Combined Metabolic Activators Accelerates Recovery in Mild‐to‐Moderate COVID‐19

  1. Ozlem Altay
  2. Muhammad Arif
  3. Xiangyu Li
  4. Hong Yang
  5. Mehtap Aydın
  6. Gizem Alkurt
  7. Woonghee Kim
  8. Dogukan Akyol
  9. Cheng Zhang
  10. Gizem Dinler‐Doganay
  11. Hasan Turkez
  12. Saeed Shoaie
  13. Jens Nielsen
  14. Jan Borén
  15. Oktay Olmuscelik
  16. Levent Doganay
  17. Mathias Uhlén
  18. Adil Mardinoglu

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Abstract

COVID‐19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD + ) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID‐19 patients. CMAs include l ‐serine, N ‐acetyl‐ l ‐cysteine, nicotinamide riboside, and l ‐carnitine tartrate, salt form of l ‐carnitine. Placebo‐controlled, open‐label phase 2 study and double‐blinded phase 3 clinical trials are conducted to investigate the time of symptom‐free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID‐19 with CMAs lead to a more rapid symptom‐free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.

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  1. Version published to 10.1002/advs.202101222
  2. ScreenIT

    SciScore for 10.1101/2020.10.02.20202614: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Unfortunately, due to access limitations to the patients during the study, we were unable to sample the patients directly following the end of HQ or FP treatment. An additional mid-point analysis at 7 days may have provided additional data related to the HQ metabolites in response to the inclusion of CMA. Many COVID-19 patients are at risk for detrimental outcomes due to systemic inflammatory responses referred to as a cytokine storm, a life-threatening condition is dependent on downstream processes that lead to oxidative stress, dysregulation of iron homeostasis, hypercoagulability, and thrombocytopenia (46, 47). Several studies have proposed that CMA components may effectively inhibit the production of proinflammatory molecules (e.g., IL-6, CCL-5, CXCL-8, and CXCL-10) and improve impaired mitochondrial functions by reducing oxidative damage, lipid peroxidation, and disturbed glucose tolerance (44, 48). Based on integrative analysis, we observed that CMA may interrupt the overactive immune response and early treatment with CMA may reduce the risk of progression to severe respiratory distress and lung damage. In conclusion, we evaluated the efficacy and safety of CMA in combination with HQ or FP therapy in patients with mild-to-moderate COVID-19 and observed that combination therapy is safe and beneficial in patients with mild-to-moderate COVID-19. Our analysis suggests that CMA is am effective treatment for COVID-19. 4.4 EXPERIMENTAL SECTION:

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04573153RecruitingMetabolic Cofactor Supplementation and Hydroxychloroquine Co…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

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  3. Version published to 10.1101/2020.10.02.20202614v2 on medRxiv
  4. Version published to 10.1101/2020.10.02.20202614v1 on medRxiv