine sulfate (16 mg/kg) demonstrated anticonvulsant activity, reduced hypersecretion, and improved motor recovery.
Conclusions:
- Diazepam and MK-801 are effective anticonvulsants in soman poisoning when co-administered with atropine sulfate.
- Atropine sulfate plays a critical role in enhancing anticonvulsant activity and mitigating toxicity of certain agents against soman.
- The study provides insights into the neuropharmacological mechanisms of soman toxicity and potential therapeutic interventions.