Celebrex Adjuvant Therapy on Coronavirus Disease 2019: An Experimental Study

Wenxin Hong, Yan Chen, Kai You, Shenglin Tan, Feima Wu, Jiawang Tao, Xudan Chen, Jiaye Zhang, Yue Xiong, Fang Yuan, Zhen Yang, Tingting Chen, Xinwen Chen, Ping Peng, Qiang Tai, Jian Wang, Fuchun Zhang, Yin-Xiong Li, Wenxin Hong, Yan Chen, Kai You, Shenglin Tan, Feima Wu, Jiawang Tao, Xudan Chen, Jiaye Zhang, Yue Xiong, Fang Yuan, Zhen Yang, Tingting Chen, Xinwen Chen, Ping Peng, Qiang Tai, Jian Wang, Fuchun Zhang, Yin-Xiong Li

Abstract

Background: The pandemic of coronavirus disease 2019 (COVID-19) resulted in grave morbidity and mortality worldwide. There is currently no effective drug to cure COVID-19. Based on analyses of available data, we deduced that excessive prostaglandin E2 (PGE2) produced by cyclooxygenase-2 was a key pathological event of COVID-19. Methods: A prospective clinical study was conducted in one hospital for COVID-19 treatment with Celebrex to suppress the excessive PGE2 production. A total of 44 COVID-19 cases were enrolled, 37 cases in the experimental group received Celebrex as adjuvant (full dose: 0.2 g, bid; half dose: 0.2 g, qd) for 7-14 days, and the dosage and duration was adjusted for individuals, while seven cases in the control group received the standard therapy. The clinical outcomes were evaluated by measuring the urine PGE2 levels, lab tests, CT scans, vital signs, and other clinical data. The urine PGE2 levels were measured by mass spectrometry. The study was registered and can be accessed at http://www.chictr.org.cn/showproj.aspx?proj=50474. Results: The concentrations of PGE2 in urine samples of COVID-19 patients were significantly higher than those of PGE2 in urine samples of healthy individuals (mean value: 170 ng/ml vs 18.8 ng/ml, p < 0.01) and positively correlated with the progression of COVID-19. Among those 37 experimental cases, there were 10 cases with age over 60 years (27%, 10/37) and 13 cases (35%, 13/37) with preexisting conditions including cancer, atherosclerosis, and diabetes. Twenty-five cases had full dose, 11 cases with half dose of Celebrex, and one case with ibuprofen. The remission rates in midterm were 100%, 82%, and 57% of the full dose, half dose, and control group, respectively, and the discharged rate was 100% at the endpoint with Celebrex treatment. Celebrex significantly reduced the PGE2 levels and promoted recovery of ordinary and severe COVID-19. Furthermore, more complications, severity, and death rate were widely observed and reported in the COVID-19 group of elders and with comorbidities; however, this phenomenon did not appear in this particular Celebrex adjunctive treatment study. Conclusion: This clinical study indicates that Celebrex adjuvant treatment promotes the recovery of all types of COVID-19 and further reduces the mortality rate of elderly and those with comorbidities.

Keywords: COVID-19; COX-2; PGE2; celebrex; prostaglandins.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2020 Hong, Chen, You, Tan, Wu, Tao, Chen, Zhang, Xiong, Yuan, Yang, Chen, Chen, Peng, Tai, Wang, Zhang and Li.

Figures

FIGURE 1
FIGURE 1
Urinary prostaglandin E2 (PGE2) levels of coronavirus disease 2019 (COVID-19) patients were significantly increased. Urinary prostaglandin E2 concentrations of COVID-19 patients, who were hospitalized within 2 days, were significantly higher than the health individuals (170 ± 40 ng/ml vs. 18.8 ± 3.8 ng/ml, p < 0.01). **p < 0.01.
FIGURE 2
FIGURE 2
Celebrex treatment accelerated the recovery of those ordinary coronavirus disease 2019 (COVID-19) patients and prevented the progression toward severe stage. (A) Control case C1, the dynamic changes of the urinary prostaglandin E2 were correlated with the COVID-19 prognosis; (B) experimental case E20, the dynamic reduction of prostaglandin E2 was matched with the improvements of COVID-19 conditions; (C,D) representation of sequential chest CT images illustrated therapeutic outcomes of these two cases, respectively.
FIGURE 3
FIGURE 3
Celebrex treatment promoted the improvement of severe stage of coronavirus disease 2019 (COVID-19) and blocked the progression toward critical stage. (A) Control case C2, the dynamic changes of the urinary prostaglandin E2 were correlated with its COVID-19 prognosis; (B) experimental case E6, the dynamic reduction of prostaglandin E2 was matched with the improvements of COVID-19 conditions; (C,D) representation of sequential chest CT images illustrated therapeutic outcomes of these two cases, respectively.
FIGURE 4
FIGURE 4
Celebrex intervention reversed the progressed severe stage under routine treatment. (A,B) Two ordinary cases received routine treatment for 12 and 15 days, respectively, and the conditions gradually progressed into severe stage; upon the Celebrex treatment, the prostaglandin E2 levels were decreased along with the improvements of coronavirus disease 2019; (C,D) representation of sequential chest CT images illustrated therapeutic outcomes of these two cases under Celebrex intervention, respectively.

