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Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig

Price, M.E., Docx, C.J., Rice, H., Fairhall, S.J., Poole, S.J.C., Bird, M., Whiley, L.ORCID: 0000-0002-9088-4799, Flint, D.P., Green, A.C., Timperley, C.M. and Tattersall, J.E.H. (2016) Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig. Toxicology Letters, 244 . pp. 154-160.

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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 1,1′-(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 kg−1) or the oxime HI-6 DMS (0–100 mg kg− 1), in combination with atropine and avizafone (each at 3 mg kg−1) 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 kg−1 (MB327) or 30 mg kg−1 (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10 mg kg−1 (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 kg−1 or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30 mg kg−1) 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.

Item Type: Journal Article
Publisher: Elsevier B.V.
Copyright: © 2015 Elsevier B.V.
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