Quinine

• 1. Introduction

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  Quinine is the reason that, behind many bars, the tonic water button on the soda gun is marked with a single letter, Q. That letter stands for a bitter compound taken from the bark of a tree native to Peru. Using it against malaria marks the first known time a chemical compound was used to treat an infectious disease. It still appears on the World Health Organization's List of Essential Medicines. How did a bark from Peru end up in hospitals, on battlefields and in cocktail glasses? Who controlled the supply, and what did that control cost the people who gathered it? And why does a substance so prized come with such stern warnings today?

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• 2. The Bark Of Bark

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  Among the Quechua people of Peru, Bolivia and Ecuador, ground cinchona bark was stirred into sweetened water to stop shivering. The sugar hid the bitterness, and the result was something close to tonic water. Spanish observers noticed. By the 1570s, Nicolás Monardes in 1571 and Juan Fragoso in 1572 had each described a tree whose bark made a drink for diarrhea. That tree was later identified as cinchona.

  Rome in the 17th century supplied the demand. Malaria was endemic in the swamps and marshes around the city, and it had killed several popes, many cardinals and countless ordinary Romans. Priests trained there knew the shivering of the fever stage well.

  In Lima, a Jesuit named Agostino Salumbrino, who lived from 1564 to 1642 and trained as an apothecary, watched the Quechua use the bark against shivering. The shivering that bark calms and the shivering of malaria have different causes, yet the bark worked against malaria anyway. Salumbrino sent a small quantity to Rome for testing at the first opportunity. Bark extracts were treated as a malaria remedy since at least 1632, and Jesuit missionaries returning from the New World brought it to Spain as early as 1636. Known as Jesuit's bark or Peruvian bark, it became one of the most valuable commodities shipped from Peru to Europe.

  At the end of the 17th century, King Charles II was cured of malaria with it, and the remedy became fashionable in London. In 1737, Charles Marie de La Condamine identified the form of the bark that worked best. A popular tale credits the Countess of Chinchon with bringing the bark to Europe, but the medical historian Alec Haggis debunked it around 1941.

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• 3. Frontier Fever Pills

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  In central Missouri, a man named John S. Sappington began importing cinchona bark from Peru in 1820. Working on his own, he turned quinine from that bark into a pill. By 1832 it was ready, and he aimed it at a range of fevers, including scarlet fever, yellow fever and influenza, as well as malaria. Those illnesses were widespread across the Missouri and Mississippi valleys.

  He sold the product as Dr. Sappington's Anti-Fever Pills. Demand grew so fast that within three years he founded a company, Sappington and Sons, to sell the pills across the country.

  Quinine also reached the medicine shelf in other forms. Bromo Quinine, a brand of cold tablets made by Grove Laboratories, was first marketed in 1889 and stayed on sale until at least the 1960s.

  All of these products rested on bark from Peru, a supply that Peru and its neighbors had already begun trying to lock down.

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• 4. Empire And Monopoly

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  One historian wrote that "it was quinine's efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa." The availability of the drug has been called the prime reason Africa stopped being known as the "white man's grave." Large-scale use of quinine to prevent malaria began around 1850.

  Peru and surrounding countries tried to protect their monopoly by outlawing the export of cinchona seeds and saplings in the early 19th century. In 1865, Manuel Incra Mamani collected seeds from a plant unusually rich in quinine and gave them to Charles Ledger. Ledger sent them to his brother, who sold them to the Dutch government. In 1871, Mamani was arrested on another seed-collecting trip. He was beaten so severely that he died soon afterward, probably because he had given seeds to foreigners.

  By the late 19th century, the Dutch were growing cinchona on plantations in Indonesia, and they soon became the main suppliers. In 1913 they set up the Kina Bureau, a cartel of producers charged with controlling price and production. By the 1930s, Dutch plantations on Java were producing 22 million pounds of bark, which was 97% of the world's quinine. American attempts to prosecute the Kina Bureau failed.

  That grip on the world supply held until Germany conquered the Netherlands.

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• 5. Cut Off In War

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  When Germany conquered the Netherlands and Japan took control of the Philippines and Indonesia, the Allied powers lost their quinine. The United States had obtained four million cinchona seeds from the Philippines and began running cinchona plantations in Costa Rica. It also sent teams to harvest wild cinchona bark in what were called the Cinchona Missions.

  The supplies came too late. Tens of thousands of American troops in Africa and the South Pacific died of malaria for lack of quinine.

  Controlling the supply did not save the Japanese either. They did not make effective use of the quinine they held, and thousands of Japanese troops in the southwest Pacific died of malaria.

  After the war, quinine lost its place as the first choice against malaria. Other drugs with fewer side effects, such as chloroquine, largely replaced it.

  Wartime pressure also sent chemists searching for a way to build quinine from scratch.

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• 6. Quinine In The Lab

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  In 1820, the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou first isolated quinine from the bark of a Cinchona tree, probably Cinchona pubescens. They named it from the Quechua word quina or quina-quina, which means "bark of bark" or "holy bark." Until then, the bark had been dried, ground to a fine powder and stirred into a liquid, commonly wine.

