Hydroxychloroquine – a name familiar only to a few people until early 2020, has now become known to millions around the world. Its popularity took a huge flight after the POTUS himself mentioned it a few times in the news. More recently, in early April 2020, hydroxychloroquine became a hot point of discussion as a result of discussion between the Prime Minister of India and other world leaders in connection with COVID-19.  So, what exactly is hydroxychloroquine and how did it become a common household term in such a short time? In this write-up, I will cover the evolution of hydroxychloroquine from ancient to current times. Hydroxychloroquine is a synthetic version of quinine, which is derived from a tree we all know as cinchona. Hydroxychloroquine, which is the less toxic of the two, is generally used as an anti-inflammatory drug to treat rheumatoid arthritis and lupus, particularly in the west (AFP, 2020). Currently many countries are expanding access to hydroxychloroquine and chloroquine.

Cinchona and Quinine

Cinchona, or the quina tree as it is known to the indigenous Quechua people of South America, is a small tree, growing 5 to 15 m (15 to 50 ft) in height, belonging to the family Rubiaceae (Fig 1).  It is native to the western parts of South America, in the Andean forests. From there it spread, and currently is seen as far as South and Southeast Asia in India and Indonesia, where it is cultivated as a crop. There are several theories behind the name Cinchona, one of them being that it was named by the famous botanist Carl Linnaeus as a tribute to the plant curing the ‘Count of Cinchon’. Whether it is true or not, Cinchona has been historically sought after for its medicinal value, as the bark contains several alkaloids including quinine, the only effective treatment against malaria, a disease that was just as devastating as COVID-19 during the height of European colonialism. There has been considerable debate on who is behind the spread of this tree as well as who discovered the medicinal nature of it. This includes claims stating that Italians, Spaniards, Portuguese, British and Dutch as those responsible for its identification and spread, although the original ‘discoverers’ were the indigenous people of South America. However, between late 1600-1800, all these people were dealing with various species of cinchona, predominantly Cinchona officinalis, C. succirubra and C. calisaya, which were introduced to their respective colonies in the old world. Structured research during the early 1800s resulted in the identification of two key alkaloids, quinidine and cinchonidine, in addition to quinine. However, the yield of quinine in all these species was quite low (<3%) which could not produce enough medication for the control of malaria.

In the meantime, Charles Ledger, a French man working in Peru for the British, collected another species from Bolivia. He offered the seeds to the British, but they did not show much interest as they were already distributing another species. Hence Ledger sold the seeds to the Dutch. The Dutch somehow realized the potential of this new species and multiplied the stock. Eventually, this species was named Cinchona ledgeriana to honour Ledger as this species yielded 8 to 13 percent quinine in the bark of trees grown in Dutch Indonesia. Such a high yield essentially outcompeted the British Indian production of the drug. The British, having later realized its potential, obtained the seeds and started growing C. ledgeriana.  Thus, C. ledgeriana became the main species that is still currently used to produce quinine.

Quinine, Hydroxychloroquine and Gin

The connection between quinine and gin goes all the way to the defeat of Tipu Sultan, the ruler of the Kingdom of Mysore. In 1799, when Tipu was defeated by the British, the whole of Mysore Kingdom came under British control. However, soon after the battle, many British soldiers fell sick due to malaria with severe mosquito trouble in the Mysore area. Consequently, the British Army shifted their station to Bangalore (by establishing the Bangalore Cantonment region), which was a welcome change, especially due to a cool weather, but the malaria problem persisted as Bangalore (now renamed Bengaluru) was no exception to mosquitoes. It was around the same time that European scientists discovered that quinine could be used to treat malaria. Quinine was imported and distributed to all their soldiers, who were instructed to take regular dosages to build immunity. However, it was later found that many were not taking quinine, due to its extreme bitterness. This forced the top British officers and scientists to find a way to convince their soldiers to strictly take these dosages. In the process of experimentation, they found when quinine was mixed with Juniper based liquor, it was more palatable. This juniper-based liquor was gin. When gin was mixed with quinine solution that also contained a bit of sugar, it was nicknamed “Gin & Tonic”, which immediately became an instant hit among British soldiers.

