Promethazine as a Novel Prophylaxis and Treatment for Nerve Agent Poisoning

摘要

The present study evaluated promethazine, an FDA-approved antihistamine, for treating the toxic effects of soman (GD). Male Sprague- Dawley rats, weighing 240-300 g, were pretreated 30 minutes prior to or treated less than or equal 1 minute after GD administration (180 mg/kg, sc) with promethazine alone (40 mg/kg, ip) or in combination with oxime reactivator HI-6 (125 mg/kg, ip) and atropine methylnitrate (AMN; 2.0 mg/kg, im). The incidence of convulsions, percentage of mortality, and extent of neuropathology were assessed during the first 24 hour following soman exposure. Promethazine given as a pretreatment or treatment in combination with HI-6 and AMN was effective in reducing the occurrence of convulsions, the incidence of mortality and the development of brain pathology in the piriform cortex, laterodorsal thalamus, basolateral amygdala, dentate hilus and lateral cortex, which are brain regions known to be vulnerable to GD-induced damage. HI-6 pretreatment and AMN treatment without promethazine did not prevent the development of convulsions, improve survival or reduce brain damage in GD-exposed animals. Promethazine given alone as either a pretreatment or treatment also significantly reduced the incidence of convulsions, improved mortality rate and prevented brain pathology in all five brain regions examined. These observations suggest that promethazine is effective in preventing GD-induced convulsions, death and brain pathology, which are all medical challenges of severe nerve agent exposure. The present study provided strong evidence that promethazine either used as an adjunct or alone is an effective countermeasure against GD poisoning. Moreover, as an FDA-approved drug, promethazine could be transitioned quickly from the laboratory to the public without the need for conducting clinical safety trials.