Efficacy of immediate and subsequent therapies against soman-induced seizures and lethality in rats.
The purpose of the present study was to examine the efficacy of a triple combination of drugs with adequate anticonvulsant effects and a dual combination with inadequate anticonvulsant effects followed by adjunct therapy. The results showed that combined intramuscular injections of HI-6 (42 mg/kg), atropine (14 mg/kg), and avizafone (3 mg/kg) administered 1, 16, and 31 min. after exposure to a soman dose of 4 x LD(50) completely terminated seizures with a moderate mortality rate (25%). When the soman dose was lowered to 3 x LD(50) the anticonvulsant effect was complete, and no rats died within 24 hr. Rats challenged with 5 x LD(50) of soman all died within 10 min. Without avizafone in the combination, seizures induced by 3 or 4 x LD(50) of soman could not be terminated unless an adjunct therapy consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg), and pentobarbital (30 kg/kg) was given, and the mortality rate was comparatively high (78%). Administration of the adjunct therapy alone 6-16 min. after 4 x LD(50) of soman stopped the seizure activity, but all the rats died within 24 hr. Marked neuropathology was found in the piriform cortex and amygdala, whereas the hippocampal CA1 field was effectively protected when both the triple combination and the dual combination plus adjuncts had stopped seizures 35-55 min. after onset. It is concluded that termination of soman-induced seizures at an early stage (<20 min.) is crucial to avoid neuronal pathology.
Myhrer
Trond
T
Norwegian Defence Research Establishment, Protection Division, P.O. Box 25, NO-2027 Kjeller, Norway. trond.myhrer@ffi.no
Enger
Siri
S
Aas
Pål
P
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003975:Diazepam / Q000627:therapeutic use; D004151:Dipeptides / Q000627:therapeutic use; D004338:Drug Combinations; D007928:Lethal Dose 50; D008297:Male; D010091:Oximes; D010424:Pentobarbital / Q000627:therapeutic use; D011352:Procyclidine / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D012999:Soman / Q000633:toxicity*
D000927:Anticonvulsants; D004151:Dipeptides; D004338:Drug Combinations; D010091:Oximes; D011726:Pyridinium Compounds; C065249:pro-diazepam; D001285:Atropine; D012999:Soman; D011352:Procyclidine; C022870:asoxime chloride; D010424:Pentobarbital; D003975:Diazepam