The variations of selected serum cytokines involved in cytokine Storm after Omega-3 daily supplements: A Randomized Clinical Trial in Jordanians with vitamin D deficiency
Main Article Content
Keywords
Omega-3, unsaturated fatty acid, cytokine storm, IL-1β, IL-6, IL-10, TNF-α
Abstract
The aim of this study was to investigate the effects of supplementing unsaturated free fatty acids (n-3FA) on the levels of specific cytokines associated with cytokine storm in the blood of 72 Jordanian individuals (both men and women) who had insufficient vitamin D. The study was conducted using a randomized controlled design (RCT). Individuals eligible for the study were randomly assigned to either the n-3FA supplemented (intervention) group or the non-supplemented (control) group. The intervention group received 1,000 mg of wild salmon and fish oil complex, which is equivalent to 300 mg of n-3FA, for a duration of eight weeks, while the control group did not. Blood tests to assess tumor necrosis factor-α (TNF-α), lipid profile, and fasting blood sugar were conducted at baseline and after ten weeks (with a two-week washout period). Additionally, interleukin-6 (IL-6), interleukin-1β (IL-1β), and interleukin-10 (IL-10) levels were measured. Our research indicates that taking n-3FA supplements significantly raised IL-1 β, IL-6, and IL-10 levels compared to their initial levels. However, TNF-α levels did not show any significant changes. The interesting results of this randomized controlled trial could be due to a possible harmful effect of n-3FA supplementation during cytokine storms (CS), specifically on IL-6. Therefore, additional clinical studies are needed in the target patients during cytokine storm to determine if this supplement could affect the treatment with IL-6 antagonists.
References
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13. Bader DA, Abed A, Mohammad BA, et al. The Effect of Weekly 50,000 IU Vitamin D(3) Supplements on the Serum Levels of Selected Cytokines Involved in Cytokine Storm: A Randomized Clinical Trial in Adults with Vitamin D Deficiency. Nutrients. 2023;15(5):1188. https://doi.org/10.3390/nu15051188
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15. Al-Shaer AH, Abu-Samak MS, Hasoun LZ, et al. Assessing the effect of omega-3 fatty acid combined with vitamin D3 versus vitamin D3 alone on estradiol levels: a randomized, placebo-controlled trial in females with vitamin D deficiency. Clinical Pharmacology: Advances and Applications. 2019:25-37. https://doi.org/10.2147/cpaa.s182927
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20. Satoh-Asahara N, Shimatsu A, Sasaki Y, et al. Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia. Diabetes Care. 2012;35(12):2631-9. https://doi.org/10.2337/dc12-0269
21. Gutierrez S, Svahn SL, Johansson ME. Effects of Omega-3 Fatty Acids on Immune Cells. Int J Mol Sci. 2019;20(20):5028. https:// doi.org/10.3390/ijms20205028
22. Foitzik T, Eibl G, Schneider P, et al. Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and attenuates systemic disease sequelae in experimental pancreatitis. JPEN J Parenter Enteral Nutr. 2002;26(6):351-6. https://doi.org/10.11 77/0148607102026006351
23. Sierra S, Lara-Villoslada F, Comalada M, et al. Dietary fish oil n-3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation. Lipids. 2006;41(12):1115-25. https://doi.org/10.1007/ s11745-006-5061-2
24. Rutting S, Papanicolaou M, Xenaki D, et al. Dietary omega-6 polyunsaturated fatty acid arachidonic acid increases inflammation, but inhibits ECM protein expression in COPD. Respir Res. 2018;19(1):211. https://doi.org/10.1186/s12931-018-0919-4
25. Kiecolt-Glaser JK, Belury MA, Andridge R, et al. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun. 2011;25(8):1725-34. https://doi.org/10.1016/j.bbi.2011.07.229
26. Grimble RF, Howell, W. M., et al. The ability of fish oil to suppress tumor necrosis factor α production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor α production. The American journal of clinical nutrition. 2002;76(2):454-459. https://doi.org/10.1093/ajcn/76.2.454
27. Karachentsev Y, Gorshunska M, Krasova N, et al. The influence of interleukin-6 gene polymorphism on omega-3 fatty acid effect in type 2 diabetic patients. Diabetes & Metabolism. 2016;42(4):300.
