Quinine

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Quinine
Quinine structure.svg
Quinine-3D-balls.png
Clinical data
Pronunciation US: /ˈkwnn/ , /kwɪˈnn/ or UK: /ˈkwɪnn/ KWIN-een
Trade names Qualaquin, Quinbisul, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a682322
License data
Pregnancy
category
Routes of
administration
By mouth, intramuscular, intravenous, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 70–95% [3]
Metabolism Liver (mostly CYP3A4 and CYP2C19-mediated)
Elimination half-life 8–14 hours (adults), 6–12 hours (children) [3]
Excretion Kidney (20%)
Identifiers
  • (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.550 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H24N2O2
Molar mass 324.424 g·mol−1
3D model (JSmol)
Melting point 177 °C (351 °F)
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  • InChI=1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1 Yes check.svgY
  • Key:LOUPRKONTZGTKE-WZBLMQSHSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Quinine is a medication used to treat malaria and babesiosis. [4] This includes the treatment of malaria due to Plasmodium falciparum that is resistant to chloroquine when artesunate is not available. [4] [5] While sometimes used for restless legs syndrome, quinine is not recommended for this purpose due to the risk of serious side effects. [4] It can be taken by mouth or intravenously. [4] Malaria resistance to quinine occurs in certain areas of the world. [4] Quinine is also the ingredient in tonic water that gives it its bitter taste. [6]

Contents

Common side effects include headache, ringing in the ears, trouble seeing, and sweating. [4] More severe side effects include deafness, low blood platelets, and an irregular heartbeat. [4] Use can make one more prone to sunburn. [4] While it is unclear if use during pregnancy causes harm to the baby, treating malaria during pregnancy with quinine when appropriate is still recommended. [4] Quinine is an alkaloid, a naturally occurring chemical compound. [4] How it works as a medicine is not entirely clear. [4]

Quinine was first isolated in 1820 from the bark of a cinchona tree, which is native to Peru. [4] [7] [8] Bark extracts had been used to treat malaria since at least 1632 and it was introduced to Spain as early as 1636 by Jesuit missionaries from the New World. [9] It is on the World Health Organization's List of Essential Medicines. [10]

Uses

Medical

As of 2006, quinine is no longer recommended by the World Health Organization (WHO) as a first-line treatment for malaria, because there are other substances that are equally effective with fewer side effects. They recommend that it be used only when artemisinins are not available. [11] [12] [13] [14] Quinine is also used to treat lupus and arthritis.

Quinine was frequently prescribed as an off-label treatment for leg cramps at night, but this has become less common due to a warning from the US Food and Drug Administration (FDA) that such practice is associated with life-threatening side effects. [15] [16] [17]

Available forms

Quinine is a basic amine and is usually provided as a salt. Various existing preparations include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin.

All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR). [18] [19] The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; in practice, this is corrected by giving a further half dose. No injectable preparation of quinine is licensed in the US; quinidine is used instead. [20] [21]

Quinine base in various salts
NameQuinine base equivalence
Quinine base100 mg
Quinine bisulfate169 mg
Quinine dihydrochloride122 mg
Quinine gluconate160 mg
Quinine hydrochloride111 mg
Quinine sulfate dihydrate [(quinine)2H2SO4∙2H2O]121 mg

Beverages

Tonic water, in normal light and ultraviolet "black light". The quinine content of tonic water causes it to fluoresce under black light. Tonic water uv.jpg
Tonic water, in normal light and ultraviolet "black light". The quinine content of tonic water causes it to fluoresce under black light.

