We Americans have a long and glorious history of snake oil salesmen peddling useless or sometimes harmful concoctions to desperate rubes suffering all manner of ailments. John D. Rockefeller’s father was just such an itinerant quack. What finer pedigree could you ask for?
It should be no surprise then that here in the US of A we’ve taken the most dubious claims of hydroxychloroquine’s effects on COVID-19, and hyped them from the highest podium in the land: “What do you have to lose?”.
What do you have to lose? Well that hyping has caused unnecessary deaths from the drug’s harsh and sometimes lethal side effects. And the hyping has also caused a stampede on a limited supply of the drug which is needed by patients who have been suffering debilitating chronic diseases long before COVID-19 came along.
So, what is hydroxychloroquine anyways and where does it come from?
A little Googling revealed that hydroxychloroquine is a modification of an earlier drug called chloroquine, which in turn is a synthetic version of a natural drug derived from tree bark that many of us have heard of called quinine. Quinine has a veeery long history as an antimalarial drug, but is also commonly known an additive in tonic water (as in gin and tonic) giving it its characteristic bitter taste. Quinine is a plant alkaloid. Alkaloids can be toxic and are known for their bitterness. Think of caffeine which is a classic alkaloid…
Of course, there is much (much!) more information, with some very smart commentators blogging on current issues with these drugs (Derek Lowe on the Science Magazine website is particularly good).
But rather than spiral into that black hole of technical information, I got distracted and thought the back story was even more interesting…
It all starts with Ana de Osorio, wife of Luis Jeronimo de Cabrera, Count of Chinchon and importantly, Viceroy of Peru from 1629 to 1639.
I love the names and titles.
Ana de Osorio, Countess of Chinchon…
In 1638, the story goes, Ana de Osorio became very sick from malaria. The governor of Loxa wrote to the viceroy claiming to have been cured by the bark of the quinaquina tree. The governor was summoned, the medicine administered, and Ana was cured. Ana returned soon after to Spain bringing this miraculous bark of the tree that was eventually named after her as the Cinchona tree.
It turns out that this story, documented in 1663 by an Italian, Sebastian Bado, was wrong on most counts and was disproved by the discovery in 1930 of the Viceroy’s official diary. Oops. It turns out for example that Ana, the first Countess of Chinchon, died three years before Luis even went to Peru as viceroy. The second Countess of Chinchon who did accompany Luis, was the picture of health the whole time but died on the journey from Peru back to Spain. But the (mis)story of Ana de Osorio persists to this day, like a virus that has become integrated into the DNA of our culture.
The bark of the Cinchona tree nonetheless bent the curve of medical and human history. It was brought by Jesuit priests to Europe where the Spanish apparently knew of the bark’s medicinal value as early as the 1570’s, and was first used to treat malaria in Rome in 1631 (long before the mythical Ana even fell ill).
This bark, also called at the time Jesuit’s bark or Peruvian bark, became one of the most valuable exports from Peru when it became clear that it successfully treated malaria patients in Rome. Rome was once surrounded by marshes, and the name malaria comes from the medieval Italian words mala (bad) and aria (air), as the disease was associated with the “bad air” emanating from swamps. Today we know that the cause of the disease is a single-celled parasite, Plasmodium falciparum, carried by mosquitoes endemic to marshland.
Bad air was a typical medieval Western understanding of disease, consistent with the miasmic theory passed down almost unchanged from the ancient Greeks a couple millennia before then. Microscopic organisms were not even known until Robert Hooke published his findings on them in 1665, followed soon after by Anton van Leeuwenhoek’s observations with his famous homemade microscopes. The role played by some of these microorganisms in human disease was not recognized until Louis Pasteur’s experiments in the 1860’s and Lister’s treatise on antisepsis which was published in 1867. Too late to mitigate the savagery of the American Civil War which killed 2% of the population, most from disease (like malaria) and infection (doctors did not wash their hands or otherwise use aseptic technique while sawing off soldier’s mangled limbs).
But back to Rome where malaria killed indiscriminately: popes, cardinals, priests, and many other Romans rich and poor died miserably from the disease. The Jesuit’s knowledge of this bark’s curative abilities eventually led to its explosive value and demand throughout 17th and 18th century Europe.
