Fevers have always haunted mankind and several ingenious remedies were tried to combat the fevers. In the ancient times, limb blood-letting, emesis, amputation and skull operations were tried in the treatment of malarial fever. In England, opium from locally grown poppies and opium-laced beer were tried. Even the help of astrology was sought as the periodicity of malarial fevers suggested a connection with astronomical phenomena!
Claudius Galenus of Pergamum (131-201 AD), more popularly known as Galen, was an ancient Greek physician who worked in Rome from 162 AD. He suggested that the normal humoral balance should be restored by bleeding, purging, or both. Vomiting accompanying malaria was believed to be the body’s attempt to expel poisons. The bleeding supposedly rid the body of “corrupt humors.” These tenets were accepted without question for the next fifteen hundred years. Countless malaria patients were subjected to blood-letting and purgation with disastrous results: repeated bleedings only made the anemia of malaria much worse and the powerful purgatives on top of the debilitating effects of the disease itself often finished off most sufferers in a short time. The country folk and very poor who could not afford the help of the medical profession managed to survive!
Many turned to witchcraft. Allowing the insects to devour 77 small cakes made from a dough prepared by mixing flour and patient’s urine was one such suggested by the Dominican scholar Albertus Magnus. If this did not work, Albertus had another remedy: Let the matron of a noble family cut the ear of a cat, add three drops of its blood to brandy along with some pepper and administer it to the patient. Rubbing the patient’s body with chips from a gallows on which a criminal had been recently executed was yet another method.
Thus, until the early 17th century, European physicians had found no truly effective cure for malaria and their patients continued to die.
Artemisinin: The herb Artemisia annua (sweet wormwood) was known to the Chinese as qing-hao for more than 2000 years. The Mawanhgolui Han dynasty tombs, dating to 168 BC, mention it as a treatment for hemorrhoids. In 340 AD, the anti-fever properties of qinghao were first described by Ge Hong of the East Yin Dynasty.
An appeal for help from Ho Chi Minh to Zhou En Lai during the Vietnam War triggered the work on this herb and in 1967, the Chinese scientists set up Project 523. The active ingredient of qinghao was isolated by Chinese scientists in 1971. An ethyl ether extract of qinghao fed to mice infected with the rodent malaria strain, Plasmodium berghei, was found to be as effective as chloroquine and quinine at clearing the parasite. The human trails were published in the Chinese Medical Journal in 1979. Many active derivatives of artemisinin have since been synthesized and it is today a very potent and effective antimalarial drug, particularly against drug resistant malaria in many areas of southeast Asia. So far, clinically relevant genetic resistance to artemisinin has not been reported, although tolerance has been noted.
The history of cinchona bark, of more than 350 years, is full of intrigue and drama, greatly influencing that of pharmacy, botany, medicine, trade, theoretical and practical chemistry and tropical agriculture.
The origin of cinchona remains shrouded in mystery. Historians debate whether cinchona was an indigenous medicine or was discovered by Europeans. Evidence suggests that malaria did not exist in the New World before the arrival of the Spanish. It is said that the early Inca pharmacopoeias do not mention of cinchona, suggesting that its use followed the entry of the spaniards. However, even if malaria was not indigenous to South America, many years passed between the first arrival of the Spanish (and, presumably, malaria) and the earliest writings about cinchona by Europeans. Apparently during this interval, the native people would have developed a cure. Such a view is supported by the vast array of medicinal plants used by native healers and the large number of these plants transplanted to Europe from South and Central America at this time. Native plant remedies and treatment from native healers were more effective than the techniques of European physicians of the time.
One of the tales attributes the identification of cinchona bark to South American Indians. These natives supposedly noted that sick mountain lions chewed on the bark of certain trees. Malaria patients were given the bark and were helped.
Another holds that a member of a Peruvian Spanish garrison first discovered the bark. This soldier, overcome by malaria, was left behind to die by his comrades. Tortured by thirst, he crawled to a shallow pond, where he drank deeply and fell asleep. On awakening he found that his fever had disappeared, and then he remembered that the water had a bitter taste. A large tree trunk, split by lightning, had fallen into the pool; the bark from this tree, the soldier soon discovered, had both the bitter taste and the remarkable power to cure malaria.
