Cinchona bark is one of the most important naturally occurring drugs in the medical pharmacopoeia. Although the circumstances surrounding cinchona's discovery in Peru in the early part of the 17th century are clouded by unreliable sources, apocryphal ornament, and botanical confusion, there is little doubt that cinchona bark was the first specific treatment for malaria, or indeed for any other disease, in Western medicine. Given the wide geographic distribution of malaria, and the high rates of morbidity and mortality associated with the disease, it is probably no exaggeration to say that cinchona is the remedy that has spared, or at least ameliorated, the greatest number of lives in human history. Indeed, cinchona bark is one of the most enduring antimalarials ever discovered, and will probably continue to have benefits for the treatment of severe and drug-resistant malaria well into the 21st century.

A member of the Rubiaceae (madder) family, Cinchona, according to the latest classification, comprises 23 species of plants (Andersson, 1998). Broadly speaking, the genus consists of evergreen shrubs or trees distinguished by their ovate or lanceolate finely veined leaves, arranged in pairs at right angles to one another, and by their capsular fruit containing numerous winged albuminous seeds. The fruit dehisces from the base into two valves that are held together at the apex by a thick permanent calyx, while the flowers are tubular and can be rose coloured or yellowish white (see Figure 2.1). Unfortunately, species of cinchona are so much alike that they can only be distinguished by resorting to a number of morphological characteristics that, taken singly, are of no great significance. Historically, this has led to taxonomical confusion, particularly since until the early 18 th century no European botanist had described the tree and naturalists had to attempt a classification solely on the basis of bark imported to Europe from South America. Even after the studies of Ruiz and Pavon (1792) and Weddell (1849, 1871), confusion remained with some botanical authorities listing as many as 36 species, while others listed 33.

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FIGURE 2.1 C. ledgeriana in flower. (Copyright 2000, Merlin Willcox.)

Although cinchonas are now cultivated throughout the tropics (Figure 2.2), the genus is native only to South America, occurring between 10° North latitude and 22° South latitude, a range corresponding roughly to Merida in Venezuela and Santa Cruz in Bolivia. The average altitudinal range is 1200 to 3000 meters, but species of cinchona have also been found below and above these limits. The most important species from a pharmaceutical and commercial point of view are Cinchona ledgeriana of Bolivia, Cinchona succirubra of Ecuador, and Cinchona officinalis of Ecuador and Peru.


Variously known in earlier historical periods as quinquina, Peruvian bark, or Jesuits' bark, cinchona bark is indelibly associated with the name of the earliest and most illustrious patient to have supposedly benefited from its antimalarial action — Francisca Henriquez de Ribera, the fourth Condesa (Countess) de Chinchón. The tree was assigned the botanical nomenclature Cinchona by the Swedish botanist Carl von Linné, or Linnaeus, in his Genera Plantarum of 1742, presumably to memorialise the story of the Countess of Chinchón's cure in Lima with a maceration of powdered bark. In the process, Linnaeus inexplicably left out the first h in Chinchón, resulting in the spelling

FIGURE 2.2 Cinchona plantation in Mandraka, Madagascar. (Copyright 2000, Merlin Willcox.)

that persists to this day. However, as the medical scholars Haggis (1942) and Jaramillo-Arango (1949) have shown, the story of the countess's cure is almost certainly apocryphal, and the origins of the discovery and entry of the bark into the materia medica remain a matter for conjecture.

The earliest reference to the febrifugal properties of the cinchona tree comes in a book by an Augustin monk, Father Antonio de la Calancha, published in Barcelona in 1638, but bearing a Lima imprimatur dated 1633. De la Calancha (1638) writes:

There is a tree of "fevers" in the land of Loja, with cinnamon-coloured bark of which the Lojans cast powders which are drunk in the weight of two small coins, and [thereby] cure fevers and tertians; [these powders] have had miraculous effects in Lima.

