Chlordiazepoxide toxicity

It was conclusively shown that deoxychlordiazepoxide (393) had none of the phototoxic properties of the parent drug, at least in the rat [225]. Chlordiazepoxide, demethylchlordiazepoxide, demoxepam and diazepam-4-oxide were all phototoxic to a bacterial cell preparation. There was a close relationship between the phototoxicities of the A-oxides and the toxicity in the dark of their oxaziridines. The reduced forms of the four compounds were not phototoxic [ 228 ]. Kinetic studies demonstrated that the oxaziridine (390) covalently bonds to plasma proteins. The half-life of the oxaziridine in the presence of high concentrations of protein was about 30 min. It therefore has time not only to bind to biomolecules in the skin surface, but also to attack internal organs. This was put forward as the explanation of previously observed kidney and liver damage in the rat [229]. 

Oxazepam is similar to chlordiazepoxide in terms of pharmacological properties however, it has a somewhat less harsh effect, is less toxic, and exhibits a less expressed myorelax-ant effect. It is often tolerated better by patients than other tranquilizers. It is used in neurosis, conditions of anxiety, fear, stress, trouble falhng asleep, and psychovegatative disorders. The most common synonyms are nozepam and tazepam. 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

Toxicity. Toxic reactions may be produced by plasma concentrations greater than 3 pg/ml plasma concentrations in the region of 20 pg/ml may produce coma or death, but fatalities caused by chlordiazepoxide alone are rare. Recoveries have occurred after the ingestion of single doses of about 2 g. 

An isolated report describes temazepam toxicity due to disulfiram. The serum levels of chlordiazepoxide and diazepam are increased by the use of disulfiram and some patients may possibly experience increased drowsiness. Alprazolam, oxazepam and lorazepam are either not affected, or only minimally affected, by disulfiram. 

Compound (XXII) resulted from a study of several 7-trifluoromethoxy and 7-trifluoro methylthio derivatives of 1,4-benzodiazepines When tested for its ability to induce ataxia, to decrease locomotor activity and to afford protection against electroshock and strychnine-induced convulsions in mice, it had activity, potency and acute toxicity similar to those of chlordiazepoxide (XXIII). The utility of XXIII and diazepam (XXIV) as useful anticonvulsants has been demonstrated ... 

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