28. Lalia AZ, Lanza IR. Insulin-Sensitizing Effects of Omega-3 Fatty Acids: Lost in Translation? Nutrients. 2016;8(6):329. https://doi. org/10.3390/nu8060329
29. Muldoon MF, Laderian B, Kuan DC, et al. Fish oil supplementation does not lower C‐reactive protein or interleukin‐6 levels in healthy adults. Journal of internal medicine. 2016;279(1):98-109. https://doi.org/10.1111/joim.12442
30. Costenbader KH, MacFarlane LA, Lee IM, et al. Effects of One Year of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Biomarkers of Systemic Inflammation in Older US Adults. Clin Chem. 2019;65(12):1508-1521. https://doi.org/10.1373/ clinchem.2019.306902
31. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383(23):2255-2273. https://doi.org/10.1056/NEJMra2026131
32. Kothapalli KS, Park HG, Brenna JT. Polyunsaturated fatty acid biosynthesis pathway and genetics. Implications for interindividual variability in prothrombotic, inflammatory conditions such as COVID-19✰,✰✰,★,★★. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2020;162:102183. https://doi.org/10.1016/j.plefa.2020.102183
33. Panigrahy D, Gilligan MM, Huang S, et al. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Metastasis Rev. 2020;39(2):337-340. https://doi.org/10.1007/s10555-020-09889-4
34. Suh W, Urits I, Viswanath O, et al. Three cases of COVID-19 pneumonia that responded to icosapent ethyl supportive treatment. The American Journal of Case Reports. 2020;21:e928422-1. https://doi.org/10.12659/ajcr.928422
35. Asher A, Tintle NL, Myers M, et al. Blood omega-3 fatty acids and death from COVID-19: A pilot study. Prostaglandins Leukot Essent Fatty Acids. 2021;166:102250. https://doi.org/10.1016/j.plefa.2021.102250
36. Bailey RL, Gahche JJ, Miller PE, et al. Why US adults use dietary supplements. JAMA Intern Med. 2013;173(5):355-61. https:// doi.org/10.1001/jamainternmed.2013.2299
37. Yates CM, Calder PC, Ed Rainger G. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol Ther. 2014;141(3):272-82. https://doi.org/10.1016/j.pharmthera.2013.10.010
38. Li K, Huang T, Zheng J, et al. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor alpha: a meta-analysis. PLoS One. 2014;9(2):e88103. https://doi.org/10.1371/journal.pone.0088103
39. Rangel-Huerta OD, Aguilera CM, Mesa MD, et al. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. Br J Nutr. 2012;107 Suppl 2(S2):S159-70. https:// doi.org/10.1017/S0007114512001559
40. Sindhu S, Thomas R, Shihab P, et al. Obesity is a positive modulator of IL-6R and IL-6 expression in the subcutaneous adipose tissue: significance for metabolic inflammation. PloS one. 2015;10(7):e0133494. https://doi.org/10.1371/journal. pone.0133494
41. Remla N, Hadjidj Z, Ghezzaz K, et al. Increased Gustatory Response Score in Obesity and Association Levels with IL-6 and Leptin. J Nutr Metab. 2016;2016:7924052. https://doi.org/10.1155/2016/7924052
42. El-Mikkawy DM, EL-Sadek MA, EL-Badawy MA, et al. Circulating level of interleukin-6 in relation to body mass indices and lipid profile in Egyptian adults with overweight and obesity. Egyptian Rheumatology and Rehabilitation. 2020;47(1):1-7.
43. Mahase E. Covid-19: Why are age and obesity risk factors for serious disease? : British Medical Journal Publishing Group; 2020.
