INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.
INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.
Authors: Michael D Weiss; Eric A Macklin; Zachary Simmons; Angela S Knox; David J Greenblatt; Nazem Atassi; Michael Graves; Nicholas Parziale; Johnny S Salameh; Colin Quinn; Robert H Brown; Jane B Distad; Jaya Trivedi; Jeremy M Shefner; Richard J Barohn; Alan Pestronk; Andrea Swenson; Merit E Cudkowicz Journal: Neurology Date: 2016-02-24 Impact factor: 9.910
Authors: Björn Oskarsson; Dan Moore; Tahseen Mozaffar; John Ravits; Martina Wiedau-Pazos; Nicholas Parziale; Nanette C Joyce; Ross Mandeville; Namita Goyal; Merit E Cudkowicz; Michael Weiss; Robert G Miller; Craig M McDonald Journal: Muscle Nerve Date: 2018-03-06 Impact factor: 3.217
Authors: James B Caress; Stephanie L Ciarlone; Elizabeth A Sullivan; Leah P Griffin; Michael S Cartwright Journal: Muscle Nerve Date: 2015-09-28 Impact factor: 3.217
Authors: Michael D Weiss; Eric A Macklin; Courtney E McIlduff; Steve Vucic; Brian J Wainger; Matthew C Kiernan; Stephen A Goutman; Namita A Goyal; Seward B Rutkove; Shafeeq S Ladha; I-Hweii Amy Chen; Matthew B Harms; Thomas H Brannagan; David Lacomis; Sasha Zivkovic; Maxwell Ma; Leo H Wang; Zachary Simmons; Michael H Rivner; Jeremy M Shefner; Merit E Cudkowicz; Nazem Atassi Journal: Muscle Nerve Date: 2020-12-31 Impact factor: 3.217