ABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic , Fenfluramine , Heart Valve Diseases , Adolescent , Child , Child, Preschool , Echocardiography , Epilepsies, Myoclonic/diagnostic imaging , Epilepsies, Myoclonic/drug therapy , Epileptic Syndromes , Fenfluramine/administration & dosage , Fenfluramine/adverse effects , Heart Valve Diseases/chemically induced , Heart Valve Diseases/drug therapy , Humans , Young AdultSubject(s)
Anticonvulsants/therapeutic use , Epilepsies, Myoclonic/drug therapy , Fenfluramine/therapeutic use , Adolescent , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Child , Child, Preschool , Dose-Response Relationship, Drug , Double-Blind Method , Drug Approval , Drug Interactions , Fenfluramine/administration & dosage , Fenfluramine/adverse effects , Humans , Randomized Controlled Trials as Topic , United States , United States Food and Drug AdministrationABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/drug therapy , Fenfluramine/administration & dosage , Seizures/diagnosis , Seizures/drug therapy , Selective Serotonin Reuptake Inhibitors/administration & dosage , Adolescent , Child , Child, Preschool , Double-Blind Method , Epilepsies, Myoclonic/epidemiology , Female , Fenfluramine/adverse effects , Fever/chemically induced , Humans , Longitudinal Studies , Male , Seizures/epidemiology , Selective Serotonin Reuptake Inhibitors/adverse effects , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic/drug therapy , Fenfluramine/administration & dosage , Seizures/drug therapy , Selective Serotonin Reuptake Inhibitors/administration & dosage , Adolescent , Adult , Anorexia/chemically induced , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Child , Child, Preschool , Epilepsies, Myoclonic/diagnostic imaging , Epilepsies, Myoclonic/physiopathology , Female , Fenfluramine/adverse effects , Follow-Up Studies , Humans , Male , Prospective Studies , Seizures/diagnostic imaging , Seizures/physiopathology , Selective Serotonin Reuptake Inhibitors/adverse effects , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic/drug therapy , Fenfluramine/administration & dosage , Lennox Gastaut Syndrome/drug therapy , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Anticonvulsants/pharmacology , Epilepsies, Myoclonic/physiopathology , Fenfluramine/adverse effects , Fenfluramine/pharmacology , Humans , Lennox Gastaut Syndrome/physiopathology , Precision Medicine , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Treatment OutcomeABSTRACT
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.
Subject(s)
Electrocardiography/drug effects , Epilepsies, Myoclonic/diagnostic imaging , Epilepsies, Myoclonic/drug therapy , Fenfluramine/administration & dosage , Heart Valve Diseases/diagnostic imaging , Selective Serotonin Reuptake Inhibitors/administration & dosage , Adolescent , Child , Child, Preschool , Double-Blind Method , Electrocardiography/methods , Female , Fenfluramine/adverse effects , Heart Valve Diseases/chemically induced , Humans , Longitudinal Studies , Male , Prospective Studies , Selective Serotonin Reuptake Inhibitors/adverse effects , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Epilepsies, Myoclonic/drug therapy , Fenfluramine/therapeutic use , Seizures/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Administration, Oral , Adolescent , Anticonvulsants/therapeutic use , Child , Child, Preschool , Double-Blind Method , Female , Fenfluramine/administration & dosage , Fenfluramine/adverse effects , Humans , Male , Observational Studies as Topic , Placebos , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effects , Treatment OutcomeSubject(s)
Anticonvulsants/therapeutic use , Drug Repositioning/methods , Epilepsies, Myoclonic/drug therapy , Fenfluramine/therapeutic use , Adolescent , Adult , Child , Child, Preschool , Drug Repositioning/standards , Epilepsies, Myoclonic/genetics , Female , Fenfluramine/administration & dosage , Fenfluramine/adverse effects , Humans , Infant , Male , Middle Aged , NAV1.1 Voltage-Gated Sodium Channel , Young AdultABSTRACT
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 DATSubject(s)
Fenfluramine/administration & dosage
, Illicit Drugs/pharmacology
, Methamphetamine/analogs & derivatives
, Propiophenones/administration & dosage
, Selective Serotonin Reuptake Inhibitors/administration & dosage
, Self Stimulation/drug effects
, Animals
, Conditioning, Operant/drug effects
, Conditioning, Operant/physiology
, Drug Administration Schedule
, Electrodes, Implanted
, Male
, Methamphetamine/administration & dosage
, Rats
, Rats, Sprague-Dawley
, Self Stimulation/physiology
, Transcranial Direct Current Stimulation/methods
Subject(s)
