Treatment of the cytokine storm in COVID-19: review of clinical pharmacology

Aisyah Nur Sapriati; Fita Rahmawati; Titik Nuryastuti

doi:10.25077/jsfk.10.2.162-183.2023

Treatment of the cytokine storm in COVID-19: review of clinical pharmacology

Aisyah Nur Sapriati, Fita Rahmawati, Titik Nuryastuti

10.25077/jsfk.10.2.162-183.2023

Abstrak

The cause of the COVID-19 pandemic can be attributed to the Acute Respiratory Syndrome Virus-2 (SARS-CoV-2). COVID-19 manifests with severe symptoms in the upper respiratory tract and can progress to a critical condition due to an acute hyperinflammatory response that triggers a cytokine storm. The cytokine storm refers to an excessive or impaired production of proinflammatory cytokines, resulting in immune dysregulation and uncontrolled inflammatory activity. To effectively address the hyperinflammatory state induced by SARS-CoV-2 infection, it is imperative to explore promising strategies aimed at overcoming the cytokine storm, such as the prompt initiation of anti-inflammatory therapy. Several classes of drugs can potentially prevent the deterioration of COVID-19 patients by mitigating immune system dysregulation and suppressing uncontrolled inflammatory responses. These drug classes encompass corticosteroids, chloroquine and hydroxychloroquine, inhibitors of interleukin-1 (IL-1), inhibitors of interleukin-6 (IL-6), inhibitors of tumor necrosis factor (TNF), and anti-inflammatory drugs. Additionally, tumor necrosis factor alpha (TNF-α) inhibitors, as well as inhibitors targeting the Janus kinase signaling pathway and activator of transcription (JAK/STAT), have exhibited efficacy in treating COVID-19. This efficacy is evident when considering the drug's mechanism of action and pharmacokinetics, while also taking into account the tolerable side effects associated with their usage

Kata Kunci

Clinical pharmacology, COVID-19, Coronavirus, Cytokine storm, Cytokine storm therapy

Teks Lengkap:

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Referensi

. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020;215:108427. https://doi.org/10.1016/J.CLIM.2020.108427

. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497. https://doi.org/10.1016/S0140-6736(20)30183-5

. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934–43. https://doi.org/10.1001/JAMAINTERNMED.2020.0994

. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. Journal of Heart and Lung Transplantation. 2020;39(5):405–7. https://doi.org/10.1016/j.healun.2020.03.012

. Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. Journal of Infection. 2020;80(6):656–65. https://doi.org/10.1016/j.jinf.2020.03.041

. Zhao M. Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies. Int J Antimicrob Agents. 2020;55(6). https://doi.org/10.1016/J.IJANTIMICAG.2020.105982

. Thevarajan I, Buising KL, Cowie BC. Clinical presentation and management of COVID-19. Med J Aust. 2020;213(3):134–9. https://doi.org/10.5694/MJA2.50698

. Altan-Bonnet G, Mukherjee R. Cytokine-mediated communications: a quantitative appraisal of immune complexity. Nat Rev Immunol. 2019;19(4):205. https://doi.org/10.1038/S41577-019-0131-X

. de la Rica R, Borges M, Gonzalez-Freire M. COVID-19: In the Eye of the Cytokine Storm. Front Immunol. 2020;11:2313. https://doi.org/10.3389/FIMMU.2020.558898/BIBTEX

. Fajgenbaum DC, June CH. Cytokine Storm. New England Journal of Medicine. 2020;383(23):2255–73. https://doi.org/10.1056/NEJMRA2026131/SUPPL_FILE/NEJMRA2026131_DISCLOSURES.PDF

. Takimoto CH, Wick MJ, Agoram B, Jin D. Nonclinical drug development [Internet]. Atkinson’s Principles of Clinical Pharmacology. Elsevier; 2021. 573–588 p. https://doi.org/10.1016/B978-0-12-819869-8.00031-8

. Alrahmany D, Ghazi IM. Cytokine storm is the cryptic killer behind coronavirus disease-2019 infections, review of the current evidence to identify therapeutic options. Reviews and Research in Medical Microbiology. 2021;32(1):57–65. https://doi.org/10.1097/MRM.0000000000000242

. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clinical Immunology. 2020;214:108393. https://doi.org/10.1016/J.CLIM.2020.108393

. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033. https://doi.org/10.1016/S0140-6736(20)30628-0

. Iannaccone G, Scacciavillani R, Del Buono MG, Camilli M, Ronco C, Lavie CJ, et al. Weathering the Cytokine Storm in COVID-19: Therapeutic Implications. Cardiorenal Med. 2020;10(5):277–87. https://doi.org/10.1159/000509483

