Quinine and Cinchona
In the sixteenth century, a serendipitous discovery led to a treatment for the ague. In the Viceroyâs Palace in Lima, Peru, the beautiful Countess of Chinchon lay gravely ill with the ague. Her husband, the Count, fearful she would die, called the court physician to provide a remedy, but none was at hand. In desperation, the physician obtained a native Indian prescription: an extract from the bark of a tree growing in the Andes Mountains. The concoction was given to the Countess in a glass of wine, and the symptoms abated. The physician was rewarded, the Count relieved, and the Countess returned to Spain where she lived happily thereafter. The remedy that had been provided, and called by the Indians of Peru âquina-quina,â literally âbark of barks,â came to be known in Europe as the Countessâ powder or the Countessâ bark. This story of the Countessâ recovery from her afflictionâsurely it must have been malaria that she hadâcirculated for 300 years in Europe; regrettably the story appears to be a fable. Who then first introduced fever bark into Europe? The most plausible explanation (and this is only a guess) is that the medicinal effect of the bark was discovered by the Spanish missionaries who came to Peru four decades after Pizarroâs conquest of the Incas, and either by following the practices of local Indian herbalists or by trial and error its fever-curing properties were found.
Malignant fevers were so common in Europe during the seventeenth and eighteenth centuries that there was an increased demand for the powdered bark. The Jesuits through their missions had easy access to the bark; arranged for the collection of the bark in Peru, Ecuador, and Bolivia; powdered it, and then sold it in Europe for the benefit of the Society of Jesus. Because the Jesuit fathers were the promoters and exporters of the remedy, it was called Jesuitsâ bark or Jesuitsâ powder.
In the 1600s, Jesuitsâ bark was used almost everywhere in Europe; however, in one country, where the ague was a national calamity, it was shunned. The England of 1650 was âPuritan England,â and there was general prejudice against the Roman Catholic Church. Oliver Cromwell (1599â1658), the nationâs Protector, was a zealous guardian of the Protestant faith who hated both the papacy and Spain. As a result, no one had the temerity to bring to England a medicine sponsored by the Vatican and known by the abhorrent name, Jesuitsâ powder. Although 2 years after the death of Cromwell (from malaria!) the first prescription of the powder in England was written the medicine did not become popular until 1682 when Robert Talborâs âsecret for curing malariaâ was disclosed.
Talbor, almost unknown today for his work with fever bark, was born in Ely in 1642 in the ague-ridden English fens and was determined to find a cure. He was not trained as a scientist, nor was he a member of the Royal Society of London, and he did not read or write in Latin as his medical contemporaries did. In 1661, Talbor was working as an apothecaryâs assistant and had access to Jesuitsâ bark, which he was quick to recognize its value if administered safely and effectively. He left his apprenticeship and conducted âfield studiesâ on ague patients in the Essex marshes using different formulations and procedures. In 1672, he was appointed one of the Kingâs Physicians in the Ordinary and styled himself as a specialist in fevers, and when in 1678 he was called to Windsor Castle and successfully cured the ague-suffering King Charles II, who knighted him for his service, Talborâs fame spread and in sympathy for his friends in France, King Charles allowed Talbor to visit the French court where he cured the Dauphin of his fever. The secret of Talborâs cure became a subject of intense interest and in 1679 the Dauphinâs father, King Louis XIV, paid a large sum for the secret, provided it was not revealed until after Talborâs death. In 1682, following Talborâs death King Louis XIV published the remedyâthe English âbitter solution.â There was no real secret; rather, it was the simplicity of the method for administration and the dosage. He gave larger doses more frequently and rarely bled or purged his patients. The Jesuitsâ powder, infused with white wine to disguise its bitter taste, was sprinkled with the juices of various herbs and flowers and given immediately after the fit. One piece of information not revealed was which of the several different kinds of barks he used. Now the challenge for the rest of the world was to discover the kinds of bark that would have the greatest effectiveness against malaria.
The rising demand for the new remedy and a desire to better understand the trees that produced the useful bark led to a series of botanical expeditions to the New World to find trees in the wild that would ensure a predictable supply of high-quality barks. The earliest, in 1753, was sponsored by the French Academy of Sciences. The specimens were sent to Carolus Linneaus, the Swedish naturalist. Wishing to immortalize the name of the Countess of Chinchon, Linnaeus gave the tree the name Cinchona. However, in his Genera Plantarum (1742) and his Materia Medica (1749), he misspelled it, leaving out the first âhâ of the Chinchon family name; despite the error, Cinchona remains enshrined as the name for the fever bark tree. Linnaeus prepared the first botanical description of two species, although only one, C. officianalis, had any fever-reducing properties.
