Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5859860 | Toxicology Letters | 2016 | 7 Pages |
Abstract
Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1â²-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113 mg kgâ1) or the oxime HI-6 DMS (0-100 mg kgâ 1), in combination with atropine and avizafone (each at 3 mg kgâ1) was administered to guinea-pigs 1 min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p < 0.01) at the 33.9 mg kgâ1 (MB327) or 30 mg kgâ1 (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10 mg kgâ1 (i.m.), MB327 DMS reached plasma Cmax of 22 μM at 12 min with an elimination t1/2 of 22 min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100 mg kgâ1 or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30 mg kgâ1) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30 min, although the animals remained incapacitated to 4 h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision.
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Authors
Matthew E. Price, Cerys J. Docx, Helen Rice, Sarah J. Fairhall, Sarah J.C. Poole, Michael Bird, Luke Whiley, Daniel P. Flint, A. Christopher Green, Christopher M. Timperley, John E.H. Tattersall,