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Combination of a Beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor for the treatment of obesity.

ABSTRACT: We report the novel combination of a selective beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for the treatment of obesity. The synthesis and characterization of 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), a human ?3-adrenergic receptor agonist and ?1- and ?2-adrenergic receptor antagonist with no sympathomimetic activity at the ?1- and ?2-adrenergic receptors, is reported. Some in vivo data in both rats and humans is presented.

SUBMITTER: Jesudason CD

PROVIDER: S-EPMC4018109 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Combination of a Beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor for the treatment of obesity.

Jesudason Cynthia D CD Baker James E JE Bryant Robert D RD Fisher Jack W JW O'Farrell Libbey S LS Gaich Gregory A GA He Minxia M MM Kahl Steven D SD Kriauciunas Aidas V AV Heiman Mark L ML Peters Mary A MA Rito Christopher J CJ Satterwhite Julie H JH Tinsley Frank C FC Trankle William G WG Shuker Anthony J AJ

ACS medicinal chemistry letters 20110523 8

We report the novel combination of a selective beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for the treatment of obesity. The synthesis and characterization of 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), a human β3-adrenergic receptor agonist and β1- and β2-adrenergic receptor antagonist with no sympathomimetic activity at the β1- and β2-adrenergic receptors, is ...[more]

PMID: 24900353

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Project description:Importance:In 2006, the US Food and Drug Administration (FDA) issued an advisory warning on the risk of serotonin syndrome with concomitant use of triptans and selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) antidepressants, but the true risk of serotonin syndrome in these patients remains unknown. Objective:To assess the risk of serotonin syndrome with concomitant use of triptans and SSRI or SNRI antidepressants. Design, Setting, and Participants:This study used electronic health record data from the Partners Research Data Registry (RPDR) to identify patients who had received an International Classification of Diseases, Ninth Revision diagnosis compatible with serotonin syndrome who had been coprescribed triptans and SSRI or SNRI antidepressants in the Greater Boston, Massachusetts, area from January 1, 2001, through December 31, 2014 (14 years). Clinical information was extracted to determine whether the case met formal diagnostic criteria and had coprescription within a calendar year. Both conservative and broad case definitions were used to better characterize the spectrum of risk. Data analysis was performed from November 23, 2016, to July 15, 2017. Main Outcomes and Measures:Incidence of serotonin syndrome. Results:The RPDR search revealed 47?968 (±3) unique patients who were prescribed triptans during the 14-year period of the study. A total of 19?017 (±3) patients were coprescribed triptans and antidepressants during the study, with a total of 30?928 person-years of exposure. Serotonin syndrome was suspected in 17 patients. Only 2 patients were classified as having definite serotonin syndrome (incidence rate, 0.6 cases per 10?000 person-years of exposure; 95% CI, 0.0-1.5). Five patients were classified as having possible serotonin syndrome (incidence rate with these 5 cases added to the 2 definite cases, 2.3 cases per 10?000 person-years of exposure; 95% CI, 0.6-3.9). The proportion of patients with triptan prescriptions who were coprescribed an SSRI or SNRI antidepressant was relatively stable during the study, ranging from 21% to 29%. Conclusions and Relevance:The risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low. Coprescription of these drugs is common and did not decrease after the 2006 FDA advisory. Our results cast doubt on the validity of the FDA advisory and suggest that it should be reconsidered.

Project description:Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.To determine the efficacy and tolerability of low-dose oral 17?-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.Participants were randomized to double-blind treatment with low-dose oral 17?-estradiol (0.5 mg/d) (n?=?97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n?=?96), or placebo (n?=?146) for 8 weeks.The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P?<?.001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P?=?.005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P?=?.09). Treatment satisfaction was highest (70.3%) for estradiol (P?<?.001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P?=?.06 vs placebo). Both interventions were well tolerated.Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.clinicaltrials.gov Identifier: NCT01418209.

Dataset Information

Combination of a Beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor for the treatment of obesity.

Publications

Combination of a Beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor for the treatment of obesity.

Similar Datasets

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