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Benfluorex is a pharmacological agent with antidiabetic and antihyperlipidemic properties. In this study, the brain's oxidative and non-enzymatic antioxidant status in diabetic and benfluorex administrated diabetic rats have been investigated. For the experimental procedures, three groups of 18 Wistar albino rats were used as the control, diabetes (induced by streptozotocin), and benfluorex treated diabetic rats (benfluorex administration intragastric 50 mg/kg daily for 21 days). Brain NOx, TBARS, GSH, AA levels, and MPO activity were determined spectrophotometrically. Benfluorex administration was caused that decreased lipid peroxidation and MPO activity while increased non-enzymatic antioxidant and NOx levels. These results showed that benfluorex treatment positively affects lipid peroxidation and non-enzymatic antioxidant status of the brain during diabetes.

We report the discovery of strong HNF4α agonists and their use to uncover a previously unknown pathway by which HNF4α controls the level of fat storage in the liver. This involves the induction of lipophagy by dihydroceramides, the synthesis and secretion of which is controlled by genes induced by HNF4α. The HNF4α activators are N-trans caffeoyltyramine (NCT) and N-trans feruloyltyramine (NFT), which are structurally related to the known drugs alverine and benfluorex, which we previously showed to be weak HNF4α activators. In vitro, NCT and NFT induced fat clearance from palmitate-loaded cells. In DIO mice, NCT led to recovery of hepatic HNF4α expression and reduction of steatosis. Mechanistically, increased dihydroceramide production and action downstream of HNF4α occurred through increased expression of HNF4α downstream genes, including SPNS2 and CYP26A1. NCT was completely nontoxic at the highest dose administered and so is a strong candidate for an NAFLD therapeutic.

Background Drug-induced valvular heart disease (DI-VHD) is a well-defined condition associated with specific pathology features. However, clinical presentations may broadly vary and thereby make DI-VHD diagnosis more challenging. Case summary We report two patients with a history of benfluorex administration, who developed extensive mitral calcific lesions which evolved towards caseous necrosis. Discussion Prospective follow-up over several years of these two patients who initially had typical DI-VHD findings provided monitoring evidence of extensive calcifications and subsequent caseous necrosis. These reports suggest a link between calcific heart injury and benfluorex exposure. The diagnosis of DI-VHD may be overlooked at this late stage.

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 μM Benfluorex, 5 μM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.

Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.

International audience; 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

To answer the questions that arise in relation to a patient’s clinical situation, medical decisions need to be made according to the principles of evidence-based medicine. At this time, the benefits and risks of glycaemic control in patients with type 2 diabetes require painstaking reconsideration.1 Even if chronic hyperglycaemia is a risk marker for some macro- and microvascular complications, that does not mean ipso facto that its reduction by one or several hypoglycaemic drugs is systematically beneficial to patients from a clinical point of view. The potential benefits derived from pharmacological glycaemic control can be counterbalanced by frequent and/or severe clinical adverse events. For example, numerous hypoglycaemic drugs have either not been made commercially available or have been withdrawn from the market in France because their risk–benefit ratio was deemed unfavourable: tolbutamide, phenformin, troglitazone, rosiglitazone, pioglitazone, benfluorex, rimonabant, muraglitazar, and aleglitazar. This was even though they pronouncedly reduced blood glucose level (on average from 0.5% to 2% of HbA1c). The main reason has had less to do with their clinical adverse events than with the lack of evidence of their clinical benefits. Had the efficacy of these drugs been demonstrated in terms of reduced morbidity and/or mortality, they would probably be on the market. To sum up, the scientific rationale for pharmacological treatment of patients with type 2 diabetes depends on the answers to two major questions: Several RCTs2–5 have evaluated the intensified glycaemic control strategies targeting an HbA1c level

Benfluorex is responsible for the development of restrictive valvular regurgitation due to one of its metabolites, norfenfluramine. The 5-HT2B receptor, expressed on heart valves, acts as culprit receptor for drug-induced valvular heart disease (VHD). Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways. Valve lesions essentially involve the mitral and/or aortic valves. The randomised prospective REGULATE trial shows a threefold increase in the incidence of valvular regurgitation in patients exposed to benfluorex. A cross-sectional trial shows that about 7% of patients without a history of VHD previously exposed to benfluorex present echocardiographic features of drug-induced VHD. The excess risks of hospitalisation for cardiac valvular insufficiency and of valvular replacement surgery were respectively estimated to 0.5 per 1000 and 0.2 per 1000 exposed patients per year. Recent data strongly suggest an aetiological link between benfluorex exposure and pulmonary arterial hypertension (PAH). The PAH development may be explained by serotonin, which creates a pulmonary vasoconstriction through potassium-channel blockade. Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects.

