Comparison of bromisoval and carbromal in the rat

Abstract

Distribution experiments in vitro and in vivo with bromisoval and carbromal have shown carbromal to be more lipophilic and cumulative in brain and fat tissue. The half-life of bromisoval in the rat is approximately 2.5 h, that of carbromal is longer and variable. Stimulation and inhibition experiments revealed that both drugs are metabolized and follow different patterns. Carbromal toxicity is enhanced by bromide treatment, whereas bromisoval toxicity is not. The results show that carbromal is more toxic than bromisoval for the rat.The hypnotic bromocarbamides (or bromoureides) carbromal and bromisoval, introduced in the beginning of this century, have largely been superseded by the evolution of the barbiturate hypnotics except as household remedies in some countries. Being effective and apparently innocuous when used occasionally they gave little cause for worry. When, however, in the years after the Second World War misuse and abuse of drugs became more widespread, the chronic and acute toxicity of both bromocarbamides became a source for concern (Magnussen, 1947; Anonymous comment, 1947;Karber, 1952;Copas, Kay & Longman, 1959 ;Atkinson, 1960;Pihkanen & Harenko, 1962 ;van Heyst, 1966).As pharmacological and toxicological knowledge of both drugs was defective, some of their properties which were expected to be related to their toxicity have been investigated. The tissue distribution and relative lipid solubilities were determined. Plasma half-lives were estimated and their dependence on sex and other factors were assessed. As acute intoxication with bromocarbamides often follows a period of prolonged misuse, the influence of bromide intoxication on the toxicity of both drugs was also determined. E X P E R I M E N T A LMaterials. Bromisoval (Ph.Ned. Ed. VI) and carbromal (Ph.Ned. Ed.VI) were used and were shown to be pure by thin-layer chromatography. They were dissolved in propylene glycol B.P. for administration.Wistar rats of either sex, approximately 150 g were used and were obtained from the TNO animal breeding farm, Zeist, the Netherlands, or from the breeding department of our own institute (RIV).The bromocarbamide (5 mg) dissolved in deionized water (10 ml) was extracted for 4 h with an equal volume of organic solvent (nitrobenzene, chloroform, light petroleum b.p. SO-looo). Samples of both phases were taken, and the bromocarbamide content was determined as described by Rauws (1969), directly in the water phase and, after evaporation of the chloroform or light petroleum phase, in the residue taken up in water. After preceding alkaline hydrolysis of the bromocarbamide, the nitrobenzene phase was removed by steam distillation and bromide was determined in an aliquot of the aqueous residue. Animals.Partition coeficients.

Comparison of the Bromureide Sedative-Hypnotic Drugs, Bromvaletone (Bromisoval) and Carbromal, and Their Chloro Analogues in Mice

“…(bromism) resulting from chronic overdosage with these drugs (Rauws, 1969). We have investigated some non-bromo analogues of bromvaletone and carbromal to determine whether they shared the depressant actions on the central nervous system of the parent compounds since they might prove useful as sedative or mild hypnotic drugs without the particular disadvantage of the bromureides.…”