Where did cinchona, the first medication to cure malaria, come from? This episode explores the murky history of the bark of the fever tree and its derivative chloroquine with mysterious pre-Columbian Pacific crossings of the plasmodium parasite, Jesuit priests and Inca healers, a Chinese Emperor performing a clinical trial to treat his fever, chemistry leading to the first modern pharmaceuticals, and imperialism on a global scale. This episode is the first of a multi-part series exploring how hydroxychloroquine became the great hope for treating COVID-19.

Sources:

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31. Cook H (2010). Testing the effects of Jesuit’s bark in the Chinese Emperor’s court. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/testing-the-effects-of-jesuits-bark-in-the-chinese-emperors-court/)

Transcript

Please note that the transcript is based off editorial copies of the script and may not be the same as what is in the episode.

This is Adam Rodman, and you’re listening to Bedside Rounds, a monthly podcast on the weird, wonderful, and intensely human stories that have shaped modern medicine, brought to you in partnership with the American College of Physicians. 

What a difference a couple of months can make! As I made my last peer reviewed episode, were were just becoming aware of the breadth of transmission of COVID-19 in the United States, and I had a busy spring planned with live podcasts at the Kaiser Clinical Educators Conference in Portland, OR, and the American College of Physicians national meeting in Los Angeles — and an opportunity to see all my internist friends from various parts of my life. Which, come to think of it,  is the sad consequence of medical training, how much you physically distance from your friends from medical training. But, of course, there’s also all of you guys, all the internist friends that I’ve met through podcasting and Twitter, and this big ol’ virtual medical community.  

Well, at least I was right about it being busy. Instead of traveling with a 15 month-old, I’ve been decked out in full PPE and working with my residents to take care of the deluge of very sick and very scared patients during the COVID-19 “Surge” in Boston. I’m sure that everyone can relate, but in those early days of working on the wards, my mind was in a state of Plague Fugue — full of nervous energy, but really unable to concentrate on anything but the task in front of me. But now that I’ve finished my fourth week on the COVID wards, my anxieties have coalesced into, well, normalcy, including my normal state of curiosity. Now, I want to be very clear here — I’m not downplaying the severity of the disease, because it is bad — not only in what it does to the body, but in how it physically separates patients from their loved ones in their most desperate hours. 

One of the effects of this pandemic has been to make every single doctor — and for the first time since I’ve practiced medicine, our society — put our epistemological chips on the table. How do we evaluate what treatments work best for our patients when your wards are rapidly filling up, when you see health systems pushed to the edge of collapse, and when you and everyone else around is, for lack of a better word, scared? The minutiae of epistemology — how do we obtain knowledge — and efficacy — how do we prove that something works — are suddenly being discussed breathlessly on the news each night.  Remdesivir, boosted lopinavir, decoctions of traditional Chinese medicine, azithromycin, tocilizumab, TPA, and of course chloroquine and hydroxychloroquine. Here’s just a brief clip of some of these: (play clip from Maddow) .

I have watched, as I assume you have, with, let’s just say, a curious dis-ease as these complex questions have increasingly become a chum bucket for all of society’s anxieties. I think this struck me most profoundly when I came across “chloroquine trolls” on Twitter — that the efficacy of this drug in treating COVID-19 had suddenly become a target for partisan trolling.

All of this is a fancy introduction to this episode, which is called “The Fever Tree,” and is the first of several parts. Because the hopes that we have pinned on chloroquine and hydroxychloroquine — both analogues of quinine, which itself is derived from the bark of cinchona, the Fever Tree — is not truly based on science, or at least science the way that we usually think of medical science, even if many of the good-faith actors sincerely feel that way. It, like so much in medicine, is contingent on a history stretching back over 400 years, in mysterious pre-Columbian Pacific crossings of the plasmodium parasite, on Jesuit priests and Inca healers, on a Chinese Emperor performing a clinical trial to treat his fever, on chemistry leading to the first modern pharmaceuticals, and on imperialism on a global scale. In this episode, we’re going to talk about this history and the baggage surrounding quinine; in the next episode, I’ll be joined by Dr. Rahul Ganatra as we talk about how this history led to an unlikely treatment in the first global influenza epidemic and bring the story to the present day, with hydroxychloroquine positioned as a miraculous cure for COVID-19.

