Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy-a randomised controlled trial.

TRIAL DESIGN: Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control. METHODS: Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment. RESULTS: Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment. CONCLUSION: This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

Fampridine treatment and walking distance in multiple sclerosis: A randomised controlled trial.

OBJECTIVE: To explore the benefits of modified-release fampridine on walking distance in MS. METHODS: This was a randomised double-blind, placebo-controlled crossover trial of fampridine in 25 MS patients. The primary outcome measure was the six minute walk test (6MWT). A p-value<10% led to rejection of the null hypothesis. RESULTS: The pre-specified criterion for statistical significance was met, with a 17m improvement in 6MWT in the treatment arm. In addition, baseline S2 accommodation, a nerve excitability parameter that reflects slow K+ channel activity, modified the effect of fampridine. For patients who had abnormally high S2 accommodation values, there was a 28m improvement in the 6MWT (p=0.04). In contrast, for patients with low S2 values, a 0m improvement was noted (p=1.0). CONCLUSION: The study provides evidence that fampridine may improve walking distance. Nerve excitability assessment may be useful in selecting those patients who are most likely to gain benefit from fampridine. SIGNIFICANCE: Fampridine may improve walking distance in MS. Nerve excitability assessment may assist in identifying those patients most likely to respond to fampridine.

Effect of fampridine on axonal excitability in multiple sclerosis.

OBJECTIVE: To investigate the effects of fampridine on nerve excitability, the present study utilized peripheral axonal excitability techniques in 18 MS patients receiving treatment with fampridine. METHODS: Studies were performed at baseline and repeated 3months after institution of fampridine at standard dosing. RESULTS: Following treatment with fampridine there were significant changes in axonal excitability for those parameters associated with fast K(+) channels that shifted towards normal control values. Specifically, increases were noted in the peak superexcitability of recovery cycle (fampridine, -25.6±1.6%; baseline -22.8±1.7%; p<0.004), peak depolarizing threshold electrotonus (fampridine, 69.1±1.0%; baseline 67.0±1.4%; p<0.004), and depolarizing threshold electrotonus between 40 and 60ms after onset of depolarization (fampridine, 52.8±1.3%; baseline 49.9±1.4%; p=0.02). CONCLUSION: The present study has established that fampridine at standard doses exerts effects on peripheral nerve function that may be mediated by reduction of fast K(+) conductances. SIGNIFICANCE: Modulation of fast K(+) conductances by fampridine may contribute to the improvement observed in MS symptoms including motor fatigue.