The Experts below are selected from a list of 255 Experts worldwide ranked by ideXlab platform
Christophe Tribouilloy - One of the best experts on this subject based on the ideXlab platform.
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Sub-aortic obstruction of left ventricular outflow tract secondary to Benfluorex-induced endocardial fibrosis
Elsevier, 2015Co-Authors: Catherine Szymanski, Michel Andrejak, Sylvestre Marechaux, Patrick Bruneval, Vincent Thomas De Montpréville, Emre Belli, Christophe TribouilloyAbstract:Patients exposed to Benfluorex have an increased risk of restrictive organic valvular heart disease. Aortic and mitral regurgitations caused by fibrotic valve disease are the most common features observed in exposure to fenfluramine derivatives in general and Benfluorex in particular. We report here, for the first time to our knowledge, a well-documented case in which obstructive sub-aortic endocardium fibrosis within the left ventricular outflow tract is related with exposure to a drug that modifies the metabolism of serotonin. It now remains to be established whether extensive fibrosis of the myocardium in addition to well-documented valvular fibrosis may develop in patients exposed to amphetamine-derived drugs affecting the serotonin system
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frequency of drug induced valvular heart disease in patients previously exposd to Benfluorex a multicentre prospective study
European Heart Journal, 2013Co-Authors: Christophe Tribouilloy, Yannick Jobic, Sylvestre Marechaux, Stephane Ederhy, Erwan Donal, Patricia Reant, Elise Arnalsteen, Jacques Boulanger, Thierry Garban, Pierrevladimir EnnezatAbstract:Aims The epidemiologic link between Benfluorex use and an increased global frequency of left heart valve regurgitation has been well documented. However, no data linking previous drug exposure to the frequency of diagnosis of drug-induced valvular heart disease (DI-VHD) are available. The present study was conducted to address this issue. Methods and results This echocardiography reader-blinded, controlled study conducted in 10 centres between February 2010 and February 2012 prospectively included 835 subjects previously exposed to Benfluorex referred by primary care physicians for echocardiography. Based on blinded off-line analysis, echocardiography findings were classified as: (i) DI-VHD (+) for patients with an echocardiographic diagnosis of DI-VHD, (ii) inconclusive, and (iii) DI-VHD (−) for patients without signs of DI-VHD. Fifty-seven (6.8%) patients exposed to Benfluorex were classified as DI-VHD (+), 733 (87.8%) patients were classified as DI-VHD (−), and 45 (5.4%) were classified as inconclusive. Mitral and aortic DI-VHD were reported in 43 patients (5.1%) and 30 (3.6%) patients, respectively. Longer duration of exposure, female gender, smoking, and lower BMI were independently associated with a diagnosis of DI-VHD. Good inter-observer reproducibility was observed for the echocardiography classification (Kappa = 0.83, P < 0.00001). Conclusions About 7% of patients without a history of heart valve disease previously exposed to Benfluorex present echocardiography features of DI-VHD. Further studies are needed to study the natural history of DI-VHD and to identify risk factors for the development of drug-induced valve lesions.
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drug induced valvular heart disease an update
Archives of Cardiovascular Diseases, 2013Co-Authors: Michel Andrejak, Christophe TribouilloyAbstract:Summary Numerous reports have shown an unquestionable association between fibrotic valve disease and the following drugs: ergot alkaloids (such as methysergide and ergotamine), ergot-derived dopaminergic agonists (such as pergolide and cabergoline) and drugs metabolized into norfenfluramine (such as fenfluramine, dexfenfluramine and Benfluorex). This review focuses on different aspects of drug-induced valvular heart disease: historical background; echocardiographic features; different drugs recognized as being responsible for valvular heart disease; and pathophysiology.
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CLINICAL/ORIGINAL PAPERS
2010Co-Authors: Florent Le Ven, Christophe Tribouilloy, Gilbert Habib, Jean-pierre Gueffet, Jean-christophe EicherAbstract:Valvular heart disease associated with Benfluorex therapy: results from the French multicentre registr
Yannick Jobic - One of the best experts on this subject based on the ideXlab platform.
