5-Hydroxytryptamine (5HT)-induced valvulopathy: Compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats

Elangbam, Chandikumar S.; Job, Lauren E.; Zadrozny, Leah M.; Barton, Joanna C.; Yoon, Lawrence; Gates, Lisa; Slocum, Nikki

doi:10.1016/j.etp.2008.03.005

Cited by 100 publications

(86 citation statements)

References 33 publications

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“…There is increasing evidence that 5-hydroxytryptamine 2B receptor (5HT2BR) activation and/or increased circulating 5-hydroxytryptamine (5-HT) may play a significant role in drug-induced valvulopathy (Elangbam et al 2008;Fitzgerald et al 2000). Compounds in this study were screened against 5HT1A, 5HT2A, 5HT2B, 5HT3, and 5HT4 receptors and found to be inactive at a concentration of 10 mM (<5% inhibition; data not shown).…”

Section: Discussionmentioning

confidence: 99%

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

et al. 2011

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Aberrant signaling by transforming growth factor-b (TGF-b) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-b signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-b signaling via ALK5 plays a critical role in maintaining heart valve integrity.

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Section: Discussionmentioning

confidence: 99%

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

et al. 2011

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“…Additional evidence implicating 5-HT 2B receptors in drug-induced VHD came from the observations that 1) 5-HT 2B receptors are enriched in heart valve tissue from various species (Fitzgerald et al, 2000;Setola et al, 2003;Elangbam et al, 2005;Regard et al, 2008); 2) activation of human valvular interstitial 5-HT 2B receptors is mitogenic, resulting in ERK1/2 phosphorylation and [ 3 H]deoxythymidine incorporation (Setola et al, 2003); 3) 5-HT 2B receptor activation has been implicated in 5-HTinduced valvulopathy in experimental animals (Elangbam et al, 2008); and 4) other drugs with potent 5-HT 2B agonist activity [pergolide, cabergoline, MDMA, 3,4-dimethoxyamphetamine (Setola et al, 2003)] induce valvular heart disease in humans (Droogmans et al, 2007;Schade et al, 2007;Zanettini et al, 2007), whereas chemically similar drugs lacking 5-HT 2B agonism [e.g., lisuride and bromocriptine (Roth, 2007;Berger et al, 2009)] are not associated with an increased risk of VHD (Schade et al, 2007;Zanettini et al, 2007).…”

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confidence: 99%

Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine_2BReceptor Agonists: Implications for Drug Safety Assessment

Huang

Setola²,

Yadav³

et al. 2009

Mol Pharmacol

121

130

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Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine 2B (5-HT 2B ) receptor agonists. We have shown that activation of 5-HT 2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT 2B receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT 2B receptor agonists (hits); 14 of these had previously been identified as 5-HT 2B receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twentythree of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT 2B receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC 50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT 2B receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.In 1997, the anorexigen fenfluramine was voluntarily withdrawn from the U.S. market because of its association with valvular heart disease (VHD) and pulmonary hypertension

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“…2,4,26 Lorcaserin was designed to stimulate the 5-HT 2C receptor without activating the 5-HT 2B receptor at therapeutic doses, thereby minimizing the risk of valvular heart disease. 7,9,11 The phase 3 safety and efficacy studies of lorcaserin included a comprehensive echocardiographic monitoring program that evaluated the potential risk of valvular heart disease, and the integrated analysis of those echocardiograms, described in this report, rules out a ≥1.25% risk difference in valvular regurgitation after 1 year in the lorcaserin group versus the placebo group.…”

Section: Discussionmentioning

confidence: 99%

“…7,[9][10][11] The 5-HT 2B receptors are expressed on cardiac valvular interstitial cells and when stimulated produce a characteristic valvulopathy that is also observed with the nonselective dopamine agonists pergolide and cabergoline. …”

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confidence: 99%

Echocardiographic Assessment of Cardiac Valvular Regurgitation With Lorcaserin From Analysis of 3 Phase 3 Clinical Trials

Weissman

Sanchez

Koch

et al. 2013

Circ: Cardiovascular Imaging

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560S erotonin (5-hydroxytryptamine [5-HT]) receptors regulate feelings of satiety and food intake.1 The serotonergic antiobesity compounds fenfluramine and dexfenfluramine were effective in causing weight loss but were associated with valvular heart disease, especially aortic and mitral valve insufficiency.2-5 These compounds were nonselective, affecting serotonin transporters as well as multiple serotonin receptor subtypes.6-8 Subsequent research and clinical observations implicated activation of the 5-HT 2B receptor subtype as the cause of serotonergic valvulopathy. 7,[9][10][11] The 5-HT 2B receptors are expressed on cardiac valvular interstitial cells and when stimulated produce a characteristic valvulopathy that is also observed with the nonselective dopamine agonists pergolide and cabergoline. 12 Clinical Perspective on p 567The 5-HT 2C receptor has since been recognized as an important satiety mediator in humans, and recently the selective 5-HT 2C receptor agonist lorcaserin was approved by the US Food and Drug Administration (FDA) as an adjunct to diet and exercise for chronic weight management in obese (body mass index [BMI] ≥30 kg/m 2 ) adults or overweight adults (BMI,) with ≥1 weight-related comorbidity, on the basis of 3 large phase 3 clinical trials of 1-to 2-year duration. [13][14][15] Lorcaserin was designed to be a selective agonist of the 5-HT 2C receptor. 16,17 In preclinical studies, lorcaserin had ≈60-fold selectivity at 5-HT 2C receptors relative to 5-HT 2B receptors and essentially no activity for serotonin release or reuptake. 16 In addition to evaluating efficacy and general safety, the phase 3 trials of lorcaserin incorporated serial echocardiograms to monitor cardiac valvular function. [13][14][15] Identical echocardiographic methodology was used in all 3 studies so that the data sets could be combined for Background-Lorcaserin is a selective 5-HT 2C agonist evaluated for weight management in clinical trials. Echocardiographic monitoring was conducted to test the hypothesis that selective 5-HT 2C agonism would avoid valvular heart disease. Methods and Results-Echocardiographic and weight change data from 5249 obese and overweight patients in 3 phase 3 trials were integrated. Treatment duration with 10 mg lorcaserin twice daily or placebo was 52 weeks. The proportions of patients who developed Food and Drug Administration-defined valvulopathy (≥ mild aortic or ≥ moderate mitral regurgitation) and changes in regurgitant grade at each heart valve were evaluated. Possible associations between weight or body mass index change and valvulopathy were explored. New valvulopathy was present in 2.04% of placebo and 2.37% of lorcaserin recipients at 52 weeks (risk difference, 0.33%; 95% confidence interval, −0.46 to 1.13; risk ratio, Methods Design and Study PopulationThe studies were conducted at academic and private research sites in the United States. Institutional review boards reviewed and approved the protocols for each research site. All patients provided written informed consent before pa...

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5-Hydroxytryptamine (5HT)-induced valvulopathy: Compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats

Cited by 100 publications

References 33 publications

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine_2BReceptor Agonists: Implications for Drug Safety Assessment

Echocardiographic Assessment of Cardiac Valvular Regurgitation With Lorcaserin From Analysis of 3 Phase 3 Clinical Trials

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5-Hydroxytryptamine (5HT)-induced valvulopathy: Compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats

Cited by 100 publications

References 33 publications

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors

Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2BReceptor Agonists: Implications for Drug Safety Assessment

Echocardiographic Assessment of Cardiac Valvular Regurgitation With Lorcaserin From Analysis of 3 Phase 3 Clinical Trials

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Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine_2BReceptor Agonists: Implications for Drug Safety Assessment