44. Zhu Z, Cai T, Fan L, et al. The potential role of serum angiotensin-converting enzyme in coronavirus disease 2019. BMC Infect Dis. 2020;20(1):883. https://doi.org/10.1186/s12879-020-05619-x
45. Schmidt FM, Weschenfelder J, Sander C, et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS One. 2015;10(3):e0121971. https://doi.org/10.1371/journal.pone.0121971
46. Cozier YC, Castro-Webb N, Hochberg N. S, et al. Lower serum 25 (OH) D levels associated with higher risk of COVID-19 infection in US Black women. PLoS One. 2021;16(7):e0255132. https://doi.org/10.1371/journal.pone.0255132
47. D’Avolio A, Avataneo V, Manca A, et al. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARSCoV- 2. Nutrients. 2020;12(5):1359. https://doi.org/10.3390/nu12051359
48. Baktash V, Hosack T, Patel N, et al. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad Med J. 2021;97(1149):442-447. https://doi.org/10.1136/postgradmedj-2020-138712
49. Pereira M, Dantas Damascena A, Galvao Azevedo LM, et al. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2022;62(5):1308-1316. https://doi.org/10.1080/10408398.2020.1841090
50. Contreras-Bolívar V, García-Fontana B, García-Fontana C, et al. Vitamin D and COVID-19: where are we now?. Postgraduate Medicine. 2023;135(3):195-207. https://doi.org/10.1038/s41577-022-00765-6
51. Hao W, Wong OY, Liu X, et al. omega-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes. J Pediatr Surg. 2010;45(12):2412-8. https://doi.org/10.1016/j.jpedsurg.2010.08.044
2. Kempuraj D, Selvakumar GP, Ahmed ME, et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist. 2020;26(5-6):402-414. https://doi.org/10.1177/1073858420941476
3. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, et al. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62-75. https://doi.org/10.1016/j.cytogfr.2020.06.001
4. Bader DA, Abed A, Mohammad BA, et al. The Effect of Weekly 50,000 IU Vitamin D3 Supplements on the Serum Levels of Selected Cytokines Involved in Cytokine Storm: A Randomized Clinical Trial in Adults with Vitamin D Deficiency. Nutrients. 2023;15(5):1188. https://doi.org/10.3390/nu15051188
5. Daboul SM, Abusamak M, Mohammad BA, et al. The effect of omega-3 supplements on the serum levels of ACE/ACE2 ratio as a potential key in cardiovascular disease: A randomized clinical trial in participants with vitamin D deficiency. Pharmacy Practice. 2023;21(1):1-9. https://doi.org/10.18549/pharmpract.2023.1.2761
6. BourBour F, Mirzaei Dahka S, Gholamalizadeh M, et al. Nutrients in prevention, treatment, and management of viral infections; special focus on Coronavirus. Arch Physiol Biochem. 2023;129(1):16-25. https://doi.org/10.1080/13813455.2020.1791188
7. Radzikowska U, Rinaldi AO, Celebi Sozener Z, et al. The Influence of Dietary Fatty Acids on Immune Responses. Nutrients. 2019;11(12):2990. https://doi.org/10.3390/nu11122990
8. Harris WS, Tintle NL, Etherton MR, et al. Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: The Framingham Heart Study. J Clin Lipidol. 2018;12(3):718-727 e6. https://doi. org/10.1016/j.jacl.2018.02.010
9. Szabo Z, Marosvolgyi T, Szabo E, et al. The Potential Beneficial Effect of EPA and DHA Supplementation Managing Cytokine Storm in Coronavirus Disease. Front Physiol. 2020;11:752. https://doi.org/10.3389/fphys.2020.00752
10. Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem. 2008;49:133-43. https://doi.org/10.1007/978-1-4020-8831-5_5
11. Balic A, Vlasic D, Zuzul K, et al. Omega-3 Versus Omega-6 Polyunsaturated Fatty Acids in the Prevention and Treatment of Inflammatory Skin Diseases. Int J Mol Sci. 2020;21(3):741. https://doi.org/10.3390/ijms21030741
12. Meftahi GH, Jangravi Z, Sahraei H, et al. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”. Inflamm Res. 2020;69(9):825-839. https://doi.org/10.1007/s00011020-01372-8
13. Bader DA, Abed A, Mohammad BA, et al. The Effect of Weekly 50,000 IU Vitamin D(3) Supplements on the Serum Levels of Selected Cytokines Involved in Cytokine Storm: A Randomized Clinical Trial in Adults with Vitamin D Deficiency. Nutrients. 2023;15(5):1188. https://doi.org/10.3390/nu15051188