The next reference comes in Father Bernabé Cobo's History of the New World, first published in 1653 (Cobo, 1943). Cobo devotes a whole chapter of his book to the Arbol de Calenturas (Fever Tree), agreeing with de la Calancha that the tree is found in Loja, has a cinnamon-coloured bark, and that the febrifuge is taken as a powder "to the weight of two reales, in wine or some other liquid." Cobo also writes that the bark is coarse and very bitter and that its powders "are now very well known and esteemed, not only in all the Indies but in Europe, and are urgently sent for and demanded from Rome."

However, from the point of view of the history of taxonomical and etymological confusion surrounding the identification of cinchona, the most significant entry in Cobo's book is contained in another chapter, entitled "Quina-Quina." Cobo's description of quina-quina makes it clear that this was the original Quechua term for the Peruvian balsam tree, Myroxylon peruiferum, and not, as later European naturalists erroneously argued, for cinchona. The resin of the balsam tree achieved popularity as a remedy for various ailments at a much earlier date than cinchona (Haggis, 1942). Monardes of Seville (1574) wrote about its medicinal properties, and the French savant CharlesMarie de la Condamine (1738) reports that the Jesuits of La Paz exported the bark to Rome in the early 17th century, where it was distributed as a febrifuge. However, de la Condamine mistakenly claimed that quina-quina was the original Peruvian term for the cinchona tree, and that quina was the Quechua term for "cloak" or "bark." In French, the compound Indian word was written as quinquina, hence the term commonly applied to cinchona bark from the late 17th century onward.

In fact, quina does not appear in any Quechua dictionary. However, there are entries for quinua-quinua, meaning "a certain leguminous plant so-called," which in all probability refers to the seed pods of the balsam tree that at first sight have the appearance of a legume (Jaramillo-Arango, 1949). In all probability the reason for the confusion is that for some time the medicinal properties of cinchona were little appreciated and merchants illicitly exported it to Europe in substitution for, or mixed with, the bark of the balsam tree, where it was distributed under the same name, quinaquina, or quinquina. Indeed, the merchants of Loja soon began referring to cinchona bark as Cascarilla, meaning "little bark," a term that implies comparison with the bark of another, more superlative tree, presumably Myroxylon (Haggis, 1942). The later substitution of the popular terms Jesuits' bark and Peruvian bark for cinchona did little to clear up the confusion, as both could also be applied to the balsam barks that, like cinchona, the Jesuits had introduced to Europe from Peru.

The origins of the discovery of cinchona's febrifugal powers are similarly fraught with confusion and error. The early Spanish religious chroniclers locate the discovery of cinchona to Loja, a province in the far north of what was once the Spanish Viceroyalty of Peru, now southern Ecuador. But they are mute as to who first applied the bark to the treatment of malarial fevers, leaving open the possibility that the knowledge may originally have been transmitted to the Jesuits by native Indian healers. Unfortunately, there are two major problems with this theory. The first is the complete absence of cinchona in the hieroglyphics and archaeological remains of the Inca, or in the lists of Indian remedies recorded by Spanish chroniclers of the conquest, such as Nicolas Monardes (1574). The second is that it is widely accepted that malaria almost certainly did not exist in South America prior to Columbus, but was imported from the middle 16th century onward, first by Spanish colonists and later by black Africans brought to the Americas as slaves by the Spanish, Portuguese, and British. Although cinchona bark has other medical applications — to this day it is used by native healers in Ecuador to treat diarrhoea, to induce labor, and as a dentrifice* — it is thought that the probable absence of malaria prior to the Spanish conquest means that native American Indian peoples could not have known of its specific application to the disease. Moreover, it is also considered unlikely that they would have used cinchona bark to treat other types of fevers, as quinine initially raises the body's temperature, thus seeming to exacerbate the symptoms of an infection (Hobhouse, 1999). It is only in the specific case of malaria that quinine is also an antipyretic. But even then it acts slowly, and its effect is not apparent for at least a couple of days. De la Condamine, Humboldt, and Spruce — scientists who traveled in Loja and other parts close to the time of cinchona's discovery — all commented on the native Ecuadorians' aversion to Cinchona precisely because its chemotherapeutic action was counterintuitive to their medical prejudices, namely, that fevers should be treated with calafrios (chilled drinks) and colds with hot infusions.

