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Current Status of Antioxidants in clinical practices - A Review
Corresponding Author(s) : Anjali Suryakant Bhure
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 11 No. 4 (2023): 2023 Volume -11 - Issue 4
Abstract
Rationale: Now a days, prescribing antioxidant drugs has become very much common. Their usefulness in certain long term, chronic conditions where oxidative stress plays a vital role is well explained. But in many other conditions, their role is yet not fully discovered or explained as well their duration of use, type of antioxidant to be used, their pros and cons as well as role of free radicals in our body need to be understood by the prescribing physicians. Up to date research on this and knowledge will change attitude and practice and therefore will have positive impact on physical, mental and economic wellbeing of the patients.
Aim: It is to study the use of antioxidants in clinical practice and analyze the rationality in terms of their appropriate use, duration, cost, safety and efficacy.
Methodology: This review article has been prepared by going through various literature like research articles, text books and drug indexes available on the same topic. This review article focuses on various research on the pharmacological activities of natural and synthetic antioxidant molecules as well as addresses their rationality in current practice.
Discussion and Conclusion: Free radicals (FR) are atoms or molecules with unpaired electrons. Endogenous production of free radicals takes place in mitochondria, peroxisomes, endoplasmic reticulum, etc. Exogenous factors like cigarette smoking, chronic alcohol intake, toxic environmental products, etc. also contribute to the production of FR. When pro-oxidative processes overwhelm cellular antioxidant defense, there is a development of oxidative stress. Antioxidants protect cells from damages caused by free radicals. Antioxidants act as free radical scavengers and further classified into endogenous & exogenous antioxidants. Antioxidants prolong or delay the occurrence of neurodegenerative disorders, eye diseases, liver diseases, cancer and ageing. Also, antioxidants are found useful in some dermatological conditions, endometriosis and periodontitis. But studies conducted throughout world shows that free radicals are harmful but are also important in human body for many physiological processes and antioxidants though considered protective and useful may have their own harmful effects. So a balance has to be maintained to get a positive outcome in clinical practice
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- Tvrdá E, Benko F. Free radicals: what they are and what they do. Pathology. 2020:3-13.
- Stunda-Zujeva A, Berele M, Lece A, Šķesters A. Comparison of antioxidant activity in various Spirulina containing products and factors affecting it. Sci Rep. 2023;13(1):4529.
- Martínez MC, Andriantsitohaina R. MC, Andriantsitohaina R. ReaMartínez ctive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid Redox Signal. 2009 Mar;11(3):669-702.
- Biochemistry of free radicals and oxidative stress. Available from: https://www.scienceinternational.com/fulltext/? [accessed: May 15 2023].
- Bhardwaj V, He J. Reactive oxygen species, metabolic plasticity, and drug resistance in cancer. Int J Mol Sci. 2020;21(10):3412.
- Schieber M, Chandel NS. Ros function in redox signaling and oxidative stress. Curr Biol. 2014;24(10):R453-62.
- Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008 Jun;4(2):89-96.
- Halliwell B. Biochemistry of oxidative stress. Biochem Soc Trans. 2007;35(5):1147-50.
- Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. 2004 Nov;266(1-2):37-56.
- Senoner T, Dichtl W. Oxidative stress in cardiovascular diseases: still a therapeutic target? Nutrients. 2019 Sep 4;11(9):2090.
- Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004 Mar;3(3):205-14.
- Santus P, Corsico A, Solidoro P, Braido F, Di Marco F, Scichilone N. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. COPD. 2014 Dec;11(6):705-17.
- Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev. 2010 Jul;4(8):118-26.
- NCI Dictionary of Cancer terms; n.d.. National Cancer Institute [cited May 28, 2023]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antioxidant.
- Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002 Aug 1;33(3):337-49.
- Johnson F, Giulivi C. Superoxide dismutases and their impact upon human health. Mol Aspects Med. 2005 Aug-Oct;26(4-5):340-52.
- Wuerges J, Lee JW, Yim YI, Yim HS, Kang SO, Djinovic Carugo K. Crystal structure of nickel-containing superoxide dismutase reveals another type of active site. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8569-74.