Dyspnea , Echocardiography, Transesophageal/methods , Fenfluramine/adverse effects , Mitral Valve Insufficiency , Mitral Valve , Phentermine/adverse effects , Appetite Depressants/administration & dosage , Appetite Depressants/adverse effects , Diagnosis, Differential , Dyspnea/diagnosis , Dyspnea/etiology , Fenfluramine/administration & dosage , Humans , Male , Middle Aged , Mitral Valve/diagnostic imaging , Mitral Valve/drug effects , Mitral Valve/pathology , Mitral Valve Insufficiency/diagnosis , Mitral Valve Insufficiency/etiology , Mitral Valve Insufficiency/physiopathology , Overweight/drug therapy , Phentermine/administration & dosage , Stroke VolumeABSTRACT
Multiple laboratories have shown that the stimulation of µ-opioid receptors in the nucleus accumbens (NAcc) powerfully increases intake of palatable and high-fat diets. Separate studies have demonstrated that serotonin agonists advance satiety processes, and several serotonin-targeting agents have been prescribed to promote weight loss. However, it is unknown if serotonin signaling can modulate the increased feeding elicited by activation of NAcc µ-opioid receptors. These experiments assessed the effects of systemic treatments with the serotonin agonists d-fenfluramine and lorcaserin on the binge-like feeding induced by µ-opioid receptor stimulation of the NAcc in Sprague-Dawley rats. Consistent with previous reports, stimulation of NAcc µ-opioid receptors (with 0.025 µg/0.5 µl/side DAMGO) significantly increased consumption of high-fat vegetable shortening, and systemic treatment with d-fenfluramine and lorcaserin dose-dependently decreased intake. Interestingly, d-fenfluramine and lorcaserin reversed the binge-like feeding observed following stimulation of NAcc µ-opioid receptors. Both serotonergic drugs also attenuated the increases of ambulation observed following administration of DAMGO in the NAcc. These data demonstrate that serotonergic anorectics, in addition to their known role in advancing satiety processes during normal feeding, can also inhibit the binge-like feeding that is elicited by activation of µ-opioid receptors within the ventral striatum.
Subject(s)
Benzazepines/administration & dosage , Binge-Eating Disorder/chemically induced , Binge-Eating Disorder/drug therapy , Fenfluramine/administration & dosage , Nucleus Accumbens/drug effects , Receptors, Opioid, mu/agonists , Analgesics, Opioid/administration & dosage , Animals , Binge-Eating Disorder/metabolism , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/administration & dosage , Infusions, Intraventricular , Locomotion/drug effects , Locomotion/physiology , Male , Nucleus Accumbens/physiology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, mu/physiologyABSTRACT
OBJECTIVE: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS. METHODS: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years. RESULTS: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10-20 mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period. CONCLUSIONS: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.
Subject(s)
Appetite Depressants/administration & dosage , Epilepsies, Myoclonic/drug therapy , Fenfluramine/administration & dosage , Adult , Appetite Depressants/adverse effects , Dexfenfluramine/administration & dosage , Dexfenfluramine/adverse effects , Fenfluramine/adverse effects , Heart Valve Diseases/epidemiology , Humans , Hypertension, Pulmonary/epidemiology , Incidence , Obesity/drug therapy , Phentermine/administration & dosage , Phentermine/adverse effectsABSTRACT
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.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsies, Myoclonic/drug therapy , Fenfluramine/therapeutic use , Seizures/drug therapy , Adolescent , Adult , Anticonvulsants/administration & dosage , Child , Child, Preschool , Drug Therapy, Combination , Female , Fenfluramine/administration & dosage , Humans , Infant , Male , Prospective Studies , Treatment Outcome , Young AdultABSTRACT
Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.
Subject(s)
Growth and Development , Hypothalamus/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Animals, Newborn , Arcuate Nucleus of Hypothalamus/drug effects , Arcuate Nucleus of Hypothalamus/metabolism , Body Weight/drug effects , Dietary Proteins/pharmacology , Feeding Behavior/drug effects , Female , Fenfluramine/administration & dosage , Fenfluramine/pharmacology , Fetus/drug effects , Fetus/metabolism , Growth and Development/drug effects , Hypothalamus/anatomy & histology , Hypothalamus/drug effects , Hypothalamus/growth & development , Laser Capture Microdissection , Male , Neurons/metabolism , Oligonucleotide Array Sequence Analysis , Organ Size/drug effects , Pregnancy , Rats, Wistar , Reproducibility of Results , Serotonin/metabolism , Time Factors , Tryptophan/metabolismABSTRACT
Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects.