Cinchona trees, of which there are 23 different kinds, grow in a narrow swath in cool climates on the slopes and valleys of the Andes; the trees do not grow lower than 2500 ft or higher than 9000 ft above sea level, and the forests are thick with hornets, mosquitoes, and vicious biting ants. The hardship of collecting the bark was considerableâthe climate was variable; there was often a thick mist, sunshine alternated with showers and storms, and temperatures were near freezing. As a consequence, bark collection was relegated to the Indians, called cascadores or cascarilleros, who had found a clump of the desirable cinchona trees in the dense forest and proceeded to cut away the surrounding vegetation, removing the vines and parasitic plants that encircled the trunk; the bark of trunk was then beaten and longitudinal and circular cuts were made; and the tree was felled and the bark stripped. Slabs were dried over an open fire; the thickest parts were dried flat and the thin pieces from the branches were rolled into tubes. Both were packed into bales or put into sacks and transported down the torturous mountain trail to market. Until 1776, nearly all the bark collected was from C. officinalis.
The active component of the cinchona bark was unknown until Pierre Pelletier and Joseph Caventou isolated it in 1820. Pelletier was the son of a French pharmacist and had begun his work at the Ecole de Pharmacie in Paris and later became a retail apothecary in Paris. Caventou was another young Parisian pharmacist with a penchant for plant chemistry, who assisted Pelletier. The two began working on the bark in 1818 when Pelletier was 32 and Caventou 25. Both already had experience with other plant extracts including the isolation of strychnine and emetine. An alcoholic extract of the bark did not produce a precipitate when diluted with water; however, when alkali (caustic potash or potassium hydroxide) was added, it produced a pale yellow gummy substance that could be dissolved in ether, water, or alcohol, and they named the bitter-tasting alkaloid quinine after the Indian word âquina-quina.â Pelletier and Caventou took out no patents for their discovery or the manufacture of quinine (as would be the common practice today); however, in 1827, the French Institute of Science rewarded them with a small sum of 10,000 francs. Pelletier began to manufacture quinine commercially in 1826, and in that same year a Swiss apothecary, Riedel, began its manufacture in Berlin for which he received $8 per ounce. In 1823, Farr and Kunzl (Philadelphia) manufactured quinine, and in 1824, Rosengarten & Sons (Philadelphia) began to manufacture the âessenceâ of the cinchona bark, actually quinine sulfate, a more soluble salt that had the advantage of being more easily swallowed than powdered bark and was less likely to induce vomiting. Both firms eventually merged with the German company Merck, and in 1837, it began to prepare quinine sulfate. This company was purchased by Engelmann & Boehringer, and in 1892, one of the Boehringer familyâs partners, Friedrich Engelhorn, became the sole owner, though he kept the name Boehringer. Boehringer became the biggest manufacturer of quinine and quinine products, and under Engelhornâs stewardship, a new company seal and trademark was designed, featuring a branch from the cinchona tree.
By the 1840s, export of the bark to Europe from the Andean republics amounted to millions of tons. The Spanish government stepped in and funded expeditions that found several new species of cinchona. In 1844, Bolivia passed laws that prohibited the collection and export of seeds and plants without a license because 15% of the countryâs tax revenue came from bark exports. The idea was to protect their monopoly, to discourage reckless stripping of the forests, and to prevent smuggling. In 1852, the Dutch sent a botanist to Bolivia and Peru, who narrowly succeeded in obtaining cinchona seeds that were used to start a plantation in Java in 1854. By 1850, the British had decided that a controlled supply of cinchona was necessary. The British Army in India estimated that it needed an annual supply of 1.5 million pounds in order to prevent 2 million adults from dying of malaria in India, and rehabilitating the 25 million survivors of malaria would require 10 times as much. And then there was Africa with a malaria fever rate up to 60% in some regions. In 1860, a British expedition managed to procure 100,000 seeds of C. succirubra that were used for plantings in British India and Ceylon. Because it had a quinine content of only 2% when compared to 17% from the red bark cinchona C. calisaya from Bolivia, it was a financial failure, and by 1900, the entire British venture was found to be unprofitable and a million trees were destroyed. Clearly, the seeds obtained by the Dutch and British were not of the best yielding varieties of cinchona growing in the Andes.
The most successful collector of cinchona seeds was a short, barrel-chested Englishman, a real cockney, Charles Ledger (1818â1905). At the age of 18, Ledger was working as a trader in alpaca wools in Peru. Ledger collected a herd of alpacas and walked them more than 1500 miles over the mountain passes from Bolivia to the coast of Chile where they were sent to Australia. However, the enterprise failed; the flock was decimated by disease, and finally broken up and sold leaving Ledger bankrupt. He returned to Peru making friends with the Indians and local traders; by living in the cinchona area, he was able to differentiate between the less and more active barks. Knowing of the world market for Jesuitsâ bark, he sent his servant Manuel Incra Mamani, a Bolivian cascarillero, to search for seeds from a stand of 50 huge C. calisaya trees that they had seen in flower in Bolivia 9 years earlier (1851) during the exploration of a mountainous passage for alpacas. Mamani was gone for 5 years because four April frosts destroyed the flowers and prevented the ripening of the fruit to produce seeds. But finally in 1865, he succeeded. He had walked more than 1000 miles from Bolivia to bring the seeds to Ledger. Sent out again by Ledger to collect more seeds, he was seized by the Bolivian officials who had banned the collection and export of the seeds. For refusing to tell for whom he was collecting, Mamani was imprisoned, beaten, starved, and robbed of his possessions. At last, he was set free only to die shortly thereafter from his ill treatment.
