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1.
Lancet ; 394(10216): 2243-2254, 2020 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
3.
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
4.
Pharmacoepidemiol Drug Saf ; 28(3): 370-376, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29992679

RESUMO

BACKGROUND: Change-point analysis (CPA) is a powerful method to analyse pharmacovigilance data but it has never been used on the disproportionality metric. OBJECTIVES: To optimize signal detection investigating the interest of time-series analysis in pharmacovigilance and the benefits of combining CPA with the proportional reporting ratio (PRR). METHODS: We investigated the couple benfluorex and aortic valve incompetence (AVI) using the French National Pharmacovigilance and EudraVigilance databases: CPA was applied on monthly counts of reports and the lower bound of monthly computed PRR (PRR-). We stated a CPA hypothesis that the substance-event combination is more likely to be a signal when the 2 following criteria are fulfilled: PRR- is greater than 1 with at least 5 cases, and CPA method detects at least 2 successive change points of PRR- which made consecutively increasing segments. We tested this hypothesis by 95 test cases identified from a drug safety reference set and 2 validated signals from EudraVigilance database: CPA was applied on PRR-. RESULTS: For benfluorex and AVI, change points detected by CPA on PRR- were more meaningful compared with monthly counts of reports: More change points detected and detected earlier. In the reference set, 14 positive controls satisfied CPA hypothesis, 6 positive controls only met first requirements, 3 negative controls only met first requirement, and 2 validated signals satisfied CPA hypothesis. CONCLUSIONS: The combination of CPA and PRR represents a significant advantage in detecting earlier signals and reducing false-positive signals. This approach should be confirmed in further studies.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Farmacovigilância , Insuficiência da Valva Aórtica/induzido quimicamente , Insuficiência da Valva Aórtica/epidemiologia , Depressores do Apetite/efeitos adversos , Interpretação Estatística de Dados , Bases de Dados Factuais , Fenfluramina/efeitos adversos , Fenfluramina/análogos & derivados , França/epidemiologia , Humanos
5.
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
7.
Behav Pharmacol ; 30(4): 376-382, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30480550

RESUMO

Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the α2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9°C) increase in tail skin temperature and delayed decreases (~1-3°C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Transtorno de Pânico/fisiopatologia , Animais , Temperatura Corporal/fisiologia , Carbolinas/farmacologia , Fenfluramina/farmacologia , Masculino , Modelos Animais , Pânico/fisiologia , Ratos , Ratos Sprague-Dawley , Temperatura Cutânea/efeitos dos fármacos , Temperatura Cutânea/fisiologia , Ioimbina/farmacologia
8.
Int J Clin Pharmacol Ther ; 57(1): 11-19, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30336805

RESUMO

OBJECTIVE: Phase I, open-label, randomized, single-dose, 3-period crossover study assessing pharmacokinetics (PK) and safety of ZX008, a liquid oral formulation of fenfluramine (FFA) under development for adjunctive treatment of Dravet syndrome and Lennox-Gastaut syndrome, administered with and without a combined antiepileptic drug (AED) regimen of stiripentol (STP), valproate (VPA), and clobazam (CLB) (STP regimen). MATERIALS AND METHODS: 26 healthy adults were administered the following treatments: ZX008 0.8 mg/kg; STP 3,500 mg, CLB 20 mg, VPA 25 mg/kg (max. 1,500 mg); and ZX008 0.8 mg/kg + STP regimen. Dose periods were 17 days apart. Blood samples were obtained for 72 hours after drug administration and used to calculate non-compartmental PK parameters. RESULTS: Statistical bioequivalence-type analysis demonstrated ZX008 had no significant impact on the PK of any drug in the STP regimen, while the STP regimen moderately affected FFA PK. The 3-drug combination increased the geometric mean Cmax, AUC0-t, and AUC0-inf of FFA while reducing the Cmax and AUC0-t of its major metabolite, norfenfluramine (norFFA). Adverse events (AEs) were mild to moderate and resolved spontaneously. ZX008 + STP regimen co-administration to healthy adult subjects modestly impacted the number but not severity of AEs. CONCLUSION: Results show that the STP regimen had a moderate impact on FFA and norFFA PK and ZX008 had no significant impact on the 3 STP regimen drugs. ZX008 would not be expected to alter the clinical response of patients to this regimen by means of an effect on PK. When administering these drugs together, a downward dose adjustment of ZX008 may be warranted.
.