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drug induced or rheumatic valvular heart disease in patients exposed to Benfluorex
PLOS ONE, 2016Co-Authors: Zarrin Alavi, Yannick Jobic, Yves Etienne, Romain Didier, Raphael PorcherAbstract:: There is a risk of misdiagnosis between Benfluorex-induced VHD and acute rheumatic fever (ARF)-related VHD due to common characteristics of both etiologies. We aimed at estimating the probability for a patient exposed to Benfluorex presenting with VHD to have, at the same time, a history of ARF-related VHD. Such epidemiological approach could help at reducing the risk of misdiagnosis. We used INSEE data and related literature as well as various modeling hypotheses to drive and test a formula for calculating the probability of a patient presenting with VHD and a history of Benfluorex intake to have a prior history of ARF-related VHD. Different scenarios were estimated by a Markov model on the life course of people born in France between 1940 and 1960. Sensitivity analyses were performed under these scenarios. According to the different scenarios and gender, the probability that a patient born between 1940 and 1960 presenting with VHD and a history of Benfluorex intake would have had a prior history of ARF-related VHD varied from 0.2% to 2.7%. The probabilities by the year of birth were as follows: 0.8%-2.7% for a patient born in 1940, < 0.5% in all scenarios for patients born after 1955, and < 0.2% in all scenarios for patients, born in 1960. Our results indicate that the burden of ARF-related VHD is low in the patient population exposed to Benfluorex. The probability of ARF related VHD should not be over-estimated in the diagnostic procedure of VHD.
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Estimated probability of a history of ARF-related VHD in a patient born between 1940 and 1960 presenting with VHD and a history of Benfluorex intake under the different scenarios.
2016Co-Authors: Florent Le Ven, Yannick Jobic, Zarrin Alavi, Yves Etienne, Romain Didier, Raphael PorcherAbstract:Results are expressed as percent. Estimates are obtained with a probability of VHD in patients treated by Benfluorex of 16%, whereas the range obtained with probabilities varying from 7% to 22% are given in parentheses.
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ARF incidence rates and resulting probability of ARF-related VHD.
2016Co-Authors: Florent Le Ven, Yannick Jobic, Zarrin Alavi, Yves Etienne, Romain Didier, Raphael PorcherAbstract:Panel A displays the shape of the incidence rate of ARF according to patient age between 0 and 30 years, for a reference incidence rate of 50 per 100,000. Panel B presents the reference incidence rate for each year between 1940 and 1986 for the three core scenarios. The results on the probability of ARF-related VHD in a patient presenting in 2013 with VHD and a history of Benfluorex are given on the panel C, according to the year of birth of the patient.
