ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Recent advances in molecular pharmacology have allowed the characterization of the specific isoforms that mediate the metabolism of various medications.This information can be integrated with older clinical observations to begin to develop specific mechanistic and predictive models of psychotropic drug interactions. The polymorphic cytochrome P450 2D6 has gained much attention, because competition for this isoform is responsible for serotonin reuptake inhibitor-induced increases in tricyclic antidepressant concentrations in plasma. However, the cytochrome P450 3A subfamily and the 3A3 and 3A4 isoforms (CYP3A3/4) in particular are becoming increasingly important in psychopharmacology as a result of their central involvement in the metabolism of a wide range of steroids and medications, including antidepressants, benzodiazepines, calcium channel blockers, and carbamazepine. The inhibition of CYP3A3/4 by medications such as certain newer antidepressants, calcium channel blockers, and antibiotics can increase the concentrations of CYP3A3/4 substrates, yielding toxicity. The induction of CYP3A3/4 by medications such as carbamazepine can decrease the concentrations of CYP3A3/4 substrates, yielding inefficiency. Thus, knowledge of the substrates, inhibitors, and inducers of CYP3A3/4 and other cytochrome P450 isoforms may help clinicians to anticipate and avoid pharmacokinetic drug interactions and improve rational prescribing practices. (J Clin Psychopharmacol 1995;15:387-398).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and alprazolam after single-and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in 48 healthy male volunteers. A group of 12 subjects received either placebo twice daily, 1 mg of alprazolam twice daily, 200 mg of nefazodone twice daily, or the combination of 1 mg of alprazolam and 200 mg of nefazodone twice daily for 7 days. Serial blood samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 6, and 6 for the determination of alprazolam and its metabolites alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (40H) and nefazodone and its metabolites hydroxynefazodone (HO-nefazodone), m-chlorophenylpiperazine (mCPP), and a triazole dione metabolite (dione) by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for alprazolam, 40H, nefazodone, HO-nefazodone, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that at steady state, alprazolam Cmaxand AUCtauvalues significantly increased approximately twofold and 40H Cmaxand AUCtauvalues significantly decreased by 40 and 26%, respectively, when nefazodone was coadministered with alprazolam. There was no effect of alprazolam on the single-dose or steady-state pharmacokinetics of nefazodone, HO-nefazodone, or dione after the coadministration of alprazolam and nefazodone. However, the mean steady-state mCPP Cmaxand AUCtausignificantly increased by approximately threefold and t1/2values significantly increased by approximately twofold after the coadministration of alprazolam and nefazodone in comparison to those when nefazodone was given alone. Competitive inhibition between alprazolam and nefazodone metabolism at cytochrome P450 3A4 may be responsible for the pharmacokinetic interaction when alprazolam and nefazodone were coadministered. No adjustment of nefazodone dosage is required when nefazodone and alprazolam are coadministered. Because alprazolam concentrations in plasma are increased in the presence of nefazodone, a reduction in alprazolam dosage is recommended when the two agents are coadministered. (J Clin Psychopharmacol 1996;15:399-408).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This study was conducted to determine the potential for an interaction between nefazodone (NEF), a new antidepressant, and lorazepam (LOR) after single-and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in healthy male volunteers. A total of 12 subjects per group received either placebo (PLA) twice daily, 2 mg of LOR twice daily, 200 mg of NEF twice daily, or the combination of 2 mg of LOR and 200 mg of NEF (LOR + NEF) twice daily for 7 days. Plasma samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of LOR, NEF, and NEF metabolites hydroxy (HO)-NEF, m-chlorophenylpiperazine (mCPP), and dione by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for LOR, NEF, HO-NEF, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that there was no effect of LOR on the single dose or steady-state pharmacokinetics of NEF, HO-NEF, or dione after coadministration. The steady-state mCPP Cmaxvalues decreased 36% for the LOR + NEF group in comparison to that when NEF was given alone. There was no effect of NEF on the pharmacokinetics of LOR after coadministration. The absence of an interaction appears to be attributable to LOR's metabolic clearance being dependant on conjugation rather than hydroxylation. Overall, no change in LOR or NEF dosage is necessary when the two drugs are coadministered. (J Clin Psychopharmacol 1995;15:409-416).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Prospectively identified flouxetine-exposed pregnancies were evaluated to determine whether fluoxetine, a serotonin reuptake inhibitor commonly used for the treatment of depression and obsessive-compulsive disorder, might be associated with neonatal complications after maternal fluoxetine exposure during the third trimester through delivery. The outcomes of all prospectively identified, spontaneously reported pregnancies with confirmed fluoxetine exposure during the third trimester through delivery were evaluated. Postnatal complications unrelated to malformations were reported in 15 of the 112 identified pregnancies (115 infants), but there was neither a consistent or recurring pattern nor a dose relationship. On the basis of this survey and comparison with reported rates from the National Hospital Discharge Survey, it is unlikely that maternal fluoxetine use during the third trimester results in significant postnatal complications. (J Clin Psychopharmacol 1995;15:417-420).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

