Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

Magnetic stimulation of the central and peripheral nervous systems.

Since 1985, when the technique of transcranial magnetic stimulation (TMS) was first developed, a wide range of applications in healthy and diseased subjects has been described. Comprehension of the physiological basis of motor control and cortical function has been improved. Modifications of the basic technique of measuring central motor conduction time (CMCT) have included measurement of the cortical silent period, paired stimulation in a conditioning test paradigm, repetitive transcranial magnetic stimulation (rTMS), and peristimulus time histograms (PSTH). These methods allow dissection of central motor excitatory versus inhibitory interplay on the cortical motor neuron and its presynaptic connections at the spinal cord, and have proven to be powerful investigational techniques. TMS can be used to assess upper and lower motor neuron dysfunction, monitor the effects of many pharmacological agents, predict stroke outcome, document the plasticity of the motor system, and assess its maturation and the effects of aging, as well as perform intraoperative monitoring. The recent use of rTMS in the treatment of depression and movement disorders is novel, and opens the way for other potential therapeutic applications.