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Quinine

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Quinine, was the first known antimalarial. It is a 4-quinolinemethanol derivative bearing a substituted quinuclidine ring. The use of quinine in Europe began in the seventeenth century, after the Incas of Peru informed the Spanish Jesuits about the antimalarial properties of the bark of an evergreen mountain tree they called quinquina (later called cinchona, after Dona Franciscoa Henriquez de Ribera [1576–1639], Countess of Chinchon and wife of the Peruvian Viceroy).

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Quinine is odorless, but has an intense, bitter taste

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Appearance: white granular or microcrystalline powder. No smell, slightly bitter. Solubility: easily dissolved in ethanol, chloroform, and ethyl. Slightly soluble in water and glycerol. Melting point: 173–175 °C. Specific optical rotation: ?172° (ETOH, C = 1).

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Reported present in Cinchona officinalis.

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Quinine is a white crystalline alkaloid best known for treating malaria. Quinine is derived from the bark of several species of trees in the genus Cinchona in the Rubiaceae family. Cinchona trees grow on the eastern slopes of the Andes Mountains at elevations of several thousand feet. Because these symptoms were associated with malaria, Cinchona bark powder was recognized as a possible treatment in the 1600s by Jesuit missionaries.
After decades of work by numerous investigators, quinine was finally isolated in 1820 by Pierre-Joseph Pelletier (1788–1842) and Joseph-Bienaimé Caventou (1795–1877). The name quinine originates from the native word for the Cinchona tree quina quina, which became the Spanish word quino for cinchona. The development of organic synthesis in the middle of the 19th century and the limited supply of quinine stimulated attempts to synthesize it. William Henry Perkins’s (1838–1907) attempt to synthesize quinine in 1856 led to his discovery of mauve, which was a signifi cant discovery in the dye industry (see Indigo).

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Because of its relatively constant and well-known fluorescence quantum yield, quinine is also used in photochemistry as a common fluorescence standard. It has been used for imaging of oxygen evolution and oxide formation. Chloride and bromide have been sh

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By reaction from cinchona bark (Cinchona officinalis), where it is present at approximately 8%.

Indications

Quinine is one of several alkaloids derived from the bark of the cinchona tree. The mechanism by which it exerts its antimalarial activity is not known. It does not bind to DNA at antimalarial dosages. It may poison the parasite’s feeding mechanism, and it has been termed a general protoplasmic poison, since many organisms are affected by it.
Quinine is rapidly absorbed following oral ingestion, with peak blood levels achieved in 1 to 4 hours. About 70 to 93% of the drug is bound to plasma proteins, depending on the severity of the infection. Quinine is extensively metabolized, with only about 20% of the parent compound eliminated in the urine.
The primary present-day indication for quinine and its isomer, quinidine, is in the intravenous treatment of severe manifestations and complications of chloroquine- resistant malaria caused by P. falciparum.
Aside from its use as an antimalarial compound, quinine is used for the prevention and treatment of nocturnal leg muscle cramps, especially those resulting from arthritis, diabetes, thrombophlebitis, arteriosclerosis, and varicose veins.

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quinine: A white solid,C₂₀H₂₄N₂O₂·3H₂O, m.p. 57°C. It is apoisonous alkaloid occurring in thebark of the South American cinchonatree, although it is now usually producedsynthetically. It forms saltsand is toxic to the malarial parasite,and so quinine and its salts are used to treat malaria; in small doses itmay be prescribed for colds and influenza.In dilute solutions it has apleasant astringent taste and is addedto some types of tonic water.

Antimicrobial activity

Quinine inhibits the erythrocytic stages of human malaria parasites at <1 mg/L, but not the liver stages. It is active against the gametocytes of P. vivax, P. ovale and P. malariae, but not P. falciparum. The dextrarotatory stereoisomer, quinidine, is more active than quinine, but epiquinine (cinchonine) and epiquinidine (cinchonidine) have much lower antimalarial activities.

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Resistance is now widespread in South East Asia, where some strains are also resistant to chloroquine, sulfadoxine– pyrimethamine and mefloquine. Cross-resistance with mefloquine has been demonstrated in P. falciparum, but genetic polymorphisms associated with chloroquine resistance are not associated with quinine resistance.

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Quinine, a cinchona alkaloid found in the bark of the cinchona tree, is known for its anti-malarial property.

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Skin irritant, ingestion of pure substance adversely affects eyes.

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The toxicity of quinine is characterized bycinchonism, a term that includes tinnitus,vomiting, diarrhea, fever, and respiratorydepression. Other effects include stimulationof uterine muscle, analgesic effect,and dilation of the pupils. Severe poisoningmay produce neurosensory disorders, causingclouded vision, double vision, buzzing of theears, headache, excitability, and sometimescoma (Ferry and Vigneau 1983). Death fromquinine poisoning is unusual. Massive dosesmay be fatal, however.
LD50 value, oral (guinea pigs): 1800 mg/kg.

