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1.
Lancet ; 394(10216): 2243-2254, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31862249

RESUMO

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.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Convulsões/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Administração Oral , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Fenfluramina/administração & dosagem , Fenfluramina/efeitos adversos , Humanos , Masculino , Estudos Observacionais como Assunto , Placebos , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento
2.
Epilepsia ; 60(3): 485-494, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30719703

RESUMO

OBJECTIVE: Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure-induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure-induced respiratory arrest (S-IRA) in DBA/1 mice. METHODS: The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz-induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi-square test. RESULTS: Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S-IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20-40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S-IRA susceptibility occurred, which were long-lasting (≥48 hours). The median effective dose (ED50 ) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg. SIGNIFICANCE: This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S-IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S-IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.


Assuntos
Anticonvulsivantes/uso terapêutico , Fenfluramina/uso terapêutico , Convulsões/tratamento farmacológico , Serotoninérgicos/uso terapêutico , Morte Súbita Inesperada na Epilepsia/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Respiração/efeitos dos fármacos , Convulsões/complicações
3.
Behav Brain Res ; 357-358: 82-87, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-29113874

RESUMO

The effects of the 5-HT1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22-49 y (mean ±â€¯SD, 32.9 ±â€¯8) received single doses of d-fenfluramine (n = 10; 30 mg, p.o.), pindolol (n = 10; 5 mg, p.o.), or placebo (n = 10) 90 and 45 min before a challenge test with flumazenil (1.5 mg, i.v., in 10 min), under double-blind conditions. Panic attacks occurred in 5 control subjects (placebo-flumazenil group), 5 subjects in the pindolol group and in 7 in the d-fenluramine pre-treated patients. Patients experiencing anxiety attacks following flumazenil reported higher increases in anxiety scores. Respiratory rate increases were not different between patients experiencing or not a panic attack. Despite sample size limitation, this study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects.


Assuntos
Ansiedade/tratamento farmacológico , Fenfluramina/uso terapêutico , Pindolol/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , Ansiedade/induzido quimicamente , Ansiedade/etiologia , Feminino , Flumazenil/efeitos adversos , Moduladores GABAérgicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/complicações , Escalas de Graduação Psiquiátrica , Análise de Regressão , Adulto Jovem
4.
Expert Opin Emerg Drugs ; 23(4): 261-269, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30482063

RESUMO

Introduction: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment. Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil, and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS. Expert opinion/commentary: A recent large randomized controlled trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Animais , Canabidiol/uso terapêutico , Fenfluramina/uso terapêutico , Humanos , Serotoninérgicos/uso terapêutico , Verapamil/uso terapêutico
5.
Epilepsia ; 59(10): 1881-1888, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30146701

RESUMO

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a drug-resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX008 (fenfluramine HCl oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open-label, dose-finding study of add-on ZX008 in patients with LGS (NCT02655198). METHODS: Eligible treatment-refractory patients with LGS aged 3-18 years with ≥4 documented convulsive seizures (CS) in the prior 4 weeks were administered adjunctive ZX008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long-term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram. RESULTS: Thirteen patients were enrolled (mean age = 11.7 years, range = 3-17). Ten (77%) patients completed 20 weeks of ZX008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS; median reduction was 60% in the 10 completers. Eight patients (62%) had a ≥50% CS reduction; three (23%) patients had a ≥75% reduction. Nine (69%) patients entered the long-term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ≥50% reduction, and three (33%) patients had a ≥75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. SIGNIFICANCE: ZX008 provided clinically meaningful reduction (≥50%) in CS frequency in the majority of patients with LGS in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.


Assuntos
Anticonvulsivantes/uso terapêutico , Fenfluramina/uso terapêutico , Síndrome de Lennox Gastaut/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Projetos Piloto , Resultado do Tratamento
6.
Eur J Neurol ; 24(2): 309-314, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27790834

RESUMO

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.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Convulsões/tratamento farmacológico , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Fenfluramina/administração & dosagem , Humanos , Lactente , Masculino , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
7.
Epilepsia ; 57(7): e129-34, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27197941