Background Enrolling cancer patients into clinical trials is an endearing process. Pharmaceutical companies fund nearly 40% of these cancer trials. A variety of considerations take part in a patient's decision to participate to a clinical trial, including their opinion regarding the pharmaceutical industry. Recently, benfluorex (Mediator®), a drug first marketed in 1976 for hyperlipidemia and diabetes by a French pharmaceutical company, has filled the French headlines repeatedly because of efficacy and safety issues. The impact of this scandal on French cancer patients’ attitude toward clinical trials is not known. The aims of this study were to determine i) cancer patients’ opinion toward the pharmaceutical industry, physicians, and research, and ii) their willingness to participate to clinical trials, in the context of the benfluorex scandal. Methods To investigate this issue, a self-administered anonymous survey was performed in 221 French cancer patients. The survey instrument collected information about age, gender, and whether the patient already participated to a clinical trial. A question with multiple answers queried whether the benfluorex situation casted suspicion on the pharmaceutical industry, physicians, clinical research funded by the pharmaceutical industry, or research as a whole. A yes or no question queried patients’ willingness to participate to clinical trials funded by the pharmaceutical industry. Logistic regression was used to examine the relationship between patients’ characteristics and the dependent variables. Results Median age was 64 years (range 19 to 86 years) and 57% of the patients were female. Thirty three percent of the patients had already participated to a clinical trial. Eighty five percent of the patients declared that clinical research was necessary, 11% that it was useful, less than 1% that it was not useful, and 4% of the patients did not know. The benfluorex scandal induced distrust toward the pharmaceutical companies in 75% of the patients, toward research funded by these companies in 43% of the patients, research as a whole in 20% of the patients, and toward physicians in 14% of the patients. These results were not influenced by age, gender, or previous participation to a clinical trial. Regarding their attitude toward clinical trials funded by the pharmaceutical industry, 60% of the patients declared that they were not willing to participate, 25% of them that they would participate, and 15% that they did not know. A negative answer was less likely when patients had previously participated to a clinical trial. Conclusions Although no connection exists between benfluorex and cancer, these results show that this scandal significantly impaired French cancer patients’ trust toward the pharmaceutical companies and research, and their willingness to participate to clinical trials funded by the pharmaceutical industry. These results highlight the need to better understand patients’ motivation to help implement strategies to maintain their participation to clinical trials. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-09-21.

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.

Summary Background Given the association between valvular heart disease and drugs that alter serotonin metabolism, concerns have been raised about the possibility of an association between selective serotonin reuptake inhibitor (SSRI) use and drug-induced valvular disease. In France, SSRI use has been suggested to be an important confounding factor in the development of heart valve lesions in patients exposed to benfluorex in the context of the ‘Mediator scandal’. Aims To address the relationship between SSRI use and valve regurgitation and morphology in a large cohort of patients exposed to benfluorex. Methods Overall, 832 consecutive patients exposed to benfluorex prospectively referred to 10 centres underwent complete echocardiography examinations according to a standardized protocol. Echocardiograms were independently and blindly read off-line by two experts. Results Ninety patients had been exposed to SSRIs for 3 months or more. The proportions of patients with no or trivial, mild, moderate or severe mitral regurgitation (MR) or aortic regurgitation (AR) were not different between SSRI patients and non-SSRI patients (P = 0.63 and 0.58, respectively). The frequencies of AR ≥ mild (20 [22.2%] vs 145 [19.5%]; P = 0.55) and MR ≥ mild (14 [15.6%] vs 118 [15.9%]; P = 0.93) were similar in SSRI patients and non-SSRI patients. The frequencies of aortic and mitral valve abnormalities suggestive of drug-induced toxicity were also similar in the two patient groups. Multivariable logistic regression analysis confirmed the absence of any identifiable relationship between AR or MR and morphological abnormalities and SSRI use in the present cohort. Conclusion Exposure to SSRIs was not associated with an increased risk of heart valve regurgitation or morphological abnormalities suggestive of drug-induced toxicity in this large cohort of patients exposed to benfluorex.

In January 2011, the French General Inspectorate for Social Affairs (IGAS) issued a special report on the drug called Mediator, a benfluorex preparation, which had been marketed in the country sinc...

The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings and previously unknown to share mechanistic or structural similarity, activated the nuclear receptor transcription factor HNF4α. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path towards the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.

SummaryNumerous 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.