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food and drug administration criteria for the diagnosis of drug induced valvular heart disease in patients previously exposed to Benfluorex a prospective multicentre study
European Journal of Echocardiography, 2015Co-Authors: Sylvestre Marechaux, Yannick Jobic, Stephane Ederhy, Erwan Donal, Patricia Reant, Elise Arnalsteen, Jacques Boulanger, Thierry Garban, Dan Rusinaru, Pierrevladimir EnnezatAbstract:Aims The Food and Drug Administration (FDA) criteria for diagnosis of drug-induced valvular heart disease (DIVHD) are only based on the observation of aortic regurgitation ≥ mild and/or mitral regurgitation ≥ moderate. We sought to evaluate the diagnostic value of FDA criteria in a cohort of control patients and in a cohort of patients exposed to a drug (Benfluorex) known to induce VHD. Methods and results This prospective, multicentre study included 376 diabetic control patients not exposed to valvulopathic drugs and 1000 subjects previously exposed to Benfluorex. Diagnosis of mitral or aortic DIVHD was based on a combined functional and morphological echocardiographic analysis of cardiac valves. Patients were classified according to the FDA criteria [mitral or aortic-FDA(+) and mitral or aortic-FDA(−)]. Among the 376 control patients, 2 were wrongly classified as mitral-FDA(+) and 17 as aortic-FDA(+) (0.53 and 4.5% of false positives, respectively). Of those exposed to Benfluorex, 48 of 58 with a diagnosis of mitral DIVHD (83%) were classified as mitral-FDA(−), and 901 of the 910 patients (99%) without a diagnosis of the mitral DIVHD group were classified as mitral-FDA(−). All 40 patients with a diagnosis of aortic DIVHD were classified as aortic-FDA(+), and 105 of the 910 patients without a diagnosis of aortic DIVHD (12%) were classified aortic-FDA(+). Older age and lower BMI were independent predictors of disagreement between FDA criteria and the diagnosis of DIVHD in patients exposed to Benfluorex (both P ≤ 0.001). Conclusions FDA criteria solely based on the Doppler detection of cardiac valve regurgitation underestimate for the mitral valve and overestimate for the aortic valve the frequency of DIVHD. Therefore, the diagnosis of DIVHD must be based on a combined echocardiographic and Doppler morphological and functional analysis of cardiac valves
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frequency of drug induced valvular heart disease in patients previously exposd to Benfluorex a multicentre prospective study
European Heart Journal, 2013Co-Authors: Christophe Tribouilloy, Yannick Jobic, Sylvestre Marechaux, Stephane Ederhy, Erwan Donal, Patricia Reant, Elise Arnalsteen, Jacques Boulanger, Thierry Garban, Pierrevladimir EnnezatAbstract:Aims The epidemiologic link between Benfluorex use and an increased global frequency of left heart valve regurgitation has been well documented. However, no data linking previous drug exposure to the frequency of diagnosis of drug-induced valvular heart disease (DI-VHD) are available. The present study was conducted to address this issue. Methods and results This echocardiography reader-blinded, controlled study conducted in 10 centres between February 2010 and February 2012 prospectively included 835 subjects previously exposed to Benfluorex referred by primary care physicians for echocardiography. Based on blinded off-line analysis, echocardiography findings were classified as: (i) DI-VHD (+) for patients with an echocardiographic diagnosis of DI-VHD, (ii) inconclusive, and (iii) DI-VHD (−) for patients without signs of DI-VHD. Fifty-seven (6.8%) patients exposed to Benfluorex were classified as DI-VHD (+), 733 (87.8%) patients were classified as DI-VHD (−), and 45 (5.4%) were classified as inconclusive. Mitral and aortic DI-VHD were reported in 43 patients (5.1%) and 30 (3.6%) patients, respectively. Longer duration of exposure, female gender, smoking, and lower BMI were independently associated with a diagnosis of DI-VHD. Good inter-observer reproducibility was observed for the echocardiography classification (Kappa = 0.83, P < 0.00001). Conclusions About 7% of patients without a history of heart valve disease previously exposed to Benfluorex present echocardiography features of DI-VHD. Further studies are needed to study the natural history of DI-VHD and to identify risk factors for the development of drug-induced valve lesions.
Junliang Chen - One of the best experts on this subject based on the ideXlab platform.
