Cholinolytics in the Treatment of Anticholinesterase Poisoning: I. The Effectiveness of Certain Cholinolytics in Combination With an Oxime for Treatment of Sarin Poisoning

Abstract

The protection to sarin poisoning afforded mice by treatment with N-methylpyridinium-2-aldoxime methanesulphonate (P-2-S) in combination with each of 34 cholinolytic compounds used as substitutes for atropine sulphate has been assessed. Twenty-two of the drugs examined in the mouse at a dosage of 50 μmoles/kg gave protection equal to or greater than that afforded by atropine sulphate. The most potent drug was 4′-N-methylpiperidyl 1-phenylcyclopen-tanecarboxylate hydrochloride (G-3063), which was 2.3-fold as effective as atropine sulphate.l-2′-Diethylaminoethyl α-cyclohexyl-α-2″-thienyl glycolate d-bitartrate (Win 5779-6),2′ -diethylaminoethyl 1-phenylcyclopentanecarboxylate hydrochloride (Parpanit), and l-tropyl α-methyltropate hydrochloride were 1.8-, 1.5-, and 1.4-fold as effective, respectively. Eighteen of the compounds were examined in the rat, with 11 showing potency equal to or greater than that shown by atropine sulphate. In this species the most potent drugs were G-3063, which had 4.0 times the activity of atropine sulphate, Win 5779–6 (4.8-fold), and atropine methanesulphonate, followed by 1-cyclohexyl-1-(2′-thienyl)-3-(1″-piperidyl)-propanol-1 hydrochloride (Win 12085) and Parpanit.

The protective actions of some anticholinergic drugs in sarin poisoning

“…It might be expected that anticholinergic drugs which are more active centrally than the standard therapeutic drug atropine would be more effective in the treatment of anticholinesterase poisoning since Coleman, Little & Bannard (1962) failed to show any correlation between the therapeutic effectiveness of a series of drugs used in conjunction with an aldoxime in sarin-poisoned mice and their peripheral anticholinergic activity. The experiments reported here were designed to make a comparison between therapeutic effectiveness and both peripheral and central anticholinergic potency.…”

Preparation of antidotes for anticholinesterase poisoning. IV. Synthesis and protective effectiveness of 2′-(cis- and trans-2″-hydroxycyclohexyl)aminoethyl 1-phenylcyclopentanecarboxylate hydrochlorides

“…The residue was fractionated yielding 2'-chloroethyl l-phenylcyclopentanecarboxylate as a colorless oil, b.p. 170-171.5"/10 mm, t1DZ5 1 This compound was stable even after storage for 4 years as indicated by n o change in either its i.r. spectrum or its refractive index.…”

“…In connection with our continuing studies on the effectiveness of Parpanit (2'-diethylaminoethyl 1-phei~ylcyclopentanecarboxylate hydrochloride) and its analogues as substitutes for, or adjuncts to, atropine in the treatment of rodents which have been poisoned with organophosphorus anticholinesterases (1)(2)(3)(4)(5) it was desired to examine compounds containing a hydroxyl group close to and in known stereochemical relationship with the amino group in Parpanit. To this end the synthesis of compounds of the type 1 and 2 (R = C,H, or H) has been briefly examined and the in vivo protective effectiveness of compounds 1 and 2 (R = H) was determined.…”

Dual mechanism of the antidotal action of atropine-like drugs in poisoning by organophosphorus anticholinesterases

“…The potential usage of synthetic organophosphorus compounds as chemical warfare agents (Heath, 1961) and the increasing use of organophosphorus compounds as insecticides (Eto,I974), make poisoning by anticholinesterases a serious problem (Namba, 1971) and many attempts have been made (Coleman, Little & Bannard, 1962, 1963Wills, 1964;Madill, Stewart & Savoie, 1967;Brimblecombe, Green & others, 1970) to improve therapeutic procedures, most of which involve atropine-oxime mixtures, by replacing atropine by other antimuscarinic drugs. In these investigations no clear relation was demonstrated between the protection afforded by atropine-like drugs against poisoning by organophosphorus anticholinesterases and their antimuscarinic activity in the pns and cns.…”