Possible Association Between 3,4-Methylenedioxymethamphetamine Abuse and Valvular Heart Disease

Droogmans, Steven; Cosyns, Bernard; D’Haenen, Hugo; Creeten, E.; Weytjens, Caroline; Franken, Philippe; Scott, Benjamin; Schoors, Danny; Kemdem, Arsène; Close, L; Vandenbossche, Jean‐Luc; Bechet, Serge; Camp, Guy Van

doi:10.1016/j.amjcard.2007.06.045

Cited by 81 publications

(45 citation statements)

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“…These drugs have some unique therapeutic effects but have been associated with valvular heart disease (2,26,31). The simultaneous use of these drugs with a 5-HT antagonist, such as cyproheptadine, may prevent the develop- Fig.…”

Section: Discussionmentioning

confidence: 99%

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Droogmans¹,

Roosens

Cosyns

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Serotonergic drugs, such as pergolide, have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (5-HT)(2B) receptor (5-HT(2B)R). Therefore, we sought to determine whether cyproheptadine, a 5-HT(2B)R antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, 50 male Wistar rats received daily intraperitoneal injections of pergolide (0.5 mg/kg, n = 14), pergolide (0.5 mg/kg) combined with cyproheptadine (10 mg/kg, n = 12), cyproheptadine (10 mg/kg, n = 12), or no injections (control, n = 12) for 20 wk. Echocardiography was performed blindly at baseline and at 10 and 20 wk followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 wk, aortic regurgitation was present in all pergolide-treated animals, whereas it was less frequently observed in the other groups (P < 0.0001). For the other valves, this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid, and exhibited more 5-HT(2B)R-positive cells in pergolide-treated animals compared with the other groups. Moreover, regurgitant aortic and mitral valves were thicker than nonregurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats, which was associated with a reduced number of 5-HT(2B)R-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.

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Section: Discussionmentioning

confidence: 99%

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Droogmans¹,

Roosens

Cosyns

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…and that these drugs stimulated heart valve cell proliferation in vitro (Setola et al, 2003). Thus, we predicted that MDMA and pergolide use might be associated with VHD-predictions that were validated in 2007 (Droogmans et al, 2007;Roth, 2007;Schade et al, 2007;Zanettini et al, 2007). Therefore, there is precedent for predicting VHD liability based solely on agonist activity at recombinant 5-HT 2B receptors.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

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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“…On ne connaît pas la prévalence de ces régurgitations valvulaires, mais les fuites sévères, qui peuvent conduire au remplacement valvulaire aortique et/ou mitral, seraient rares, estimées à moins d'une pour 1000 patients exposés suivis un an. fuite est rapporté en 2003 avec des agonistes dopaminergiques ergotés [1,4], le pergolide retiré de la vente en France en février 2011 (Célance W ) et la cabergoline (Dostinex W ) aux doses où elle est utilisée dans certains pays autres que la France comme antiparkinsonien, puis avec une drogue dite « récréative », le 3,4 méthylène-dioxy-méthyl-amphétamine, ou MDMA, plus connue sous la dénomination d'ecstasy [5]. Enfin, suite à l'évaluation de données sur le risque de valvulopathie, la commercialisation du benfluorex (Médiator W ) a été suspendue en France le 30 novembre 2009, précédant le retrait officiel de son autorisation de mise sur le marché (AMM) qui ne pouvait se faire qu'au niveau européen et qui a eu lieu en juin 2010.…”

Section: Points Essentielsunclassified

Benfluorex (Mediator®) et atteintes valvulaires

et al. 2011

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Possible Association Between 3,4-Methylenedioxymethamphetamine Abuse and Valvular Heart Disease

Cited by 81 publications

References 8 publications

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

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

Benfluorex (Mediator®) et atteintes valvulaires

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Possible Association Between 3,4-Methylenedioxymethamphetamine Abuse and Valvular Heart Disease

Cited by 81 publications

References 8 publications

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

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

Benfluorex (Mediator®) et atteintes valvulaires

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