RESUMEN
AIMS: Apelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans. MATERIALS AND METHODS: Healthy overweight men were enrolled in this randomized, double-blind, placebo-controlled, cross-over study that successively considered the efficacy and the tolerance of 2 doses of (pyr1)-Apelin-13. A first group of subjects received 9 nmol/kg (n = 8) of (pyr1)-Apelin-13 and, after examination of safety data, a second group received 30 nmol/kg (n = 8). Each volunteer underwent 2 hyperinsulinaemic-euglycaemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minute (level 1). Continuous intravenous administration of apelin or placebo was ongoing for 2 hours and GIR was finally evaluated from the 210th to the 240th minute (level 2). Primary evaluation endpoint was the difference in GIR between level 2 and level 1 (ΔGIR). RESULTS: A slight increase in ΔGIR was observed with the low apelin dose (0.65 ± 0.71 mg/kg/min, P = .055) whereas the highest dose significantly improved insulin sensitivity (0.82 ± 0.71 mg/kg/min, P = .033). Cardiovascular monitoring and safety reports did not reveal any side effect of apelin administration. CONCLUSION: As the first demonstration of the insulin-sensitizing action of apelin in humans, alongside numerous studies in rodents, this trial confirms that the apelin/APJ pathway should be considered as a new target to design alternative therapeutic strategies to control insulin resistance in type 2 diabetic patients.
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Fármacos Antiobesidad/uso terapéutico , Receptores de Apelina/agonistas , Apelina/análogos & derivados , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Sobrepeso/tratamiento farmacológico , Adolescente , Adulto , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/efectos adversos , Apelina/efectos adversos , Apelina/sangre , Apelina/uso terapéutico , Receptores de Apelina/metabolismo , Índice de Masa Corporal , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Infusiones Intravenosas , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/efectos adversos , Péptidos y Proteínas de Señalización Intercelular/farmacocinética , Masculino , Sobrepeso/sangre , Sobrepeso/metabolismo , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/efectos adversos , Fragmentos de Péptidos/farmacocinética , Fragmentos de Péptidos/uso terapéutico , Prueba de Estudio Conceptual , Adulto JovenRESUMEN
BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. METHODS: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society.
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Cisteamina/farmacología , Depletores de Cistina/farmacología , Enfermedad de Huntington/tratamiento farmacológico , Adulto , Anciano , Cisteamina/administración & dosificación , Cisteamina/efectos adversos , Depletores de Cistina/administración & dosificación , Depletores de Cistina/efectos adversos , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed. FINDINGS: Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36-57) in the riluzole group and 49 years (40-56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5-16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of -10·3% (95% CI -37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR -1·5 to 1·5) in the riluzole group versus 0·3 points (-1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49). INTERPRETATION: We were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials. FUNDING: French Ministry of Health.
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Riluzol , Ataxias Espinocerebelosas , Adulto , Encéfalo , Método Doble Ciego , Femenino , Humanos , Riluzol/efectos adversos , Ataxias Espinocerebelosas/tratamiento farmacológico , Ataxias Espinocerebelosas/genética , Resultado del TratamientoRESUMEN
Patients with Parkinson's disease (PD) frequently experience pain that could be in part due to central modification of nociception. In this randomized controlled double blind study, we compared the effect of apomorphine versus placebo on pain thresholds and pain-induced cerebral activity in 25 patients with PD. Subjective pain threshold (using thermal stimulation, thermotest), objective pain threshold (nociceptive flexion reflex), and cerebral activity (H(2)(15)O PET) during noxious and innocuous stimulations were performed. Neither subjective nor objective pain thresholds nor pain activation profile were modified by apomorphine compared with placebo in 25 PD patients. Apomorphine has no effect on pain processing in PD. We suggest that other monoamine systems than dopaminergic system could be involved.
