Cinchona

Cinchona (pronounced /sɪŋˈknə/ or /sɪnˈnə/[1]) 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 Andean forests 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
Cinchona.pubescens01.jpg
Cinchona pubescens - flowers
Scientific classification e
Domain: Eukaryota
Kingdom: Plantae
Clade: Tracheophytes
Clade: Angiosperms
Clade: Eudicots
Clade: Asterids
Order: Gentianales
Family: Rubiaceae
Subfamily: Cinchonoideae
Tribe: Cinchoneae
Genus: Cinchona
L.
Type species
Cinchona officinalis
Species

about 38 species; see text

Cinchona has been historically sought after for its medicinal value, as the bark of several species yields quinine and other alkaloids that were the only effective treatments against malaria during the height of European colonialism, which made them of great economic and political importance. Carl Linnaeus named the genus in 1742 based on a claim that the plant had cured the wife of the Count of Chinchón, a Spanish viceroy in Lima, in the 1630s, though the veracity of this story has been refuted. The curative properties of cinchona were known much earlier. The history of the plants and the identification of the precise origins of their various extracts and medicinal uses are still disputed; though certain fever cures from South America known as Jesuit's bark and Jesuit's powder have been traced to Cinchona, there is also evidence of ingredients derived from other species such as Myroxylon. Linnaeus used the Italian spelling Cinchona, but the name Chinchón (pronounced [tʃinˈtʃon] in Spanish) led to Clements Markham and others proposing a correction of the spelling to Chinchona, and some prefer the pronunciation /ɪnˈnə/ for the common name of the plant.

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, but academic interest continues, as many cinchona alkaloids show promise in treating 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.[2]

DescriptionEdit

Cinchona plants belong to the family Rubiaceae and are large shrubs or small trees with evergreen foliage, growing 5 to 15 m (16 to 49 ft) in height. The leaves are opposite, rounded to lanceolate, and 10–40 cm long. The flowers are white, pink, or red, and produced in terminal panicles. The fruit is a small capsule containing numerous seeds. A key character of the genus is that the flowers have marginally hairy corolla lobes. The tribe Cinchoneae includes the genera Cinchonopsis, Jossia, Ladenbergia, Remijia, Stilpnophyllum, and Ciliosemina.[3] In South America, natural populations of Cinchona species have geographically distinct distributions. During the 19th century, the introduction of several species into cultivation in the same areas of India and Java, by the English and Dutch East India Company, respectively, led to the formation of hybrids.[4]

Carl 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.[5][6] Nearly 300 species were later described and named in the genus, but a revision of the genus in 1998 identified only 23 distinct species.[4][7]

HistoryEdit

Early referencesEdit

The febrifugal properties of bark from trees now known to be in the genus Cinchona were used by many South American cultures prior to European contact,[8] but malaria is an Old World disease that was introduced into the Americas by Europeans only after 1492. The origins and claims to the use of febrifugal barks and powders in Europe, especially those used against malaria, were disputed even in the 17th century. Jesuits played a key role in the transfer of remedies from the New World.

The traditional story connecting cinchona with malaria treatment was first recorded by the Italian physician Sebastiano Bado in 1663.[9] 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. It was his second wife, Francisca Henriques de Ribera, who 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".[10][11] 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; it has been suggested that they were referring to Cinchona species.[12]

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. Italian sources spelt quina as "cina" which was a source of confusion with Smilax from China.[13] 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 we now know as Cinchona.[14] 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 London Pharmacopoeia in 1677.

Scientific identificationEdit

 
Cortex peruvianus study by Antonie van Leeuwenhoek, 1706

The "fever tree" was finally described carefully by the astronomer Charles Marie de la Condamine, who visited Quito in 1735 on a quest to measure an arc of the meridian. The species he described, Cinchona officinalis, was, however, found to be of little therapeutic value. The first living plants seen in Europe were C. calisaya plants grown at the Jardin des Plantes from seeds collected by Hugh Algernon Weddell from Bolivia in 1846.[15] José Celestino Mutis, physician to the Viceroy of Nueva Granada, Pedro Messia de la Cerda, gathered information on cinchona in Colombia from 1760 and wrote a manuscript, El Arcano de la Quina (1793), with illustrations. He proposed a Spanish expedition to search for plants of commercial value, which was approved in 1783 and was continued after his death in 1808 by his nephew Sinforoso Mutis.[16] As demand for the bark increased, the trees in the forests began to be destroyed. To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings beginning in the early 19th century.[17]

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 sent Justus Hasskarl, who brought plants that were then cultivated in Java from 1854. The English explorer Clements Markham went to collect plants that were introduced in Sri Lanka and the Nilgiris of southern India in 1860.[18] The main species introduced were Cinchona 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 it took a while to develop sustainable methods to extract bark.