Phew, I think that was the longest introduction I’ve ever given. But hey, I’m back from my hiatus, so I think I’ve earned it. So that’s a ton to cover, so let’s get started!

Well, let’s actually, let’s lay out some basic terms first. In this episode, I’m going to be talking about the disease we know today as malaria, stretching from the 16th century roughly to 1880 — so right the point where Laveran first sees parasites in the red blood cells in a military hospital in Algeria, and a decade before Ross describes the entire life cycle of the plasmodium species and later won the 1902 Nobel in Medicine. One of the confusing things about the history of medicine is that we have a tendency to project today’s understanding of a disease backwards in time. It doesn’t help that we continue to use much of the same terminology. This episode is a veritable time travel of epistemological framing. When we start, medicine is still framed as a Galenic understanding of disease, then has some flirtations with Paracelsianism, then redefines disease on a nosological terms before settling on pathological anatomy. And even within the most recent era, we start with a miasmatic theory of disease, flirting with a number of contagionist theories, before finally settling on germ theory. And during this entire period, doctors use the words “malaria,” “ague,” “tertians,” “quartans,” and even simply “fever” to talk about a variety of diseases which also includes the disease we call malaria today. See why it’s confusing?!

So let’s start with a dramatically simplified 21st century explanation of malaria. It’s a disease caused by single-celled parasites of the plasmodium group, which have a complicated life cycle that at some point in medical school I was forced to memorize, but it involves both mosquito and human hosts. I’m massively oversimplifying here, but the parasite first silently replicates in the liver before spreading to the blood, replicating and bursting red blood cells in wave after wave, causing flu-like symptoms and high fevers every 48 to 72 hours, depending on the organism. Plasmodium falciparum is the most common — and most deadly — subtype; P vivax, ovale, and malariae cause milder disease. Malaria is not an “ancient” disease — it still causes a huge burden worldwide, with over 400,000 deaths last year and 228 million cases; these days it’s found in a band surrounding the equator, mostly in Africa where 93% of cases are found. But it wasn’t always this way — malaria has traditionally been endemic throughout the world, and it was only in the middle of the 20th century that the disease was eliminated from North America and Europe. 

But this was not the traditional Western understanding of the disease, where malaria would have been lumped into a general category called “fever.” This goes all the way back to the Hippocratics. Take, for example, in the Epidemics. The author describes the periodicity of fevers with tertian and quartan patterns — every 48 and 72 hours, and he describes an association with the summer and marshes. These clearly match up with our understanding of falciparum and vivax and ovale. But in that same section, he discussed additional fever patterns, including continuous, sub-tertian, quartan, quintans, septans, and nonanes — none of which fit our current understanding of malaria. The traditional Western understanding of “fever” was codified centuries later by Galen, who saw fever as a unitary disease, rather than a symptom as we see it today. Avicenna had given the most quoted and widely understood definition of a fever in the middle ages: “Fever is extraneous heat, kindled in the heart, from which it is diffused to the whole body through the arteries and veins, by means of the spirit and blood, reaching a heat in the body itself which is sufficient to injure the natural functions.” This extraneous, or acquired, heat was viewed through a humoral lens — it was “earthy and fiery” as opposed to the cool and wet innate heat.  From Galen forward, intermittent fevers — especially “tertians” — had been viewed as a specific subtype strongly associated with putrefaction, first for the association with swamps, and second for what appeared to be “fetid” excreta, referring to the tendency to cause blackwater fever, which we now now is caused by massive destruction of red blood cells leading to hemoglobinuria. Treatment, as you can imagine, was humoral in nature, favoring bloodletting in particular, but also calomel and other purgatives.

By the time out story begins, in the sixteenth century, a Galenic understanding of fever remained dominant, but there were some heretical ideas starting to bubble up. The most notable was by Jean Fernel, the French royal who physician, probably best known today for coining the word “physiology.” He argued that there must be a distinction between continuous fevers, and tertians, quartans, and intermittent fevers. This admittedly to us is a subtle distinction — placing intermittent fevers as a first order distinction rather than a second-order —  but the idea of specificity of fevers would have major intellectual consequences when a mysterious new powder from the recently discovered New World came on the scene. 