It is widely accepted that the source of the bark was clearly identified by Jesuit priests. After Francisco Pizarro’s conquest of Peru in 1532, the Jesuit priests arrived there in 1568. Although the Jesuit doctrine forbid them from studying medicine, as it could detract from their primary focus of spiritual matters, they were allowed to study pharmacy and herbalism. In their studies of medical botany, the Jesuit priests undertook numerous field expeditions to describe and characterize the flora of remote forests in this newly discovered land. During an expedition between 1620 and 1630, to Loxa in the Southern district of Equador, bordering Peru, the Jesuit’s observed that the Incans, the indigenous people, were making teas out of the bark of certain trees to treat shivers from exposure to the cold. It is said that at Malacatos, 30 Km away from Loja, the Indian chief of the community, Pedro de Leiva provided tea made of this bark to a Jesuit priest who was sick with malaria and thereby cured him. Loxa (or Loja) being the natural habitat of this tree, the bark also came to be known as the Loja Bark.
The priest took samples of the bark to Lima, capital of Perú. The first written record of a malaria cure with cinchona bark dates back to 1630, mentioning that Juan López de Cañizares, Spanish governor of Loja (Ecuador), sent the same bark to Lima to cure the wife of the Count of Cinchón who was also sick with malaria fever, and this name also stuck to the bark.
It is not very clear as to who brought the cinchona bark to Europe. Sebastiano Bado, an Italian, gives this honor to the Countess of Chinchón, in an account published in 1663. The fourth Count of Chinchón, Don Luis Gerónimo Fernández de Cabrera de Bobadilla Cerda y Mendoza, was appointed by Philip IV to rule the vast Spanish South American Empire. The count and his wife, Señora Ana de Osorio, arrived in Lima in 1629. Shortly thereafter, according to Bado, the countess became severely ill with tertian fever, and news of her suffering soon spread throughout the colony. The governor of Loxa wrote the count, recommending that some of the same medicine by which he had been recently cured be given to Señora Ana. Don Juan was summoned to Lima, the remedy given, and the countess cured. Soon the natives were swarming around the palace, both to express their joy at the recovery and to learn the secret of the remedy. Upon hearing the people’s pleas, the generous Señora Ana ordered a large quantity of the bark and gave it personally to the sick. The grateful sufferers, all of whom were cured, named the new remedy los polvos de la condeça, “the countess’ powder.” In 1639, according to Bado, the countess returned to Spain, bringing a large quantity of bark with her. She distributed her remedy among the peons on the Chinchón estate, and also sent some to an ailing theology professor at the University of Alcalá de Henares. At the same time, Juan de Vega, Señora Ana’s physician, who had also returned to Spain with a supply of bark, sold part in Seville at an exorbitant price, one hundred reals per pound. This unscrupulous practice was to be repeated by many men in many places before the precious bark became readily available.
But the official diary of the Count of Chinchón, written by his secretary Don Antonio Suardo, was discovered in 1930. This contradicts many of the claims made by Bodo. The diary states that Ana de Osorio, the first Countess of Chinchón, died in Spain at least three years before Philip IV appointed the count viceroy of Peru. The second countess, Francisca Henríquez de Ribera, accompanied her husband to South America. And while Doña Francisca continued to enjoy excellent health, the count had several episodes of fever, none of which was treated with bark. Don Antonio also records that even the second countess never returned to Spain; instead, she died in the port of Cartagena, Colombia, during the trip home. Juan de Vega, her supposed physician, who, according to Bado, extorted enormous prices in Seville for the bark, never in fact left Peru because of an appointment as professor of medicine at the University of Lima. The count himself did return to Spain in 1641, and though he probably brought some bark with him, none reached the professor at the University of Alcalde de Henares, for this theologian had already been cured of his fever two years earlier.
In light of the evidence in Don Antonio’s diary, historians have been forced to conclude that cinchona bark appeared in Europe entirely by accident.
