Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Label_Title

Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Label_Title

Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Vitamin C Supplementation in Rheumatological Diseases: A Systematic Review

Aaron Lerner*, Jozélio Freire de Carvalho*, Motti Haimi, Carina Benzvi

Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, IsraelNúcleo de Pesquisa em Doenças Crônicas não Transmissíveis (NUPEN), School of Nutrition from the Federal University of Bahia, Salvador, Bahia, Brazil

Abstract: Vitamin C (VC) is a potent antioxidant that was tested in a few rheumatic diseases. However, no updated systematic review is available in the literature. PubMed/MEDLINE, EMBASE, and Scielo were searched for articles on VC and rheumatologic diseases between 1966 and March 2023. Eight articles were found, including 227 patients. The investigated diseases were fibromyalgia (n=2), rheumatoid arthritis (n=2), systemic lupus erythematosus (n=1), antiphospholipid syndrome (n=1), Kawasaki disease (n=1) and vasculitis (Wegener’s granulomatosis and microscopic polyangiitis) (n=1). Age varied from 7.1 to 53.5±2.7 years old, and female gender ranged from 50% to 100% in the included articles. Disease duration ranged from 10.2 to 14 ± 8 years. VC dosage ranged from 133 mg to 3,000 mg/day. Concerning outcomes, the fibromyalgia studies showed an improvement in clinical and laboratory parameters. Interestingly, one study in RA showed a significant decrease in disease activity after VC. The other studies showed an improvement in these oxidant levels. Specifically, the Kawasaki disease article showed an improvement in vasodilation after intravenous VC injection; while the lupus study did not observe this benefit. Vitamin C is a safe therapy for various rheumatologic diseases. The improved subjective complaints, objective signs and laboratory parameters are promising. However, reconfirmation in more well-controlled, double-blind, cross-over studies, is highly needed.

Keywords: Vitamin C, anti-oxidants, anti-inflammatory, rheumatoid arthritis, fibromyalgia

Received November 14, 2024; Revised December 16, 2024; Accepted December 22, 2024

Citation: Aaron Lerner, Jozélio Freire de Carvalho, Motti Haimi, Carina Benzvi, Vitamin C Supplementation in Rheumatological Diseases: A Systematic Review. International Journal of Celiac Disease, 12 (1). 22-27. January 2024. doi:10.12691/ijcd-12-1-5

1. Introduction

Pro-oxidant/antioxidant imbalance in patients with rheumatological diseases, including rheumatoid arthritis (RA) is extensively reported. The most accepted explanation is the acceleration of some cellular metabolic reactions or insufficiency of the antioxidant defense system [1]. Antioxidant supplementation might be an option to counterbalance, stabilize and restore balance in these inflammatory conditions. A series of antioxidant substances are described including vitamins (C and E), resveratrol, coenzyme Q10, lipoic acid and many others [2]. Vitamin C or ascorbic acid is a well-known free radical scavenger and is one of the hydrophilic antioxidants that accumulates in the aqueous phase of the cell. The hydroxyl groups at the double bond in the lactone ring are donors of protons and electrons, turning into the diketone moiety of DHA, which determines the strong reducing properties of VC and protects other cellular components from oxidation [3].

There are some studies investigating the use of VC in rheumatological conditions [4] [5]. In fact, highly inflammatory diseases, e.g.: RA and gout, were treated with vitamin C, showing beneficial effects on the oxidative process [4].

In this line, the present study aimed to systematically review all studies that evaluated VC in rheumatic diseases, excluding gout in which systematic reviews are available [6].

2. Methods

2.1. Literature Review

A systematic search of articles published in PubMed/MEDLINE, EMBASE, and Scielo from 1966 to March 2023, using the following MeSH entry terms: "vitamin C" OR “ascorbic acid” AND "rheumatic" OR “rheumatologic” OR “systemic lupus erythematosus” OR “lupus” OR “fibromyalgia” OR “ rheumatoid arthritis” OR “spondyloarthritis” OR “ Sjögren’s syndrome” OR “ myositis” OR “ systemic sclerosis” OR “ vasculitis” OR “Takayasu disease” OR “Wegener’s disease” OR “granulomatosis with polyangiitis” OR “Kawasaki’s disease” OR “polyarteritis nodosa” OR “Livedoid vasculitis” OR Churg-Strauss” OR “eosinophilic granulomatosis with polyangiitis” OR "osteoarthritis" OR " gout" were used. The search had no language restriction. The reference lists of the selected articles were analyzed to identify additional publications.