  Adolph Strecker worked out its molecular formula in 1854. Quinine is an alkaloid, a naturally occurring chemical compound, and it contains a quinoline group, which is a pyridine ring fused to a benzene ring. The family of related compounds became known as the cinchona alkaloids.

  In 1856, William Henry Perkin tried to synthesize quinine and failed. Instead he discovered mauveine, the first synthetic organic dye.

  A formal synthesis was finally achieved in 1944 by the American chemists R.B. Woodward and W.E. Doering. Several more efficient syntheses have followed, but none can compete economically with extracting the alkaloid from nature. Cinchona trees remain the only practical source.

  Quinine also glows. Its ultraviolet absorption peaks around 350 nm, and it emits a bright blue-cyan light at around 460 nm. In 0.1 M sulfuric acid its fluorescence quantum yield is about 0.58, a value steady and well known enough that photochemists use quinine as a standard for measuring fluorescence.

  Chemists have also put quinine to work in other reactions. It and quinidine supply the chiral part of the ligands in Sharpless asymmetric dihydroxylation, a method for controlling which mirror-image form of a molecule gets made. Quinine-catalyzed addition of malononitrile to certain enones gives a high degree of that same control.

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• 7. Narrow Margins

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  Against the parasite Plasmodium falciparum, quinine works by interfering with its ability to dissolve and metabolize hemoglobin. The leading explanation, borrowed from the closely related drug chloroquine, is that quinine blocks the parasite from crystallizing heme into hemozoin. Toxic heme then builds up inside the parasite and kills it. The precise mechanism has still not been fully resolved, and quinine may also target an enzyme called malaria purine nucleoside phosphorylase.

  The gap between a helpful dose and a harmful one is narrow. The usual trouble is cinchonism, which brings headache, sweating, nausea, ringing in the ears, dizziness, blurred vision and disturbed color perception. Severe cases bring vomiting, deafness, blindness and disturbed heart rhythms. Oral quinine is exceedingly bitter, and many people vomit after swallowing the tablets.

  Other reactions are less predictable. Quinine can cause a dangerous drop in platelets, long QT syndrome with serious arrhythmias, and blackwater fever. Some people who developed one blood disorder from it went on to kidney failure. It also strongly inhibits an enzyme called CYP2D6, and it boosts the anticoagulant effect of warfarin.

  The United States Food and Drug Administration received 157 reports of health problems tied to quinine between 1969 and 1992, including 23 deaths. In 1994 it banned the over-the-counter marketing of quinine for nocturnal leg cramps. Pfizer had been selling Legatrin for that purpose, and SmithKlineBeecham sold a softgel called Q-vel. A further warning in 2010 made off-label prescribing for cramps less common. Malaria is life-threatening, so the risks are judged acceptable when quinine treats it.

  Since 2006, the World Health Organization has not recommended quinine as a first-line malaria treatment, because other drugs work equally well with fewer side effects. It advises using quinine only when artemisinins are unavailable. In the United States, quinine sulfate is sold by prescription as Qualaquin in 324 mg tablets. The Centers for Disease Control and Prevention reported only 1,347 confirmed cases of malaria in the country in 2004.

  The record includes darker uses. For much of the 20th century, an overdose of quinine was a relatively common method of ending a pregnancy in various parts of the world, including China. Quinine has also turned up as a cutting agent in street drugs such as cocaine and heroin. Veterinary use is gentler: it treats white spot infection, caused by Cryptocaryon irritans, in marine aquarium fish.

  Even the small amounts found in common beverages can cause severe reactions in some people.

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• 8. Glass And Bar

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  In France, quinine flavors an apéritif called quinquina, also sold as Cap Corse, and the wine-based Dubonnet. Spain blends it into sweet Malaga wine to make Malaga Quina. Italy infuses the traditional wine Barolo Chinato with quinine and local herbs and serves it as a digestif.

  Tonic water began as a way to deliver quinine as protection against malaria. According to tradition, British colonials in India found the bitterness hard to take and mixed the tonic with gin, creating the gin and tonic. A person can drink enough tonic water to reach protective levels of quinine for a while, but that is not a sustainable way to prevent the disease.

  Britain's A.G. Barr uses quinine in Irn-Bru, a carbonated and caffeinated drink. In Uruguay and Argentina, it goes into a PepsiCo tonic water called Paso de los Toros. In Denmark, Royal Unibrew puts it in the sports drink Faxe Kondi.

  Regulators set ceilings on the bitterness. As a flavoring, quinine is limited to 83 ppm in the United States, 85 mg/L in Taiwan and 100 mg/L in the European Union. The United States also allows cinchona bark itself in beverages, with the same 83 ppm cap on total cinchona alkaloids in the finished drink.

  Some of that bitterness may not come from cinchona at all. The bark of Remijia contains 0.5-2% quinine, costs less than cinchona bark and tastes intense, so it is used to make tonic water.

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