Coronavirus (13) Popular drugs tested for effectiveness in COVID-19 treatment (c)

Continued from my blog post on 27th May.
8. Umifenovir
Umifenovir (Arbidol, Pharmstandard Group, Moscow, Russia) is a broad-spectrum antiviral drug similar to favipiravir, and has shown efficacy in Russia and China in the prophylactic (prevention) or treatment of infection by influenza viruses.^1,2 It is a viral entry inhibitor, working by interacting with the virus hemagglutinin and thus preventing fusion of the viral envelope with the target human cell membranes. The molecule also affects other stages of the virus life cycle, either by direct targeting viral proteins or virus-associated host factors.³ The drug is licensed only in China and Russia; it is not approved for use in other countries. It is not in the US FDA's list of approved drugs for prevention of influenza.⁴

Since 2004, umifenovir has been patented for its medicinal use as an antiviral agent against atypical pneumonia induced by SARS-CoV.³ An in vitro study showed that umifenovir efficiently inhibited SARS-CoV-2 infection with 50% maximal effective concentration (EC50) of 4.11uM, which is within the range of safe clinical dose.⁵ However, the drug is less effective than favipiravir in a comparative study on COVID-19 patients. The seven-day recovery rate for the umifenovir group was significantly lower than that for the favipiravir group (55.86% vs 71.43%, p= 0.0199). Patients with hypertension or diabetes also showed better improvement in the favipiravir group than in the umifenovir group.⁶

Umifenovir has recently been added to the Guidelines for the Diagnosis and Treatment of COVID-19 (sixth and seventh editions) in China. Many phase 4 clinical trials, mainly performed in China, are currently running for umifenovir in the treatment of COVID-19.^7,8,9

9. Remdesivir
Remdesivir (GS-5734) was developed by Gilead Sciences Inc. It is an adenosine analogue. It shuts down viral replication by inhibiting RNA-dependent RNA polymerase, and blocks the virus from making its genetic material. Research on the drug began in 2009 and antiviral profiling of the drug suggested it has the potential of a broad spectrum of antiviral activity. Before the outbreak of COVID-19, it was still an investigational product and had not been approved anywhere globally. Its safety and efficacy for any use had not been determined.¹⁰

The drug was first used to combat Ebola and related viruses but did not show effectiveness. In 2017, researchers at the University of North Carolina showed in in vitro and animal studies that the drug can inhibit the coronaviruses that cause SARS and MERS.¹¹ Promising results suggested it may have some effect in patients infected with SARS-CoV-2.

Remdesivir was given to the first COVID-19 patient diagnosed in the United States when his condition worsened. The man improved the next day.¹² A double-blind, randomized, placebo-controlled trial including 1,063 patients in hospitals around the world indicated that the drug shortened the length of illness from 15 days to 11 days.¹³

Gilead has initiated its own two phase 3 studies of the drug.¹⁰ Moreover, the drug is one of the candidates in WHO's megatrial SOLIDARITY and in the INSERM-sponsored DisCoVeRy trial in Europe.^14,15

The Department of Health and Social Care has approved the drug as the first medicine to treat COVID-19 in the UK. It is likely that those patients with the most severe cases of the disease will have priority in receiving the drug treatment. However, there is a concern over the side effects related to the liver and kidneys. Moreover, whether the manufacturer can provide enough supply for the exponential demand of the drug is another concern.¹⁶ Outisde the UK, the US and Japan are also using this drug to treat COVID-19 patients.^17,18

10. Sarilumab (Immune system inhibitors, anti-inflammatory drug)
Sarilumab (Kevzara®, Sanofi, New York, NY, USA and Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA) is approved for the treatment of rheumatoid arthritis in multiple countries. It is an antibody against the interleukin 6 (IL-6) receptor and can effectively block IL-6 signal transduction. IL-6 is one of the excessive cytokines produced as a result of COVID-19 infection and causes lung inflammation.¹⁹

A single group study of another IL-6 inhibitor similar to sarilumab, tocilizumab, with 21 severe, febrile hospitalized COVID-19 patients, showed fever returned to normal and improved oxygenation upon tocilizumab treatment.²⁰

Based on the above findings, the two developers of sarilumab, Sanofi and Regeneron, are in partnership with Northwell Health's Feinstein Institutes for Medical Research, to evaluate the effects of sarilumab on fever and the need for supplemental oxygen in a phase 2/3 trial. Preliminary analysis showed that sarilumab, similar to tocilizumab, rapidly lowered C-reactive protein, a key marker of inflammation.^20,21 However, sarilumab did not show notable clinical benefit versus placebo when combining the severe group (patients who required oxygen supplementation without mechanical or high-flow oxygenation) and the critical group (patients who required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit). On the other hand, positive trends were reported for all outcomes in the critical group. They have now set a phase 3 trial with two amendments so that only the more advanced critical patients continue to be enrolled to receive treatment, and all new patients are to receive either higher-dose Kevzara or placebo.²¹

11. Colchicine
Colchicine is an anti-inflammatory drug used for rheumatic and non-rheumatic diseases such as gout, familial Mediterranean fever, and pericarditis (a condition in which the sac around the heart becomes inflamed).²² Colchicine prevents microtubule assembly and disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of cytokines, phagocytosis, and migration of neutrophils.²³

Due to its ability to suppress the generation of cytokines, it has been suggested that colchicine may be effective in relieving cytokine storm seen during SARS-CoV-2 infection. The drug thus has been widely tested in clinical trials in the world for its efficiency in severe COVID-19 patients of different levels.^24-26

However, there is a concern of causing of acute respiratory distress syndrome and multi-organ failure, the two common causes of death in COVID-19 patients, if an inappropriate dose of colchicine is used.^27,28

