No abstract

This report presents the results of a retrospective analysis of pooled efficacy data from eight studies in which buspirone was compared to placebo in 520 patients with generalized anxiety disorder (GAD). In addition to evaluating overall efficacy in the composite patient data base, four criteria were used to identify subsets of patients with GAD who had coexisting depressive symptoms of at least moderate intensity: (1) a score of ≧ 2 on the Hamilton Anxiety (HAM-A) Rating Scale item 6 (depressed mood), (2) a score of ≧ 2 on the Hamilton Depression (HAM-D) Rating Scale item 1 (depressed mood), (3) a HAM-D total score of ≧ 18, or (4) a HAM-D Retardation Factor value (items 1,7,8, and 14) greater than the median for the group. Overall, patients treated with buspirone demonstrated significant (p ≤ 0.001) improvement over baseline in total HAM-A scores compared to patients who received placebo. Buspirone also produced significant (p ≤ 0.001) global improvement compared to placebo as assessed by the attending physician. Of the GAD patients stratified according to the four criteria for coexisting depressive symptoms, a substantial percentage (44-64%) of the total patient sample exhibited significant depressive symptoms as part of their anxiety disorder. Patients with GAD and coexisting depressive symptoms of at least moderate intensity exhibited significantly greater improvement with buspirone compared to placebo treatment regardless of the stratification criterion used. They also responded at least as well or better to buspirone therapy as did those with GAD who had less intense depressive symptoms. Weekly ratings indicated that buspirone produced a progressively increasing anxiolytic response relative to placebo throughout the 4-week double-blind treatment period. These findings indicate that buspirone is an effective anxiolytic for patients with GAD who experience coexisting depressive symptoms regardless of the intensity of those symptoms.

No abstract

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.

No abstract

This 7- to 8-week, multicenter, randomized, double-blind, placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder. Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects. The study enrolled 600 outpatients, male and female, age 18-65, meeting DSM-III-R criteria for major depressive disorder. A 13-item subscore of the standard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score. Secondary efficacy assessments included the HAM-D retardation factor, HAM-D depressed mood item, CGI-severity of illness item, and SCL depression factor. Fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy. Based on the HAM-D depressed mood item, efficacy was dose dependent. The minimum effective dose was 50 mg/day. Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder.

No abstract

The regulation of plasma renin activity (PRA) by thromboxane (Tx) A2 was studied in anesthetized rats by measuring PRA before and after administration of drugs that block cyclooxygenase (CO) (indomethacin [INDO], 5 mg/kg), thromboxane synthase (TS) (UK 38485 [UK], 100 mg/kg), or Tx receptors (SQ 29548 [SQ], 8 mg/kg or L 641953 [L], 50 mg/kg) or that activate Tx receptors (U 46619 [U], 10 ng.kg-1.min-1). PRA (ng ANG I.ml-1.h-1) was unaffected by vehicle; it was reduced by INDO (25 +/- 2 to 13 +/- 3, n = 13, P less than 0.001) but was increased by UK (24 +/- 3 to 50 +/- 6, n = 18, P less than 0.005), SQ (27 +/- 4 to 44 +/- 7, n = 6, P less than 0.05), and L (32 +/- 4 to 51 +/- 7, n = 10, P less than 0.05). U reduced PRA in each rat (17 +/- 3 to 10 +/- 3, n = 6, P less than 0.005). UK caused dose-dependent stimulation of PRA (mean effective dose 50 mg/kg) and inhibition of TxB2 excretion (mean inhibitory dose 15 mg/kg). After INDO, SQ no longer changed PRA (-1 +/- 10, n = 7). Prolonged administration of SQ for 4-6 days (20 mg.kg-1.day-1 ip) did not change Na+ or K+ balances, blood pressure, renal hemodynamics, or urine flow. However, SQ stimulated PRA (P less than 0.007) independent of prior salt intake. In conclusion in anesthetized rats 1) PRA is stimulated by products of CO but inhibited by products of TS and by a Tx mimetic; 2) stimulation of PRA by SQ depends on ongoing PG and Tx synthesis; 3) rise in PRA with Tx antagonists is not closely related to changes in salt balance, blood pressure, or renal hemodynamics.