The Peruvian quinaquina tree eventually yielded a purified drug, the active ingredient called quinine, in 1820. Pierre Joseph Pelletier and Joseph Bienaime Caventou, the French chemists who discovered quinine, also discovered caffeine and strychnine among many other alkaloid plant compounds.
Quinine as a drug enabled Europeans to colonize Africa. Native Africans had evolved certain traits, associated with sickle-cell anemia and other genetic diseases, which gave them some resistance to malaria. Europeans did not have these genetic characteristics and were much more susceptible to the parasite, and so Africa became known as the White Man’s Grave. Quinine rectified that deficiency and led to the European’s rapid colonization and chopping up of the African continent in a global game of Risk.
The European’s colonial drive took them around the world, and quinine clearly enabled that global competition for territory, resources, and subjects, especially in equatorial and malaria-infested regions of the world. Although quinine is credited with saving many millions of lives over the centuries - one of the unintended consequences was that it enabled the Western power’s colonial ambitions and conflicts, thus setting the stage for the slaughterhouse of World War I and its domino effect of WWII.
Quinine’s bitterness spurred British officials in various early 19th century colonial outposts to mix their medicine with soda and sugar - which is the origin of tonic water. The British in colonial India mixed their tonic water with gin, creating a classic cocktail that still seems embedded in our culture to this day.
The value of quinine rose rapidly causing Jesuit’s bark to be the focus of global games of Risk and Monopoly. Peru and neighboring countries tried to corner the market for their native Cinchona trees, but the Dutch managed to smuggle seeds out of South America. Eventually Dutch plantations in Indonesia became the dominant world suppliers. The wily Dutch outplayed the South Americans and ended up with as much as 97% of the global market and set up a quinine cartel in 1913 to control global supply and prices.
Quinine played a key role in one of the biggest successes and engineering marvels of the 20th century - the Panama Canal, built between 1904-1914 - driven by the big stick policies and willfulness of Teddy Roosevelt. There are many reasons for the failure of the early French efforts to build a canal across Central America, but the immense casualty rate among the engineering and labor forces certainly played a key role in their abandoning the project to the Americans. Tropical diseases such as malaria were a major if not top contributor to French casualties. Central to the success of the American project was the groundbreaking public health initiatives driven by Dr. William Gorgas and his team - and their application of new scientific understanding of malaria and other tropical diseases being transmitted by mosquitos. Mosquito control and prophylactic administration of quinine were among the cornerstones of their efforts.
Malaria also played an outsized role in the number of casualties during the First World War (disease was usually the main killer of soldiers in historical wars, not other solders). Prior to WWI scientists and public health experts first showed major successes in controlling malaria in parts of Europe like Italy and Greece. The implementation of these measures clearly lapsed during the war and afterwards, and malaria became a global scourge again well into the 20th century including in the US. Prophylactic use of quinine was studied and implemented by some countries during the Great War.
The late 19th century into the early 20th were a sort of golden age of synthetic and organic chemistry, and quinine played a Muse’s role in this. Chemists tried to synthesize quinine since it was an expensive natural product (remember the Dutch cartel). Their efforts often failed miserably - but in a classic example of experimental serendipity - the failures sometimes bore fruit. William Perkin’s attempt in 1856 to make quinine resulted in abject failure and a mess, but the mess yielded a brilliant purple dye which made him a fortune. He was 18 years old.
Synthetic organic dyes, triggered by Perkin’s success, were one of the economic foundations of Germany starting in the late 1860s with the formation of well known companies that exist to this day: Bayer, BASF, Hoechst, etc. And a number of dyes were proposed as treatments for malaria, including methylene blue developed by Paul Ehrlich in 1890 and first used by him to treat malaria patients in 1891. Aside from not being as effective as naturally derived quinine, the dye-based malaria drugs had the unfortunate side effect of turning patients various unnatural colors.
Finally, Hans Andersag, a researcher at Bayer AG in Germany, discovered a synthetic version of the drug in 1934 which eventually became known as chloroquine. Bayer ran clinical trials of these drugs in North Africa in the early 1940’s during WWII and this information fell into Allied hands around 1943. US doctors eventually recognized the efficacy of chloroquine, and it was approved for clinical use in the US in 1947.