Pharmaceutical Applications

A quinolinemethanol from the bark of the Cinchona tree; the laevorotatory stereoisomer of quinidine. Formulated as the sulfate, bisulfate or ethylcarbonate for oral use and as the dihydrochloride for parenteral administration. The salts are highly soluble in water.

Pharmacokinetics

Oral absorption: 80–90%
C_max 600 mg oral: 5 mg/L after 1–3 h
Plasma half-life: 8.7 h
Volume of distribution: 1.8 L/kg
Plasma protein binding: c. 70%
Quinine is well absorbed by the oral route. Intramuscular administration gives more predictable data than intravenous administration and may be more useful in children. Plasma protein binding rises to 90% in uncomplicated malaria and 92% in cerebral malaria due to high levels of acute-phase proteins. Similarly, the elimination half-life rises to 18.2 h in severe malaria. There is extensive hepatic metabolism to hydroxylated derivatives. Urinary clearance is <20% of total clearance.

Pharmacology

In terms of its type of action, quinine is an antimalarial drug similar to chloroquine, although it is inferior in its activity.
Like chloroquine, quinine binds with plasmodium DNA, thus interfering in the synthesis of nucleic acids and preventing its replication and transcription. Quinine also suppresses a large portion of the enzymatic system and therefore it is characterized as a general protoplasmid toxin. This fact agrees well with the action of quinine on membranes, its local anesthetizing and its cardiodepressive effects.
Upon oral administration, quinine effectively acts in combination with pyrimethamine, sulfadiazine, and/or tetracycline for treating uncomplicated incidents of chloroquineresistant forms of P. falciparum. Because of the many associated side effects, its use is extremely limited. Currently, the only indication for use is for forms of malaria that are resistant to other synthetic drugs. Synonyms of this drug are bronchopulmin, nicopriv, quinnam, and others.

Clinical Use

Falciparum malaria (alone or in combination with tetracycline, doxycycline, clindamycin or pyrimethamine–sulfadoxine)
Babesiosis (in combination with clindamycin)
It is particularly used in cerebral malaria if chloroquine resistance is suspected (Ch. 62). It is not recommended for treatment of uncomplicated falciparum malaria.

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Up to 25% of patients experience cardiac dysrhythmia, hypoglycemia, cinchonism (tinnitus, vomiting, diarrhea, headache). Severe effects, including hypotension and hypoglycemia, are of particular importance in children, pregnant women and the severely ill. Rarely, it can induce hemolytic anemia (‘blackwater fever’). Quinine inhibits tryptophan uptake into cells.

Safety Profile

Human poison by unspecified route. Experimental poison by subcutaneous, intravenous, intramuscular, and intraperitoneal routes. Moderately toxic experimentally by ingestion. An experimental teratogen. Human systemic effects by ingestion: visual field changes, tinnitus, and nausea or vomiting. Human teratogenic effects by ingestion: developmental abnormahties of the central nervous system, body wall, and musculoskeletal, cardovascular, and hepatoblltary systems. Experimental reproductive effects. Mutation data reported. Can cause temporary loss of vision. Quinine dermatitis is an occupational hazard to barbers particularly, and generally to people who work with quinine tonics, medcaments, or cosmetics. An irritant to mucous membranes. Combustible when exposed to heat or flame. Decomposes on exposure to light. When heated to decomposition it emits toxic fumes of NOx. Used to treat malaria.

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Quinine is metabolized in the liver to the 2′-hydroxy derivative, followed by additional hydroxylation on the quinuclidine ring, with the 2,2′-dihydroxy derivative as the major metabolite. This metabolite has low activity and is rapidly excreted. The metabolizing enzyme of quinine is CYP3A4. With the increased use of quinine and its use in combination with other drugs, the potential for drug interactions based on the many known substrates for CYP3A4 is of concern.

Purification Methods

Crystallise the quinine from absolute EtOH. It has been used as a chiral catalyst (see previous entry). [Beilstein 23 H 511, 23 I 166, 23 II 416, 23 III/IV 3265, 23/13 V 395.]

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Pelletier, Dumas., Ann. Chim. Phys., 15,291,1337 (1820)
Hesse., Annalen, 258, 133 (1890)
Fiihner., Arch. Pharm., 244, 602 (1906)
Seekles., Rev. Trav. Chim., 42, 72 (1923)
Kindler., Chem. Ztg., 56, 165 (1932)
Cohen.,J. Chem. Soc., 999 (1933)
Velter., Festschrift., 542 (Basle, 1936)
Woodward, Doering.,J. Amer. Chem. Soc., 67,860 (1945)
Pharmacology :
Acton, King., Biochem. J., 15,53 (1921)
Sterkin, Helfgat., Biochem. Zeit., 207, 8 (1929)
Wagenaar.,Pharm. Weekbl., 66, 177, 197,250,261 (1929)
Wagenaar., ibid, 71,316 (1934)
Monnet., J. Pharm. Chim., 18, 94 (1933)
Buttle, Henry, Trevan., Biochem. J., 28,426 (1934)
Seeler, Dusenbery, Malanga.,J. Pharm. Exp. Ther., 78, 159 (1943)
Marshall., ibid, 85, 299 (1945)

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