References

1. V.M. Gagarinova, G.S. Ignat'eva, L.V. Sinitskaia, et al. The new chemical preparation arbidol: its prophylactic efficacy during influenza epidemics. Zh. Mikrobiol. Epidemiol. Immunobiol. 1993;5:40-43. (Article in Russian, abstract available in English)
2. M.Z. Wang, B.Q. Cai, L.Y. Li, J.T. Lin, et al. Efficacy and safety of arbidol in treatment of naturally acquired influenza. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004;26:289-293. (Article in Chinese, abstract available in English)
3. J. Blaising, S.J. Polyak, & E.I. Pecheur. Arbidol as a broad-spectrum antiviral: an update. Antivir. Res. 107, 84-94 (2014). 4. "FDA approved drugs for influenza" https://www.fda.gov/drugs/information-drug-class/influenza-flu-antiviral-drugs-and-related-information#ApprovedDrugs
5. X. Wang, R. Cao, H. Zhang, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discovery, 6, Article number: 28 (2020).
6. C. Chen, Y. Zhang, J. Huang J, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. MedRxiv preprint doi: https://doi.org/10.1101/2020.03.17.20037432 this version posted April 15, 2020.
7. "Clinical study of Arbidol hydrochloride tablets in the treatment of pneumonia caused by novel coronavirus." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04260594
8. "A prospective, randomized controlled clinical study of antiviral therapy in the 2019-nCoV pneumonia." ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04255017
9. "The clinical study of carrimycin on treatment patients with Covid-19." ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04286503
10. "Development of Remdesivir" https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf
11. T.P. Sheahan, A.C. Sims, R.L. Graham, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine. Vol. 9, Issue396, eaal3653.
12. M.L. Holshue, C. DeBolt, S. Lindquist, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382:929-936.
13. J.H. Beigel, K.M. Tomashek, L.E. Dodd, et al. Remdesivir for the treatment of Covid-19 - preliminary report. NEJM. 2020 May 22;NEJMoa2007764. doi: 10.1056/NEJMoa2007764.
14. ""Solidarity" clinical trial for COVID-19 treatments" WHO. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
15."Launch of a European clinical trial against COVID-19" https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/
16. "Gilead's virus drug seen in short supply for Americans" Bloomberg News. https://www.bloomberg.com/news/articles/2020-05-11/gilead-s-covid-19-drug-seen-in-short-supply-for-americans.
17. "Gilead's investigational antiviral Remdesivir receives U.S. Food and Drug Administration emergency use authorization for the treatment of COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gileads-investigational-antiviral-remdesivir-receives-us-food-and-drug-administration-emergency-use-authorization-for-the-treatment-of-covid19
18. "Gilead announces approval of Veklury® (remdesivir) in Japan for patients with severe COVID-19" https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gilead-announces-approval-of-veklury-remdesivir-in-japan-for-patients-with-severe-covid19
19. W. Ahsan, S. Javed, M.A. Bratty, et al. Treatment of SARS-CoV-2: How far have we reached? Review. Drug Discoveries & Therapeutics. 2020; 14(2):67-72.
20. X. Xu, M. Han, T. Li, et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. http://www.chinaxiv.org/abs/202003.00026
21. "Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients" https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00
22. Y.Y. Leung, L.L.Y. Hui, and V.B. Kraus. Colchicine-update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum., 2015, 45:341-350.
23. N. Dalbeth, T.J. Lauterio, and H.R. Wolfe. Mechanism of action of colchicine in the treatment of gout. Clin Ther., 2014, 36:1465-1479.
24. "Could the ancient drug colchicine help fight COVID-19?" MedicineNet, 23rd April, 2020. https://www.medicinenet.com/script/main/art.asp?articlekey=230649
25. S.G. Deftereos, G. Siasos, G. Gianopouolos, et al. The Greek study in the effects of colchicine in COVID-19 complications prevention (GRECCO-19 Study): rationale and study design. Hellenic J Cardio. 2020 Apr 3;S1109-9666(20)30061-0. doi:10.1016/j.hjc.2020.03.002.
26. "The effects of standard protocol with or without colchicine in Covid-19 infection" (NCT04360980) https://clinicaltrials.gov/ct2/show/NCT04360980
27. M. Maurizi, N. Delorme, M.C. Laprévote-Heully, et al. Acute respiratory distress syndrome in adults in colchicine poisoning. Ann Fr Anesth Reanim., 1986, 5:530-532.
28. M.C.Cure, A. Kucuk, and E. Cure. Colchicine may not be effective in COVID-19 infection; it may even be harmful? Letter to the editor. Clinical Rheumatology, 2020. https://doi.org/10.1007/s10067-020-05144-x

Coronavirus (12) Popular drugs tested for effectiveness in COVID-19 treatment (b)

Continued from my last blog post.

5. Corticosteroids (e.g. dexamethasone, hydrocortisone, methylprednisolone, prednisolone)

Corticosteroids are steroidal hormones that have anti-inflammatory functions, and are normally used to suppress inflammatory conditions resulting from immune system overdrive in fighting off infection. They were widely used in Hong Kong in the 2003 SARS epidemic.¹

The results of using corticosteroids on coronavirus infected patients were contradictory and mostly unfavourable. A study comparing 1287 steroid-treated and no-steroid-treated patients in Hong Kong showed that corticosteroid groups had a lower crude death rate.² However, a retrospective cohort study of SARS patients showed adverse outcomes (either ICU admission or mortality) following corticosteroid therapy.³ Early treatment of hydrocortisone in SARS patients was associated with a higher subsequent plasma viral load.⁴ Similarly, a delayed clearance of viral RNA from the respiratory tract was also observed in MERS patients with corticosteroid treatment.⁵ It seems that by reducing the inflammatory response, corticosteroids also reduce the rest of the immune response and prolong the viral load. Moreover, a meta-analysis synthesized from 10 trials suggested that higher cumulative doses and longer treatment durations of corticosteroids are more likely to develop osteonecrosis in SARS patients.⁶

In view of no unique reason existing to expect that COVID-19 patients will benefit from corticosteroids, and they might be more likely to be harmed with such treatment, a recent review in The Lancet suggested that corticosteroids should not be used for the treatment of COVID-19-induced lung injury or shock outside of a clinical trial.⁷ Based on the fact of lack of effectiveness and possible harm, WHO advises against the use of corticosteroids for COVID-19 unless they are indicated for another reason.⁸

There are, however, study results from several reports demonstrating that the timing, dosage, and duration of corticosteroid therapy are critical if this intervention is to be beneficial in patients.^2,9 In a systematic review and meta-analysis including 15 studies published since 2002 and a total of 5,270 patients infected with SARS-CoV, MERS-CoV or SARS-CoV-2, it is suggested that moderate corticosteroids can be used in patients with severe conditions to suppress the immune response and reduce symptoms.¹⁰

A UK-based clinical trial RECOVERY (Randomised Evaluation of COVid-19 thERapY) and a global REMAP-CAP trial collaborated together to test the effectiveness of dexamethasone in critically ill patients.¹¹

6. Favipiravir

Favipiravir (Avigan®, FUJIFILM Toyama Chemical Co., Ltd., Tokyo, Japan) is an approved influenza antiviral drug. It is a purine nucleic acid analogue and broad spectrum inhibitor of RNA-dependent RNA polymerase (RdRp) associated with viral replication. As the drug specifically blocks RNA polymerase, the mechanism is expected to have an antiviral effect on SARS-CoV-2 as this is a single-stranded RNA virus like the influenza virus.¹² Favipiravir has molecular mechanical activity similar to Remdesivir. While Remdesivir is intended for use in the most severe cases of COVID-19 and reduces their recovery time, favipiravir is tested in the hope that it may help a wider range of patients.

Ebola patients treated with favipiravir showed a trend toward improved survival.¹³ A retrospective analysis showed a higher overall survival rate and longer average survival time on Ebola patients with additional favipiravir treatment, in comparison with patients with the WHO-recommended supportive therapy. In addition, a higher percentage of Ebola patients who received favipiravir treatment had a more than 100-fold viral load reduction.¹⁴

A clinical trial (ChiCTR2000029600) conducted in Shenzhen recruiting 80 patients showed that 35 patients in the favipiravir arm demonstrated significantly shorter viral clearance time, compared with the 45 patients in the control arm (median 4 days vs. 11 days). X-ray chest image confirmed a higher rate of improvement in the favipiravir arm.¹⁵ For ordinary patients with COVID-19, the 7-day clinical recovery rate increased from 55.86% to 71.43% with favipiravir treatment. The time of fever reduction and cough relief also decreased significantly.¹⁶

The drug is currently in phase 3 development by the original manufacturer (NCT04358549).¹⁷ It may be added to the trial SOLIDARITY later by WHO.

