{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T11:06:39Z","timestamp":1781175999727,"version":"3.54.1"},"reference-count":14,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology, Israel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Mannitol, a natural alcoholic-sugar, was recently suggested as a potential disease-modifying agent in Parkinson's disease. In animal models of the disease, mannitol interferes with the formation of \u03b1-synuclein fibrils, inhibits the formation of \u03b1-synuclein oligomers and leads to phenotypic recovery of impaired motor functions. Parkinson's patients who consume mannitol report improvements of both motor and non-motor symptoms. Safety of long-term use of oral mannitol, tolerable dose and possible benefit, however, were never clinically studied. We studied the safety of oral mannitol in Parkinson's disease and assessed the maximal tolerable oral dose by conducting a phase IIa, randomized, double-blind, placebo-controlled, single-center, dose-escalating study (ClinicalTrials.gov Identifier: NCT03823638). The study lasted 36 weeks and included four dose escalations of oral mannitol or dextrose to a maximal dose of 18 g per day. The primary outcome was the safety of oral mannitol, as assessed by the number of adverse events and abnormal laboratory results. Clinical and biochemical efficacy measures were collected but were not statistically-powered. Fourteen patients receiving mannitol completed the trial (in addition to eight patients on placebo). Mannitol-related severe adverse events were not observed. Gastrointestinal symptoms limited dose escalation in 6\/14 participants on mannitol. None of the clinical or biochemical efficacy secondary outcome measures significantly differed between groups. We concluded that long-term use of 18 g per day of oral mannitol is safe in Parkinson's disease patients but only two third of patients tolerate this maximal dose. These findings should be considered in the design of future efficacy trials.<\/jats:p>","DOI":"10.3389\/fneur.2021.716126","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T06:23:07Z","timestamp":1641190987000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease"],"prefix":"10.3389","volume":"12","author":[{"given":"Eduard","family":"Linetsky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suaad","family":"Abd Elhadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiva","family":"Gallant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montaser","family":"Namnah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagit","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Segal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronit","family":"Sharon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Arkadir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"14669","DOI":"10.1073\/pnas.251341998","article-title":"Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease","volume":"98","author":"Du","year":"2001","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4539","DOI":"10.1172\/JCI129987","article-title":"Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases","volume":"129","author":"Cai","year":"2019","journal-title":"J Clin Invest."},{"key":"B3","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1001\/jamaneurol.2014.131","article-title":"A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit","volume":"71","author":"Parkinson Study Group QE3","year":"2014","journal-title":"JAMA Neurol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1001\/jamaneurol.2013.5528","article-title":"Investigators, Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial","volume":"71","year":"2014","journal-title":"JAMA Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"17579","DOI":"10.1074\/jbc.M112.434787","article-title":"Blood-Brain Barrier (BBB) disrupter is also a potent \u03b1-Synuclein aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease","volume":"288","author":"Shaltiel-Karyo","year":"2013","journal-title":"J Biol Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1002\/acn3.50944","volume":"6","author":"Abd Elhadi","year":"2019","journal-title":"Ann Clin Transl Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J Biol Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"18076","DOI":"10.1074\/jbc.RA120.015319","volume":"295","author":"Schechter","year":"2020","journal-title":"J Biol Chem"},{"key":"B9","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s13024-020-00370-y","article-title":"role for \u03b1-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson's disease","volume":"15","author":"Schechter","year":"2020","journal-title":"Mol Neurodegeneration."},{"key":"B10","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1097\/00000441-196908000-00003","article-title":"Mannitol absorption and metabolism in man","volume":"258","author":"Nasrallah","year":"1969","journal-title":"Am J Med Sci."},{"key":"B11","unstructured":""},{"key":"B12","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1136\/pgmj.72.845.164","article-title":"Intestinal permeability and orocaecal transit time in elderly patients with Parkinson's disease","volume":"72","author":"Davies","year":"1996","journal-title":"Postgrad Med J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1111\/j.1748-1716.1980.tb06678.x","article-title":"Estimation of capillary permeability of inulin, sucrose and mannitol in rat brain cortex","volume":"110","author":"Amtorp","year":"1980","journal-title":"Acta Physiol Scand."},{"key":"B14","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1111\/ics.12386","article-title":"Free radical scavenging properties of mannitol and its role as a constituent of hyaluronic acid fillers: a literature review","volume":"39","author":"Andr\u00e9","year":"2017","journal-title":"Int J Cosmet Sci."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.716126\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T06:23:10Z","timestamp":1641190990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.716126\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,3]]},"references-count":14,"alternative-id":["10.3389\/fneur.2021.716126"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.716126","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,3]]},"article-number":"716126"}}