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