Quinine is a flavor component of tonic water and bitter lemon drink mixers. On the soda gun behind many bars, tonic water is designated by the letter "Q" representing quinine. [22]

According to tradition, because of the bitter taste of anti-malarial quinine tonic, British colonials in India mixed it with gin to make it more palatable, thus creating the gin and tonic cocktail, which is still popular today. [23]

In France, quinine is an ingredient of an apéritif known as quinquina , or "Cap Corse," and the wine-based apéritif Dubonnet. In Spain, quinine (also known as "Peruvian bark" for its origin from the native cinchona tree) is sometimes blended into sweet Malaga wine, which is then called "Malaga Quina". In Italy, the traditional flavoured wine Barolo Chinato is infused with quinine and local herbs, and is served as a digestif . In Scotland, the company A.G. Barr uses quinine as an ingredient in the carbonated and caffeinated beverage Irn-Bru. In Uruguay and Argentina, quinine is an ingredient of a PepsiCo tonic water named Paso de los Toros. In Denmark, it is used as an ingredient in the carbonated sports drink Faxe Kondi made by Royal Unibrew.

As a flavouring agent in drinks, quinine is limited to less than 83 parts per million in the United States, and 100 mgl in the European Union. [24] [25] [26]

Scientific

Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation as well as for numerous other chiral catalyst backbones. Because of its relatively constant and well-known fluorescence quantum yield, quinine is used in photochemistry as a common fluorescence standard. [27] [28]

Contraindications

Because of the narrow difference between its therapeutic and toxic effects, quinine is a common cause of drug-induced disorders, including thrombocytopenia and thrombotic microangiopathy. [29] Even from minor levels occurring in common beverages, quinine can have severe adverse effects involving multiple organ systems, among which are immune system effects and fever, hypotension, hemolytic anemia, acute kidney injury, liver toxicity, and blindness. [29] In people with atrial fibrillation, conduction defects, or heart block, quinine can cause heart arrhythmias, and should be avoided. [30]

Quinine can cause hemolysis in G6PD deficiency (an inherited deficiency), but this risk is small and the physician should not hesitate to use quinine in people with G6PD deficiency when there is no alternative. [31]

Adverse effects

Quinine can cause unpredictable serious and life-threatening blood and cardiovascular reactions including low platelet count and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), long QT syndrome and other serious cardiac arrhythmias including torsades de pointes, blackwater fever, disseminated intravascular coagulation, leukopenia, and neutropenia. [4] Some people who have developed TTP due to quinine have gone on to develop kidney failure. [4] [31] It can also cause serious hypersensitivity reactions include anaphylactic shock, urticaria, serious skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, granulomatous hepatitis, and itchiness. [4] [31]

The most common adverse effects involve a group of symptoms called cinchonism, which can include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. [4] [29] [31] More severe cinchonism includes vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in heart rhythms. [31] Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many people will vomit after ingesting quinine tablets). [4] Other drugs, such as Fansidar (sulfadoxine with pyrimethamine) or Malarone (proguanil with atovaquone), are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless, [32] but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.

Quinine has diverse unwanted interactions with numerous prescription drugs, such as potentiating the anticoagulant effects of warfarin. [4]

Mechanism of action

Quinine is used for its toxicity to the malarial pathogen, Plasmodium falciparum , by interfering with the parasite's ability to dissolve and metabolize hemoglobin. [4] [33] As with other quinoline antimalarial drugs, the precise mechanism of action of quinine has not been fully resolved, although in vitro studies indicate it inhibits nucleic acid and protein synthesis, and inhibits glycolysis in P. falciparum. [4] The most widely accepted hypothesis of its action is based on the well-studied and closely related quinoline drug, chloroquine. This model involves the inhibition of hemozoin biocrystallization in the heme detoxification pathway, which facilitates the aggregation of cytotoxic heme.[ medical citation needed ] Free cytotoxic heme accumulates in the parasites, causing their deaths. [34] Quinine may target the malaria purine nucleoside phosphorylase enzyme. [35]

Chemistry

Robert B. Woodward Robert Burns Woodward in 1965.jpg
Robert B. Woodward

The UV absorption of quinine peaks around 350 nm (in UVA). Fluorescent emission peaks at around 460 nm (bright blue/cyan hue). [36] Quinine is highly fluorescent (quantum yield ~0.58) in 0.1 M sulfuric acid solution. [27] [28] The 3D structure of quinine can be viewed using QRChem.net.