Assuntos
Clobazam/farmacologia , Dioxolanos/farmacologia , Fenfluramina/farmacologia , Ácido Valproico/farmacologia , Administração Oral , Adulto , Estudos Cross-Over , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , não Fumantes , Adulto Jovem
9.
Psychopharmacology (Berl) ; 236(3): 1057-1066, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30232529

RESUMO

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

Assuntos
Fenfluramina/administração & dosagem , Drogas Ilícitas/farmacologia , Metanfetamina/análogos & derivados , Propiofenonas/administração & dosagem , Autoestimulação/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Esquema de Medicação , Eletrodos Implantados , Masculino , Metanfetamina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Autoestimulação/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodos
10.
Pharmacol Res ; 140: 43-49, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30189295

RESUMO

Perivascular adipose tissue (PVAT) modulates vascular tone and altered PVAT function is observed in vascular diseases such as hypertension and atherosclerosis. We discovered that the PVAT surrounding rat thoracic aorta (RA) and the superior mesenteric artery (SMA) contain significant amounts of 5-hydroxytryptamine (5-HT). We hypothesized that the 5-HT contained within the PVAT is functional and vasoactive. Isolated tissue baths were used for isometric contractility studies and high performance liquid chromatography was used to quantitatively measure amines in the PVAT and release studies. The 5-HT releaser fenfluramine (10 nM-100 µM) was tested for its ability to contract arteries with and without PVAT. Contraction was reported as a percentage of the initial contraction to 10 µM phenylephrine. The RA with PVAT contracted to fenfluramine to a greater maximum (98 ± 10%) than RA without PVAT (24 ± 4%), while no difference in contraction of SMA to maximum fenfluramine with (78 ± 2%) and without (75 ± 6%) PVAT was observed. Contradicting our hypothesis, the maximum contraction of RA with PVAT to fenfluramine was diminished by the alpha-1 adrenoreceptor antagonist prazosin (100 nM; vehicle: 71 ± 4%, prazosin: 24 ± 2%) and the norepinephrine transporter (NET) inhibitor nisoxetine (1 µM; vehicle: 71 ± 4%, nisoxetine: 25 ± 4%) but not the 5-HT2A/2C receptor antagonist ketanserin (10 nM) or serotonin specific reuptake inhibitor fluoxetine (10 µM). To test if fenfluramine caused release of 5-HT or NE from PVAT, PVAT from RA was incubated with vehicle or fenfluramine (10 µM-10 mM), and amines released into the incubating buffer were quantified. A pronounced concentration-dependent NE-release (more than 5-HT) was observed. Collectively, this research illustrates the pharmacology of fenfluramine to primarily stimulate NE release (better than 5-HT) in a NET-dependent manner, leading to vasoconstriction. This adds additional support to PVAT as being an important reservoir of amines.


Assuntos
Tecido Adiposo/fisiologia , Aorta Torácica/efeitos dos fármacos , Fenfluramina/farmacologia , Norepinefrina/fisiologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Aorta Torácica/fisiologia , Masculino , Ratos Sprague-Dawley , Serotonina/fisiologia , Vasoconstrição/efeitos dos fármacos
11.
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
12.
Eur Neuropsychopharmacol ; 28(12): 1429-1438, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30454909

RESUMO

Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M = 37, F = 3), ages 23-26 (m-24.57, sd-2.33) diagnosed with childhood ADHD into 2 groups: participants with (n = 21) and without (n = 19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald = 4.427, p = .035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD.


Assuntos
Transtorno da Personalidade Antissocial/complicações , Transtorno da Personalidade Antissocial/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Serotonina/metabolismo , Adulto , Feminino , Fenfluramina , Seguimentos , Humanos , Hidrocortisona/metabolismo , Estudos Longitudinais , Masculino , Prognóstico , Prolactina/metabolismo , Serotoninérgicos , Adulto Jovem
13.
Neurosci Lett ; 687: 43-48, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30227154

RESUMO

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.


Assuntos
Benzazepinas/administração & dosagem , Transtorno da Compulsão Alimentar/induzido quimicamente , Transtorno da Compulsão Alimentar/tratamento farmacológico , Fenfluramina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Receptores Opioides mu/agonistas , Analgésicos Opioides/administração & dosagem , Animais , Transtorno da Compulsão Alimentar/metabolismo , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , Infusões Intraventriculares , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Núcleo Accumbens/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/fisiologia
14.
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
15.
Clin Ther ; 40(8): 1338-1346, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29941151