This powdered bark, cinchona, emerged in 17th century Europe cloaked in mystery. The tree is native to South America, growing in the wet forests of the Andes, far above the dense jungles of the lowlands. But that exact moment that we became aware that the bark had the ability to treat malaria, that it was a febrifuge to use the parlance of the day, is lost in the fog of colonization, and in a civilization that was technologically advanced yet lacked writing. All we have left now are legends, recorded by Europeans,

The first, and most famous, was recorded by the Italian physician Bado is 1663, and tells that story of the wife of Luis Jeronimo de Cabrebra, the Count of Chinchon, which is located right outside of Madrid. The Count was serving as a viceroy in Lima, and as the story goes, his wife fell ill with fever, and was cured by the bark of what was then called “the fever tree”. Greatly impressed by this, the Countess gave the drug to the citizens of Lima, and then imported a large amount back to Europe. This story is almost certainly not true — 20th century historians have analyzed the timeline, and even read the Countess’ journals, and while there was plenty of mention about the Count’s fevers, there was nothing about the Countess falling ill, nor about the bark of the fever tree. Bado’s legend is important, though, because it gave the drug its name — Chinchona is “Cinchona” in Italian, and when Linnaeus gave the plant its scientific name in the 18th century, he used the Italian spelling from the legend. I love that a second-order legend has formed around the name of the drug — it is said that either Linnaeus made an error and left out the “h” in Chinchona, or that his typesetter did. In any event, that one’s not true either; Linnaeus used the Italian name, and wrote “Cinchona’ many times throughout his life, but that hasn’t stopped many generations of passionate physicians and naturalists from insisting that we say “Chinchona” and “chinconism” instead.

The second story is purported to be a native legend. A traveling warrior is overcome with fever, and lies down on the bank of a lake, expecting to die, and takes one last large drink before drifting to sleep. But the lake is surrounded by fever trees, and their bark is slowly decomposing in the lake. When he awakes, he has not only been cured of his fever, but has discovered a potent new medication.

The first written textual mention comes from Augustinian friar Antonio de la Calancha, who was born in the new world in what is now Bolivia, and traveled throughout Peru, essentially a Cathologic proto-anthropologist documenting religious and cultural beliefs from still un-contacted peoples. In 1633, he wrote in an official ecclesiastic booklet:

 A tree grows which they call “the fever tree” in  the country of Loxa, whose bark, of the colour of

 cinnamon, made into powder amounting to the weight  of two small silver coins and given as a beverage, cures the fevers and tertianas; it has produced  miraculous results in Lima.

Antionio uses the name “arbol de calenturas,” literally fever tree, which turns up a lot in the 17th century, The Quechua, or Incan, name is used as well in this period — quina, or quina-quina, the holy bark. In Spanish, this is spelled with a Qui; it’s spelled Cina in Latin and Italian. The historian Jaime Jaramillo-Arango performed an impressive literature review in the 1940s, and concludes that by the 1640s, cinchona had been brought back by Jesuits to both Spain and Italy. 

All of these legends and historical records suggest what seems to be a pretty self-evident fact — cinchona was used as a traditional medicine for fever by healers in the Inca world, which was then introduced to Europeans via the Jesuits, and occasionally by the traditional healers themselves. This is clearly what those writing in the 17th century felt — there are a number of other primary sources from this period, not only Spanish, but Scottish and French all attesting to this fact. Yet this has actually been a product of historical controversy for much of the past two hundreds years, with the majority view actually being that Europeans themselves discovered cinchona. This alternative history comes from naturalists and physicians in the 19th century, who noted that natives were very reticent to use quinine (or really any European medicine), and from that rather arrogantly determined that it could not have been discovered by the Inca. But there has been considerable fairer debate among 20th century historians as well, which mostly hinges on a fascinating controversy that I had no idea about before I started researching this episode — was malaria present in the New World prior to the Columbian exchange? Or was it another horrific disease foisted upon the peoples of South America by colonialists?

There are a couple of fascinating ways to tackle this question. The first is the historical record, which, unfortunately, comes only from Europeans, since the Inca and other people conquered lacked any written language. Arguing against New World malaria are some of the first documents written about Brazil. Pero Vaz de Caminha, for example, wrote on May 1st, 1500 to the King that Brazil “reveals a very promising land, with good air and climate, and a very healthy indigenous population.” The leader or the first Jesuit mission likewise wrote that he had no knowledge of anyone dying of disease, but only old age, and another Jesuit from that mission wrote that the “air was healthy, and people lived into their 90s.”