Synthesis

Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure during World War II, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering. [37] Since then, several more efficient quinine total syntheses have been achieved, [38] but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.

Biosynthesis

Quinine biosynthesis Quinine Biosynthesis.png
Quinine biosynthesis

In the first step of quinine biosynthesis, the enzyme strictosidine synthase catalyzes a stereoselective Pictet–Spengler reaction between tryptamine and secologanin to yield strictosidine. [39] [40] Suitable modification of strictosidine leads to an aldehyde. Hydrolysis and decarboxylation would initially remove one carbon from the iridoid portion and produce corynantheal. Then the tryptamine side-chain were cleaved adjacent to the nitrogen, and this nitrogen was then bonded to the acetaldehyde function to yield cinchonaminal. Ring opening in the indole heterocyclic ring could generate new amine and keto functions. The new quinoline heterocycle would then be formed by combining this amine with the aldehyde produced in the tryptamine side-chain cleavage, giving cinchonidinone. For the last step, hydroxylation and methylation gives quinine. [41] [42]

History

19th-century illustration of Cinchona calisaya Cinchona calisaya - Kohler-s Medizinal-Pflanzen-179.jpg
19th-century illustration of Cinchona calisaya

Quinine was used as a muscle relaxant by the Quechua people, who are indigenous to Peru, Bolivia and Ecuador, to halt shivering. [43] The Quechua would mix the ground bark of cinchona trees with sweetened water to offset the bark's bitter taste, thus producing something similar to tonic water. [44]

Spanish Jesuit missionaries were the first to bring cinchona to Europe. The Spanish had observed the Quechua's use of cinchona and were aware of the medicinal properties of cinchona bark by the 1570s or earlier: Nicolás Monardes (1571) and Juan Fragoso (1572) both described a tree, which was subsequently identified as the cinchona tree, whose bark was used to produce a drink to treat diarrhea. [45] Quinine has been used in unextracted form by Europeans since at least the early 17th century. [46]

A popular story of how it was brought to Europe by the Countess of Chinchon was debunked by medical historian Alec Haggis around 1941. [47] During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome. It had caused the deaths of several popes, many cardinals and countless common Roman citizens. Most of the Catholic priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the febrile phase of the disease.

The Jesuit Agostino Salumbrino (1564–1642), [48] an apothecary by training who lived in Lima (now in present-day Peru), observed the Quechua using the bark of the cinchona tree to treat such shivering. While its effect in treating malaria (and malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was a successful medicine against malaria. At the first opportunity, Salumbrino sent a small quantity to Rome for testing as a malaria treatment. [49] In the years that followed, cinchona bark, known as Jesuit's bark or Peruvian bark, became one of the most valuable commodities shipped from Peru to Europe. When King Charles II was cured of malaria at the end of the 17th Century with quinine, it became popular in London. [50] It remained the antimalarial drug of choice until the 1940s, when other drugs took over. [51]

The form of quinine most effective in treating malaria was found by Charles Marie de La Condamine in 1737. [52] [53] In 1820, French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou first isolated quinine from the bark of a tree in the genus Cinchona – probably Cinchona officinalis – and subsequently named the substance. [54] The name was derived from the original Quechua (Inca) word for the cinchona tree bark, quina or quina-quina, which means "bark of bark" or "holy bark". Prior to 1820, the bark was dried, ground to a fine powder, and mixed into a liquid (commonly wine) in order to be drunk. Large-scale use of quinine as a malaria prophylaxis started around 1850. In 1853 Paul Briquet published a brief history and discussion of the literature on "quinquina". [55]

Quinine played a significant role in the colonization of Africa by Europeans. The availability of quinine for treatment had been said to be the prime reason Africa ceased to be known as the "white man's grave". A historian said, "it was quinine's efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa". [56]

