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1.
Mol Genet Metab ; 141(1): 108113, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38113551

RESUMEN

Nizubaglustat is a novel, orally available, brain penetrant, potent, and selective dual inhibitor of ceramide glucosyltranferase and non-lysosomal neutral glucosylceramidase (NLGase), which is currently under development for the treatment of subjects with neurological manifestations in primary and secondary gangliosidoses. The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics (PD) of single oral doses of nizubaglustat after single (1, 3, and 9 mg) and multiple oral doses (9 mg once per day (QD) over 14 days) in healthy adults. Nizubaglustat was rapidly absorbed and systemic exposure was dose-proportional. Steady-state was achieved after three days of QD multiple dosing with minimal accumulation. Renal clearance accounted for around 15% of nizubaglustat elimination. Following multiple dosing, plasma concentrations of glucosylceramide (GlcCer), lactosylceramide (LacCer), and monosialodihexosylganglioside (GM3) decreased to a nadir at Day 10. PD target engagement of GCS inhibition was shown by a median decrease from baseline of plasma concentrations of GlcCer, LacCer, and GM3 ganglioside by 70%, 50%, and 48%, respectively. NLGase inhibition was also manifested by increased concentrations of GlcCer in cerebrospinal fluid from Day 1 to Day 14. Nizubaglustat was safe and well-tolerated at all doses tested. Consistent with the high selectivity, and the absence of intestinal disaccharidases inhibition, no cases of diarrhea were reported. No decreased appetite or weight loss was noted. Only treatment-emergent adverse events with preferred terms belonging to the system organ class skin and subcutaneous disorders of mild intensity were reported as drug-related in the nizubaglustat arm, in line with the pharmacological mechanism targeting glucosylceramide metabolism. Taken together, these data support QD dosing of nizubaglustat and its ongoing development in patients with primary and secondary forms of gangliosidoses.


Asunto(s)
Gangliosidosis , Glucosilceramidasa , Adulto , Humanos , Glucosilceramidas , Glucosiltransferasas , Hidrolasas , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Administración Oral
2.
J Inherit Metab Dis ; 35(6): 1093-9, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22350617

RESUMEN

BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain.


Asunto(s)
Cognición , Enfermedad de Gaucher/psicología , Adolescente , Adulto , Anciano , Atención , Estudios de Casos y Controles , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/psicología , Estudios de Cohortes , Europa (Continente) , Femenino , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/genética , Humanos , Estudios Longitudinales , Masculino , Memoria , Memoria a Corto Plazo , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios Prospectivos , Adulto Joven
3.
Mol Genet Metab ; 99(4): 351-7, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20045366

RESUMEN

A randomized, controlled trial of miglustat indicated that miglustat (Zavesca) stabilized neurological disease over 12 months in adult and juvenile patients with Niemann-Pick disease type C (NP-C). We report data from a non-controlled, open-label extension to this initial randomized trial. All patients completing the randomized trial were allowed to continue treatment in a 12-month, non-controlled open-label extension. Those completing 12 months of extension therapy could continue further on miglustat in a 'continued extension' phase. From a total of 29 patients in the randomized phase (mean [+/-SD] age 24.6+/-9.1 ears; 52% female), 21 completed 12 months of therapy with miglustat (17 of whom received miglustat in the initial randomized phase, and four in the extension phase), and 15 patients (all from the miglustat-randomized group) completed 24 months on miglustat. Mean horizontal saccadic eye movement velocity (HSEM-alpha) indicated improvement in the 12-month miglustat group, and stabilization in the 24-month group; swallowing was improved or stable in 86% and in up to 93%, respectively. Ambulation was stabilized in both the 12- and 24-month groups. In an exploratory disease stability analysis of prospective data on key parameters of disease progression (HSEM-alpha, swallowing, ambulation and cognition), 13/19 (68%) patients receiving >or= 12 months' miglustat therapy had stable disease. Among all patients receiving >or= 1 dose of miglustat (n=28), the most frequent adverse events were diarrhoea, weight decrease, flatulence and tremor. Overall, these data suggest that long-term miglustat therapy stabilizes neurological disease and is well tolerated in adult and juvenile patients with NP-C.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 1-Desoxinojirimicina/efectos adversos , 1-Desoxinojirimicina/uso terapéutico , Adolescente , Adulto , Niño , Deglución/efectos de los fármacos , Diarrea/inducido químicamente , Femenino , Humanos , Caminata , Pérdida de Peso
4.
Genet Med ; 11(6): 425-33, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19346952