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hnf4α is involved in lc pufa biosynthesis by up regulating gene transcription of elongase in marine teleost siganus canaliculatus
International Journal of Molecular Sciences, 2018Co-Authors: Xiaowei Zeng, Cuihong You, Yewei Dong, Cuiying Chen, Guoxia Tang, Junliang ChenAbstract:The rabbitfish Siganus canaliculatus is the first marine teleost shown to be able to biosynthesize long-chain polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors catalyzed by two fatty acyl desaturases (fad) including Δ4 Fad and Δ6/Δ5 Fad as well as two elongases (Elovl4 and Elovl5). Previously, hepatocyte nuclear factor 4α (Hnf4α) was demonstrated to be predominant in the transcriptional regulation of two fads. To clarify the regulatory mechanisms involved in rabbitfish lipogenesis, the present study focused on the regulatory role of Hnf4α to elovl5 expression and LC-PUFA biosynthesis. Bioinformatics analysis predicted two potential Hnf4α elements in elovl5 promoter, one binding site was confirmed to interact with Hnf4α by gel shift assays. Moreover, overexpression of hnf4α caused a remarkable increase both in elovl5 promoter activity and mRNA contents, while knock-down of hnf4α in S. canaliculatus hepatocyte line (SCHL) resulted in a significant decrease of elovl5 gene expression. Meanwhile, hnf4α overexpression enhanced LC-PUFA biosynthesis in SCHL cell, and intraperitoneal injection to rabbitfish juveniles with Hnf4α agonists (Alverine and Benfluorex) increased the expression of hnf4α, elvol5 and Δ4 fad, coupled with an increased proportion of total LC-PUFA in liver. The results demonstrated that Hnf4α is involved in LC-PUFA biosynthesis by up-regulating the transcription of the elovl5 gene in rabbitfish, which is the first report of Hnf4α as a transcription factor of the elovl5 gene in vertebrates.
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hnf4α is involved in the regulation of vertebrate lc pufa biosynthesis insights into the regulatory role of hnf4α on expression of liver fatty acyl desaturases in the marine teleost siganus canaliculatus
Fish Physiology and Biochemistry, 2018Co-Authors: Shuqi Wang, Cuihong You, Yewei Dong, Junliang Chen, Danli Jiang, Qinghao Zhang, Douglas R Tocher, Oscar MonroigAbstract:Long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis is an important metabolic pathway in vertebrates, especially fish, considering they are the major source of n-3 LC-PUFA in the human diet. However, most fish have only limited capability for biosynthesis of LC-PUFA. The rabbitfish (Siganus canaliculatus) is able to synthesize LC-PUFA as it has all the key enzyme activities required including Δ6Δ5 Fads2, Δ4 Fads2, Elovl5, and Elovl4. We previously reported a direct interaction between the transcription factor Hnf4α and the promoter regions of Δ4 and Δ6Δ5 Fads2, which suggested that Hnf4α was involved in the transcriptional regulation of fads2 in rabbitfish. For functionally investigating it further, a full-length cDNA of 1736-bp-encoding rabbitfish Hnf4α with 454 amino acids was cloned, which was highly expressed in intestine, followed by liver and eyes. Similar to the expression characteristics of its target genes Δ4 and Δ6Δ5 fads2, levels of hnf4α mRNA in liver and eyes were higher in fish reared at low salinity than those reared in high salinity. After the rabbitfish primary hepatocytes were, respectively, incubated with alverine, Benfluorex or BI6015, which were anticipated agonists or antagonist for Hnf4α, the mRNA level of Δ6Δ5 and Δ4 fads2 displayed a similar change tendency with that of hnf4α mRNA. Furthermore, when the mRNA level of hhf4α was knocked down using siRNA, the expression of Δ6Δ5 and Δ4 fads2 also decreased. Together, these data suggest that Hnf4α is involved in the transcriptional regulation of LC-PUFA biosynthesis, specifically, by targeting Δ4 and Δ6Δ5 fads2 in rabbitfish.
