{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T02:32:18Z","timestamp":1784255538519,"version":"3.55.0"},"reference-count":17,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","award":["Gilead Sciences Inc. provided the study drug"],"award-info":[{"award-number":["Gilead Sciences Inc. provided the study drug"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction\/Aims<\/jats:title><jats:p>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\u2010target engagement by assessing muscle cramp characteristics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed an open\u2010label dose\u2010ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500\u2009mg (cohort 1) and 1000\u2009mg (cohort 2) orally twice daily. Each had a 2\u2010week run\u2010in period, 4\u2010week drug administration, and 6\u2010week safety follow\u2010up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale\u2010\u2010\u2010Revised score, and forced vital capacity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2010related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%\u201070.8%) and severity decreased by 46.3% (95% CI, 29.5\u201063.3%), which appeared to be dose\u2010dependent, with decreased awakening due to cramps. Other outcomes showed no change.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Ranolazine was well tolerated in ALS up to 2000\u2009mg\/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\u2010controlled trial.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mus.27560","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T05:18:25Z","timestamp":1650863905000},"page":"71-75","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Open\u2010label pilot study of ranolazine for cramps in amyotrophic lateral sclerosis"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2389-5364","authenticated-orcid":false,"given":"Swathy","family":"Chandrashekhar","sequence":"first","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anai C.","family":"Hamasaki","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Oklahoma Health Sciences Center  Oklahoma City Oklahoma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Clay","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayla","family":"McCalley","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Herbelin","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamatha","family":"Pasnoor","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Jawdat","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazen M.","family":"Dimachkie","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Barohn","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Missouri System  Columbia Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0790-5315","authenticated-orcid":false,"given":"Jeffrey","family":"Statland","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24892"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2016.1245755"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00573"},{"key":"e_1_2_11_5_1","first-page":"1","article-title":"Treatment for cramps in amyotrophic lateral sclerosis\/motor neuron disease","volume":"4","author":"Baldinger R","year":"2012","journal-title":"Cochrane DB Syst Rev."},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26117"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002507"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27146"},{"key":"e_1_2_11_9_1","first-page":"1","article-title":"Safety and efficacy of Ranolazine for the treatment of chronic angina pectoris","volume":"2013","author":"Aldakkak M","year":"2013","journal-title":"Clin Med Insights Ther."},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24331"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/146608200300079536"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(99)00210-5"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-1163"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2017.02.015"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318233b3c4"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2021.117543"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2017.07.026"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101087"}],"container-title":["Muscle &amp; 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