The Efficacy of the Czech Original Prophylactic Mixture, Called Panpal, as Pharmacological Pretreatment of Tabun or Soman-poisoned Rats and Mice

The potency of the Czech original pharmacological pretreatment consisting of pyridostigmine, benactyzine and trihexyphenidyle, designated PANPAL, to increase the resistance of rats and mice against tabun or soman and to increase the therapeutic efficacy of standard antidotal treatment of tabun or soman-poisoned experimental animals was studied and compared with commonly used pyridostigmine alone. While PANPAL significantly increased the resistance of animals against tabun or soman and increased the efficacy of currently used antidotal treatment of tabun or soman poisoning, pyridostigmine alone was not able to sufficiantly protect experimental animals against tabun or soman-induced acute toxicity. Our findings confirm that PANPAL, lincensed and introduced to the Czech Army, seems to be promising and beneficial pharmacological pretreatment in the case of the threat of exposure to nerve agents, especially tabun or soman. It appears to be more suitable than currently used pyridostigmine alone. INTRODUCTION Despite of the entry into force in April 1997 of the Chemical Weapons Convention forbidding the production, storage and use of chemical warfare agents, the world has seen a rapid proliferation of such agents. Till now, highly toxic organophosphorus compounds (OPs), called nerve agents, are considered to be the most dangerous chemical warfare agents. They pose potential neurotoxic threats to both military and civilian populations, as evidenced in recent terroristic attacks (1) as well as occupational hazard to individuals exposed to certain organophosphorus insecticides. OPs toxicity results from the irreversible binding to and inactivation of acetylcholinesterase (AChE, EC 3.1.1.7) and subsequent acetylcholine (ACh) accumulation leading to severe respiratory distress, prolonged limbic seizures, convulsive status and death (2,3). The current standard treatment for poisoning by OPs consists of the combined administration of atropine sulfate and AChE reactivators (oximes). Atropine blocks the effects of overstimulation by accumulated ACh at muscarinic receptor sites while AChE reactivators (generally nucleophilic compounds with high affinity for phosphorus) repair the biochemical lesion by dephosphonylation of AChE molecule and restore its activity (2-4). Unfortunately, some OP compounds, especially soman and tabun, were found to be resistant to standard antidotal treatment. The relatively unsatisfactory treatment available for acute tabun and soman poisoning has prompted study of pretreatment possibilities that allow survival and increase resistance of organisms exposed to nerve agents. Currently used method of protection against nerve agent poisoning is the use of pyridostigmine bromide, a reversible carbamate AChE inhibitor (5). The prophylactic effect of pyridostigmine can result from its reversible inhibition of AChE. It binds a small fraction of AChE in the periphery and reversibly shields it from irreversible inhibition by nerve agents (6). However, pyridostigmine-induced increase in the level of ACh can itself cause symptoms of poisoning. Therefore, it would be useful to counteract the effects of the accumulated ACh by using anticholinergic drugs. In addition, the combination of pyridostigmine with anticholinergic drugs allows the dose of pyridostigmine that is otherwise limited by symptoms cause by elevated level of ACh to be increased and results in higher prophylactic efficacy than that observed for pyridostigmine alone (7,8). One of these mixtures, pyridostigmine in combination with benactyzine (BNZ) and