On the other hand, Jaramillo-Arrango argues that the Emperor Pachachuti’s army was greatly weakened by a fever during his conquest of the Empire — decades prior to European arrival, and that the first two Spanish settlements on the mainland likewise were abandoned because of “fever and other diseases induced by the hot damp atmosphere of the lower stretches of the river.” The challenge with this, of course, is that “fever” hardly is specific for malaria.

Next, the archaeological record. People tend to settle around waterways, so-called “riverine settlements,” and for obvious reasons — rivers provide ample sources of food, water, and transportation. Even today, less than 10% of the world’s population lives further than 10 km away from bodies of water (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110782/). This was even more important in the densely jungled Amazon, where waterways were the main form of transport between settlements. Unfortunately, low-lying bodies of water are also hotbeds of malaria. The archaeological record of riverine sites in the Amazon suggests a population density as high as 18,000 people per 80 hectares, compared to just one family in the same area in the 1970s. The size of these sites as well suggests cities with advanced agriculture supporting far more people than today. There’s also some compelling evidence that this collapse was caused by disease — these sites were abandoned in the 1600s, long before the Portuguese moved inland. 

And now this is where things start to get really interesting — the genetic evidence for pre-Columbian malaria. Based on our latest understanding of migration patterns in the New World, the first migrants moved into the Americas about 15,000 years ago. Given that this was the late Pleistocene from Siberia to Alaska, this group of migrants was exceedingly unlikely to carry plasmodium parasites. Malaria has exerted evolutionary pressures on humans over the millenia, and in places where malaria is endemic — African and Eurasia — we see a number of genetic traits that confer some degree of protection, such as sickle cell disease and trait, glucose-6-phosphate dehydragenase (G-6-PD) deficiency, and Duffy antigen/receptor for chemokines (DARC) negativity. These mutations are all absent from modern-day Amerindian populations. Based on this, by the 1980s the bulk of evidence suggested that plasmodium falciparum at least did not exist in the precolumbian New World and had been introduced by the Portguese, Spanish, and the enslaved Africans that they had brought sometime after contact.

As PCR techniques improved, it also became possible to amplify plasmodium DNA; this technique was first used on a Roman infant, showing plasmodium falciparum in the early 2000s. In 2012, a review of 155 livers and spleens from South American mummies dated between 3,000 to 600 years ago showed that 67% of them showed reactivity to P Vivax, and that actual malarial pigment was present in 30 percent of these. There was no reaction to P. falciparum. 

So pretty convincing evidence of the less serious P vivax being endemic prior to the Columbian exchange. Now here is where things get really crazy — how did P vivax arrive in South America? It has a remarkably long life cycle — the incubation period can last a year, and relapses can happen for up to five years. But the late Pleistocene and the climate of Siberia and Alaska still makes that an exceedingly unlikely route. In 2018, researchers analyzed a group of mitochondrial genomes from a global collection of malarial parasites to try and answer the question of where malaria in South America came from. They confirmed earlier suspicions — the falciparum was indeed from African populations, likely diverging with the slave trade. But the P. vivax was closest related to Melanesia in the Pacific — modern day Fiji, Vanuatu, the Solomon Islands, Papua New Guinea, and East Timor. They conclude that P. vivax was introduced into South America from the “reverse Kon-Tiki route” — essentially by sea, and that the life cycle of vivax would allow for an ocean crossing. I’m just going to quote their conclusion, “These findings are consistent with two founding populations – one from Eurasia and one from Australasia – entering the Americas.”

So how does this all relate to the discovery of cinchona? I think we can likely safely assume that the Jesuits and early naturalists who visited South America were correct. Cinchona, or quinaquina, likely was a long-standing treatment for fevers from P. vivax, which was almost certainly endemic in the region. And it makes perfect sense, since the Inca pharmacopeia was extensive and involved many different natural remedies. It was the far more deadly falciparum that devastated the riverine cities in the Amazon, and like so much about the 19th century, the idea that Europeans themselves discovered cinchona was truly just Western ethnocentrism. 