The first Europeans to appreciate the true value of cinchona were the Jesuits. As they cared for the natives throughout the Spanish New World Empire, Jesuit priests ascertained the medicinal properties of the Peruvian bark. Jesuit Barnabé de Cobo (1582-1657), who explored Mexico and Peru, is credited with taking Cinchona bark to Europe (hence called the Cobæa plant). He brought the bark from Lima to Spain, and afterwards to Rome and other parts of Italy, in 1632. The properties of the bark of the cinchona tree in the treatment of malaria were first written around 1633 by an Augustinian monk, Father Antanio de la Calancha, who lived in Peru. He wrote thus in a work on the Augustinian Order: “A tree grows which they call ‘the fever tree’ in the country of Loxa, whose bark, of the color of cinnamon, made into powder amounting to the weight of two small silver coins and given as a beverage, cures the fevers and tertiana; it has produced miraculous results in Lima.” Another Jesuit Bartolomé Tafur, came to Spain in 1643 and proceeded through France and took it to Italy as far as Rome.
The celebrated Jesuit theologian Juan de Lugo heard of the cinchona from Tafur. In 1640, Juan de Lugo first employed the tincture of the cinchona bark for treating malaria. Juan de Lugo (made cardinal in 1643) was entrusted by Pope Innocent X to learn more about the bark. De Lugo had the bark analysed by the pope’s physician, Gabriele Fonseca, who reported on it very favourably. In the late 1640s, directions for the use of the bark were published as the Schedula Romana. While on a visit to Paris in 1649 the cardinal even used some of his cinchona to treat the young Louis XIV. After the king’s recovery, the French eagerly embraced the new remedy. Juan de Lugo remained a faithful advocate, zealous defender, and generous, disinterested dispenser of the bark in Italy and the rest of Europe until his death in 1660. He was honoured at many places and several portraits of him were painted.
The Jesuit priests got natives to harvest the bark and the workers were made to replant five trees, arranged in the shape of a cross, for every tree they cut down. The bark was harvested around what is now the Peruvian and Ecuadorian border. From there it was carried to Paita on the coast and transferred onto ships bound for Panama. Once in Panama, it was carried north across the isthmus to Portobelo during the dry season, or taken via the Chagres River during the rainy season. At Portobelo the bark was once again loaded onto ships and sent to Spain via Havana. Occasionally, smuggling also took place, but rather than transport the bark via the western seaboard, smugglers carried it eastward, across most of the continent, following the course of rivers to the Atlantic. Once in Europe, the bark was distributed by a variety of means. Jesuits often gave it away, merchants sold it, and the nobility sometimes used it as gifts.
Pietro Paolo Pucciarini of Rome, Honoré Fabri, a French Jesuit and others helped in spreading the use of the bark across Europe and the “Jesuit Bark” also reached England. By 1657, it reached India. Under the pseudonym of Antimus Conygius, Fabri wrote in 1655 the first paper on cinchona published in Italy. The first prescription of cinchona in England is attributed to Robert Brady, a Professor of Physic in Cambridge, who in 1658 began prescribing the powder of the ‘Jesuits’ bark’ to treat an outbreak of malaria. Thomas Sydenham, an eminent English physician, published a book called Method for Curing the Fever (Methodus curandi febres) in 1666. A firm believer in the remedies of Hippocrates and Galen, Sydenham staunchly adhered to the old humoral theory of malaria. Grudgingly, though, he admitted that cinchona might be of some benefit if given after the fever had declined. Physician Bado declared that this bark had proved more precious to mankind than all the gold and silver which the Spaniards obtained from South America. The Italian professor of medicine Ramazzini said that the introduction of Peruvian bark would be of the same importance to medicine that the discovery of gunpowder was to the art of war.
Despite positive results and the backing of the Vatican, the use of cinchona was not universally adopted in 17th century Europe; many orthodox physicians in Protestant England in particular were prejudiced against its use. Many factors contributed to the delay in acceptance. First, the bark often did not work. Cinchona could not cure all fevers except those of malaria. Furthermore, unscrupulous dealers might have sold inferior bark or the bark of some other tree, and after the long journey from New Spain to Europe the bark sometimes arrived too rotten to use. The use of cinchona had not been mentioned in and even contradicted the teachings of the ancient author Galen, according to whom, a patient with malaria needed to release humors, making bleeding, purging, and the use of emetics the preferred treatments. The use of a hot, bitter drink seemed to conflict with both Galenic medicine and common sense. Lack of a reliable prescription also distanced physicians from prescribing it. The support of the Vatican for the drug and the fact that its export from Peru and Bolivia was in the hands of Catholics also worked against its acceptance in some regions, particularly in England. The close association of the drug with Catholicism made many Protestants fear it was part of a “Popish plot” against them. Oliver Cromwell, who had ordered the execution of Charles I, steadfastly refused cinchona during a severe attack of malaria in 1658, and died as a result (and that supposedly changed the history of England!).
