Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.

Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long-term open-label safety extension study.

OBJECTIVE: Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. METHODS: Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. RESULTS: A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. SIGNIFICANCE: Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.

Fenfluramine HCl (Fintepla® ) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study.

OBJECTIVE: Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS: Patients enrolling in the OLE study initiated fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS: A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE: Study results demonstrate that fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and fenfluramine was generally well tolerated.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients.

BACKGROUND AND PURPOSE: Dravet syndrome (DS) is a severe, drug-resistant epilepsy. Fenfluramine has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS. METHODS: This prospective, open-label study assessed the safety and effectiveness of low-dose fenfluramine in a new cohort of patients with DS. Following a 3-month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25-1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic-clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety. RESULTS: Nine patients (aged 1.2-29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3-5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28-100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed. CONCLUSIONS: The effectiveness and safety of low-dose fenfluramine as an add-on therapy for DS in this new prospective cohort supports previous findings.

Rate-dependent effects of monoamine releasers on intracranial self-stimulation in rats: implications for abuse liability assessment.

'Rate dependency' in the discipline of behavioral pharmacology describes a phenomenon wherein the effect of a drug on the rate of a behavior varies systematically as a function of the baseline, predrug rate of that behavior. Historically, rate-dependency studies have compared drug effects on different baseline rates of behavior maintained either by different schedules of reinforcement or during sequential segments of a fixed-interval schedule. The current experiment generated different baseline rates of behavior by altering frequency of electrical stimulation in an intracranial self-stimulation assay. Amphetamine and 10 other monoamine releasers were analyzed for their ability to produce rate-dependent effects in this assay. There were three main findings. First, all compounds produced rate-dependent effects at some dose. Second, one parameter of rate-dependency plots (peak Y-intercept of the regression line) correlated with in-vitro neurochemical data on selectivity of these compounds to release dopamine versus serotonin (P<0.025, R=0.50). Lastly, a correlation between peak Y-intercept and breakpoints under a progressive-ratio procedure in nonhuman primates was also significant (P<0.05, R=0.64). Overall, these results extend the rate-dependent effects of monoamine releasers to behavior maintained under intracranial self-stimulation and suggest that, at least for monoamine releasers, the Y-intercept parameter of rate-dependency plots might be a useful metric of drug reward and predictor of drug self-administration measures of drug reinforcement.

Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments.

OBJECTIVE: To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. METHODS: Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4-6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. RESULTS: A total of 327 patients (median age, 9.0 years; range, 2-19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2-42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. SIGNIFICANCE/INTERPRETATION: This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome.

Valvular heart disease associated with benfluorex therapy: results from the French multicentre registry.

AIMS: The aim of this paper is to report clinical characteristics, consequences, echocardiographic features, and pathological findings encountered in patients suffering from valvular disease associated with benfluorex exposure in a multicentre French registry. METHODS AND RESULTS: Forty patients suffering from unexplained restrictive valvular disease with a previous exposition to benfluorex, a fenfluramine derivative, were identified from eight French university hospitals. Patients were mostly women (87.5%) with a mean age of 57 ± 9 years and high body mass index of 30 ± 7 kg/m²; 37.5% of them presented with severe heart failure symptoms (NYHA class III and IV). Benfluorex mean daily dose was 415 ± 131 mg with total therapy duration of 72 ± 53 months. Resulting cumulative dose was 910 ± 675 g. Common echocardiographic findings were leaflets and sub-valvular apparatus thickening and retraction. Aortic and mitral valve regurgitations resulting from leaflets loss of coaptation were the most frequent findings (87.5 and 82.5%) and were severe in 29 patients (72.5%). Multiple valve involvements were present in 31 cases (77.5%). Pulmonary arterial hypertension was identified in 20 cases (50%). Histopathological examination demonstrated abundant extra cellular matrix encasing the leaflets without modification of valve architecture. Fifteen patients (37.5%) underwent valvular surgery. CONCLUSION: Benfluorex-related valvulopathy shares numerous characteristics with other drug-induced valvular disease. Clinical consequences may be serious with severe heart failure symptoms that may lead to surgical treatment.

Pharmacokinetic properties of N-nitrosofenfluramine after its administration to rats.