In the meantime, Charles Ledger and his native assistant Manuel collected another species from Bolivia. Manuel was caught and beaten by Bolivian officials, leading to his death, but Ledger obtained seeds of high quality. 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[19] yielded 8 to 13 percent quinine in bark grown in Dutch Indonesia, which effectively out-competed the British Indian production. It was only later that the English saw the value and sought to obtain the seeds of C. ledgeriana from the Dutch.[20][21]

Francesco Torti used the response of fevers to treatment with cinchona as a system of classification of fevers or a means for diagnosis. The use of cinchona in the effective treatment of malaria brought an end to treatment by bloodletting and long-held ideas of humorism from Galen.[22] For his part in obtaining and helping the establishment of cinchona in British India, Clements Markham was knighted. For his role in establishing cinchona in Indonesia, Hasskarl was knighted with the Dutch order of the Lion.[23]

EcologyEdit

Cinchona species are used as food plants by the larvae of some Lepidoptera species, including the engrailed, the commander, and members of the genus Endoclita, including E. damor, E. purpurescens, and E. sericeus.

Cinchona pubescens has grown uncontrolled on some islands, such as the Galapagos, where it has posed the risk of out-competing native plant species.[24]

Medicinal useEdit

 
Cinchona officinalis, the harvested bark
 
Peru offers a branch of cinchona to science (from a 17th-century engraving).
 
A 19th-century illustration of Cinchona calisaya

Traditional medicineEdit

In herbalism, cinchona bark was used as an adulterant in Jesuit's bark or Peruvian bark which originally is thought to have referred to Myroxylon peruiferum, another fever remedy. The bark of cinchona can be harvested in a number of ways. One approach was to cut the tree but this and girdling are equally destructive and unsustainable so small strips were cut and various techniques such as "mossing", the application of moss to the cut areas, were used to allow the tree to heal. Other approaches involved coppicing and chopping of side branches which were then stripped of bark. The bark was dried into what were called quills and then powdered for medicinal uses. The bark contains alkaloids, including quinine and quinidine.[25] Cinchona is the only economically practical source of quinine, a drug that is still recommended for the treatment of falciparum malaria.[26][27]

EuropeEdit

The Italian botanist Pietro Castelli wrote a pamphlet noteworthy as being the first Italian publication to mention the cinchona. By the 1630s (or 1640s, depending on the reference), the bark was being exported to Europe. In the late 1640s, the method of use of the bark was noted in the Schedula Romana.

English King Charles II called upon Robert Talbor, who had become famous for his miraculous malaria cure.[28] 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.[29]

In 1679, Talbor was called by the King of France, Louis XIV, whose son was suffering from malaria 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.[29] 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".[30]

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.[31]

HomeopathyEdit

The birth of homeopathy was based on cinchona bark testing. The founder of homeopathy, Samuel Hahnemann, when translating William Cullen's Materia medica, noticed Cullen had written that Peruvian bark was known to cure intermittent fevers.[32] Hahnemann took daily a large, rather than homeopathic, dose of Peruvian bark. After two weeks, he said he felt malaria-like symptoms. This idea of "like cures like" was the starting point of his writings on homeopathy. Hahnemann's symptoms have been suggested by researchers, both homeopaths and skeptics, as being an indicator of his hypersensitivity to quinine.[33]

Widespread cultivationEdit

The bark was very valuable to Europeans in expanding their access to and exploitation of resources in distant colonies and at home. Bark gathering was often environmentally destructive, destroying huge expanses of trees for their bark, with difficult conditions for low wages that did not allow the indigenous bark gatherers to settle debts even upon death.[34]

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. Mr. [Thaddäus] 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.[35] 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.[36] James Taylor, the pioneer of tea planting in Sri Lanka, was one of the pioneers of cinchona cultivation.[37] By 1883, about 64,000 acres (260 km2) were in cultivation in Sri Lanka, with exports reaching a peak of 15 million pounds in 1886. The cultivation (initially of Cinchona succirubra (now C. pubescens) and later of C. calisaya[38]) was extended through the work of George King and others into the hilly terrain of Darjeeling District of 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.[21][39][40]