In other countries that initially accepted cinchona the drug was sometimes used improperly. For example, the Austrian governor general of the Netherlands, Archduke Leopold William, was given cinchona with excellent results by Chifflet, his physician. But when the malaria recurred a month later, the archduke blamed the cinchona and foolishly refused to take more. His subsequent demise gave the medicine a bad name throughout Europe, and even Chifflet somehow came to believe that cinchona “fixed the humors” while reducing the fever, making recurrence certain and death likely.
It took an untrained “quack” to popularize cinchona in England in a highly unorthodox manner. Robert Talbor was born in Cambridge in 1642. He entered St. John’s College but dropped out at the age of twenty-one, becoming apprenticed to a Cambridge apothecary from whom he first learned of cinchona. He abandoned his apprenticeship and moved to Essex and then to London. He used the prevalent fears and confusion about the Jesuits’ Bark to make his name as a “feverologist” by treating malaria patients with what he called a ‘secret remedy’. He developed a safe dosage and an effective treatment regimen: “I planted myself in Essex near the sea side, in a place where agues are the epidemical diseases, where you will find but few persons but either are, or have been afflicted with a tedious quartan.” After several years of study and testing, he developed a secret formulation that was essentially an infusion of cinchona powder, skillfully disguising the bitter taste of the cinchona with opium and wine. His secret remedy cured many sufferers in the Fens and Essex marshes. In 1672, Talbor wrote a small book titled “Pyretologia: A Rational Account of the Cause and Cure of Agues”. But all along, Talbor avoided mention of actually having used ‘Jesuit’s bark’ himself and to protect his secret, he made careful slurs against the Jesuit’s bark. He solemnly warned his patients and the public to “Beware of all palliative Cures and especially of that known by the name of Jesuits powder….. for I have seen most dangerous effects following the taking of that medicine,” thus cornering himself a lucrative monopoly of both the patients and the remedy. Thanks to this book, his reputation grew. The success of his treatments became widely known and brought him rapid fame and fortune. Charles II appointed him Physician Royal in 1672 and he was knighted in 1678. The Royal College of Physicians was furious at Talbor’s doings and advocated his prosecution for practicing medicine without a license. But the king would not hear of such a thing; in an angry, threatening letter, he warned the College members that any interference with Talbor would be certain to arouse the royal displeasure. When the dauphin, last living son of Louis XIV, became ill with fever, Charles II sent Talbor to the French court as a gesture of goodwill. Louis had sheltered the English monarch in his period of exile during the Protectorate of Cromwell. Now the favor was returned. Sir Robert cured the stricken dauphin. With the additional title of Chevalier Talbot, he became famous throughout Europe, curing Louisa Maria, Queen of Spain, Prince de Condé, the Duc de Roche-foucauld, and hundreds of other royal and aristocratic persons. But this again met with hostility from physicians in Paris and Madrid. Forbidden to employ the new remedy, the jealous French physicians tried vainly to humiliate this foreign upstart. “What is fever?” they asked. “I do not know,” replied the wily Talbor. “You gentlemen may explain the nature of fever; but I can cure it, which you cannot.”
In 1679, King Charles II fell ill with tertian fever and was cured by Talbor’s ‘remedy’. Louis XIV of France, in recognition of the life of his son being saved, paid 3000 gold crowns, a large pension and a title and sought to know the ‘secret’ of his ‘remedy’. Talbor agreed on the condition that the formula would not be revealed during his lifetime. After returning to England, Talbor, now rich, tried to become even richer. Covertly he cornered the cinchona market by buying all the bark he could find. But he did not live long enough to enjoy his wealth. He died in 1681 at the age of thirty-nine, and was interred in Cambridge’s Holy Trinity Church. Fearing that in death his enemies in the medical profession would defame his memory, Talbor included a bit of professional advertising in his epitaph: “most honourable Robert Talbor, Knight and Singular Physician, unique in curing Fevers of which he had delivered Charles II King of England, Louis XIV King of France, the Most Serene Dauphin, Princes, many a Duke and a large number of lesser personages.”
