Adverse effects of benfluorex on heart valves and pulmonary circulation.

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.

Frequency of drug-induced valvular heart disease in patients previously exposd to benfluorex: a multicentre prospective study.

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.

Valvular heart disease associated with long-term treatment by methysergide: a case report.

This case report concerns a woman treated continuously since at least 10 years by methysergide for cluster headache. The echocardiographic and histological features of the severe valve fibrosis presented by this patient are very similar to those described with 5 HT(2B) receptors agonistic drugs.

The end-of-treatment ribavirin concentration predicts hepatitis C virus relapse.

BACKGROUND: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse. METHODS: Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass-spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers. RESULTS: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 ± 312 ng/mL for relapsers and 2278 ± 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24-∞; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin-28B genotype, and response to previous courses of treatment. CONCLUSIONS: Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse.

[Sarcoïdosis and anti-TNF: a paradoxical class effect? Analysis of the French Pharmacovigilance system database and literature review]. / Sarcoïdose et anti-TNF : un effet paradoxal de classe? Analyse des cas de la base française de Pharmacovigilance et revue de la littérature.

OBJECTIVES: To identify and characterize the observations of sarcoidosis occurring during anti-TNF blockade collected in the French Pharmacovigilance system database and reported in the literature. RESULTS: Seven cases were reported in the French Pharmacovigilance system database and 39 cases (37 original) have been reported internationally. Monoclonal antibodies (infliximab and adalimumab) and fusion protein (etanercept) are equally involved. Sarcoidosis have been confirmed histologically and occurred predominantly in the rheumatoid arthritis (22) and spondylarthropathy (16). CONCLUSION: The lack of protopathic bias suggests that these paradoxical sarcoidosis occurring during treatment with anti-TNF are a class-effect, as with psoriasis, uveitis, and IBD reported under similar conditions. Their pathogenesis remains unclear.

Mechanisms of aortic and cardiac dysfunction in uremic mice with aortic calcification.

BACKGROUND: Chronic renal failure (CRF) is associated with cardiac dysfunction and increased aortic stiffness. The mechanisms involved are not clearly understood. We examined changes over time in cardiac and aortic function in a murine CRF model. METHODS AND RESULTS: Eight-week-old mice were randomly assigned to 1 of 4 groups: wild-type non-CRF, wild-type CRF, apolipoprotein E knockout non-CRF, and apolipoprotein E knockout CRF. Echocardiography was performed and blood samples were taken at baseline and after 6 and 10 weeks of CRF. Vascular reactivity and adhesion molecule expression were studied after 6 and 10 weeks of CRF. Left ventricular hypertrophy, altered left ventricular relaxation, and increased aortic stiffness were observed after 6 weeks of CRF and persisted after 10 weeks. The 4 groups of mice did not significantly differ in terms of arterial blood pressure and aortic structure. The degree of vascular calcification and serum total cholesterol concentration were higher in the CRF groups than in the non-CRF groups. These changes, however, could not explain the cardiac and vascular differences seen in the 2 CRF groups. In contrast, alterations in vascular reactivity, the upregulation of adhesion molecule expression, and CRF status were significantly associated with these changes. CONCLUSIONS: In a mouse model of CRF, left ventricular hypertrophy, cardiac diastolic dysfunction, and increased aortic stiffness were not related to structural changes in the aorta (including aortic calcification) or high serum cholesterol levels. However, cardiac and aortic abnormalities were associated with the extent of subendothelial dysfunction and the severity of CRF.

Bronchial fistula associated with sunitinib in a patient previously treated with radiation therapy.

