The Fenphen Story Serotonergic Mechanisms Determine Drug Induced Valvular Heart Disease

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Appetite suppressant medications have been used worldwide for decades for the treatment of obesity. One of the most widely prescribed anorectic agents was fenfluramine either alone or in combination with the noradrenergic drug phen-termine (''fen-phen''). When used in combination, the drugs may be just as effective as either drug alone, with the added advantage of the need for lower doses of each agent and perhaps fewer side effects. Each drug received FDA approval individually in 1996, but the combination was not approved. In that year, the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million.

However, the situation changed abruptly in 1997 with a report by Heidi Connolly and co-workers of heart valve regurgitation in 24 women who had taken fenfluramine and phentermine for an average of 11 months (range 1-28 months).138 Echocardiograms demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved, and the five patients who underwent cardiac surgery had valvular heart disease (VHD) with histological features resembling changes seen in carcinoid syndrome (a mitogenic, serotonin-secreting tumor), or ergotamine-induced valve disease. Eight of the patients also had newly documented pulmonary hypertension. In a population-based study of the appetite suppressants that was reported simultaneously, Hershel Jick and colleagues found there were 11 cases of valvular disorders after the use of fenfluramine including cases of aortic regurgitation, mitral regurgitation, and combined aortic and mitral regurgitation.139 Notably, phentermine, which had long been used alone as an appetite suppressant, was not known to be associated with cardiopulmonary side effects, and in the study of Jick et al., none was found among those who took only phentermine. These cases aroused concern that fenfluramine-phentermine therapy might be associated with valvular heart disease and in 1997 the manufacturer voluntarily withdrew the combination of appetite suppressants from the market. However, the validity and magnitude of the association were left in doubt as this action was based on incomplete information.

In an attempt to understand the molecular basis of the side effects associated with these appetite suppressants, particularly with fenfluramine, researchers initially suspected that GPCRs, or ligand-gated ion channels, and/or monoamine transporters were likely to be involved. At that same time, ''receptorome screening'' of drugs and their metabolites held promise as a method to search for the mechanism responsible for drug-induced side effects, and to predict their occurrence. Then Rothman and colleagues performed a receptorome screen.

In light of the established role of serotonin (5-HT) as an mitogen, Rothman and colleagues performed a receptorome screen of fenfluramine and its in vivo metabolite norfenfluramine, along with the valvular heart disease- and pulmonary hypertension-associated ergoline methylsergide and its in vivo metabolite me-thylergonovine. The serotonin transporter inhibitor fluoxetine and its in vivo metabolite norfluoxetine were included as negative controls. Results of the re-ceptorome screen and additional in vitro studies indicated that activation of the 5-HT2B receptor was necessary to produce VHD, and that serotonergic medications that did not activate 5-HT2B receptors were unlikely to produce VHD.140 At about the same time Fitzgerald and co-workers independently reported that nor-fenfluramine was a potent 5-HT2B agonist.141 In contrast to its activity at 5-HT2B receptors, norfenfluramine was devoid of appreciable activity at many other types of receptors that are plentiful in cardiac tissue, including known biogenic amine (a1-, a2-, and p-adrenergic) receptors and peptide receptors. Rothman et al. suggested that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians consider suspending the use of medications with significant activity at 5-HT2B receptors. In subsequent studies, several other valvulopathic drugs including ergotamine and methylergonovine were found to be 5-HT2B agonists, further implicating the activation of 5-HT2B receptors as a key step in drug-induced VHD. Later, Launay et al.142 discovered that 5-HT2B receptor activation is also responsible for fenfluramine-induced pulmonary hypertension.

Valvulopathic drugs have been shown to induce mitogenesis in cultured interstitial cells from human cardiac valves. Roth and co-workers have thus proposed that damage to heart valves induced by 5-HT2B may involve inappropriate mitogenic stimulation of normally quiescent valve cells, resulting in overgrowth, although the signaling pathways whereby leaflet surfaces overgrow is not known.

Subsequently, Roth and co-workers found that two antiparkinsonian dopamine agonists, pergolide and cabergoline, were potent 5-HT2B agonists. They were predicted to be valulopathic agents143 and case reports of pergolide- and cabergoline-induced VHD soon appeared.144 Recently, two large European studies have verified the association of VHD with these two drugs.145,146

The ''fen-phen'' story is an excellent example of how receptorome screening facilitated the discovery that the fenfluramine metabolite norfenfluramine is the agent causing VHD, and how the screen facilitated the discovery of the mechanism underlying fenfluramine-induced VHD.143 A receptorome screen was also performed with MDMA (3,4-methylenedioxymethamphetamine, the recreational drug, also known as Ecstacy), which is a drug similar to fenfluramine. It was found that MDMA, and to a greater extent its N-demethylated metabolite 3,4-methylene-dioxyamphetamine (MDA), are both 5-HT2B agonists. Whether MDMA abuse is associated with VHD in humans is not known, but MDMA and MDA both elicit proliferative responses of heart valve cells in vitro, an activity similar to that which in vivo gives rise to fibrotic lesions that compromise valve function. Future studies revealing increased risk for VHD among chronic MDMA users would better validate the value of receptorome screening for the prediction of adverse drug responses.

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