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Hnf4α Is Involved in LC-PUFA Biosynthesis by Up-Regulating Gene Transcription of Elongase in Marine Teleost Siganus canaliculatus
'MDPI AG', 2018Co-Authors: Xiaowei Zeng, Cuihong You, Yewei Dong, Cuiying Chen, Guoxia Tang, Junliang Chen, Shuqi WangAbstract:The rabbitfish Siganus canaliculatus is the first marine teleost shown to be able to biosynthesize long-chain polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors catalyzed by two fatty acyl desaturases (fad) including Δ4 Fad and Δ6/Δ5 Fad as well as two elongases (Elovl4 and Elovl5). Previously, hepatocyte nuclear factor 4α (Hnf4α) was demonstrated to be predominant in the transcriptional regulation of two fads. To clarify the regulatory mechanisms involved in rabbitfish lipogenesis, the present study focused on the regulatory role of Hnf4α to elovl5 expression and LC-PUFA biosynthesis. Bioinformatics analysis predicted two potential Hnf4α elements in elovl5 promoter, one binding site was confirmed to interact with Hnf4α by gel shift assays. Moreover, overexpression of hnf4α caused a remarkable increase both in elovl5 promoter activity and mRNA contents, while knock-down of hnf4α in S. canaliculatus hepatocyte line (SCHL) resulted in a significant decrease of elovl5 gene expression. Meanwhile, hnf4α overexpression enhanced LC-PUFA biosynthesis in SCHL cell, and intraperitoneal injection to rabbitfish juveniles with Hnf4α agonists (Alverine and Benfluorex) increased the expression of hnf4α, elvol5 and Δ4 fad, coupled with an increased proportion of total LC-PUFA in liver. The results demonstrated that Hnf4α is involved in LC-PUFA biosynthesis by up-regulating the transcription of the elovl5 gene in rabbitfish, which is the first report of Hnf4α as a transcription factor of the elovl5 gene in vertebrates
Tribouilloy Christophe - One of the best experts on this subject based on the ideXlab platform.
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Sub-aortic obstruction of left ventricular outflow tract secondary to Benfluorex-induced endocardial fibrosis
2017Co-Authors: Catherine Szymanski Catherine Szymanski, Sylvestre Maréchaux, Patrick Bruneval Patrick Bruneval, Michel Andréjak, Montpréville Vincent, Emre Belli Emre Belli, Tribouilloy ChristopheAbstract:Patients exposed to Benfluorex have an increased risk of restrictive organic valvular heart disease. Aortic and mitral regurgitations caused by fibrotic valve disease are the most common features observed in exposure to fenfluramine derivatives in general and Benfluorex in particular. We report here, for the first time to our knowledge, a well-documented case in which obstructive sub-aortic endocardium fibrosis within the left ventricular outflow tract is related with exposure to a drug that modifies the metabolism of serotonin. It now remains to be established whether extensive fibrosis of the myocardium in addition to well-documented valvular fibrosis may develop in patients exposed to amphetamine-derived drugs affecting the serotonin system
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142: Increased Risk of Left Heart Valve Regurgitation Associated with Benfluorex Use in Patients with Diabetes Mellitus. A Multicentre Study
Elsevier Masson SAS., 2013Co-Authors: Tribouilloy Christophe, Rusinaru Dan, Maréchaux Sylvestre, Jeu Antoine, Ederhy Stéphane, Donal Erwan, Réant Patricia, Arnalsteen Elise, Boulanger Jacques, Ennezat Pierre-vladimirAbstract:BackgroundBenfluorex was withdrawn from European markets in June 2010 following reports of an association with heart valve lesions. The link between Benfluorex and valve regurgitations was based on small observational studies and retrospective estimations. We therefore designed an echocardiography-based multicenter study to compare the frequency of left heart valve regurgitations in diabetic patients exposed to Benfluorex for at least three months and in diabetic controls never exposed to the drug.MethodsThis reader-blinded controlled study conducted in ten centres in France included prospectively between November 2009 and September 2011 393 consecutive diabetic subjects previously exposed to Benfluorex referred by primary care physicians for echocardiography screening and 393 diabetic controls. Using propensity scores, 303 patients and 303 controls were matched for age, gender, body mass index, smoking, dyslipidemia, hypertension, coronary artery disease, and previous use of other drugs associated with valve lesions. The main outcome measure was the frequency of mild or greater left heart valve regurgitations.FindingsIn the matched sample, the frequency and relative risk (OR) of mild or greater left heart valve regurgitations were significantly increased in Benfluorex patients compared to controls: 30·0% vs. 13·5% (OR 2.96[1·94-4·53]) for aortic and/or mitral regurgitation; 21·1% vs. 5·0% (OR 5·63[3·08-10·3]) for aortic regurgitation, and 17·2% vs. 10·2% (OR 1·99[1·22-3·25]) for mitral regurgitation. The frequency of moderate left heart valve regurgitations was also increased among Benfluorex patients vs. controls (7·3% vs. 0·7%; OR 13·9[3·21-60·7].InterpretationOur results indicate that use of Benfluorex is associated with significant increase in the frequency of left heart valve regurgitations. The natural history of Benfluorex-induced valve abnormalities needs further research.FigureLeft heart regurgitations in patients vs. control
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Frequency of drug-induced valvular heart disease in patients previously exposd to Benfluorex: a multicentre prospective study.