. World Health Organization. Manajemen klinis COVID-19: panduan sementara, 27 Mei 2020 [Internet]. World Health Organization. 2020 [cited 2023 Apr 5]. p. 1–62. Available from: https://apps.who.int/iris/handle/10665/332196

. Williams DM. Clinical Pharmacology of Corticosteroids. Respir Care. 2018;63(6):655–70. https://doi.org/10.4187/RESPCARE.06314

. Schijvens AM, ter Heine R, de Wildt SN, Schreuder MF. Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome. Pediatr Nephrol. 2019;34(3):389–403. https://doi.org/10.1007/S00467-018-3929-Z

. Yasir M, Goyal A, Sonthalia S. Corticosteroid Adverse Effects. StatPearls. 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK531462/

. Sato S, Takaoka A. Interleukins [Internet]. Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research. Elsevier; 2021. 437–439 p. https://doi.org/10.1016/B978-0-12-820649-2.00113-3

. McKay LI, Cidlowski JA. Pharmacokinetics of Corticosteroids. 2003; Available from: https://www.ncbi.nlm.nih.gov/books/NBK13300/

. Allen MJ, Sharma S. Physiology, Adrenocorticotropic Hormone (ACTH). StatPearls. 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK500031/

. Samuel S, Nguyen T, Choi HA. Pharmacologic Characteristics of Corticosteroids. Journal of Neurocritical Care. 2017;10(2):53–9. https://doi.org/10.18700/JNC.170035

. Paradkar S. Reported Adverse Drug Reactions During the Use of Corticosteroids in a Tertiary Care Hospital. Ther Innov Regul Sci. 2019;53(1):128–31. https://doi.org/10.1177/2168479018776262/SUPPL_FILE/APPENDIX_1.PDF

. Chen M, Fu W, Xu H, Liu C. Pathogenic mechanisms of glucocorticoid-induced osteoporosis. Cytokine Growth Factor Rev. 2023;70:54–66. https://doi.org/10.1016/J.CYTOGFR.2023.03.002

. Peng CH, Lin WY, Yeh KT, Chen IH, Wu WT, Lin M Der. The molecular etiology and treatment of glucocorticoid-induced osteoporosis. Tzu Chi Med J. 2021;33(3):212–23. https://doi.org/10.4103/TCMJ.TCMJ_233_20

. Nagpal S, Tierney M. Corticosteroid Induced Myopathy. Canadian Journal of Hospital Pharmacy. 2023;48(4):242–3. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557731/

. Motta F, Timilsina S, Gershwin ME, Selmi C. Steroid-induced osteonecrosis. J Transl Autoimmun. 2022;5:100168. https://doi.org/10.1016/J.JTAUTO.2022.100168

. Kulkarni S, Durham H, Glover L, Ather O, Phillips V, Nemes S, et al. Metabolic adverse events associated with systemic corticosteroid therapy—a systematic review and meta-analysis. BMJ Open. 2022;12(12):e061476. https://doi.org/10.1136/BMJOPEN-2022-061476

. Macleod C, Hadoke PWF, Nixon M. Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers? Int J Mol Sci. 2021;22(14). https://doi.org/10.3390/IJMS22147622

. Rostaing L, Malvezzi P. Steroid-Based Therapy and Risk of Infectious Complications. PLoS Med. 2016;13(5):e1002025. https://doi.org/10.1371/JOURNAL.PMED.1002025

. Aggarwal S, Brian Ta. OCULAR SIDE-EFFECTS OF CORTICOSTEROIDS [Internet]. Moran Center University of Utah Health Care. 2018 [cited 2023 Apr 21]. Available from: https://morancore.utah.edu/basic-ophthalmology-review/ocular-side-effects-of-corticosteroids/

. Kazi SE, Hoque S. Acute Psychosis Following Corticosteroid Administration. Cureus. 2021;13(9). https://doi.org/10.7759/CUREUS.18093

. van Paassen J, Vos JS, Hoekstra EM, Neumann KMI, Boot PC, Arbous SM. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care. 2020;24(1):1–22. https://doi.org/10.1186/S13054-020-03400-9/FIGURES/3

. Ebrahimi Chaharom F, Pourafkari L, Ebrahimi Chaharom AA, Nader ND. Effects of corticosteroids on Covid-19 patients: A systematic review and meta-analysis on clinical outcomes. Pulm Pharmacol Ther. 2022;72:102107. https://doi.org/10.1016/J.PUPT.2021.102107

. Li H, Chen C, Hu F, Wang J, Zhao Q, Gale RP, et al. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis. Leukemia 2020 34:6. 2020;34(6):1503–11. https://doi.org/10.1038/s41375-020-0848-3