N-nitrosofenfluramine (N-Fen), a synthetic adulterant in Chinese herbal diet products, is believed to cause hepatotoxicity in people who use these products. N-Fen is a relatively new compound, and thus pharmacological and toxicological studies are insufficient. The aim of this work was to (1) define N-Fen's plasma pharmacokinetics and tissue distribution after single intraperitoneal (i.p.) administration of 25 mg/kg to rats; (2) define its bioavailability; and (3) identify fenfluramine (Fen) and norfenfluramine (Norf) as N-Fen metabolites. N-Fen rapidly appeared in the circulation and was distributed to all tissues. Norf was found to be the primary metabolite and not Fen. Plasma and tissue levels of N-Fen and Norf were low with bioavailability of N-Fen after i.p. administration was <3%. The AUC(0) (-t) of N-Fen in the liver and kidney were 6.6 and 12.1 times, respectively, greater than the brain, and 17.8 and 32.6 times, respectively, greater than the plasma. In conclusion, N-Fen did not show local accumulation in the liver, the site of toxicity, with concentrations represented as percentage of the total dose ranging from 0.008 to 0.122%; hence the cause of hepatotoxicity could be related to the mechanisms other than toxicity consequences accumulation.

Fenfluramine-induced serotonin release decreases [11C]AZ10419369 binding to 5-HT1B-receptors in the primate brain.

The need for positron emission tomography (PET)-radioligands that are sensitive to changes in endogenous serotonin (5-HT) levels in brain is recognized in experimental and clinical psychiatric research. We recently developed the novel PET radioligand [(11)C]AZ10419369 that is highly selective for the 5-HT(1B) receptor. In this PET-study in three cynomolgus monkeys, we examined the sensitivity of [(11)C]AZ10419369 to altered endogenous 5-HT levels. Fenfluramine-induced 5-HT release decreased radioligand binding in a dose-dependent fashion with a regional average of 27% after 1 mg/kg and 50% after 5 mg/kg. This preliminary study supports that [(11)C]AZ10419369 is sensitive to endogenous 5-HT levels in vivo and may serve as a tool to examine the pathophysiology and treatment of major psychiatric disorders.

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.

Fenfluramine for the Treatment of Dravet Syndrome and Lennox-Gastaut Syndrome.

The last 50 years has seen the introduction of a great number of antiepileptic drugs, relieving the burden of seizures for many patients. However, some conditions remain a challenge for epileptologists, especially Dravet syndrome and Lennox-Gastaut syndrome, which are severe epileptic and developmental encephalopathies characterized by multiple seizure types and electroencephalographic abnormalities that are often unresponsive to combinations of antiepileptic drugs. The re-purposing of an old drug such as fenfluramine could provide an indispensable tool for clinicians, especially because only a few drugs have been tested in relatively homogeneous populations, like Dravet syndrome. It could also provide insights into precision medicine approaches to the treatment of epileptic syndromes. We searched for relevant papers within MEDLINE, EMBASE, and the Clinical Trial Database, considering publications through July 2020. Pre-clinical studies show a mechanism of action for fenfluramine that goes beyond its pro-serotoninergic activity and that is at the intersection of several pathways involved in excitation/inhibition balance. From the ongoing clinical trial data, it is evident that fenfluramine is proving to be a promising antiepileptic drug with very favorable pharmacokinetics and with a good overall safety profile when used at a lower dosage (0.2-0.7 mg/kg/day), despite its previously link to major cardiac adverse events that prompted its withdrawal from the market in 1997. Here, we review the experimental and clinical evidence of the efficacy of fenfluramine, including the latest results from ongoing clinical trials, and critically discuss the future potential of fenfluramine in terms of safety and precision medicine. Available data from the literature suggest a very good efficacy for both epileptic syndromes with a reduction in seizure burden and a longer seizure-free interval. We note the higher prevalence of evidence in patients with Dravet syndrome. Fenfluramine has been used in association with both first- and second-line medications, while its use in monotherapy still needs to be assessed.

The development of tolerance to drugs that suppress food intake.