No consensus exists regarding whether early response to an antidepressant strongly predicts a good outcome, what is the criterion for early response, or when to measure it.We hypothesized that early response (greater or equal to 20% decrease in HAM-D21) after any of weeks 1, 2, or 3 of fluoxetine treatment of major depression in geriatric outpatients would predict a favorable outcome by week 6 or an earlier endpoint accurately enough for clinical use. We also hypothesized that the week 1, 2, and 3 percent changes in 21-item Hamilton Rating Scale for Depression (HAM-D21) would predict the percent change at week 6 (or endpoint) accurately enough for clinical use. We enrolled 671 elderly outpatients with unipolar DSM-III-R major depression in a double-blind, placebo-controlled trial of fluoxetine, 20 mg/day. For analysis, fluoxetine-treated patients were randomly divided into a development set (N = 154) for a preliminary test of our criteria and a validation set (N = 181) to validate the development data set's results. Early responders at weeks 1, 2, and 3 were statistically significantly more likely to experience marked improvement or remission than those lacking early response. However, at week 3, this criterion correctly classified only about three-fourths of patients with regard to marked improvement and only about two-thirds with regard to remission. Moreover, about one-third of patients predicted to experience marked improvement and about three-fifths of those predicted to remit did not. The continuous variable, percent change in HAM-D21, did not produce predictive results of any greater clinical utility. We believe that the sensitivity, specificity, false-positive rate, false-negative rate, and kappa of outcome predictions all should be reported in future studies. Without a full set of descriptive statistics, clinicians can be misled by statistically significant results. (J Clin Psychopharmacol 1995;15:421-427).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This multicenter, double-blind, placebo-controlled, parallel-group, randomized study assessed the efficacy, safety, and tolerability of a novel CCK-B antagonist CI-988 in the treatment of generalized anxiety disorder (GAD). Patients received placebo or CI-988 (300 mg/day, thrice daily) for 4 weeks. Patients with a primary diagnosis of GAD according to DSM-III-R criteria were randomized. The study design included a 1- to 2-week single-blind placebo baseline phase, followed by a 4-week double-blind treatment phase. Efficacy was measured weekly by Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impressions of Severity and Change, UCLA-Multi Dimensional Anxiety Scale, and Hamilton Rating Scale for Depression. Patients were also evaluated to determine whether they met criteria for irritable bowel syndrome (IBS) at screening and were evaluated with a gastrointestinal visual analog scale at each visit. Eighty-eight patients were randomized to CI-988 (N = 45) and placebo (N = 43) at three centers. CI-988 did not demonstrate an anxiolytic effect superior to placebo in this clinical trial. There was no significant difference in mean change in HAM-A total between placebo (-7.73) and CI-988 (-8.64). However, a significant treatment-by-center interaction and a highly variable placebo response rate among the three centers limit the interpretation of the results. CI-988 did not have an effect on symptoms of IBS other than diarrhea, which worsened in patients with IBS. Other than a higher incidence of some gastrointestinal symptoms (diarrhea, dyspepsia, flatulence, and nausea), CI-988 was well tolerated. Results suggest that testing higher oral doses of CI-988 may be warranted. (J Clin Psychopharmacol 1995;15:428-434).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Data from a therapeutic drug monitoring service, in total 2,393 observations in 1,606 patients, were used to analyze factors associated with the prescribed daily doses of the tricyclic antidepressants amitriptyline and nortriptyline.The achieved concentrations in plasma were evaluated in relation to suggested therapeutic ranges. The doses of both drugs were greatly reduced with increasing age, despite the fact that age is of minor importance for their kinetics. Interactions with concomitantly given drugs were not handled by dose adjustments of the antidepressant. Therapeutic drug monitoring increased the proportion of concentrations within the therapeutic range for patients on amitriptyline, but not for those on nortriptyline. The large interindividual kinetic variability for most antidepressants requires individualized dosing, but this individualization is performed on incorrect grounds. (J Clin Psychopharmacol 1995;15:435-439).

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0271-0749    

出版商:OVID    

年代:1995

数据来源: OVID