RESUMEN
OBJECTIVES: This international, open-label, multicentre extension of riluzole pivotal studies was designed to assess the long-term safety of riluzole in the treatment of amyotrophic lateral sclerosis (ALS). METHOD: The studies were carried out at 31 different centres, 23 in Europe and eight in North America. 516 patients with diagnosed probable or definite ALS and who had participated previously in one of two international multicentre randomized double-blind placebo-controlled, parallel-group trials, were enrolled in the extensions. 58 of these patients had taken part in a randomized phase II trial (placebo or riluzole 100 mg/day) and 458 in a randomized, dose-ranging phase III trial (placebo or riluzole, 50, 100 or 200 mg/day). All participants in the open-label continuation received 100 mg/day of riluzole (50 mg b.i.d.) RESULTS: At the end of the open-label study, the average exposure time of the patients to riluzole was 28.7 +/- 14.4 months, with a maximum exposure time of 81 months. Most of the adverse events recorded reflected the progression of ALS, in particular the deterioration of the respiratory status of the patients. No particular adverse event, or frequency of adverse event, appeared to be related to the dose level of the previous double-blind riluzole treatment. Nor were any adverse events associated with the switch-over from double-blind placebo to open-label riluzole. CONCLUSIONS: This open-label extension study reinforces and extends the results of the preceding double-blind trials regarding the safety of riluzole and shows that the drug is well tolerated for long periods of up to almost 7 years.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/mortalidad , Enfermedades Hematológicas/inducido químicamente , Enfermedades Respiratorias/inducido químicamente , Riluzol/efectos adversos , Adulto , Anciano , Canadá/epidemiología , Seguridad de Productos para el Consumidor , Europa (Continente)/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Vigilancia de Productos Comercializados , Estados Unidos/epidemiologíaRESUMEN
Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Tolerancia a Medicamentos/fisiología , Fármacos Neuroprotectores/administración & dosificación , Riluzol/administración & dosificación , Riluzol/efectos adversos , Factores de Edad , Anciano , Esclerosis Amiotrófica Lateral/fisiopatología , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Fármacos Neuroprotectores/efectos adversos , Selección de Paciente , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The neuroprotective drug riluzole (Rilutek) is a sodium channel blocker and anti-excitotoxic drug which is marketed for the treatment of amyotrophic lateral sclerosis (ALS). Previous studies have shown that riluzole prolongs survival of transgenic mice harboring the mutated form of Cu,Zn-superoxide dismutase found in familial forms of the human disease. In this study we have examined the effect of treatment with riluzole in mice suffering from progressive motor neuronopathy (pmn), a hereditary autosomal recessive wasting disease which shares some symptoms of ALS. These mutants display hind limb weakness starting during the 3rd week of life and leading to paralysis and death during the 7th week of life. Daily treatment with 8 mg/kg of riluzole by oral route significantly retarded the appearance of paralysis, increased life span and improved motor performance on grip test and electromyographic results in the early stage of the disease. There was no effect of riluzole on weight gain. These data demonstrate that riluzole significantly prolongs life span, retards the onset of paralysis and slows the evolution of functional parameters connected with muscle strength in the pmn mouse model of motor neuron disease.
Asunto(s)
Enfermedad de la Neurona Motora/tratamiento farmacológico , Debilidad Muscular/prevención & control , Riluzol/farmacología , Tasa de Supervivencia , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Fuerza de la Mano/fisiología , Ratones , Ratones Transgénicos/genética , Enfermedad de la Neurona Motora/fisiopatología , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Resultado del TratamientoRESUMEN
Hemodynamic evaluation of a vasodilator drug is a difficult exercise in which Doppler echocardiography can be a useful tool. We studied the hemodynamic effect of isosorbide dinitrate (ISDN) by Doppler echocardiography in 7 patients with severe cardiac failure despite prolonged therapy with usually effective doses of captopril. The patients were evaluated before (H0) and 24 hours after treatment by ISDN (120 mg/24 hr) (H24) and 10 minutes after sublingual 0.75 mg of trinitrin (H24 + T). M mode echocardiography did not show any significant changes in chamber dimension as reported after vasodilator therapy in patients without cardiac dilation: in patients with severe left ventricular dilatation a reduction in LV filling pressures causes little if any changes in fractional shortening and ventricular dimensions. Two-dimensional echocardiography showed a reduction in end systolic volume and an increase in ejection fraction, emphasizing the superiority of this technique in cases of abnormal left ventricular function and the sensitivity of indices of systolic function to changes in afterload in these patients. Cardiac output measured by Doppler increased during the study. The maximal acceleration did not change significantly and pulmonary artery pressures were stable after administration of nitrates. ISDN caused a marked change in diastolic mitral flow patterns for which there are several explanations: an effect of ISDN on relaxation or LV compliance or on the conditions of LV filling or on both factors together. The presence of mitral regurgitation and/or atrial arrhythmia prevents the use of Doppler indices for analysis of diastolic LV function.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Captopril/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Dinitrato de Isosorbide/uso terapéutico , Anciano , Captopril/farmacología , Quimioterapia Combinada , Ecocardiografía Doppler , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Hemodinámica/efectos de los fármacos , Humanos , Dinitrato de Isosorbide/farmacología , Masculino , Persona de Mediana Edad , Función Ventricular IzquierdaRESUMEN
Forty patients with low cardiac output (cardiac index less than 2.2 l/mn/m2 and pulmonary wedge pressure greater than 15 mmHg) after valvular surgery were randomised into two groups. Patients in Group 1 were given 5 to 10 micrograms/Kg/mn of Dobutamine (D) and those In Group 2 a bolus of Enoximone (E) 1 mg/kg followed by an intravenous infusion of 5 to 10 micrograms/Kg/mn. Holter ECG monitoring over 42.65 +/- 6.02 hrs (24-48 hours) was obtained and interpreted blindly in 37/40 patients (19 Group D and 18 Group E). The results were analysed by the t and X2 tests. A p value of less than .05 was considered statistically significant. The two groups were comparable. No deaths occurred during the protocol period. The total duration of inotropic therapy (86 +/- 49 hours) and the period spent in the intensive care unit (155 +/- 129 hours) were longer in Group D than in Group E (60 +/- 23 hrs and 92 +/- 37 hrs, respectively; p less than .05). Antiarrhythmic therapy was used more often in Group D (4 patients) than in group E (1 patient) (p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)