Appetite suppressants have been available as weight-reducing aids for over 50 years. The first discovered was amphetamine, which was potent, but possessed undesirable side effects (it is a stimulant and elevates blood pressure). Subsequently, a variety of appetite drugs was developed, all structurally related to amphetamine, but mostly lacking unwanted side effects. Until recently, fenfluramine (FEN) was the most widely used; presently, sibutramine is the most commonly used appetite suppressant. While these appetite suppressants are effective at reducing hunger and food intake when given as a single dose or for short periods of time, their effectiveness diminishes when administered chronically. The biological mechanisms underlying this tolerance have not been carefully studied, but many possibilities have been identified, including the down-regulation in brain of neurotransmitter receptors that might mediate the action of these drugs and adaptive responses of the appetite control circuitry in brain. To date, however, few studies have examined these possibilities in any detail. This article focuses on the question of why appetite suppressants lose efficacy, when given chronically, because this issue is important to the development of the next generation of appetite suppressants. Chronic efficacy should be an issue studied relatively early in the drug development process. This issue is of particular relevance, since obesity treatment is now recognized as a long-term, not a short-term, process. If appetite suppressants are to become a more important tool in obesity treatment, agents that do not lose efficacy when administered for extended periods of time must be identified.

Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey.

Fenfluramine, over a dose range from 0.003 to 3 milligrams per kilogram of body weight, failed to maintain self-injection behavior in rhesus monkeys that had initiated and maintained responding for cocaine or methohexital. This absence of a positive reinforcing effect could not be attributed to a slow onset of drug effect or to the use of behaviorally inactive doses. Fenfluramine, because of its distinctive properties, may produce fewer problems of human abuse than do amphetamine-type agents.

Local perfusion of corticosterone in the rat medial hypothalamus potentiates D-fenfluramine-induced elevations of extracellular 5-HT concentrations.

The dorsomedial hypothalamus (DMH) plays an important role in coordinating physiological and behavioral responses to stress-related stimuli. In vertebrates, DMH serotonin (5-HT) concentrations increase rapidly in response to acute stressors or corticosterone (CORT). Recent studies suggest that CORT inhibits postsynaptic clearance of 5-HT from the extracellular fluid in the DMH by blocking organic cation transporter 3 (OCT3), a polyspecific CORT-sensitive transport protein. Because OCTs are low-affinity, high-capacity transporters, we hypothesized that CORT effects on extracellular 5-HT are most pronounced in the presence of elevated 5-HT release. We predicted that local application of CORT into the DMH would potentiate the effects of d-fenfluramine, a 5-HT-releasing agent, on extracellular 5-HT. These experiments were conducted using in vivo microdialysis in freely-moving male Sprague-Dawley rats implanted with a microdialysis probe into the medial hypothalamus (MH), which includes the DMH. In Experiment 1, rats simultaneously received intraperitoneal (i.p.) injections of 1 mg/kg D-fenfluramine or saline and either 200 ng/mL CORT or dilute ethanol (EtOH) vehicle delivered to the MH by reverse-dialysis for 40 min. In Experiment 2, 5 microM D-fenfluramine and either 200 ng/mL CORT or EtOH vehicle were concurrently delivered to the MH for 40 min using reverse-dialysis. CORT potentiated the increases in extracellular 5-HT concentrations induced by either i.p. or intra-MH administration of D-fenfluramine. Furthermore, CORT and D-fenfluramine interacted to alter home cage behaviors. Our results support the hypothesis that CORT inhibition of OCT3-mediated 5-HT clearance from the extracellular fluid contributes to stress-induced increases in extracellular 5-HT and 5-HT signaling.

Effects of repeated treatment with methcathinone, mephedrone, and fenfluramine on intracranial self-stimulation in rats.

RATIONALE: Synthetic cathinones constitute a class of abused drugs that can act at dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively). Intracranial self-stimulation (ICSS) is a preclinical procedure that can be used to evaluate abuse potential of drugs, and prior studies have indicated that abuse-related ICSS effects of monoamine-transporter substrates, including some synthetic cathinones, are positively correlated with drug selectivity for DAT vs. SERT. Abuse potential of drugs can also be influenced by regimens of repeated drug exposure, but the role of repeated exposure on abuse-related ICSS effects of synthetic cathinones has not been examined. OBJECTIVES: This study used ICSS to evaluate effects of repeated treatment with the DAT>SERT substrate methcathinone, the DAT

Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases.