RESUMO

PURPOSE: Fenfluramine is being developed as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome and other epileptic encephalopathies, including Lennox-Gastaut syndrome. Most patients with Dravet syndrome receive multiple antiepileptic drugs, making it challenging for caregivers to track correct administration times. The present Phase I study was conducted to determine the effect of food on the pharmacokinetic properties of fenfluramine. METHODS: Healthy nonsmoking subjects aged 18 to 50 years were enrolled in an open-label, crossover, Phase I pharmacokinetic and safety profile study and received 2 single 0.8-mg/kg doses of ZX008 (fenfluramine hydrochloride oral solution), 1 after a 10-hour overnight fast and the other 30 minutes after the start of consumption of a high-fat breakfast, in a randomly assigned order. A washout period of at least 9 days separated the 2 treatment periods. Venous blood samples were taken before each dose and periodically for 72 hours after each dose for determination of concentrations of fenfluramine and its active metabolite norfenfluramine. Plasma pharmacokinetic parameters were estimated for each subject by noncompartmental analysis. FINDINGS: In the 13 subjects completing both treatment periods, food had no effect on the rate or extent of absorption and bioavailability of fenfluramine as assessed by fed vs fasted adjusted geometric mean observed plasma Cmax (59.1 vs 56.7 ng/mL; NS) and AUC0-∞ (1640 vs 1600 ng ·â€¯h/mL; NS). Additionally, there was no impact of food on systemic exposure of norfenfluramine. Seven subjects reported at least 1 treatment-emergent adverse event; all treatment-emergent adverse events were mild in severity. IMPLICATIONS: The bioequivalence and tolerability of single 0.8-mg/kg oral doses of ZX008 in the fed and fasted states support ZX008 administration without regard to meals.


Assuntos
Anticonvulsivantes/farmacologia , Fenfluramina/farmacologia , Interações Alimento-Droga , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Alimentos , Voluntários Saudáveis , Humanos , Absorção Intestinal , Masculino , Equivalência Terapêutica , Adulto Jovem
17.
Toxicol Lett ; 285: 113-120, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29306027

RESUMO

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


Assuntos
Poluentes Ambientais/toxicidade , Coração/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Transcrição Genética/efeitos dos fármacos , Tricloroetileno/toxicidade , Animais , Embrião de Galinha , Relação Dose-Resposta a Droga , Ecocardiografia , Fenfluramina/análogos & derivados , Fenfluramina/farmacologia , Genes Reporter , Coração/diagnóstico por imagem , Coração/embriologia , Células Hep G2 , Fator 4 Nuclear de Hepatócito/agonistas , Humanos , Miocárdio/metabolismo
18.
Cardiovasc Res ; 113(8): 849-857, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28863437

RESUMO

Heart valve diseases (HVDs) arise from a number of different processes that affect both the structure and function of the valve apparatus. Despite diverse aetiologies, treatments for HVDs are limited to percutaneous or surgical interventions. The search for medical therapies to prevent or slow the progression of HVDs has been hampered by our poor understanding of the progression from subclinical to symptomatic phases, and our limited knowledge of the molecular signals that control the susceptibility of valve interstitial cells to pathological remodeling. Clinical evidence has suggested a link between certain neurotransmitters and valvular diseases of the heart. The fenfluramine-phentermine appetite suppressants popular in the 1980s were linked to mitral valve dysfunction, and ergot-derived dopamine agonists for Parkinson's disease have been associated with an increased risk of mitral and aortic valve regurgitation. The effect does not appear to be limited to medications, as valvular pathologies have also been observed in patients with carcinoid tumours of serotonin-producing enterochromaffin cells. The role of neurotransmitter molecules in valve pathology has not been adequately characterized and may represent a target for future medical therapies. Here we present current evidence from both clinical and basic science suggesting a link between neurotransmitters and HVDs, opening the door to future research in this area.


Assuntos
Catecolaminas/metabolismo , Progressão da Doença , Doenças das Valvas Cardíacas/metabolismo , Neurotransmissores/metabolismo , Serotonina/metabolismo , Animais , Fenfluramina/metabolismo , Humanos
19.
Int J Neuropsychopharmacol ; 20(9): 683-691, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28911007

RESUMO

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain.


Assuntos
Benzilaminas/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Fenfluramina/farmacologia , Fenetilaminas/farmacocinética , Receptor 5-HT2A de Serotonina/metabolismo , Serotoninérgicos/farmacologia , Adamantano/análogos & derivados , Adamantano/farmacocinética , Aminoquinolinas/farmacocinética , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Feminino , Fenfluramina/sangue , Fluorbenzenos/farmacocinética , Macaca mulatta , Imagem por Ressonância Magnética , Piperidinas/farmacocinética , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacocinética
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