奎宁是一种用于治疗疟疾和巴贝斯虫病的药物。[1]可用于治疗在青蒿琥酯缺乏时对氯喹具有耐药性的恶性疟原虫引起的疟疾。[1][2]虽然可以用于治疗不宁腿综合征，但由于有副作用的风险，不建议用。[1]它可以口服或静脉注射。[1]疟疾对奎宁的耐药性出现在世界某些地区。[1]奎宁也是汤力水的成分，使它具有苦味。[3]常见的副作用包括头痛、耳鸣、视力障碍和出汗。[1]更严重的副作用包括耳聋、血小板减少和心律不齐。[1]使用奎宁还会使人更容易晒伤。[1]虽然尚不清楚怀孕期间使用是否会对婴儿造成伤害，但仍建议用于治疗孕期疟疾。[1]奎宁是生物碱，一种天然存在的化合物。[1]它作为一种药物是如何起作用的还不完全清楚。[1]
1820年，奎宁首次从金鸡纳树的树皮中被分离出来。[1][4][5]树皮提取物至少从1632年开始就被用来治疗疟疾。[6]它被列入世界卫生组织的基本药物清单，是卫生系统所需的最有效和最安全的药物。[7]在发展中国家，奎宁的批发价约为每疗程1.70至3.40美元。[8]在美国，一个疗程的治疗费用超过200美元。[9]
自2006年起，世卫组织(世界卫生组织)不再建议将其作为疟疾的一线治疗方法，仅在青蒿素不可用时使用。[10][11][12][13]奎宁也用于治疗狼疮和关节炎。
在过去，奎宁经常被作为治疗夜间腿部抽筋的非标签药物，但由于食品和药物管理局警告称这种做法可能会导致危及生命的副作用，这种情况变得不那么常见了。[14]
可用形式
奎宁是一种碱性胺，通常以盐的形式存在。现有的各种制剂包括盐酸盐、二盐酸盐、硫酸盐、硫酸氢盐和葡萄糖酸盐。在美国，硫酸奎宁在市场上以324毫克片剂的形式出售，品牌为Qualaquin。
所有奎宁盐可以口服或静脉注射(四)；葡萄糖酸奎宁也可以肌肉注射或直肠注射。[15][16]直肠注射的主要问题是剂量在被完全吸收之前就会被排出体外；临床中，这可以通过再给一半剂量来弥补。奎宁注射制剂在美国没有被许可使用；取而代之的是奎尼丁。[17][18]
| 姓名 | 奎宁碱当量 |
|---|---|
| 奎宁碱 | 100毫克 |
| 硫酸奎宁 | 169毫克 |
| 盐酸奎宁 | 122毫克 |
| 葡萄糖酸奎宁 | 160毫克 |
| 盐酸奎宁 | 111毫克 |
| 硫酸奎宁二水合物 | 121毫克 |
奎宁是汤力水和苦味柠檬混合饮料的风味成分。在许多酒吧后的苏打枪上，奎宁水由代表奎宁的字母“Q”表示。[19]
根据传统，抗疟药奎宁汤剂的苦味导致在印度的英国殖民者将其与杜松子酒混合，从而创造出至今仍受欢迎的标志性杜松子奎宁鸡尾酒。如今，奎宁补剂中奎宁的含量要低得多，饮用它来治疗疟疾是没有用的。在美国，奎宁被列为一些调味Snapple饮料 (包括蔓越莓-覆盆子口味)的一种成分。
在法国，奎宁是一种叫做quinquina或"Cap Corse"的开胃酒和一种以葡萄酒为基础的开胃杜本内酒的成分。在西班牙，奎宁(“秘鲁树皮”)有时被混入甜马拉加酒，然后被称为“Malaga Quina”。在意大利，传统风味葡萄酒Barolo Chinato被注入奎宁和当地草药，并被用作餐后酒。在加拿大和意大利，奎宁是碳酸圣培露果汁饮料Brio和San Pellegrino的一种成分。在苏格兰，A.G. Barr公司使用奎宁作为碳酸饮料和含咖啡因饮料Irn-Bru的成分。在乌拉圭和阿根廷，奎宁是百事可乐公司汤力水的一种成分。在丹麦，它被用作Royal Unibrew公司生产的碳酸运动饮料Faxe Kondi的成分。
作为饮料中的调味剂，奎宁含量在美国被限制在百万分之83以下，在欧盟被限制在百万分之100毫克。[20][21][22]
奎宁(和奎尼丁)被用作手性配体，用于Sharpless不对称二羟基化中，也是许多其他手性催化剂的骨架。奎宁由于其众所周知且相对恒定的荧光量子产率，在光化学中被用作常见的荧光标准物质。
由于奎宁的治疗作用和毒性作用差别很小，因此奎宁是药物性疾病的常见原因，包括血小板减少症和血栓性微血管病。 即使普通饮料中含有少量奎宁，奎宁也可能对多器官系统产生严重的副作用，其中包括免疫系统效应和发烧、低血压、溶血性贫血、急性肾损伤、肝毒性和失明。 对于患有心房颤动、传导缺陷或心脏传导阻滞的患者，奎宁可导致心律失常，应避免摄入。
奎宁可导致G6PD缺乏症(一种遗传性缺陷)的溶血，但这种风险很小，当别无选择时，医生应该毫不犹豫地对UIG6PD缺乏症患者使用奎宁。
奎宁可导致不可预测且严重危及生命的血液和心血管反应，包括血小板计数低和溶血性尿毒症综合征/血栓性血小板减少性紫癜(HUS/TTP)、长QT综合征和其他严重心律失常，包括尖端扭转型室性心动过速、黑水热、弥散性血管内凝血、白细胞减少和中性粒细胞减少。一些由于奎宁而发展成TTP的人，后来发展成肾衰竭。[23] 它还可引起严重过敏反应，包括过敏性休克、荨麻疹、严重皮疹(包括史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症)、血管性水肿、面部水肿、支气管痉挛、肉芽肿性肝炎和瘙痒。[23]
最常见的副作用包括一组称为金鸡纳病的症状，包括头痛、血管扩张和出汗、恶心、耳鸣、听力损伤、眩晕或头晕、视力模糊和色觉障碍。[23][23] 更严重的金鸡纳病包括呕吐、腹泻、腹痛、耳聋、失明和心律失常。[23] 当口服奎宁时，金鸡纳病不太常见，但口服奎宁耐受性不好(奎宁非常苦，许多患者在服用奎宁片后会呕吐):当需要口服治疗时，通常会使用其他药物，如西达 (磺胺多辛和乙胺嘧啶)或马拉酮(丙胍和阿托瓦酮)。碳酸奎宁乙酯无臭无味，[23] 但仅在日本有售。口服奎宁时，不需要血糖、电解质和心脏监测。