In the same church, another imposing tablet hailed him even more eloquently as “Febrium Malleus,” smasher of fevers. In 1682, King Louis arranged for a small volume to be published that year. Nicholas de Blegny, physician-in-ordinary to the king, thereupon wrote a small book which was quickly translated into English: The English Remedy: Or Talbor’s Wonderful Secret for the Curing of Agues and Fevers–Sold by the Author, Sir Robert Talbor to the Most Christian King and since his Death ordered by His Majesty to be published in French, for the Benefit of his Subjects. The formula contained rose leaves, lemon juice, wine and a strong infusion of Peruvian bark! These revelations and a subsequent book, in 1712, on the therapeutic properties of the bark, by Fransesco Torti, professor of medicine at Modena, helped to popuarize the use of the treatment.
For a hundred years after it had been brought to Europe the bark remained difficult to obtain and Peru was its only source. Attempts to remove cinchona plants from the country were not successful. Charles de la Condamine, a French naturalist and explorer, was one of the first to make such an attempt in 1735. Condamine was determined to bring the trees back to France and grow rich selling the bark. He collected a large number of seedlings, planted them in boxes of earth, and then braved swamps, jungles, hostile natives, dangerous animals, and wild river rapids to reach the coast. After a perilous eight-month journey, within sight of the ship for Paris, his small boat was swamped by a wave and his plants washed away. However, with the help of the specimens of the bark that Condamine had obtained, Carolus Linnaeus, a Swedish botanist, classified the family of the Peruvian bark in 1742. He named the tree cinchona after the Countess, apparently accepting Sebastiano Bado’s account. Linnaeus misspelled the name, or rather he spelled it as had Bado, who had partially Italianized the count’s name, since c before i in Italian is pronounced like the Spanish (and English) ch. After Linnaeus’s death the error was discovered, much too late to change.
One member of Condamine’s expedition, Joseph de Jussieu, remained in the South American jungles for seventeen years to study cinchona. When he decided to return to France in 1761, he carried with him cinchona seeds packed into a wooden strongbox. But on the day of departure from Buenos Aires, a “trusted servant” made off with the box in the mistaken belief that it was filled with money. Jussieu returned to France ten years later, hopelessly insane. A Jesuit expedition was able to transport cinchona seedlings to Algeria, but the plants died in their new home. Success in this regard had to wait for another century.
At the beginning of the eighteenth century, as the use of cinchona spread throughout Europe, apothecaries and chemists attempted to extract the active ingredient of the bark so as to standardise the treatment. The first attempt to isolate the active principle in cinchona was made by Count Claude de la Garaye, a French pharmacist. In 1745 Garaye announced that he had successfully extracted the “essential salt,” but this was soon found to be not effective against malaria. Another French chemist, Antoine François Fourcroy in 1790 extracted a resinous substance with the characteristic color of the bark but that was not effective in treatment of malaria. Armand Seguin, Fourcroy’s student, came to the absurd conclusion that the active principle in cinchona was gelatin and published his findings despite inadequate experimental data. For years thereafter, many physicians reading Seguin’s paper adopted clarified glue to treat their malaria patients.
The first partially successful separation of the active principle from cinchona was achieved in 1811 by a Portuguese naval surgeon named Bernadino A. Gomez. He extracted the gray bark of poor variety with dilute acid and then neutralized it with alkali and managed to obtain a few crystals which he named cinchonin (later, to be known as cinchonine).
French pharmacists, Joseph Pelletier and Joseph Bienaimé Caventou, appointed a full professor of toxicology at the École de Pharmacie in Paris at age 22, isolated a medicinally worthless quinine poor powder, from the gray bark in 1817. In 1819, Friedlieb Runge isolated a base from cinchona, which he named “China base” – which was different from cinchonine. Later, in 1820, Pelletier and Caventou isolated from the yellow bark a sticky, pale yellow gum that could not be induced to crystallize. The gum was soluble in acid, alcohol, and ether and highly effective against malaria. The properties of the gum were seen to be identical to “China” base; but Runge`s prior discovery was overlooked. The two men named the new chemical quinine after quinquina, the name given by Peruvian Indians to the bark, meaning medicine of medicines or bark of barks. Pelletier and Caventou refused any profit from their discovery. Instead of patenting the extraction process, they published all the details so that anyone could manufacture quinine. They received many honors, the most lucrative of which was the Prix Monthyon of ten thousand francs awarded by the French Institute of Science. A monument was erected in Paris commemorating this achievement of Pelletier and Caventou.
