Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepam-dependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the halazepam-dependent dogs. Further, the precipitated abstinence observed in the halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.
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PMID:Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog. 168 20

The ability of graded doses of flumazenil (2, 6, 18, 36 and 72 mg/kg) and a lactose placebo to precipitate abstinence was studied in dogs treated chronically with diazepam, nordiazepam, flunitrazepam, alprazolam, oxazepam, halazepam and lorazepam by oral dosing. A scale comprised of 10 precipitated abstinence signs, the Benzodiazepine Precipitated Abstinence Scale, was developed, which yielded linear flumazenil log-dose response lines with significant slopes in dogs dependent on diazepam, nordiazepam and flunitrazepam. The effects of 18, 36 and 72 mg/kg of flumazenil in otherwise drug naive dogs were studied. In naive dogs, the most prominent effect of flumazenil was to reduce activity. All benzodiazepines studied produced dependence that was characterized by signs of precipitated abstinence; however, the intensity and quality of abstinence varied from one benzodiazepine to another. Precipitated abstinence in dogs treated chronically with diazepam and flunitrazepam was characterized by a dose-related increase in clonic convulsions and Benzodiazepine Precipitated Abstinence Scale scores. This pattern differed from that seen in nordiazepam- and alprazolam-dependent dogs, which showed a comparable flumazenil dose-related increase in clonic convulsion but only a modest increase in Benzodiazepine Precipitated Abstinence Scale scores. Oxazepam and lorazepam produced dependence that was less intense than that seen with the other benzodiazepines. Plasma levels of the benzodiazepines and their metabolites were repeatedly determined after single doses and during addiction cycles. Nordiazepam accumulated in diazepam- and nordiazepam-dependent dogs and alpha-OH alprazolam accumulated in alprazolam-dependent dogs. Other drugs and metabolites did not. These observations suggest that: 1) different benzodiazepines or their metabolites produce different types of physical dependence, suggesting that they or their metabolites have different mechanisms and sites of action; 2) plasma cumulation of the benzodiazepines or their active metabolites is an important factor in the genesis of physical dependence; and 3) metabolism of benzodiazepines plays an important role in their dependence-producing capacity, and because of differences in the way species metabolize benzodiazepines, the type of dependence produced in different species may differ.
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PMID:Precipitated abstinence in orally dosed benzodiazepine-dependent dogs. 197 31