. Instiaty, Darmayani IGAAPS, Marzuki JE, Angelia F, William, Siane A, et al. View of Pengobatan antivirus COVID-19: cerminan naratif farmakologi klinis | Jurnal Kedokteran Indonesia [Internet]. Medical Journal of Indonesia Vol 29 No 3. 2020 [cited 2023 Apr 7]. https://doi.org/https://doi.org/10.13181/mji.rev.204652

. Delang L, Neyts J. Medical treatment options for COVID-19. Eur Heart J Acute Cardiovasc Care. 2020;9(3):209–14. https://doi.org/10.1177/2048872620922790

. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565–74. https://doi.org/10.1016/S0140-6736(20)30251-8

. Yao TT, Qian JD, Zhu WY, Wang Y, Wang GQ. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option. J Med Virol. 2020;92(6):556–63. https://doi.org/10.1002/JMV.25729

. Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al. Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis. 2020;7(4). https://doi.org/10.1093/OFID/OFAA130

. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5). https://doi.org/10.1016/J.IJANTIMICAG.2020.105938

. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020;55(4). https://doi.org/10.1016/J.IJANTIMICAG.2020.105945

. Pahan P, Pahan K. Smooth or Risky Revisit of an Old Malaria Drug for COVID-19? J Neuroimmune Pharmacol. 2020;15(2):174–80. https://doi.org/10.1007/S11481-020-09923-W

. Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55(5). https://doi.org/10.1016/J.IJANTIMICAG.2020.105960

. Satarker S, Ahuja T, Banerjee M, E VB, Dogra S, Agarwal T, et al. Hydroxychloroquine in COVID-19: Potential Mechanism of Action Against SARS-CoV-2. Curr Pharmacol Rep. 2020;6(5):203. https://doi.org/10.1007/S40495-020-00231-8

. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020;75(7):1667–70. https://doi.org/10.1093/JAC/DKAA114

. Sahu P, Mudgal J, Arora D, Kinra M, Mallik SB, Rao CM, et al. Cannabinoid receptor 2 activation mitigates lipopolysaccharide-induced neuroinflammation and sickness behavior in mice. Psychopharmacology (Berl). 2019;236(6):1829–38. https://doi.org/10.1007/S00213-019-5166-Y

. Sameer AS, Nissar S. Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. Biomed Res Int. 2021;2021. https://doi.org/10.1155/2021/1157023

. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology 2020 16:3. 2020;16(3):155–66. https://doi.org/10.1038/s41584-020-0372-x

. Carvalho AA de S. Chloroquine and Hydroxychloroquine: A Closer Look on Skeletal Muscle. Lupus: Open Access. 2020;6(1):1–4. Available from: https://www.longdom.org/open-access/chloroquine-and-hydroxychloroquine-a-closer-look-on-skeletal-muscle-61056.html

. Carvalho AA de S. Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review. Curr Pharmacol Rep. 2020;6(6):364. https://doi.org/10.1007/S40495-020-00243-4

. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. https://doi.org/10.1038/s41584-020-0372-x

. Tett S, Cutler D, Day R, Brown K. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol. 1989;27(6):771–9. https://doi.org/10.1111/J.1365-2125.1989.TB03439.X

. Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. https://doi.org/101177/0961203396005001041. 1996;5(SUPPL. 1). https://doi.org/10.1177/0961203396005001041

. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015;23(5):231–69. https://doi.org/10.1007/S10787-015-0239-Y

. Lofgren SM, Nicol MR, Bangdiwala AS, Pastick KA, Okafor EC, Skipper CP, et al. Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19. Open Forum Infect Dis. 2020;7(11). https://doi.org/10.1093/OFID/OFAA500

. Meyerowitz EA, Vannier AGL, Friesen MGN, Schoenfeld S, Gelfand JA, Callahan M V., et al. Rethinking the role of hydroxychloroquine in the treatment of COVID-19. The FASEB Journal. 2020;34(5):6027–37. https://doi.org/10.1096/FJ.202000919

. Dogar MU, Shah NN, Ishtiaq S, Shah PN, Shah P, Mathew S, et al. Hydroxychloroquine-induced restrictive cardiomyopathy: a case report. Postgrad Med J. 2018;94(1109):185–6. https://doi.org/10.1136/POSTGRADMEDJ-2017-135236

. Chang ICY, Bois JP, Bois MC, Maleszewski JJ, Johnson GB, Grogan M. Hydroxychloroquine-Mediated Cardiotoxicity With a False-Positive 99mTechnetium-Labeled Pyrophosphate Scan for Transthyretin-Related Cardiac Amyloidosis. Circ Cardiovasc Imaging. 2018;11(1). https://doi.org/10.1161/CIRCIMAGING.117.007059

. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf. 2018;41(10):919–31. https://doi.org/10.1007/S40264-018-0689-4

. Stokkermans TJ, Goyal A, Trichonas G. Chloroquine And Hydroxychloroquine Toxicity. StatPearls. 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK537086/

. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine retinopathy. Eye (Lond). 2017;31(6):828–45. https://doi.org/10.1038/EYE.2016.298

. Carvalho AA de S. Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review. Curr Pharmacol Rep. 2020;6(6):364. https://doi.org/10.1007/S40495-020-00243-4

. Wondafrash DZ, Desalegn TZ, Yimer EM, Tsige AG, Adamu BA, Zewdie KA. Potential Effect of Hydroxychloroquine in Diabetes Mellitus: A Systematic Review on Preclinical and Clinical Trial Studies. J Diabetes Res. 2020;2020. https://doi.org/10.1155/2020/5214751

. Dai Y, Lin G, Shi D. Hypoglycemia Induced by Hydroxychloroquine Sulfate in a Patient Treated for Connective Tissue Disease Without Diabetes Mellitus. Clin Ther. 2020;42(5):940–5. https://doi.org/10.1016/J.CLINTHERA.2020.03.011

. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732–9. https://doi.org/10.1093/CID/CIAA237

. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6(1). https://doi.org/10.1038/S41421-020-0156-0

. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71. https://doi.org/10.1038/S41422-020-0282-0

. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1). https://doi.org/10.5582/BST.2020.01047

. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis. 2020;34. https://doi.org/10.1016/J.TMAID.2020.101663

. Group TRC. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020;383(21):2030–40. https://doi.org/10.1056/NEJMOA2022926

. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018;281(1):8–27. https://doi.org/10.1111/IMR.12621

. Zhong J, Tang J, Ye C, Dong L. The immunology of COVID-19: is immune modulation an option for treatment? Lancet Rheumatol. 2020;2(7):e428. https://doi.org/10.1016/S2665-9913(20)30120-X

. Malcova H, Strizova Z, Milota T, Striz I, Sediva A, Cebecauerova D, et al. IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives. Front Immunol. 2021;11:3658. https://doi.org/10.3389/FIMMU.2020.619257/BIBTEX

. Cavalli G, Colafrancesco S, Emmi G, Imazio M, Lopalco G, Maggio MC, et al. Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2021;20(3):102763. https://doi.org/10.1016/J.AUTREV.2021.102763

. Teufel LU, Arts RJW, Netea MG, Dinarello CA, Joosten LAB. IL-1 family cytokines as drivers and inhibitors of trained immunity. Cytokine. 2022;150:155773. https://doi.org/10.1016/J.CYTO.2021.155773

. Behzadi P, Sameer AS, Nissar S, Banday MZ, Gajdács M, García-Perdomo HA, et al. The Interleukin-1 (IL-1) Superfamily Cytokines and Their Single Nucleotide Polymorphisms (SNPs). J Immunol Res. 2022;2022. https://doi.org/10.1155/2022/2054431

. Dinarello CA, Simon A, Van Der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633. https://doi.org/10.1038/NRD3800

. Pile KD, Graham GG, Mahler SM. Interleukin 1 Inhibitors. Encyclopedia of Inflammatory Diseases. 2015;1–5. https://doi.org/10.1007/978-3-0348-0620-6_29-1

. Emmi G, Urban ML, Imazio M, Gattorno M, Maestroni S, Lopalco G, et al. Use of Interleukin-1 Blockers in Pericardial and Cardiovascular Diseases. Curr Cardiol Rep. 2018;20(8). https://doi.org/10.1007/S11886-018-1007-6

. Geng J, Wang F, Huang Z, Chen X, Wang Y. Perspectives on anti-IL-1 inhibitors as potential therapeutic interventions for severe COVID-19. Cytokine. 2021;143:155544. https://doi.org/10.1016/J.CYTO.2021.155544

. Acosta-Rodriguez E V., Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8(9):942–9. https://doi.org/10.1038/NI1496

. Stefania S, Colia R, Cinzia R, Corrado A, Cantatore FP. Off-label use of anti-IL-1 drugs in rheumatic diseases. https://doi.org/101177/20587384211006584. 2021;35:205873842110065. https://doi.org/10.1177/20587384211006584

. Calabrese L, Fiocco Z, Satoh TK, Peris K, French LE. Therapeutic potential of targeting interleukin-1 family cytokines in chronic inflammatory skin diseases*. British Journal of Dermatology. 2022;186(6):925–41. https://doi.org/10.1111/BJD.20975

