Fehr AR, Perlman S. Coronaviruses: methods and protocols. In: Maier HJ (ed) Methods Mol Biol. Springer Science; 2015. p. 1–282.

Yamamoto M, Kiso M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Imai M, Takeda M, et al. The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects. bioRxiv. 2020;1–19.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Li K, Meyerholz DK, Bartlett JA, McCray PB. The TMPRSS2 inhibitor nafamostat reduces SARS-CoV-2 pulmonary infection in mouse models of COVID-19. Am Soc Microbiol. 2021;12:1–11.

Google Scholar 

Yamamoto M, Matsuyama S, Li X, Takeda M, Kawaguchi Y, Inoue JI, et al. Identification of Nafamostat as a potent inhibitor of middle east respiratory syndrome coronavirus S protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay. Antimicrob Agents Chemother. 2016;60:6532–9.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Hoffmann M, Schroeder S, Kleine-Weber H, Müller MA, Drosten C, Pöhlmann S. Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19. Antimicrob Agents Chemother. 2020;64:1–3.

Article  Google Scholar 

Ko M, Jeon S, Ryu W-S, Kim S. Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells: Nafamostat is the most potent antiviral drug candidate. J Med Virol. 2020;93:1403–8.

PubMed  PubMed Central  Article  Google Scholar 

National Center for Biotechnology Information. PubChem Compound Summary for CID 4413, Nafamostat [Internet]. https://pubchem.ncbi.nlm.nih.gov/compound/Nafamostat. Accessed 15 Nov 2021

Okajima K, Uchiba M, Murakami K. Nafamostat Mesilate. Cardiovasc Drug Rev. 1995;13:51–65.

CAS  Article  Google Scholar 

Nichi-Iko Pharmaceutical Co. Ltd. Nafamostat mesylate Pharmaceutical Interview Form [Internet]. Ja; 2019. https://www.nichiiko.co.jp/medicine/file/31050/interview

Minakata D, Fujiwara SI, Ikeda T, Kawaguchi SI, Toda Y, Ito S, et al. Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies. Int J Hematol. 2019;109:141–6. https://doi.org/10.1007/s12185-018-02567-w (Springer Japan).

CAS  PubMed  Article  Google Scholar 

Asakura H, Ogawa H. COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol [Internet]. Springer Singapore; 2020. https://doi.org/10.1007/s12185-020-03029-y

McFadyen JD, Stevens H, Peter K. The emerging threat of (Micro)thrombosis in COVID-19 and its therapeutic implications. Circ Res. 2020;127:571–87.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Nichi-Iko Pharmaceutical Co. L. Pharmaceutical interview form for FUTHAN 10 INJ., FUTHAN 50 INJ. 6th Edition [Internet]. 2019. https://www.nichiiko.co.jp/medicine/file/31050/interview

Hempel T, Raich L, Olsson S, Azouz NP, Klingler AM, Hoffmann M, et al. Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat. Chem Sci. 2021;12:983–92.

CAS  PubMed  Article  Google Scholar 

Ohtake Y, Hirasawa H, Sugai T, Oda S, Shiga H, Matsuda K, et al. Nafamostat mesylate as anticoagulant in continuous hemofiltration and continuous hemodiafiltration. Contrib Nephrol. 1991;93:215–7.

CAS  PubMed  Article  Google Scholar 

Choi J-Y, Kang Y-J, Jang HM, Jung H-Y, Cho J-H, Park S-H, et al. Nafamostat mesilate as an anticoagulant during continuous renal replacement therapy in patients with high bleeding risk. A randomized clinical trial. Medicine (Baltimore). 2015;94:1–7.

Google Scholar 

Tsukagoshi S. Pharmacokinetics studies of nafamostat mesilate (FUT), a synthetic protease inhibitor, which has been used for the treatments of DIC and acute pancreatitis, and as an anticoagulant in extracorporeal circulation. Jpn J Cancer Chemother. 2000;27:767–74.

CAS  Google Scholar 

Hirayama T, Nosaka N, Okawa Y, Ushio S, Kitamura Y, Sendo T, et al. AN69ST membranes adsorb nafamostat mesylate and affect the management of anticoagulant therapy: a retrospective study. J Intensive Care. 2017;5:1–7.

