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Cinchona (pronounced or ) is a genus of flowering plants in the family Rubiaceae containing at least 23 species of trees and shrubs. All are native to the Tropical Andes of western South America. A few species are reportedly naturalized in Central America, Jamaica, French Polynesia, Sulawesi, Saint Helena in the South Atlantic, and São Tomé and Príncipe off the coast of tropical Africa, and others have been cultivated in India and Java, where they have formed hybrids.
Cinchona has been historically sought after for its medicinal value, as the bark of several species yields quinine and other . These were the only effective treatments against malaria during the height of European colonialism, which made them of great economic and political importance. Trees in the genus are also known as fever trees because of their antimalarial properties.
The artificial synthesis of quinine in 1944, an increase in resistant forms of malaria, and the emergence of alternate therapies eventually ended large-scale economic interest in Cinchona cultivation. Cinchona alkaloids show promise in treating Plasmodium falciparum malaria, which has evolved resistance to synthetic drugs. Cinchona plants continue to be revered for their historical legacy; the national tree of Peru is in the genus Cinchona.
Linnaeus described the genus based on the species Cinchona officinalis, which is found only in a small region of Ecuador and is of little medicinal significance. Linné, Carolus von. Genera Plantarum 2nd edition 1743. page 413Linné, Carolus von. Species Plantarum. 1st edition. 1752. volume 1. page 172.[2] Nearly 300 species were later described and named in the genus, but a revision of the genus in 1998 identified only 23 distinct species. Cinchona. Selected Rubiaceae Tribes and Genera. Tropicos. Missouri Botanical Garden.
The traditional story connecting Cinchona species with malaria treatment was first recorded by Italian physician Sebastiano Bado in 1663. It tells of the wife of Luis Jerónimo de Cabrera, 4th Count of Chinchón and Viceroy of Peru, who fell ill in Lima with a tertian fever. A Spanish governor advised a traditional remedy, which resulted in a miraculous and rapid cure. The countess then supposedly ordered a large quantity of the bark and took it back to Europe. Bado claimed to have received this information from an Italian named Antonius Bollus, who was a merchant in Peru. Clements Markham identified the countess as Ana de Osorio, but this was shown to be incorrect by Haggis. Ana de Osorio married the Count of Chinchón in August 1621 and died in 1625, several years before the count was appointed viceroy of Peru in 1628. His second wife, Francisca Henriques de Ribera, accompanied him to Peru. Haggis further examined the count's diaries and found no mention of the countess suffering from fever, although the count himself had many malarial attacks. Because of these and numerous other discrepancies, Bado's story has been generally rejected as little more than a legend.
Quina bark was mentioned by Fray Antonio de La Calancha in 1638 as coming from a tree in Loja (Loxa). He noted that bark powder weighing about two coins was cast into water and drunk to cure fevers and "tertians". Jesuit Father Bernabé Cobo (1582–1657) also wrote on the "fever tree" in 1653. The legend was popularized in English literature by Markham, and in 1874, he also published a "plea for the correct spelling of the genus Chinchona". Spanish physician and botanist Nicolás Monardes wrote of a New World bark powder used in Spain in 1574, and another physician, Juan Fragoso, wrote of bark powder from an unknown tree in 1600 that was used for treating various ills. Both identify the sources as trees that do not bear fruit and have heart-shaped leaves; they were suggested to have been referring to Cinchona species.
The name quina-quina or quinquina was suggested as an old name for Cinchona used in Europe and based on the native name used by the Quechua people which means 'bark of barks'. Italian sources spelt quina as " cina", which was a source of confusion with Smilax from China. Haggis argued that qina and Jesuit's bark actually referred to Myroxylon peruiferum, or Peruvian balsam, and that this was an item of importance in Spanish trade in the 1500s. Over time, the bark of Myroxylon may have been adulterated with the similar-looking bark of what is now known as Cinchona. Gradually, the adulterant became the main product that was the key therapeutic ingredient used in malarial therapy. The bark was included as Cortex Peruanus in the Pharmacopoeia in 1677.
The colonial European powers eventually considered growing the plant in other parts of the tropics. The French mission of 1743, of which de la Condamine was a member, lost their cinchona plants when a wave took them off their ship. The Dutch Empire sent Justus Hasskarl, who brought plants that were then cultivated in Java from 1854. English explorer Clements Markham went to collect plants that were introduced in Sri Lanka and the Nilgiris of southern India in 1860. The main species introduced were C. succirubra, or red bark, (now C. pubescens) as its sap turned red on contact with air, and Cinchona calisaya. The alkaloids quinine and cinchonine were extracted by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 1820. Two more key alkaloids, quinidine and cinchonidine, were later identified and it became a routine in quinology to examine the contents of these components in assays. The yields of quinine in the cultivated trees were low and time was needed to develop sustainable methods to extract bark.
In the meantime, Charles Ledger and his native assistant Manuel Incra Mamani collected another species from Bolivia. Mamani was caught and beaten by Bolivian officials, leading to his death, but Ledger obtained seeds containing high levels of quinine. These seeds were offered to the British, who were uninterested, leading to the rest being sold to the Dutch. The Dutch saw their value and multiplied the stock. The species later named Cinchona ledgeriana yielded 8 to 13% quinine in bark grown in Dutch Indonesia, which effectively outcompeted the British Indian production which focused on a range of alkaloids other than quinine. Only later did the English see the value and sought to obtain the seeds of C. ledgeriana from the Dutch.
