A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis.

BACKGROUND: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS. OBJECTIVE: To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS). METHODS: Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse. RESULTS: Patients with RMS on GA (N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg (n = 40), 7 mg (n = 42), or placebo (n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306). CONCLUSIONS: Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Long-term safety of riluzole in amyotrophic lateral sclerosis.

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.

A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis.

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.

The Rilutek (riluzole) Global Early Access Programme: an open-label safety evaluation in the treatment of amyotrophic lateral sclerosis.

OBJECTIVES: This study had two main objectives: 1. To enable patients with amyotrophic lateral sclerosis (ALS) who had not participated in previous riluzole trials to receive riluzole therapy, and 2. To expand safety experience with the drug in a broad patient population. METHODS: This was a Phase IIIb multicentre, multinational, open-label, uncontrolled single treatment study of riluzole. Patients with diagnosed possible or probable ALS were administered 100 mg of riluzole/day (50 mg b.i.d.). Clinical and laboratory adverse events were recorded every month for the first 3 months and thereafter at 3-monthly intervals. RESULTS: 8383 patients from 44 countries were entered into the study; 7916 of these patients with recorded data were administered the study drug. The mean duration of riluzole treatment was 202.1 days, with a range of 1-630 days. The most frequently reported serious and non-serious adverse events were common symptoms of ALS (respiratory symptoms and dysphagia), and only 1.9% of serious adverse events were considered to be related to the study drug. CONCLUSIONS: The safety results with this broad population (over 10% of the estimated ALS population worldwide) were consistent with those previously reported from placebo-controlled trials. No increase in adverse events and no unexpected adverse events were observed.

Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia.

OBJECTIVE: The authors' objective was to assess the potential efficacy of fananserin (RP62203), a potent antagonist at the D4 and serotonin2A (5-HT2A) receptors, on symptoms of schizophrenia. METHOD: A double-blind, placebo-controlled study was conducted in 97 patients. Doses of fananserin reached 250 mg b.i.d. over 28 days, starting with an 8-day escalation. Most of the patients were men with paranoid schizophrenia; they were approximately 38 years old. The primary outcome measure was the total Positive and Negative Syndrome Scale score. The patients' mean score on the Positive and Negative Syndrome Scale at entry was 91.8 (SD=16.5). A low dropout rate was observed in both groups of patients (19 [30%] of those given fananserin and nine [27%] of those given placebo). RESULTS: The total Positive and Negative Syndrome Scale score of the patients given fananserin decreased at endpoint by a mean of 4.2 points (SD=15.4); the score of the patients given placebo decreased by 6.7 points (SD=19.6). No differences between treatments were found on secondary measures such as the Clinical Global Impression, Positive and Negative Syndrome Scale subscores or individual items, and Brief Psychiatric Rating Scale total score. The patients' extrapyramidal symptoms did not worsen during the trial, but the patients given fananserin had an increase in akathisia. The safety profile was good in both groups of patients. CONCLUSIONS: The results of this study do not support the prediction that a selective D4 antagonist associated with strong 5-HT2A antagonism will exhibit an antipsychotic effect.

Single- and multiple-dose pharmacokinetics of riluzole in white subjects.

Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single- and multiple-dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50-mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were linearly related to dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half-life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high-fat meal significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng.mL-1 compared to 387 ng.mL-1) and extent of absorption (AUC = 1,047 ng.hr.mL-1 versus 1,269 ng.hr.mL-1). With multiple-dose administration, riluzole showed dose-related absorption, although the terminal plasma half-life was prolonged slightly. Steady-state plasma concentrations were achieved within 5 days. Steady-state trough plasma concentrations were significantly higher with a 75-mg dose twice daily than with a 50-mg dose three times daily, although AUC values did not differ.

Natural autoantibodies in schizophrenia.

Autoantibodies reacting with cell constituents other than antinuclear antibodies have seldom been reported in the literature on schizophrenia. Serum of 41 DSM-III-R schizophrenic patients was examined for the presence of various autoantibodies and compared with that of healthy volunteers (n = 10) and hospitalized controls. Titers of IgG, IgA and IgM autoantibodies directed against actin, tubulin, myosin, DNA, thyroglobulin, elastin, albumin, DNA and trinitrophenyl groups were determined using enzyme immunoassay. IgG and IgA titers were significantly decreased in schizophrenic patients. These results contrast with those obtained with various other autoimmune and nonautoimmune diseases in which titers are either unchanged or increased. A significant increase of various autoantibody levels was observed in the paranoid subgroup of schizophrenics compared with the disorganized subgroup. These autoantibodies possess characteristics similar to those of natural autoantibodies, which seem to play several biological roles.

[Bulimic behaviors. Clinical, biochemical, pharmacologic data]. / Comportements boulimiques. Données cliniques, biochimiques, pharmacologiques.

Bulimia nervosa has been recently identified. DSM III-R gives more restrictive criteria for the trouble than DSM III. One may doubt it allows to better understand the probable psychopathological heterogeneity of this eating disorder. Biological indexes up to now only led to partial results. Their interpretation is made more difficult because of the small size of the samples of patients, studied in conditions which are often ill-defined. The biological parameters which are investigated are similar to those studied in depression: monoamines, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, hypothalamic-pituitary-gonadal axis, Growth Hormone, prolactin , melatonin, beta-endorphin, EEG mapping. Antidepressants and anticonvulsants remain the most often mentioned drugs. Tryptophane, lithium, opiate antagonists, amphetamines, serotoninergic drugs are currently being studied.

[Cortisol secretion in depressed patients. Review of the literature]. / La sécrétion de cortisol chez le déprimé. Revue de la littérature.

The authors present a critical overview of the multiple and contradictory studies of cortisol production in depressed patients. Some notions of physiology are first recalled. A main part of the review discusses the dexamethasone suppression test, but studies of the cortisol secretion profile and of other dynamic tests are also presented. One can describe in depressed people: cortisol overproduction, an impaired negative feedback mechanism, an adrenocortical hyperreactivity to ACTH and a phase advance in the circadian rhythm of cortisol secretion. These anomalies are more frequently encountered in patients exhibiting severe depressions of the endogenomorphic type. However, none of them can be considered as a biological marker of depression, nor as a marker for a particular type of depression. The relation between endocrine disturbances and the clinical parameters of depression is still controversial.