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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) [...]

Background: Arsenic, the 50th most abundant element of the earth crust, is an ubiquitously distributed contaminant of the environment including air, water and soil. Some areas in Argentina, Chile, Taiwan, India and Bangladesh are strongly contaminated leading to chronic arsenic poisoning in the population. Medicinal and homicidal use of arsenicals is known since ancient times. Agricultural (herbicides, rodenticides, pesticides) and industrial (smelters, alloys, glass) uses are declining, but are still an important source of poisoning. A newer source is semiconductor production (gallium arsenide). Arsine, a non-irritant gas with a slight garlic odor can be formed in the processing of metals containing arsenic and is used in gallium arsenide production. Four to six hours after exposure it can cause depletion of glutathione stores in erythrocytes, and hemolysis. The mechanism of effect is not understood and no specific therapy is known. Exchange transfusion and hemodialysis may become necessary in the case of hemolysis.[1] Pentavalent organic and inorganic arsenicals exhibit a much lower toxicity compared to the trivalent compounds. It is proposed that the toxicity of pentavalent arsenicals may be attributed at least partly to their trivalent metabolites.[2] Trivalent arsenicals: The highest toxicological relevance is attributed to organic and inorganic compounds containing trivalent arsenic with at least two reactive binding sites, such as sodium arsenite and the chemical warfare agent chlorovinylarsinedichloride (Lewisite). These compounds form stable rings with molecules bearing adjacent SH groups[3]. The author postulated the pronounced cytotoxicity of these compounds to be based on their reaction with the dihydrolipoyl moiety of pyruvate dehydrogenase, leading to inhibition of carbohydrate metabolism in the citric acid cycle, acetyl coenzyme A depletion, and thereby reduced oxygen consumption and ATP formation. An early consequence of citric acid cycle impairment was shown to be gluconeogenesis inhibition in the main gluconeogenic tissues (hepatocytes and kidney tubules) of rats and mice.[4] In agreement, Berry and Smythe[5] showed complete carbohydrate depletion (glycogen and glucose) in mice dying by arsenite poisoning and Reichl et al.[6] demonstrated improved survival after glucose treatment indicating glucose solutions to be useful in arsenic poisoning. In this context it is interesting to note that sodium arsenite as well as Lewisite only poorly penetrate the blood-brain barrier, the concentration of arsenic in the brain being much lower as compared to the tissues, especially liver and kidney[7]. This is not well in agreement with signs of CNS damage (seizures) caused directly by arsenic, indicating secondary effects are involved i.e. capillary (endothelial) damage or hypoglycemia. Treatment: Peters[3] and Whittaker[8] recognized early that the five-membered ring of dithiols with arsenic is more stable than the six-membered with dihydrolipoic acid and introduced 2,3-dimercapto-1-propanol (dimercaprol; BAL) in the treatment of arsenical poisoning to mobilize the poison from the tissues and increase renal elimination. The relatively high toxicity of BAL with local and systemic side-effects and only the IM route for treatment soon stimulated a search for more adequate compounds. At present the best investigated compounds are 2,3-dimercapto-1-propane sulfonate (DMPS) and 2,3-dimercaptosuccinic acid (DMSA).[9,10] DMSA is an approved drug in the USA (p.o.) and DMPS in Germany (p.o., IM, IV). A serious disadvantage with BAL is the finding of increased arsenic content in the brain of treated animals not observed with DMPS and DMSA.[10,11] The significance of this finding has not yet been elucidated but in patients treated with BAL polyneuropathy is not uncommon and progression of neurological complications during therapy has been reported.[12] In contrast, in severe cases of arsenic poisoning treated with DMPS,[13] polyneuropathy was not found and recovery following IV DMPS treatment was reported in a patient with polyneuropathy requiring ventilatory support.[14] As oral DMSA given before was ineffective, the route of treatment might have been decisive in this patient. In the Toxicology Department of the Technical University in Munich, 6 patients with arsenic poisoning were treated with BAL since 1984, 4 survived, one developed neuropathy. Three patients were treated with DMPS, all survived and none developed neuropathy. Interestingly, the patient with neuropathy (treated with BAL) showed much lower serum arsenic concentrations (0.55 mg/ L at admission) than the patient with the highest serum level treated with DMPS (2.24 mg/L at admission). The time of initiating BAL treatment relative to the end of exposure to arsenicals is important for its efficacy.[15] Oral DMSA had no effect on arsenic elimination in subjects terminating the exposure 1 to 5 months before treatment[16] These findings indicate that irreversible tissue changes or mechanisms not primarily based on reactions with adjacent SH groups were involved. Extracorporeal elimination techniques (EET): In two patients with arsenic poisoning (see above), one with BAL the other with DMPS treatment[17] hemodialysis-hemoperfusion or hemodialysis and CAVHDF was assessed. In both patients kidney function was not impaired and the arsenic portion removed by EET was negligible. The results are in agreement with the findings and conclusions of Vaziri et al.