Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients

Abstract

<jats:p> 1 The effectiveness of oxime therapy in organophos phate poisoning is still a matter of debate. It appears, however, that the often cited ineffectiveness of oximes may be due to inappropriate dosing. By virtue of in vitro findings and theoretical considerations we concluded in the preceding paper that oximes should preferably be administered by continuous infusion following an initial bolus dose for as long as reactiva tion of inhibited acetylcholinesterase (AChE) can be expected. This conclusion has called for a clinical trial to evaluate such oxime therapy on the basis of objective parameters. </jats:p><jats:p> 2 Before transfer to the intensive care unit (ICU), 5 patients received primary care by an emergency physician. In the ICU, atropine sulphate was adminis tered IV upon demand according to the endpoints: no bronchorrhoea, dry mucous membranes, no axillary sweating, heart rate of about 100/min. Obidoxime (Toxogonin®) was given as an IV bolus (250 mg) followed by continuous infusion of 750 mg/24 h. </jats:p><jats:p> 3 Intoxication and therapy were monitored by determin ing erythrocyte AChE (eryAChE) activity, reactivat ability of the patient's eryAChE ex vivo, plasma cholinesterase activity, the presence of AChE inhibit ing compounds, as well as the concentrations of obidoxime and atropine in plasma. </jats:p><jats:p> 4 Obidoxime was effective in life-threatening parathion poisoning, in particular when the dose absorbed was comparably low. In mega-dose poisoning, net reacti vation was not achieved until several days after ingestion, when the concentration of active poison in plasma had declined. Reactivatability in vivo lasted for a longer period than expected from in vitro experiments. </jats:p><jats:p> 5 Obidoxime was quite ineffective in oxydemeton- methyl poisoning, when the time elapsed between ingestion and oxime therapy was longer than 1 day. When obidoxime was administered shortly after ingestion (1 h) reactivation was nearly complete. </jats:p><jats:p> 6 Obidoxime levels of 10-20 μM were achieved by our regimen, and atropine could rapidly be reduced to approx. 20 nM, as attained by continuous infusion of 1 mg atropine sulphate/h. Maintenance of the desired plasma levels was not critical even when renal function deteriorated. </jats:p><jats:p> 7 Signs of transiently impaired liver function were observed in patients who showed transient multi- organ failure. In the present stage of knowledge, we feel it advisable to keep the plasma concentration of obidoxime at 10 - 20 μM, although the full reactivating potential of obidoxime will not then be exploited. Still, the reactivation rate, with an apparent half-time of some 3 min, is twice that estimated for a tenfold higher pralidoxime concentration. </jats:p>

Red Blood Cell Acetylcholinesterase and Plasma Butyrylcholinesterase Status: Important Indicators for the Treatment of Patients Poisoned by Organophosphorus Compounds

“…Moreover, enormous differences between species have to be considered (12). Based on reaction constants derived from experiments with human RBC-AChE, reasonable plasma concentrations of oximes for reactivation of insecticide as well as nerve agentinhibited AChE can be calculated (2,11,(13)(14)(15)(16)(17)(18)(19). Results indicate that AChE inhibited by most nerve agents and insecticide OPs can be reactivated with obidoxime at a plasma concentration of approximately 10 µmol L -1 .…”

“…bolus dose of 250 mg, followed by 750 mg of obidoxime per day. In actual emergency situations, this regimen proved effective in reactivating AChE inhibited by insecticide OP (11,16,20).…”

“…artificial ventilation, sedation). To monitor the course of poisoning in OP-poisoned patients, a laboratory test system, called cholinesterase status, was developed (16,22) and used in intensive care units ( Figure 1) (11,20,23,24). The cholinesterase status consisted of:…”

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

“…The obidoxime treatment of OPP poisoned patients was better reported. The combined obidoxime-atropine treatment was effective in patients poisoned by smaller doses of parathion, while the poisoning by the high dose of parathion was not successfully reactivated until parathion levels declined (Thiermann 1997). In the same study, obidoxime was reported as ineffective for oxydemetonmethyl poisoning, but the time elapsed between ingestion and oxime therapy was longer than one day (Thiermann 1997).…”

“…The combined obidoxime-atropine treatment was effective in patients poisoned by smaller doses of parathion, while the poisoning by the high dose of parathion was not successfully reactivated until parathion levels declined (Thiermann 1997). In the same study, obidoxime was reported as ineffective for oxydemetonmethyl poisoning, but the time elapsed between ingestion and oxime therapy was longer than one day (Thiermann 1997). The enzyme-based assay for quantification of paraoxon in blood of parathion poisoned patients confirmed significant obidoxime reactivation of low plasma paraoxon concentration, whilst diethylphosphoryloxime formation during obidoxime-induced reactivation did not markedly contribute to the reinhibition of AChE (Eyer 1998).…”