14. Al-Shaer AH, Abu-Samak MS, Hasoun LZ, et al. Assessing the effect of omega-3 fatty acid combined with vitamin D3 versus vitamin D3 alone on estradiol levels: a randomized, placebo-controlled trial in females with vitamin D deficiency. Clin Pharmacol. 2019;11:25-37. https://doi.org/10.2147/CPAA.S182927
15. Al-Shaer AH, Abu-Samak MS, Hasoun LZ, et al. Assessing the effect of omega-3 fatty acid combined with vitamin D3 versus vitamin D3 alone on estradiol levels: a randomized, placebo-controlled trial in females with vitamin D deficiency. Clinical Pharmacology: Advances and Applications. 2019:25-37. https://doi.org/10.2147/cpaa.s182927
16. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32(7):1195-1198. https://doi.org/10.1007/s40520-020-01570-8
17. Meltzer DO, Best TJ, Zhang H, et al. Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence. medRxiv. 2020:2020:20095893. https://doi.org/10.1101/2020.05.08.20095893
18. Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12(4):988. https://doi.org/10.3390/nu12040988
19. Takruri HR, Alkurd RA. Intakes of Fats, Cholesterol, Fiber and Micronutrients as Risk Factors for Cardiovascular Disease in Jordan. Jordan Journal of Biological Sciences. 2014;7(2)
20. Satoh-Asahara N, Shimatsu A, Sasaki Y, et al. Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia. Diabetes Care. 2012;35(12):2631-9. https://doi.org/10.2337/dc12-0269
21. Gutierrez S, Svahn SL, Johansson ME. Effects of Omega-3 Fatty Acids on Immune Cells. Int J Mol Sci. 2019;20(20):5028. https:// doi.org/10.3390/ijms20205028
22. Foitzik T, Eibl G, Schneider P, et al. Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and attenuates systemic disease sequelae in experimental pancreatitis. JPEN J Parenter Enteral Nutr. 2002;26(6):351-6. https://doi.org/10.11 77/0148607102026006351
23. Sierra S, Lara-Villoslada F, Comalada M, et al. Dietary fish oil n-3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation. Lipids. 2006;41(12):1115-25. https://doi.org/10.1007/ s11745-006-5061-2
24. Rutting S, Papanicolaou M, Xenaki D, et al. Dietary omega-6 polyunsaturated fatty acid arachidonic acid increases inflammation, but inhibits ECM protein expression in COPD. Respir Res. 2018;19(1):211. https://doi.org/10.1186/s12931-018-0919-4
25. Kiecolt-Glaser JK, Belury MA, Andridge R, et al. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun. 2011;25(8):1725-34. https://doi.org/10.1016/j.bbi.2011.07.229
26. Grimble RF, Howell, W. M., et al. The ability of fish oil to suppress tumor necrosis factor α production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor α production. The American journal of clinical nutrition. 2002;76(2):454-459. https://doi.org/10.1093/ajcn/76.2.454
27. Karachentsev Y, Gorshunska M, Krasova N, et al. The influence of interleukin-6 gene polymorphism on omega-3 fatty acid effect in type 2 diabetic patients. Diabetes & Metabolism. 2016;42(4):300.
28. Lalia AZ, Lanza IR. Insulin-Sensitizing Effects of Omega-3 Fatty Acids: Lost in Translation? Nutrients. 2016;8(6):329. https://doi. org/10.3390/nu8060329
29. Muldoon MF, Laderian B, Kuan DC, et al. Fish oil supplementation does not lower C‐reactive protein or interleukin‐6 levels in healthy adults. Journal of internal medicine. 2016;279(1):98-109. https://doi.org/10.1111/joim.12442
30. Costenbader KH, MacFarlane LA, Lee IM, et al. Effects of One Year of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Biomarkers of Systemic Inflammation in Older US Adults. Clin Chem. 2019;65(12):1508-1521. https://doi.org/10.1373/ clinchem.2019.306902
31. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383(23):2255-2273. https://doi.org/10.1056/NEJMra2026131
32. Kothapalli KS, Park HG, Brenna JT. Polyunsaturated fatty acid biosynthesis pathway and genetics. Implications for interindividual variability in prothrombotic, inflammatory conditions such as COVID-19✰,✰✰,★,★★. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2020;162:102183. https://doi.org/10.1016/j.plefa.2020.102183
33. Panigrahy D, Gilligan MM, Huang S, et al. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Metastasis Rev. 2020;39(2):337-340. https://doi.org/10.1007/s10555-020-09889-4
