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Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease

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 α-synuclein fibrils, inhibits the formation of α-synuclein oligomers and leads to phenotypic reco...

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Autores principales: Linetsky, Eduard, Abd Elhadi, Suaad, Bauer, Max, Gallant, Akiva, Namnah, Montaser, Weiss, Sagit, Segal, Daniel, Sharon, Ronit, Arkadir, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761891/
https://www.ncbi.nlm.nih.gov/pubmed/35046880
http://dx.doi.org/10.3389/fneur.2021.716126
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author Linetsky, Eduard
Abd Elhadi, Suaad
Bauer, Max
Gallant, Akiva
Namnah, Montaser
Weiss, Sagit
Segal, Daniel
Sharon, Ronit
Arkadir, David
author_facet Linetsky, Eduard
Abd Elhadi, Suaad
Bauer, Max
Gallant, Akiva
Namnah, Montaser
Weiss, Sagit
Segal, Daniel
Sharon, Ronit
Arkadir, David
author_sort Linetsky, Eduard
collection PubMed
description 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 α-synuclein fibrils, inhibits the formation of α-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.
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spelling pubmed-87618912022-01-18 Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease Linetsky, Eduard Abd Elhadi, Suaad Bauer, Max Gallant, Akiva Namnah, Montaser Weiss, Sagit Segal, Daniel Sharon, Ronit Arkadir, David Front Neurol Neurology 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 α-synuclein fibrils, inhibits the formation of α-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. Frontiers Media S.A. 2022-01-03 /pmc/articles/PMC8761891/ /pubmed/35046880 http://dx.doi.org/10.3389/fneur.2021.716126 Text en Copyright © 2022 Linetsky, Abd Elhadi, Bauer, Gallant, Namnah, Weiss, Segal, Sharon and Arkadir. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Linetsky, Eduard
Abd Elhadi, Suaad
Bauer, Max
Gallant, Akiva
Namnah, Montaser
Weiss, Sagit
Segal, Daniel
Sharon, Ronit
Arkadir, David
Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease
title Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease
title_full Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease
title_fullStr Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease
title_full_unstemmed Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease
title_short Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease
title_sort safety and tolerability, dose-escalating, double-blind trial of oral mannitol in parkinson's disease
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761891/
https://www.ncbi.nlm.nih.gov/pubmed/35046880
http://dx.doi.org/10.3389/fneur.2021.716126
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