Since September 1st 2011, the National Bureau for Compensation of Medical Accidents represents a unique portal for out-of-court settlement of litigations concerning the harm caused by benfluorex. In December 2012, its official record is as follows: 7627 patients files have been received, 1378 have been studied, 797 led to a recommendation, and compensation by the drug company Servier has been recommended for 46 cases. The large number of rejections raises a problem which needs to be examined in the light of the available evidence on benfluorex associated heart valve disease. This evidence concerns both the morphological characteristics of the disease and the epidemiology of its association with benfluorex. More than 90% of emergent double valve disease (aortic and mitral regurgitation), of emergent aortic valve regurgitation, and of prevalent grade 2 aortic valve regurgitation are attributable to benfluorex. The proportion of benfluorex-attributable disease is larger than 75% for prevalent double valve disease, or for prevalent aortic valve regurgitation of any grade. This probabilistic information, derived from the available epidemiological studies, needs to be considered as part of the evidence to establish or refute a causal link between benfluorex and valvular disease for a given patient, particularly if the patient has a low grade valvular insufficiency or no morphological anomaly.

While statisticians and quantitative social scientists typically study the "effects of causes" (EoC), Lawyers and the Courts are more concerned with understanding the "causes of effects" (CoE). EoC can be addressed using experimental design and statistical analysis, but it is less clear how to incorporate statistical or epidemiological evidence into CoE reasoning, as might be required for a case at Law. Some form of counterfactual reasoning, such as the "potential outcomes" approach championed by Rubin, appears unavoidable, but this typically yields "answers" that are sensitive to arbitrary and untestable assumptions. We must therefore recognise that a CoE question simply might not have a well-determined answer. It is nevertheless possible to use statistical data to set bounds within which any answer must lie. With less than perfect data these bounds will themselves be uncertain, leading to a compounding of different kinds of uncertainty. Still further care is required in the presence of possible confounding factors. In addition, even identifying the relevant "counterfactual contrast" may be a matter of Policy as much as of Science. Defining the question is as non-trivial a task as finding a route towards an answer. This paper develops some technical elaborations of these philosophical points, and illustrates them with an analysis of a case study in child protection. Keywords: benfluorex, causes of effects, counterfactual, child protection, effects of causes, Fre'chet bound, potential outcome, probability of causation, Comment: 27 pages, 1 table, 9 figures. This is a fairly substantial revision of version 1

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.

Objective: To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of medicines from European market due to safety reasons. Methods: Medicines with data from longitudinal studies were included. Studies were identified from European Medicines Agency’s Reports. Meta-analyses were performed to pool odds ratios (OR) with 95% confidence-intervals (CI). Published control event rates were applied to ORs to calculate NNTHs (95%CI) for selected adverse events. Results: NNTH (95%CI) decreased from pre- to post-marketing for the eight medicines included: peripheral neuropathy (∞ vs. 12[non-significant; NS] with almitrine; heart valve disease with benfluorex (∞ vs. NNTH ranging from 7[4–13] to 7[5–9]); myopathy (−4096[NS] vs. 797[421–1690]), new-onset diabetes (113[NS] vs. 390[425–778]), bleeding (∞ vs. 517[317–1153]), and infection (∞ vs. 253[164–463]) with niacin-laropiprant; psychiatric disorders (12[7–34] vs. 9[5–24]) with rimonabant; myocardial infarction (MI) [−1305 vs. 270[89–4362]) with rofecoxib; MI (−510 vs. NNTH ranging from 152[55–4003] to 568[344–1350]) with rosiglitazone; cardiovascular events (∞ vs. 245[129–1318]) with sibutramine; and liver injury (∞ vs. 5957[NS]) with ximelagatran. Conclusion: NNTH have potential of use as a supportive tool in benefit-risk re-evaluations of medicines and may help regulators to making decisions on drug safety.

A simple LC/UV method for the simultaneous identification and quantification of Fluoxetine, Tiratricol, Benfluorex and Pseudoephedrine in slimming formulation is proposed. The method demonstrated effective in the analyses of herbal mixtures marketed in Italy as slimming capsules. Sixteen different herbal mixtures, selected among the most frequently compounded in Italian pharmacies, were tested as matrices. HPLC analyses were performed in a gradient mode on a C18 stationary phase The method was validated for accuracy, precision, linearity and selectivity. The limits of detection (LOD) were 3.4 μg/mL for Pseudoephedrine, 1.1 μg/mL for Triac, 0.9 μg/mL for Fluoxetine, and 0.8 μg/mL for Benfluorex. Repeatability and intermediate precision, expressed as percent of relative standard deviation, ranged from 3 to 7 and from 7 to 12, respectively. Given these limits, the developed method is proposed for the simple and cost effective screening of herbal products illegally adulterated with these four drugs known to enhance slimming effects.