Although the using of favipiravir for COVID-19 treatment sounds promising, the Health Minister of Japan, Katsunobu Kato, revealed on May 26 that his ministry has given up on the government's end-May target for approving the drug for the treatment of COVID-19, as no sufficient data to support its efficacy are yet available.¹⁸ In fact, favipiravir has a risk for teratogenicity and embryotoxicity.¹⁹ The mechanism that makes the drug effective against viruses also makes it destructive to fetuses with rapid cell growth.

7. Interferon beta (e.g. Betaferon (INF-β1b), Rebif (INF-β1a))

Human recombinant interferon beta (INF-β) was originally developed for chronic obstructive pulmonary disorder. Subcutaneous injections of INF-β have been used for the treatment of multiple sclerosis for more than 20 years.²⁰ The human body naturally produce INF-β as a defensive response to viruses.²¹ It is involved in regulating inflammation in the body and is known to improve the lung's condition and enhance the lung's ability to fight viral infections. A decrease in INF-β production is directly linked to increased susceptibility of people to develop severe respiratory diseases resulting from viral infections; SARS-CoV-2 infection can suppress the INF-β production in the body.²²

Interferon beta has shown antiviral effects in vitro and in marmosets infected with MERS.^23-26 However, the molecule generally failed to show significant improvement on humans with MERS and SARS infection.²⁷ On the other hand, a recent in vitro study showed that human recombinant INF-β1a inhibits SARS-CoV-2 virus load in cultured cells, at concentrations that are clinically achievable in patients, demonstrating the therapeutic potential of the molecules against COVID-19.²⁸ According to the researcher of the study, "the data may provide an explanation, at least in part, to the observation that approximately 80% of patients actually develop mild symptoms and recover. It is possible that many of them are able to mount IFN-β-mediated innate immune response upon SARS-CoV-2 infection, which helps to limit virus infection/dissemination at an early stage of disease."

The timing for INF-β administration and the application of the molecules to the right people is critical. An in vivo study demonstrated that INF-β administration shortly after infection protected mice from lethal MERS-CoV infection, by inhibiting virus replication and inflammatory cytokine production. On the other hand, delayed administration caused the failure to inhibit viral replication and had adverse events.²⁹ It is also important to apply INF-β treatment to patients only if they don't have comorbidities.^30,31

Due to its unspecific antiviral effects, the molecule is often evaluated, usually in combination with other drugs, before specific treatments are developed. For example, a combination of IFN-β with lopinavir/ritonavir was used against MERS-CoV and showed improvement in pulmonary function.³²

In clinical trials for COVID-19 treatment, IFN-β is usually used in combination with lopinavir/ritonavir. Subcutaneous IFN-β1a in combination with lopinavir/ritonavir is being tested in the WHO global megatrial Solidarity.³³ Subcutaneous IFN-β1b in combination with lopinavir/ritonavir and ribavirin was also tested in other clinical trials such as the open-label one performed in Hong Kong (NCT04276688), for the treatment of COVID-19.³⁴ The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days) than the control group (12 days).

An inhaled form of IFN-β1a, called SNG001, produced by Synairgen, is also being tested in a placebo-controlled trial led by Tom Wilkinson at the University of Southampton. The trial will use the drug much earlier in the course of the illness, to find out if the drug can protect the lungs and prevent the development of the severe lower respiratory tract illness.³⁵ The participants of the trial will receive either SNG001 or placebo, inhaled once daily for 14 days in their homes. Their general medical condition, levels of breathlessness, cough and sputum (mucus from the lungs) will be recorded every day, along with any safety information.

References

1. L.K. So, A.C. Lau, L.Y. Yam, et al. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003; 361: 1615-1617.

2. Y.C. Yam, C.W. Lau, Y.L. Lai, et al. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. Journal of Infection. (2007) 54, 28-39.

3. T.W. Auyeung, S.W. Lee, W.K. Lai, et al. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study. J Infect. (2005) 51(2):98-102.

4. N. Lee, K.C. Chan, S. Hui, et al. Effects of early corticosteroid treatment on plasma SARS-associatedCoronavirusRNA concentrations in adult patients. Journal of Clinical Virology, 31 (2004) 304-309.

5. Y.M. Arabi, Y. Mandourah, F. Al-Hameed, et al. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir Crit Care Med. 2018; 197: 757-767.

6. R. Zhao, H. Wang, X. Wang, et al. Steroid Therapy and the Risk of Osteonecrosis in SARS Patients: A Dose-Response Meta-Analysis. Osteoporos Int, 2017 Mar;28(3):1027-1034.

7. C.D. Russell, J.E. Millar & J.K. Baillie. Lancet. 2020; 395 (10223): 473-475.

8. Clinical management of COVID-19. Interim guidance, 27th May, 2020. World Health Organization.

9. Y. Wang, W.W. Jiang, Q. He, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. MedRxiv, doi: https://doi.org/10.1101/2020.03.06.20032342

10. Z.W. Yang, J.L. Liu, Y.J. Zhou, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020 Apr 10;S0163-4453(20)30191-2.

11. "Coordination of RECOVERY and REMAP-CAP trials" https://www.recoverytrial.net/files/professional-downloads/coordination-of-recovery-and-remap-cap.pdf

12. Y. Furuta, T. Komeno, & T. Nakamura. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93, 449-463 (2017).

13. D. Sissoko, C. Laouenan, E. Folkesson, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea. Plos Med. 2016 Mar 1;13(3):e1001967.

14. C.Q. Bai, J.S. Mu, D. Kargbo,et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone, 2014. Clin. Infect. Dis. 63, 1288-1294 (2016).

15. Q. Cai, M. Yang, D. Liu, et al. Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering. https://doi.org/10.1016/j.eng.2020.03.007

16. C. Chen, Y. Zhang, J. Huang, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. bioRxiv preprint. https://doi.org/10.1101/2020.03.17.20037432

17. "Fujifilm commences Phase III trial of Avigan for Covid-19" Clinial Trials Area news. 1st April, 2020. https://www.clinicaltrialsarena.com/news/fujifilm-avigan-covid-19-trial-japan/)

18. "Japan approval for Avigan to treat COVID-19 delayed" The Pharma Letter. https://www.thepharmaletter.com/article/japan-approval-for-avigan-to-treat-covid-19-delayed

19. T. Nagata, A.K. Lefor, M. Hasegawa, et al. Favipiravir: A New Medication for the Ebola Virus Disease Pandemic. Disaster Med Public Health Prep, 2015 Feb;9(1):79-81.

