Plasma concentrations of the oxime Pralidoxime Mesylate (P2S) after repeated oral and intramuscular administration.

Abstract

concentrations of the oxime Pralidoxime Mesylate (P2S) after repeated oral and intramuscular administration. The use of the oxime P2S as intravenous therapy for organophosphorus anticholinesterase poisoning is well known. In emergency situations this route of administration may prove impractical due to severe symptoms of anticholinesterase poisoning and therefore the intramuscular route is to be preferred. The absolute intramuscular dose of P2S per man, recommended as necessary for adequate therapy of anticholinesterase poisoning, is 500 mg. In practical situations this dose may have to be repeated at intervals resulting in overdosage, and therefore the clinical side-effects which this regimen might have on normal subjects has been determined. It has also been suggested that where organophosphorus anticholinesterase compounds are handled continuously for many months in the year, for example, in crop spraying and in industry, P2S might be taken prophylactically. The effects that such a regimen might have when combined with therapeutic procedures in human subjects have therefore been evaluated. The absolute intramuscular P2S dose of 500 mg when repeated three times at 20-minute intervals in normal subjects produces no clinical sideeffects. However, when this procedure is superimposedupon an oral P2S prophylactic regimen, up to 60% of the individuals complain of visual side-effects which may prove a hazard in cases of mild anticholinesterase poisoning. It is suggested that these visual side-effects are caused by an accumulation of P2S in the eye during prolonged oral administration.

Organophosphorus compounds and oximes: a critical review

“…Data on toxicity of oximes in non-poisoned humans are sparse and are mainly a by-product of pharmacokinetic investigations. Only 2-PAM (P2S), TMB-4, obidoxime and HI-6 were tested in humans at doses related to the assumed therapeutic dose and only mild to moderate side effects (circulatory, gastrointestinal, sensory) were observed, TMB-4 being considered to be the most toxic of these oximes Calculations are based on experimental reactivation constants of obidoxime (tabun: k r 0.04 min −1 , K D 97.3 µM; sarin: k r 0.937 min −1 , K D 31.3 µM) and 2-PAM (tabun: k r 0.01 min −1 , K D 695 µM; sarin: k r 0.25 min −1 , K D 27.6 µM) and the bimolecular inhibi-tion rate constants k i of tabun (7.4 × 10 6 M −1 min −1 ) and sarin (2.7 × 10 7 M −1 min −1 ) (Worek et al 2004) (Calesnick et al 1967;Wiezorek et al 1968;Sidell and Groff 1970;Erdmann et al 1965;Holland and Parkes 1976;Xue et al 1985;Clement et al 1995).…”

Organophosphorus poisoning and anaesthesia

“…However, it should follow two intravenous bolus doses of 30 mg.kg À1 4 h apart. Pralidoxime mesylate (P2S) is less effective in producing sustained oxime concentrations and requires 4-hourly dosing [136]. It is believed that when effective concentrations of oxime are achieved, the balance between ageing and reactivation reaction rates for the inhibited acetylcholinesterase is altered in favour of the latter.…”

Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma

“…They found that oximes are able to reactivate alkylphosphate inhibited AChE. This basic information was soon outlined by characterizing their absorption, distribution and elimination (Vojvodic and Maksimovic, ; Holland and Parkes, ). K‐series reactivators are a promising group of newly synthesized oximes (Kovarik et al , ; Musilek et al ., 2006; Musilek et al , ; Petroianu et al , ).…”