- Younus H. Therapeutic potentials of superoxide dismutase. Int J Health Sci (Qassim). 2018 May-Jun;12(3):88-93.
- Jeeva JS, Sunitha J, Ananthalakshmi R, Rajkumari S, Ramesh M, Krishnan R. Enzymatic antioxidants and its role in oral diseases. J Pharm Bioallied Sci. 2015 Aug;7;Suppl 2:S331-3.
- Catalase; n.d. Catalase - an Overview Sciencedirect Topics [cited Jul 05 2023]. Available from: https://www.sciencedirect.com/topics/earth-and-planetary-sciences/catalase.
- Nandi A, Yan LJ, Jana CK, Das N. Role of catalase in oxidative stress- and Age-associated degenerative diseases. Oxid Med Cell Longev. 2019 Nov 11;2019:9613090.
- Arthur JR. The glutathione peroxidases. Cell Mol Life Sci. 2000 Dec;57(13-14):1825-35.
- Meyer M, Pahl HL, Baeuerle PA. Regulation of the transcription factors NF-kappa B and AP-1 by redox changes. Chem Biol Interact. 1994;91(2-3):91-100.
- Imai H, Nakagawa Y. Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med. 2003 Jan 15;34(2):145-69.
- Walston J, Xue Q, Semba RD, Ferrucci L, Cappola AR, Ricks M et al. Serum antioxidants, inflammation, and total mortality in older women. Am J Epidemiol. 2006 Jan 1;163(1):18-26.
- Ho HY, Cheng ML, Chiu DT. Glucose-6-phosphate dehydrogenase--from oxidative stress to cellular functions and degenerative diseases. Redox Rep. 2007;12(3):109-18.
- Loniewska MM, Gupta A, Bhatia S, MacKay-Clackett I, Jia Z, Wells PG. DNA damage and synaptic and behavioural disorders in glucose-6-phosphate dehydrogenase-deficient mice. Redox Biol. 2020;28:101332.
- Fiedor J, Burda K. Potential role of carotenoids as antioxidants in human health and disease. Nutrients. 2014 Jan 27;6(2):466-88.
- El-Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG et al. Carotenoid radical chemistry and antioxidant/pro-oxidant properties. Arch Biochem Biophys. 2004 Oct 1;430(1):37-48.
- Carr AC, Maggini S. Vitamin C and immune function. Nutrients. 2017 Nov 3;9(11):1211.
- Chakraborthy A, Ramani P, Sherlin HJ, Premkumar P, Natesan A. Antioxidant and pro-oxidant activity of vitamin C in oral environment. Indian J Dent Res. 2014 Jul-Aug;25(4):499-504.
- Tucker JM, Townsend DM. Alpha-tocopherol: roles in prevention and therapy of human disease. Biomed Pharmacother. 2005 Aug;59(7):380-7.
- Rizvi S, Raza ST, Ahmed F, Ahmad A, Abbas S, Mahdi F. The role of vitamin E in human health and some diseases. Sultan Qaboos Univ Med J. 2014 May;14(2):e157-65.
- Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR. Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept. 2000 May-Aug;9(3-4):137-59.
- Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients. 2010 Dec;2(12):1231-46.
- Safaeian L, Javanmard SH, Mollanoori Y, Dana N. Cytoprotective and antioxidant effects of human lactoferrin against H2O2-induced oxidative stress in human umbilical vein endothelial cells. Adv Biomed Res. 2015 Aug 31;4:188.
- Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L et al. N-acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018 Jul;52(7):751-62.
- Azad GK, Tomar RS. Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways. Mol Biol Rep. 2014 Aug;41(8):4865-79.
- Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008 Mar;13(2):102-8.
- Wu Q, Liu L, Miron A, Klímová B, Wan D, Kuča K. The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: an overview. Arch Toxicol. 2016 Aug;90(8):1817-40.
- Poljsak B, Milisav I. The role of antioxidants in cancer, friends or foes? Curr Pharm Des. 2018;24(44):5234-44.
- Athreya K, Xavier MF. Antioxidants in the treatment of cancer. Nutr Cancer. 2017 Nov-Dec;69(8):1099-104.