20. D. Jakimovski, C. Kolb, M. Ramanathan, et al. Interferon ? for multiple sclerosis. Cold Spring Harb. Perspect. Med., 8 (2018), pp. 1-20

21. Y.J. Liu. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23 (2005), pp. 275-306.

22. E. Sallard, F.X. Lescure, Y. Yazdanpanah, et al. Type 1 interferons as a potential treatment against COVID-19. Antivir Res. 2020; 178:104791.

23. L.E. Hensley, E.A. Fritz, P.B. Jahrling, et al. INF-?1a and SARS coronavirus replication. Emerg. Infect. Dis., 10 (2004), pp. 317-319.

24. J.F.W. Chan, K.H. Chan, R.Y.T. Kao, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect. 67 (2013), pp. 606-616.

25. B.J. Hart, J. Dyall, E. Postnikova, et al. Interferon-? and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol., 95 (2014), pp. 571-577.

26. J.F. Chan, Y. Yao, M.L. Yeung, et al. Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis, 2015 Dec 15;212(12):1904-1913.

27. L.J. Stockman, R. Bellamy and P. Garner. SARS: systematic review of treatment effects. PLoS Med., 3 (2006), pp. 1525-1531.

28. E. Mantlo, N. Bukreyeva, J. Maruyama, et al. Antiviral Activities of Type I Interferons to SARS-CoV-2 Infection. Antiviral Res. 2020 Apr 29;179:104811.

29. R. Channappanavar, A.R. Fehr, J. Zheng, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Invest., 129 (2019), pp. 3625-3639.

30. J.A. Al-Tawfiq, H. Momattin, J. Dib, et al. Ribavirin and ingerferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an obsevtional study. Int. J. Infect. Dis. 20 (2014), pp. 42-46.

31. S. Shalhoub, F. Farahat, A. Al-Jiffri, et al. INF-a2a or INF-b1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study.J. Antimicrob. Chemother., 70 (2015), pp. 2129-2132.

32. T.P. Sheahan, A.C. Sims, S.R. Leist, et al. Comparative therapeutic efficacy of Remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020 Jan 10;11(1):222.

33. ""Solidarity" clinical trial for COVID-19 treatments." World Health Organization. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

34. F.N. Hung, K.C. Lung, Y.K. Tso, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet, 2020, Vol.395, 10238, p.1695-1704.

35. "University-led COVID19 drug trial expands into home testing" Medical Express. 27th May, 2020. https://medicalxpress.com/news/2020-05-university-led-covid19-drug-trial-home.html

Coronavirus (11) Popular drugs tested for effectiveness in COVID-19 treatment (a)

Continuing from my last blog post, this one will introduce the popular drugs currently being clinically tested for effectiveness in COVID-19 treatment. The drugs are listed in order of highest popularity first according to the figure in the Cytel's Global coronavirus COVID-19 trial tracker.¹ However, it should be noted that there may be some drugs which are not listed here but are still effective at treating the disease.

1. Chloroquine/Hydroxychloroquine
These drugs have been used for decades in the treatment of malaria, and are FDA approved. They are also frequently used in treating autoimmune diseases such as rheumatoid arthritis and lupus.² Hydroxychloroquine has a hydroxyl group which makes it less toxic than chloroquine while maintaining similar activity.

Chloroquine blocks virus infection by increasing endosomal pH required for virus-cell fusion, as well as by interfering with the glycosylation of receptors of SARS-CoV.³ This suggests that chloroquine treatment might be more effective in the early stages of infection. Preclinical studies showed that chloroquine functioned at both entry and post-entry stages of the SARS-CoV-2 infection in Vero E6 cells.⁴ Besides its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses by inhibiting the lipopolysaccharide-induced release of inflammatory cytokines.⁵

Early clinical trials conducted in COVID-19 Chinese patients showed that chloroquine had a significant effect, both in terms of clinical outcome and viral clearance, when compared to control groups.⁶ As chloroquine was identified to disrupt the early stages of coronavirus replication, a Correspondence article in The Lancet even suggested the use of chloroquine or hydroxychloroquine for prophylaxis.⁷ US President Donald Trump tweeted earlier this month that he was taking hydroxychloroquine as a preventative measure against COVID-19.

However, a multinational registry analysis of 96,032 patients found that people taking chloroquine or hydroxychloroquine with or without a azithromycin (macrolide) were at higher risk of death and de-novo ventricular arrhythmia.⁸ In view of this, the WHO announced the pausing of the testing of hydroxychloroquine and its combination from the global megatrial SOLIDARITY, and reviewed all evidence available globally to evaluate the potential benefits and risks of hydroxychloroquine.⁹*

2. Lopinavir/ritonavir
This two-drug combination is FDA approved for HIV treatment. It was developed by Abbot Laboratory and is sold under the brand name Kaletra.¹⁰ It is being tested in the WHO global megatrial SOLIDARITY. Lopinavir is specifically designed to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses, thus blocking the HIV replication. Ritonavir, another protease inhibitor, is used in combination with lopinavir to slow down the decomposition of lopinavir in the human body by our own proteases.¹¹

Kaletra has shown efficacy in MERS infected marmosets.¹² A retrospective matched cohort study including 1,052 SARS patients (75 treated patients and 977 control patients) showed that the addition of the drug as an initial treatment was associated with a reduced death rate and intubation rate compared with that in a matched cohort who received standard treatment (2.3% vs 11.0% and 0% vs 15.6%, respectively, P < .05).¹³

However, the first trial with COVD-19 was not encouraging. The study in Wuhan showed no significant difference between the groups receiving the lopinavir/ritonavir and the group receiving standard care alone.¹⁴ The authors explained that the treatment may have been given too late to help, as the patients were very ill.

The drug combination is generally safe, but it may interact with drugs that usually given to severely ill patients, and it could cause significant liver damage.¹⁵

3. Azithromycin
Azithromycin (AZ) is an antibiotic with the brand name Zithromaz®(Pfizer Inc., New York, NY, USA). The drug is a broad-spectrum macrolide antibiotic with a long half-life. It has not yet been approved for antiviral therapy, although preclinical and clinical data suggest that it has antiviral properties.^{16,17,18,19,20}

Similar to chloroquine/hydroxychloroquine, the drug confers its antiviral activity by changing the acidic environment of the endosomes and lysosomes, thus potentially blocking endocytosis and/or viral genetic shedding from lysosomes, thereby limiting viral replication. The alkaline environment also prevents the uncoating of enveloped viruses in host cells, thus further inhibiting the virus's replication.^21,22 AZ has the ability to induce pattern-recognition receptors, IFNs, and IFN-stimulated genes, leading to a reduction of viral replication.²³ In addition, AZ directly acts on bronchial epithelial cells to maintain their function and reduce mucus secretion to facilitate lung function.^20,24

The drug is usually used in combination with chloroquine or hydroxychloroquine in clinical trials for COVID-19. An open-label study in France found a significant reduction of viral load in COVID-19 patients using a combination of hydroxychloroquine and AZ.²⁵

