Delving into the Latest Updates on Wyeth-Ayerst with Synapse

Overview

Clinical augmentation strategies have shown that some improvement in antidepressant efficacy can be achieved by combining the β-adrenergic/serotonin (5-HT)1A/1B receptor antagonist (±)pindolol with a selective serotonin reuptake inhibitor (SSRI). This has lead to the hypothesis that a combination of a 5-HT1A receptor antagonist with an SSRI will lead to a faster onset of antidepressant action. Although there is a significant accumulation of acute preclinical data supporting this rationale, until recently, there have been no investigations examining the chronic effects of combining an SSRI with a 5-HT1A receptor antagonist. Here, we determined the chronic effects of fluoxetine (10 mg/kg o.d.), administered in combination with the selective 5-HT1A receptor antagonist WAY-100635 (1 mg/kg b.i.d.), on serotonergic neurotransmission in the frontal cortex using in-vivo microdialysis. Following chronic administration of fluoxetine ± WAY-100635, functional changes in serotonergic neurotransmission, as well as 5-HT1A autoreceptors, were assessed by administering fluoxetine or (±) 8-hydroxy-2-(di-n-propylamino)tetralin [(±) 8-OH-DPAT] 24 h after the last chronic dose. Chronic administration of WAY-100635 alone produced no detectable change in the functional status of the 5-HT1A receptor. However, fluoxetine alone produced a time-dependent adaptation in serotonergic transmission such that fluoxetine (acutely administered on day 15) was able to produce a two fold increase in extracellular 5-HT levels but the decrease in response to 8-OH-DPAT was completely attenuated. These data indicate that the fluoxetine-induced adaptation was mediated by desensitization of the 5-HT1A receptor. WAY-100635 given chronically in combination with fluoxetine blocked the SSRI-induced desensitization of the 5-HT1A receptor. Furthermore, chronic treatment with this combination produced no tolerance in terms of its ability to acutely increase forebrain 5-HT levels. These data suggest that augmentation of an SSRI by combined pharmacotherapy with a 5-HT1A antagonist would be effective upon prolonged exposure.

06 Feb 2001·CirculationQ1 · MEDICINE

The Heart and Estrogen-progestin Replacement Study (HERS)

Q1 · MEDICINE

Article

Author: Hulley, Stephen B. ; Barrett-Connor, Elizabeth ; Harris, Fran ; Hsia, Judith ; Fong, Josephine ; Cauley, Jane A. ; Simon, Joel A. ; Richards, Cynthia

Background —Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial. Methods and Results —Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), or transient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk. Conclusions —Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease.

Cardiovascular effects of hormone replacement therapy: what factors may influence risk?

Author: de Vane, P.

A review on the cardiovascular effects of estrogen replacement therapy (ERT)/hormone replacement therapy (HRT), and the possible mechanisms to explain why the cardioprotective effects of estrogen may not be available to all postmenopausal women.ERT or HRT has been clin. demonstrated to improve the health and well-being of postmenopausal women in a number of major areas, including in reducing the incidence of hot flushes and/or sweating in peri- and postmenopausal women, alleviating osteoporosis, and relieving manifestations of vaginal atrophy.In addition to these benefits, a sound, internally consistent body of clin., preclin. and observational data supports the beneficial effects of ERT and HRT on cardiovascular diseases in postmenopausal women.Randomized, cross-over trials have also shown that HRT can act synergistically with therapies designed for cardioprotection.

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Pipeline

Pipeline Snapshot as of 22 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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