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1.
Orphanet J Rare Dis ; 12(1): 160, 2017 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-28969699

RESUMEN

BACKGROUND: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. RESULTS: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. CONCLUSIONS: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.


Asunto(s)
Hemiplejía/tratamiento farmacológico , Triglicéridos/uso terapéutico , Adolescente , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Masculino , Adulto Joven
2.
J Neurol Neurosurg Psychiatry ; 87(5): 550-3, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26536893

RESUMEN

OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (± 27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (± 2.9, 76% motor events) during the treatment phase (p = 0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (± 21.9, 52% motor events; p = 0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p = 0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. TRIAL REGISTRATION NUMBER: NCT02014883.


Asunto(s)
Corea/tratamiento farmacológico , Corea/genética , Transportador de Glucosa de Tipo 1/deficiencia , Transportador de Glucosa de Tipo 1/genética , Triglicéridos/uso terapéutico , Adolescente , Adulto , Niño , Metabolismo Energético/efectos de los fármacos , Femenino , Neuroimagen Funcional , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Lóbulo Occipital/metabolismo , Fosfatos/metabolismo , Fosfocreatina/metabolismo , Proyectos Piloto , Triglicéridos/farmacología , Adulto Joven
3.
Neurology ; 84(5): 490-5, 2015 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-25568297

RESUMEN

OBJECTIVE: Based on our previous work in Huntington disease (HD) showing improved energy metabolism in muscle by providing substrates to the Krebs cycle, we wished to obtain a proof-of-concept of the therapeutic benefit of triheptanoin using a functional biomarker of brain energy metabolism validated in HD. METHODS: We performed an open-label study using (31)P brain magnetic resonance spectroscopy (MRS) to measure the levels of phosphocreatine (PCr) and inorganic phosphate (Pi) before (rest), during (activation), and after (recovery) a visual stimulus. We performed (31)P brain MRS in 10 patients at an early stage of HD and 13 controls. Patients with HD were then treated for 1 month with triheptanoin after which they returned for follow-up including (31)P brain MRS scan. RESULTS: At baseline, we confirmed an increase in Pi/PCr ratio during brain activation in controls-reflecting increased adenosine triphosphate synthesis-followed by a return to baseline levels during recovery (p = 0.013). In patients with HD, we validated the existence of an abnormal brain energy profile as previously reported. After 1 month, this profile remained abnormal in patients with HD who did not receive treatment. Conversely, the MRS profile was improved in patients with HD treated with triheptanoin for 1 month with the restoration of an increased Pi/PCr ratio during visual stimulation (p = 0.005). CONCLUSION: This study suggests that triheptanoin is able to correct the bioenergetic profile in the brain of patients with HD at an early stage of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for patients with HD, treatment with triheptanoin for 1 month restores an increased MRS Pi/PCr ratio during visual stimulation.


Asunto(s)
Encéfalo/metabolismo , Metabolismo Energético/fisiología , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/metabolismo , Triglicéridos/uso terapéutico , Adulto , Encéfalo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Triglicéridos/farmacología , Adulto Joven
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