 
Cinchona pubescens fruit

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.[41]

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[42]), 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.[43]

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[44] 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.[44] As well as being ultimately successful in their primary aim, these expeditions also identified new species of plants[44] and created a new chapter in international relations between the United States and other nations in the Americas.[45]

ChemistryEdit

Cinchona alkaloidsEdit

 
General structure of Cinchona alkaloids

The bark of trees in this genus is the source of a variety of alkaloids, the most familiar of which is quinine, an antipyretic (antifever) agent especially useful in treating malaria.[46][47] For a while the extraction of a mixture of alkaloids from the cinchona bark, known in India as the cinchona febrifuge, was used. The alkaloid mixture or its sulphated form mixed in alcohol and sold quinetum was however very bitter and caused nausea, among other side effects.[48]

Cinchona alkaloids include:

They find use in organic chemistry as organocatalysts in asymmetric synthesis.

Other chemicalsEdit

Alongside the alkaloids, many cinchona barks contain cinchotannic acid, a particular tannin, which by oxidation rapidly yields a dark-coloured phlobaphene[49] called red cinchonic,[50] cinchono-fulvic acid, or cinchona red.[51]

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.[52][53]

SpeciesEdit

There are at least 24 species of Cinchona recognized by botanists.[4][54] There are likely several unnamed species and many intermediate forms that have arisen due to the plants' tendency to hybridize.[7]