More than 30 alkaloids are known from the bark of this genus. Formerly, the bark in different forms was used as a drug, but later natural harvesting formed the base of the production of cinchona alkaloids. This industry was carried on principally in Germany, and the Dutch and English cinchona plantations in Java, Ceylon and India were the chief sources whence the raw material was supplied. Its main active principle, quinine is now chemically synthesized. In 1823, Dr. John Sappington of Philadelphia acquired several pounds of quinine and issued “Dr. Sappington’s Fever Pills.” He persuaded ministers in the Mississippi River Valley to ring the church bells every evening to alert people to take the pills, and through that enterprise, Sappington became a very wealthy man.
By the mid-19th century the Dutch and English began claiming that the South American supply of cinchona was threatened by the non-sustainable cutting practices of the indigenous harvesters. In 1839, William Dawson Hooker, son of the renowned botanist William Jackson Hooker, wrote his dissertation on cinchona. He claimed that completely cutting the trees, rather than harvesting pieces of bark, was a better method, because insects would attack cinchona plants that had simply been debarked. On completely cut plants, new growth quickly appeared, and could be harvested again in 6 years. Years later it was also discovered that cut and regrown cinchona had higher levels of the effective alkaloids in its bark, and this method of harvesting became common on many plantations.
Attempts were continued to grow cinchona in other parts of the world. Seeds carried to Paris and Java by French and Dutch expeditions failed to germinate. In 1860 an English government clerk, Clements Robert Markham, carried seedlings to England; shortly thereafter, a distinguished botanist, Dr. Richard Spruce, did the same. These plants supplied the London market for only six years before being destroyed by insects.
In the meantime, to protect their monopoly, Peruvian authorities had barred foreigners from the cinchona forests. But in 1865 Charles Ledger, an Englishman living in Peru, obtained sixteen pounds of seed from a loyal native servant Manuel Incra Mamani for a fee of about 20 dollars. Mamani was jailed, beaten, and eventually starved to death for his act. A pound of this seed was sold to the Dutch in Java, and though apparently decayed on arrival, it germinated readily, giving birth to an enormous Dutch cinchona industry, destroying the South American monopoly on quinine and establishing a new Dutch monopoly. By grafting what was eventually named C. ledgeriana onto the hardier C. succirubra, the Dutch soon dominated cinchona cultivation, eventually producing 80 percent of the world’s quinine on the Indonesian island of Java. The high price of quinine was driven down and the drug was made available to large numbers of impoverished malaria sufferers.
The widespread use of cinchona came about because of the colonizing efforts of Europeans, and the drug, in turn, aided Europe in expanding its colonization even further. However, the world supply of cultivated quinine trees in Asia (especially in Indonesia and Java) was captured by Japan in 1942 during World War II and Germany captured the quinine reserves in Amsterdam, so Allied forces had to use emergency measures during World War II. Before the fall of the Philippines, the U.S. managed to escape with four million seeds, which were germinated back in Maryland and then transplanted in Costa Rica and other Latin American countries. Meanwhile, a Smithsonian botanist named Raymond Fosberg was able to secure millions of pounds ofCinchona bark in 1943 and 1944 for the Allies from forests and plantations in northern South America.
Even today quinine remains an important and effective treatment for malaria in most parts of the world, although resistance has been reported sporadically in 1844 and 1910.
Chloroquine: Many drugs were developed to protect the troops from malaria, particularly during World War II. Chloroquine, Primaquine, Proguanil, amodiaquine and Sulfadoxine/Pyrimethamine were all developed during this time.
During World War I, Java and its valuable quinine stores fell into Japanese forces. As a result, the German troops in East Africa suffered heavy casualties from malaria. In a bid to have their own antimalarial drugs, the German government initiated research into quinine substitutes and entrusted it to Bayer Dye Works. Most of the work was done at Bayer Farbenindustrie A.G. laboratories in Eberfeld, Germany. Several thousands of compounds were tested and some were found to be useful. Plasmochin naphthoate (Pamaquine) in 1926 and quinacrine, mepacrine (Atabrine) in 1932 were the first to be found. Plasmochin, an 8 amino quinoline, was quickly abandoned due to toxicity, although its close structural analog primaquine is now used to treat latent liver parasites of P. vivax and P. ovale. Atabrine, although found superior and persisting in the blood for at least a week, had to be abandoned due to side effects like yellowing of the skin and psychotic reactions. The breakthrough came in 1934 with the synthesis of Resochin (chloroquine) by Hans Andersag, followed by Sontochin or Sontoquine (3 methyl chloroquine). These compounds belonged to a new class of antimalarials known as 4 amino quinolines. But Farben scientists overestimated the compounds’ toxicity and failed to explore them further. Moreover, they passed the formula for Resochin to Winthrop Stearns, Farben’s U.S. sister company, in the late 1930s. Resochin was then forgotten until the outbreak of World War II.