RESUMEN

PURPOSE: To evaluate the safety and efficacy of miglustat in patients with GM2 gangliosidosis. METHODS: A randomized, multicenter, open-label, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or "no miglustat treatment." This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. RESULTS: Thirty patients (67% male, age range 18-56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to "no miglustat treatment." Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. CONCLUSION: Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Enfermedad de Tay-Sachs/tratamiento farmacológico , 1-Desoxinojirimicina/efectos adversos , 1-Desoxinojirimicina/uso terapéutico , Adolescente , Adulto , Edad de Inicio , Diarrea/inducido químicamente , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Fatiga/inducido químicamente , Femenino , Inhibidores de Glicósido Hidrolasas , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Tay-Sachs/epidemiología , Factores de Tiempo , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacos , Adulto Joven
5.
PLoS One ; 13(11): e0206583, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30408072

RESUMEN

Despite their wide-spread use, only limited information is available on the comparative test-retest reliability of task-based functional and resting state magnetic resonance imaging measures of blood oxygen level dependence (tb-fMRI and rs-fMRI) and cerebral blood flow (CBF) using arterial spin labeling. This information is critical to designing properly powered longitudinal studies. Here we comprehensively quantified and compared the test-retest reliability and reproducibility performance of 8 commonly applied fMRI tasks, 6 rs-fMRI metrics and CBF in 30 healthy volunteers. We find large variability in test-retest reliability performance across the different tb-fMRI paradigms and rs-fMRI metrics, ranging from poor to excellent. A larger extent of activation in tb-fMRI is linked to higher between-subject reliability of the respective task suggesting that differences in the amount of activation may be used as a first reliability estimate of novel tb-fMRI paradigms. For rs-fMRI, a good reliability of local activity estimates is paralleled by poor performance of global connectivity metrics. Evaluated CBF measures provide in general a good to excellent test-reliability matching or surpassing the best performing tb-fMRI and rs-fMRI metrics. This comprehensive effort allows for direct comparisons of test-retest reliability between the evaluated MRI domains and measures to aid the design of future tb-fMRI, rs-fMRI and CBF studies.


Asunto(s)
Circulación Cerebrovascular , Neuroimagen Funcional/estadística & datos numéricos , Imagen por Resonancia Magnética/estadística & datos numéricos , Oxígeno/sangre , Adulto , Encéfalo/anatomía & histología , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Femenino , Humanos , Imagenología Tridimensional , Masculino , Modelos Neurológicos , Reproducibilidad de los Resultados , Descanso/fisiología , Marcadores de Spin , Análisis y Desempeño de Tareas , Adulto Joven
7.
Orphanet J Rare Dis ; 7: 102, 2012 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-23270487

RESUMEN

BACKGROUND: Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy. METHODS: Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count. RESULTS: Forty-two patients were enrolled (mean±SD age, 45.1±12.7 years; previous enzyme therapy duration 9.5±4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3-765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (-1.1%; 95%CI -6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, -0.95 (-1.38, -0.53) g/dL and -44.1 (-57.6, -30.7) ×109/L, respectively. CONCLUSIONS: The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00319046.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Terapia Enzimática , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/terapia , 1-Desoxinojirimicina/efectos adversos , 1-Desoxinojirimicina/uso terapéutico , Adulto , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
8.
J Child Neurol ; 25(3): 300-5, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19822772

RESUMEN

Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months' treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Inhibidores Enzimáticos/uso terapéutico , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 1-Desoxinojirimicina/administración & dosificación , 1-Desoxinojirimicina/efectos adversos , 1-Desoxinojirimicina/uso terapéutico , Niño , Preescolar , Deglución/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Masculino , Actividad Motora/efectos de los fármacos , Estudios Prospectivos , Movimientos Sacádicos/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento
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