On the other hand, it is known that the Yanomami in the northern Amazon region of Brazil responded quickly to malaria introduced in the 1980s by gold miners. They had never seen it before and quickly tried their various febrifuges, finding that the most bitter worked the best. This information spread throughout the Yanomami region (Milliken and Albert, 1997). It is possible that this empirical approach may have led Ecuadorian traditional healers to try known remedies for the new disease and to find that quina-quina worked. If this were the case, they would probably have kept the remedy secret from their Spanish enemies until the Jesuits had converted them to Catholicism. However, there is no evidence for this, and it is equally likely that the Jesuits first discovered the application through their own experimentation. They are known to have been excellent empirical scientists, and it was their custom to examine native remedies to see if they could be applied to other diseases.

In 1801, while passing through Loja, Ecuador, the German geographer and naturalist Alexander von Humboldt (1821) observed that while

* Information supplied to M.H. by Jorge Mendietta, an Ecuadorian herbalist, during a visit to the cinchona forests of Hinuma, near Vilcambamba, Ecuador.

agues are extremely common ... the natives there ... would die rather than have recourse to cinchona bark, which, together with opiates, they place in the class of poisons exciting mortification. The Indians cure themselves by lemonades, by oleaginous aromatic peel of the small green wild lemon, by infusions of Scoparia dulcis, and by strong coffee.

Von Humboldt (1821) insists categorically that the antimalarial properties of cinchona bark were discovered by the Jesuits. He claims this occurred by chance when they were testing various trees that had been felled in the forest in Loja:

There being always medical practitioners among the missionaries, it is said they had tried an infusion of the cinchona in the tertian ague, a complaint which is very common in that part of the country.

Unfortunately, Humboldt does not say how he came by his information, and his conclusion that "this tradition is less improbable than the assertion of European authors ... who ascribe the discovery to the Indians" [my italics] suggests that he was unsure of his source.

Ironically, given the subsequent doubts that have been cast on the story, the best evidence that South American medical historians can produce for the pre-Colombian knowledge of cinchona is the legend of the Countess of Chinchón's cure. The story was first recorded by Sebastiano Bado (1663), physician to the influential Spanish cardinal Juan de Lugo and later the head of Genoa's two city hospitals. According to Bado, he derived his information from a letter written by an Italian merchant, Antonius Bollus, who had lived for many years in Peru and who had told him that the countess had fallen ill in Lima "thirty or forty years before" — thus placing the time of her cure in 1623-1633. Unfortunately, Bollus's original letter is missing or lost, so the only account that we are left with is the one contained in Bado's book. According to Bado, the countess was suffering a "tertian fever, which in that part is by no means mild but severe and dangerous."* When news of her illness reached Loja, the corregidor (governor) of the province wrote to her husband, the Viceroy of Peru, to inform him of a remedy for fever prepared from the bark of the tree that grew there. The viceroy summoned the governor to Lima, where he verbally confirmed what he had written in his letter in the presence of the countess. "Having heard this, she decided to take the remedy, and after taking it, to the amazement of all, she recovered sooner than you can say it," writes Bado.

Bado continues, quoting Bollus, that "the bark was known to the Indians and that they used it upon themselves in disease; but that they always tried with all means in their power to prevent the remedy becoming known to the Spaniards, who of all Europeans particularly aroused their ire" — presumably because of their leading role in the conquest of Peru and subjugation of Indian culture. The other significant details he gives are that after the countess's recovery, she ordered large quantities of the bark to be sent to her in Lima, whereupon she distributed it free to the sick and, after her return to Spain, to tenant farmers on her husband's estates at Chinchón, near Madrid. As in Lima, the remedy was distributed in powdered form, gaining the familiar name pulvis comitisae (countess's powder).