RESUMO

Dravet syndrome (DS) is a rare and therapy-resistant epilepsy syndrome. A retrospective analysis of add-on fenfluramine treatment in 12 patients with DS was published in 2012 and provided evidence of a meaningful long-term response. Herein we present the results of a subsequent 5-year prospective observation of this original cohort. Ten patients with a mean current age of 24 years were followed prospectively from 2010 until 2014. The mean current dose of fenfluramine was 0.27 mg/kg/day, with a mean treatment duration of 16.1 years. Seizure frequency was derived from a seizure diary. Cardiac examinations and assessments of clinical effectiveness and adverse events were performed at least annually. Three patients were seizure-free for the entire 5 years, and an additional four patients experienced seizure-free intervals of at least 2 years. Fenfluramine was generally well-tolerated. Two patients had mild (stable) valve thickening on the last echocardiography that was deemed clinically insignificant. No patient had any clinical or echocardiographic signs of pulmonary hypertension. These findings support the long-term control of convulsive seizures by low-dose fenfluramine while being well tolerated in this cohort of patients with DS. After up to 27 years of treatment, no patient has developed any clinical signs or symptoms of cardiac valvulopathy or pulmonary hypertension.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Adulto , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
PLoS One ; 10(5): e0125898, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25965391

RESUMO

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.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Fenfluramina/administração & dosagem , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Inibidores de Captação de Serotonina/administração & dosagem , Proteínas de Peixe-Zebra/genética , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Epilepsias Mioclônicas/patologia , Fenfluramina/uso terapêutico , Técnicas de Silenciamento de Genes , Humanos , Morfolinos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Oligonucleotídeos Antissenso/metabolismo , Inibidores de Captação de Serotonina/uso terapêutico , Ácido Valproico/administração & dosagem , Ácido Valproico/uso terapêutico , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
12.
J Neuropsychiatry Clin Neurosci ; 26(3): 262-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25093765

RESUMO

Serotonergic dysfunctions are implicated in conduct disorder, impulsivity, and aggression. Early adverse experiences increase the risk for these behaviors in adolescents. The authors investigated serotonergic activity in one adolescent male who experienced maternal abandonment and childhood abuse and exhibited severely aggressive sexual offenses. Platelet serotonin (5-HT) concentration, [14C]-5HT uptake kinetics, and plasma prolactin, cortisol response to D,L-fenfluramine (D,L-FEN) were measured. Results showed extremely low 5-HT concentration (2.9+/-0.7 ng/108 platelets), [14C]-5HT uptake rate (0.5+/-0.04 mM/min/107 platelets), undetectable Km and Vmax, and abnormally blunted prolactin, cortisol response to D,L-FEN. These abnormalities in this sexually aggressive adolescent may be a consequence of childhood abuse.


Assuntos
Agressão , Serotonina/sangue , Disfunções Sexuais Fisiológicas/sangue , Disfunções Sexuais Fisiológicas/metabolismo , Adolescente , Análise de Variância , Isótopos de Carbono/metabolismo , Fenfluramina/uso terapêutico , Humanos , Masculino , Prolactina/sangue , Radioimunoensaio , Inibidores de Captação de Serotonina/uso terapêutico , Disfunções Sexuais Fisiológicas/tratamento farmacológico
13.
Endocrinology ; 155(10): 3732-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25051442

RESUMO

The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population.


Assuntos
Envelhecimento/metabolismo , Fenfluramina/uso terapêutico , Obesidade/tratamento farmacológico , Pró-Opiomelanocortina/metabolismo , Inibidores de Captação de Serotonina/uso terapêutico , Serotonina/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Opiomelanocortina/genética , Resultado do Tratamento
14.
Int J Neuropsychopharmacol ; 17(3): 383-91, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24300434

RESUMO

Dopaminergic function is thought to be altered in major depression and, in animal studies, is reduced in omega-3 polyunsaturated fatty acid (PUFA) deficiency states. Therefore we studied PUFAs and resting prolactin, a marker for dopaminergic tone, and cerebrospinal fluid homovanillic acid (HVA), the chief dopamine metabolite. In medication-free adults (n = 23) with DSM-IV major depressive disorder (MDD), we measured plasma phospholipid levels of omega-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the omega-6 PUFA arachidonic acid (AA), and plasma prolactin levels before and after administration of dl-fenfluramine (FEN). In a subset of patients (n = 14), cerebrospinal fluid levels of HVA and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were obtained through lumbar puncture. Baseline prolactin was negatively correlated with omega-3 PUFAs (logDHA, F(1,21) = 20.380, p < 0.001; logEPA, F(1,21) = 10.051, p = 0.005) and positively correlated with logAA:DHA (F(1,21) = 15.263, p = 0.001), a measure of omega-6/omega-3 balance. LogDHA was negatively correlated with CSF HVA (Spearman's ρ = -0.675, p = 0.008) but not 5-HIAA (Spearman's ρ = -0.143, p = 0.626) after controlling for sex and HVA - 5-HIAA correlation. PUFAs did not predict the magnitude of the FEN-stimulated change in prolactin, considered to be a serotonin effect. The robust relationship of omega-3 PUFAs with dopaminergic but not serotonergic indices suggests that omega-6:omega-3 balance may impact depression pathophysiology through effects on the dopaminergic system.


Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/líquido cefalorraquidiano , Ácidos Graxos Insaturados/sangue , Ácido Homovanílico/líquido cefalorraquidiano , Adulto , Idoso , Análise de Variância , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Fenfluramina/uso terapêutico , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Escalas de Graduação Psiquiátrica , Análise de Regressão , Adulto Jovem
15.
Exp Clin Psychopharmacol ; 21(5): 345-54, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24099355

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is more prevalent in children with Down syndrome than in typically developing children. The defining characteristics of ADHD include inattention, impulsivity, and hyperactivity. The main purpose of this study was to determine whether a mouse model of Down syndrome exhibited higher levels of impulsivity than controls. A secondary aim was to examine the effects of d-amphetamine (0.1-10 mg/kg) and fenfluramine (0.3-10 mg/kg) on impulsivity. Seven male Ts65Dn and 9 male littermate control (LC) mice were trained under a response inhibition schedule of reinforcement; the main measure of impulsivity under this schedule is the mean wait time. After behavior stabilized, the mean wait time for the Ts65Dn mice was indistinguishable from that of the LC mice. Administration of 1 mg/kg d-amphetamine increased the mean wait time in both Ts65Dn and LC, though it was statistically significant only for the LC. However, no dose of fenfluramine altered the mean wait time in Ts65Dn or LC mice. An additional aim of these studies was to determine whether Ts65Dn mice displayed higher levels of motor activity than LC mice. A comparison of running wheel activity revealed no difference between Ts65Dn and LC mice. Thus, the results of the current studies suggest that aged, male Ts65Dn mice are no different from age-matched LC mice in terms of impulsivity or motor activity.


Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Comportamento Impulsivo , Atividade Motora , Envelhecimento/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/uso terapêutico , Condicionamento Operante/efeitos dos fármacos , Dextroanfetamina/farmacologia , Dextroanfetamina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Síndrome de Down/psicologia , Fenfluramina/farmacologia , Fenfluramina/uso terapêutico , Comportamento Impulsivo/tratamento farmacológico , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Esquema de Reforço
16.
Cochrane Database Syst Rev ; (8): CD004677, 2013 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-23959778

RESUMO

BACKGROUND: Autism spectrum disorders (ASD) are characterised by abnormalities in social interaction and communication skills, as well as stereotypic behaviours and restricted activities and interests. Selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of conditions often comorbid with ASD such as depression, anxiety and obsessive-compulsive behaviours. OBJECTIVES: To determine if treatment with an SSRI:1. improves the core features of autism (social interaction, communication and behavioural problems);2. improves other non-core aspects of behaviour or function such as self-injurious behaviour;3. improves the quality of life of adults or children and their carers;4. has short- and long-term effects on outcome;5. causes harm. SEARCH METHODS: We searched the following databases up until March 2013: CENTRAL, Ovid MEDLINE, Embase, CINAHL, PsycINFO, ERIC and Sociological Abstracts. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). This was supplemented by searching reference lists and contacting known experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any dose of oral SSRI compared with placebo, in people with ASD. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data and appraised each study's risk of bias. MAIN RESULTS: Nine RCTs with a total of 320 participants were included. Four SSRIs were evaluated: fluoxetine (three studies), fluvoxamine (two studies), fenfluramine (two studies) and citalopram (two studies). Five studies included only children and four studies included only adults. Varying inclusion criteria were used with regard to diagnostic criteria and intelligence quotient of participants. Eighteen different outcome measures were reported. Although more than one study reported data for Clinical Global Impression (CGI) and obsessive-compulsive behaviour (OCB), different tool types or components of these outcomes were used in each study. As such, data were unsuitable for meta-analysis, except for one outcome (proportion improvement). One large, high-quality study in children showed no evidence of positive effect of citalopram. Three small studies in adults showed positive outcomes for CGI and OCB; one study showed improvements in aggression, and another in anxiety. AUTHORS' CONCLUSIONS: There is no evidence of effect of SSRIs in children and emerging evidence of harm. There is limited evidence of the effectiveness of SSRIs in adults from small studies in which risk of bias is unclear.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , Fatores Etários , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/psicologia , Criança , Citalopram/uso terapêutico , Fenfluramina/uso terapêutico , Fluoxetina/uso terapêutico , Fluvoxamina/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Presse Med ; 42(4 Pt 1): 411-8, 2013 Apr.
Artigo em Francês | MEDLINE | ID: mdl-23490638

