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Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis
OBJECTIVE: To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS). METHODS: This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292193/ https://www.ncbi.nlm.nih.gov/pubmed/30564619 http://dx.doi.org/10.1002/acn3.671 |
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author | Nicholson, Katharine Chan, James Macklin, Eric A. Levine‐Weinberg, Mark Breen, Christopher Bakshi, Rachit Grasso, Daniela L. Wills, Anne‐Marie Jahandideh, Samad Taylor, Albert A. Beaulieu, Danielle Ennist, David L. Andronesi, Ovidiu Ratai, Eva‐Maria Schwarzschild, Michael A. Cudkowicz, Merit Paganoni, Sabrina |
author_facet | Nicholson, Katharine Chan, James Macklin, Eric A. Levine‐Weinberg, Mark Breen, Christopher Bakshi, Rachit Grasso, Daniela L. Wills, Anne‐Marie Jahandideh, Samad Taylor, Albert A. Beaulieu, Danielle Ennist, David L. Andronesi, Ovidiu Ratai, Eva‐Maria Schwarzschild, Michael A. Cudkowicz, Merit Paganoni, Sabrina |
author_sort | Nicholson, Katharine |
collection | PubMed |
description | OBJECTIVE: To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS). METHODS: This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores. RESULTS: Twenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions. INTERPRETATION: Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS. |
format | Online Article Text |
id | pubmed-6292193 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62921932018-12-18 Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis Nicholson, Katharine Chan, James Macklin, Eric A. Levine‐Weinberg, Mark Breen, Christopher Bakshi, Rachit Grasso, Daniela L. Wills, Anne‐Marie Jahandideh, Samad Taylor, Albert A. Beaulieu, Danielle Ennist, David L. Andronesi, Ovidiu Ratai, Eva‐Maria Schwarzschild, Michael A. Cudkowicz, Merit Paganoni, Sabrina Ann Clin Transl Neurol Research Articles OBJECTIVE: To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS). METHODS: This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores. RESULTS: Twenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions. INTERPRETATION: Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS. John Wiley and Sons Inc. 2018-10-22 /pmc/articles/PMC6292193/ /pubmed/30564619 http://dx.doi.org/10.1002/acn3.671 Text en © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Nicholson, Katharine Chan, James Macklin, Eric A. Levine‐Weinberg, Mark Breen, Christopher Bakshi, Rachit Grasso, Daniela L. Wills, Anne‐Marie Jahandideh, Samad Taylor, Albert A. Beaulieu, Danielle Ennist, David L. Andronesi, Ovidiu Ratai, Eva‐Maria Schwarzschild, Michael A. Cudkowicz, Merit Paganoni, Sabrina Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
title | Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
title_full | Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
title_fullStr | Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
title_full_unstemmed | Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
title_short | Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
title_sort | pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292193/ https://www.ncbi.nlm.nih.gov/pubmed/30564619 http://dx.doi.org/10.1002/acn3.671 |
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