34. Suh W, Urits I, Viswanath O, et al. Three cases of COVID-19 pneumonia that responded to icosapent ethyl supportive treatment. The American Journal of Case Reports. 2020;21:e928422-1. https://doi.org/10.12659/ajcr.928422
35. Asher A, Tintle NL, Myers M, et al. Blood omega-3 fatty acids and death from COVID-19: A pilot study. Prostaglandins Leukot Essent Fatty Acids. 2021;166:102250. https://doi.org/10.1016/j.plefa.2021.102250
36. Bailey RL, Gahche JJ, Miller PE, et al. Why US adults use dietary supplements. JAMA Intern Med. 2013;173(5):355-61. https:// doi.org/10.1001/jamainternmed.2013.2299
37. Yates CM, Calder PC, Ed Rainger G. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol Ther. 2014;141(3):272-82. https://doi.org/10.1016/j.pharmthera.2013.10.010
38. Li K, Huang T, Zheng J, et al. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor alpha: a meta-analysis. PLoS One. 2014;9(2):e88103. https://doi.org/10.1371/journal.pone.0088103
39. Rangel-Huerta OD, Aguilera CM, Mesa MD, et al. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. Br J Nutr. 2012;107 Suppl 2(S2):S159-70. https:// doi.org/10.1017/S0007114512001559
40. Sindhu S, Thomas R, Shihab P, et al. Obesity is a positive modulator of IL-6R and IL-6 expression in the subcutaneous adipose tissue: significance for metabolic inflammation. PloS one. 2015;10(7):e0133494. https://doi.org/10.1371/journal. pone.0133494
41. Remla N, Hadjidj Z, Ghezzaz K, et al. Increased Gustatory Response Score in Obesity and Association Levels with IL-6 and Leptin. J Nutr Metab. 2016;2016:7924052. https://doi.org/10.1155/2016/7924052
42. El-Mikkawy DM, EL-Sadek MA, EL-Badawy MA, et al. Circulating level of interleukin-6 in relation to body mass indices and lipid profile in Egyptian adults with overweight and obesity. Egyptian Rheumatology and Rehabilitation. 2020;47(1):1-7.
43. Mahase E. Covid-19: Why are age and obesity risk factors for serious disease? : British Medical Journal Publishing Group; 2020.
44. Zhu Z, Cai T, Fan L, et al. The potential role of serum angiotensin-converting enzyme in coronavirus disease 2019. BMC Infect Dis. 2020;20(1):883. https://doi.org/10.1186/s12879-020-05619-x
45. Schmidt FM, Weschenfelder J, Sander C, et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS One. 2015;10(3):e0121971. https://doi.org/10.1371/journal.pone.0121971
46. Cozier YC, Castro-Webb N, Hochberg N. S, et al. Lower serum 25 (OH) D levels associated with higher risk of COVID-19 infection in US Black women. PLoS One. 2021;16(7):e0255132. https://doi.org/10.1371/journal.pone.0255132
47. D’Avolio A, Avataneo V, Manca A, et al. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARSCoV- 2. Nutrients. 2020;12(5):1359. https://doi.org/10.3390/nu12051359
48. Baktash V, Hosack T, Patel N, et al. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad Med J. 2021;97(1149):442-447. https://doi.org/10.1136/postgradmedj-2020-138712
49. Pereira M, Dantas Damascena A, Galvao Azevedo LM, et al. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2022;62(5):1308-1316. https://doi.org/10.1080/10408398.2020.1841090
50. Contreras-Bolívar V, García-Fontana B, García-Fontana C, et al. Vitamin D and COVID-19: where are we now?. Postgraduate Medicine. 2023;135(3):195-207. https://doi.org/10.1038/s41577-022-00765-6
51. Hao W, Wong OY, Liu X, et al. omega-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes. J Pediatr Surg. 2010;45(12):2412-8. https://doi.org/10.1016/j.jpedsurg.2010.08.044
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The variations of selected serum cytokines involved in cytokine Storm after Omega-3 daily supplements: A Randomized Clinical Trial in Jordanians with vitamin D deficiency. Pharm Pract (Granada) [Internet]. 2024 May 31 [cited 2024 Dec. 2];22(2):1-10. Available from: https://www.pharmacypractice.org/index.php/pp/article/view/2951
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The variations of selected serum cytokines involved in cytokine Storm after Omega-3 daily supplements: A Randomized Clinical Trial in Jordanians with vitamin D deficiency. Pharm Pract (Granada) [Internet]. 2024 May 31 [cited 2024 Dec. 2];22(2):1-10. Available from: https://www.pharmacypractice.org/index.php/pp/article/view/2951