'Oxford University Press (OUP)', 2013Co-Authors: Tribouilloy Christophe, Jobic Yannick, Maréchaux Sylvestre, Jeu Antoine, Ederhy Stéphane, Donal Erwan, Réant Patricia, Arnalsteen Elise, Boulanger Jacques, Garban ThierryAbstract:International audienceAIMS: The epidemiologic link between Benfluorex use and an increased global frequency of left heart valve regurgitation has been well documented. However, no data linking previous drug exposure to the frequency of diagnosis of drug-induced valvular heart disease (DI-VHD) are available. The present study was conducted to address this issue. METHODS AND RESULTS: This echocardiography reader-blinded, controlled study conducted in 10 centres between February 2010 and February 2012 prospectively included 835 subjects previously exposed to Benfluorex referred by primary care physicians for echocardiography. Based on blinded off-line analysis, echocardiography findings were classified as: (i) DI-VHD (+) for patients with an echocardiographic diagnosis of DI-VHD, (ii) inconclusive, and (iii) DI-VHD (-) for patients without signs of DI-VHD. Fifty-seven (6.8%) patients exposed to Benfluorex were classified as DI-VHD (+), 733 (87.8%) patients were classified as DI-VHD (-), and 45 (5.4%) were classified as inconclusive. Mitral and aortic DI-VHD were reported in 43 patients (5.1%) and 30 (3.6%) patients, respectively. Longer duration of exposure, female gender, smoking, and lower BMI were independently associated with a diagnosis of DI-VHD. Good inter-observer reproducibility was observed for the echocardiography classification (Kappa = 0.83, P < 0.00001). CONCLUSIONS: About 7% of patients without a history of heart valve disease previously exposed to Benfluorex present echocardiography features of DI-VHD. Further studies are needed to study the natural history of DI-VHD and to identify risk factors for the development of drug-induced valve lesions
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Increased risk of left heart valve regurgitation associated with Benfluorex use in patients with diabetes mellitus: a multicenter study.
'Ovid Technologies (Wolters Kluwer Health)', 2012Co-Authors: Tribouilloy Christophe, Rusinaru Dan, Maréchaux Sylvestre, Jeu Antoine, Ederhy Stéphane, Donal Erwan, Réant Patricia, Arnalsteen Elise, Boulanger Jacques, Ennezat Pierre-vladimirAbstract:International audienceBACKGROUND: Benfluorex was withdrawn from European markets in June 2010 after reports of an association with heart valve lesions. The link between Benfluorex and valve regurgitations was based on small observational studies and retrospective estimations. We therefore designed an echocardiography-based multicenter study to compare the frequency of left heart valve regurgitations in diabetic patients exposed to Benfluorex for at least 3 months and in diabetic control subjects never exposed to the drug. METHODS AND RESULTS: This reader-blinded, controlled study conducted in 10 centers in France between February 2010 and September 2011 prospectively included 376 diabetic subjects previously exposed to Benfluorex who were referred by primary care physicians for echocardiography and 376 diabetic control subjects. Through the use of propensity scores, 293 patients and 293 control subjects were matched for age, sex, body mass index, smoking, dyslipidemia, hypertension, and coronary artery disease. The main outcome measure was the frequency of mild or greater left heart valve regurgitations. In the matched sample, the frequency and relative risk (odds ratio) of mild or greater left heart valve regurgitations were significantly increased in Benfluorex patients compared with control subjects: 31.0% versus 12.9% (odds ratio, 3.55; 95% confidence interval, 2.03-6.21) for aortic and/or mitral regurgitation, 19.8% versus 4.7% (odds ratio, 5.29; 95% confidence interval, 2.46-11.4) for aortic regurgitation, and 19.4% versus 9.6% (odds ratio, 2.38; 95% confidence interval, 1.27-4.45) for mitral regurgitation. CONCLUSIONS: Our results indicate that the use of Benfluorex is associated with a significant increase in the frequency of left heart valve regurgitations in diabetic patients. The natural history of Benfluorex-induced valve abnormalities needs further research
Marc Humbert - One of the best experts on this subject based on the ideXlab platform.