4. Tocilizumab
Tocilizumab (Actemra/RoActemra®, F. Hochmann-La Roche AG, Basel, Switzerland) is an FDA approved drug for rheumatoid arthritis. It is a recombinant humanized monoclonal anti-interleukin6 receptor (anti-IL-6R) antibody. It binds to both soluble and membrane-bound IL-6R to inhibit IL-6-mediated signalling. IL-6 is one of the excessive cytokines produced by activated macrophages as a result of COVID-19 infection.²⁶

Evidence from independent studies of tocilizumab appear promising. In preliminary data from a non-peer reviewed study, patients showed rapid fever reduction and a reduced need for supplemental oxygen withina few days of receiving tocilizumab, in a single-arm Chinese trial involving 21 patients with severe or critical COVID-19 infection.²⁷

Roche has launched a global, randomised, double-blind, placebo-controlled phase 3 trial (NCT04320615) with tocilizumab, in collaboration with the US Health and Human Services Biomedical Advanced Research and Development Authority (BARDA), for the treatment of people hospitalised with COVID-19 pneumonia. The study will evaluate the safety and efficacy of tocilizumab (in combination with a high standard of care) compared with placebo.²⁸

The National Health Commission of China have included tocilizumab in their 7th updated diagnosis and treatment plan issued for COVID-19 patients with extensive lung lesions and severe cases who also show an increased level of IL-6 in laboratory testing.²⁹

The other popular drugs currently being clinically tested for effectiveness in COVID-19 treatment will be introduced in my next blog post.



*According to the WHO, "chloroquine and hydroxychloroquine had both been selected as potential drugs to be tested within the Solidarity Trial as per the initial trial protocol. However the trial was only ever pursued with hydroxychloroquine, so chloroquine was removed from this page as a listed treatment option under study." They did not explain clearly the reason for removing of chloroquine in the SOLIDARITY study. However, it is understandable, as hydroxychloroquine is safer than chloroquine for usage while having similar antiviral effects.

References

1. Global coronavirus COVID-19 trial tracker. https://www.covid19-trials.com/
2. Rynes R. Antimalarial drugs in the treatment of rheumatological diseases. Rheumatology. 1997;36(7):799-805.
3. M.J. Vincent, E. Bergeron, S. Benjannet, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal, 2005 Aug 22;2:69. doi: 10.1186/1743-422X-2-69.
4. M. Wang, R. Cao, L. Zhang, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020 Mar;30(3):269-271.
5. S. Grassin-Delyle, H.Salvator, M. Brollo, et al. Chloroquine inhibits the release of inflammatory cytokines by human lung explants. Clinical Infectious Diseases, 2020 May 8;ciaa546. doi: 10.1093/cid/ciaa546.
6. J. Gao, Z. Tian, and X. Yang. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends, 2020 Mar 16;14(1):72-73.
7. N. Principi, and S. Esposito. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis. 2020 Apr 17:S1473-3099(20)30296-6. doi: 10.1016/S1473-3099(20)30296-6.
8. M.R. Mehra, S.S. Desai, F. Ruschitzka, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 22:S0140-6736(20)31180-6.
9. ""SOLIDARITY" clinical trial for COVID-19" https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021251s058slp. KALETRA (lopinavir and ritonavir) tablet. 12/2019.
11. European Medicines Agency. European public assessment report (EPAR) for Kaletra. https://www.ema.europa.eu/en/documents/overview/kaletra-epar-summary-public_en.pdf
12. J.F. Chan, Y. Yao, M.L. Yeung, et al. Treatment with lopinavir/ritonavir or interferon-?1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis, 2015 Dec 15;212(12):1904-13.
13. K.S. Chan, S.T. Lai, C.M. Chu, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.
14. B. Cao, Y. Wang, D. Wen, et al. A Trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787-1799.
15. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]: Lopinavir. https://www.ncbi.nlm.nih.gov/books/NBK547961/
16. B. Damle, M. Vourvahis, E. Wang, et al. Clinical pharmacology perspectives on the antiviral activity of Azithromycin and use in COVID-19. Review. Clin Pharmacol Ther, 2020 Apr 17. doi: 10.1002/cpt.1857.
17. H. Retallack, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl. Acad. Sci. 113, 14408-14413 (2016).
18. D.H. Tran, R. Sugamata, T. Hirose, et al. Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process. J. Antibiot. 72, 759-768 (2019).
19. J. Kouznetsova, W. Sun, C. Martinez-Romero, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg. Microbes Infect. 3, 1-7 (2014).
20. V. Gielen, S.L. Johnston, and M.R. Edwards. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur. Respir. J. 36, 646-654 (2010).
21. D. Tytec, P.V. Smissen, M. Marcel, et al. Azithromycin, a lysosomotropic antibiotic, has distinct effects on fluid-phase and receptor-mediated endocytosis, but does not impair phagocytosis in J774 macrophages. Exp. Cell Res. 281, 86-100 (2002).
22. U.F. Greber, I. Singh, & A. Helenius. Mechanisms of virus uncoating. Trends Microbiol. 2, 52-56 (1994).
23. Li, C, S. Zhu, Y. Deng, et al. Azithromycin protects against Zika virus infection by upregulating virus-induced type I and III interferon responses. Antimicrob Agents Chemother 63, e00394-e00419 (2019).
24. C.L. Cramer, A. Patterson, A. Alchakaki, et al. Immunomodulatory indications of azithromycin in respiratory disease: a concise review for the clinician. Postgrad. Med. 129, 493-499 (2017).
25. P. Gautret, J. Lagier, P. Parola, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents, 2020 Mar 20;105949.
26. "Actemra/RoActemra (tocilizumab)" https://www.roche.com/products/product-details.htm?productId=42bf9d08-8573-491a-944a-fdbc030ec44b
27. E.A. Coomes, and H. Haghbayan. Interleukin-6 in COVID-19: a systematic review and meta-analysis. https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1.full.pdf
28. "Roche initiates Phase III clinical trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 pneumonia" https://www.roche.com/media/releases/med-cor-2020-03-19.htm
29. "Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7)." https://www.chinadaily.com.cn/pdf/2020/1.Clinical.Protocols.for.the.Diagnosis.and.Treatment.of.COVID-19.V7.pdf

Coronavirus (10) How existing drugs are chosen to test for effectiveness in COVID-19 treatment

Since the outbreak from Wuhan, COVID-19 has infected over 5 million people and caused the death of 350 thousand worldwide. There are no regulatory approved drugs specific for COVID-19 patients, despite the fact that much effort has been put into finding or developing effective drugs for the treatment of the disease, or vaccines to prevent the disease. Therefore, repurposing of existing drugs, which already have the regulatory approval or are in the late stages of clinical trials, is the main direction of clinical research for COVID-19 treatment nowadays. This blog post will explain the reason for this phenomenon and how these drugs are chosen.