To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings in the early 19th century. The Dutch government persisted in its attempts to smuggle the seeds, and by the late 19th century the Dutch grew the plants in Indonesian plantations. Soon they became the main suppliers of the tree. In 1913 they set up the Kina Bureau, a cartel of cinchona producers charged with controlling price and production. [57] By the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the world's quinine production. [56] U.S. attempts to prosecute the Kina Bureau proved unsuccessful. [57]

During World War II, Allied powers were cut off from their supply of quinine when Germany conquered the Netherlands, and Japan controlled the Philippines and Indonesia. The US had obtained four million cinchona seeds from the Philippines and began operating cinchona plantations in Costa Rica. Additionally, they began harvesting wild cinchona bark during the Cinchona Missions. Such supplies came too late. Tens of thousands of US troops in Africa and the South Pacific died of malaria due to the lack of quinine. [56] Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the southwest Pacific died as a result. [58] [59] [60] [61]

Quinine remained the antimalarial drug of choice until after World War II. Since then, other drugs that have fewer side effects, such as chloroquine, have largely replaced it. [62]

Bromo Quinine were brand name cold tablets containing quinine, manufactured by Grove Laboratories. They were first marketed in 1889 and available until at least the 1960s. [63]

Conducting research in central Missouri, Dr. John S. Sappington independently developed an anti-malaria pill from quinine. Sappington began importing cinchona bark from Peru in 1820. In 1832, using quinine derived from the cinchona bark, Sappington developed a pill to treat a variety of fevers, such as scarlet fever, yellow fever, and influenza in addition to malaria. These illnesses were widespread in the Missouri and Mississippi valleys. He manufactured and sold "Dr. Sappington's Anti-Fever Pills" across Missouri. Demand became so great that within three years, Dr. Sappington founded a company known as Sappington and Sons to sell his pills nationwide. [64]

Society and culture

Natural occurrence

The bark of Remijia contains 0.5–2% of quinine. The bark is cheaper than bark of Cinchona . As it has an intense taste, it is used for making tonic water. [65]

Regulation in the US

From 1969, to 1992, the US Food and Drug Administration (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death. [66] In 1994, the FDA banned the marketing of over-the-counter quinine as a treatment for nocturnal leg cramps. Pfizer Pharmaceuticals had been selling the brand name Legatrin for this purpose. Also sold as a Softgel (by SmithKlineBeecham) as Q-vel.[ citation needed ] Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. The FDA is also cautioning consumers about off-label use of quinine to treat leg cramps. [15] [16] Quinine is approved for treatment of malaria, but was also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that affliction. [67]

Though Legatrin was banned by the FDA for the treatment of leg cramps, the drug manufacturer URL Mutual has branded a quinine-containing drug named Qualaquin. It is marketed as a treatment for malaria and is sold in the United States only by prescription. In 2004, the CDC reported only 1,347 confirmed cases of malaria in the United States. [68]

Cutting agent

Quinine is sometimes detected as a cutting agent in street drugs such as cocaine and heroin. [69]

Other animals

Quinine is used as a treatment for Cryptocaryon irritans (commonly referred to as white spot, crypto or marine ich) infection of marine aquarium fish. [70]

Related Research Articles

Malaria Mosquito-borne infectious disease

Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause yellow skin, seizures, coma, or death. Symptoms usually begin ten to fifteen days after being bitten by an infected mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.

<i>Cinchona</i> genus of flowering plants in the coffee family Rubiaceae, source of quinine

Cinchona 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.

Tonic water Carbonated soft drink in which quinine is dissolved

Tonic water is a carbonated soft drink in which quinine is dissolved. Originally used as a prophylactic against malaria, tonic water usually now has a significantly lower quinine content and is consumed for its distinctive bitter flavor, though it is nowadays also often sweetened. It is often used in mixed drinks, particularly in gin and tonic.

