This study examines clinical predictors of outcome for patients with panic disorder and depression in a 16 week, placebo-controlled trial of alprazolam and imipramine (n = 126). Baseline global severity of illness and phobic avoidance were differentially predictive of acute response to treatment. Patients in the mild to moderate range of global distress experienced smaller degrees of improvement on alprazolam than on imipramine at week 4. At endpoint, the relative effectiveness of the active medication versus placebo was diminished in patients with higher levels of phobic avoidance. This relationship was not evident for completers, suggesting that the adverse effects of avoidance on outcome after sustained treatment was reduced. 相似文献
Rationale: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration
of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or
monoamine oxidase inhibitor (MAOI) antidepressants. Objective: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments.
Methods: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11–14 ml
water/session (unpunished responding) and accepted 25–40 shocks/session (punished responding) during control (i.e., non-drug)
10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of
conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated
subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5–40 mg/kg) or alprazolam (0.3–2.5 mg/kg)
were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily
for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined
in additional groups of DSP4- or vehicle-pretreated subjects. Results: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect)
relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital
treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine
treatment. Conclusions: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant
treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines.
Received: 6 August 1998/Final version: 16 October 1998 相似文献
Background: Alprazolam is a commonly used benzodiazepine in clinical practice, and when coingested with ethanol, alprazolam can increase behavioral irritability and aggression. However, the mechanism of its interaction with ethanol remains unknown.
Research design and methods: The pharmacokinetics of alprazolam was studied in vivo in rat experiments involving the simultaneous administration of alprazolam and ethanol, and the interactions between ethanol and alprazolam were investigated in vitro in human liver microsomes. In silico molecular docking was applied to analyze the change in the CYP3A4–alprazolam-binding conformation when ethanol was coadministered with alprazolam.
Results: Compared with alprazolam administered alone (2 mg/kg), the Cmax of alprazolam increased when ethanol was simultaneously administered at 3 g/kg. The concentrations of alprazolam significantly increased by 39%, 17%, 105%, and 642% at 5, 10, 30, and 120 min intervals in the brain when coadministered with ethanol, respectively. Molecular docking results suggested that the conformation of CYP3A4 with alprazolam changed when ethanol was bound to the SER119 residue, which seems critical in the process of CYP3A4–alprazolam binding.
Conclusions: Ethanol might increase the toxicity of alprazolam by inhibiting the activity of CYP3A4, although other pharmacokinetic processes may be affected. Ethanol could change the conformation of CYP3A4 and affect alprazolam binding. 相似文献