[18] Elimination enhancement: Arsenic is mainly eliminated by the kidney, but treatment with DMPS increases biliary excretion. Experimental data in guinea pigs show that by inhibiting enterohepatic circulation, i.e. by i.p. and p.o. treatment with DMPS the latter combined with oral cholestyramine, fecal arsenic excretion could be increased from 6 to 18.5% of the dose administered, the increase in renal excretion by i.p. and p.o. DMPS (14 to 33.4%) remaining unchanged.[19] Hypotension: Vomiting, diarrhea, capillary leak, myocardial dysfunction, and decreased peripheral resistance may lead to severe hypotension and shock needing careful attention to electrolyte and fluid balance. Conclusions: Besides arsine and the organic trivalent irritants, the main risk from arsenicals is due to trivalent compounds with two reactive binding sites. Hypoglycemia by gluconeogenesis inhibition may become a serious problem, masked by stress-induced hyperglycemia. Elimination enhancement by chelating dithiols is the main specific and effective treatment in arsenic poisoning, DMPS and DMSA are similarly effective, both being superior and safer than BAL in arsenic poisoning. DMPS has the advantage of IV injection. Extracorporeal elimination enhancement procedures are useful only in patients with impaired renal function. Experimental data in guinea-pigs indicate that a further increase in elimination is possible by enhancement of faecal excretion using oral DMPS with cholestyramine in combination with parenteral DMPS. References: [1] Hall AH. Arsenic and arsine. In: Clinical Management of Poisoning and Drug Overdose. Haddad LM, Shannon MW, Winchester JF, eds., Philadelphia, Pennsylvania: WB Saunders Co. 1988. [2] Vahter M, Marafante E. Intracellular interactions and metabolic fate of arsenite and arsenate in mice and rabbits. Chem Biol Interact 1983;47:29-44. [3] Peters RA. Biochemistry of some toxic agents. I. Present state of knowledge of biochemical lesions induced by trivalent arsenical poisoning. Bull John Hopkins Hosp 1955;97:1-20. [4] Szinicz L, Forth W. Effect of [As.sub.2][O.sub.3] on gluconeogenesis. Arch Toxicol 1988;61:444-449. [5] Berry LJ, Smythe DS. Carbohydrate metabolism in normal and altitude-exposed mice following arsenite poisoning. Am J Physiol 1959;197: 37-40. [6] Reichl FX, Szinicz L, Kreppel H, Fichtl B, Forth W. Effect of glucose in mice after acute experimental poisoning with arsenic trioxide ([As.sub.2][O.sub.3]). Arch Toxicol 1990;64:336-338. [7] Inns RH, Bright JE, Marrs TC. Comparative acute systemic toxicity of sodium arsenite and dichloro(2-chlorovinyl)arsine in rabbits. Toxicology 1988;51:213-222. [8] Whittaker VP. An experimental investigation on the `ring hypothesis' of arsenical toxicity. Biochem J 1947;41:56-62. [9] Aposhian HV, Carter DE, Hoover TD, Hsu CA, Maiorino RM, Stine E. DMSA, DMPS, and DMPA-as arsenic antidotes. Fundam Appl Toxicol 1984;4:58-70. [10] Kreppel H, Reichl FX, Szinicz L, Fichtl B, Forth W. Efficacy of various dithiol compounds in acute [As.sub.2][O.sub.3] poisoning in mice. Arch Toxicol 1990;64:387-392. [11] Hoover TD, Aposhian HV. BAL increases the arsenic-74 content of rabbit brain. Toxicol Appl Pharmacol 1983;70:160-162. [12] Rezuke WN, Anderson C, Pastuszak WT, Conway SR Firshein SI. Arsenic intoxication presenting as a myelodysplastic syndrome: a case report. Am J Hematol 1991;36:291-293. [13] Moore DF, O'Callaghan CA, Berlyne G, et al. Acute arsenic poisoning: absence of polyneuropathy after treatment with 2,3-dimercaptopropanesulphonate (DMPS). J Neurol Neurosurg Psychiatry 1994;57:1133-1135. [14] Wax PM, Thornton CA. Recovery from severe arsenic peripheral neuropathy with DMPS. J Toxicol Clin Toxicol 1996;34:587. [15] Ford MD, Arsenic. In: Goldfrank's Toxicologic Emergencies, Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RS, eds., Stamford, Connecticut, Appleton & Lange, 1998. 1261-1273. [16] Angle CR, Centeno JA, Guha Mazumder DN. DMSA, DMPS treatment of chronic arsenicism. J Toxicol Clin Toxicol 1998;36:495. [17] Zilker T, Felgenhauer N, Pfab R, Drasch G, Roider G, Roos G. Little effect of hemodialysis and CAVHDF on the elimination of arsenic compared to DMPS treatment. J Toxicol Clin Toxicol 1999;37:400. [18] Vaziri ND, Upham T, Barton CH. Hemodialysis clearance of arsenic. J Toxicol Clin Toxicol 1980;17: 451-456. [19]Reichl FX, Hunder G, Liebl B, Fichtl B, Forth W. Effect of DMPS and various adsorbents on the arsenic excretion in guinea-pigs after injection with [As.sub.2][O.sub.3]. Arch Toxicol 1995;69:712-717. Szinicz L(1), Mueckter H(2), Felgenhauer N(3), Zilker Th(3) (1) Institut fuer Pharmakologie und Toxikologie, Sanitaetsakademie der Bundeswehr, BSW, Garching, Germany (2) Walther-Straub-Institut fuer Pharmakologie und Toxikologie, Ludwig-Maximilians Universitaet Muenchen, Germany (3) Toxikologische Abteilung der II. Medizinischen Klinik, Technische Universitaet Muenchen, Klinikum rechts der Isar, Muenchen, Germany

Objectives: Oximes are used to reactivate inhibited acetylcholinesterase (ACHE) in patients intoxicated with organophosphorus compounds (OPs). For this purpose, oximes are to be administered at appropriate dose as soon as [...]