Back to cinchona. The Catholic Church back in Rome was naturally skeptical of claims of a miracle cure, and Cardinal de Lugo instructed the Pope’s personal physician to perform detailed experiments both on efficacy, and finding the most appropriate dose. These were published in the Schedula Romana in 1649, the pharmacopoeia of the church — and I think this fact is a particularly crazy example of path dependence, but this became the standard for quinine dosing up until the 1970s. The dose, by the way, was to give two drachms of the powdered bark just before the beginning of a paroxysm. I still get confused with apothecary weights, but that is a solid, so 120 grains, or roughly 8 grams in metric. Thank God that we use the metric system in the US for medicine, even if it’s not always SI. When quinine was finally isolated, the dosing was based on an estimation of the amount of quinine in the bark in 1650, which came out to about 5 grains of quinine, or 325 mg.

An early series of Italian physicians felt that the medicine was a game changer — Bado, the  physician who recounted the story of the Countess of Chinchon, wrote that the “Jesuit bark” or Peruvian bark as it was increasingly known was more precious to mankind than all the gold and silver that the Spanish had brought back from the New World. One of my favorite stories from this era actually comes from China. In 1692, the Jesuit priest Jean de Fontenay was summoned from his base in Canton to Beijijng by the Kangxi Emperor. The Emperor had been suffering from a “malignant fever” in Jean’s words, and had tried a French medicinal lozenge (presumably containing some amount of cinchona) with good effec t, but he still had some residual “ague.” The Jesuits were fortunate to have just received a pound of cinchona, which they brought with them to the Forbidden City. The Emperor had summoned all of his citizens suffering from ague to present to the palace. The Jesuits prepared cinchona in the traditional manner, and then four noblemen selected patients in various stages of the disease to take a decoction of the bark. All were cured of the ague with no ill effects. The four noblemen then tried the drug on themselves; they too suffered no ill effects. Only then did the Kangxi Emperor take the drug himself with a complete cure.

You would think that cinchona would spread rapidly after this, but it took well over a century, for several different reasons. First, like I mentioned at the beginning of the episode, medicine was still in a Galenic thrall, perched right before a period of massive intellectual and epistemic shift. I talked about this in the syphilis episode with Tony Breu that I gave at ACP last year, traditional humoral medicine didn’t have room for specific treatments. Cinchona was given not only as a cure for “tertians” and “quartans,” but for all types of fever. As you can imagine, it worked only sporadically, since fevers can be caused by any number of things that are not malaria. Adding to this, there was considerable confusion, especially outside Italy, about whether cinchona was a new drug at all. In the Schedula Romana, it was listed as “Cina”, the Latinization of “quina”. Cina, unfortunately, was also the common name of the medicinal herb smilax (S. china), which led to the widespread substitution. Smilax, unfortunately, does not work against malaria. Add onto this that there are many different subspecies of the fever trees with different amounts of the effective alkaloids in their bark, the risk of rotting on the Atlantic transfer, as well as unscrupulous merchants intentionally adulterating samples, there was plenty of reason for cinchona skepticism. And that’s even before we talk about the Protestant reformation. Cinchona was, after all, the Jesuit’s bark, and its use was seen as an extension of the power of the Catholic church. Oliver Cromwell, dying of malaria in 1658, refused the cinchona offered by his physicians, insisting that he did not want the “Pope-ish remedy” or to be “Jesuited to Death.” He was malaria-ed to death instead, and Charles II was returned to the throne two years later, changing the course of English history. And under Charles II, things started to change, with the irregular (or quack) physician Robert Talbor. Talbor had developed a secret concoction for curing ague, which he described in his treatise Pyretologia. It had four ingredients, two of which were native to England — and one of which was cinchona, presumably obtained from smuggling contacts in Essex. The final ingredient was opium, and it was mixed in a sweet wine to disguise the bitter taste. He too performed a variety of experiments on the citizens of Essex; his reputation grew so great that Charles II appointed him Royal Physician against the wishes of the Royal College of Physicians. He was then sent to cure Louis XIV’s heir, and later even Charles II himself. After Talbor’s death at the age of 39, his secret ingredient was published, with cinchona’s popularity cemented in the Protestant world. 

