{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:59:59Z","timestamp":1784177999868,"version":"3.55.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100024089","name":"Above and Beyond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100024089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg\/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg\/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics.\u201d<\/jats:p>","DOI":"10.1371\/journal.pone.0277718","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T13:30:06Z","timestamp":1692711006000},"page":"e0277718","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1040-0983","authenticated-orcid":true,"given":"Orion P.","family":"Keifer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanmarco","family":"Gutierrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Butt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4687-1971","authenticated-orcid":true,"given":"Sarah D.","family":"Cramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Bartus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malu","family":"Tansey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Deaver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Betourne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7271-3953","authenticated-orcid":true,"given":"Nicholas M.","family":"Boulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"issue":"5","key":"pone.0277718.ref001","first-page":"1185","article-title":"ALS and other motor neuron diseases","volume":"20","author":"E Tiryaki","year":"2014","journal-title":"Continuum (Minneap Minn)."},{"issue":"8","key":"pone.0277718.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss6508a1","article-title":"Prevalence of Amyotrophic Lateral Sclerosis\u2014United States, 2012\u20132013.","volume":"65","author":"P Mehta","year":"2016","journal-title":"MMWR Surveill Summ."},{"key":"pone.0277718.ref003","first-page":"15","article-title":"Clinical limits of amyotrophic lateral sclerosis.","volume":"36","author":"DW Mulder","year":"1982","journal-title":"Adv Neurol"},{"issue":"22","key":"pone.0277718.ref004","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM200105313442207","article-title":"Amyotrophic lateral sclerosis","volume":"344","author":"LP Rowland","year":"2001","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0277718.ref005","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.neurol.2017.03.029","article-title":"Clinical features of amyotrophic lateral sclerosis and their prognostic value.","volume":"173","author":"C Tard","year":"2017","journal-title":"Rev Neurol (Paris)."},{"issue":"6","key":"pone.0277718.ref006","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/BF00839964","article-title":"The prognosis of adult-onset motor neuron disease: a prospective study based on the Scottish Motor Neuron Disease Register","volume":"240","author":"AM Chancellor","year":"1993","journal-title":"J Neurol"},{"issue":"1","key":"pone.0277718.ref007","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1136\/jnnp.2006.104828","article-title":"Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues","volume":"79","author":"G Logroscino","year":"2008","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"4","key":"pone.0277718.ref008","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1212\/CPJ.0b013e3182a1b8ab","article-title":"Prognosis and epidemiology of amyotrophic lateral sclerosis: Analysis of a clinic population, 1997\u20132011.","volume":"3","author":"K Traxinger","year":"2013","journal-title":"Neurol Clin Pract."},{"issue":"7","key":"pone.0277718.ref009","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1136\/jnnp.74.7.995","article-title":"Prolonged survival in motor neuron disease: a descriptive study of the King\u2019s database 1990\u20132002","volume":"74","author":"MR Turner","year":"2003","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"1","key":"pone.0277718.ref010","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/0022-510X(93)90245-T","article-title":"Onset, natural history and outcome in idiopathic adult motor neuron disease","volume":"118","author":"F Norris","year":"1993","journal-title":"J Neurol Sci"},{"issue":"7\u20138","key":"pone.0277718.ref011","doi-asserted-by":"crossref","first-page":"610","DOI":"10.3109\/21678421.2014.959024","article-title":"Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients.","volume":"15","author":"K Abe","year":"2014","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"7","key":"pone.0277718.ref012","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S1474-4422(17)30115-1","article-title":"Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial","volume":"16","author":"G Writing","year":"2017","journal-title":"Lancet Neurol"},{"issue":"9","key":"pone.0277718.ref013","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1056\/NEJM199403033300901","article-title":"A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS\/Riluzole Study Group","volume":"330","author":"G Bensimon","year":"1994","journal-title":"N Engl J Med"},{"issue":"9013","key":"pone.0277718.ref014","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/S0140-6736(96)91680-3","article-title":"Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis\/Riluzole Study Group II","volume":"347","author":"L Lacomblez","year":"1996","journal-title":"Lancet"},{"issue":"6","key":"pone.0277718.ref015","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/BF00370302","article-title":"Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre","volume":"419","author":"E Benoit","year":"1991","journal-title":"Pflugers Arch"},{"issue":"5","key":"pone.0277718.ref016","first-page":"1055","article-title":"Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole","volume":"45","author":"T Hebert","year":"1994","journal-title":"Mol Pharmacol"},{"issue":"5","key":"pone.0277718.ref017","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.3390\/molecules20057775","article-title":"Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside.","volume":"20","author":"N Nagoshi","year":"2015","journal-title":"Molecules."