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The substitution of either bromazepam, diazepam, methaqualone, mazindol, nortriptyline or bupropion for pentobarbital, in dependent rats, was assessed using a continuous drug infusion method. Male, Sprague-Dawley rats were made dependent on pentobarbital during 12 days of continuous, intraperitoneal, pentobarbital infusion. On Day 13, pentobarbital was replaced with either saline, vehicle, or one of the drugs of interest and rats were infused for 24 h. On Day 14, all rats were infused, for 24 h, with saline. Changes in both body weight and behavioral indices of withdrawal were assessed during Day 13 and 14. It was observed that bromazepam and methaqualone substituted for pentobarbital in a dose-dependent fashion. Diazepam also substituted in pentobarbital dependent rats but, inexplicably, the low dose of diazepam provided better substitution than did the higher dose. On the other hand, neither mazindol or nortriptyline substituted for pentobarbital and there was a tendency for exacerbation of the withdrawal signs. Finally, it was noted that the low dose of bupropion appeared to decrease the severity of the withdrawal symptoms. The data supports the view that the substitution of compounds for pentobarbital, in dependent rats, is limited to those compounds which, presumably, possess similar mechanisms of action in the CNS.

Low passage-number cultured Chinese hamster cells were used to assess the ability of four benzodiazepines, namely diazepam, medazepam, midazolam and bromazepam, to induce numerical and structural chromosome aberrations. It was observed that diazepam, medazepam and midazolam treatment produced dose-dependent reductions in the number of diploid cells, with medazepam and midazolam inducing significant levels of hyperdiploidy and diazepam inducing low levels of hypodiploidy (at toxic doses). In contrast, bromazepam-treated cultures showed no significant changes in the level of aneuploidy even when exposed to toxic concentrations. All four sedatives were seen to induce low levels of chromosome aberrations, with bromazepam showing the most potent effect (albeit at a single toxic dose). These observations indicate that these structurally related benzodiazepines could be regarded as potentially genotoxic.

The laboratories reported data on CPDD 1 that was indeed very similar to that of their direct or historical controls for diazepam. It is clear that the antagonists used in the program will reverse only a benzodiazepine-induced behavioral effect. The data on bromazepam suggest a very similar pattern and potency for this benzodiazepine compared to diazepam.