Comparative efficacy of diazepam and avizafone against sarin-induced neuropathology and respiratory failure in guinea pigs: influence of atropine dose.
This investigation compared the efficacy of diazepam and the water-soluble prodiazepam-avizafone-in sarin poisoning therapy. Guinea pigs, pretreated with pyridostigmine 0.1 mg/kg, were intoxicated with 4LD(50) of sarin (s.c. route) and 1 min after intoxication treated by intramuscular injection of atropine (3 or 33.8 mg/kg), pralidoxime (32 mg/kg) and either diazepam (2 mg/kg) or avizafone (3.5 mg/kg). EEG and pneumo-physiological parameters were simultaneously recorded. When atropine was administered at a dose of 3 mg/kg, seizures were observed in 87.5% of the cases; if an anticonvulsant was added (diazepam (2 mg/kg) or avizafone (3.5 mg/kg)), seizure was prevented but respiratory disorders were observed. At 33.8 mg/kg, atropine markedly increased the seizure threshold and prevented early respiratory distress induced by sarin. When diazepam was administered together with atropine, seizures were not observed but 62.5% of the animals displayed respiratory difficulties. These symptoms were not observed when using avizafone. The pharmacokinetic data showed marked variation of the plasma levels of atropine and diazepam in different antidote combination groups, where groups receiving diazepam exhibited the lowest concentration of atropine in plasma. Taken together, the results indicate that avizafone is suitable in therapy against sarin when an anticonvulsant is judged necessary.
Taysse
L
L
Centre d'Etudes du Bouchet, Defense Research Centre, BP No. 3, Vert-Le-Petit 91710, France. laurent.taysse@ceb.etca.fr
Calvet
J-H
JH
Buée
J
J
Christin
D
D
Delamanche
S
S
Breton
P
P
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001285:Atropine / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D003975:Diazepam / Q000493:pharmacokinetics / Q000494:pharmacology*; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004569:Electroencephalography; D006168:Guinea Pigs; D006651:Histocytochemistry; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D009422:Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D012131:Respiratory Insufficiency / Q000188:drug therapy; D012524:Sarin / Q000037:antagonists & inhibitors / Q000506:poisoning*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D004151:Dipeptides; D018727:Muscarinic Antagonists; D011220:Pralidoxime Compounds; D011355:Prodrugs; C065249:pro-diazepam; D001285:Atropine; D012524:Sarin; D011729:Pyridostigmine Bromide; C028797:pralidoxime; D003975:Diazepam