To cater to the growing demand of gin and other forms of liquor among British soldiers, the British East India Company built several local breweries in and around Bengaluru, which could then be transported to all other parts of India.  This led to the large number of breweries and liquor distillation factories in Bengaluru. That’s how Gin & Tonic became a popular cocktail and is a popular drink even today. Since that sweetened quinine solution, a.k.a. Tonic was also prescribed for patients who needed a cure for fever, the word “Tonic” became a colloquial word for “Western medicine” in India. However, it must be noted that ‘Tonic Water’ is credited to Erasmus Bond, who introduced it in 1858.  Even now, the ‘tonic water’ that is produced by popular soda companies such as Schweppes’s contain a very low amount of quinine in it. Over the years, quinine was developed further and one such synthetic descendent of quinine is Hydroxychloroquine, which is an effective cure for malaria, and is now suddenly a very sought-after drug in the world today.

Hydroxychloroquine and COVID-19

So how did this ancient drug suddenly become the cynosure of the world? Sometime in late 2019, an outbreak of a viral disease caused by a novel coronavirus started in Wuhan, China and within a few weeks it rapidly spread throughout  China and globally This prompted the World Health Organization (WHO) to declare the epidemic of COVID-19 as a pandemic on March 12th, 2020. Not surprisingly, many research projects around the world began combatting this deadly disease. Since the development and testing of a new drug to treat such a novel viral disease   takes considerable time, researching old drugs for use as an antiviral treatment is an effective strategy because of the pre-existing knowledge on such drugs including safety profiles, side effects, and drug interactions.

Recent studies indicated a potential inhibitory effect of remdesivir (a new antiviral drug) and chloroquine (an old antimalarial drug) on the growth of COIVD-19 in vitro bioassays. Similarly, an early clinical trial conducted on Chinese patients showed that chloroquine had a significant effect in reducing the effects of COVID 19. This prompted the Chinese experts to recommend chloroquine as a possible treatment for COVID 19. At the same time, hydroxychloroquine was also shown to have an effect on COVID-19 and due to its higher clinical safety profile, it was preferred over chloroquine. Based on this, Gautret et al (2020) studied the effect of hydroxychloroquine in a small, open-label study in France and showed that hydroxychloroquine (alone or in combination with azithromycin) might be effective in reducing viral load in nasopharyngeal samples (Fig 3). However, this information must be used cautiously and as per the Canadian Pharmacists Association (CPA) the evidence was conflicting and unconvincing due to small size of experiment, absence of a control group or significant baseline differences between control and intervention groups. Thus, it is premature to determine the effectiveness of these drugs in the treatment of COVID-19. Until more data become available, the CPA classified the use of these drugs as strictly experimental and allowed to be used only by the infectious disease specialists on hospitalized patients.

Figure 3. Effect of hydroxychloroquine and azithromycin on COVID positive (PCR) patients (adapted from Gautret et al., (2020)

Concluding thoughts

Currently, human beings are experiencing a once in a century event, the COVID 19 pandemic. While many leading thinkers thought that we were already overdue for a pandemic, others had the notion that we were equipped to combat anything that is thrown at us. But this pandemic has certainly taught us a lesson that we are not invincible.  That said, a cure is not far away and perhaps we may have already found one in hydroxychloroquine or another similar molecule.

About the Author

Dr. Jayasankar Subramanian is a Professor in Tree Fruit Breeding and Biotechnology at the University of Guelph, Canada. For the past 25 years, he has worked with diverse crop species such as mango, grapes and tender fruits using conventional and contemporary biotechnology approaches. Dr Subramanian has led several provincial, national and International projects including those from the IDRC and released 14 improved plant varieties in India and Canada.


References

AFP, 2020. What is chloroquine and can this decades-old drug cure the coronavirus? https://economictimes.indiatimes.com/magazines/panache/what-is-chloroquine-and-can-this-decades-old-drug-cure-the-coronavirus/articleshow/74839529.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst

Bergman, M.J. 2015. The Nine Lives of Hydroxychloroquine. http://rheumnow.com/blog/nine-lives-hydroxychloroquine

Canadian Pharmacists Association, 2020. https://www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/CQ-HCQ-COVID-FINAL-EN.pdf

Gao J, Tian Z, Yang X. 2020. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. doi: 10.5582/bst.2020.01047

Gautret P, Lagier JC, Parola P et al. 2020. 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. [Epub ahead of print].

Keel, T. Curious Questions: Who invented the gin and tonic? https://www.countrylife.co.uk/food-drink/curious-questions-invented-gin-tonic-206058

Raustiala, K. 2013. The Imperial Cocktail: How the gin and tonic became the British Empire’s secret weapon. https://slate.com/technology/2013/08/gin-and-tonic-kept-the-british-empire-healthy-the-drinks-quinine-powder-was-vital-for-stopping-the-spread-of-malaria.html

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;10-0282.


Posted by Shweta Dixit