. Meibohm B, Zhou H. Characterizing the Impact of Renal Impairment on the Clinical Pharmacology of Biologics. The Journal of Clinical Pharmacology. 2012;52(S1):54S-62S. https://doi.org/10.1177/0091270011413894

. Yang BB, Baughman S, Sullivan JT. Pharmacokinetics of anakinra in subjects with different levels of renal function. Clin Pharmacol Ther. 2003;74(1):85–94. https://doi.org/10.1016/S0009-9236(03)00094-8

. Chang DM, Chang SY, Yeh MK, Lai JH. The pharmacokinetics of interleukin-1 receptor antagonist in Chinese subjects with rheumatoid arthritis. Pharmacol Res. 2004;50(3):371–6. https://doi.org/10.1016/J.PHRS.2004.02.002

. Moll M, Kuemmerle-Deschner JB. Inflammasome and cytokine blocking strategies in autoinflammatory disorders. Clin Immunol. 2013;147(3):242–75. https://doi.org/10.1016/J.CLIM.2013.04.008

. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58. https://doi.org/10.1038/CLPT.2008.170

. Chakraborty A, Tannenbaum S, Rordorf C, Lowe PJ, Floch D, Gram H, et al. Pharmacokinetic and Pharmacodynamic Properties of Canakinumab, a Human Anti-Interleukin-1β Monoclonal Antibody. Clin Pharmacokinet. 2012;51(6):e1. https://doi.org/10.2165/11599820-000000000-00000

. Radin A, Marbury T, Osgood G, Belomestnov P. Safety and Pharmacokinetics of Subcutaneously Administered Rilonacept in Patients With Well-Controlled End-Stage Renal Disease (ESRD). The Journal of Clinical Pharmacology. 2010;50(7):835–41. https://doi.org/10.1177/0091270009351882

. Joseph D, Tintinger GR, Ker JA, Pannell N. Adverse effects of biologic anti-inflammatory agents on the respiratory system: A review. African Journal of Thoracic and Critical Care Medicine. 2021;27(2):53–9. https://doi.org/10.7196/AJTCCM.2021.V27I2.117

. Lyseng-Williamson KA. Canakinumab: A guide to its use in acute gouty arthritis flares. BioDrugs. 2013;27(4):401–6. https://doi.org/10.1007/S40259-013-0037-2/METRICS

. Huang E, Isonaka S, Yang H, Salce E, Rosales E, Jordan SC. Tocilizumab treatment in critically ill patients with COVID-19: A retrospective observational study. International Journal of Infectious Diseases. 2021;105:245–51. https://doi.org/10.1016/j.ijid.2021.02.057

. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762–8. https://doi.org/10.1093/CID/CIAA248

. Coomes EA, Haghbayan H. Interleukin-6 in Covid-19: A systematic review and meta-analysis. Rev Med Virol. 2020;30(6):1–9. https://doi.org/10.1002/RMV.2141

. Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584(7821):463–9. https://doi.org/10.1038/S41586-020-2588-Y

. Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325–31. https://doi.org/10.1016/S2665-9913(20)30127-2

. Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393–400. https://doi.org/10.1016/S2665-9913(20)30164-8

. Wang Y, Zhu K, Dai R, Li R, Li M, Lv X, et al. Specific Interleukin-1 Inhibitors, Specific Interleukin-6 Inhibitors, and GM-CSF Blockades for COVID-19 (at the Edge of Sepsis): A Systematic Review. Front Pharmacol. 2022;12:3631. https://doi.org/10.3389/FPHAR.2021.804250/BIBTEX

. Ucciferri C, Auricchio A, Di Nicola M, Potere N, Abbate A, Cipollone F, et al. Canakinumab in a subgroup of patients with COVID-19. Lancet Rheumatol. 2020;2(8):e457. https://doi.org/10.1016/S2665-9913(20)30167-3

. Caracciolo M, Macheda S, Labate D, Tescione M, La Scala S, Vadalà E, et al. Case Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome. Front Immunol. 2020;11. https://doi.org/10.3389/FIMMU.2020.01942

. Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58(8):2443–52. https://doi.org/10.1002/ART.23687

. Ilowite NT, Prather K, Lokhnygina Y, Schanberg LE, Elder M, Milojevic D, et al. The RAndomized Placebo Phase Study Of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis (RAPPORT). Arthritis Rheumatol. 2014;66(9):2570. https://doi.org/10.1002/ART.38699

. Garg M, de Jesus AA, Chapelle D, Dancey P, Herzog R, Rivas-Chacon R, et al. Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight. 2017;2(16). https://doi.org/10.1172/JCI.INSIGHT.94838