Mefloquine

Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken by mouth.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

Cinchonism is a pathological condition caused by an overdose of quinine or its natural source, cinchona bark. Quinine and its derivatives are used medically to treat malaria and lupus erythematosus. In much smaller amounts, quinine is an ingredient of tonic drinks, acting as a bittering agent. Cinchonism can occur from therapeutic doses of quinine, either from one or several large doses. Quinidine can also cause cinchonism symptoms to develop with as little as a single dose.

<i>Plasmodium falciparum</i> Protozoan species of malaria parasite

Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as Group 2A carcinogen.

Quinidine

Quinidine is a medication that acts as a class I antiarrhythmic agent (Ia) in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval.

Quinquina Variety of apéritif wines

Quinquina, an aromatised wine, is a variety of apéritif wine. Traditionally quinquinas contain cinchona bark, which provides quinine. Quinine was used in treating malaria.

Artemether

Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also available by mouth in combination with lumefantrine, known as artemether/lumefantrine.

Artesunate

Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of malaria. Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.

Chloroquine Medication used to treat malaria

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.

Primaquine

Primaquine is a medication used to treat and prevent malaria and to treat Pneumocystis pneumonia. Specifically it is used for malaria due to Plasmodium vivax and Plasmodium ovale along with other medications and for prevention if other options cannot be used. It is an alternative treatment for Pneumocystis pneumonia together with clindamycin. It is taken by mouth.

Quinic acid is a cyclitol, a cyclic polyol, and a cyclohexanecarboxylic acid. It is a colorless solid that can be extracted from plant sources. Quinic acid is implicated in the perceived acidity of coffee.

<i>Cinchona officinalis</i> Species of plant

Cinchona officinalis is a South American tree in the family Rubiaceae. It is native to wet montane forests in Colombia, Ecuador, Peru and Bolivia, between 1600–2700 meters above sea level.

Malaria prophylaxis is the preventive treatment of malaria. Several malaria vaccines are under development.

<i>Cinchona pubescens</i> Species of plant

Cinchona pubescens, also known as red cinchona and quina (Quechua), is native to Central and South America. It is known as a medicinal plant for its bark's high quinine content- and has similar uses to Cinchona officinalis in the production of quinine, most famously used for treatment of malaria.

History of malaria

The history of malaria stretches from its prehistoric origin as a zoonotic disease in the primates of Africa through to the 21st century. A widespread and potentially lethal human infectious disease, at its peak malaria infested every continent, except Antarctica. Its prevention and treatment have been targeted in science and medicine for hundreds of years. Since the discovery of the Plasmodium parasites which cause it, research attention has focused on their biology, as well as that of the mosquitoes which transmit the parasites.

Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. It contains atovaquone and proguanil. It is not recommended for severe or complicated malaria. It is taken by mouth.

John Sappington American physician

John S. Sappington (1776-1856) was an American physician known for developing a quinine pill to treat malarial and other fever diseases in the Missouri and Mississippi valleys, where the disease was widespread. He later used the pill to prevent malaria. Because he both manufactured and sold "Dr. Sappington's Anti-Fever Pills", he became wealthy from his bestseller.