OBJECTIVE: To report a case of bronchial fistula associated with sunitinib in a patient previously treated with radiation therapy. CASE SUMMARY: A 40-year-old man with renal cell cancer diagnosed in 2005 and initially treated by radical nephrectomy presented in March 2007 with a recurrence with cerebral, mediastinal, and lung metastases. A thoracic computed tomography (CT) scan showed a subcarinal tumor obstructing the bronchus intermedius. The patient was initially treated with cerebral and thoracic radiotherapy and then with sunitinib 50 mg/day (4 weeks on, 2 weeks off). Two months after the beginning of treatment, a CT scan revealed a dramatic reduction in the size of the tumor, associated with a bronchial fistula. This was confirmed by flexible bronchoscopy, which showed complete necrosis of the tumor and a large perforation of the bronchus intermedius. Sunitinib was immediately withdrawn and antibiotic prophylaxis was instituted. It was not possible to place an endobronchial stent. Two weeks later, flexible bronchoscopy revealed the reappearance of a yellowish mass protruding into the bronchus intermedius (40% obstruction). A few months later, the obstruction of the bronchus intermedius progressed to 90% and was associated with a contralateral obstruction of the left mainstem bronchus (20%). A rigid bronchoscopy was then performed to clear the obstruction and an endobronchial stent was placed, with satisfactory initial results. In February 2008, the patient presented with new bronchial obstruction under the endobronchial stent but refused a rigid bronchoscopy and died in March 2008. DISCUSSION: Sunitinib, a multitarget tyrosine kinase inhibitor with antiangiogenic and antitumoral activities, has been approved for the treatment of advanced renal cell carcinoma. This treatment is generally well tolerated. Serious complications may occur, however. According to the Naranjo probability scale, the bronchial fistula was possibly related to sunitinib treatment. CONCLUSIONS: This is a rare case of a bronchial perforation leading to a fistula associated with sunitinib treatment after mediastinal radiation therapy. Clinicians may consider strict follow-up of patients with proximal lung metastases treated with sunitinib (CT scan and, if appropriate, placement of an endobronchial stent).

Restrictive organic mitral regurgitation associated with benfluorex therapy.

AIMS: To investigate the association between benfluorex use and organic restrictive mitral regurgitation (MR) in patients admitted to hospital for diagnostic work-up of MR of unclear aetiology. METHODS AND RESULTS: Among patients referred between 2003 and 2008 to our tertiary centre for diagnostic work-up of MR, we retrospectively identified 22 consecutive patients (65 +/- 12 years, 64% women) with restrictive organic MR of unclear aetiology. Using propensity scores, 22 out of 156 patients who underwent surgery for dystrophic MR due to flail leaflets during the same time period were matched for age, sex, height, body weight, and diabetes with the study population. Eight of the 22 patients with restrictive organic MR of unclear aetiology (36.4%) had a history of benfluorex use, and in one patient (4.5%) we identified previous exposure to both benfluorex and fenfluramine. The frequency of benfluorex treatment in patients with restrictive organic MR of unclear aetiology was significantly higher compared with that observed in the dystrophic MR group (36.4 vs. 4.5%; P-value 0.039). Patients with restrictive MR treated with benfluorex (body mass index 31 +/- 6 kg/m(2)) were all dyslipidaemic and 67% had diabetes. Echocardiography identified moderate or severe restrictive organic MR in all cases. Median total duration of benfluorex therapy was 63(12-175) months, at a daily dose of 450 (300-450) mg, leading to a cumulative dose of 850 (108-2363) g. CONCLUSION: Although it cannot affirm a definitive causal relationship, the present study strongly suggests that patients treated with benfluorex might incur a risk of restrictive organic valvular heart disease. Therefore, echocardiography should be performed in patients exposed to benfluorex in case of occurrence of symptoms or signs of valvular disease. Further data are needed to confirm these findings.

[Quantification of the part allocated to the preventability of vitamin K antagonists therapy bleeding events]. / Evaluation de l'évitabilité des accidents hémorragiques sous antivitamines K.

