Protective Effect of Reversible Cholinesterase Inhibitors

Nerve agents are among the most dangereous chemical warfare agents (3, 29, 40, 45). They can be (and have been) misused by terrorists (4, 31). Moreover, the whole spectrum of these agents of the same basic chemical structure covers organophosphorus insecticides (OP) – chemicals easily available, frequently used over the world and causing professional, suicidal or accidental intoxications (4). All these facts underline the necessity to study these agents to achieve better diagnosis, prophylaxis and treatment. Sarin, soman, tabun, and VX etc. are the most important representatives of the nerve agents. Keeping acetylcholinesterase (AChE, EC 3.1.1.7) – the main target for nerve agent action – intact is a basic requirement for effective prophylaxis. It can be achieved using reversible inhibitors which are able to inhibit AChE reverzíbly, and after spontaneous recovery of the activity (decarbamylation), normal AChE serves as a source of the active enzyme. Pyridostigmine and other carbamates were tested as the most promising prophylactic drugs (e.g. 3, 14, 16, 33). Pyridostigmine was introduced into some armies as a prophylactic antidote against nerve agents. Its prophylactic effect (like the effects of other carbamates) is limited by its dose. With a higher dose, a higher efficacy was observed, but the side effects were more expressed too (for a review, see 3, 5, 33). This problem can be solved by adding pyridostigmine antagonizing drugs – anticholinergics. The prophylactic combination of pyridostigmine with trihexyphenidyle and benactyzine called PANPAL was introduced into the Czech Army (3, 14). The presence of these two anticholinergics allowed us to increase the pyridostigmine dose and to increase its prophylactic efficacy. Structurally different drugs/inhibitors were also studied. Petroianu et al. (34, 37) compared pretreatment with pyridostigmine and tiapride against paraoxon intoxication. The best results were achieved with pyridostigmine pretreatment only. Some protective effects against paraoxon were achieved by pretreatment with ranitidine (35) or metoclopramide (21). From other studies of compounds preferably binding to the AChE anionic site, tacrine, 7-methoxytacrine (7-MEOTA) and huperzine A were considered and experimentally studied with respect to prophylaxis against nerve agents in vitro and in vivo (3, 6, 17, 27, 33). Diminishing the level of OP using enzymes which hydrolyze these agents or enzymes which bind the agents (to specific proteins or to antibodies) and thus reducing the OP level and inhibition of cholinesterases – AChE and butyrylcholinesterase (BuChE, EC 3.1.1.8) (scavenger effect) – in the organism can be described as detoxification (11, 12, 41, 42). Another approach to prophylaxis is based on using present antidotes, especially reactivators such as HI6 and other drugs (3, 5, 15). New reversible inhibitors of acridine type or naturally occurring agents are being studied (3, 5, 32, 33). The aim of this present study was to compare the prophylactic effect of reversible acridine inhibitor – tacrine (1,2,3,4-tetrahydroaminoacridine) and its combinations with presently used prophylactics and equine butyrylcho-