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Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.
Price, Matthew E; Docx, Cerys J; Rice, Helen; Fairhall, Sarah J; Poole, Sarah J C; Bird, Michael; Whiley, Luke; Flint, Daniel P; Green, A Christopher; Timperley, Christopher M; Tattersall, John E H.
Afiliación
  • Price ME; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. Electronic address: meprice1@dstl.gov.uk.
  • Docx CJ; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Rice H; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Fairhall SJ; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Poole SJC; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Bird M; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Whiley L; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Flint DP; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Green AC; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Timperley CM; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
  • Tattersall JEH; Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Toxicol Lett ; 244: 154-160, 2016 Feb 26.
Article en En | MEDLINE | ID: mdl-26325216
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 1,1'-(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 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22µM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Intoxicación / Compuestos de Piridinio / Soman / Antagonistas Nicotínicos / Agentes Nerviosos / Antídotos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Toxicol Lett Año: 2016 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Intoxicación / Compuestos de Piridinio / Soman / Antagonistas Nicotínicos / Agentes Nerviosos / Antídotos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Toxicol Lett Año: 2016 Tipo del documento: Article