Article  Google Scholar 

Doi Y, Kondo M, Ando M, Kuwatsuka Y, Ishihara T. COVID-19 Nafamostat Observational Study in Japan: Preliminary Report. Japan; 2020.

Muto S, Imai M, Asano Y. Mechanisms of hyperkalemia caused by nafamostat mesilate. Gen Pharmacol. 1995;26:1627–32.

CAS  PubMed  Article  Google Scholar 

Kitagawa H, Chang H, Fujita T. Hyperkalemia due to nafamostat mesylate. N Engl J Med. 1995;332:687.

CAS  PubMed  Article  Google Scholar 

Park J-H, Her C, Min H-K, Kim D-K, Park S-H, Jang H-J. Nafamostat mesilate as a regional anticoagulant in patients with bleeding complications during extracorporeal membrane oxygenation. Int J Artif Organs. 2015;38:595–9.

CAS  PubMed  Article  Google Scholar 

Ookawara S, Saitoh M, Yahagi T, Tabei K, Asano Y. Two cases of nafamostat mesilate-induced hyperkalemia. Jpn Soc Dial Ther. 1995;28.

Okajima M, Takahashi Y, Kaji T, Ogawa N, Mouri H. Nafamostat mesylate-induced hyperkalemia in critically ill patients with COVID-19: four case reports. World J Clin Cases. 2020;8:5320–5.

PubMed  PubMed Central  Article  Google Scholar 

Muto S, Imai M, Asano Y. Mechanisms of the hyperkalaemia caused by nafamostat mesilate: effects of its two metabolites on Na+ and K+ transport properties in the rabbit cortical collecting duct. Br J Pharmacol. 1994;111:173–8.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Ookawara S, Tabei K, Sakurai T, Sakairi Y, Furuya H, Asano Y. Additional mechanisms of nafamostat mesilate-associated hyperkalaemia. Eur J Clin Pharmacol. 1996;51:149–51.

CAS  PubMed  Article  Google Scholar 

Quinn TM, Gaughan EE, Bruce A, Antonelli J, O’Connor R, Li F, et al. Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics. eBioMedicine [Internet]. 2022;76:103856. http://medrxiv.org/content/early/2021/10/07/2021.10.06.21264648.abstract

Cao Y-G, Chen Y-C, Hao K, Zhang M, Liu X-Q. An in vivo approach for globally estimating the drug flow between blood and tissue for Nafamostat Mesilate: the main hydrolysis site determination in human. Biol Pharm Bull. 2008;31:1985–9.

CAS  PubMed  Article  Google Scholar 

Yamamoto M, Kiso M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Imai M, Takeda M, et al. The anticoagulant nafamostat potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and viral infection in vitro in a cell-type-dependent manner. Viruses. 2020;12.

Hoffmann M, Schroeder S, Kleine-Weber H, Müller MA, Drosten C, Pöhlmann S. Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19. Antimicrob Agents Chemother. 2020;64:19–21.

Article  Google Scholar 

Li P, Wang Y, Lavrijsen M, Lamers MM, de Vries AC, Rottier RJ, et al. SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination. Cell Res. 2022;32:322–4.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Doi K, Ikeda M, Hayase N, Moriya K, Morimura N, Maehara H, et al. Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series. Crit Care. 2020;24.

Jang S, Rhee J. Three cases of treatment with nafamostat in elderly patients with COVID-19 pneumonia who need oxygen therapy. Int J Infect Dis. 2020;96:500–2.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Mittal A, Khattri A, Verma V. Structural and antigenic variations in the spike protein of emerging SARS-CoV-2 variants. PLoS Pathog. 2022;18:1–25. https://doi.org/10.1371/journal.ppat.1010260.

CAS  Article  Google Scholar 

Planas D, Saunders N, Maes P, Guivel-Benhassine F, Planchais C, Buchrieser J, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. Springer US; 2021;602:671–5.