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Antiparkinsonianos/farmacología , Apomorfina/farmacología , Umbral del Dolor/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Antiparkinsonianos/uso terapéutico , Apomorfina/uso terapéutico , Corteza Cerebral/diagnóstico por imagen , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/diagnóstico , Neuralgia/etiología , Isótopos de Oxígeno , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Tomografía de Emisión de Positrones/métodosRESUMEN
The aim of the study was to investigate, with an rTMS/PET protocol, the after-effects induced by 1-Hz repetitive transcranial magnetic stimulation (rTMS) in the regional cerebral blood flow (rCBF) of the primary motor cortex (M1) contralateral to that stimulated during a movement. Eighteen healthy subjects underwent a baseline PET scan followed, in randomized order, by a session of Real/Sham low-frequency (1 Hz) subthreshold rTMS over the right M1 for 23 min. The site of stimulation was fMRI-guided. After each rTMS session (real or sham), subjects underwent behavioral hand motor tests and four PET scans. During the first two scans, ten subjects (RH group) moved the right hand ipsilateral to the stimulated site and eight subjects (LH group) moved the left contralateral hand. All remained still during the last two scans (rest). Two stroke patients underwent the same protocol with rTMS applied on contralesional M1. Compared with Sham-rTMS, Real-rTMS over the right M1 was followed by a significant increase of rCBF during right hand movement in left S1M1, without any significant change in motor performance. The effect lasted less than 1 h. The same rTMS-induced S1M1 overactivation was observed in the two stroke patients. Commissural connectivity between right dorsal premotor cortex and left M1 after real-rTMS was observed with a psychophysiological interaction analysis in healthy subjects. No major changes were found for the left hand. These results give further arguments in favor of a plastic commissural connectivity between M1 both in healthy subjects and in stroke patients, and reinforce the potential for therapeutic benefit of low-frequency rTMS in stroke rehabilitation.
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Actividad Motora/fisiología , Corteza Motora/fisiología , Accidente Cerebrovascular/fisiopatología , Estimulación Magnética Transcraneal , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico , Electroencefalografía , Femenino , Lateralidad Funcional , Mano , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Corteza Motora/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Tomografía de Emisión de Positrones , Accidente Cerebrovascular/diagnóstico por imagen , Análisis y Desempeño de TareasRESUMEN
OBJECTIVE: Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France. METHODS: Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier. Standardized incidence ratios (SIR), based on age- and sex-adjusted rate of the French population, were assessed for different types of cancer. RESULTS: We questioned 372 patients with HD and 134 patients with SCA. SIR showed significantly reduced risk of cancer in HD: 23 observed cases vs 111.05 expected ones (SIR 0.21, 95% confidence interval [CI] 0.13-0.31), as well as in SCA: 7 observed cases vs 34.73 expected (SIR 0.23, 95% CI 0.08-0.42). This was surprising since risk behavior for cancer was increased in these patients, with significantly greater tobacco and alcohol consumption in patients with HD vs patients with SCA (p < 0.0056). There was no association between CAG repeat size and cancer or cardiovascular disease. However, in patients with HD, skin cancers were more frequent than expected (5 vs 0.98, SIR 5.11, 95% CI 1.65-11.95). CONCLUSIONS: There was a decreased cancer rate in PolyQ diseases despite high incidence of risk factors. Intriguingly, skin cancer incidence was higher, suggesting a crosstalk between neurodegeneration and skin tumorigenesis.
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Predisposición Genética a la Enfermedad/epidemiología , Enfermedad de Huntington/epidemiología , Neoplasias/epidemiología , Péptidos/genética , Ataxias Espinocerebelosas/epidemiología , Europa (Continente)/epidemiología , Femenino , Humanos , Enfermedad de Huntington/genética , Masculino , Persona de Mediana Edad , Neoplasias/genética , Estudios Retrospectivos , Factores de Riesgo , Ataxias Espinocerebelosas/genéticaRESUMEN
BACKGROUND: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. METHODS/DESIGN: This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. DISCUSSION: By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.