ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Studies on the association between long-term benzodiazepine use and brain abnormalities have yielded conflicting results. The computed tomographic (CT) scans of 20 long-term users of benzodiazepine (65% men; mean age ± SD [range], 42 ± 12.1 years [23-59]; mean daily benzodiazepine dose [diazepam equivalents], 19.5 ± 16.2 mg [2.5-70]; mean cumulative benzodiazepine exposure, 55.2 g [1.8-198]) were compared with 36 age- (±3 years) and sex-matched controls. Controls were prospectively recruited from 96 patients attending a neurology clinic and were interviewed to screen for alcohol and substance use disorders and other conditions possibly leading to brain atrophy. Three neuroradiologists blindly assessed each CT scan for atrophy and measured ventricles (V1, V2, V3), sulci, fissures, cisterns, and folia. Reliability among observers ranged from 0.92 to <0.1, in which case deleting one observer increased all reliabilities to >0.45. No difference in atrophy was found between benzodiazepine users and controls. V1 measures were significantly higher for benzodiazepine users than for controls (mean ± SD, 12.1 ± 1.3 vs. 11.1 ± 2.0;p= 0.02), but measures of third and fourth largest sulci were significantly higher in controls than in benzodiazepine users. Right third and fourth largest sulci (mean ± SD), respectively, were the following: controls, 0.72 ± 0.4 and 0.74 ± 0.7; benzodiazepine users, 0.51 ± 0.3 and 0.46 ± 0.3 (p< 0.02). Left third and fourth largest sulci, respectively, were the following: controls, 0.77 ± 0.6 and 0.65 ± 0.3; benzodiazepine users, 0.53 ± 0.3 and 0.5 ± 0.3 (p< 0.02). Long-term benzodiazepine therapy does not result in brain abnormalities that can be demonstrated on CT scans.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Several case reports have suggested that treatment with the benzodiazepine alprazolam can result in behavioral disinhibition. To address this question, the authors reviewed the medical records (blinded to all pharmacologic treatments the patients received) of 323 psychiatric inpatients treated with alprazolam (108 patients), clonazepam (111 patients), or no benzodiazepine (104 patients) between January 1989 and June 1990. During benzodiazepine treatment, there were no significant differences among the three groups on the following measures: (1) acts of self-injury (alprazolam, 1.9%; clonazepam, 1.8%; no benzodiazepine, 2.9%); (2) assaults on staff or other patients (alprazolam, 0%; clonazepam, 0.9%; no benzodiazepine, 1.0%); (3) need for seclusion or restraints (alprazolam, 3.7%; clonazepam, 6.3%; no benzodiazepine, 4.8%); (4) increased need for observation by hospital staff (alprazolam, 8.3%; clonazepam, 7.2%; no benzodiazepine, 6.7%); and (5) decrease in patient privileges (alprazolam, 11.1%; clonazepam, 12.6%; no benzodiazepine, 11.5%). The results indicate that in an inpatient psychiatric population, the frequency of behavioral disturbances with alprazolam, clonazepam, or no benzodiazepine does not differ. This suggests that alprazolam does not possess unique disinhibitory activity. Second, these data suggest that disinhibition may not be an important clinical problem associated with benzodiazepine use. The design of the study does not allow one to establish a relationship between the prescription of the benzodiazepine and worsening behaviors, and the findings need to be interpreted conservatively because it was a retrospective review of a heterogeneous population. However, it is noteworthy that the incidence of adverse events was low even in this high-risk population, and because the patients were in the hospital and under constant observation, the objective assessment of so-called paradoxical reactions was undertaken in a controlled setting.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In a multicenter, double-blind trial, 310 patients who had received a diagnosis of generalized anxiety disorder were treated for 6 weeks with either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of diazepam administered three times daily. Patients who were improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. The maintenance treatment phase allowed the comparison of taper results for the three treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12 weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6-week study than abecarnil patients (66%). At intake and baseline, after a 1-week placebo washout, the