See alsoEdit

NotesEdit

  1. ^ The variety of Calisayan cinchona introduced to the Dutch East Indies was also sometimes distinguished as Cinchona pahudiana,[55] named in honor of the Dutch colonial minister C.F. Pahud.
  1. ^ "Cinchona (two pronunciations)". Merriam-Webster, Incorporated. 2019. Retrieved 20 September 2019.
  2. ^ Deborah Kopka (12 January 2011). Central & South America. Milliken Pub. Co. p. 130. ISBN 978-1429122511. Retrieved 15 April 2013.
  3. ^ Andersson, Lennart; Antonelli, Alexandre (2005). "Phylogeny of the tribe Cinchoneae (Rubiaceae), its position in Cinchonoideae, and description of a new genus, Ciliosemina". Taxon. 54 (1): 17–28. doi:10.2307/25065412. JSTOR 25065412.
  4. ^ a b c Andersson, Lennart (1998). "A revision of the genus Cinchona (Rubiaceae-Cinchoneae)". Memoirs of the New York Botanical Garden. 80: 1–75.
  5. ^ Linné, Carolus von. Genera Plantarum 2nd edition 1743. page 413
  6. ^ Linné, Carolus von. Species Plantarum. 1st edition. 1752. volume 1. page 172.[1]
  7. ^ a b Cinchona. Selected Rubiaceae Tribes and Genera. Tropicos. Missouri Botanical Garden.
  8. ^ Crawford, Matthew James (1 January 2014). "An Empire's Extract: Chemical Manipulations of Cinchona Bark in the Eighteenth-Century Spanish Atlantic World". Osiris. 29 (1): 215–229. doi:10.1086/678104. ISSN 0369-7827. PMID 26103756.
  9. ^ Meyer, Christian G.; Marks, Florian; May, Jürgen (1 December 2004). "Editorial: Gin tonic revisited". Tropical Medicine & International Health. 9 (12): 1239–1240. doi:10.1111/j.1365-3156.2004.01357.x. ISSN 1365-3156. PMID 15598254.
  10. ^ Markham, Clements (1874). A memoir of the Lady Ana de Osorio Countess of Chinchon and Vice-queen of Peru. London: Trubner & Co.
  11. ^ Markham, Clements (1880). Peruvian bark. A popular account of the introduction of Chinchona cultivation into British India. 1800-1880. London: John Murray.
  12. ^ Crespo, Fernando I. Ortiz (1995). "Fragoso, Monardes and pre-Chinchonian knowledge of Cinchona". Archives of Natural History. 22 (2): 169–181. doi:10.3366/anh.1995.22.2.169.
  13. ^ Bergman, George J (1948). "The history and importance of cinchona bark as an anti-malarial febrifuge". Science Education. 32 (2): 93–103. Bibcode:1948SciEd..32...93B. doi:10.1002/sce.3730320205.
  14. ^ Haggis, A.W. (1941). "Fundamental errors in the early history of Cinchona". Bulletin of the History of Medicine. 10 (3–4): 417–459, 568–592.
  15. ^ King, George (1880). A manual of Cinchona cultivation in India (2 ed.). Calcutta: Government Press. pp. 1–2.
  16. ^ Kirkbride, Jr., Joseph H. (1982). "The Cinchona Species of Jose Celestino Mutis". Taxon. 31 (4): 693–697. doi:10.2307/1219686. JSTOR 219686.
  17. ^ Jaramillo-Arango, Jaime (1949). "A critical review of the basic facts in the history of Cinchona". Journal of the Linnean Society of London, Botany. 53 (352): 272–311. doi:10.1111/j.1095-8339.1949.tb00419.x.
  18. ^ Rice, Benjamin Lewis (1897). Mysore: A Gazetteer Compiled for Government Vol. 1. Westminster: A Constable. p. 892.
  19. ^ Holmes, Edward Morell (1885). "Remarks on Cinchona ledgeriana as a Species". Journal of the Linnean Society of London, Botany. 21 (136): 374–380. doi:10.1111/j.1095-8339.1885.tb00567.x.
  20. ^ Russell, Paul F. (1943). "Malaria and its influence on world health". Bulletin of the New York Academy of Medicine. 19 (9): 599–630. PMC 1934033. PMID 19312337.
  21. ^ a b Williams, Donovan (1962). "Clements Robert Markham and the Introduction of the Cinchona Tree into British India, 1861". The Geographical Journal. 128 (4): 431–442. doi:10.2307/1792039. JSTOR 1792039.
  22. ^ Jarcho, Saul (1993). Quinine's predecessor: Francesco Torti and the early history of cinchona. Baltimore: Johns Hopkins University Press.
  23. ^ Roth, Klaus; Streller, Sabine (2013). "From Pharmacy to the Pub — A Bark Conquers the World: Part 1". ChemViews. doi:10.1002/chemv.201300056.
  24. ^ Jäger, Heinke; Kowarik, Ingo (2010). "Resilience of Native Plant Community Following Manual Control of Invasive Cinchona pubescens in Galápagos". Restoration Ecology. 18: 103–112. doi:10.1111/j.1526-100X.2010.00657.x.
  25. ^ Christensen, Søren Brøgger (2015). "Drugs and Drug Leads Based on Natural Products for Treatment and Prophylaxis of Malaria". Evidence-Based Validation of Herbal Medicine. pp. 307–319. doi:10.1016/B978-0-12-800874-4.00014-3. ISBN 9780128008744.
  26. ^ Guidelines for the treatment of malaria (PDF) (2 ed.). World Health Organization. 2010.
