Associated Inosine to interferon: results of a clinical trial in multiple sclerosis

García, Delicias Muñoz; Midaglia, Luciana; Vilela, J. Martinez; Sánchez, Miguel; González, F. J. López; Gómez, Manuel; Bolaño, D. Dapena; Castañón, Alfonso Iglesias; Alonso‐Alonso, Miguel; López, Jesús Romero

doi:10.1111/ane.12333

Cited by 23 publications

(15 citation statements)

References 36 publications

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“…They went on to show that by contrast, oral administration of its precursor inosine increased both serum and likely CSF urate levels in MS patients (240). Though several MS trials of urate-elevating inosine did not consistently demonstrate slowed clinical progression, these studies established the feasibility of chronic urate elevation as a neurotherapeutic strategy and identified nephrolithiasis as the most common adverse effect and safety concern (241–244). …”

Section: Urate Elevation Therapymentioning

confidence: 99%

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

112

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Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants. Urate, the main antioxidant found in plasma as well as the end product of purine metabolism in humans, has emerged as a promising potential neuroprotectant with advantages that distinguish it from previously tested antioxidant agents. Uniquely, higher urate levels in plasma or cerebrospinal fluid (CSF) have been linked to both a lower risk of developing PD and to a slower rate of its subsequent progression in numerous large prospective epidemiological and clinical cohorts. Laboratory evidence that urate confers neuroprotection in cellular and animal models of PD, possibly via the Nrf2 antioxidant response pathway, further strengthened its candidacy for rapid clinical translation. An early phase trial of the urate precursor inosine demonstrated its capacity to safely produce well tolerated, long-term elevation of plasma and CSF urate in early PD, supporting a phase 3 trial now underway to determine whether oral inosine dosed to elevate urate to concentrations predictive of favorable prognosis in PD slows clinical decline in people recently diagnosed, dopamine transporter-deficient PD.

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Section: Urate Elevation Therapymentioning

confidence: 99%

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

112

View full text Add to dashboard Cite

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“…Given that the study duration was only 6 months, however, these safety profiles should be carefully interpreted. According to the longer duration of previous SURE‐PD trial 21 and multiple sclerosis studies, 22,25 inosine treatment was known to be associated with a higher number of symptomatic nephrolithiasis or asymptomatic crystalluria. Additionally, asymptomatic pyuria was frequently reported across all participants without a group difference.…”

Section: Discussionmentioning

confidence: 99%

Inosine 5'‐Monophosphate to Raise Serum Uric Acid Level in Multiple System Atrophy (IMPROVE‐MSA study)

Lee

Yoon

Kim

et al. 2020

Clin Pharma and Therapeutics

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The aim of this trial was to investigate the safety, tolerability, and capability of serum uric acid (UA) elevation of inosine 5'‐monophosphate (IMP) in multiple system atrophy (MSA). The IMPROVE‐MSA trial was a randomized, double‐blind, placebo‐controlled trial in patients with MSA with no history of hyperuricemia‐related disorders. The participants were assigned to placebo (n = 25) or IMP (n = 30) in a 1 to 1 ratio, and then followed up for 24 weeks. The primary end points included safety, tolerability, and alteration of the serum UA level during the follow‐up period. The secondary end points were changes in scores of the unified MSA rating scale (UMSARS) and the Mini‐Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The total number of adverse events (AEs) and serious AEs was comparable between the active and placebo groups. Serum UA level (mg/dL) was significantly increased from baseline (active vs. placebo, 4.57 vs. 4.58; P = 0.98) to study end point (6.96 vs. 4.43; P < 0.001) in the active group compared with the placebo group (time × group interaction; P < 0.001). The change in UMSARS scores did not differ between the active and placebo groups. However, the active group showed better alterations in MoCA scores with nominal significance (P < 0.001) and tendency for better alterations in MMSE scores (P = 0.09) than the placebo group. Our data demonstrated that IMP treatment was generally safe and well‐tolerated in patients with MSA. A further trial with a long‐term follow‐up is required to examine whether UA elevation will slow clinical progression in early MSA.

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“…Based on those observations, several clinical trials have been designed to test the effect of Ino supplementation in neurodegenerative disorders, with the expectation being that Ino degradation in the body would increase blood and cerebrospinal fluid (CSF) levels of UA to presumably more protective levels. Three trials examined its use in MS patients, and while one suggested some effect (Markowitz et al, 2009), the other two that had larger sample-sizes showed no benefit of the Ino treatment (Gonsette et al, 2010; Muñoz García et al, 2015). More recently, the SURE-PD study was initiated to investigate Ino treatment in PD patients (The Parkinson Study Group SURE-PD Investigators et al, 2014).…”

Section: Cellular Energy-charge and Atp Turnovermentioning

confidence: 99%

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

2019

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Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably, mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and kidneys, which are the body’s top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption. AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic heart failure patients. That may reflect decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain after treatment with allopurinol or febuxostat to inhibit xanthine oxidoreductase, which catalyzes hypoxanthine -> xanthine and xanthine -> urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of ATP re-synthesis due to increased hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with xanthine oxidoreductase inhibitors plus inosine had the strongest impact for increasing the pool of salvageable purines and leading to increased ATP levels in humans, thereby suggesting that this combination is more beneficial than a xanthine oxidoreductase inhibitor alone to treat disorders with ATP deficiency.

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Associated Inosine to interferon: results of a clinical trial in multiple sclerosis

Cited by 23 publications

References 36 publications

Targeting urate to reduce oxidative stress in Parkinson disease

Targeting urate to reduce oxidative stress in Parkinson disease

Inosine 5'‐Monophosphate to Raise Serum Uric Acid Level in Multiple System Atrophy (IMPROVE‐MSA study)

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

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