To develop a new drug to be used for a disease, its functions against the disease need to be tested on cellular level, and then on animal modals. After that it has to undergo 3 phases of clinical trials to test the safety, effectiveness, efficacy, and side effects on humans, which usually takes years. Even after passing all the clinical trials, manufacturing and distributing the new drug at the scale needed to tackle this pandemic, can also be significantly challenging. On the other hand, the drugs currently being used to treat other illnesses have been carefully examined before and found to be safe to use. Moreover, as these drugs have existed for quite a while, they are cheap to produce, easy to manufacture, and are scalable. Furthermore, the dosage information is largely in hand. Therefore, they can be used immediately if they are proven to be effective for COVID-19 treatment.^1,2 

You may have heard of Remdesivir (a drug developed for Ebola), or Chloroquine / Hydroxychloroquine (malaria medications), quite frequently from the news recently. However, apart from those, there are dozens more existing drug candidates currently being tested for COVID-19, some as a single entity or some in combination, in over 1000 clinical trials worldwide as of 18th May from the data of Cytel's global COVID-19 clinical trial tracker.^3,4

As there are huge numbers of existing drugs or compounds, you may wonder how these are being selected to be tested for COVID-19 treatment. Ideally, the findings about 1) the genetic components and the structure of the virus; 2) the molecular mechanisms involving in the virus invasion to the host; and 3) the biological reactions, including the immune response, in COVID-19 cases, are useful to help looking for candidate drugs. For example, two anti-inflammatory drugs were selected by scientists in the UK for COVID-19 treatment as cytokine storm, resulting from the hyper-reaction of the host immune system, is observed in serious cases.⁵ However, the molecular mechanisms underlying the virus invasion is not much understood as the disease has newly emerged. This limits the finding of drugs to be tested.

A study conducted by a group of scientists from multiple disciplines, mainly from the San Francisco area, gives us a good example of how the selection of drugs and compounds is made for a newly emerged disease, when not many molecular mechanisms are known.⁶ The study first started by sequence analysis of available SARS-CoV-2 isolates, and identified 29 viral proteins to be translated and processed from the 14 open reading frames in the virus genome. Based on the analysis results, the scientists then cloned 26 of the 29 viral sequences into streptavidin-tagged expression vectors. Using the 26 tagged viral protein as baits, they were able to identify 332 high-confidence SARS-CoV-2-human protein-protein interactions in human embryonic kidney cells by affinity purification mass spectrometry.

By analysing these virus-human protein-protein interactions, the molecular mechanisms underlying the virus infection becomes clearer. These interactions unveiled the molecular pathways in protein trafficking, translation, transcription, and ubiquitination in the infected cells. Moreover, the interactome also unveiled the molecules involved in several innate immune signalling pathways. Any drugs/compounds able to intervene with the interactions could be candidates to be tested for treatment of COVID-19.

The finding of these interactions enable the scientists to identify 62 human proteins that are targeted by existing drugs or compounds: 29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds. These drugs and compounds were then examined with their antiviral activity. Preliminary results showed that protein biogenesis inhibitors (zotatifin, ternatin-4, and PS3061), and ligands of the Sigma1 and Sigma1 receptors (haloperidol, PB28, PD-144418 and hydroxychloroquine), are effective in reducing viral infectivity.*

Besides identifying drugs by first identifying molecular mechanisms underlying the viral infection from laboratory experiments, artificial intelligence (AI) has been started to be used in searching for drugs repurposed for a newly emerged pandemic.^7,8,9,10,11 By feeding in 1) databases of existing drugs or compounds, or 2) data on the molecular structures of the drugs and the virus, and 3) data on research findings of the molecular mechanisms of diseases or symptoms that may be involved, and by making use of the training/algorithm system for analysis, AI is able to help scientists to find candidate drugs without performing any laboratory work. However, as with the other method, selected drugs are still needed to be tested for their antiviral efficiency on a cellular level before proceeding to clinical trials.

According to Cytel's global COVID-19 clinical trial tracker, there are currently a dozen popular drugs being tested for their efficiency in the treatment of COVID-19. In my next blog post, I am going to introduce these drugs and their functions, and explain the reason of their being chosen for clinical studies.

*The main drawback of this study is the lack of an in vivo experiment to proof the in vitro findings of the interactome. The 26 viral proteins were ectopically expressed in modified embryonic kidney cells. Further verification of the expression of the viral proteins and those virus-human protein-protein interactions in the commonly infected cells should be performed in the future. Apart from this, the study was undertaken very nicely, providing quite a full picture of the molecular mechanisms underlying the virus invasion in just 2 to 3 months since the viral outbreaks.

References

1. "Repurposing existing drugs for COVID-19 a more rapid alternative to a vaccine, say researchers" Research news of the University of Cambridge. https://www.cam.ac.uk/research/news/repurposing-existing-drugs-for-covid-19-a-more-rapid-alternative-to-a-vaccine-say-researchers

2. S.P.H. Alexander, J. Armstrong, and A.P. Davenport, et al. A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development. IUPHAR review 29. British Journal of Pharmacology; 1 May 2020; DOI: 10.1111/bph.15094.

3. K. Thorlund, L. Dron, and J. Park, et al. A real-time dashboard of clinical trials for COVID-19. The Lancet, published online April 24, 2020. https://doi.org/10.1016/S2589-7500(20)30086-8.

4. Global coronavirus COVID-19 trial tracker. https://www.covid19-trials.com/

5. "National trial launched to find Covid-19 treatment" Addenbrook's Hospital news, 16th May, 2020. https://www.cuh.nhs.uk/news/communications/national-trial-launched-covid-19-treatment.

6. David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. 2020 Apr 30. doi: 10.1038/s41586-020-2286-9.

7. N.L. Bragazzi, H. Dai, G. Damiani, et al. How Big Data and Artificial Intelligence Can Help Better Manage the COVID-19 Pandemic. Int J Environ Res Public Health. 2020 May 2;17(9):E3176. doi: 10.3390/ijerph17093176.

8. McCall, B. COVID-19 and artificial intelligence: Protecting health-care workers and curbing the spread. Lancet Digit. Health 2020, 2, e166-e167.

9. P. Richardson, I. Griffin, C. Tucker, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020, 395, e30-e31.

10. Y. Ke, T. Peng, T.Yeh, et al. Artificial intelligence approach fighting COVID-19 with repurposing drugs. 2020 May 15. doi: 10.1016/j.bj.2020.05.001.

11. "AI VIVO identifies list of 31 drugs that show potential for Covid-19 treatment" Cambridge Independent, 22nd April, 2020. https://www.cambridgeindependent.co.uk/business/ai-vivo-identifies-list-of-31-drugs-that-show-potential-for-covid-19-treatment-9107179/

Plain soap and water is enough

When SARS-CoV-2 began to spread in England, antibacterial/antiviral hand wash and hand sanitizer became a target of panic buyers. While hand sanitizer with at least 70% alcohol to kill germs is important when we are outdoors and have no proper facilities to wash our hands, have you ever wondered whether it is necessary for us to use hand washing liquid, or soap with antibacterial/antiviral ingredients, at the sink or basin? Well, the U.S. Food and Drug Administration (FDA) says no to this.¹ Instead, they said "plain soap and water" is enough to kill germs.

In 2016, the U.S. FDA announced the banning of 19 common ingredients,² including triclosan and triclocarbon, in "antibacterial" soaps and body washes that are used with water. The FDA were concerned about the effects of these antibacterial ingredients in hand soaps and body washes when they are used on a long-term regular basis by consumers.