With the German invasion of Holland and the Japanese occupation of Java, the Allied forces were cut off from quinine. This stimulated a renewed search for other antimalarials both in the United Kingdom and in the United States. After the Allied occupation of North Africa, the French soldiers raided a supply of German manufactured Sontochin in Tunis and handed it over to the Americans. Winthrop researchers made slight adjustments to the captured drug and this new formulation was called chloroquine. Later, it was found to be identical to the older and supposedly toxic Resochin. However it was not available for the troops until the end of the War. But following World War II, chloroquine and DDT became the two principal weapons in the global malaria control campaign.
However, after only about ten to twelve years of use, chloroquine resistance appeared in P. falciparum. Two initial foci of resistance developed simultaneously in Colombia and on the Cambodia-Thailand border. From these loci, resistance spread throughout South America and southern Asia. By the late 1970s chloroquine resistance had reached Africa and has since spread across sub-Saharan Africa.
Other antimalaria drugs: The formula of Atabrine (mepacrine, a 9-amino-acridine), was also soon solved by Allied chemists and it was produced in large scale in the U.S. It immediately gained widespread acceptance as an excellent therapeutic agent. After the experiments of Brigadier N. Hamilton Fairley in Australia in l943, it was also found to be useful as a prophylactic agent, protecting the troops in malarious areas. It is no longer used in view of many undesirable side effects.
The success of chloroquine led to the exploration of many (nearly 15000) compounds in the United States and another 4-aminoquinoline Camoquin (amodiaquin) was discovered. Studies on 8-aminoquinolines led to the discovery of Primaquine by Elderfield in 1950. Meanwhile, British investigators at ICI also carried out extensive studies on malaria drugs and Curd, Davey and Rose synthesised antifolate drugs proguanil or Paludrine (chlorguanide hydrochloride) in 1944 and Daraprim or Malocide (pyrimethamine) was developed in 1952. However, resistance to proguanil was observed within a year of introduction in Malaya in 1947. P. falciparum strains resistant to pyrimethamine, and cross-resistant to proguanil emerged in 1953 in Muheza, Tanzania. Sulfadoxine-pyrimethamine combination was introduced in Thailand in 1967. Resistance to this was first reported in Thailand later that year and spread quickly throughout Southeast Asia and recently appeared in Africa.
Mefloquine was jointly developed by the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche, Inc. After World War II, about 120 compounds were produced at the Walter Reed Army Institute of Research and WR142490 (mefloquine), a 4-quinoline methanol was developed. Its efficacy in preventing and treating resistant P. falciparum was proved in 1974-75 and was useful for the US Army in Southeast Asia and South America. By the time the drug became widely available in 1985, evidence of resistance to mefloquine also began to appear in Asia.
Malarone: In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. The synergistic combination with proguanil is found to be an effective antimalarial treatment.
It is thus clear that the plant-derived drugs have outlived many of the synthetic drugs, to which resistance has developed!
- Greenwood D. Conflicts of interest: the genesis of synthetic antimalarial agents in peace and war. J Antimicrob Chemother. 1995 Nov;36(5):857-72.
- http://www.hanmat.org/links.htm http://www.perc.org/perc.php?subsection=5&id=454
- Kuhn KG, Campbell-Lendrum DH, Armstrong B, Davies CR. Malaria in Britain: Past, present, and future. Proc Natl Acad Sci U S A. 2003 August 19; 100(17): 9997–10001. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=188345
- Sophia Colantonio. Bloodletting to bark: Observations on how the Cinchona bark came to be used to treat malaria. Available at http://www.med.uottawa.ca/historyofmedicine/hetenyi/Sophia-Colantonio-Bloodletting.pdf
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