The aim of the present study was to describe a large cohort of fenfluramine-associated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers. The records of all patients with a diagnosis of fen-PAH evaluated at the present authors' centre from 1986-2004 were retrospectively studied. Baseline clinical and haemodynamic data were collected, as well as survival times. The median duration of fenfluramine exposure was 6 months, with a median of 4.5 yrs between exposure and onset of symptoms. Nine (22.5%) out of 40 patients evaluated resulted positive for the presence of germline bone morphogenetic protein receptor (BMPR) type 2 mutations. In these patients, the duration of exposure to fenfluramine was significantly lower than in patients without mutation. The median survival was 6.4 yrs, without significant difference between fen-PAH and a control group of idiopathic and familial pulmonary arterial hypertension patients referred to the present authors' centre during the same time frame and treated identically. Duration of fenfluramine exposure showed no relation to survival, while cardiac index was the only independent predictor of multivariate analysis. Fenfluramine-associated pulmonary arterial hypertension shares clinical, functional, haemodynamic and genetic features with idiopathic pulmonary arterial hypertension, as well as overall survival rates. Therefore, the present authors conclude that fenfluramine exposure characterises a potent trigger for pulmonary arterial hypertension without influencing its clinical course.

Chronic fenfluramine administration increases plasma serotonin (5-hydroxytryptamine) to nontoxic levels.

Large elevations in blood serotonin (5-hydroxytryptamine; 5-HT) can produce valvular heart disease in humans and laboratory animals. In accordance, one prevailing hypothesis (i.e., the "5-HT hypothesis") suggests that 5-HT transporter substrates like fenfluramine increase the risk for valvular heart disease by elevating plasma 5-HT, secondary to the release of 5-HT from platelets. The main purpose of this study was to determine whether chronic administration of fenfluramine increases plasma 5-HT to concentrations that are associated with the development of valvular heart disease. To the best of our knowledge, this is the first study to address this issue using an in vivo microdialysis method that measures plasma 5-HT in nonhypoxic rats. We examined the effects of chronic (+/-)-fenfluramine and fluoxetine on plasma levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in blood samples from conscious catheterized rats. Plasma indoles were measured by high-performance liquid chromatography with electrochemical detection in the dialysates of whole blood. The baseline plasma 5-HT level was <1.0 nM. Chronic fenfluramine (14-day minipump infusion) produced small increases in baseline plasma 5-HT ( approximately 2-4-fold), whereas chronic fluoxetine had no effect. Chronic fenfluramine and fluoxetine markedly decreased whole-blood 5-HT and reduced the ability of acute fenfluramine to evoke 5-HT release. Elevations in baseline plasma 5-HT produced by chronic fenfluramine are far below the micromolar levels necessary to produce valvular heart disease. Furthermore, chronic fenfluramine reduces the ability of acute fenfluramine to increase plasma 5-HT, suggesting that the 5-HT hypothesis cannot explain the increased risk of valvular heart disease in patients treated with fenfluramine.

Mice overexpressing the 5-hydroxytryptamine transporter show no alterations in feeding behaviour and increased non-feeding responses to fenfluramine.

RATIONALE: The 5-HT transporter (5-HTT) is implicated in the regulation of appetite. Expression of the 5-HTT varies in the human population, and this variation may determine both individual differences in feeding and abnormal feeding behaviours such as eating disorders. OBJECTIVES: The effects of 5-HTT expression on feeding and satiety were examined in a transgenic mouse model of 5-HTT overexpression. MATERIALS AND METHODS: We measured free-feeding food intake and observed the behavioural satiety sequence (BSS) after food deprivation in mice at baseline and after administration of the anorectic drug fenfluramine. RESULTS: 5-HTT overexpressing mice were both lighter and shorter than their wildtype littermates. Despite this size difference, food intake by transgenic and wildtype mice did not differ. There was no effect of genotype on the BSS or on food intake during the test at baseline. Increasing doses of fenfluramine reduced food intake in a similar manner in both transgenic and wildtype mice. After 0.3 and 1 mg/kg fenfluramine, the temporal pattern of the BSS was the same for both groups, whereas 3 and 10 mg/kg fenfluramine disrupted the BSS. In transgenic mice, this disruption was evident at the 3 mg/kg dose, while in wildtypes, it emerged only at the 10-mg/kg dose. CONCLUSION: These data suggest that overexpression of the 5-HTT does not lead to alterations in feeding or satiety in food-deprived mice but does increase the occurrence of other non-feeding behaviours in response to the 5-HT releasing agent fenfluramine.