patient was required to have a Hamilton Rating Scale for Anxiety score of ≥20. Major adverse events for both abecarnil and diazepam were drowsiness, dizziness, fatigue, and coordination difficulties. Clinical improvement data showed that both abecarnil and diazepam produced statistically significantly more symptom relief than did placebo after 1 week of treatment. At 6 weeks treatment (using last observation carried forward analysis), however, only diazepam still differed significantly (p< 0.01) from placebo. High placebo response (56% moderate to marked global improvement) at 6 weeks, as well as a slightly lower nonsignificant improvement rate observed with abecarnil, a partial γ-aminobutyric acid (GABA) agonist, when compared with diazepam, a full GABA agonist, most likely contributed to our findings. Finally, taper results showed that only diazepam and not abecarnil caused the presence of temporary discontinuation symptoms, but only in patients who had been treated for at least 12 weeks.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Thirteen subjects (seven men, six women) completed a placebo-controlled, randomized, double-blind, crossover study to determine whether an interaction occurs between clonazepam and sertraline. Ten days of once-daily doses of either clonazepam 1 mg and placebo (CZ + PL) or clonazepam 1 mg and sertraline 100 mg (CZ + SR) were administered; there was an 11-day washout period. Sertraline did not significantly affect the pharmacokinetics of clonazepam (p> 0.13). Clonazepam apparent oral clearance, volume of distribution, and half-life were 3.9 ± 0.2 L/hr, 233 ± 11 L, and 40.5 ± 0.3 hours, respectively. The kinetics of the inactive metabolite 7-aminoclonazepam were marginally affected by sertraline, with a 21% decrease in the elimination half-life (p= 0.03) relative to CZ + PL and no significant difference between treatments in area under the curve or metabolite ratio. Card sorting (CS), digit-symbol substitution test (DSST), nurse-rated sedation scale (NRSS), and self-rated sedation scores were assessed four times daily on days −1 (PL + PL), 1, 4, 7, and 10. There were no differences between treatments in area under the effect curve or maximum observed effect for CS, DSST, or NRSS. Maximum impairment on all assessment days was low, with a less than 10% change from the drug-free values for CS and DSST. Despite higher clonazepam concentrations, predose (time 0) psychomotor and sedation scores did not differ among days −1, 1, 4, 7, and 10 or between treatments. These results in healthy volunteers indicate that sertraline does not affect the pharmacokinetics or pharmacodynamics of clonazepam.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The efficacy and tolerability of reboxetine, a unique selective noradrenaline reuptake inhibitor, were compared with those of placebo in a 6-week, randomized, double-blind study of hospitalized patients with a DSM-III-R diagnosis of major depressive disorder. Fifty-two patients (25 in the placebo group, 27 in the reboxetine group) were included in the efficacy analysis. Sixteen (64%) of those in the placebo group and four (15%) in the reboxetine group were withdrawn during the study because of lack of efficacy. Improvement in the mean Hamilton Rating Scale for Depression (HAM-D) total score at last assessment was significantly greater in the reboxetine group than in the placebo group (p< 0.001). Similarly, the response rate to treatment, defined as ≥50% reduction in HAM-D total score, was 74% for patients who received reboxetine compared with 20% for those who received placebo (p< 0.001). A significantly greater response with reboxetine than with placebo was seen as early as day 10 of treatment (p= 0.006). The therapeutic efficacy of reboxetine was substantiated by improvement in mean scores on the Zung Self-Rating Scale and on the Clinical Global Impression Severity of Illness and Global Improvement scales. Reboxetine was well tolerated, and only one patient in each group withdrew because of adverse events. Dry mouth, insomnia, blurred vision, sweating, and constipation were recorded more frequently in the reboxetine group than in the placebo group. There was a tendency toward orthostatic changes in the systolic blood pressure, but this was not clinically significant. This study demonstrated that reboxetine is significantly more effective than placebo in the treatment of hospitalized patients with severe major depressive disorder and is well tolerated.