- Lai GY, Weinstein SJ, Taylor PR, McGlynn KA, Virtamo J, Gail MH et al. Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study. Br J Cancer. 2014 Dec 9;111(12):2220-3.
- Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014 Feb 5;6(222):222ra18.
- Klein EA, Thompson IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011 Oct 12;306(14):1549-56.
- Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44.
- Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK. Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules. 2019 Dec 30;10(1):59.
- Kryscio RJ, Abner EL, Caban-Holt A, Lovell M, Goodman P, Darke AK et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol. 2017 May 1;74(5):567-73.
- Lem DW, Davey PG, Gierhart DL, Rosen RB. A systematic review of carotenoids in the management of Age-related macular degeneration. Antioxidants (Basel). 2021 Aug 5;10(8):1255.
- Sackett CS, Schenning S. The Age-Related Eye Disease Study: the results of the clinical trial. Insight. 2002 Jan-Mar;27(1):5-7.
- Chew EY, Clemons TE, Agrón E, Domalpally A, Keenan TDL, Vitale S et al. Long-term Outcomes of Adding lutein/zeaxanthin and ω-3 Fatty Acids to the AREDS Supplements on Age-Related Macular Degeneration Progression: AREDS2 Report 28 Report 28. JAMA Ophthalmol. 2022 Jul 1;140(7):692-8.
- Davis MG, Piliang MP, Bergfeld WF, Caterino TL, Fisher BK, Sacha JP et al. Scalp application of the antioxidant piroctone olamine reduces hair shedding in an 8-week randomized, double-blind, placebo-controlled clinical study. Int J Cosmet Sci. 2021 Nov;43;Suppl 1:S26-33.
- Humbert PG, Haftek M, Creidi P, Lapière C, Nusgens B, Richard A et al. Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Exp Dermatol. 2003 Jun;12(3):237-44.
- Rattanawiwatpong P, Wanitphakdeedecha R, Bumrungpert A, Maiprasert M. Anti-aging and brightening effects of a topical treatment containing vitamin C, vitamin E, and raspberry leaf cell culture extract: A split-face, randomized controlled trial. J Cosmet Dermatol. 2020 Mar;19(3):671-6.
- Amini L, Chekini R, Nateghi MR, Haghani H, Jamialahmadi T, Sathyapalan T et al. The effect of combined vitamin C and vitamin E supplementation on oxidative stress markers in women with endometriosis: A randomized, triple-blind placebo-controlled clinical trial. Pain Res Manag. 2021 May 26;2021:5529741.
- Steiner AZ, Hansen KR, Barnhart KT, Cedars MI, Legro RS, Diamond MP et al. Steiner Az et al. Reproductive Medicine Network. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril. 2020 Mar;113(3):552-560.e3.
- Dabaja AA, Schlegel PN. Medical treatment of male infertility. Transl Androl Urol. 2014 Mar;3(1):9-16.
- Wasti J, Wasti A, Singh R. Efficacy of antioxidants therapy on progression of periodontal disease – A randomized control trial. Indian J Dent Res;2021(Apr-Jun); 32(2):187-91.
References
Tvrdá E, Benko F. Free radicals: what they are and what they do. Pathology. 2020:3-13.
Stunda-Zujeva A, Berele M, Lece A, Šķesters A. Comparison of antioxidant activity in various Spirulina containing products and factors affecting it. Sci Rep. 2023;13(1):4529.
Martínez MC, Andriantsitohaina R. MC, Andriantsitohaina R. ReaMartínez ctive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid Redox Signal. 2009 Mar;11(3):669-702.
Biochemistry of free radicals and oxidative stress. Available from: https://www.scienceinternational.com/fulltext/? [accessed: May 15 2023].
Bhardwaj V, He J. Reactive oxygen species, metabolic plasticity, and drug resistance in cancer. Int J Mol Sci. 2020;21(10):3412.
Schieber M, Chandel NS. Ros function in redox signaling and oxidative stress. Curr Biol. 2014;24(10):R453-62.
Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008 Jun;4(2):89-96.
