In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2

Pantea Kiani, Andrew Scholey, Thomas A Dahl, Lauren McMann, Jacqueline M Iversen, Joris C Verster, Pantea Kiani, Andrew Scholey, Thomas A Dahl, Lauren McMann, Jacqueline M Iversen, Joris C Verster

Abstract

The 2019 coronavirus infectious disease (COVID-19) is caused by infection with the new severe acute respiratory syndrome coronavirus (SARS-CoV-2). Currently, the treatment options for COVID-19 are limited. The purpose of the experiments presented here was to investigate the effectiveness of ketotifen, naproxen and indomethacin, alone or in combination, in reducing SARS-CoV-2 replication. In addition, the cytotoxicity of the drugs was evaluated. The findings showed that the combination of ketotifen with indomethacin (SJP-002C) or naproxen both reduce viral yield. Compared to ketotifen alone (60% inhibition at EC50), an increase in percentage inhibition of SARS-CoV-2 to 79%, 83% and 93% was found when co-administered with 25, 50 and 100 μM indomethacin, respectively. Compared to ketotifen alone, an increase in percentage inhibition of SARS-CoV-2 to 68%, 68% and 92% was found when co-administered with 25, 50 and 100 μM naproxen, respectively. For both drug combinations the observations suggest an additive or synergistic effect, compared to administering the drugs alone. No cytotoxic effects were observed for the administered dosages of ketotifen, naproxen, and indomethacin. Further research is warranted to investigate the efficacy of the combination of ketotifen with indomethacin (SJP-002C) or naproxen in the treatment of SARS-CoV-2 infection in humans.

Keywords: COVID-19; SARS-CoV-2; SJP-002C; antiviral; drug repurposing; indomethacin; ketotifen; mast cell stabilizer; naproxen.

Conflict of interest statement

Over the past 36 months, A.S. has held research grants from Abbott Nutrition, Arla Foods, Bayer, BioRevive, DuPont, Fonterra, Kemin Foods, Nestlé, Nutricia-Danone, Verdure Sciences. He has acted as a consultant/expert advisor to Arepa Nootroptics, Bayer, Coca-Cola, Danone, Naturex, Nestlé, Pfizer, Sanofi, Sen-Jam Pharmaceutical, and has received travel/hospitality/speaker fees from Bayer, Sanofi, and Verdure Sciences. Over the past 36 months, J.C.V. has held grants from Janssen and Sequential Medicine, and acted as a consultant/expert advisor to More Labs, Red Bull, Sen-Jam Pharmaceutical, Toast!, Tomo, and ZBiotics. T.A.D. is partner and Head of Product Development and Regulatory Affairs of Sen-Jam Pharmaceutical. J.M.I. is founder and Head of Clinical Development of Sen-Jam Pharmaceutical. L.M. was intern at Sen-Jam Pharmaceutical when the study was conducted. P.K. has nothing to declare. This independent study was conducted by 360biolabs, without involvement of the authors and the funder. The funder was involved in the design of the study, interpretation of data, writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
COVID-19 disease progression.
Figure 2
Figure 2
Dose–response curves for naproxen and ketotifen, alone and in combination. EC50 is the effective concentration of product, i.e., the concentration at which virus infection is inhibited by 50 percent.
Figure 3
Figure 3
Dose–response curves for indomethacin and ketotifen, alone and in combination.

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