pralidoxime and methyl-demeton

Acute organophosphate poisoning leads to a cholinergic crisis secondary to an acetylcholine rise, developed by an acetylcholinesterase inhibition. In some cases, after the resolution of the initial cholinergic signs and symptoms, an intermediate syndrome occurs, characterized by a delayed development of proximal and diaphragmatic muscle paralysis. We describe a case of a 67-year-old man who developed an intermediate syndrome after oxydemeton-metryl ingestion in a suicide attempt, despite a continuous pralidoxime infusion. Several hypotheses have been developed to explain the aetiology of this intermediate syndrome (neuromuscular junction dysfunction, inadequate poisoning treatment, late beginning of the oxime administration, etc). Intermediate syndrome manifestation will depend on the organophosphate's organism persistence and its chemical structure, and also on the time elapsed between the poisoning and the antidote administration.

Topics: Aged; Antidotes; Humans; Insecticides; Male; Organophosphate Poisoning; Organothiophosphorus Compounds; Pralidoxime Compounds; Respiratory Paralysis; Suicide, Attempted; Treatment Failure

Human poisoning by organophosphates bearing two methoxy groups, e.g. by malathion, paraoxon-methyl, dimethoate and oxydemeton-methyl, is generally considered to be rather resistant to oxime therapy. Since the oxime effectiveness is influenced not only by its reactivating potential but also by inhibition, aging and spontaneous reactivation kinetics, experiments were performed with human acetyl- (AChE) and butyrylcholinesterase (BChE) to determine the respective kinetic constants. The efficacy of obidoxime in reactivating dimethylphosphoryl-AChE was 40, 9 and 3 times higher than of HI 6, pralidoxime and HLö 7, respectively. Aging (t1/2 3.7 h) and spontaneous reactivation (t1/2 0.7 h) occurred concomitantly, with the portion of the aged enzyme being dependent on the presence of excess inhibitor. Calculation of steady-state AChE activity in the presence of inhibitor and oxime revealed that obidoxime was superior to pralidoxime. In addition, organophosphate concentrations up to 10(-6) M (paraoxon-methyl) and 10(-4) M (oxydemeton-methyl) could be counteracted at clinically relevant oxime concentrations (10 microM). These data indicate that oximes may effectively reactivate human dimethylphosphoryl-AChE. Failure of oximes may be attributed to megadose intoxications and to prolonged time intervals between poison uptake and oxime administration. The potency of the oximes to reactivate dimethylphosphoryl-BChE was much lower and the spontaneous reactivation slower (t1/2 9 h), while aging proceeded at a comparable rate. Thus, BChE activity determination for diagnosis and therapeutic monitoring may give no reliable information on AChE status.

Topics: Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cholinesterases; Humans; Insecticides; Kinetics; Obidoxime Chloride; Organophosphorus Compounds; Organothiophosphorus Compounds; Oximes; Paraoxon; Pralidoxime Compounds; Pyridines; Pyridinium Compounds; Time Factors