Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole.

The objective of this study was to identify prognostic factors for survival in amyotrophic lateral sclerosis from a large prospective observational study performed in France. The study included a cohort of 2069 patients fulfilling broad entry criteria treated with riluzole. Over 100 demographic, biological, clinical and quality-of-life variables were monitored and assessed for their effect on survival. Patients were randomized post hoc into two groups: one group (two-thirds of the patients) to generate the prognostic models and one group (one-third of the patients) to validate the resulting models. Thirteen variables were found to affect survival independently and were used to construct a survival prediction score, RL401. These included age, disease duration, slow vital capacity, intensity of tiredness (visual analogue scale), number of body levels with spasticity, atrophy and/or fasciculations, cough, distal muscle strength, household income, depression and two biological parameters, plasma creatinine levels and neutrophil counts. A simplified score, RL401S, was constructed, designed to be easy to use and interpret. The predictive powers of the two scores were similar.

[Tolerance of riluzole in a phase IIIb clinical trial]. / Tolérance du riluzole dans un essai ouvert (phase IIIb).

Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.

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.

Blood oxidative stress in amyotrophic lateral sclerosis.

It has been suggested that amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder resulting in motor neuron death, is associated with oxidative damage induced by free radicals. Our study aimed to get an assessment of the blood oxidative stress status in a population of 167 ALS patients (aged 59+/-13 years), treated or not with riluzole, compared with 62 age-matched healthy control subjects (aged 60+/-11 years) simultaneously included in the study. We determined the level of plasma lipid peroxidation (thiobarbituric acid-reactive substances, TBARS); the status of the major lipophilic plasma antioxidant defenses (vitamin E, vitamin A and beta-carotene); the activities of erythrocyte Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and of plasma and erythrocyte glutathione peroxidase (GSH-Px). Plasma selenium was also determined as a trace element essential to the activity of the GSH-Px. In comparison with controls, we observed in ALS patients (mean+/-S.D.) significantly higher TBARS values (ALS=1.34+/-0.28 micromol/l; controls=1.11+/-0. 20 micromol/l) and a significant enhancement of the erythrocyte SOD activity (ALS=710+/-114 U/g Hb; controls=667+/-93 U/g Hb). No differences were observed for selenium level, GSH-Px activity, plasma vitamin E, beta-carotene and vitamin A concentrations. These data confirm the presence of an oxidative stress in blood of ALS patients. The elevated plasma TBARS, without any deficiency in plasma lipophilic antioxidants such as vitamin E, vitamin A and beta-carotene, suggest an enhancement in the production of free radicals. No correlation was found in our study between the level of any of the blood oxidative stress markers and the disease duration. Comparison between patients treated or not with riluzole did not display any modification of the plasma TBARS concentration, but we observed a slight decrease of erythrocyte SOD activity in treated patients (treated=705+/-113 U/g Hb; not treated=725+/-118 U/g Hb), suggesting a possible activity of riluzole on the oxygenated free radical production.

Bullous pemphigoid and amyotrophic lateral sclerosis: a new clue for understanding the bullous disease?

BACKGROUND: Bullous pemphigoid (BP) occurs in many patients with multiple sclerosis. Isolated cases of BP in patients with other neurological disorders further support a pathogenic association between cutaneous and neurological diseases. Any description of BP in patients with amyotrophic lateral sclerosis is lacking. OBSERVATIONS: We studied a French population of 168 patients with typical amyotrophic lateral sclerosis. Among these, 3 had clinical and histological features of BP. The mean age of the patients was 54 years. None was known to have autoimmune disorders. Results of immunoblot analysis disclosed both anti-BP antigen 1 and anti-BP antigen 2 antibodies. CONCLUSIONS: Bullous pemphigoid seems to be unexpectedly associated with amyotrophic lateral sclerosis. On the basis of the cases presented herein, we discuss the epidemiological significance of the association and the possible interrelation between BP antigen 1 and neurofilaments in the pathogenesis of both disorders.