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5 to 10. The authors undertookin vitrostudies to disclose the mechanism behind this clinically important interaction. In a human liver microsome preparation, fluvoxamine showed a concentration-dependent inhibition of clozapine N-demethylation. Fluvoxamine was much less effective as an inhibitor of clozapine N-oxidation. Fluvoxamine also inhibited in a concentration-dependent manner the activity of all five cytochrome P450 (CYP) isoforms previously determined to be capable of catalyzing the demethylation of clozapine. Fluvoxamine inhibited CYP1A2 and 2C19 with the highest affinities (Kivalues of 0.041 and 0.087 μM, respectively). TheKivalues for CYP2C9 and 2D6 were 2.2 and 4.9 μM, respectively, whereas theKifor CY3A4 was 24 μM. Assuming a hepatic tissue concentration of fluvoxamine in the range of 4 to 7 μM under therapeutic conditions, a clinically significant inhibition of all but CYP3A4 is expected in relation to clozapine N-demethylation. No significant effect of fluvoxamine on clozapine N-oxidation is to be expected under therapeutic conditions. Because of the large interindividual variability of the quantity of the various CYP isoforms in liver tissue, it is not possible to predict the fluvoxamine-induced increase in the plasma concentration of clozapine of an individual patient.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Oral opioid analgesics such as codeine are used extensively worldwide and are frequently misused. Codeine is a substrate of CYP2D6, a genetically polymorphic P450 enzyme, and is metabolized to the more potent drug morphine. CYP2D6 activity can be inhibited by fluoxetine, and the inhibition of morphine formation may help individuals reduce their use of codeine. Fourteen long-term users of oral opiates (principally codeine) were assessed for an open-label pilot treatment study of fluoxetine 20 mg/day combined with a brief behavioral intervention and structured tapering of the opiate. Eight subjects entered and completed the 8-week treatment. Opiate use decreased by 30% to 100% of baseline use (p< 0.0001) in parallel with a decrease in CYP2D6 activity. Fluoxetine may have a role in the treatment of opiate dependence by decreasing opiate-reinforcing properties.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day washout phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (±8.44) to 74.98 (±12.88) μg·hr/mL (p< 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (±1.16) to 5.71 (±0.52) μg·hr/mL (p< 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (±3,768) to 542 (±191) ng·hr/mL, and the AUCs of its metabolites (hydroxynefazodone,meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p< 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Eleven patients with Parkinson's disease (PD) and acute psychosis received flexible doses of quetiapine between 25 and 300 mg/day based on clinical response and tolerance. Ten patients were receiving dopaminergic agents at baseline. Serial efficacy ratings (Brief Psychiatric Rating Scale, Clinical Global Impressions Scale), neuromuscular symptom assessments (Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Unified Parkinson's Disease Rating Scale [UPDRS]), and adverse events monitoring were performed for up to 52 weeks. The patients had moderate hallucinations and/or delusions at baseline before the initiation of quetiapine. Nine of the 11 patients completed at least 12 weeks of treatment. Quetiapine was well tolerated in all but one patient, who became dizzy within the first week and withdrew from the study. Ten patients presented with moderate visual hallucinations. Quetiapine was markedly effective in controlling visual hallucinations in six of these patients. Symptoms of paranoia or delusions were less responsive to quetiapine. Four patients withdrew because of adverse events or comorbid medical problems, two withdrew because of a lack of efficacy, and five completed 52 weeks of treatment. The introduction of quetiapine did not exacerbate parkinsonian symptoms. Motor dysfunction, as measured by the UPDRS, revealed a slow, gradual worsening consistent with the progression of PD. Atypical antipsychotic medications such as quetiapine have a reduced likelihood of causing adverse drug-induced parkinsonism and therefore a possible role in treating psychotic symptoms in patients with PD.

ISSN:0271-0749    

出版商:OVID    

年代:2000

数据来源: OVID