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Benfluorex and Unexplained Valvular Heart Disease: A Case-Control Study
2013Co-Authors: Irène Frachon, Yves Etienne, Grégoire Le Gal, Marc HumbertAbstract:Background: Recent case reports suggest that Benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation. Methods: We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1 st 2003 and June 30 th 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an ‘‘explained’ ’ mitral regurgitation. Other patients were considered as having an ‘‘unexplained’ ’ mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an ‘‘explained’ ’ mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians. Results: Out of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of Benfluorex wa
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Drug-induced pulmonary arterial hypertension: a recent outbreak.
European respiratory review : an official journal of the European Respiratory Society, 2013Co-Authors: David Montani, Gérald Simonneau, Andrei Seferian, Laurent Savale, Marc HumbertAbstract:Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and Benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.
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Benfluorex and unexplained valvular heart disease: a case-control study.
PLoS ONE, 2010Co-Authors: Irène Frachon, Yannick Jobic, Marc Humbert, Yves Etienne, Grégoire Le Gal, Christophe LeroyerAbstract:BACKGROUND: Recent case reports suggest that Benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation. METHODS: We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1(st) 2003 and June 30(th) 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an "explained" mitral regurgitation. Other patients were considered as having an "unexplained" mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an "explained" mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians. RESULTS: Out of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of Benfluorex was reported in 22 patients: 19 of the 27 cases, versus 3 of the 54 controls, odds-ratio 17.1 (3.5 to 83), adjusted for body mass index, diabetes and dexfenfluramine use. CONCLUSION: The use of Benfluorex is associated with unexplained mitral regurgitation.
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Fenfluramine-like cardiovascular side-effects of Benfluorex.
European Respiratory Journal, 2009Co-Authors: K. Boutet, Irène Frachon, Yannick Jobic, Christophe Gut-gobert, Christophe Leroyer, Dominique Carlhant-kowalski, Olivier Sitbon, Gérald Simonneau, Marc HumbertAbstract:Since 1976, Benfluorex has been approved in Europe as a hypolipidemic and hypoglycemic drug, and is commonly used in the treatment of the metabolic syndrome. As a derivative of fenfluramine with an appetite suppressant action, Benfluorex is preferentially used in overweight patients. In contrast to fenfluramine and dexfenfluramine, to date, Benfluorex has not been reported to be associated with frequent cardiovascular side-effects. The present study reports five cases of severe pulmonary arterial hypertension and one case of valvular heart disease occurring in patients exposed to Benfluorex. These individuals were middle age, diabetic females with a body mass index ranging 24.2-49 kg x m(-2). No definite causal effect for cardiovascular disease with Benfluorex can be drawn from such case reports. However, as Benfluorex, like dexfenfluramine and fenfluramine, is metabolised into active metabolite norfenfluramine, further extensive assessment of drug exposure in newly diagnosed pulmonary arterial hypertension or valvular heart disease patients is warranted.