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  33. Wishart, David S.; Djombou Feunang, Yannick; Guo, An Chi; Lo, Elvis J.; Marcu, Ana; Grant, Jason R.; Sajed, Tanvir; Johnson, Daniel; Li, Carin; Sayeeda, Zinat; Assempour, Nazanin; Iynkkaran, Ithayavani; Liu, Yifeng; Maciejewski, Adam; Gale, Nicola; Wilson, Alex; Chin, Lucy; Cummings, Ryan; Le, Diana; Pon, Allison; Knox, Craig; Wilson, Michael. "Quinine | DrugBank Online". DrugBank . 5.0.
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  45. See:
    • Ortiz Crespo, Fernando Ignacio (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. ISSN   0260-9541.
    • Stuart, David C. (2004). Dangerous Garden: The Quest for Plants to Change Our Lives. Cambridge, MA: Harvard University Press. p. 28. ISBN   978-0-674-01104-5.
    • Monardes, Nicolás (1580). Primera y segunda y tercera partes de la Historia medicinal, de las cosas que se traen de nuestras Indias Occidentales, que sirven en Medicina (in Spanish). Seville, Spain: Fernando Díaz. pp. 74–75. Del nuevo Reyno, traen una corteza, que dizen ser de un arbol, que es de mucha grandeza: el qual dizen que lleva unas hojas en forma de coraçon, y que no lleva fruto. Este arbol tiene una corteza gruessa, muy solida y dura, que en esto y en el color parece mucho a la corteza del palo que llaman Guayacan: en la superficie tiene una pelicula delgada blanquisca, quebrada por toda ella: tiene la corteza mas de un dedo de gruesso, solida y pesada: la qual gustada tiene notable amargor, como el de la Genciana: tiene en el gusto notable astriction, con alguna aromaticidad, porque al fin de mascar la respica della buen olor. Tienen los Indios esta corteza en mucho, y usan della en todo genero de camaras, que sean con sangre, o sin ella. Los Españoles fatigados de aquesta enfermedad, por aviso de los Indios, han usado de aquesta corteza y han sanado muchos dellos con ella.
      Toman della tanto como una haba pequeña hecha polvos, tomase en vino tinto, o en agua apropiada, como tienen la calentura, o mal: hase de tomar por la mañana en ayunas, tres o quatro vezes: usando en lo demas, la orden y regimiento que conviene a los que tienen camaras.
      [From the new kingdom, there is brought a bark, which is said to be from a tree, which is very large: it is said that it bears leaves in the form of a heart, and that it bears no fruit. This tree has a thick bark, very solid and hard, that in this and in its color looks much like the bark of the tree that is called guayacán : on the surface, it has a thin, discontinuous whitish film throughout it: it has bark more than one finger thick, solid and heavy: which, when tasted, has a considerable bitterness, like that of the gentian: it has in its taste a considerable astringency, with some aromaticity, because at the end of chewing it, one breathes with a sweet odor. The Indians hold this bark in high regard, and use it for all sorts of diarrhea, that are with blood [i.e., bloody] and without it. The Spanish [who are] tired of this disease, on the advice of the Indians, have used this bark and have healed many of those with it. They take as much as a small bean, make [it into] powder, take it in red wine or in appropriate water, if they have fever or illness: it must be taken in the morning on an empty stomach, three or four times: otherwise, using the order and regimen that suits those who have diarrhea.]
    • Fragoso, Juan (1572). Discursos de las cosas aromaticas, arboles y frutales, y de otras muchas medicinas simples que se traen de la India Oriental y que sirven al uso de medicina [Discourse on fragrant things, trees and fruits, as well as many other ordinary medicines that have been brought from India and the Orient and are of use to medicine] (in Spanish). Madrid, Spain: Francisco Sánchez. p. 35. En el nuevo mundo ay un grande arbol que lleva las hojas a forma de coraçon, y carece de fruto. Tiene dos cortezas, la una gruessa muy solida y dura, que assi en la sustancia como en el color es muy semejante al Guayacan: la otra es mas delgada y blanquezina, la qual es amarga con alguna estipticidad: y demas desto es aromatica. Tienenla en mucho nuestros Indios, porque la usan contra qualesquier camaras, tomando del polvo peso de una drama o poco mas, desatado en agua azerada, o vino tinto.[In the new world, there is a big tree that bears leaves in the form of a heart, and lacks fruit. It has two barks, one [is] thick, very solid, [and] hard, which in substance as well as in color is much like guayacan [i.e., lignum vitae]: the other is thinner and whitish, which is bitter with some styptic [i.e., astringent] quality: and besides this, it is aromatic. Our Indians regard it highly, because they use it against any diarrheas, taking a weight of a dram or a bit more of the powder, mixing it in mineral water, or red wine.]