Subsequent to Bado a number of important details were added to Bollus's account. In 1737, de la Condamine and the French botanist Joseph de Jussieu arrived in Ecuador on a scientific mission for the French Academy of Sciences. Although their main object was to measure one degree of latitude at the equator, de la Condamine and de Jussieu also made a study of the cinchona forests and questioned the Lojans about the origins of the remedy. According to de la Condamine (1738), local legend had it that the Indians had discovered the bark's febrifugal powers after observing

* Before the identification of malaria with specific plasmodia, the disease was defined by the interval between attacks: thus Plasmodium vivax was known as benign tertian because of the relative mildness of the paroxysms and the fact that the fever occurred every second day, with the remission coming on the third day; Plasmodium malariae was known as quartan because the attacks occurred every fourth day; while Plasmodium falciparum was known as malignant tertian or pernicious fever because of the severity of the attacks, lasting anywhere from 24 to 36 hours, with only about 12 hours of intermission.

pumas, who suffered their own form of intermittent fever, drinking from a lake that had been suffused with the trunks of fallen quinine trees. De Jussieu (1936) was more specific, writing that "it is certain" that the discovery was owed to the Malacatos Indians, a tribe who had settled in a malarious valley near Vilcabamba, some 60 miles south of the town of Loja:

Since they had endured much suffering from the hot and humid climate and from intermittent fevers, they were forced to find a remedy against the maladie aussi importune. After experimenting on various plants, they discovered that the bark of quinquina was the last and almost unique remedy against intermittent fevers.

According to de Jussieu, the Malacatos Indians called the cure yarachucchu carachucchu, meaning "bark of the tree for the cold of fevers," or simply ayac cara — "bitter bark." The Spanish had discovered the secret around 1600 when a Jesuit was passing through Malacatos and fell ill with fever. Taking pity on him, the local cacique (chief) offered to cure him and went to fetch some bark from the nearby mountains. On his return he prepared an infusion and the missionary recovered. According to de Jussieu, the Jesuits later noticed similar trees growing throughout Peru and exported the bark to Spain.

De Jussieu makes no mention of the legend of the countess's cure. However, de la Condamine incorporated the story as told by Bado into his account, adopting at the same time the usage quinaquina, which had first been used by Bado. In addition, de la Condamine added new details, including that it was not the corregidor but the viceroy's physician, Juan de Vega, who suggested the countess take the powder and who, on her recovery and return to Spain in 1640, brought a quantity of the bark with him, selling it at Seville, a then very malarious area of Spain, for an English sovereign an ounce (about £75 an ounce in today's money).

In fact, as Haggis (1942) has shown, neither Bado's nor de la Condamine's versions can be true for three reasons. First, Doña Francisca Henriquez de Ribera, the fourth countess of Chinchón, died on January 14, 1641, in Cartagena. In other words, she never returned to Spain and thus could not have brought cinchona with her to Madrid. The records do not give the cause of her death but suggest that it was from some epidemic disease then sweeping the Colombian port — most likely yellow fever. Second, from 1630 to 1638 the viceroy kept a meticulous diary in which he never once refers to his wife suffering a tertian or any other recognisably malarial fever, although he does mention her other ailments. Finally, records show that de Vega never left Peru but continued to practice medicine in Lima until at least 1650.

The confusions and contradictions surrounding the discovery of cinchona's therapeutic properties and the correct identification of its barks inevitably fueled medical scepticism about the remedy. This scepticism was compounded by the fact that for the first 100 years of knowledge of the cure no European botanist had seen the tree in nature. All that was known was that cinchona barks came in four distinct colours — red, yellow, orange, and gray — and that each produced powders of varying efficacy.

The first reference to what may have been the use of cinchona in medical practice came in Belgium in 1643, when a public health official in Ghent recommended a powder, pulvis indicus, for the treatment of tertian fevers (Jarcho, 1993). The first indisputable reference, however, is the Schedula Romana, a handbill issued by the Pharmacy of the Collegio Romano in 1649 and again in 1651, containing precise instructions on dosage and administration. Entitled "Instructions for the Use of the Bark Called Fever Bark," the Schedula says the bark has been imported from Peru under the name China Febris and should be administered, in the case of tertian fevers, as a finely ground or sieved powder to the amount of 2 drachms (a quarter of an ounce or 8 g) in a glass of strong white wine "three hours before the fever is due and as soon as the shivers begin, or the first symptoms are noted" (Jaramillo-Arango, 1949). The Schedula also says that constant use of powdered bark has "cured practically all the patients who have taken it." But while it cautioned that the remedy should be administered only by competent physicians, other doctors were far from ready to accept the Roman claims that cinchona was a specific treatment for tertian and other intermittent fevers.