A prospective cohort of patients with a high INR (>or=5) and being treated by vitamin K antagonists (VKA) was assessed in the Amiens University Hospital. One of the purposes of the study was to assess the preventability of the haemorrhages due to VKA. The preventability concept is not very used in France. Identifying the preventability part of a side effect of a drug needs an adapted and reliable tool. Although different methods of assessment of preventability have been developed, none of them is unquestionable. For the needs of our study, we built a scale of measure adapted from a scale of preventability already published by defining more accurately some items and by reducing the subjective part of the interpretation. We were able to confirm the relevance of our revised scale by testing it by two experts. After consensus on the conflicting data, two thirds of the severe bleedings were considered as "potentially or totally preventable". These data are in agreement with published data. Indeed the data found in the literature are concordant to consider that an important part of VKA bleedings events can be prevented by a better management of the treatment.

[Recommended dosage adaptation based on renal function is not always sufficient to avoid betalactam antibiotics side effects]. / Les recommandations d'adaptation posologique à la fonction rénale ne sont pas toujours suffisantes pour éviter la neurotoxicité des bêtalactamines.

The potential neurotoxicity of betalactam antibiotics are well-known and is frequently associated with drug accumulation in patients with renal failure since these antibiotics are eliminated mostly by kidneys. The regional center of pharmacovigilance of Amiens has collected since 10 years, 20 notifications of neurotoxicity induced by betalactam antibiotics. The series included eight women and 12 men. Mean age was 65 years (26-84). The drug accumulation hypothesis was strengthened in nine cases by assays of plasma levels residual concentrations. In 17 cases, betalactam antibiotics dosage was adapted to creatinin clearance in accordance to the Summary of the Product Characteristics' (SPC) recommendations. For several drugs, no adaptation to renal function was proposed by SPC. Dosage adaptation based only on renal function as it's recommended is not always efficient to avoid neurological side effects.

[Nephrogenic systemic fibrosis and gadolinium-based contrast media]. / Fibrose systémique néphrogénique et produits à base de gadolinium: données disponibles début 2007.

Nephrogenic systemic fibrosis (NSF) is a recently characterized systemic fibrosing disorder occurring in patients with underlying renal disease. This condition principally leads to skin thickening and hardening and may induce joint immobility and inability to walk. In 2006, clusters of NSF were associated to an exposure to gadolinium containing contrast agents during magnetic resonance imaging. Gadolinium has been detected in skin tissue of patients with NSF. Gadodiamide, a linear gadolinium chelate appears to be particularly at risk. During renal failure, gadodiamide accumulation may explain the development of NSF. Regulatory decisions have been taken to contraindicate gadodiamide in patients with severe renal impairment.

[Iatrogenic angioedema: the role of angiotensin converting enzyme inhibitor and angiotensin II receptor blockers]. / Angio-oedèmes iatrogènes: rôle des inhibiteurs de l'enzyme de conversion et des antagonistes des récepteurs à l'angiotensine II (sartans).

Nephrologists should be aware the fact that the angioedema is a common side effect not only under angiotensin-converting enzyme (ACE) inhibitors treatment but also under sartans therapy. The frequency of angioedema under ACE inhibitors is estimated at 1 to 7 per thousand. The physiopathology of ACE angioedema implicates the lack of degradation of kinines due to the inhibition of multiple enzymes activity including ACE. Angioedema under sartans seems less frequent than this observed under ACE inhibitors. Its mechanism remains poorly defined, but implicates the increase of kinine production via the stimulation of angiotensin receptor type II, and/or the lack of degradation of kinines via multiple enzymes other than ACE. The frequency of the apparition of angioedema under sartans in patients who had have angioedema under ACE inhibitors is inconsistent and varied from 7.7% to 50%. Reports indicated that angioedema under ACE or sartans could have a spontaneous regression. However, the relapse of angioedema under these drugs should lead to the diagnosis of iatrogenic etiology, and to the drugs withdrawal. ACE inhibitors/Sartans-associated angioedema episodes need to be reported to the French Adverse Event Reporting System database to evaluate their frequency and to avoid severe consequences.

From evidence-based medicine to personalized medicine, with particular emphasis on drug-safety monitoring.