Two authors (JFC and AL) initially performed the literature search and independently selected the study abstracts. Then, in the second stage, the same reviewers independently read the full-text articles selected by abstracts. The authors followed PRISMA guidelines [7]. Finally, a standardized form was designed to extract the information from relevant articles, including authors, year of publication, number of patients studied, demographic data, disease duration, study follow-up, vitamin C posology, outcomes, and side effects.

Table 1. Studies of Vitamin C in Rheumatic Diseases

3. Results

Table 1 summarizes the results of VC supplementation in rheumatic disease subjects. Eight articles were found, including 227 patients. The countries that reported those selected articles were China (n=1), Hong Kong (n=1), India (n=1), Italy (n=1), Korea (n=1), Turkey (n=1), United Kingdom (n=1), and the United States (n=1). Three studies were randomized and controlled; two were double-blinded non-randomized, two were open prospective, one was cross-sectional and one controlled non-randomized or double-blinded trial. The investigated diseases were fibromyalgia FM (n=2), RA (n=2), followed by systemic lupus erythematosus (n=1), antiphospholipid syndrome (n=1), Kawasaki disease (n=1) and vasculitis (Wegener’s granulomatosis and microscopic polyangiitis) (n=1). Age varied from 7.1 ± 2.7 to 53.5 years old, and female gender ranged from 50% to 100% in the included articles. Disease duration ranged from 10.2 to 14 ± 8 years, although these data were available only in two studies. The VC dosage ranged from 133 mg to 3,000 mg/day, all but one study gave VC per oral, and 1 study gave it intravenously. The follow-up of all studies ranged from minutes to 16 weeks.

Concerning outcomes, the first FM study showed an improvement in laboratory parameters such as lipid peroxidation and reduction in malondialdehyde (MDA) levels [8]. The other article showed that patients improved at 8 weeks with the Myers cocktail that contains VC: tender points, pain, depression, and quality of life directly following treatment, while the placebo had improved tender points only [9]. Of the studies on RA, one of them did not observe any difference after VC supplementation [10]; and the other one observed decreased lipid peroxidation and MDA levels [11]. Interestingly, the study showed a significant decrease in disease activity after VS measured by the RA disease activity index (RADAI) [11]. The other studies showed an improvement in these oxidant levels [8] [13] [15] Specifically, the Kawasaki disease article showed an improvement in vasodilation after intravenous VC injection [14]; while the lupus study did not observe this benefit [12].

All the above-sited articles demonstrated improvements in diverse rheumatic diseases parameters, including pain intensity, function, disease activity (DAS 28), swelling joints, and reduced inflammatory biomarkers (interleukins 1 and 6, tumor necrosis factor, C-reactive protein, and erythrocyte sedimentation rate). Regarding side effects, they were not described in 6/8 studies, not present in 1/8 [15] and one patient had a moderate adverse effect in 1/8 study [9].

4. Discussion

This is the first study to systematically review the topic of vitamin C supplementation used in RDs.

Clinical evidence has suggested oxidative stress is elevated in RA and osteoarthritis patients implying reactive oxygen species are possible mediators of tissue damage [16]. Rheumatoid arthritis patients revealed higher levels of plasma malondialdehyde and lower plasma total antioxidant capacity, free thiols, and antioxidant enzyme activity compared to those of the healthy controls. The elevated level of reactive oxygen species (ROS) in synovial fluid of RA patients is thought to be generated by activated macrophages, monocytes, and granulocytes, as well as anoxic reperfusion reactions that may occur with the movement of affected joints [17]. ROS triggers a cascade of events through NFkB activation, which up-regulates gene expression of proinflammatory cytokines that mediates the immune responses causing inflammation. In-vitro studies have shown that dietary antioxidants effectively suppress the release of inflammatory cytokines by reducing available ROS [18].

Vitamin C has been successfully documented to restore exercise blood flow responses in older but not young individuals [19], which has been confirmed mechanistically to represent an improvement via endothelial NO availability [20]. Overall, these findings suggest that oxidative stress may contribute to exercise-blood flow impairments, which may be particularly beneficial in patient populations with increased ROS. In this manner, several authors documented the benefit of vitamin C-induced, flow-mediated dilation, in patients with Kawasaki disease [21] [22].