For instance, John Jacob Chifflet (1653), physician to Leopold William, Archduke of Austria, Belgium, and Burgundy, penned a critique, Exposure of the Febrifuge Powder from the American World, describing the archduke's failed treatment the previous year with cinchona for a double quartan fever. Remarkably, Chifflet managed to both defend his treatment of the archduke and attack the use of cinchona bark at the same time. Chifflet had treated the archduke with cinchona, but when his malaria had relapsed a month later, instead of taking more bark the archduke became angry and ordered Chifflet to warn the public against the powdered febrifuge. Accordingly, Chifflet explained how the bark merely lengthened the intervals between fever attacks and did not cure the disease. Challenging Rome's advocacy of cinchona, he pointed out that though the bark had been introduced into Belgium by the Jesuits, it was not needed, as many other febrifuges were available.

Chifflet's book was interpreted as an affront to the authority of the influential Spanish cardinal Juan de Lugo, then the leading advocate of cinchona therapy. In 1644, de Lugo had instructed the Pope's physician, Gabriel Fonseca, to subject cinchona to empirical study. Fonseca's report was favorable, and as a result, de Lugo had begun distributing the bark gratis to the poor of Rome from his palace, and at the Hospital of Santo Spirito, where it was known as pulvis cardinalis or pulvis Jesuiticus — "Jesuits' bark." In 1649, at a gathering in Rome of the Jesuit Order, de Lugo recommended the powder to the assembled delegates, ensuring the remedy's dissemination to missions throughout Europe (Duran-Reynals, 1946). The meeting also coincided with the arrival in Seville of large, regular shipments of cinchona from Peru, and under the supervision of the Jesuits it was soon being traded on mercantile exchanges where it acquired the popular name Peruvian bark.

In 1655, Honoré Fare, a Jesuit priest and nonphysician who used the pseudonym Antimus Conygius, was instructed to reply to Chifflet, possibly at the instigation of de Lugo and Fonseca, both of whom approved his work. Fare described how the powder had cured more than 100 people in Rome, including cardinals, princes, and high government officials, as well as many poor people.

More important, from the point of view of convincing sceptical physicians elsewhere in Europe, may have been the defense of the bark mounted by Roland Sturm, a native of Louvain who practiced medicine in Delft, the center of a large outbreak of quartan fever in 1657-1658. Sturm (1659) listed 13 cases in Belgium of quartan and tertian fevers, describing how in most instances the Jesuit prescription of two drachms of powdered bark had sufficed to quell the attacks, although relapses were frequent. Sturm mentioned the difficulty of determining from which plant the drug was obtained, but reproduced the Schedula Romana in both its original Italian and a Latin translation, commenting that the authorities in Rome would not have allowed it to be printed unless a proper investigation had been made (Jarcho, 1993).

Despite these eloquent defenses, however, the correct administration and optimum dosage remained largely a matter of guesswork. Although some physicians recommended administering cinchona in the intervals between fever attacks, others prescribed it only at the height of the paroxysm. Moreover, the efficacy of a dosage could vary widely depending on the way the febrifuge was prepared and the amount of cinchona alkaloids in a particular species of bark.

In England, the adoption of cinchona therapy was further hampered by Puritan prejudices against so-called Popish remedies and the deliberate obfuscation by quack practitioners such as Robert Talbor. Talbor enjoyed considerable success promoting a cure for the ague — as malaria was known in England — the formula for which he deliberately kept secret. Born in Cambridge, he had settled on the coast of Essex — then one of the most malarious regions of England — to experiment with different combinations of bark, gradually perfecting his own mixture of powders. In 1671 he moved to London and the following year published his Pyretologia, or a Rational Account of the Cause and Cure of Agues in which he boasted that he had developed a secret remedy for tertian and quartan agues consisting of four ingredients, two of which were native to England, the other two from abroad (Dobson, 1988). After curing Charles II of fever in 1679, Talbor was made physician to the royal household and granted a royal patent.