RESUMO

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


Assuntos
Insuficiência da Valva Aórtica/induzido quimicamente , Depressores do Apetite/efeitos adversos , Compensação e Reparação/legislação & jurisprudência , Indústria Farmacêutica/legislação & jurisprudência , Medicamentos Genéricos/efeitos adversos , Prova Pericial/legislação & jurisprudência , Fenfluramina/análogos & derivados , Insuficiência da Valva Mitral/induzido quimicamente , Insuficiência da Valva Aórtica/epidemiologia , Depressores do Apetite/uso terapêutico , Causalidade , Estudos Transversais , Diagnóstico Diferencial , Medicamentos Genéricos/uso terapêutico , Definição da Elegibilidade , Fenfluramina/efeitos adversos , Fenfluramina/uso terapêutico , França , Humanos , Insuficiência da Valva Mitral/epidemiologia , Probabilidade , Fatores de Risco
18.
PLoS One ; 7(6): e38273, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22723853

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Fenfluramina/análogos & derivados , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/etiologia , Hipoglicemiantes/efeitos adversos , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ecocardiografia , Feminino , Fenfluramina/administração & dosagem , Fenfluramina/efeitos adversos , Fenfluramina/uso terapêutico , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
19.
Epilepsia ; 53(7): 1131-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22554283

RESUMO

PURPOSE: Despite the development of new antiepileptic drugs, Dravet syndrome frequently remains therapy resistant and is a catastrophic epilepsy syndrome. Fenfluramine is an amphetamine-like drug that has been used in the past as a part of antiobesity treatments. Because of the possible cardiac adverse effects (valve thickening, pulmonary hypertension) associated with use of fenfluramine, it was withdrawn from the market in 2001. In Belgium, a Royal Decree permitted examination of the potential anticonvulsive effects of fenfluramine in a clinical trial consisting of a small group of patients diagnosed with Dravet syndrome. METHODS: Herein, we report 12 patients, 7 female and 5 male, with a genetically proven (11 of 12) diagnosis of Dravet syndrome who received fenfluramine as add-on therapy. KEY FINDINGS: Their ages at their last evaluation ranged from 3-35 years. The mean dosage of fenfluramine was 0.34 (0.12-0.90) mg/kg/day. Exposure duration to fenfluramine ranged from 1-19 years. Seven of the patients who were still receiving the fenfluramine treatment at the time of the last visit had been seizure-free for at least 1 year. In total, patients had been seizure-free for a mean of 6 (1-19) years. In seven patients, the fenfluramine treatment was interrupted once during the follow-up; seizures reappeared in three of the seizure-free patients. Subsequent reintroduction of fenfluramine controlled the seizures in these three patients again. Only two patients exhibited a mild thickening of one or two cardiac valves without clinical significance. SIGNIFICANCE: Compared with a recent long-term follow-up series in which a maximum of 16% of patients with Dravet syndrome were seizure-free, our result of 70% of patients with Dravet syndrome remaining seizure-free is noteworthy. Given the limitations of this observational study, a larger prospective study should be undertaken to confirm these promising results.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Adulto , Pré-Escolar , Eletroencefalografia , Feminino , Seguimentos , Humanos , Masculino , Adulto Jovem
20.
Fundam Clin Pharmacol ; 26(2): 215-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22320434

RESUMO

The authors describe the case of a simultaneous mitral bioprosthesis hypertrophic scaring and native aortic valve fibrosis during benfluorex therapy in a 40-year-old woman. Four years before, she underwent a mitral valve replacement after the diagnosis of mitral regurgitation during benfluorex treatment (150 mg/day). This drug was reintroduced postoperatively. She presented with exercise and sometimes resting dyspnoea. The bioprosthesis and aortic valves exhibited similar histopathological lesions. Thickening and plaque deposits made by smooth muscle alpha actin- and vimentin-positive cells in a glycosaminoglycan matrix were observed. The study discusses the putative contribution of circulating progenitor cells activated by 5-HT(2B) receptor agonists in the development of drug-induced heart disease.


Assuntos
Fenfluramina/análogos & derivados , Doenças das Valvas Cardíacas/induzido quimicamente , Insuficiência da Valva Mitral/induzido quimicamente , Adulto , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Bioprótese , Cicatriz Hipertrófica/induzido quimicamente , Feminino , Fenfluramina/efeitos adversos , Fenfluramina/uso terapêutico , Fibrose , Doenças das Valvas Cardíacas/patologia , Implante de Prótese de Valva Cardíaca/métodos , Humanos , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Insuficiência da Valva Mitral/cirurgia
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