Protective Effects of Midazolam and MMB‐4 plus Atropine Sulfate in Nerve Agent Intoxication

This study utilized the guinea pig nerve agent‐seizure model to measure the protective effectiveness of midazolam, a more rapidly acting benzodiazepine, and of MMB‐4, a more efficacious oxime ChE reactivator, in comparison with current antidotes 2‐PAM and diazepam. One week after implantation of cortical electroencephalographic (EEG) electrodes, animals were pretreated with pyridostigmine bromide (0.026 mg/kg, im) 30 min prior to exposure to a 2.0 × LD50 subcutaneous dose of a nerve agent (GB, GD, GF, or VX). One min after agent exposure, animals were treated im with atropine sulfate (0.1 mg/kg) and either 2‐PAM (25 mg/kg) or MMB‐4 (26 mg/kg). At the onset of EEG seizures, a dose of diazepam (range 1.0–10.0 mg/kg, im) was administered to those animals treated with 2‐PAM or a dose of midazolam (range 0.5–5.0 mg/kg, im) to animals treated with MMB‐4. The anticonvulsant ED50 dose of midazolam (in the presence of MMB‐4) or diazepam (in the presence of 2‐PAM) was determined. The MMB‐4/midazolam combination therapy produced similar (against GD) or significantly better (against GB, GF and VX) anticonvulsant effects than did the 2‐PAM/diazepam therapy. The MMB‐4/midazolam combination also reduced the latency to seizure termination, especially in the GF‐exposed group. These results demonstrate the effectiveness of the MMB‐4/midazolam combination over current therapy for improved protection against nerve agents.