Re-recognizing bromhexine hydrochloride: pharmaceutical properties and its possible role in treating pediatric COVID-19.

All data generated or analyzed during this study are included in this letter. World Health Organization (2020) Coronavirus disease (COVID-19) outbreak situation Report – 145. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200613-covid-19-sitrep-145.pdf?sfvrsn=bb7c1dc9_2. Accessed 14 June 2020 Shen K, Yang Y (2020) Diagnosis and treatment of 2019 novel coronavirus infection in children: a pressing issue. World J Pediatr 16:219–221. https://doi.org/10.1007/s12519-020-00344-6 CAS Article PubMed Google Scholar Feng K, Yun Y, Wang X, Yang G, Zheng Y, Lin C, Wang L (2020) Analysis of CT features of 15 children with 2019 novel coronavirus infection. Zhonghua Er Ke Za Zhi 58:275–278. https://doi.org/10.3760/cma.j.cn112140-20200210-00071 (in Chinese) CAS Article PubMed Google Scholar Cai J, Wang X, Ge Y et al (2020) First case of 2019 novel coronavirus infection in children in Shanghai. Zhonghua Er Ke Za Zhi 58:86–87. https://doi.org/10.3760/cma.j.issn.0578-1310.2020.02.002 (in Chinese) CAS Article PubMed Google Scholar Zhang Y, Lin D, Xiao M et al (2020) 2019-novel coronavirus infection in a three-month-old baby. Zhonghua Er Ke Za Zhi 58:E006. Advance online publication. https://doi.org/10.3760/cma.j.issn.0578-1310.2020.0006 (in Chinese) Zeng L, Tao X, Yuan W et al (2020) First case of neonate infected with novel coronavirus pneumonia in China. Zhonghua Er Ke Za Zhi 58:E009. Advance online publication. https://doi.org/10.3760/cma.j.issn.0578-1310.2020.0009 (in Chinese) Chen Z, Fu J, Shu Q (2020) New coronavirus: new challenges for pediatricians. World J Pediatr 16:222. https://doi.org/10.1007/s12519-020-00346-4 CAS Article PubMed Google Scholar Shen K, Yang Y, Wang T et al (2020) Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement. World J Pediatr 16:223–231. https://doi.org/10.1007/s12519-020-00343-7 CAS Article PubMed Google Scholar Pediatric Branch of Hubei Medical Association, Pediatric Branch of Wuhan Medical Association, Pediatric Medical Quality Control Center of Hubei (2020) Zhongguo Dang Dai Er Ke Za Zhi 22:96–99 (in Chinese) Google Scholar Chen Z, Fu J, Shu Q et al (2020) Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus. World J Pediatr 16:240–246. https://doi.org/10.1007/s12519-020-00345-5 CAS Article PubMed Google Scholar Hoffmann M, Kleine-Weber H, Schroeder 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. https://doi.org/10.1016/j.cell.2020.02.052 CAS Article PubMed PubMed Central Google Scholar Laporte M, Naesens L (2017) Airway proteases: an emerging drug target for influenza and other respiratory virus infections. Curr Opin Virol 24:16–24. https://doi.org/10.1016/j.coviro.2017.03.018 CAS Article PubMed PubMed Central Google Scholar Shen L, Mao H, Wu Y et al TMPRSS2: a potential target for treatment of influenza virus and coronavirus infections. Biochimie 142:1–10. https://doi.org/10.1016/j.biochi.2017.07.016 Lucas JM, Heinlein C, Kim T et al (2014) The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov 4:1310–1325. https://doi.org/10.1158/2159-8290.CD-13-1010 CAS Article PubMed PubMed Central Google Scholar European Medicines Agency. Ambroxol and bromhexine Article 31 Referral- PRAC assessment report. https://www.ema.europa.eu/en/documents/referral/ambroxol-bromhexine-article-31-referral-prac-assessment-report_en.pdf. Accessed 25 March 2020 Chang C, Cheng A, Chang A (2014) Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database Syst Rev 3:CD006088. https://doi.org/10.1002/14651858.CD006088.pub4 Article Google Scholar Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S (2020) Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? [published online ahead of print, 2020 May 26]. Intern Emerg Med 1–12. doi:https://doi.org/10.1007/s11739-020-02383-3 Maggio R, Corsini G (2020) Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection. Pharmacol Res 157:104837. https://doi.org/10.1016/j.phrs.2020.104837 CAS Article PubMed PubMed Central Google Scholar Habtemariam S, Nabavi S, Ghavami S, Cismaru C, Berindan-Neagoe I, Nabavi S (2020) Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the transmembrane serine protease 2. Pharmacol Res 157:104853. https://doi.org/10.1016/j.phrs.2020.104853 CAS Article PubMed PubMed Central Google Scholar Rimsza M, Newberry S (2008) Unexpected infant deaths associated with use of cough and cold medications. Pediatrics 122:e318–e322. https://doi.org/10.1542/peds.2007-3813 Article PubMed Google Scholar Yang L, Yuan Y, Tu X (2000) Determination of Bromhexine in plasma by gas chromatography-electron capture detection and pharmacokinetic studies. Se Pu 18:543–545 (in Chinese) CAS PubMed Google Scholar Zhang W, Feng F, Wang Y (2008) HPLC-MS assay for the determination of bromhexine in human plasma and application to bioequivalence studies. Yao Xue Yu Lin Chuang Yan Jiu 16:114–117 (in Chinese) Google Scholar Yang Y, Shen H (2020) Potential mechanistic investigation of Bromhexine for the treatment of COVID-19. Zhongguo Zhong Yao Za Zhi 55:679–684 (in Chinese) Google Scholar Lu X, Zhang L, Du H, Zhang J et al (2020) SARS-CoV-2 infection in children. N Engl J Med 382:1663–1665. https://doi.org/10.1056/NEJMc2005073 Article PubMed PubMed Central Google Scholar Chinese Clinical Trial Registry...