Prophylaxis by a reversible cholinesterase inhibitor and the NMDA receptor antagonist treatment as combinatorial countermeasure against nerve agent poisoning in mice model

Abstract

The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (K1959) and the therapeutic efficacy of a novel NMDA receptor antagonist (K2060) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed. The novel dually acting prophylactic drug (K1959) did not bring any additional benefit compared to the commonly used pyridostigmine. By contrast, an increase in the therapeutic efficacy of classic antidotal treatment was observed when the novel NMDA receptor antagonist (K2060) was combined with commonly used antidotes (oxime reactivator in combination with atropine). This novel combination reduced the acute toxicity of tabun, soman, and sarin more than two-fold, four-fold, and five-fold, respectively. These results highlight the possibility of NMDA antagonists such as K2060 as a supportive drug for the classic therapy of organophosphorus poisoning.