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Objectives: Reactivation of inhibited acetylcholinesterase (ACHE) with oximes is a causal approach for therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when appropriate doses of oxime are administered as soon as possible and as long as reactivation can be anticipated. The proof of oxime effectiveness in intoxicated patients, however, is difficult due to atropinization, sedation, and artificial ventilation during the life-threatening phase of cholinergic crisis. Additionally, differences of individual courses during the acute phase of intoxication (e.g. amount and type of OP, time elapsing to first symptoms and treatment) result in different toxicokinetics and -dynamics (toxication and elimination of the poison as well as ageing). All these variables are obscure a clear look on oxime effectiveness. To unravel the characteristic oxime effect we analyzed the reactivation of AChE using red blood cells (RBC) as an accessible enzyme source that reflects synaptic ACHE. To foster the appropriateness of this approach, neuromuscular function was monitored following nerve stimulation. Based on these considerations a clinical trial was initiated according to ICH-GCP guidelines. 18 OP-intoxicated patients with life-threatening cholinergic crisis were included and received as specific treatment atropine at low dosage and obidoxime by continuous infusion. Methods: Obidoxime, 250 mg IV as bolus, followed by 750 mg/24h, was administered as long as reactivation was possible. Neuromuscular transmission was estimated after stimulation of the N. ulnaris by recording the compound muscle action potential of the M. abductor dig. V. RBC-AChE and plasma-BChE were determined by a modified Ellman procedure. Reactivatability was checked by incubating patient's RBC with obidoxime in vitro. Inhibitory activity as measure of poison load was assessed by incubation of donor RBC with patient's plasma. Plasma concentrations of obidoxime were determined by HPLC and of atropine with a radioreceptor assay. Results: Reactivation by about 10 [micro]M obidoxime was possible for about one week after intoxication with OPs leading to diethylphosphoryl-AChE. In contrast, due to fast ageing of dimethylphosphoryl-AChE, its reactivation was restricted to the first two days after intoxication. In both types, high poison load may result in faster reinhibition than reactivation of ACHE, thereby preventing net reactivation. Irrespective of the OP used, increase of inhibited RBC-AChE activity to values above 20 per cent of normal correlated with normal neuromuscular function and with reduced atropine demand. In cases with lethal outcome, death occurred several days after subsidence of cholinergic crisis, mostly due to preclinical complications (late resuscitation, aspiration followed by ARDS) and problems arising from long-lasting intensive therapy (e.g. cardiac infarction, lung emboli). Conclusions: To assess effectiveness of treatment with enzyme reactivators an exact individual judgment is necessary. The therapeutic effect of oximes can be clearly evaluated using neuromuscular function and cholinesterase status. In cases where an increase of RBC-AChE activity by more than 20% was observed an improvement of neuromuscular function occurred indicating therapeutic benefit. Oxime administration may be reasonable for up to one week in poisoning with diethyl-OPs, whereas oximes should be subsided on the second day after intoxication with dimethyl-OPs. Moreover, oximes should be administered as long as reactivation is possible. We feel that lethality alone, if not properly specified, is a poor parameter to judge effectiveness of oxime treatment., Thiermann H(1), Worek F(1), Szinicz L(1), Haberkorn M(2), Felgenhauer N(2), Zilker T(2), Kiderlen D(3), Krummer S(3), Eyer P(3). (1) Institut fuer Pharmakologie und Toxikologie, Sanitaetsakademie der Bundeswehr Garching-Hochbrueck, Germany; (2) [...]

Objectives: The lethality of acute intoxications with organophosphorus compounds (OP) is still high (approx. 40%). The inactivation of acetylcholinesterase (ACHE) during OP poisoning results from phosphorylation of the enzyme, which can be reversed by oximes. For monitoring the oxime effects we determined the erythrocyte AChE (Ery-AChE) status and applied electrophysiologic methods to control the neuromuscular transmission (NT) in order to reveal reactivation of the endplate AChE. Methods: In 9 cases of severe OP pesticide poisoning following suicide attempts, obidoxime was given as an IV bolus (250 mg) followed by continuous infusion of 750 mg/d. In all patients the NT studies were performed before and during oxime therapy. Supramaximal single and repetitive nerve stimulation (RNS; 3-50 Hz) were applied to the ulnaris nerve at the wrist using surface electrodes. The compound muscle action potential (CMAP) was recorded from the M. abductor digiti minimi. Results: In OP poisoning the RNS revealed a decrement or decrement-increment phenomenon, indicating neuromuscular dysfunction due to inactivation of AChE at the motor endplate. The single CMAP showed repetitive discharges. A dramatic electrophysiologic improvement was seen in 4 cases of parathion intoxication after obidoxime. One patient received 250 mg obidoxime initially upon primary care whereas the continuous infusion was started after 85 h; a reactivation was still possible. In 3 cases of intoxication with oxydemeton-methyl an improvement of the neuromuscular block after obidoxime was weak or absent, and reactivation of Ery-AChE was not observed. Conclusions: The efficacy of oximes in AChE reactivation can be determined using electrophysiologic methods. Because of rapid aging of the AChE-OP complex oxime therapy appears inappropriate in oxydemeton-methyl intoxications when given too late. In parathion poisoning even delayed continuous obidoxime infusion (up to 85 h) allowed reactivation up to 40% of normal. A correlation of Ery-AChE activity and NT seems to exist. Ery-AChE levels between 20 and 30% appear predictive for normal NT. Haberkorn M(1), Thiermann H(2), Eyer P(3), Felgenhauer N(1), Zilker Th(1) (1) Toxikologische Abteilung der II. Medizinischen Klinik, Technische Universitat, Ismaninger Strasse 22, 81664 Munchen, Germany (2) Institut fur Pharmakologie und Toxikologie, Sanitatsakademie der Bundeswehr, Ingolstadter Landstrasse 100, 85748 Garching, Germany (3) Walther-Straub-Institut fur Pharmakologie und Toxikologie, Nu[Beta]baumstrasse 26, 80336 Munchen, Germany