Francesco Torti used the response of fevers to treatment with Cinchona as a system of classification of fevers or a means for diagnosis between malarial and non-malarial fevers. Its use in the effective treatment of malaria brought an end to treatment by bloodletting and long-held ideas of humorism from Galen. Clements Markham was knighted for his role in establishing Cinchona species in Indonesia. Hasskarl was knighted with the Dutch order of the Lion.
C. pubescens has grown uncontrolled on some islands, such as the Galapagos, where it has posed the risk of outcompeting native plant species.
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English King Charles II called upon Robert Talbor, who had become famous for his miraculous malaria cure.See:
Because at that time the bark was in religious controversy, Talbor gave the king the bitter bark decoction in great secrecy. The treatment gave the king complete relief from the malaria fever. In return, Talbor was offered membership of the prestigious Royal College of Physicians.
In 1679, Talbor was called by the King of France, Louis XIV, whose son was suffering from malarial fever. After a successful treatment, Talbor was rewarded by the king with 3,000 gold crowns and a lifetime pension for this prescription. Talbor was asked to keep the entire episode secret. After Talbor's death, the French king published this formula: seven grams of rose leaves, two ounces of lemon juice and a strong decoction of the cinchona bark served with wine. Wine was used because some alkaloids of the cinchona bark are not soluble in water, but are soluble in the ethanol in wine. In 1681 Água de Inglaterra was introduced into Portugal from England by Dr. Fernando Mendes who, similarly, "received a handsome gift from (King Pedro) on condition that he should reveal to him the secret of its composition and withhold it from the public".
In 1738, Sur l'arbre du quinquina, a paper written by Charles Marie de La Condamine, lead member of the expedition, along with Pierre Godin and Louis Bouger that was sent to Ecuador to determine the length of a degree of the 1/4 of meridian arc in the neighbourhood of the equator, was published by the French Academy of Sciences. In it he identified three separate species.
Further exploration of the Amazon Basin and the economy of trade in various species of the bark in the 18th century is captured by Lardner Gibbon:
... this bark was first gathered in quantities in 1849, though known for many years. The best quality is not quite equal to that of Yungas, but only second to it. There are four other classes of inferior bark, for some of which the bank pays fifteen dollars per quintal. The best, by law, is worth fifty-four dollars. The freight to Arica is seventeen dollars the mule load of three quintals. Six thousand quintals of bark have already been gathered from Yuracares. The bank was established in the year 1851. [w:Haenke|Mr. Haenke]] mentioned the existence of cinchona bark on his visit to Yuracares in 1796
- — Exploration of the Valley of the Amazon, by Lieut. Lardner Gibbon, USN. Vol. II, Ch. 6, pp. 146–47.
It was estimated that the British Empire incurred direct losses of 52 to 62 million pounds a year due to malaria sickness each year. It was therefore of great importance to secure the supply of the cure. In 1860, a British expedition to South America led by Clements Markham smuggled back cinchona seeds and plants, which were introduced in several areas of British India and Sri Lanka. In India, it was planted in Ootacamund by William Graham McIvor. In Sri Lanka, it was planted in the Hakgala Botanical Garden in January 1861. James Taylor, the pioneer of tea planting in Sri Lanka, was one of the pioneers of cinchona cultivation. By 1883, about were in cultivation in Sri Lanka, with exports reaching a peak of 15 million pounds in 1886. The cultivation (initially of C. succirubra (now C. pubescens) and later of C. calisaya) was extended through the work of George King and others into the hilly terrain of Darjeeling District of West Bengal. Cinchona factories were established at Naduvattam in the Nilgiris and at Mungpoo, Darjeeling, West Bengal. Quinologists were appointed to oversee the extraction of alkaloids with John Broughton in the Nilgiris and C.H. Wood at Darjeeling. Others in the position included David Hooper and John Eliot Howard.
In 1865, "New Virginia" and "Carlota Colony" were established in Mexico by Matthew Fontaine Maury, a former Confederate in the American Civil War. Postwar Confederates were enticed there by Maury, now the "Imperial Commissioner of Immigration" for Emperor Maximillian of Mexico, and Archduke of Habsburg. All that survives of those two colonies are the flourishing groves of cinchonas established by Maury using seeds purchased from England. These seeds were the first to be introduced into Mexico.Sources: Life of Maury by Diane Corbin and Scientist of the Sea by Frances Leigh Williams.
The cultivation of cinchona led from the 1890s to a decline in the price of quinine, but the quality and production of raw bark by the Dutch in Indonesia led them to dominate world markets. The producers of processed drugs in Europe (especially Germany), however, bargained and caused fluctuations in prices, which led to a Dutch-led Cinchona Agreement in 1913 that ensured a fixed price for producers. A Kina Bureau in Amsterdam regulated this trade.
During World War II, the Japanese conquered Java and the United States lost access to the cinchona plantations that supplied war-critical quinine medication. Botanical expeditions called Cinchona Missions were launched between 1942 and 1944 to explore promising areas of South America in an effort to locate cinchona species that contained quinine and could be harvested for quinine production. As well as being ultimately successful in their primary aim, these expeditions also identified new species of plants and created a new chapter in international relations between the United States and other nations in the Americas.
Cinchona alkaloids include:
They find use in organic chemistry as in asymmetric synthesis.
In 1934, efforts to make malaria drugs cheap and effective for use across countries led to the development of a standard called "totaquina" proposed by the Malaria Commission of the League of Nations. Totaquina required a minimum of 70% crystallizable alkaloids, of which at least 15% was to be quinine with not more than 20% amorphous alkaloids.
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