奎宁也是第一种用于治疗疟疾的药物。[35] 奎宁被秘鲁、玻利维亚和厄瓜多尔土著奎丘亚人用作肌肉松弛剂，以治疗因低温而引起的颤抖。[36] 奎丘亚人会将金鸡纳树的树皮与甜味水混合，以抵消树皮的苦味，从而制作汤力水。
耶稣会士是第一个把金鸡纳带到欧洲的人。西班牙人在17世纪70年代或更早就知道金鸡纳树皮的药用价值:尼古拉斯·莫纳德斯(1571)和胡安·弗拉戈索(1572)都描述了一种后来被确定为金鸡纳树的树，其树皮被用来生产治疗腹泻的饮料。[37] 奎宁至少从17世纪早期开始就被欧洲人以未提纯的形式使用。1631年，它首次在罗马被用于治疗疟疾。在17世纪，疟疾是罗马城周围沼泽和湿地的地方病。疟疾导致了几位教皇、许多红衣主教和无数普通罗马公民的死亡。在罗马接受训练的大多数牧师都见过疟疾患者，并且熟悉该疾病发热阶段颤抖的症状。[38] 一个住在利马接受训练的药剂师，耶稣会修士阿戈斯蒂诺·萨伦比诺(1564-1642)，观察到奎丘亚人使用金鸡纳树的树皮来达到治疗疟疾的目的。虽然它在治疗疟疾(以及疟疾引起的颤抖)方面的效果与它在治疗寒颤的效果无关，但它是一种成功的抗疟疾药物。很快，萨伦比诺就派了少量人员到罗马进行疟疾治疗试验。[39] 在接下来的几年里，金鸡纳树皮，被称为耶稣会树皮或秘鲁树皮，成为从秘鲁运往欧洲的最有价值的商品之一。当查理二世国王在17世纪末用奎宁治愈疟疾时，它在伦敦开始流行起来。[40]在20世纪40年代其他药物取代它之前，它一直是首选的抗疟药。[41]
查理·玛丽·德·拉·孔达明在1737年发现了治疗疟疾最有效的奎宁。[42][43]1820年，法国研究人员皮埃尔·约瑟夫·佩尔蒂埃和约瑟夫·别奈姆·卡旺图首先从金鸡纳属的树皮中分离出奎宁，并随后用金鸡纳命名了这种物质。[44]这个名字来源于金鸡纳树皮的最初的盖丘亚(印加)单词，quina或quinaquina, 意思是“树皮的树皮”或“神圣的树皮”。在1820年之前，树皮首先被干燥，磨成细粉，然后混合成液体(通常是葡萄酒)，然后被饮用。奎宁作为疟疾预防药物的大规模使用始于1850年左右。1853年，保罗·布利特出版了《奎那》的简史和文献讨论。[45]
奎宁在欧洲人对非洲的殖民统治中发挥了重要作用。奎宁被认为是非洲不再被称为“白人坟墓”的主要原因。一位历史学家曾说过，“奎宁的功效给了殖民者涌入黄金海岸、尼日利亚和西非其他地区的新机会”。[46]
为了保持对金鸡纳树皮的垄断，秘鲁及其周边国家在19世纪初开始禁止金鸡纳种子和树苗的出口。荷兰政府仍然持续走私奎宁种子，在19世纪晚期，荷兰人在印度尼西亚种植园种植这种植物。很快他们成为了工厂的主要供应商，并在1913年成立了Kina Bureau，一个金鸡纳生产卡特尔（垄断集团），负责控制价格和生产。[47]到20世纪30年代，爪哇的荷兰种植园生产了2200万磅金鸡纳树皮，占世界奎宁产量的97%。[46]美国尝试起诉Kina Bureau，但是没有成功。[47]第二次世界大战期间，德国占领荷兰，日本在控制菲律宾和印度尼西亚的同时，切断了同盟国奎宁的供应。美国从菲律宾获得了400万颗金鸡纳种子，并开始在哥斯达黎加经营金鸡纳种植园。但这些物资来得太晚了，成千上万的美国驻非洲和南太平洋部队因缺乏奎宁而死亡。[46]尽管控制了奎宁的供应，日本人并没有有效利用奎宁，结果成千上万的日本军队在西南太平洋阵亡。[48][49][50][51]奎宁一直是抗疟疾的首选药物，直到二战后，其他副作用较少的药物，如氯喹，基本上取代了奎宁。[52]
Bromo Quinine是格罗夫实验室生产的含有奎宁的品牌感冒药。它们第一次上市是在1889年，但至少在20世纪60年代才能买到。[53]
从1969年到1992年，美国食品和药物管理局(FDA)收到了157份与奎宁使用有关的健康问题报告，其中包括23份导致死亡的报告。[54]1994年，美国食品和药物管理局禁止销售非处方药奎宁来治疗夜间腿部痉挛。为此，辉瑞制药一直在出售品牌为Legatrin的药品。也作为软胶囊出售(由史密斯公司出品)。医生仍可能开含奎宁的处方，但是食品和药物管理局已经命令公司停止销售未经批准的含奎宁的药品。美国食品和药物管理局也警告消费者在使用非标签奎宁药品治疗腿部痉挛需谨慎。奎宁被批准用于治疗疟疾，但也常用于治疗腿部痉挛和类似疾病。因为疟疾威胁生命，使用奎宁治疗这种疾病的风险被认为是可以接受的。[55]
虽然Legatrin被美国食品和药物管理局禁止用于治疗腿部痉挛，但药品制造商URL Mutual已经给一种含有奎宁的药物命名为Qualaquin。它作为治疗疟疾的药物在市场上销售，在美国只能通过处方购买。2004年，美国疾病预防控制中心仅报告了1347例确诊疟疾病例。[56]
奎宁有时被发现用于可卡因和海洛因等街头毒品的切割剂。[57]
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^History of quinine: Friedrich A. Flückiger and Daniel Hanbury, Pharmacographia: A history of the principal drugs of vegetable origin, met with in Great Britain and British India (London, England: Macmillan and Co., 1874), pages 302-331: Cortex Cinchonæ Archived 11 11月 2014 at the Wayback Machine..
