Evaluation of the benefit of the bispyridinium compound MB327 for the antidotal treatment of nerve agent-poisoned mice

Abstract

The potency of the bispyridinium non-oxime compound MB327 [1,1′-(propane-1,3-diyl)bis(4-tert-butylpyridinium) diiodide] to increase the therapeutic efficacy of the standard antidotal treatment (atropine in combination with an oxime) of acute poisoning with organophosphorus nerve agents was studied in vivo. The therapeutic efficacy of atropine alone – or atropine in combination with an oxime, MB327, or both an oxime and MB237 – was evaluated by the determination of LD₅₀ values of several nerve agents (tabun, sarin and soman) in mice with and without treatment. The addition of MB327 increased the therapeutic efficacy of atropine alone, and atropine in combination with an oxime, against all three nerve agents, although differences in the LD₅₀ values only reached statistical significance for sarin. In conclusion, the addition of the compound MB327 to the standard antidotal treatment of acute poisonings with nerve agents was beneficial regardless of the chemical structure of the nerve agent, although at the dose employed, MB327 in combination with atropine, or atropine and an oxime, provided only a modest increase in protection ratio. These results from mice, and previous ones from guinea-pigs, provide consistent evidence for additional, albeit modest, efficacy resulting from the inclusion of the antinicotinic compound MB327 in standard antidotal therapy. Given the typically steep probit slope for the dose–lethality relationship for nerve agents, such modest increases in protection ratio could provide significant survival benefit.

• Atropine
• MB327
• mice
• nerve agents
• oximes

Acknowledgements

The authors would like to thank to Mrs Jana Uhlirova for her skillful technical assistance.

Declaration of interest

The study was funded by a grant from the Czech Ministry of Defence called “Long-term organization development plan 1011”. The authors report no declarations of interest.