Efficacy of the antinicotinic compound MB327 against soman poisoning – Importance of experimental end point

Abstract Medical countermeasures for acute poisoning by organophosphorus nerve agents are generally assessed over 24 h following poisoning and a single administration of treatment. At 24 h, the antinicotinic bispyridinium compound MB327 (1,10-(propane-1,3-diyl)bis(4- tert -butylpyridinium)) dimethanesulfonate is as effective as the oxime HI-6 against poisoning by soman, when used as part of a treatment containing atropine and avizafone. In this study, we hypothesised that an earlier endpoint, at 6 h, would be more appropriate for the pharmacokinetics and mechanism of action of MB327 and would therefore result in improved protection. MB327 diiodide (33.8 mg/kg) or the oxime HI-6 DMS (30 mg/kg), in combination with atropine and avizafone (each at 3 mg/kg) was administered intramuscularly to guinea pigs 1 min following subcutaneous soman and the LD 50 of the nerve agent was determined at 6 h after poisoning for each treatment. The treatment containing HI-6 gave a similar level of protection at 6 h as previously determined at 24 h (protection ratios 3.9 and 2.9, respectively). In contrast, the protection achieved by treatment containing MB327 showed a striking increase at 6 h (protection ratio >15.4) compared to the 24 h end point (protection ratio 2.8). The treatment gave full protection for at least 5 h against doses of soman up to 525 μg/kg; in contrast, mortality began in animals treated with HI-6 after 1 h. This study demonstrates the importance of using an appropriate end point and has shown that treatment including MB327 was far superior to oxime-based treatment for poisoning by soman, when assessed over a pharmacologically-relevant duration. The improved outcome was seen following a single dose of treatment: it is possible that additional doses to maintain therapeutic plasma concentrations would further increase survival time. Antinicotinic compounds therefore offer a promising addition to treatment, particularly for rapidly aging or oxime-insensitive nerve agents.