^See: Fernando I. Ortiz Crespo (1995) "Fragoso, Monardes and pre-Chinchonian knowledge of Cinchona," Archives of Natural History, 22 (2) : 169–181. David C. Stuart, Dangerous Garden: The Quest for Plants to Change Our Lives (London, England: Frances Lincoln Ltd., 2004), p. 28. Archived 4 6月 2016 at the Wayback Machine Nicolás Monardes, Primera, segunda y tercera partes de la Historia Medicinal de las cosas que le traen de nuestras Indias Occidentales y que sirven en Medicina [First, second and third parts of the medical history of things that have been brought from the new West Indies and that are of use in medicine] (Seville, Spain: Fernando Diaz, 1580), pp. 74-75. Archived 8 5月 2016 at the Wayback Machine From p. 74: "Del nuevo Reyno, traen una corteza, que dizen ser de un arbol, que es de mucha grandeza: el qual dize, que lleva unas hojas de 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 superfiecie 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 dela Genciana: tiene en el gusto notable astriction, con alguna aromaticidad, porque al fin del mascar la respira della buen olor. Tienen los Indios esta corteza en mucho, y usan de lla 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 del los con ella. Toman della tanto como una hava pequeña hecha poluos, toma se en vino tinto, o en agua apropiada, como tienen la calentura, o mal: ha se 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 [i.e., lignum vitae]: 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, Discursos de las cosas Aromáticas, árboles y frutales, y de otras muchas medicinas simples que se traen de la India y Oriental y sirven al uso de la 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] (Madrid, Spain: Francisco Sanchez, 1572), p. 35. Archived 5 5月 2016 at the Wayback Machine From 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 dura, que assi en la sustancia como en el color es muy semejante al Guayacan: la otra es mas delgada y blaquezina, la qual es amarga con alguna estipticidad: y de mas desto es aromatica. Tienen la en mucho nuestros Indios, porque la usan contra qualesquier camaras, tomando de poluo peso de uno 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.).