By the dawn of the 18th century, cinchona was well known around the world. But the concept of fever as a disease starts to change as well. The nosologists, first led by Thomas Sydenham,started to classify diseases based on their symptomatology, and started divvying up fevers to the point that by 1794, Vicq d’Ayzr had described 128 different fevers. I’ve talked about Cullen’s nosology a lot on the show, mostly because of the influence on American physicians. I’ve included a link to his genus “Pyrexiae” if you want to see how sliced and diced them. But one of the ideas of these nosologists was that intermittent fevers were a disease independent of other fevers; by the mid 18th century the Italian word “malaria” when being used as a synonym for tertians and quartans, literally meaning “bad air” and referencing the miasmatic theory of disease that was becoming more ascendent in this period — that noxious odors themselves actually caused diseases. One of the promises of the nosologists — a promise that would never truly be met — was that these new specific diseases would have specific treatments. Sydenham was the first to define malaria by its specific treatment — malaria was an intermittent fever that responded to cinchona. This was not without controversy — likely due to varying preparations of the drugs, a number of naval studies suggested limited efficacy. And it was hard to contextualize positive trials — Robert Robertson, a naval surgeon, compared cinchona with antimony in ship fever in 1789. One of 216 in the cinchona group died, while 19 or 296 in the antimony group died. Robertson felt this was a great win for cinchona — but as modern commentators have pointed out, “ship fever” in this case was almost certainly typhus rather than malaria, and the difference probably had more to do with the toxicity of antimony than the effectiveness of cinchona. And of course, cinchona was also used to treat any number of other, non-malarial conditions with similar enthusiasm, including ulcers, hemorrhoids, neuralgia, and hemoptysis — all conditions that show some degree of recurrence or periodicity. Ultimately, these are all pre-germ theory ideas — the thought was that some periodic miasma led to these conditions, with cinchona somehow interrupted. 

With this new enthusiasm, a proto-scientific medicine started to turn its interest into just how cinchona worked. The first scientific expedition was sent by the French government — Charles Marie de la Condamine set off to South America in 1735, technically as part of the French Geodesic Mission to measure the arc of the meridian in Quito to attempt to finally accurately measure the diameter of the earth, and by extension give the length of “meter” and the birth of the metric system  (which is an awesome story in and of itself), but with a secondary mission to identify and classify the fever free. He found it just where it was first described — 20 miles outside of Loja, in modern day Ecuador. They collected a large amount of the bark to transfer back to France for further study. However, La Condamine had run out of money, and took the far more dangerous route back via the Amazon river, and lost all of his samples in a heavy storm near the mouth. He called the tree “Quina primativa;” but when Linnaeus wrote his classification several years later he gave it the name that stands today: cinchona officinalis. 

As the botanical understanding of the plant grew, the new burgeoning field of chemistry tried to extract the active ingredient. The first French attempts failed –Fourcroy felt that the deep red tannin that he extracted was the source, but his experiments failed. Seguin went even further and extracted gelatin, which he felt could treat fever, and for a few disastrous decades, physicians would prescribe clarified glue for malaria, as well as gelatin-containing wine. I’ve posted to Twitter an absurd bulletin published in 1870 of a French pharmacist who was fined 100 francs for dispensing the French formulary for cinchona wine, instead of the gelatin-containing Seguin’s wine. 

As chemistry and laboratory techniques improved in the early 1800s, pharmacists and chemists got closer to developing an effective isolate, eventually culminating in Pelletier and Caventou’s isolation of a sticky substance that was fully soluble in alcohol, which they called “quinine” to honor the Quechua name of quinquina. Joseph Bienaime Caventou deserves a brief aside — he was a brilliant young toxicologist at the Ecole de Pharmacy in Paris — only 25 when he discovered quinine. After it became clear that their drug was a potent treatment for malaria, they declined to patent their process, and in fact published them freely so that all of humanity might benefit. Other compounds discovered by the two: colchicine, chlorophyll, and caffeine. Not too shabby.

