key: cord-0996858-xc85f7ho
authors: Sagawa, Tomoya; Inoue, Kenichiro; Takano, Hirohisa
title: Use of protease inhibitors for the prevention of COVID-19
date: 2020-10-06
journal: Prev Med
DOI: 10.1016/j.ypmed.2020.106280
sha: 8507951d4d8fce6d9ba94b4f9d1e77d58e5db618
doc_id: 996858
cord_uid: xc85f7ho

nan

evidence, and national insurance approval status in the context of prevention.

Recently, Ansarin et al. reported a randomized clinical trial in which early oral administration of bromhexine hydrochloride, a protease inhibitor, reduced the transfer to intensive care unit, intubation, and the mortality rate in patients with COVID-19 (Ansarin et al., 2020) . Additionally, Maggio and Corsini suggested repurposing bromhexine hydrochloride either as a treatment for full-blown COVID-19 infections or as a prophylactic agent to prevent SARS-CoV-2 infection in high-risk subjects (Maggio and Corsini., 2020) . Bromhexine hydrochloride is an inexpensive, affordable, safe, and over-the-counter medication used as a mucolytic agent in most countries. Although the suppression of viral entry itself has not been proven, bromhexine hydrochloride can inhibit TMPRSS2 and suppress subsequent inflammation (Ansarin et al., 2020) , and can be used as a prophylactic option for the COVID-19 treatment.

Oral camostat mesylate, used to treat chronic pancreatitis mainly in Japan, is another potential prophylactic treatment option against COVID-19. Compared to bromhexine hydrochloride, it is relatively expensive, but it inhibits TMPRSS2 at lower concentrations (Hoffmann et al., 2020 ) (Lucas et al., 2014 . Studies have J o u r n a l P r e -p r o o f Journal Pre-proof demonstrated that it suppresses TMPRSS2 and inhibits the entry of SARS-CoV-2 into cells, thus suggesting its promising treatment efficacy (Hoffmann et al., 2020) .

Intravenous nafamostat mesylate, an anticoagulant, has been widely used for extracorporeal circulation and in patients with disseminated intravascular coagulation mainly in Japan. In the autopsy series of patients with COVID-19, the presence of thrombosis and microangiopathy in the small vessels and capillaries of the lungs with associated hemorrhage has been reported to contribute significantly to death (Fox et al., 2020) . The combination of nafamostat mesylate and fapiviravir has been reported to be potentially effective in critically ill patients, suggesting that inhibition of intravascular coagulopathy may be a contributing factor (Doi et al., 2020) . In addition, in vitro studies have shown that nafamostat mesylate blocked SARS-CoV-2 infection of cells (Yamamoto et al., 2020) . Thus, nafamostat mesylate should be considered as a promising prophylactic option for the clinical manifestations and disease progression of COVID-19, especially in cases with possible coagulopathies and in those in whom coagulopathies are predicted to be critical for their unfavorable prognosis. 

We greatly appreciate your helpful comment.

Based on your suggestions, we have added the following text on page 2, line 18-28:

"Recently, Ansarin et al. reported a randomized clinical trial in which early oral administration of bromhexine hydrochloride, a protease inhibitor, reduced the transfer to intensive care unit, intubation, and the mortality rate in patients with COVID-19 (Ansarin et al., 2020) . Additionally, Maggio and Corsini suggested repurposing bromhexine hydrochloride either as a treatment for full-blown COVID-19 infections or as a prophylactic agent to prevent SARS-CoV-2 infection in high-risk subjects (Maggio and Corsini., 2020) . Bromhexine hydrochloride is an inexpensive, affordable, safe, and over-the-counter medication used as a mucolytic agent in most countries. Although the suppression of viral entry itself has not been proven, bromhexine hydrochloride can inhibit TMPRSS2 and suppress subsequent inflammation (Ansarin et al., 2020) , and can be used as a prophylactic option for the COVID-19 treatment."

We believe that incorporating your advices has improved the revised manuscript.

In addition to this, we have revised the manuscript substantially after consulting with the editorial office. We are very sorry to take up your time again, but we would like you to review the manuscript again.

Thank you once again.

We thank the editor and the reviewers, once again, for their review and valuable comments. Thank you for considering our revised manuscript for publication in Preventive Medicine.

J o u r n a l P r e -p r o o f

Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial

Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

involving components of the tumor microenvironment and promotes prostate cancer metastasis

Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection

Preventing the clinical manifestations and disease progression of coronavirus disease using clinically proven protease inhibitors

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