The present systematic review shows that almost all studies, herein included, VC supplementation reduced oxidative levels of substances such as MDA and lipid peroxidation, and also of inflammatory cytokines. Furthermore, a benefit on disease activity was reported in RA. In fact, patients reduced significantly the RA disease activity index (RADAI) after antioxidant intake, including VC [11] [23]. Intriguingly and logically, intravenous VC was recently suggested to be beneficial in the oxidative stress and hyper-Inflammation in severe covid-19 and long covid syndrome [24] and to modulate the overwhelming oxidative stress in critically ill patients with organ failure, severe sepsis, trauma, and reperfusion after ischemia [25] [26] [27]. Recently, VC was suggested to be an effective alternative therapy in boosting myelin repair in demyelinating conditions [28] in various respiratory, allergic and immunological diseases [29] and even in gliadin-induced mucosal immune inflammatory response in celiac disease patients [30]. It can be summarized that VC is a universal antioxidant, immunomodulatory and anti-inflammatory molecule. Figure 1 summarizes the various diseases that VC might be beneficial to and the main mechanisms allocated to VC’s beneficial profile.

The present study's strengths are 1. Only patients fulfilling international criteria for RDs were included; and 2. the inclusion of all kinds of study designs applying VC in RDs, excluding human and animal studies and in vitro studies. In this way, the authors believe all published cases of VC supplementation in rheumatic patients were collected.

Some limitations are observed in the present study. No comparison was available between classical pharmaceutical treatments and VC supplementation for RDs. In addition, the number of participants was relatively low, and follow-up time was short for such chronic conditions. Finally, only a few rheumatic diseases were included (RA, SLE, Kawasaki disease and vasculitis). It is desired to evaluate the effect of VC in other rheumatological and autoimmune conditions. Future studies should include larger patient samples with more long-term observation and better academically designed protocols to decipher the therapeutic mechanism and the role of VC supplementation in rheumatic conditions.

The present study's strengths are 1. Only patients fulfilling international criteria for RDs were included; and 2. the inclusion of all kinds of study designs applying VC in RDs, excluding human and animal studies and in vitro studies. In this way, the authors believe all published cases of VC supplementation in rheumatic patients were collected.

Some limitations are observed in the present study. No comparison was available between classical pharmaceutical treatments and VC supplementation for RDs. In addition, the number of participants was relatively low, and follow-up time was short for such chronic conditions. Finally, only a few rheumatic diseases were included (RA, SLE, Kawasaki disease and vasculitis). It is desired to evaluate the effect of VC in other rheumatological and autoimmune conditions. Future studies should include larger patient samples with more long-term observation and better academically designed protocols to decipher the therapeutic mechanism and the role of VC supplementation in rheumatic conditions.

Figure 1. A summary of the various diseases that VC might be beneficial to and the main mechanisms allocated to VC’s beneficial profile. Created with BioRender.com. SLE: systemic lupus erythematosus, RADAI: RA disease activity index.

5. Conclusion

Only a few articles in the literature evaluate the effects of vitamin C in rheumatological diseases, and only five disorders were assessed: fibromyalgia, RA, lupus, and vasculitis (Kawasaki diseases, Wegener’s granulomatosis and microscopic polyangiitis). Only in RA, did one study show a decrease in disease activity. Nevertheless, almost all included studies demonstrated that this nutritional supplement is efficacious in reducing oxidative parameters such as MDA and superoxide, without side effects. Based on the above, it is concluded that VC emerges as an exciting option to be thoroughly explored in the rheumatological field.

Abbreviations

APS: antiphospholipid syndrome; FM: fibromyalgia; KD: Kawasaki diseases; MPA: microscopic polyangiitis; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; VC: vitamin C: WG: Wegener's granulomatosis; ROS: reactive oxygen species.

Conflicts of Interest

Author AL, Author JFdC, Author MH and Author CB declare that they have no conflict of interest.

Author Contributions:

Aaron Lerner: writing review and editing, supervision, Jozélio Freire de Carvalho: conceptualization, data curation, formal analysis, methodology, validation, writing the original draft. Motti Haimi: writing and editing, Carina Benzvi: writing, visualization, software.