Meng B, Ferreira IAT., Abdullahi A, Saito A, Kimura I, Yamasoba D, et al. SARS-CoV-2 Omicron spike mediated immune escape, infectivity and cell-cell fusion. bioRxiv [Internet]. 2021; https://www.biorxiv.org/content/10.1101/2021.12.17.473248v2

Meng B, Abdullahi A, Ferreira IATM, Goonawardane N, Saito A, Kimura I, et al. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. Nature. 2022;

Bojkova D, Widera M, Ciesek S, Wass MN, Michaelis M, Cinatl J. Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant of SARS-CoV-2 isolates. Cell Res. 2022;32:319–21.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Takahashi W, Yoneda T, Koba H, Ueda T, Tsuji N, Ogawa H, et al. Potential mechanisms of nafamostat therapy for severe COVID-19 pneumonia with disseminated intravascular coagulation. Int J Infect Dis [Internet]. 2021;102:529–31. https://doi.org/10.1016/j.ijid.2020.10.093.

CAS  PubMed  Article  Google Scholar 

Iwasaka S, Shono Y, Tokuda K, Nakashima K, Yamamoto Y, Maki J, et al. Clinical improvement in a patient with severe coronavirus disease 2019 after administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate. J Infect Chemother [Internet]. 2020;26:1319–23. https://doi.org/10.1016/j.jiac.2020.08.001 (Elsevier Ltd).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Hifumi T, Isokawa S, Otani N, Ishimatsu S. Adverse events associated with nafamostat mesylate and favipiravir treatment in COVID-19 patients. Crit Care 2020;24.

Koriyama N, Moriuchi A, Higashi K, Kataoka T, Arimizu T, Takaguchi G, et al. COVID-19 with rapid progression to hypoxemia likely due to imbalance between ventilation and blood flow: a case report. Clin Med Insights Circ Respir Pulm Med. 2022;16:1–7.

Article  Google Scholar 

Inokuchi R, Kuno T, Komiyama J, Uda K, Miyamoto Y, Taniguchi Y, et al. Association between Nafamostat Mesylate and In-Hospital Mortality in Patients with Coronavirus Disease 2019: A Multicenter Observational Study. J Clin Med. 2022;11

Zhuravel SV, Khmelnitskiy OK, Burlaka OO, Gritsan AI, Goloshchekin BM, Kim S, et al. Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial. EClinicalMedicine. 2021;41:101169. https://doi.org/10.1016/j.eclinm.2021.101169 (Elsevier Ltd).

PubMed  PubMed Central  Article  Google Scholar 

Hwang SD, Hyun YK, Moon SJ, Lee SC, Yoon SY. Nafamostat mesilate for anticoagulation in continuous renal replacement therapy. Int J Artif Organs. 2013;36:208–16.

PubMed  Article  Google Scholar 

Lee YK, Lee HW, Choi KH, Kim BS. Ability of Nafamostat mesilate to prolong filter patency during continuous renal replacement therapy in patients at high risk of bleeding: a randomized controlled study. PLoS ONE. 2014;9:1–8.

Google Scholar 

Bowen AC, Tong SYC, Davis JS. Australia needs a prioritised national research strategy for clinical trials in a pandemic: lessons learned from COVID-19. Med J Aust. 2021;215:56-58.e1.

PubMed  PubMed Central  Article  Google Scholar 

Ramanan M, Tong SYC, Kumar A, Venkatesh B. Geographical representation of low- and middle-income countries in randomized clinical trials for COVID-19. JAMA Netw Open. 2022;32:319–21.

Google Scholar 

Moon K, Hong K, Bae I. Treatment effect of nafamostat mesylate in patients with COVID-19 pneumonia : study protocol for a randomized controlled trial. Trials. 2021;22:832.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Rhee J. A review of the possibility of Nafamostat Mesylate in COVID-19 treatment. J Cell Immunol. 2021;3:1–7.

Google Scholar 

EUnetHTA Rolling Collaborative Review (RCR05) Authoring Team. Nafamostat for the treatment of COVID-19. Report No: RCR05, v. 7.0 [Internet]. Diemen (The Netherlands); 2021. https://www.eunethta.eu/wp-content/uploads/2021/05/EUnetHTA-Covid-19_RCR05_Nafamostat_V7.0.pdf

Denholm JT, Venkatesh B, Davis J, Bowen AC, Hammond NE, Jha V, et al. ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial. Res Sq. 2022;1–20.