According to the FDA, "the benefits of using antibacterial hand soap haven't been proven." In 2013, the FDA proposed a rule requiring safety and efficacy data from manufacturers, consumers, and others if they wanted to continue marketing antibacterial products containing those ingredients, but very little information has been provided.

What is more, according to the FDA, the "wide use" of antibacterial products "over a long time has raised the question of potential negative effects on your health." "The manufacturers have not proven that those antibacterial active ingredients-including triclosan and triclocarban-are safe for daily use over a long period of time." Triclosan is an ingredient of concern to many environmental, academic and regulatory groups. Animal studies have shown that triclosan alters the way some hormones work in the body and raises potential concerns for the effects of use in humans. "We don't yet know how triclosan affects humans and more research is needed." In addition, laboratory studies have raised the possibility that triclosan contributes to making bacteria resistant to antibiotics. This resistance may have a significant impact on the effectiveness of medical treatments, such as antibiotics.

As "there isn't enough science to show that antibacterial soaps are better at preventing illness than washing with plain soap and water," in the undesirable event of another pandemic, we don't need to panic or feel desperate if no antibacterial/antiviral hand wash or antibacterial soap can be found on the shelves of the shops. Plain soap is enough to kill germs if you wash your hands properly. And if you don't have alcoholic hand sanitizer with you, just simply stay at home as much as possible. Unnecessary outdoor activity exposes you to the virus environment and increases your risk of being infected whether or not you have alcoholic hand sanitizer with you.

References

1. "Antibacterial soap? You can skip it, use plain soap and water" The US FDA. https://www.fda.gov/consumers/consumer-updates/antibacterial-soap-you-can-skip-it-use-plain-soap-and-water

2. "Consumer antiseptic wash final rule questions and answers. Guidance for industry" The US FDA. https://www.fda.gov/media/106652/download

Wash away soap or detergent after every use

While we are washing hands frequently in order to stop the spreading of viruses, please remember to try your best to wash away the soap or detergent from your skin completely. Do not think that leaving some soap or detergent residue on the skin could be helpful in protecting your skin. Most hand wash contains sodium lauryl sulfate (SLS, also known as sodium dodecyl sulfate, SDS), which can damage the skin if left for a prolonged period of time, making the skin more vulnerable to the invasion of bacteria and viruses.

The harm SLS causes to humans

You may be familiar with SLS as it is a well-known ingredient in shampoo that can cause hair loss. However, SLS can also cause irritant skin. In fact, the SLS is such a well-known irritant that it is used as a standard irritant in the positive control in dermatological tests.¹ According to research studies, SLS causes irritation to the skin if it is left for a prolonged period of time.^1,2,3

Researchers from Germany found 42% of 1600 tested patients had an irritation due to SLS.¹ Skin irritation is usually assessed by the changing level of redness of the skin, stratum corneum thickness, and the level of transepidermal water loss (TEWL) before and after SLS treatment. Research studies on Caucasian and Japanese populations found significant erythema, stratum corneum dehydration, and elevated TEWL in a dose-dependent manner, when 0.025% to 0.75% of SLS was applied and retained in the forearm for up to 24 hours.^1,2,3 When SLS was applied repeatedly, the levels of erythema and TEWL were augmented and the reactions developed more quickly.³

There are two main ways the SLS triggers skin irritation. One way is by physiologically damaging the skin. Our skin is protected by layers of cells that are composed of oil and protein. Prolonged exposure to SLS can disrupt the natural oil in lipid membrane that protects skin and thus damages the skin. This results in cracked, dry and tender skin which makes it irritant.⁴ More importantly, this also reduces the ability of the skin to keep out bacterial and viral invasions.

Additionally, SLS triggers skin irritation on the biological level. A study using confocal Raman microscopy reported that SLS can penetrate into human skin.⁵ Research studies showed that SLS triggers the expression of two inflammatory mediators, IL-1alpha and PGE2, upon topical application of SLS on keratinocytes.^6,7 Given the recent findings that SARS-CoV-2 can also trigger a hyperinflammatory response in severe cases,⁸ we can imagine what would happen if the SARS-CoV-2 virus invaded cells which had been penetrated by SLS.

Why SLS is commonly used

SLS, with the formula CH₃(CH₂)₁₁SO₄Na, is a *surfactant (surface active agent), a substance made from molecules that have hydrophobic ("grease loving, water hating") groups as tails and hydrophillic ("water loving") groups as heads. Soap, an alkaline salt of fatty acids, is the oldest known surfactant.

Surfactant is the main ingredient in hand soaps, and is added into face washes, shaving creams and toothpastes because it lathers up to generate cleansing foam. The lather-creating feature also enables the core ingredients of the products to be dispersed effectively across the entire cleaning surface. Because of its amphiphillic property, surfactant is added in cosmetic products, dermatological products, and cleaning products, to help mixing oily ingredients with aqueous ingredients. However, when it is left in contact with the skin, the hydrophobic tail of the molecule can disrupt the lipid structure of the skin cell and causes skin damage.

SLS is a commonly used surfactant because of its easiness to produce. It is made by combining lauric acid (from coconut oil) with sulphuric acid (from petroleum) and sodium carbonate. Moreover, it has higher efficacy in generating lather, which is important for removing dirt. As an anionic surfactant, this means SLS has higher ability to solubilize fats and oil. However, unfortunately, this also means that SLS is more harmful than the other surfactants in causing more skin irritancy than non-ionic, or amphoteric surfactants.

What can we do to protect ourselves from the effects of SLS

SLS is not only commonly found in hand wash, it is also found in shampoo, toothpastes, and cleaning detergents. It is very hard to avoid using products with SLS. As there is no scientific evidence that it can cause cancer, and the skin irritation no longer exists once exposure to SLS has ceased,³ we do not need to worry overmuch about the use of SLS-containing products. However, as prolonged exposure to SLS damages the skin and make it vulnerable for virus invasion, it is important to avoid leaving SLS on the skin each time we finish using the relevant products, especially during the pandemic period.

There are a few practical tips, that you may have missed in your daily routine, to minimize the chance of leaving SLS on ourselves, apart from using SLS-free products.

1. While we should use warm water with soap for cleaning in order to increase the lather and thus increase the cleaning power to remove dirt, it is best to avoid using excessively hot water for cleaning or showering, as a high water temperature damages the skin.⁹

2. Put on gloves while we wash dishes to avoid direct contact with the detergent. Or simply use a dishwasher to do the washing.

3. All of our cells, not only the skin cells, are protected by cell membranes composed of fat which can be disrupted by the SLS. SLS left on the kitchenware or the kitchen utensils which will be used later for food will come into our body. Therefore it is really important to rinse these things in running water to get rid of the soapy water from the cleaning.