During WWII millions of US soldiers were given prophylactic antimalarial regimens which resulted in a very unexpected and positive side effect. Clinicians noted reduced symptoms in those suffering inflammatory disorders such as skin rashes and some forms of arthritis after taking the drug. Clinical trials subsequently demonstrated the efficacy of antimalarials for a range of inflammatory diseases starting with systemic lupus erythmatosus in 1951. Today chloroquine analogs are administered off-label (i.e., not approved by the FDA) for a wide range of autoimmune diseases, since they are among the few effective treatments that reduce symptoms. However, we still do not know exactly how chloroquine-based drugs blunt inflammation.
Another positive outcome of WWII was more organizational. The Office of Malaria Control in War Areas, established in 1942, was the immediate predecessor of the CDC which was first known as the Communicable Disease Center when it kicked off on July 1, 1946. Malaria was the first target on its project roster with the National Malaria Eradication Program starting a year after the CDC’s founding. Success was declared by 1951. Spraying DDT was one of the cornerstones of the CDC’s efforts to eradicate the mosquito vector of malaria, while chloroquine was the cornerstone of prophylaxis and treatment of the disease.
Hydroxychloroquine is a modification of chloroquine where a hydroxyl group (-OH) was appended to the side chain to reduce toxicity, and was approved for medical use in the US in 1955.
In the years since chloroquine and hydroxychloroquine were approved in the US, we’ve learned a few things about these antimalarial drugs. We know that these drugs accumulate in lysosomes and inhibit their acidification, which has subsequent effects on a range of cellular processes including antigen presentation. We know these drugs reduce cytokine production by macrophages, and inhibit toll-like receptor signaling and a variety of other immune pathways. But we remain far from causally linking the drugs to these disparate biological effects or ultimately to their clinical efficacy (against malaria or various inflammatory diseases).
Our long history of use with these drugs has given us some insights into their limitations, their side effects and adverse drug interactions. One of the more severe side effects includes something called QT prolongation which is an electrical disturbance of the heart that can lead to fatal arrhythmia. Another is a 30% mortality among patients administered hydroxychloroquine who also took metformin, an important anti-diabetic drug.
In the US, malaria is no longer a significant clinical problem. But hydroxychloroquine and its analogs are prescribed for a wide range of debilitating autoimmune diseases and many patients have come to rely on these drugs.
And for no good reasons, suddenly hydroxychloroquine and chloroquine are being hyped as possible treatments for COVID-19.
There are no placebo-controlled, double-blinded, sufficiently-powered clinical studies that demonstrate the efficacy of hydroxychloroquine against COVID-19. A small clinical study in China was recently released to pre-print suggesting a lack of any effect on viral load. The same study noted a reduction in symptoms and attributed it to hydroxychloroquine’s anti-inflammatory properties. A very recent Brazilian clinical study was terminated early because of excessive and fatal heart complications, one of the long-known side effects of the drug. And a retrospective analysis of uncontrolled and unblinded use of hydroxychloroquine in VA hospitals across the US has shown that there were no benefits and an increased incidence of death associated with use of the drug.
We are reading that diabetics have a worse outcome with COVID-19 and these are the very patients likely taking metformin which is known to have lethal interactions with hydroxychloroquine.
Yet here we are today - still arm-wrestling over the supply of this antimalarial drug as if the Dutch still had a monopoly of the bark-extract. But it is the millions of those suffering from a wide range of autoimmune disorders, not malaria, that are struggling for access to hydroxychloroquine and its analogs today. At least that is here in the US.
In the rest of the world over a million people per year, mostly pregnant women and young children, still die from malaria. But in a typical display of poorly allocated healthcare capital, we spend more for baldness treatments than for antimalarial treatments. Drug resistance has become a significant problem in many parts of the world so the need to invest in more antimalarial drug development is acute - but we still mostly use drugs that are almost a century old.
We’re gradually learning more and more molecular details of the intricate and complex life cycle of Plasmodium falciparum, the malaria parasite. Here are a couple beautiful animations that show how malaria moves through the human host in one video, and in the mosquito host in the other. Increasing this basic biological understanding of the disease is what will enable rational and targeted drug development for malaria - as well as COVID-19.
Enjoy!
And finally, here’s a partial list of the Googling results that I thought were most useful and interesting if you want to dig deeper yourself. I expect I’ve made errors and misinterpretations throughout this meandering story (hopefully not as bad as Sebastian Bado) so feel free to point them out to me - I always appreciate any corrections.
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