. Atagündüz P, Keser G, Soy M. Interleukin-1 Inhibitors and Vaccination Including COVID-19 in Inflammatory Rheumatic Diseases: A Nonsystematic Review. Front Immunol. 2021;12. https://doi.org/10.3389/FIMMU.2021.734279

. Martin Rumende C, Susanto EC, Sitorus TP, Martin Rumende C. The Management of Cytokine Storm in COVID-19. Acta Med Indones. 2020;52(3):306. Available from: https://www.actamedindones.org/index.php/ijim/article/view/1580

. McCarty D, Robinson A. Efficacy and safety of sarilumab in patients with active rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2018;10(3):61. https://doi.org/10.1177/1759720X17752037

. Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19. Clin Infect Dis. 2021;73(2):E445–54. https://doi.org/10.1093/CID/CIAA954

. Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016;8(8):959–70. https://doi.org/10.2217/IMT-2016-0020

. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473–4. https://doi.org/10.1126/SCIENCE.ABB8925

. Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting Interleukin-6 Signaling in Clinic. Immunity. 2019;50(4):1007–23. https://doi.org/10.1016/J.IMMUNI.2019.03.026

. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374(Pt 1):1–20. https://doi.org/10.1042/BJ20030407

. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis - shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63–8. https://doi.org/10.1038/NRRHEUM.2015.171

. Baracaldo-Santamaría D, Barros-Arias GM, Hernández-Guerrero F, De-La-Torre A, Calderon-Ospina CA. Immune-related adverse events of biological immunotherapies used in COVID-19. Front Pharmacol. 2022;13. https://doi.org/10.3389/FPHAR.2022.973246

. Food and Drug Administration (FDA). Tocilizumab Prescribing Information. 2013; Available from: www.fda.gov/medwatch

. Mould DR. Using Pharmacometrics in the Development of Therapeutic Biological Agents. Pharmacometrics: The Science of Quantitative Pharmacology. 2006;993–1033. https://doi.org/10.1002/9780470087978.CH41

. Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;1–110. https://doi.org/10.1159/000385919

. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: Concepts and lessons for drug development. BioDrugs. 2010;24(1):23–39. https://doi.org/10.2165/11530560-000000000-00000/METRICS

. Leung E, Jorgensen SCJ, Crass RL, Raybardhan S, Langford B, Moore WJ, et al. Pharmacokinetic /Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19. medRxiv. 2021;2021.08.28.21262692. https://doi.org/10.1101/2021.08.28.21262692

. Frey N, Grange S, Woodworth T. Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis. J Clin Pharmacol. 2010;50(7):754–66. https://doi.org/10.1177/0091270009350623

. Tabrizi MA, Tseng CML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11(1–2):81–8. https://doi.org/10.1016/S1359-6446(05)03638-X

. Xu C, Su Y, Paccaly A, Kanamaluru V. Population Pharmacokinetics of Sarilumab in Patients with Rheumatoid Arthritis. Clin Pharmacokinet. 2019;58(11):1455. https://doi.org/10.1007/S40262-019-00765-1

. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines [Internet]. National Institutes of Health. 2023 [cited 2023 Apr 30]. Available from: https://www.covid19treatmentguidelines.nih.gov/

. Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021;384(16):1503–16. https://doi.org/10.1056/NEJMOA2028700

. Gatti M, Fusaroli M, Caraceni P, Poluzzi E, De Ponti F, Raschi E. Serious adverse events with tocilizumab: Pharmacovigilance as an aid to prioritize monitoring in COVID-19. Br J Clin Pharmacol. 2021;87(3):1533–40. https://doi.org/10.1111/BCP.14459

. García-Vicuña R, Rodriguez-García SC, Abad-Santos F, Bautista Hernández A, García-Fraile L, Barrios Blandino A, et al. Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial. Front Med (Lausanne). 2022;9. https://doi.org/10.3389/FMED.2022.819621

. Genovese MC, Fleischmann R, Kivitz A, Lee EB, Van Hoogstraten H, Kimura T, et al. Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies. Arthritis Res Ther. 2020;22(1). https://doi.org/10.1186/S13075-020-02194-Z

. Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(1):32–40. https://doi.org/10.1001/JAMAINTERNMED.2020.6820

. Sivapalasingam S, Lederer DJ, Bhore R, Hajizadeh N, Criner G, Hosain R, et al. Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial. Clin Infect Dis. 2022;75(1):E380–8. https://doi.org/10.1093/CID/CIAC153

. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Actemra (tocilizumab). 2021; Available from: www.clinicaltrials.gov.