References

    1. Amici C., Di Caro A., Ciucci A., Chiappa L., Castilletti C., Martella V., et al. (2006). Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir. Ther. 11 (8), 1021–1030.
    1. Cao H., Xiao L., Park G., Wang X., Azim A. C., Christman J. W., et al. (2008). An improved LC-MS/MS method for the quantification of prostaglandins E2 and D2 production in biological fluids. Anal. Biochem. 372 (1), 41–51. 10.1016/j.ab.2007.08.041
    1. Ding Y., Wang H., Shen H., Li Z., Geng J., Han H., et al. (2003). The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J. Pathol. 200 (3), 282–289. 10.1002/path.1440
    1. Guan W. J., Ni Z. Y., Hu Y., Liang W. H., Ou C. Q., He J. X., et al. (2020). Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382 (18), 1708–1720. 10.1056/NEJMoa2002032
    1. Hamberg M., Samuelsson B. (1971) On the metabolism of prostaglandins E 1 and E 2 in man. J. Biol. Chem. 246 (22), 6713–6721.
    1. Hoffmann M., Kleine-Weber H., Schroeder S., Kruger N., Herrler T., Erichsen S., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8. 10.1016/j.cell.2020.02.052
    1. Hong W., Chen Y., You K., Tan S., Wu F., Tao J., et al. Celebrex adjuvant therapy on COVID-19: an experimental study. medRxiv 10.1101/2020.05.05.20077610
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 (10223), 497–506. 10.1016/s0140-6736(20)30183-5
    1. Liu M., Yang Y., Gu C., Yue Y., Wu K. K., Wu J., et al. (2007). Spike protein of SARS‐CoV stimulates cyclooxygenase‐2 expression via both calcium‐dependent and calcium‐independent protein kinase C pathways. FASEB J. 21 (7), 1586–1596. 10.1096/fj.06-6589com
    1. Liu Q., Wang R. S., Qu G. Q., Wang Y. Y., Liu P., Zhu Y. Z., et al. (2020). Gross examination report of a COVID-19 death autopsy. Fa Yi Xue Za Zhi. 36 (1), 21–23. 10.12116/j.issn.1004-5619.2020.01.005.
    1. Morimoto K., Shirata N., Taketomi Y., Tsuchiya S., Segi-Nishida E., Inazumi T., et al. (2014). Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation. J. Immunol. 192 (3), 1130–1137. 10.4049/jimmunol.1300290
    1. Ng D. L., Al Hosani F., Keating M. K., Gerber S. I., Jones T. L., Metcalfe M. G., et al. (2016). Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. Am. J. Pathol. 186 (3), 652–658. 10.1016/j.ajpath.2015.10.024
    1. Niwa H., Satoh T., Matsushima Y., Hosoya K., Saeki K., Niki T., et al. (2009). Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin. Immunol. 132 (2), 184–194. 10.1016/j.clim.2009.04.012
    1. Park G. Y., Christman J. W. (2006). Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases. Am. J. Physiol. Lung Cell Mol. Physiol. 290 (5), L797–L805. 10.1152/ajplung.00513.2005
    1. Raaben M., Einerhand A. W. C., Taminiau L. J. A., van Houdt M., Bouma J., Raatgeep R. H., et al. (2007). Cyclooxygenase activity is important for efficient replication of mouse hepatitis virus at an early stage of infection. Virol. J. 4, 55 10.1186/1743-422x-4-55
    1. Rumzhum N. N., Ammit A. J. (2016). Cyclooxygenase 2: its regulation, role and impact in airway inflammation. Clin. Exp. Allergy 46 (3), 397–410. 10.1111/cea.12697
    1. Säfholm J., Dahlén S.-E., Delin I., Maxey K., Stark K., Cardell L.-O., et al. (2013). PGE2maintains the tone of the Guinea pig trachea through a balance between activation of contractile EP1receptors and relaxant EP2receptors. Br. J. Pharmacol. 168 (4), 794–806. 10.1111/j.1476-5381.2012.02189.x
    1. Tomera K., Malone R., Kittah J. (2020) Hospitalized COVID-19 patients treated with celecoxib and high dose famotidine adjuvant therapy show significant clinical responses. SSRN. 10.2139/ssrn.3646583
    1. Yan X., Hao Q., Mu Y., Timani K. A., Ye L., Zhu Y., et al. (2006). Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int. J. Biochem. Cell Biol. 38 (8), 1417–1428. 10.1016/j.biocel.2006.02.003
    1. Zamora C. A., Baron D. A., Heffner J. E. (1985). Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury. J. Appl. Physiol. 74 (1), 224–229. 10.1152/jappl.1993.74.1.224
    1. Zheng B.-J., Chan K.-W., Lin Y.-P., Zhao G.-Y., Chan C., Zhang H.-J., et al. (2008). Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc. Natl. Acad. Sci. U.S.A. 105 (23), 8091–8096. 10.1073/pnas.0711942105
    1. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J., et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733. 10.1056/NEJMoa2001017

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