There are many milder alternatives available (eg. sodium lauryl phosphate, **sodium laureth sulfate, alkyl phenol ethoxylate, fatty alcohol ethoxylate, or fatty acid alkoxylate) to replace SLS in cosmetic and cleaning products. You can seek advice from your pharmacist or GP on the usage of these products if you think SLS might be the cause of your dermatitis or worsening of your eczema.^10,11

*Surfactant comes from the name surface active agent which means a substance that can lower the surface tension of a liquid. When surfactant is dissolved in water, the surfactant molecules orientate at the surface so that the hydrophobic regions are away from the aqueous environment. The surfactant molecules thereby adsorb at the water surface and weaken the forces between water molecules. The contraction force in the water thereby is reduced and thus the spreading and wetting properties of an aqueous solution are increased.

In water, micelles of surfactants are formed by aggregates of surfactant molecules in a way that the hydrophobic tails are directed inwards and the hydrophillic heads are directed outwards. In this way, the aggregates will form balls, cylinders or laminar layers depending on the concentration of the surfactant. When added into an aqueous solution containing oil, surfactant molecules aggregate around the oil so that the oil or fat molecules will be totally incorporated inside micelles. This way, the fat is dispersed into very small particles.

When added into non-aqueous solvent, the surfactant molecules aggregate the other way around, where hydrophilic heads form the core of the aggregate and hydrophobic tail are in contact with the surrounding fat/oil. The surfactant will act in such a way that they will disperse the water-soluble material, in the solvent, into very small parts by creating aggregation around the particle and forms a micelle. This makes it possible to remove the water-soluble material from substrates in solvent using surfactant.

** Sodium laureth sulfate, SLES, is a compound derived from SLS by introducing ethylene oxide through a process called ethoxylation. SLES is safe to use in bath and body care products and is gentler to skin than SLS. The compound won't aggravate your skin or strip any excess moisture off. On the other hand, SLES will be just as cleansing, foaming and emulsifying as SLS.

References

1. J. Geier, W. Uter, C. and Pirker, et al. Patch testing with the irritant sodium lauryl sulfate (SLS) is useful in interpreting weak reactions to contact allergens as allergic or irritant. Contact Dermatitis, 2003 Feb;48(2):99-107.

2. J. Aramaki, S. Kawana, and I. Effendy, et al. Differences of skin irritation between Japanese and European Women. Br J Dermatol., 2002 Jun;146(6):1052-1056.

3. Nara Branco, Ivy Lee, and Hongbo Zhain, et al. Long-term repetitive sodium lauryl sulfate-induced irritation of the skin: an in vivo study. Contact Dermatitis, 2005 Nov;53(5):278-284.

4. A. di Nardo, K, Sugino, and P. Wertz, et al. Sodium lauryl sulfate (SLS) induced irritant contact dermatitis: A correlation study between Ceramides and in vivo parameters of irritation. Contact Dermatitis, 1996 Aug;35(2):86-91.

5. G. Mao, C.R. Flach, and R. Mendelsohn, et al. Imaging the distribution of sodium dodecyl sulfate in skin by confocal Raman and infrared microspectroscopy. Pharm. Res. 2012, 29, 2189-2201.

6. C. Cohen, G. Dossou, and A. Rougier, et al. Measurement of inflammatory mediators produced by human keratinocytes in vitro: a predictive assessment of cutaneous irritation. Toxicol. Vitr., 1991, 5, 407-410.

7. S. Gibbs, H. Vietsch, and U. Meier, et al. Effect of skin barrier competence on SLS and water-induced IL-1? expression. Exp. Dermatol., 2002, 11, 217-223.

8. P. Mehta, D. F. McAuley, and M. Brown, et al. COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression. Lancet, 2020 Mar 28;395(10229):1033-1034.

9. E. Berardesca, G.P. Vignoli, and F. Distante, et al. Effects of water temperature on surfactant-induced skin irritation. Contact Dermatitis, 1995 Feb;32(2):83-87.

10. M. Tsang, and R.H. Guy. Effect of aqueous cream BP on human stratum corneum in vivo. Br. J. Dermatol., 2010 Nov; 163(5): 954-958.

11. N. Kuzmina, L. Hagstromer, and M. Nyren, et al. Basal electrical impedance in relation to sodium lauryl sulphate-induced skin reactions--A comparison of patients with eczema and healthy controls. Skin Res Technol. 2003 Nov; 9(4): 357-362.

How do soap molecules form

After writing a blog post about how soap can kill viruses and how it can remove viruses from the skin, I started to examine how soap is produced, as each soap molecule contains two completely different chemical properties in its two ends (one end is "water loving" while the other end is "water hating" or grease loving). I learned about the function of soap molecules when I was in high school studying chemistry, but at that time, I was not thinking about how soap is made. So a few days ago, I started searching for the answer.

There are a few websites that I found interesting, and I would like to share with you some information from these sources. In general, the basic ingredients of a soap are oil (vegetable oil or animal fat), water, and lye. Lye is an alkaline salt which can be either sodium hydroxide or potassium hydroxide. Sodium hydroxide is used to make a hard soap while potassium hydroxide is used to make a soft soap. A combination of the two is used to make a cream soap.^1,2

When oil and lye are mixed together, soap molecules (fatty acid salts) are formed in a chemical reaction called saponification.³ During the reaction, oil that contains fatty acid ester linkages undergoes alkaline hydrolysis with the metal hydroxide.

Triglyceride + 3 sodium hydroxide (or potassium hydroxide)>>>> glycerol + 3 soap molecules

Although water molecules are not involved in the saponification, water is an important mediator to mix the oil and the alkaline salt together. This is used to create the lye solution that is mixed into the oil. The correct proportion of water for saponification is crucial, as too much of it results in too soft a bar of soap. The majority of the water evaporates out of the soap as it cures and ages.

Soap has been made for thousands of years, and the basic recipe has not very much changed. Nowadays, with the help of the highly developed chemical industry, it is easy to get all the three ingredients to make soap. However, we may wonder how and where did the ancient people get the alkaline salt. The most ancient recipe for soap which was found on Babylonian clay containers dated at 2800 B.C. gives us a clue.⁴ Inscriptions on the containers showed that they used wood ashes as a source of alkaline salts.^4,5 Lye is formed when wood ash (mainly potassium carbonate) is mixed with water.

You may like to make an organic, purely natural handcrafted soap by yourself once you know the basic ingredients. However, it is extremely important to remember that lye is a corrosive strong alkaline of pH 13. You can get serious burns if you don't handle the lye solution carefully. If you start by mixing wood ash with water, the mixture can turn your skin into soap once it comes in contact with your skin and absorbs the oil in your skin. Moreover, inhalation of the lye vapour will cause serious damage to your respiratory system and can be fatal.

References

1. "Soap ingredients" https://www.soapguild.org/consumers/soap-ingredients.php

2. "Why do we use soap?" Live Science, 5th March, 2020. https://www.livescience.com/57044-science-of-soap.html

3. "Saponification definition and reaction" ThoughtCo. https://www.thoughtco.com/definition-of-saponification-605959

4. "Who invented soap?-About soap inventors" http://www.soaphistory.net/soap-history/who-invented-soap/

5. "How to Make Homemade Lye Using Two Ingredients" ThoughtCo. https://www.thoughtco.com/make-homemade-lye-using-two-ingredients-608276