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New Approaches in Therapy of Poisoning with Organophosphorus Compounds 1 Thiermann H, 2Zilker T, 1Worek F. 1 Bundeswehr Institute of Pharmacology and Toxicology, Munich; 2 Toxicological Department of 2nd Medical Clinic, Technical University, Munich, Germany. Poisoning by organophosphorus compounds (OP) is a challenge to clinical toxicologists. While the group of pesticides exhibit usually moderate toxicity, the group of nerve agents belongs to synthetic compounds with the highest toxic potency. The most important common mechanism of OP-poisoning is the inhibition of acetylcholinesterase (AChE) resulting in cholinergic crisis and finally death due to respiratory arrest. Besides routine supportive care, e.g. artificial ventilation, restoration of cardiovascular insufficiency, fluid and electrolyte balance (e.g. sodium bicarbonate administration), specific antidotes, antimuscarinics and oximes, are available. Furthermore, neuroprotectives such as benzodiazepines are required to cope with seizures and long-lasting brain damage in nerve agent poisoning. Consensus regards atropine as the cornerstone in the treatment of OP-poisoning. The drug is able to antagonize competitively acetylcholine at muscarine receptors. Generally, titration according to clinical effects is recommended. The use of oximes, however, is a matter of debate and subject of extensive investigations. Both potency and efficacy of oximes to induce reactivation of AChE is dependent on both the specific OP-compound and the oxime. In general, AChE inhibited by the most widely used pesticides can be reactivated with the clinically used oximes pralidoxime and obidoxime with the latter generally needing lower concentrations for a comparable rate of reactivation. In recent years, substantial research in civilian organisations was directed at appropriate administration protocols. Oximes should be given continuously, at appropriate doses and as long as reactivation can be expected. However, the clinically used oximes reach their limits in poisoning by most nerve agents, e.g. VR, cyclosarin, tabun and soman, as well as with some pesticides, e.g. fenamiphos. Due to these gaps, extensive research programs have been initiated over the last decades and are still ongoing to identify more effective oximes. First of all, the main scope was directed at reactivation of soman-inhibited AChE. Meanwhile, broad spectrum oximes, with special regard to nerve agents, are in the focus. Among some possible candidates, e.g. MMB 4 and TMB 4, the two Hagedorn oximes HI 6 and HLö 7 are regarded as promising compounds. In the meantime, substantial data on HI 6 safety and efficacy are available enabling military services of several countries to aim for licensing of HI 6 autoinjectors. Unfortunately, HI 6 is quite ineffective in reactivation of AChE inhibited by most pesticides and tabun. Alternative strategies, primarily supported by military forces, were developed. The pre-inhibition of AChE by carbamates was shown to be effective in several animal models up to some 5 LD50 of nerve agents. At present, pyridostigmine is licensed by the FDA for pre-treatment of soman poisoning. In Europe, a patch containing the centrally acting physostimine/hyoscyamine is under advanced development. Another, also primarily military approach, is the pre-treatment with scavengers in order to neutralize the nerve agent before it reaches its target. Since the eighties in the last century a variety of proteins, e.g. human carboxylesterase, fetal bovine serum derived acetylcholinesterase, and human butyrylcholinesterase (HuBuChe), have been under investigation. Plasma derived and recombinant forms of HuBuChE were selected for advanced development and transition to clinical trials. These scavengers bind OP stoichiometrically. The prerequisite of sufficient scavenging function is high affinity and a low poison load. Since BuChE has a high molecular weight (about 86 kDa) a comparatively large quantity is required to neutralize an equimolar amount of nerve agent. Therapeutic effectiveness in suicidal pesticide poisoning cannot be expected. The scavenging capacity of native human blood BuChE (36 pmol/ml) and AChE (3 pmol/ml blood) does not play any role in pesticide poisoning where several mmol of OP are ingested. However, the detoxification rate may be increased dramatically when a combination of AChE and oxime is

used. For rapid detoxification A-esterases, such as paraoxonase type 1 (PON1) are under investigation. The velocity of the naturally occurring human serum enzyme appears to be too slow to afford significant protection. Thus, efforts are directed to modification of the active centre by site directed mutations in order to improve catalytic properties. Stability as well as stereoselectivity of these enzymes are a matter of fundamental research. The same holds true for AChE. Using comparable techniques, a more detailed knowledge of the relevant reactions at a molecular level should be attained and contribute to developing a scavenger that in combination with a nucleophile, e.g. an oxime, could provide rapid and broad spectrum detoxification. Other experimental studies are directed to interfering with different receptor systems potentially involved in OP poisoning, e.g. adenosine receptors or nicotine receptors. Furthermore, so called direct effects of high oxime concentrations were assumed to contribute to their effectiveness in animal experiments. However, these basic experimental approaches are not yet relevant for broad clinical use.

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Microsoft Word - ClinicalToxicology_2008-46-377_2.doc