Nowadays, guidelines are derived from the findings of randomized controlled therapeutic trials. However, an overall significant P value does not exclude that some patients may be harmed by or will not respond to the therapeutic agent being studied. Trials in patients with a low risk of events and/or a limited chance of providing significant differences in therapeutic effects require a large patient population to demonstrate a beneficial effect. Composite efficacy endpoints are often employed to obviate the need for a large patient population when low rates of events or limited therapeutic efficacy are anticipated. Results of randomized controlled therapeutic trials are commonly expressed in terms of relative risk reduction, whereas absolute risk reduction allows the calculation of the "number needed to treat" to prevent an adverse outcome. The number needed to treat is a far more clinically relevant variable than relative risk reduction. The clinician's mission is to match treatment to patient with the goal of achieving optimal therapeutic response. Drug-safety monitoring is also of major importance to avoid exposing patients to irreversible adverse effects. Unfortunately, drug-safety monitoring is often overlooked in routine clinical practice. Finally, the lack of long-term therapeutic data (>5-10 years) is an unsolved dilemma, as most trials are limited to a duration of a few months or years.

[Management of dyslipidemia in diabetic CKD patients]. / Prise en charge thérapeutique de la dyslipidémie chez les patients ayant une néphropathie diabétique.

Diabetic nephropathy is a frequent complication in type 2 diabetic. Patients with diabetic nephropathy have a characteristic dyslipidemia profile associated increased concentrations of triglycerides, reduced levels of HDL cholesterol, and qualitative abnormalities of LDL. The dyslipidemia management in patients with diabetic nephropathy not yet in dialysis includes diet, insulin sensitizers (glitazones, metformin?), and hypolipemic agents, with statins as a first choice.

Adaptation and validation of an adverse drug reaction preventability score for bleeding due to vitamin K antagonists.

Although drug therapy is inherently associated with the risk of adverse drug reactions (ADRs), some of these events are preventable. The estimated proportion of preventable ADRs varies from one study or clinical context to another. Bleeding caused by antithrombotic agents (and particularly vitamin K antagonists, VKAs) constitutes one of the most frequent causes of ADR-related hospitalization.Hence, the objective of the present study was to adapt and validate an ADR preventability score for bleeding due to VKAs and evaluate the preventability of bleeding in 906 consecutive hospitalized, VKA-treated adult patients with a risk of major bleeding (defined as an international normalized ratio ≥5) over a 2-year period. A specific preventability scale for VKA-associated bleeding was developed by adapting a published tool.Overall, 241 of the 906 patients in the study experienced at least 1 VKA-associated bleeding event. The scale's reliability was tested by 2 different evaluators. The inter-rater reliability (evaluated by calculation of Cohen's kappa) ranged from "good" to "excellent." Lastly, the validated scale was used to assess the preventability of the VKA-associated bleeding. We estimated that bleeding was preventable or potentially preventable in 109 of the 241 affected patients (45.2%).We have developed a useful, reliable tool for evaluating the preventability of VKA-associated bleeding. Application of the scale in a prospective study revealed that a high proportion of VKA-associated bleeding events in hospitalized, at-risk adult patients were preventable or potentially preventable.

[Severe muscle disorders associated with statins: analysis of cases notified in France up to the end of February 2002 and data concerning the risk profile of cerivastatin]. / Atteintes musculaires sévères sous statines: bilan des cas notifies en France jusqu'a fin février 2002 et données concernant les risques liés a la cérivastatine.

BACKGROUND AND METHODS: After the withdrawal of cerivastatin from the market, a survey was performed concerning severe muscular disorders associated with statin treatments that were notified to the French national and pharmaceutical industry pharmacovigilance systems up to February 2002. RESULTS: Among the 238 cases analysed, 69 were related to cerivastatin, 86 to simvastatin, 49 to pravastatin, 23 to atorvastatin and 9 to fluvastatin. The reporting rate was six- to ten-times higher for cerivastatin than for other statins. A major risk factor for rhabdomyolysis with cerivastatin was its association with gemfibrozil. CONCLUSION: Postmarketing surveillance appears to be a major tool for early detection of safety problems with a new drug.