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

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

Furosemide in the treatment of phosgene induced acute lung injury

Method: Using previously validated methods, 16 anaesthetised large white pigs were exposed to phosgene (target inhaled dose 0.3 mg kg(-1)), established on mechanical ventilation and randomised to treatment with either nebulised furosemide (4 ml of 10 mg x ml(-1) solution) or saline control. Treatments were given at 1, 3, 5, 7, 9, 12, 16 and 20 hours post phosgene exposure; the animals were monitored to 24 hours following phosgene exposure.Results: Furosemide treatment had no effect on survival, and had a deleterious effect on PaO2: FiO2 ratio between 19 and 24 hours. All other measures investigated were unaffected by treatment.Conclusion: Nebulised furosemide treatment following phosgene induced acute lung injury does not improve survival and worsens PaO2: FiO2 ratio. Nebulised furosemide should be avoided following phosgene exposure<br/