^Juan Eusebio Nieremberg and Alonso de Andrade, Varones Ilustres en Santidad, Letras, y Zelo de las Almas. De la Compañia de Jesus. [Illustrious men in holiness, letters, and zeal for souls. Of the Society of Jesus (i.e., Jesuits).] (Madrid, Spain: Joseph Fernandez de Buendia, 1666), vol. 5, Vida del devoto Hermano Agustin Salumbrino (The life of the devout Brother Agustin Salumbrino), pp. 612–628 ; see p. 612. Archived 22 5月 2016 at the Wayback Machine From p. 612: "Nacio el Hermano Agustin Salumbrino el año de mil y quinientos y sesenta y quatro en la Ciudad de Flori en le Romania, … " (Brother Agustino Salumbrino was born in the year 1564 in the city of Flori [Note: This is an error; he was born in Forli.] in Emilia-Romagna, … ).
^See: Francisco Medina Rodríguez (July 2007) "Precisiones sobre la historia de la quina" Archived 4 3月 2016 at the Wayback Machine (Details about the history of quinine), Reumatología Clínica, 3 (4) : 194–196. (in Spanish) From p. 195: "De hecho, aunque no esté dicha la ultima palabra, hay escritos jesuitas que mencionan que la quina llegó a Roma en 1632, con el provincial de las missiones jusuitas del Perú, el padre Alonso Messia Venegas, como su introductor, cuando trajo una muestra de la corteza para presentaria como primicia, quien había partido de Lima 2 años antes, ya que consta que estuvo en Sevilla en 1632, donde publicó uno de sus libros y siguió su camino hacia Roma en calidad de procurador." (In fact, however, it is not the last word: there are Jesuit writings that mention that quinine arrived in Rome in 1632, with the provincial of the Jesuit missions of Peru, Father Alonso Messia Venegas, as its introducer, when he brought a sample of the bark so that it could be presented as a novelty, which had left Lima two years before, since in fact it had been in Seville in 1632, where he published one of his books and [then] he went his way toward Rome in the capacity of procurator.) Enrique Torres Saldamando, Los Antiguos Jesuitas del Perú [The old Jesuits of Peru] (Lima, Peru: Imprenta Liberal, 1882), pp. 180-191 ; see especially p. 181. Archived 10 4月 2016 at the Wayback Machine (in Spanish) From 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.) Alberto Bailetti, Blog: "La Misión del Jesuita AgustÍn Salumbrino, la malaria y el árbol de quina" Archived 4 3月 2016 at the Wayback Machine (The mission of the Jesuit Agustin Salumbrino, malaria and the quinine tree), Chapter 10: La Condensa de Chinchón (The countess of Chinchon). (in Spanish) From Chapter 10: "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 millonario 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.).
^Rocco F (2004). Quinine: malaria and the quest for a cure that changed the world. New York, NY: Perennial..
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^de la Condamine (1738) "Sur l'arbre du quinquina" Archived 7 5月 2016 at the Wayback Machine (On the quinquina tree) Histoire de l'Académie royale des Sciences, pp. 226–243..
^See also: Joseph de Jussieu, Description de l'arbre à quinquina: mémoire inédit de Joseph de Jussieu (1737) Archived 19 7月 2012 at the Wayback Machine (Description of the quinquina tree: unpublished memoir of Joseph de Jussieu (1737)). De Jussieu accompanied de la Condamine on the latter's expedition to Peru..
^Pelletier and Caventou (1820) "Suite: Des recherches chimiques sur les quinquinas" Archived 4 5月 2016 at the Wayback Machine (Continuation: Chemical research on quinquinas), Annales de Chimie et de Physique, vol. 15, pages 337-365. The authors name quinine on page 348: " …, nous avons cru devoir la nommer quinine, pour la distinguer de la cinchonine par un nom qui indique également son origine." ( …, we thought that we should name it "quinine" in order to distinguish it from cinchonine by means of a name that also indicates its origin.).
^Paul Briquet (1853) Traité thérapeutique du quinquina et de ses preparations from Internet Archive.
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