  27. ^ Achan, Jane; Talisuna, Ambrose O; Erhart, Annette; Yeka, Adoke; Tibenderana, James K; Baliraine, Frederick N; Rosenthal, Philip J; d'Alessandro, Umberto (2011). "Quinine, an old anti-malarial drug in a modern world: Role in the treatment of malaria". Malaria Journal. 10: 144. doi:10.1186/1475-2875-10-144. PMC 3121651. PMID 21609473.
  28. ^ See:
    • Paul Reiter (2000) "From Shakespeare to Defoe: Malaria in England in the Little Ice Age," Emerging Infectious Diseases, 6 (1) : 1-11. Available on-line at: National Center for Biotechnology Information.
    • Robert Talbor (1672) Pyretologia: a Rational Account of the Cause and Cures of Agues.
    • Robert Talbor (1682) The English Remedy: Talbor’s Wonderful Secret for Curing of Agues and Feavers.
  29. ^ a b Thompson, C. J. S. (1928). "The History and Lore of Cinchona". The British Medical Journal. 2 (3547): 1188–1190. doi:10.1136/bmj.2.3547.1188. JSTOR 25331045. S2CID 220147336.
  30. ^ D'Esaguy, Augusto (May 1936). "Água de Inglaterra". Bulletin of the Institute of the History of Medicine. 4 (5): 404–408. JSTOR 44438162.
  31. ^ Joseph P. Remington, Horatio C. Wood, ed. (1918). "Cinchona". The Dispensatory of the United States of America.
  32. ^ William Cullen, Benjamin Smith Barton (1812). Professor Cullen's treatise of the materia medica. Edward Parker. peruvian.
  33. ^ Julian, F. Bennett (1935). "Art and Fashion in Medicine". British Medical Journal. 1 (3872): 620–621. doi:10.1136/bmj.1.3872.620-b. PMC 2459939.
  34. ^ Taussig, M. (1987). Shamanism, Colonialism and the Wild Man. University of Chicago Press.
  35. ^ Cowan, J. M. (1929). "Cinchona in the Empire. Progress and prospects of its cultivation". Empire Forestry Journal. 8 (1): 45–53. JSTOR 42598886.
  36. ^ "Hakgala garden". Department of Agriculture, Government of Sri Lanka. Retrieved 11 June 2010.[permanent dead link]
  37. ^ Fry, Carolyn (6 January 2007). "The Kew Gardens of Sri Lanka". Travel. London: Timesonline, UK. Retrieved 11 June 2010.
  38. ^ Gammie, J. A. (1888). "Manufacture of Quinine in India". Bulletin of Miscellaneous Information (Royal Botanic Gardens, Kew). 1888 (18): 139–144. doi:10.2307/4114959. JSTOR 4114959.
  39. ^ "Introduction of Cinchona to India". Bulletin of Miscellaneous Information (Royal Botanic Gardens, Kew). 1931 (3): 113–117. 1931. doi:10.2307/4102564. JSTOR 4102564.
  40. ^ King, George (1876). A manual of Cinchona cultivation in India. Calcutta: Government Press.
  41. ^ Sources: Life of Maury by Diane Corbin and Scientist of the Sea by Frances Leigh Williams.
  42. ^ van der Hoogte, Arjo Roersch; Pieters, Toine (2015). "Science, industry and the colonial state: a shift from a German- to a Dutch-controlled cinchona and quinine cartel (1880–1920)". History and Technology. 31: 2–36. doi:10.1080/07341512.2015.1068005. S2CID 153489022.
  43. ^ Goss, Andrew (2014). "Building the world's supply of quinine: Dutch colonialism and the origins of a global pharmaceutical industry". Endeavour. 38 (1): 8–18. doi:10.1016/j.endeavour.2013.10.002. PMID 24287061.
  44. ^ a b c "Cinchona Missions Expedition (1942–1944)". National Museum of Natural History: Historical Expeditions. Smithsonian Institution. Retrieved 25 March 2017.
  45. ^ Cuvi, Nicolás (2011). "The Cinchona Program (1940–1945): science and imperialism in the exploitation of a medicinal plant". Dynamis. Granada. 31 (1): 183–206. doi:10.4321/S0211-95362011000100009. ISSN 0211-9536. PMID 21936230.
  46. ^ Chisholm 1911.
  47. ^ EA 1920.
  48. ^ "Cinchona Febrifuge". The Indian Medical Gazette. 13 (4): 107–108. 1878. PMC 5130665. PMID 28997438.
  49. ^ Henry G. Greenish (1920). "Cinchona Bark (Cortex Cinchonae). Part 3". A Text Book of Materia Medica, Being An Account of the More Important Crude Drugs of Vegetable And Animal Origin. J. & A. Churchill. ASIN B000J31E44.
  50. ^ Alfred Baring Garrod (2007). "Cinchonaceae. Part 2". Essentials of Materia Medica And Therapeutics. Kessinger Publishing. ISBN 978-1-4326-8837-0.
  51. ^ "Quinine". Encyclopædia Britannica (10 ed.). 1902.
  52. ^ "Totaquina". Nature. 145 (3673): 458. 1940. Bibcode:1940Natur.145R.458.. doi:10.1038/145458b0.
  53. ^ Groothoff, A.; Henry, T.A. (1933). "The Preparation, Analysis and Standardisation of Totaquina". Rivista di Malariologia. 12 (1): 87–91.
  54. ^ Maldonado, Carla; Persson, Claes; Alban, Joaquina; Antonelli, Alexandre; Rønsted, Nina (2017). "Cinchona anderssonii (Rubiaceae), a new overlooked species from Bolivia" (PDF). Phytotaxa. 297 (2): 203. doi:10.11646/phytotaxa.297.2.8. Archived from the original (PDF) on 19 March 2018. Retrieved 19 March 2018.
  55. ^ EB (1878), p. 781.

ReferencesEdit

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