  46. Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U (May 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.
  47. Stephanie Pain (15 September 2001). "The Countess and the cure". New Scientist.
  48. Alonso de Andrade (3 August 1642). "Vida del Devoto Hermano Agustin Salumbrino" [The life of the devout Brother Agustin Salumbrino]. Varones ilustres en santidad, letras y zelo de las almas de la Compañía de Jesús [Illustrious men in holiness, letters, and zeal for souls of the Society of Jesus ]. Varones ilustres de la Compañía de Jesús (in Spanish). 5. Original series by Juan Eusebio Nieremberg. Madrid, Spain: José Fernandez de Buendía (published 1666). pp. 612–628. p. 612: Naciò el Hermano Agustin Salumbrino el año de mil y quinientos y sesenta y quatro en la Ciudad de Fḷọṛi en la Romania […][Brother Agustino Salumbrino was born in the year 1564 in the city of Forlì in Romagna ]
  49. See:
    • Medina Rodríguez, Francisco; Aceves Ávila, Francisco Javier; Moreno Rodríguez, José (2007). "Precisions on the History of Quinine". Reumatología Clínica. Letters to the Editor. 3 (4): 194–196. doi:10.1016/S2173-5743(07)70246-0. ISSN   2173-5743. In fact, though the last wordon this has not yet been spoken, there are Jesuit texts thatmention that quinine reached Rome in 1632, with theprovincial of the Jesuit missions in Peru, father AlonsoMessia Venegas, as its introducer, when he brought asample of the bark to present it as a primacy, and whohad left Lima 2 years earlier, because evidence of his stayin Seville 1632 has been registered, publishing one of hisbooks there and following his way to Rome as a procurator.
    • Torres Saldamando, Enrique (June 1882). "El P. Diego de Torres Vazquez". Los antiguos jesuitas del Perú (in Spanish). Lima, Peru: Imprenta Liberal. pp. 180–181. p. 181: Al siguiente año se dirigieron á Europa los Procuradores P. Alonso Messía Venegas y P. Hernando de Leon Garavito, llevando gran cantidad de la corteza de la quina, cuyo conocimiento extendieron por el mundo los jesuitas.[In the following year [i.e., 1631] there went to Europe the procurators Father Alonso Messia Venegas and Father Hernando de Leon Garavito, taking a great quantity of cinchona bark, knowledge of which the Jesuits spread throughout the world.]
    • Bailetti, Alberto. "Capítulo 10: La Condesa de Chinchón". LA MISIÓN DEL JESUITA AGUSTÍN SALUMBRINO, la malaria y el árbol de quina. A últimas horas de la tarde del treinta y uno de mayo de 1631 se hizo a la vela la Armada Real con dirección a Panamá llevando el precioso cargamento de oro y plata.
      En una de las naves viajaban los procuradores jesuitas padres Alonso Messia y Hernando León Garavito custodiando los fardos con la corteza de quina en polvo preparados por Salumbrino. Después de casi veinte días de navegación el inapreciable medicamento llegó a la ciudad de Panamá, donde fue descargado para cruzar en mulas el agreste camino del itsmo palúdico hasta Portobelo para seguir a Cartagena y la Habana, cruzar el Atlántico y llegar a Sanlúcar de Barrameda en Sevilla. […] Finalmente siguió su camino a Roma y a su destino final el Hospital del Espíritu Santo.
      [Late in the afternoon of the 31st of May, 1631, the royal armada set sail in the direction of Panama, carrying its multimillion [dollar] cargo of gold and silver.
      On one of the ships traveled the Jesuit procurators Fathers Alonso Messia and Hernando León Garavito, guarding the cases of powdered cinchona bark, prepared by Salumbrino. After almost 20 days of sailing, medicine arrived in the city of Panama, where it was transloaded onto mules. It then traveled the malarial isthmus as far as Portobelo, thence to Cartagena [in Colombia] and Havana. It then traveled to Sanlúcar de Barrameda in Seville, [Spain]. […] Finally it followed the road to Rome and to its final destination, the Hospital of the Holy Spirit]
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