},{"issue":"6 Suppl 4","key":"pone.0277718.ref018","doi-asserted-by":"crossref","first-page":"S242","DOI":"10.1212\/WNL.47.6_Suppl_4.242S","article-title":"A confirmatory dose-ranging study of riluzole in ALS. ALS\/Riluzole Study Group-II","volume":"47","author":"L Lacomblez","year":"1996","journal-title":"Neurology"},{"key":"pone.0277718.ref019","unstructured":"Riluzole [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2008."},{"issue":"3","key":"pone.0277718.ref020","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/bdd.594","article-title":"Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotype","volume":"29","author":"HJ van Kan","year":"2008","journal-title":"Biopharm Drug Dispos"},{"issue":"12","key":"pone.0277718.ref021","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/acn3.141","article-title":"Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.","volume":"1","author":"MR Jablonski","year":"2014","journal-title":"Ann Clin Transl Neurol"},{"issue":"1","key":"pone.0277718.ref022","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/j.1471-4159.2007.04772.x","article-title":"Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood-brain barrier","volume":"103","author":"A Milane","year":"2007","journal-title":"J Neurochem"},{"issue":"2","key":"pone.0277718.ref023","doi-asserted-by":"crossref","first-page":"209","DOI":"10.18433\/J36C78","article-title":"Brain and plasma riluzole pharmacokinetics: effect of minocycline combination","volume":"12","author":"A Milane","year":"2009","journal-title":"J Pharm Pharm Sci"},{"key":"pone.0277718.ref024","doi-asserted-by":"crossref","first-page":"94","DOI":"10.3389\/fneur.2017.00094","article-title":"Dysphagia in Amyotrophic Lateral Sclerosis: Impact on Patient Behavior, Diet Adaptation, and Riluzole Management.","volume":"8","author":"E Onesti","year":"2017","journal-title":"Front Neurol."},{"issue":"1\u20132","key":"pone.0277718.ref025","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ijpharm.2012.04.022","article-title":"Swallowing dysfunction and dysphagia is an unrecognized challenge for oral drug therapy","volume":"430","author":"S Stegemann","year":"2012","journal-title":"Int J Pharm"},{"issue":"6","key":"pone.0277718.ref026","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1517\/14740338.3.6.525","article-title":"The tolerability of riluzole in the treatment of patients with amyotrophic lateral sclerosis.","volume":"3","author":"G Bensimon","year":"2004","journal-title":"Expert Opin Drug Saf"},{"issue":"5","key":"pone.0277718.ref027","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.psym.2013.02.002","article-title":"Delayed amnesic syndrome after riluzole use in major depressive disorder: a case report.","volume":"54","author":"A Cardoos","year":"2013","journal-title":"Psychosomatics."},{"issue":"11","key":"pone.0277718.ref028","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1212\/01.WNL.0000096019.71649.2B","article-title":"Dosage effects of riluzole in Huntington\u2019s disease: a multicenter placebo-controlled study","volume":"61","author":"G. Huntington Study","year":"2003","journal-title":"Neurology"},{"issue":"3","key":"pone.0277718.ref029","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1097\/JCP.0b013e3181727548","article-title":"Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a series of 13 cases, with long-term follow-up.","volume":"28","author":"C Pittenger","year":"2008","journal-title":"J Clin Psychopharmacol"},{"issue":"1","key":"pone.0277718.ref030","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1176\/appi.ajp.161.1.171","article-title":"An open-label trial of riluzole in patients with treatment-resistant major depression.","volume":"161","author":"CA Zarate","year":"2004","journal-title":"Am J Psychiatry"},{"issue":"4","key":"pone.0277718.ref031","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.biopsych.2004.11.023","article-title":"An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression","volume":"57","author":"CA Zarate","year":"2005","journal-title":"Biol Psychiatry"},{"issue":"3","key":"pone.0277718.ref032","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/mus.20900","article-title":"Intrathecal baclofen for spasticity-related pain in amyotrophic lateral sclerosis: efficacy and factors associated with pain relief","volume":"37","author":"S McClelland","year":"2008","journal-title":"Muscle Nerve"},{"issue":"1","key":"pone.0277718.ref033","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1097\/ALN.0b013e3181c38da5","article-title":"Cerebrospinal fluid and spinal cord distribution of hyperbaric bupivacaine and baclofen during slow intrathecal infusion in pigs","volume":"112","author":"SH Flack","year":"2010","journal-title":"Anesthesiology"},{"issue":"11","key":"pone.0277718.ref034","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/S1474-4422(13)70221-7","article-title":"Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial.","volume":"12","author":"ME Cudkowicz","year":"2013","journal-title":"Lancet