One of the most impressive things about quinine’s discovery is how quickly a movement coalesced to prove its efficacy. Efficacy, of course, refers to whether or not a medication actually works; this is not relevant to this discussion, but in general it is contrasted to “effectiveness,” meaning how well a medication works in a real-world, as opposed to experimental setting. In traditional Western medicine, efficacy was generally taken as self-evident — a medication worked if the patient improved. But in Paris in the 1820s, a huge debate was swirling around the efficacy of bloodletting in treating pneumonia — a debate that largely continues until today. I talked about this extensively in the two parter I did on bloodletting with Shani Herzig a couple years ago. In any event, quinine is probably the first new therapeutic that emerged in a medical culture increasingly aware of the idea of efficacy, and within days of its isolation, quinine had been sent to Francois Magendie for experiments:

This is a quote from Dr. John Elliotson at St. Thomas’ in London on those first safety experiments:

As soon as the two alkalies of Cinchona were discovered, M. Pelletier sent a quantity to Dr. Magendie, who administered them to dogs in large doses without nausea, vomiting, or other apparent result. The indefatigable and acute physiologist then injected into the veins of these animals from two to ten grains of the sulphate and of the acetate of Quinine and Cinchonina in solution, but with no more effect. Satisfied of the innocence of the substances, he ordered the sulphate of quinine to several scrofulous children affected with ulcers, and in a fortnight the most decided benefit was obtained.

Going directly from animal experiments to children with scrofula would not have been my approach, but soon after physicians throughout France were experimenting with quinine on patients with malaria, and generally finding the treatment effective. Very quickly, a very interesting debate emerged.  I wouldn’t say that quinine was the first pharmaceutical; the industrial and chemical processes that would begin that industry were another 50 years away in Germany. But like morphine, isolated a decade before, it was among the first active medications extracted from a medicinal plant. And doctors asked a very legitimate question — why should a plant extract be used, more difficult and costly to make, when cinchona bark was widely available?  

Throughout the 1820s, a number of studies sought to allay these concerns. The aforementioned Elliot, for example, performed a study of quinine in 16 patients with tertians and quartans, many of whom had already failed treatment with cinchona. His dose, by the way, should sound familiar — 5 grains every six hours — 325 mg. Every patient was cured, with the only mild side effects of vomiting. 

He concludes:

Quinine is nothing but the new form of an old medicine, but presented in such a way that no intermittent fever can resist it … It is very true that Quinine and Cinchonina cannot strictly be called new medicines, because they exist, one or both, in the Cinchona which we have all been prescribing. The patient has only to take a pill, and is spared the annoyance of swallowing any of the mass of inert powder which remains after the extraction of Quinine, and which frequently, whatever may be the disease, so disgusts him, or so oppresses his stomach, and deranges his system at large, that bark cannot be borne in efficient quantity, or at all: and, what is particularly interesting, we find that they succeed when bark has failed – that they cure cases of intermittent fever which have resisted bark, although perfectly well borne, and freely administered.

The findings of the efficacy of quinine helped to cement a new view about malaria — the disease increasingly became defined as a fever that responded to quinine. If it didn’t respond, it wasn’t malaria. But it was also responsible for launching the most influential of the alternative medicine movements in the 19th century — homeopathy. Samuel Hahnemann, after reading about cinchona’s ability to cure fever, dosed himself with the drug, and soon after developed a horrible fever himself. From this he developed his “Law of Similars,” that like cures like, and the fundamentals of homeopathy were born. Of course, cinchona and quinine do not cause fevers. Hahnemann most likely had a hypersensitivity reaction, which still occurs occasionally with tonic water (and there was a fascinating case in NEJM last year about this which I will put in the show notes).

Quinine quickly became a weapon of Empire. By the 19th century, a second wave of imperialism was propelling Europeans (and the Japanese) into equatorial and tropical areas of the world. Endemic malaria had led to the demonym “The White Man’s Grave” for Western Africa, but there was the perception that Europeans were especially susceptible to malaria in regions they were entering throughout the world, including Southern Africa, India, and Southeast Asia. A LONG time ago — right before I went to Botswana, for that matter — I produced an episode about the physician-cum-missionary David Livingstone, who was one of the earliest people to use quinine in his journeys. His pill combination was called “Livingstone Rousers” and remained popular into the 1920s. Given this, it was unsurprising that it was the British military that would pioneer the use of quinine for both prophylaxis and treatment. As early as the late 1700s, James Lind had recommended cinchona be carried by naval vessels to suppress and treat malaria. That is, of course, the famous James Lind who performed arguably the first randomized controlled trial in history, and argued for citrus to prevent scurvy. By 1814, the British admiralty had placed cinchona in the medical chest of all ships; it was replaced by quinine in 1830, though it took until 1847 for the first comparative studies to be published between cinchona and quinine for preventing malaria.  