Pandering to the prejudices of his native countrymen, Talbor cautioned against Jesuits' powder, warning that while it was an excellent cure when properly administered, it could also lead to convulsions. This was disingenuous to say the least, as it gave the impression that cinchona bark was absent from Talbor's own mixture. In fact, as was shown after his death in 1681, it was the major ingredient — along with a little wine and opium. Indeed, in his book The English Remedy, published posthumously by Louis XIV — a lifelong malaria sufferer who had paid Talbor 2000 louis d'or for his proprietary secret — Talbor wrote that "quinquina ... is without contradiction the surest of all the simple febrifuges, so is it the only basis of the English Remedy" (Jarcho, 1993).

In fact, cinchona was almost certainly used in England as early as 1655 (Baker, 1785). The Mercurius Politicus, one of the earliest English newspapers, contains in several of its editions for 1658 — a year remarkable for the prevalence in England of an epidemic remittent fever — advertisements offering for sale "the excellent Powder known by the name of Jesuit's Powder, which cureth all manner of Agues, Quotidian, Tertian and Quartan," brought over by James Thompson, merchant of Antwerp. And in 1677, cinchona bark was officially listed in the London pharmacopoeia under the name Cortex peruanus (Jaramillo-Arango, 1949).

Nonetheless, Talbor was probably the first to carry out clinical trials. One reason for his success may have been his access to the best species of Peruvian bark via his smuggling contacts in Essex. Indeed, some physicians appear to have suspected Talbor of cornering the market in red bark — one of the species now known to be richest in quinine (Dobson, 1988). Unfortunately, Talbor left no record of his purchases or details of his studies, so we do not know if the conjecture is true and whether as part of his clinical observations he included control groups.

No doubt in part due to Talbor's obfuscation and deceit, other English physicians were reluctant to embrace the implications of his results. Thomas Sydenham, often described as the Hippocrates of English medicine, who began practicing in Westminster around 1656, rejected the use of Peruvian bark in the treatment of tertian fevers in 1666 and again in 1676. Sydenham considered that the bark was only valid for the treatment of quartan fevers, although even in these cases he argued its effects were temporary. It was not until 1679 that Sydenham declared himself unequivocally in favor of Peruvian bark, describing it as "his sheet anchor," and in 1683 as "that great specific for intermittent fevers." Sydenham's method consisted of administering an ounce of finely powdered bark made into a pill and divided into 12 parts, 1 part being taken every 4 hours, beginning immediately after the paroxysm (Jarcho, 1993).

However, it fell to an Italian, Francesco Torti, to conduct the first systematic studies of the action of cinchona on different types of fever. In his Therapeutice specialis of 1712, Torti clearly identified cinchona as a specific therapy for intermittent, as opposed to continued, fevers, which he held were rarely treatable with cinchona. In particular, Torti emphasised the importance of cinchona in the treatment of pernicious intermittents or severe quartan fevers and carried out a series of trials in which he experimented with different dosages and methods of administration. As a result of these observations, Torti concluded that while the procedure described in the Schedula Romana was appropriate for simple cases of tertian fever, in the case of more complicated tertians and pernicious fevers the dosage should be increased. He held that this was particularly important at the start of the illness, with up to 6 drachms being given in divided doses when the paroxysm was most intense, up to a total of 20 drachms (2V2 ounces) spread over 3 weeks in the most severe cases (Jarcho, 1993).