. Food and Drug Administration. Tocilizumab (Actemra) [package insert]. 2022; Available from: www.fda.gov/medwatch

. Derde LPG, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Effectiveness of Tocilizumab, Sarilumab, and Anakinra for critically ill patients with COVID-19 The REMAP-CAP COVID-19 Immune Modulation Therapy Domain Randomized Clinical Trial. medRxiv. 2021;2021.06.18.21259133. https://doi.org/10.1101/2021.06.18.21259133

. Higgins AM, Berry LR, Lorenzi E, Murthy S, McQuilten Z, Mouncey PR, et al. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial. JAMA. 2023;329(1):39–51. https://doi.org/10.1001/JAMA.2022.23257

. Robinson PC, Liew DFL, Liew JW, Monaco C, Richards D, Shivakumar S, et al. The Potential for Repurposing Anti-TNF as a Therapy for the Treatment of COVID-19. Med. 2020;1(1):90–102. https://doi.org/10.1016/j.medj.2020.11.005

. Feldmann M, Maini RN, Woody JN, Holgate ST, Winter G, Rowland M, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. The Lancet. 2020;395(10234):1407–9. https://doi.org/10.1016/S0140-6736(20)30858-8

. Walsh D, McCarthy J, O’Driscoll C, Melgar S. Pattern recognition receptors—Molecular orchestrators of inflammation in inflammatory bowel disease. Cytokine Growth Factor Rev. 2013;24(2):91–104. https://doi.org/10.1016/J.CYTOGFR.2012.09.003

. Wajant H, Siegmund D. TNFR1 and TNFR2 in the control of the life and death balance of macrophages. Front Cell Dev Biol. 2019;7(May):91. https://doi.org/10.3389/FCELL.2019.00091/BIBTEX

. Gerriets V, Goyal A, Khaddour K. Tumor Necrosis Factor Inhibitors. StatPearls. 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK482425/

. Levy RA, Guzman R, Castañeda-Hernández G, Martinez-Vazquez M, Damian G, Cara C. Biology of anti-TNF agents in immune-mediated inflammatory diseases: Therapeutic implications. Immunotherapy. 2016;8(12):1427–36. https://doi.org/10.2217/IMT-2016-0067

. Cessak G, Kuzawińska O, Burda A, Lis K, Wojnar M, Mirowska-Guzel D, et al. TNF inhibitors - Mechanisms of action, approved and off-label indications. Pharmacological Reports. 2014;66(5):836–44. https://doi.org/10.1016/J.PHAREP.2014.05.004/METRICS

. Nestorov I. Clinical pharmacokinetics of tumor necrosis factor antagonists. J Rheumatol Suppl. 2005;74.

. Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF Monoclonal Antibodies in Inflammatory Bowel Disease: Pharmacokinetics-Based Dosing Paradigms. Clin Pharmacol Ther. 2012;91(4):635–46. https://doi.org/10.1038/CLPT.2011.328

. Hakim L. Farmakokinetik Klinik [Internet]. Yogyakarta: Bursa Ilmu. 2012 [cited 2023 Apr 15]. p. 216–9. Available from: https://scholar.google.co.id/scholar?hl=en&as_sdt=0,5&cluster=14263370628532706370#d=gs_cit&t=1681546351951&u=%2Fscholar%3Fq%3Dinfo%3AQpxuHQSs8cUJ%3Ascholar.google.com%2F%26output%3Dcite%26scirp%3D0%26scfhb%3D1%26hl%3Den

. Ternant D, Bejan-Angoulvant T, Passot C, Mulleman D, Paintaud G. Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis. Clinical Pharmacokinetics 2015 54:11. 2015;54(11):1107–23. https://doi.org/10.1007/S40262-015-0296-9

. Ho RJY, Chien JY. Drug Delivery Trends in Clinical Trials and Translational Medicine: Growth in Biologic Molecule Development and Impact on Rheumatoid Arthritis, Crohn’s Disease, and Colitis. J Pharm Sci. 2012;101(8):2668. https://doi.org/10.1002/JPS.23154

. Thalayasingam N, Isaacs JD. Anti-TNF therapy. Best Pract Res Clin Rheumatol. 2011;25(4):549–67. https://doi.org/10.1016/J.BERH.2011.10.004

. Rosenblum H, Amital H. Anti-TNF therapy: safety aspects of taking the risk. Autoimmun Rev. 2011;10(9):563–8. https://doi.org/10.1016/J.AUTREV.2011.04.010

. Goodman SM, Springer B, Guyatt G, Abdel MP, Dasa V, George M, et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis Care Res (Hoboken). 2017;69(8):1111–24. https://doi.org/10.1002/ACR.23274

. Guo Y, Hu K, Li Y, Lu C, Ling K, Cai C, et al. Targeting TNF-α for COVID-19: Recent Advanced and Controversies. Front Public Health. 2022;10:833967. https://doi.org/10.3389/FPUBH.2022.833967