Diaphragmatic dysfunction and dyspnoea in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive disorder of unknown origin. Respiratory involvement is the principal cause of death, and dyspnoea is a major source of discomfort. In this study, diaphragm function is described and its relationship with dyspnoea examined in 48 ALS patients (32 male, age 26-80 yrs). The detailed neurological and respiratory evaluation (clinical examination, pulmonary function tests, static pressures, mouth twitch pressures (Pm,t), electromyographic responses to phrenic nerve stimulation and cortical magnetic stimulation were analysed after stratification according to dyspnoea. Dyspnoeic (group I) and nondyspnoeic (group II) patients were similar, bulbar signs being more frequent in group I. Vital capacity was lower in group I (mean+/-SD 67.9+/-22.7 versus 87.9+/-15.6% of the predicted value, p=0.0028), as were maximal static inspiratory pressure (41+/-24 versus 60+/-27% pred, p=0.0242) maximal static inspiratory pressure (18+/-11 versus 32+/-14% pred, p=0.0042), and Pm,t (3.71+/-2.5 versus 7.26+/-3.45 cmH2O, p=0.0011). Abdominal (Abd) paradox and respiratory pulse were frequent in group I (15 of 25 and 14 of 25) but absent or rare in group II (0 of 23 and four of 23) (p<0.05). The electromyographic responses to phrenic and cortical stimulation were generally abnormal in group I but subnormal in group II. Multivariate analysis selected only signs of diaphragm dysfunction (namely, Abd paradox and abnormal electromyographic responses) as significant predictors of dyspnoea. It is concluded that dyspnoea in amyotrophic lateral sclerosis patients should prompt diaphragm function tests.

Surgical crown-lengthening procedure to enhance esthetics.

This article presents the rationale for the use of a preprosthetic surgical crown-lengthening procedure, particularly in the anterior region where esthetics is of great concern. Clinical cases illustrate the procedure and demonstrate how it can be used to provide enough sound tooth structure to restore teeth without impingement on the biologic width, at the same time reducing a "gingival smile" and creating new papillae.

A phase I/II study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma.

Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events related to M11 cell administration or GCV. Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.

A phase I/II dose-escalation study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for metastatic melanoma. Study Group on Gene Therapy of Metastatic Melanoma.

We performed a dose-escalating phase I/II study of retrovirus-mediated herpes simplex virus type 1 thymidine kinase (HSV-1-TK) suicide gene therapy for metastatic melanoma. HSV-1 TK expression, which specifically sensitizes transduced and bystander cancer cells to ganciclovir (GCV) toxicity, was mediated by one (four patients, first dose step) to three (four patients, second dose step) injections of "M11" retrovirus vector-producing cells in melanoma cutaneous nodules. After a 7-day period allowed for cancer cell transduction, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by tumor measurements and histology. M11 doses ranged from 76 to 1247 x 10(6) cells. Treatment-related adverse events were mild and transient, limited to inflammatory skin reactions at injection and fever on repeated injections. Plasma GCV was in the active range (>0.2 microg/ml); transgene was detected by polymerase chain reaction in three of six patients; treated tumor size was moderately affected under GCV as compared with untreated tumors, although 2 weeks after GCV administration important (>50%) treated-tumor necrosis was evidenced on histology in three of eight patients. All patients showed disease progression on long-term follow-up. Thus, M11-mediated HSV-1 TK gene therapy was well tolerated over a wide dose range. The limited tumor response is likely to be related to poor gene transfer efficiency. However, necrosis following GCV administration in transduced tumors indicates a potential for treatment efficacy.

A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II.

ALS is a progressive motor neuron disease with no effective treatment. The anti-excitotoxic drug riluzole (100 mg/day) has been shown to decrease mortality and muscular deterioration in ALS patients. To confirm and extend the therapeutic effect of riluzole, we performed a double-blind, placebo-controlled, multicenter, international, dose-ranging (50, 100, 200 mg/day), stratified study in 959 ALS outpatients treated for up to 18 months. Primary efficacy criterion was survival and the effect of treatment was analyzed before (Wilcoxon and log rank tests) and after adjustment on prognostic factors (Cox model). Secondary efficacy criterion was disease progression assessed through change in functional measures. Tracheostomy-free survival rates were: 50.4% (placebo), 55.3% (50 mg riluzole) (p = 0.23, Wilcoxon test; p = 0.25, log-rank test), 56.8% (100 mg riluzole) (p = 0.05, Wilcoxon test; p = 0.076, log-rank test), and 57.8% (200 mg riluzole) (p = 0.061, Wilcoxon test; p = 0.075, log-rank test). At the end of the 18-month study, there was a significant dose-related decrease in risk of death or tracheostomy (p = 0.04). Adjustment for baseline prognostic factors showed a 35% decreased risk of death with the 100-mg dose compared with placebo (p = 0.002). No significant treatment effects were detected for the functional assessments. The most frequent dose-related adverse events included nausea, asthenia, and elevated liver enzyme levels. This study confirms the therapeutic effect of riluzole in a large representative ALS sample, over an 18-month period. Riluzole is well tolerated and decreases the risk of death or tracheostomy in ALS patients.

Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease with no effective treatment. In an initial study, riluzole decreased mortality and slowed muscle-strength deterioration in ALS patients. We have carried out a double-blind, placebo-controlled, multicentre study to confirm those findings and to assess drug efficacy at different doses. METHODS: 959 patients with clinically probable or definite ALS of less than 5 years' duration were randomly assigned treatment with placebo or 50 mg, 100 mg, or 200 mg riluzole daily; randomisation was stratified by centre and site of disease onset (bulbar or limb). The primary outcome was survival without a tracheostomy. Secondary outcomes were rates of change in functional measures (muscle strength, functional status, respiratory function, patient's assessments of fasciculation, cramps, stiffness, and tiredness). The primary analysis was the comparison of the 100 mg dose with placebo by intention-to-treat. Drug-effect on survival was assessed before (log-rank test) and after adjustment for known prognostic factors (Cox's model). FINDINGS: At the end of the study, after median follow-up of 18 months, 122 (50.4%) placebo-treated patients and 134 (56.8%) of those who received 100 mg/day riluzole were alive without tracheostomy (unadjusted risk 0.79, p = 0.076; adjusted risk 0.65, p = 0.002). In the groups receiving 50 mg and 200 mg riluzole daily, 131 (55.3%) and 141 (57.8%) patients were alive without tracheostomy (relative to placebo 50 mg adjusted risk 0.76, p = 0.04; 200 mg 0.61, p = 0.0004). There was a significant inverse dose response in risk of death. No functional scale discriminated between the treatment groups. The most common adverse reactions were asthenia, dizziness, gastrointestinal disorders, and rises in liver enzyme activities; they were commonest with the 200 mg dose. INTERPRETATION: Overall, efficacy and safety results suggest that the 100 mg dose of riluzole has the best benefit-to-risk ratio. This study confirms that riluzole is well tolerated and lengthens survival of patients with ALS.

A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. METHODS: To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days). RESULTS: After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group. CONCLUSIONS: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.

[Pharmacology of the memory. Review of cognition activator pharmacology]. / Pharmacologie de la mémoire. Revue de la pharmacologie des activateurs cognitifs.

The pharmacology of memory is fraught with problems. For one thing, the lack of consensus on the definition of memory and the absence of reference compound create clinical validation problems for new drugs. Then, it is difficult to predict clinical effectiveness on the basis of animal experiments and data obtained from healthy subjects, and this is due to the lack of analogy between animal models and clinical situations. Finally, to this must be added the complexity and variety of the possible modes of action of the agents under study. Thus, the pharmacology of cognition activators is closely dependent upon both fundamental research and clinical research.

Microtubule disruption and cognitive defects: effect of colchicine on learning behavior in rats.

Neuropathological findings in Alzheimer's disease (AD) suggest a possible involvement of microtubule dysfunction in neurodegenerative process pathogenesis. Because microtubules have a major role in neuronal plasticity, microtubule disruption could be also directly responsible for cognitive defects in AD. We report that in rats, continuous microtubule disruption induced by chronic colchicine administration results in a dose-dependent learning deficit. In addition, retention is also impaired. These cognitive defects are specific, as chronic colchicine induces no other behavioral toxicity within the study dose range. Colchicine-induced cognitive defects resemble those of AD, which are characterised by amnesia of recent learning and loss of formerly established memories. This new procedure of pharmacologically induced cognitive impairment may prove useful, both towards understanding AD pathogenesis and towards drug screening.

Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.

1. The effects of zolpidem 20 mg, flunitrazepam 2 mg and placebo, administered at bed time, were studied in 12 healthy young male volunteers. 2. The assessments included, at awakening, subjective ratings of overnight sleep, cognitive function, psychomotor performance (digit symbol substitution, choice reaction time, flicker fusion threshold), subjective ratings of alertness, and plasma assay of residual drug concentration. Daytime sleep propensity during the day after dosing was evaluated with the multiple sleep latency test. 3. Compared with placebo, both active drugs improved subjective assessment of the ease of getting to sleep. At awakening, under flunitrazepam treatment, the reduction of performance, on memory and psychomotor tests, paralleled an increased subjective rating of sleepiness, but zolpidem treatment left subjects unimpaired compared with placebo. Similarly, daytime sleep propensity was enhanced throughout the following day under flunitrazepam treatment, but not under zolpidem treatment. Plasma assay for residual drug concentration at awakening found significant amounts of flunitrazepam and marginal amounts of zolpidem. 4. Results indicate that zolpidem 20 mg is devoid of residual effects in a range of tasks that were sensitive enough to demonstrate a prolonged wakefulness impairment following flunitrzepam 2 mg in healthy volunteers.