References

[1]   | Öztürk, H.S., Çimen, M.Y.B., Çimen, Ö.B., Kaçmaz, M. and Durak, I., "Oxidant/antioxidant status of plasma samples from patients with rheumatoid arthritis", Rheumatology international, 19(1–2),35–7,1999. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/10651080/.
[2]   | Mason, S.A., Trewin, A.J., Parker, L. and Wadley, G.D., "Antioxidant supplements and endurance exercise: Current evidence and mechanistic insights", Redox biology, 352020 Aug. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/32127289/.
[3]   | Kaźmierczak-Barańska, J., Boguszewska, K., Adamus-Grabicka, A. and Karwowski, B.T., "Two Faces of Vitamin C-Antioxidative and Pro-Oxidative Agent", Nutrients, 12(5) 2020 May. cited 2023 Jul 18; Available from: https:// pubmed.ncbi.nlm.nih.gov/ 32455696/.
[4]   | Brzezińska, O., Styrzyński, F., Makowska, J. and Walczak, K., "Role of Vitamin C in Prophylaxis and Treatment of Gout-A Literature Review", Nutrients, 13(2),1–20,2021 Feb. cited 2023 Jul 18; Available from: https:// pubmed.ncbi. nlm.nih.gov/33671646/.
[5]   | Colletti, A. and Cicero, A.F.G., "Nutracveutical Approach to Chronic Osteoarthritis: From Molecular Research to Clinical Evidence", International journal of molecular sciences, 22(23) 2021 Dec. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/34884724/.
[6]   | Juraschek, S.P., Miller, E.R. and Gelber, A.C., "Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials", Arthritis care & research, 63(9),1295–306,2011 Sep. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/21671418/.
[7]   | Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., et al., "The PRISMA 2020 statement: an updated guideline for reporting systematic reviews", BMJ (Clinical research ed), 3722021 Mar. cited 2023 Jul 9; Available from: https://pubmed.ncbi.nlm.nih.gov/33782057/.

[8]  
Naziroǧlu, M., Akkuş, S., Soyupek, F., Yalman, K., Çelik, Ö., Eriş, S., et al., "Vitamins C and E treatment combined with exercise modulates oxidative stress markers in blood of patients with fibromyalgia: a controlled clinical pilot study", Stress (Amsterdam, Netherlands), 13(6),498–505,2010 Nov. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/20666654/.

[9]  
Ali, A., Njike, V.Y., Northrup, V., Sabina, A.B., Williams, A.L., Liberti, L.S., et al., "Intravenous micronutrient therapy (Myers’ Cocktail) for fibromyalgia: a placebo-controlled pilot study", Journal of alternative and complementary medicine (New York, NY), 15(3),247–57,2009 Mar. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/19250003/.

[10]  
Bae, S.C., Jung, W.J., Lee, E.J., Yu, R. and Sung, M.K., "Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients", Journal of the American College of Nutrition, 28(1), 56–62,2009 Feb. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/19571161/.

[11]   | Jaswal, S., Mehta, H.C., Sood, A.K. and Kaur, J., "Antioxidant status in rheumatoid arthritis and role of antioxidant therapy", Clinica Chimica Acta, 338(1–2),123–9,2003. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/14637276/.

[12]  
Tam, L.S., Li, E.K., Leung, V.Y.F., Griffith, J.F., Benzie, I.F.F., Lim, P.L., et al., "Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: A double blind, placebo controlled pilot study", Journal of Rheumatology, 32(2),275–82,2005.

[13]  
Ferro, D., Saliola, M., Meroni, P.L., Valesini, G., Caroselli, C., Praticó, D., et al., "Enhanced monocyte expression of tissue factor by oxidative stress in patients with antiphospholipid antibodies: effect of antioxidant treatment", Journal of thrombosis and haemostasis : JTH, 1(3),523–31,2003 Mar. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/12871461/.

[14]  
Deng, Y.-B., Xiang, H.-J., Chang, Q. and Li, C.-L., "Evaluation by high-resolution ultrasonography of endothelial function in brachial artery after Kawasaki disease and the effects of intravenous administration of vitamin C", Circulation journal : official journal of the Japanese Circulation Society, 66(10),908–12,2002 Oct. cited 2023 Jul 18; Available from: https:// pubmed.ncbi. nlm.nih.gov/12381083/.

[15]  
Harper, L., Nuttall, S.L., Martin, U. and Savage, C.O.S., "Adjuvant treatment of patients with antineutrophil cytoplasmic antibody-associated vasculitis with vitamins E and C reduces superoxide production by neutrophils", Rheumatology (Oxford, England), 41(3),274–8,2002. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/11934963/.