The conclusion, which led to quinine being issued as standard on both British and American ships:

“As the sulphate of quinine is more certain in its action, infinitely less nauseous than bark, and therefore less objectionable to fastidious people, it should invariably be preferred for exhibition: whether it be given in wine, water, or rum is of no great consequence: the latter will generally be the most acceptable to seamen, although they will seldom object to it in wine.”

That brings us to the most obvious tangents on quinine and Empire — cocktails. Quinine wines, or quinquinas, are no longer used medicinally, but their popularity lives on in a variety of apertifs, most notably Dubonnet, which was my father-in-law’s favorite digestif, and Lillet Blanc, which more famously was in James Bond’s vesper martini, made with Lillet Blanc instead of vermouth. And of course, quinine powder was also dissolved in soda with sugar as a tonic to cut the bitter flavor. By 1870, Schweppe’s had begun to sell “Indian Quinine Tonic” — and add in a soldier’s gin ration, and you have the cocktail gin and tonic. “Indian Quinine Tonic” is known today as tonic water, and still enjoyed in many a G+T today — though in the US, the quinine content is limited to 83 ppm, or 83 mg/L. In comparison, a serving of “Indian Quinine Tonic” had 5 grains, 325 mg, in far less volume. In any event, this light history of tonic water betrays a much darker ironic fact — that a product taken from the first wave of imperialism, cinchona, ended up being essential to the second wave of Imperialism. Now, some modern historians have taken umbrage with placing too much importance on quinine. The French in particular barely used quinine  and did just fine seizing a large portion of the globe. But this was certainly the opinion of the British at the time; the British Surgeon Major in India famously quipped in 1897, “to England, with her numerous and extensive Colonial possessions, it is simply priceless; and it is not too much to say, that if portions of her tropical empire are upheld by the bayonet, the arm that wields the weapon would be nerveless but for Cinchona bark and its active principles.”

This has already been more than I ever thought I’d talk about quinine, but I finally want to mention that quinine was not the only alkaloid extracted from cinchona. There was cinchonidine, cinchonine, and quinidine, all used to treat malaria as well, and optochin which was used to treat streptococcus in the early 20th century. One of the major side effects of all the cinchona alkaloids is prolongation of the QT interval — that is, it lengthens the electrical signalling in the heart that controls the contraction and relaxation of the ventricles, which can in turn cause arrhythmias and even sudden cardiac death. Shortly after the EKG was invented, Wenkebach first noted that quinine could be used to treat atrial fibrillation, and by the 1910s it had been noted that quinidine has the most effect on the QT, and started to be used as what we would today call a class I antiarrhythmic. 

So this brings up to 1889, where I will pick up with Dr. Ganatra next time. Quinine’s place in the world looks very different by this time. Malaria is understood to be a likely infectious disease, though no one is quite sure what the causative organism is. Quinine’s use is widespread, both in the general public dissolved in various alcohols, mostly wine, but also prescribed by physicians. And while it is used, in fact, as a very effective treatment for malaria, it is used in a variety of other febrile circumstances as well. Osler, in his first edition of Principles and Practice of medicine, lists pneumonia, rheumatic fever, gout, tuberculous adenitis, acute myelitis, and most notably for our story, influenza as indications worthy of treating with quinine. But the world is about to explore with the first truly global influenza pandemic, and quinine will become the go-to treatment. In the next episode, Rahul and I will discuss how the world dealt with the first global flu pandemic and later the Spanish Flu, and trace how we got to the point that the quinine derivatives chloroquine and hydroxychloroquine somehow became the great hope for COVID-19. 

That’s it for the show! And guys, I am so excited to be back! Working on this podcast was almost a form of therapy for me — I love that I start looking into a clinical question about hydroxychloroquine, and then a couple hours later start delving into the literature about carbon dating and performing PCRs for P. vivax in the livers and spleens of ancient mummies. Especially as COVID-19 has really narrowed the focus of medicine, it’s a great reminder that our practice is truly tied in with the rest of humanity. In any event, what started as a “short” has now morphed into a multi-part episode — with part 2 coming next month! So let me know what you thought!