CHOLINOLYTICS IN THE TREATMENT OF ANTICHOLINESTERASE POISONING: II. TREATMENT OF SARIN POISONING WITH AN OXIME AND VARIOUS COMBINATIONS OF CHOLINOLYTIC COMPOUNDS

Abstract

Thirty-four cholinolytic compounds were screened for protective activity in mice and rats exposed to sarin. All compounds were examined at a dosage of 50 μmoles/kg in the presence of 30 mg/kg of N-methylpyridinium-2-aldoxime methanesulphonate (P-2-S). In the first trials, the compounds were administered in combination with 50 μmoles/kg of atropine sulphate. With mice, 17 of the compounds demonstrated protection significantly greater than that afforded by P-2-S and atropine sulphate alone. Best protection was obtained with the addition of 2′-diethylaminoethyl 1-phenylcyclobutanecarboxylate hydrochloride (G-5130), the combined treatment increasing the LD₅₀ of sarin 10-fold. Triflupromazine in combination with atropine sulphate raised the LD₅₀ of sarin 8.5-fold while 4′-N-methylpiperidyl 1-phenylcyclopentanecarboxylate hydrochloride (G-3063) with atropine sulphate increased the LD₅₀ of sarin by a factor of 6.6. When 16 of the combinations most active in the mouse were repeated using rats, highest protection was obtained with the l-isomer of 2′-diethylaminoethyl α-cyclohexane-α-(2″-thienyl)glycolate d-bitartrate (Win 5779-6), which increased the LD₅₀ of sarin 23-fold. Diparcol plus atropine sulphate and Parpanit plus atropine sulphate increased the LD₅₀ of sarin by factors of 19 and 14.7 respectively.In further studies on mice in which combinations of cholinolytic drugs were examined in the absence of atropine sulphate, the most effective combined treatment, which raised the LD₅₀of sarin 24-fold, involved the use of G-3063 with Triflupromazine. G-3063 in combination with atropine methylbromide or Diparcol increased the LD₅₀ of sarin 15- and 14-fold respectively.