Quinine
Malaria has plagued humanity for several millennia. The Nei Ching mentioned it more than 2000 years ago, as did the Ancient Greeks: Hippocrates wrote of the symptoms in his 400 BCE book “On Airs, Waters, and Places,” relating it to poor air, especially in the summer. Although miasmas (noxious vapors once thought to cause disease) are no longer accepted as a clinical basis for malaria or anything else, the name this disease acquired during the reign of miasma theory in Europe has persisted: “mal’aria” comes from Italian words “mal” and “aria” (meaning “bad,” “sickness,” or “ache,” and “air” or “climate,” respectively). The Sushruta Samhita, from the 6th century BCE, attributed malaria symptoms to insects, an understanding that was still not directly embraced — as my fellow Little House on the Prairie readers will know — as late as the nineteenth century in parts of the western world.
Next day he [Pa] had a little chill and a little fever. Ma blamed the watermelon. But next day she had a chill and a little fever. So, they did not know what could have caused their fever’n’ague. No one knew, in those days, that fever’n’ague was malaria, and that some mosquitos give it to people when they bite them.
– Laura Ingalls Wilder, Little House on the Prairie (NY: Harper Collins, 1981), 198.
Malaria sufferers numbered in the hundreds of millions in 2012, leaving hundreds of thousands dead. This fact has spurred global action from organizations such as the Bill and Melinda Gates Foundation, which has donated $456 million as part of their PATH Malaria Vaccine Initiative alone. Concerns today include drug resistance, vaccination coverage, and mosquito eradication, but until the time of World War I, fighting malaria came down to the bark of one genus of South American tree.
The Plant
The Cinchona plant, a genus of small trees, is native to South and Central America. Several species were additionally cultivated in Southeast Asia after European naturalists brought seeds there illegally in the mid-19th century. These plants usually have small, pink or white flowers and can be as tall as 50–65 feet high. Because they are native to the Andes mountains region, they have the capacity to grow at very high elevations.
The bark of the cinchona tree is high in alkaloid compounds, including cinchonine, cinchonidine, quinidine, and quinine. The two of these that have the most widespread use as drugs are quinine, used to treat malaria, and quinidine. Unlike quinine, quinidine is a Class I anti arrhythmic, meaning that it functions to combat heart rhythm problems by reducing the electrical stimulation to the cardiac muscle cells. It accomplishes this by interrupting sodium pumps in the cells’ membranes. Quinine, however, is considered both an antimalarial and a skeletal muscle relaxant. It fights malaria by disrupting both the parasite’s ability to copy DNA and its metabolism. Interestingly, it is active against and used in cases of chloroquine-resistant malaria.
History
In the early 17th century, Jesuit missionaries to the Andes region learned of the power of cinchona bark from indigenous populations. This fact is the origin of two other names for cinchona, Peruvian Bark or Jesuit’s Bark. The common story for the name cinchona, that it derives from the title of one of the earliest Europeans cured by it — The Countess of Chinchón, a Spanish Viceroy’s wife — has been mostly rejected, but we do know that it was brought to Jesuit colleges around the early or mid seventeenth century.
In 1820, Quinine was first isolated as a crystal. More than a century later, in 1944, d-quinotoxine was synthesized for the first time by Robert Burns Woodward and William von Eggers Doering at Harvard University. They claimed that per the results of two other scientists, Paul Rabe and Karl Kindler, who synthesized quinine from d-quinotoxine, their technique could be used to make quinine entirely from scratch. However, Woodward and Doering faced heavy criticism from contemporaries for not actually finishing the conversion. Then, in 2008, a team at the University of Colorado validated Woodward and Doering’s work by finishing the procedure. Gilbert Stork, one of the original critics of the Harvard team and himself a quinine researcher, postulated that they were afraid of tarnishing the excitement of the possibility of synthetic quinine — a major triumph in a time when the drug was desperately needed for military personnel sickened by malaria — by producing a low volume of quinine or impure final results. Regardless, the Colorado group showed that even under the conditions with which Woodward and Doering had worked in the forties, they had been absolutely correct about the possibilities of their technique and — had they tried — could have successfully finished the synthesis.
Malaria
One cannot talk about quinine without also mentioning malaria itself. It is caused by parasites of the Plasmodium genus, the most prevalent (and thus dangerous) two species being P. falciparum and P. vivax. A week or two after a bite from a mosquito carrying the parasite, an infected person will develop a fever and symptoms such as headache, chills, and vomiting. Treatment must be prompt, or else malaria can become severe, sometimes with the involvement of multiple organs, and will often be fatal. In children, anemia, respiratory distress, or neurological problems such as epilepsy can result from P. falciparum infection.
When a clinician recognizes malaria, it is usually categorized as either uncomplicated or severe, depending on the symptoms with which the patient presents. For those whose infection is uncomplicated, treatment usually consists of orally administered antimalarial medication. Severe infections, however, often require intravenous (IV) administration of antimalarials. For infections acquired in the Caribbean and Middle East, chloroquine or hydroxychloroquine is given, not quinine. Unfortunately, chloroquine-resistant malaria is endemic in many areas of the world. In the case of an infection acquired in these areas, the first drugs given are Coartem and Malarone, with quinine in addition to doxycycline, tetracycline, or clindamycin being the second option. Children are treated in much the same way as adults, but using smaller doses.
What about glowing tonic water?
Yes, tonic water glows blue under black light! It absorbs UV light, which we cannot see, and emits visible light, which we can. Tonic water owes this surprising effect to the small amount of quinine dissolved in it; quinine is a “fluorophore,” or a compound that can absorb and re-emit light. Quinine was one of the first compounds known to be fluorophorescent, and its characteristics led the National Institutes of Health to develop the spectrofluorometer.
British officers in India dreamt up the gin and tonic in the nineteenth century as a delivery mechanism for the quinine they needed to take in order to combat malaria, endemic in their new station, but not at home. Today’s tonic water contains less quinine than was drunk by the combination’s inventors, so if you enjoy the flavor, your risk of side effects is low.
Cross-posted from The Sickroom