Neurol"},{"issue":"4","key":"pone.0277718.ref035","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/papr.12099","article-title":"Spinal opioid bioavailability in postoperative pain","volume":"14","author":"BM Bujedo","year":"2014","journal-title":"Pain Pract"},{"issue":"5","key":"pone.0277718.ref036","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/sj.clpt.6100382","article-title":"An association study of riluzole serum concentration and survival and disease progression in patients with ALS","volume":"83","author":"GJ Groeneveld","year":"2008","journal-title":"Clin Pharmacol Ther"},{"issue":"2","key":"pone.0277718.ref037","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1213\/ANE.0b013e318203b7c0","article-title":"Morphine distribution in the spinal cord after chronic infusion in pigs.","volume":"112","author":"SH Flack","year":"2011","journal-title":"Anesth Analg"},{"key":"pone.0277718.ref038","article-title":"Riluzole Summary Basis of Approval (SBA) and associated documents.","author":"NDA 20\u2013599 (1995)","year":"1999","journal-title":"Received from FDA Freedom of Information Office by FOI Services Inc"},{"issue":"1","key":"pone.0277718.ref039","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1177\/0192623310391679","article-title":"Morphologic changes associated with intrathecal catheters for direct delivery to the central nervous system in preclinical studies.","volume":"39","author":"MT Butt","year":"2011","journal-title":"Toxicol Pathol"},{"issue":"2","key":"pone.0277718.ref040","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/toxsci\/71.2.263","article-title":"Effects of chronic intrathecal infusion of a partial differential opioid agonist in dogs","volume":"71","author":"K Horais","year":"2003","journal-title":"Toxicol Sci"},{"issue":"5","key":"pone.0277718.ref041","doi-asserted-by":"crossref","first-page":"493","DOI":"10.36076\/ppj.2010\/13\/493","article-title":"Clinical and histological effects of the intrathecal administration of methylprednisolone in dogs","volume":"13","author":"RM Lima","year":"2010","journal-title":"Pain Physician"},{"issue":"1","key":"pone.0277718.ref042","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1097\/00000542-200307000-00028","article-title":"Chronically infused intrathecal morphine in dogs","volume":"99","author":"TL Yaksh","year":"2003","journal-title":"Anesthesiology"},{"issue":"1","key":"pone.0277718.ref043","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/ahe.12045","article-title":"Magnetic resonance imaging (MRI) spinal cord and canal measurements in normal dogs.","volume":"43","author":"S Hecht","year":"2014","journal-title":"Anat Histol Embryol"},{"issue":"1","key":"pone.0277718.ref044","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1097\/00000542-200607000-00027","article-title":"Cerebrospinal fluid and spinal cord distribution of baclofen and bupivacaine during slow intrathecal infusion in pigs","volume":"105","author":"CM Bernards","year":"2006","journal-title":"Anesthesiology"},{"issue":"7","key":"pone.0277718.ref045","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1007\/s00586-010-1326-9","article-title":"Comparative anatomical dimensions of the complete human and porcine spine.","volume":"19","author":"I Busscher","year":"2010","journal-title":"Eur Spine J"},{"issue":"5","key":"pone.0277718.ref046","doi-asserted-by":"crossref","first-page":"E831","DOI":"10.36076\/ppj.2015\/18\/E831","article-title":"Catheter-tip Granulomas Associated with Intrathecal Drug Delivery\u2014A Two-Center Experience Identifying 13","volume":"18","author":"T Kratzsch","year":"2015","journal-title":"Cases. Pain Physician"},{"issue":"2","key":"pone.0277718.ref047","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1525-1403.2008.00147.x","article-title":"Management of intrathecal catheter-tip inflammatory masses: an updated 2007 consensus statement from an expert panel.","volume":"11","author":"T Deer","year":"2008","journal-title":"Neuromodulation."},{"issue":"5","key":"pone.0277718.ref048","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1525-1403.2012.00476.x","article-title":"Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.","volume":"15","author":"TR Deer","year":"2012","journal-title":"Neuromodulation."},{"issue":"2","key":"pone.0277718.ref049","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.nbd.2012.03.040","article-title":"Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS","volume":"47","author":"MR Jablonski","year":"2012","journal-title":"Neurobiol Dis"},{"issue":"3","key":"pone.0277718.ref050","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/j.1468-1331.2006.01575.x","article-title":"Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy","volume":"14","author":"S Zoccolella","year":"2007","journal-title":"Eur J Neurol"},{"issue":"5","key":"pone.0277718.ref051","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S1474-4422(18)30054-1","article-title":"Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study","volume":"17","author":"T Fang","year":"2018","journal-title":"Lancet Neurol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277718","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T09:41:24Z","timestamp":1702978884000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277718"}},"subtitle":[],"editor":[{"given":"Antal","family":"N\u00f3gr\u00e1di","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,22]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0277718","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.11.02.514962","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,22]]}}}