In 1865, Ledger sent 14 pounds of the high-quality seeds to his brother George in London, who attempted to sell them to the British government. The British government was not interested, and so the remaining half was sold to the Dutch for about $20. Within 18 months, the Dutch had 12,000 plants ready to set out and 5 years later their analyses of the bark showed the quinine content to be between 8% and 13%. To honor Ledger, this high-yielding species was named C. ledgeriana. Experimenting with hybrids and grafting onto suitable rootstocks, the Dutch developed the worldâs best cinchona treesâand used a process for obtaining the bark that did not destroy the tree. Ledger eventually retired to Australia where he received a miserable pension from the Dutch and in 1905 died in poverty; he was buried in a pauperâs grave in Sydney. In 1994, a tombstone was erected in his memory bearing the inscription âHere lies Charles Ledger. He gave quinine to the world.â There is, however, no monument to Manuel Incra Mamani.
The Dutch formed a cooperative, the Kina Bureau in Amsterdam, to control quinine production. Consequently, by 1918, 90% of the bark from Java, which represented 80% of the worldâs production, was sent to Amsterdam and distributed by the Kina Bureau. At the outbreak of World War II, Java had some 37,000 acres of cinchona producing more than 20 million pounds of bark a year. The Dutch quinine combine had created what amounted to the most effective crop monopoly of any kind in all history.
The Synthesis of Quinine
On December 7, 1941, the Japanese attacked Pearl Harbor, and as a consequence, the United States declared war. With the Japanese occupation of Java, the worldâs supply of quinine became limited (at the time 90% of the worldâs supply came from Java). With the shortage of quinine, there was a push by the U.S. military to synthesize quinine. News on the breakthrough in the synthesis of quinine by William Doering and Robert Woodward of Harvard University was heralded in the May 4, 1944, edition of the New York Times with the title: âSynthetic Quinine Produced Ending Century Search.â The article went on to state: âthe duplication of the highly complicated architecture of quinine molecule was achieved and ⊠considered it one of the greatest scientific achievementâs of the century.â And in the June 5th edition of Life magazine, an article appeared that was titled âQuinine: Two Young Chemists End a Centuryâs Search by Making Drug Synthetically from Coal Tar.â The Science Newsletter stated that starting with 5 pounds of chemicals, they had obtained the equivalent of 40 milligrams.
Although Woodward had promoted the synthesis of quinine beginning as early as 1942, his immediate aim was not for the use by the military, but for commercial purposes because he was supported by contracts from Edwin Landâs Polaroid Corporation with the objective of finding synthetic alternatives to quinine as a precursor to light polarizing molecules. (Land was the inventor of instant photography using his innovative Land Polaroid camera.) Woodward and Doeringâs synthesis was not amenable to commercial production, however. Indeed, their strategy for synthesis would have cost 200 times more than the naturally derived product if, indeed, it was at all feasible. Moreover, it would have taken years of research to optimize the process and to reduce the price, and by that time there were alternative synthetic drugs.
Today, approximately 300â500 tons of quinine and quinidine are produced each year by extraction of the bark from cinchona trees. Approximately 40% of quinine is used in pharmaceuticals, whereas the remainder is used by the food industry as the bitter principle in soft drinks such as bitter lemon and tonic water. (Because tonic water contains only 15 mg of quinine per liter the drink has little antimalarial benefit.)
Quinine is still used occasionally in the treatment of severe falciparum malaria. Because of its slow action and rapid elimination, it is administered not by mouth but by slow intravenous infusion at a loading dose of 20 mg/kg body weight over 4 h, followed by maintenance doses of 10 mg/kg infused over 2 h every 8â12 h. If intravenous administration cannot be used, then it is given by intramuscular injection.
Despite its use for centuries, we still do not know precisely how quinine works, but we do know that it works only on the blood-feeding stages of malaria parasites. Malaria parasites have a unique apparatus (cytostome) for the ingestion of the red blood cellâs hemoglobin, placing this in food vacuoles where by the action of protein-digesting enzymes the globin portion is broken down into smaller fragments (peptides and amino acids), releasing the potentially toxic-free heme that is polymerized into the inert, crystalline, golden brown-black, nontoxic, malaria pigment. It ha...