. Salesi M, Shojaie B, Farajzadegan Z, Salesi N, Mohammadi E. TNF-α Blockers Showed Prophylactic Effects in Preventing COVID-19 in Patients with Rheumatoid Arthritis and Seronegative Spondyloarthropathies: A Case–Control Study. Rheumatol Ther. 2021;8(3):1355–70. https://doi.org/10.1007/S40744-021-00342-8/FIGURES/3

. Kokkotis G, Kitsou K, Xynogalas I, Spoulou V, Magiorkinis G, Trontzas I, et al. Systematic review with meta-analysis: COVID-19 outcomes in patients receiving anti-TNF treatments. Aliment Pharmacol Ther. 2022;55(2):154–67. https://doi.org/10.1111/APT.16717

. Seif F, Aazami H, Khoshmirsafa M, Kamali M, Mohsenzadegan M, Pornour M, et al. JAK Inhibition as a New Treatment Strategy for Patients with COVID-19. Int Arch Allergy Immunol. 2020;181(6):467–75. https://doi.org/10.1159/000508247

. Darnell JE. STATs and gene regulation. Science. 1997;277(5332):1630–5. https://doi.org/10.1126/SCIENCE.277.5332.1630

. O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013;72(suppl 2):ii111–5. https://doi.org/10.1136/ANNRHEUMDIS-2012-202576

. O’Shea JJ, Schwartz DM, Villarino A V., Gadina M, McInnes IB, Laurence A. The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention. Annu Rev Med. 2015;66:311. https://doi.org/10.1146/ANNUREV-MED-051113-024537

. Levy DE, Darnell JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62. https://doi.org/10.1038/NRM909

. O’Shea JJ, Murray PJ. Cytokine signaling modules in inflammatory responses. Immunity. 2008;28(4):477–87. https://doi.org/10.1016/J.IMMUNI.2008.03.002

. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–70. https://doi.org/10.1056/NEJMRA1202117

. Owen KL, Brockwell NK, Parker BS. JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression. Cancers (Basel). 2019;11(12). https://doi.org/10.3390/CANCERS11122002

. Kubler P. Janus kinase inhibitors: Mechanisms of action. Aust Prescr. 2014;37(5):154–7. https://doi.org/10.18773/AUSTPRESCR.2014.061

. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis. 2018;77(2):175–87. https://doi.org/10.1136/ANNRHEUMDIS-2017-211555

. Dowty ME, Lin J, Ryder TF, Wang W, Walker GS, Vaz A, et al. The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans. Drug Metabolism and Disposition. 2014;42(4):759–73. https://doi.org/10.1124/DMD.113.054940

. Appeldoorn TYJ, Munnink THO, Morsink LM, Hooge MNL de, Touw DJ. Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. Clin Pharmacokinet. 2023;62(4):559. https://doi.org/10.1007/S40262-023-01225-7

. Chen X, Williams W V., Sandor V, Yeleswaram S. Population Pharmacokinetic Analysis of Orally-Administered Ruxolitinib (INCB018424 Phosphate) in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET MF). The Journal of Clinical Pharmacology. 2013;53(7):721–30. https://doi.org/10.1002/JCPH.102

. Rojas P, Sarmiento M. JAK/STAT Pathway Inhibition May Be a Promising Therapy for COVID-19-Related Hyperinflammation in Hematologic Patients. Acta Haematol. 2021;144(3):314–8. https://doi.org/10.1159/000510179

. Cao Y, Wei J, Zou L, Jiang T, Wang G, Chen L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. Journal of Allergy and Clinical Immunology. 2020;146(1):137-146.e3. https://doi.org/10.1016/j.jaci.2020.05.019

. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the Eye of the Cytokine Storm. Microbiol Mol Biol Rev. 2012;76(1):16. https://doi.org/10.1128/MMBR.05015-11

. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017;39(5):517–28. https://doi.org/10.1007/S00281-017-0639-8

. Melo AKG, Milby KM, Caparroz ALMA, Pinto ACPN, Santos RRP, Rocha AP, et al. Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis. PLoS One. 2021;16(6):e0253894. https://doi.org/10.1371/JOURNAL.PONE.0253894

. Cappanera S, Palumbo M, Kwan SH, Priante G, Martella LA, Saraca LM, et al. When Does the Cytokine Storm Begin in COVID-19 Patients? A Quick Score to Recognize It. J Clin Med. 2021;10(2):1–12. https://doi.org/10.3390/JCM10020297

DOI: https://doi.org/10.25077/jsfk.10.2.162-183.2023