engleski

Oximes as antidotes in therapy against tabun poisoning

To the present time, only four pyridinium oximes, TMB-4, 2-PAM, HI-6 and obidoxime, have found clinical application in the therapy of organophosphorus compounds poisoning. Treatment with these oximes still has disadvantages, in example ; they all have limited reactivation potency in nerve agent tabun poisoning. We tested different oximes varying in structure to find more effective oximes to reactivate tabun inhibited human erythrocyte AChE. Two of our tested pyridinium oximes, K048 and K074, were the most promising for AChE reactivation with the overall reactivation rate constants (kr) of 673 and 2375 M-1min-1, respectively. Oximes are also reversible inhibitors of AChE and in that way exhibit protection against phosphorylation by tabun. Therefore, we tested K048 and K074 in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. The highest TF and TD (22.5 and 10.0, respectively) were obtained when we applied K048 in a dose of 25 % of its LD50 in pretreatment and treatment. This is a considerable increase in protection of mice compared to K048 treatment alone (TF = 8.0, TD = 5.0). Whatever are the shortcomings of using the reversible inhibitors as protectors, we have shown that already promising treatment in tabun poisoning by oximes and atropine could be significantly improved if oximes are also used in pretreatment. This finding may provide a platform for further modifications and development of more potent protectors and reactivators in organophosphorus compounds poisoning.

oximes; antidotes; theraphy; pretreatment; tabun; K048; K074

nije evidentirano