Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen.
Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.
Raveh
Lily
L
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona 74100, Israel. lili@iibr.gov.il
Rabinovitz
Ishai
I
Gilat
Eran
E
Egoz
Inbal
I
Kapon
Joseph
J
Stavitsky
Ziv
Z
Weissman
Ben Avi
BA
Brandeis
Rachel
R
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001535:Benactyzine / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D003517:Cyclopentanes / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000506:poisoning*
D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D003517:Cyclopentanes; D001535:Benactyzine; C004519:caramiphen; D012524:Sarin