At the beginning of the 19th century more rigorous study of the therapeutic action of cinchona became possible thanks to the isolation of alkaloids via new chemical techniques. The first to succeed was Bernardino Antonio Gomez, a Portuguese naval surgeon. In 1812 he soaked powdered gray bark in alcohol and added caustic potash (potassium hydroxide) to the solution to crystallise out an alkaloid to which he gave the name cinchonino. But the real breakthrough came 8 years later in France when the chemists Pierre Pelletier and Joseph Caventou subjected the yellow and red cinchona barks to similar analysis. By further precipitation and crystallisation, they discovered that the base febrifuge was not cinchonino but two alkaloids that occurred separately or together in different kinds of bark. The first they called cinchonine, the second they called quinine.

The isolation of the cinchona alkaloids opened the way for comparative studies of their antimalarial action, although initially medical interest focused almost exclusively on quinine. In 1820, a French physician, F.J. Double, treated several patients diagnosed with different types of intermittent fever with quinine sulfate. In each case, he reported, they recovered. In 1821, another doctor, Auguste F. Chomel, experimented with quinine sulfate, cinchonine sulfate, and cinchona bark. He reported that of 13 individuals struck with intermittent fever and treated with quinine sulfate, 10 were cured. The three who failed to respond to quinine were then treated with cinchona bark only for it also to prove ineffective (Smith, 1976).

Although these trials were hardly scientific — not only did the dosages vary, but there were no controls — such reports quickly convinced the medical profession that quinine was superior to cinchona bark, and by 1822, quinine had superseded nearly all other remedies for intermittent fevers in both Europe and the U.S. Even when faced with results that were seemingly contradictory, the medical profession preferred quinine. In 1823, for instance, Francis Baker of Dublin reported on 30 cases of quinine therapy he had collected with the assistance of four other Dublin physicians. In four cases an effort had been made "to ascertain whether the sulphate of [quinina] would prove efficacious in cases which resisted the use of cinchona," and on each occasion the quinine succeeded where the bark failed. Yet in another case, where his supply of quinine had been exhausted, Barker reported that "the cure was completed by cinchona" (Smith, 1976).

Interestingly, it was commercial and political considerations, rather than medical ones, that would prompt further examination of the cinchona alkaloids. In 1860, the India Office, concerned that the South American forests were being overexploited and that supplies might soon be exhausted, sent a series of collectors to the Andes to gather the five most valuable species of cinchona for transplantation to the government plantations in India. These missions, which were coordinated by Clements Markham, a civil servant and historian attached to the India Office, met with mixed success. Although Markham's intention had been to proceed to Bolivia to gather the highest quinine-yielding species, known at the time as Cinchona calisaya, at the last moment he was forced to change his plans. Instead, he proceeded to Peru to collect an inferior type of C. calisaya, and a species known as C. officinalis from southern Ecuador. But neither did well in the Indian plantations, and instead, government horticulturists concentrated on propagating C. succirubra — the species of red bark that had been forwarded to the plantations from central Ecuador by another British collector, Richard Spruce (Honigsbaum, 2001). This species contained near equal amounts of the four antimalarial cinchona alkaloids, and as the Indian government's priority was the production of a cheap febrifuge that would be affordable to the mass of Indians affected by malaria, a decision was made to conduct clinical trials to ascertain whether the various alkaloids were as efficacious as quinine at treating infections.

In 1866 the secretary of state for India ordered the establishment of cinchona commissions in Calcutta, Madras, and Bombay, staffed by medical officers tasked with conducting the experiments. Scientists had yet to identify the malaria parasite, so instead of microscopic examination of blood smears, the medical officers had to rely on their readings of patients' symptoms to determine whether the alkaloids had cleared the disease. There were also no controls. Instead, each of the alkaloids was administered to a different set of patients and the results tabulated (see Table 2.1).

The commissions' conclusion was that quinidine and quinine possessed "equal febrifugal power," while cinchonidine was "only slightly less efficacious." Even cinchonine, "though considerably inferior to the other alkaloids, [was] notwithstanding a valuable remedial agent in fever" (Markham, 1980).

Markham used the commissions' findings to call for the manufacture of a "mixture of all the alkaloids which would combine cheapness and efficacy in the highest degree." Other quinologists, such as John Eliot Howard, a leading quinine manufacturer, were even more enthusiastic, arguing

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