Halliwell B. Biochemistry of oxidative stress. Biochem Soc Trans. 2007;35(5):1147-50.
Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. 2004 Nov;266(1-2):37-56.
Senoner T, Dichtl W. Oxidative stress in cardiovascular diseases: still a therapeutic target? Nutrients. 2019 Sep 4;11(9):2090.
Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004 Mar;3(3):205-14.
Santus P, Corsico A, Solidoro P, Braido F, Di Marco F, Scichilone N. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. COPD. 2014 Dec;11(6):705-17.
Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev. 2010 Jul;4(8):118-26.
NCI Dictionary of Cancer terms; n.d.. National Cancer Institute [cited May 28, 2023]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antioxidant.
Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002 Aug 1;33(3):337-49.
Johnson F, Giulivi C. Superoxide dismutases and their impact upon human health. Mol Aspects Med. 2005 Aug-Oct;26(4-5):340-52.
Wuerges J, Lee JW, Yim YI, Yim HS, Kang SO, Djinovic Carugo K. Crystal structure of nickel-containing superoxide dismutase reveals another type of active site. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8569-74.
Younus H. Therapeutic potentials of superoxide dismutase. Int J Health Sci (Qassim). 2018 May-Jun;12(3):88-93.
Jeeva JS, Sunitha J, Ananthalakshmi R, Rajkumari S, Ramesh M, Krishnan R. Enzymatic antioxidants and its role in oral diseases. J Pharm Bioallied Sci. 2015 Aug;7;Suppl 2:S331-3.
Catalase; n.d. Catalase - an Overview Sciencedirect Topics [cited Jul 05 2023]. Available from: https://www.sciencedirect.com/topics/earth-and-planetary-sciences/catalase.
Nandi A, Yan LJ, Jana CK, Das N. Role of catalase in oxidative stress- and Age-associated degenerative diseases. Oxid Med Cell Longev. 2019 Nov 11;2019:9613090.
Arthur JR. The glutathione peroxidases. Cell Mol Life Sci. 2000 Dec;57(13-14):1825-35.
Meyer M, Pahl HL, Baeuerle PA. Regulation of the transcription factors NF-kappa B and AP-1 by redox changes. Chem Biol Interact. 1994;91(2-3):91-100.
Imai H, Nakagawa Y. Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med. 2003 Jan 15;34(2):145-69.
Walston J, Xue Q, Semba RD, Ferrucci L, Cappola AR, Ricks M et al. Serum antioxidants, inflammation, and total mortality in older women. Am J Epidemiol. 2006 Jan 1;163(1):18-26.
Ho HY, Cheng ML, Chiu DT. Glucose-6-phosphate dehydrogenase--from oxidative stress to cellular functions and degenerative diseases. Redox Rep. 2007;12(3):109-18.
Loniewska MM, Gupta A, Bhatia S, MacKay-Clackett I, Jia Z, Wells PG. DNA damage and synaptic and behavioural disorders in glucose-6-phosphate dehydrogenase-deficient mice. Redox Biol. 2020;28:101332.
Fiedor J, Burda K. Potential role of carotenoids as antioxidants in human health and disease. Nutrients. 2014 Jan 27;6(2):466-88.
El-Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG et al. Carotenoid radical chemistry and antioxidant/pro-oxidant properties. Arch Biochem Biophys. 2004 Oct 1;430(1):37-48.
Carr AC, Maggini S. Vitamin C and immune function. Nutrients. 2017 Nov 3;9(11):1211.
Chakraborthy A, Ramani P, Sherlin HJ, Premkumar P, Natesan A. Antioxidant and pro-oxidant activity of vitamin C in oral environment. Indian J Dent Res. 2014 Jul-Aug;25(4):499-504.
Tucker JM, Townsend DM. Alpha-tocopherol: roles in prevention and therapy of human disease. Biomed Pharmacother. 2005 Aug;59(7):380-7.
Rizvi S, Raza ST, Ahmed F, Ahmad A, Abbas S, Mahdi F. The role of vitamin E in human health and some diseases. Sultan Qaboos Univ Med J. 2014 May;14(2):e157-65.
Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR. Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept. 2000 May-Aug;9(3-4):137-59.
Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients. 2010 Dec;2(12):1231-46.
Safaeian L, Javanmard SH, Mollanoori Y, Dana N. Cytoprotective and antioxidant effects of human lactoferrin against H2O2-induced oxidative stress in human umbilical vein endothelial cells. Adv Biomed Res. 2015 Aug 31;4:188.
Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L et al. N-acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018 Jul;52(7):751-62.
Azad GK, Tomar RS. Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways. Mol Biol Rep. 2014 Aug;41(8):4865-79.
Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008 Mar;13(2):102-8.
Wu Q, Liu L, Miron A, Klímová B, Wan D, Kuča K. The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: an overview. Arch Toxicol. 2016 Aug;90(8):1817-40.
Poljsak B, Milisav I. The role of antioxidants in cancer, friends or foes? Curr Pharm Des. 2018;24(44):5234-44.
Athreya K, Xavier MF. Antioxidants in the treatment of cancer. Nutr Cancer. 2017 Nov-Dec;69(8):1099-104.
Lai GY, Weinstein SJ, Taylor PR, McGlynn KA, Virtamo J, Gail MH et al. Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study. Br J Cancer. 2014 Dec 9;111(12):2220-3.
Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014 Feb 5;6(222):222ra18.
Klein EA, Thompson IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011 Oct 12;306(14):1549-56.
Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44.
Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK. Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules. 2019 Dec 30;10(1):59.
Kryscio RJ, Abner EL, Caban-Holt A, Lovell M, Goodman P, Darke AK et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol. 2017 May 1;74(5):567-73.
Lem DW, Davey PG, Gierhart DL, Rosen RB. A systematic review of carotenoids in the management of Age-related macular degeneration. Antioxidants (Basel). 2021 Aug 5;10(8):1255.
Sackett CS, Schenning S. The Age-Related Eye Disease Study: the results of the clinical trial. Insight. 2002 Jan-Mar;27(1):5-7.
Chew EY, Clemons TE, Agrón E, Domalpally A, Keenan TDL, Vitale S et al. Long-term Outcomes of Adding lutein/zeaxanthin and ω-3 Fatty Acids to the AREDS Supplements on Age-Related Macular Degeneration Progression: AREDS2 Report 28 Report 28. JAMA Ophthalmol. 2022 Jul 1;140(7):692-8.
Davis MG, Piliang MP, Bergfeld WF, Caterino TL, Fisher BK, Sacha JP et al. Scalp application of the antioxidant piroctone olamine reduces hair shedding in an 8-week randomized, double-blind, placebo-controlled clinical study. Int J Cosmet Sci. 2021 Nov;43;Suppl 1:S26-33.
Humbert PG, Haftek M, Creidi P, Lapière C, Nusgens B, Richard A et al. Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Exp Dermatol. 2003 Jun;12(3):237-44.
Rattanawiwatpong P, Wanitphakdeedecha R, Bumrungpert A, Maiprasert M. Anti-aging and brightening effects of a topical treatment containing vitamin C, vitamin E, and raspberry leaf cell culture extract: A split-face, randomized controlled trial. J Cosmet Dermatol. 2020 Mar;19(3):671-6.
Amini L, Chekini R, Nateghi MR, Haghani H, Jamialahmadi T, Sathyapalan T et al. The effect of combined vitamin C and vitamin E supplementation on oxidative stress markers in women with endometriosis: A randomized, triple-blind placebo-controlled clinical trial. Pain Res Manag. 2021 May 26;2021:5529741.
Steiner AZ, Hansen KR, Barnhart KT, Cedars MI, Legro RS, Diamond MP et al. Steiner Az et al. Reproductive Medicine Network. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril. 2020 Mar;113(3):552-560.e3.
Dabaja AA, Schlegel PN. Medical treatment of male infertility. Transl Androl Urol. 2014 Mar;3(1):9-16.
Wasti J, Wasti A, Singh R. Efficacy of antioxidants therapy on progression of periodontal disease – A randomized control trial. Indian J Dent Res;2021(Apr-Jun); 32(2):187-91.