[16]  
Sarban, S., Kocyigit, A., Yazar, M. and Isikan, U.E., "Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis", Clinical biochemistry, 38(11),981–6,2005 Nov. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/16150434/.

[17]   | Blake, D.R., Unsworth, J., Outhwaite, J.M., Morris, C.J., Merry, P., Kidd, B.L., et al., "Hypoxic-reperfusion injury in the inflamed human joint", Lancet (London, England), 1(8633),289–93,1989 Feb. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/2563454/.

[18]  
Surh, Y.J., Kundu, J.K., Na, H.K. and Lee, J.S., "Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals", The Journal of nutrition, 135(12 Suppl)2005. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/16317160/.

[19]   | Kirby, B.S., Voyles, W.F., Simpson, C.B., Carlson, R.E., Schrage, W.G. and Dinenno, F.A., "Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: Impact of acute ascorbic acid administration", Journal of Physiology, 587(9),1989–2003,2009.

[20]  
Crecelius, A.R., Kirby, B.S., Voyles, W.F. and Dinenno, F.A., "Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults", American journal of physiology Heart and circulatory physiology, 299(5)2010 Nov. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/20817831/.

[21]  
Deng, Y. Bin, Li, T.L., Xiang, H.J., Chang, Q. and Li, C.L., "Impaired endothelial function in the brachial artery after Kawasaki disease and the effects of intravenous administration of vitamin C", The Pediatric infectious disease journal, 22(1),34–9,2003 Jan. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/12544406/.

[22]  
Sabri, M.R., Tavana, E.N., Ahmadi, A. and Mostafavy, N., "Does Vitamin C improve endothelial function in patients with Kawasaki disease?", Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, 20(1),32,2015 Jan.; Available from: /pmc/articles/PMC4354062/.

[23]  
Khojah, H.M., Ahmed, S., Abdel-Rahman, M.S. and Hamza, A.B., "Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants", Free radical biology & medicine, 97,285–91,2016 Aug. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/27344969/.

[24]  
Vollbracht, C. and Kraft, K., "Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C", Frontiers in pharmacology, 132022 Apr. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/35571085/.

[25]   | Spoelstra-De Man, A.M.E., Elbers, P.W.G. and Oudemans-Van Straaten, H.M., "Vitamin C: should we supplement?", Current opinion in critical care, 24(4),248–55,2018 Aug. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/29864039/.
[26]   | Berger, M.M. and Oudemans-Van Straaten, H.M., "Vitamin C supplementation in the critically ill patient", Current opinion in clinical nutrition and metabolic care, 18(2),193–201,2015 Mar. cited 2023 Jul 18; Available from: https:// pubmed.ncbi. nlm.nih.gov/25635594/.

[27]  
Aisa-Álvarez, A., Pérez-Torres, I., Guarner-Lans, V., Manzano-Pech, L., Cruz-Soto, R., Márquez-Velasco, R., et al., "Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System", Cells, 12(9)2023 May. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/37174730/.

[28]  
Navidhamidi, M., Nazari, A., Dehghan, S., Ebrahimpour, A., Nasrnezhad, R. and Pourabdolhossein, F., "Therapeutic Potential of Combined Therapy of Vitamin A and Vitamin C in the Experimental Autoimmune Encephalomyelitis (EAE) in Lewis Rats", Molecular neurobiology, 59(4),2328–47,2022 Apr. cited 2023 Jul 18; Available from: https:// pubmed.ncbi. nlm.nih.gov/35072933/.

[29]  
Ghalibaf, M.H.E., Kianian, F., Beigoli, S., Behrouz, S., Marefati, N., Boskabady, M., et al., "The effects of vitamin C on respiratory, allergic and immunological diseases: an experimental and clinical-based review", Inflammopharmacology, 31(2),653–72,2023 Apr. cited 2023 Jul 18; Available from: https:// pubmed.ncbi.nlm. nih.gov/36849854/.

[30]  
Bernardo, D., Martínez-Abad, B., Vallejo-Diez, S., Montalvillo, E., Benito, V., Anta, B., et al., "Ascorbate-dependent decrease of the mucosal immune inflammatory response to gliadin in coeliac disease patients", Allergologia et immunopathologia, 40(1),3–8,2012 Jan. cited 2023 Jul 18; Available from: https://pubmed.ncbi.nlm.nih.gov/21420224/.