Subject(s)
Epilepsies, Myoclonic/drug therapy , Epilepsies, Myoclonic/genetics , Fenfluramine/administration & dosage , NAV1.1 Voltage-Gated Sodium Channel/genetics , Selective Serotonin Reuptake Inhibitors/administration & dosage , Zebrafish Proteins/genetics , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/therapeutic use , Disease Models, Animal , Epilepsies, Myoclonic/pathology , Fenfluramine/therapeutic use , Gene Knockdown Techniques , Humans , Morpholinos/metabolism , NAV1.1 Voltage-Gated Sodium Channel/metabolism , Oligonucleotides, Antisense/metabolism , Selective Serotonin Reuptake Inhibitors/therapeutic use , Valproic Acid/administration & dosage , Valproic Acid/therapeutic use , Zebrafish , Zebrafish Proteins/metabolismABSTRACT
Ketamine is a unique anesthetic reagent known to produce various psychotic symptoms. Ketamine has recently been reported to elicit a long-lasting antidepressant effect in patients with major depression. Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism has not been fully elucidated. To understand the involvement of the brain serotonergic system in the actions of ketamine, we performed a positron emission tomography (PET) study on non-human primates. Four rhesus monkeys underwent PET studies with two serotonin (5-HT)-related PET radioligands, [(11)C]AZ10419369 and [(11)C]DASB, which are highly selective for the 5-HT1B receptor and serotonin transporter (SERT), respectively. Voxel-based analysis using standardized brain images revealed that ketamine administration significantly increased 5-HT1B receptor binding in the nucleus accumbens and ventral pallidum, whereas it significantly reduced SERT binding in these brain regions. Fenfluramine, a 5-HT releaser, significantly decreased 5-HT1B receptor binding, but no additional effect was observed when it was administered with ketamine. Furthermore, pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), a potent antagonist of the glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor, blocked the action of ketamine on the 5-HT1B receptor but not SERT binding. This indicates the involvement of AMPA receptor activation in ketamine-induced alterations of 5-HT1B receptor binding. Because NBQX is known to block the antidepressant effect of ketamine in rodents, alterations in the serotonergic neurotransmission, particularly upregulation of postsynaptic 5-HT1B receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine.
Subject(s)
Antidepressive Agents/pharmacology , Basal Forebrain/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Ketamine/pharmacology , Nucleus Accumbens/metabolism , Receptor, Serotonin, 5-HT1B/metabolism , Receptors, AMPA/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Antidepressive Agents/administration & dosage , Basal Forebrain/drug effects , Carbon Radioisotopes/pharmacokinetics , Excitatory Amino Acid Antagonists/administration & dosage , Fenfluramine/administration & dosage , Fenfluramine/pharmacology , Ketamine/administration & dosage , Macaca , Male , Nucleus Accumbens/drug effects , Positron-Emission Tomography , Quinoxalines/administration & dosage , Quinoxalines/pharmacology , Receptors, AMPA/antagonists & inhibitorsABSTRACT
'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.
Subject(s)
Biogenic Monoamines/metabolism , Reinforcement Schedule , Self Stimulation/physiology , Amphetamine/pharmacology , Animals , Central Nervous System Stimulants/pharmacology , Dopamine/metabolism , Dose-Response Relationship, Drug , Fenfluramine/administration & dosage , Male , Medial Forebrain Bundle/drug effects , Medial Forebrain Bundle/physiology , Methamphetamine/pharmacology , Norethandrolone/metabolism , Rats , Rats, Sprague-Dawley , Regression Analysis , Self Stimulation/drug effects , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/administration & dosage , Time FactorsSubject(s)
Appetite Depressants/adverse effects , Bioprosthesis , Fenfluramine/analogs & derivatives , Heart Valve Prosthesis Implantation/instrumentation , Heart Valve Prosthesis , Mitral Valve Insufficiency/surgery , Prosthesis Failure , Adult , Aortic Valve Insufficiency/chemically induced , Aortic Valve Insufficiency/surgery , Appetite Depressants/administration & dosage , Device Removal , Drug Administration Schedule , Female , Fenfluramine/administration & dosage , Fenfluramine/adverse effects , Humans , Mitral Valve Insufficiency/chemically induced , Prosthesis Design , Reoperation , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. METHODS: Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA(1c). Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. RESULTS: At baseline, patients were 59.1 ± 10.5 years old with HbA1c 8.3 ± 0.8%, and DM duration 7.1 ± 6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30 ± 0.80 to 7.77 ± 1.31 versus pioglitazone: from 8.30 ± 0.80 to 7.45 ± 1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation. CONCLUSION: After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug.