历百年而弥新 —阿斯匹林(Aspirin)的故事 （旧作重贴）
阿斯匹林(Aspirin)可以说是世界上被使用最广泛的药物，含阿斯匹林成分的药方有超过四百种之多。美国每年大约生产1800万公斤的阿斯匹林，每天消费大约八千万片阿斯匹林。但很多人并不知道这小小“神奇”药片从何而来，以及它为什么可以止痛治病。它的出现和发展，是个漫长曲折的有趣故事。
阿斯匹林的出现起始于杨柳的提取物。数个世纪前，用杨柳的液汁降热止痛这一民间药方在世界各地就已广为流传。古代埃及人、希腊人(比如名医希波克里特(Hippocrates))、苏美尼亚人、印地安人和中国人都留下了相关的记载。婀娜多姿的杨柳多长在河岸边，由于关节炎症往往在阴冷潮湿的天气和地方发作，有当时的聪明人产生了一个跳跃性的联想：杨柳既然能在湿地生长，那么它一定可以提供耐潮寒的办法，所以可以用来治疗关节炎症。且不言这逻辑在今天的聪明人看来是否可笑，可贵的是，有勇于实践的聪明人做了尝试，验证了杨柳的根和皮确实可以减轻关节炎引起的肿痛。毕竟，潮湿河岸边的树并不只有杨柳一种，而潮湿引起的疾病也不仅仅只有关节炎。这一有效的民间药方代代相传，不仅仅是简单的口传心授和书本记录，更经历了数代人的仔细观察和认真的身体例行的实践证明。
很多植物的药效往往来自植物本身所含的某些化学物质。杨柳的这种止痛功能来自它所含的一种苦味的化合物—水杨苷(Salicin，来自Salix，杨柳的拉丁名)。1827年，借当时机械工业和化学产业的蓬勃发展，这种小分子化合物终于从柳树皮中被提取分离出来。水杨苷在人体中消化分解成水杨醇和单糖分子，然后水杨醇被氧化成水杨酸(Salicylic acid)。其它的一些植物也有相似的化学：在绣线菊属植物(Spiraea ulmaria)中、鹿蹄草中(Gaultheria procumbens)和西方桦(Betula lenta)中，都发现有水杨酸或甲基水杨酸盐。这些植物，经过漫长的进化和自然选择，发展出水杨酸类的分子作为天然的驱虫剂来抵御饥饿寻食的动物以保存自身物种的存在和繁衍。1835年娄卫希(Karl Lowig)从绣线菊中提取出了纯的水杨酸。1838，意大利人皮瑞阿(Raffaele Piria)将从柳树皮中提取出的水杨苷在实验室里转化成了水杨酸。这时，纯的水杨酸已经开始被当作止痛剂使用，它的降热、止痛和抗发炎疗效比水杨苷强很多。然而从天然资源中分离提取水杨酸既费时费力，又非常地消耗资源与金钱。1859年德国化学家科尔比(Herman Kolbe)发明了以苯酚为原料合成水杨酸的方法，1874年该方法被工业化后，水杨酸的市场价格马上下跌了四分之三。但水杨酸有很强烈的副作用，它刺激胃线，导致胃痛、流血和恶心。当时人们认为这种副作用可能来自水杨酸的酸性。
阿斯匹林的活性化学成分是水杨酸的一种衍生物―乙酰水杨酸(acetylsalicylic acid)，可用乙酐酯化水杨酸形成。它最早由格哈德(Çharles Gerhardt)于1853年合成，后来又有几名化学家对乙酰水杨酸的合成法和分离纯化法有所改进，然而没人登记对它任何可能的药物兴趣。乙酰水杨酸药物潜力的发掘与德国化学家霍夫曼(Felix Hoffman)紧密相关。他当时在以生产苯胺染料为主的法本公司(I.G.Farben)的子公司拜尔(Bayer)工作。一个通俗的说法是说他年迈的父亲为风湿性关节炎所痛扰，然而服用水杨酸又引起他剧烈的胃痛，孝顺儿子霍夫曼遍查文献，寻求分析测试了与水杨酸相关的系列化合物的性能，1897年他发现水杨酸被酯化后，形成的乙酰水杨酸酸性降低，它既保存了水杨酸的药效，毒性和副作用又大为降低。后来这种化合物作为药物上市时被命名为阿斯匹林(Aspirin)，‘a’ 取自‘acetyl (乙酰基)’,‘spir’来自绣线菊的‘Spiraea’，而‘in’则是当时药物名通用的后缀。
事实上霍夫曼的发现有更壮阔的背景。当时在1880年到1890年期间，医生们对发烧的机制和发烧给人体带来的副作用有很强烈的研究兴趣，使用开发降热药是医学界一个很热门的领域。当时，染料工业已经式微，拜尔公司正转向于更活跃和更有利可图的制药业，重组了药物开发实验室，并在积极地寻求与医学界的合作。药物开发的工业化是新兴的时尚，也遭到很多人的反对，也有人半信半疑。化学家霍夫曼提交了乙酰水杨酸和其它的相关化合物作为可能的候选药物；霍夫曼的上司德里舍(Hinrich Dreser)对这些化合物做了动物测试，这种在动物模型上测试药物活性和毒性在当时的制药业是没有先例的；而医生威特霍尔(C. Witthauer) 和渥赫尔格姆斯(Julius Wohlgemuth)则做了乙酰水杨酸的临床实验，这种系统的临床实验也在制药业首开先河。后来所有的结果证明了乙酰水杨酸的有效和安全，以及它确实优于当时其它的降热止痛药物。所以，阿斯匹林，一个简单的小分子化合物，作为第一个真正意义上的合成药物出现被人接受和信任，是化学实验室、制药工业和生物医学界紧密合作的结果。后来，也证明它是他们之间复杂运作的成功范例。
1899年拜尔公司开始出售袋装的粉末状阿斯匹林，1900年片剂上市。由于阿斯匹林止痛降热消炎效果好，对阿斯匹林的需求大大增加，对合成阿斯匹林所需的中间体水杨酸的需求也大大增加，拜尔采用科尔比的以工业方法制造乙酰水杨酸的工艺后，阿斯匹林的生产和销售于是扶摇直上。加上拜尔公司成功的广告宣传和对医生们的大力推销，到1909年时，阿斯匹林的销售已占了拜尔公司销售总额的三分之一。第一次世界大战中，拜尔公司的美国分公司从国内和国际上尽可能地收购了所有的苯酚来确保阿斯匹林的生产和供应。阿斯匹林的风靡给拜尔公司带来了巨大的经济利益，使之成为从传统的染料工业中崛起的第一代化学制药公司之一，迄今巍然屹立，拜尔公司也几乎成了阿斯匹林的同义词。阿斯匹林的市场盈利也使十九世纪末二十世纪初的其它化工公司相信了化学制药业的玫瑰色未来。
1917年，乙酰水杨酸的原始专利过期失效，其它公司也开始生产阿斯匹林和使用这一名称，拜尔公司曾起诉他们违反了这一商标名的专利版权。1919年，第一次世界大战后，根据凡尔赛条约，德国将阿斯匹林这一商标名也“投降”给了美英法俄四国。法官汉德(Learned Hand) 后来裁决任何一个制药公司都不得拥有阿斯匹林这个名字或收取使用这个名字的专利权税；阿斯匹林替代乙酰水杨酸这个太专业的化学名词成为更广为人知的药物名称。一个有趣的对比是，拜尔公司也研究开发出了海洛因(Heroin，取名自‘Hero’，‘英雄’ 之意)，后来因为它致瘾性太强而将其撤回并永不再生产。海洛因现在是臭名昭著的大毒品，虽然海洛因也是拜尔公司发明的商标名，但拜尔公司从未因别人使用这名称而起诉任何人。
阿斯匹林的医疗效果和声誉以及市场价值已经确定，那么阿斯匹林到底为什么可以止痛、消炎和降热呢？这谜团直到二十世纪七十年代才现出端倪来。1971年，伦敦皇家医士学院药学教授维恩(John Vane)及其同事在‹‹自然››上发表了他们的研究结果，认为阿斯匹林的功能与抑制一种荷尔蒙前列腺素(prostoglandins，PGs)的合成有关。这种前列腺素可以调节痛感信号放大，其产出受一种脂肪酸环加氧酶(fatty acid cyclooxygenase，COX)的调控。阿斯匹林能酰化这种酶的活性位点来抑制它的作用，从而抑制COX产物前列腺素的生成，痛感信号因而不能再被放大和被大脑神经中枢感应，这就是阿斯匹林止痛的生理原因。而阿斯匹林的降热机制，则与它影响视丘下部的体温调节中心有关。
关节炎病人常需要服用较大剂量的阿斯匹林，这仍然会给胃带来刺激性。对前列腺素生理功能的研究，还发现了阿斯匹林有这一副作用的真正原因。在动物体中，分别有COX-1和COX-2两种异构体：COX-1主要执行前列腺素的正常生理产出；而COX-2则在受到损伤的组织中比较常见，主要由发炎细胞中的细胞因子、促细胞分裂剂和内毒素诱导，执行发炎等异常情况下前列腺素的产生。当关节炎病人服用阿斯匹林来消炎止痛时，阿斯匹林抑制COX-2产生“异常”前列腺素，从而抑制痛感放大。在胃中，COX-1正常调控产生的前列腺素能保持胃线的强度和厚度。阿斯匹林对COX-1和COX-2这两种酶没有选择性，因而对它们调控生成的产物前列腺素们一样抑制。当胃壁因为“正常”前列腺素减少而变薄时，胃中的酸性消化液刺激胃壁，甚至导致流血。所以这刺激性并非单纯来自以前的科学家们包括霍夫曼最初认为的水杨酸或它的衍生物的酸性。
因为维恩的发现，他荣获了1982年的诺贝尔医学奖和英女王颁发的骑士勋章。
进一步的研究发现，前列腺素(PGs)在体内很多组织中都有，有复杂多样的功能，包括调节血管、肠胃和膀胱中平滑肌的收缩，调节痛感与发炎，甚至调节血小板的凝集。所以除了传统的治疗发热疼痛和发炎，后来发现阿斯匹林也可用作抗血凝剂，治疗凝血引起的血栓症，大规模的临床实验结果表明，适当的小剂量可阻止血小板凝集导致的中风和心肌梗塞(Myocardial Infarction, MI)。1982年，美国食品和药物管理局(Food and Drug Administration, FDA)通过了阿斯匹林的减少中风发作尤其是复发的新用途，1985年又通过了有不稳定心绞痛(angina pectoris)病史者或有心脏病病史者可使用阿斯匹林来预防心肌梗塞这一用途。来自瑞典、加拿大和美国的多方研究证实，每日服用阿斯匹林，对有过心脏病发作史者，MI发作率可减少五分之一，而对有不稳定心绞痛者，MI发作率可减少超过百分之五十。1996年，FDA推荐在急性心脏病疑例中可使用阿斯匹林。1998年，FDA判定，每天即使只服用81毫克的小剂量阿斯匹林，对预防心脏病和中风，尤其是对已有过相关病史的病人而言，是有益的。阿斯匹林的药学用途梅开二度。现在，阿斯匹林防治心血管病和中风的用途甚至超过了它最初的止痛功用，被认为是20年来防治心脑血管病最重大的突破。
近十年来，随着科学家们对前列腺素生理作用和许多疾病机制的研究越来越深入，发现阿斯匹林还可能对某些癌症、眼白内障、齿龈疾病、孕期内高血压、糖尿病、偏头痛和老年痴呆症等有预防和治疗作用。阿斯匹林的药物用途居然可能随着生物医学的发展与时俱进！到1999年，阿斯匹林百岁生日之年，关于阿斯匹林的科学论文已经超过了3000篇，而且绝大部分发表在二十世纪八十年代以后。但是阿斯匹林在预防和治疗这些疾病方面的有效性和安全性还没有具体的肯定性的结论。
阿斯匹林是神奇的，但绝对不是万能的。假如你不小心割伤手指，一片阿斯匹林确实可以止痛和消炎，但它只是降低了由神经传输到大脑的痛感信号强度，伤口会需要更长的时间来止血和愈合。前面已提到，如果用剂量太高或使用不当，阿斯匹林仍然对胃有刺激性，甚至引起出血性并发症。对正感冒发烧或有其它病毒感染的儿童而言，使用阿斯匹林可能会引起致命的雷意氏综合症(Reye syndrome)。阿斯匹林也影响尿液在肾脏的制造过程。阿斯匹林对某些人可能会诱发哮喘和鼻炎等维尔拉尔综合症(Wielals syndrome)。所以科学家们又开发出了其它一些与阿斯匹林相关的小分子化学药物比如布洛芬(Ibuprofen,or Motrin)，奈普生(naproxen, or Naprosyn)和热息痛(Tylenol，or acetaminophen，泰诺)，它们有部分阿斯匹林的优点和去除了它部分的缺点。然而尽管这些药物分享了阿斯匹林的部分市场，但都不能完全取代阿斯匹林，阿斯匹林的销量仍然比它们加起来的销量还要大。这百年不老药，仍然在为提高人们的生活质量而服务，也继续激励着科学家们的研究热情。拜尔公司从1994年起，专门设立了“国际阿斯匹林奖”，其中的“年轻研究员奖”，奖励和鼓舞40岁以下青年科学家们运用他们的科学创造发明能力探索和发现阿斯匹林的新用途。2003年，这一奖项被颁发给了一名中国内科药大夫—39岁的袁敏声(音译)博士，因为他的研究阐明了阿斯匹林可以降低血糖水平的作用机理，这是糖尿病研究史上的一个重要里程碑。随着人类认知水平的进一步提高，阿斯匹林的故事会更加丰富和精彩呢！
—2004.04.26
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I love traveling and have visited several places in the past few years.
I’m happy to have written several books that have contributed positively to the lives of many. My books are available in several parts of the world. And I’m currently working with companies that help people save time. Being a part of this team has open more opportunities for me to excel as a writer. I have worked with different people and met many clients as a professional.
I can handle any kind of writing and provide nothing but the best. People come to me all the time to ask if I can solve their assignment problems and I accept. I find pleasure in helping them to solve their problems as a writer.
Professional Writer – Simon - natalie.crawfordConfederation
2019年12月22日于2:51 pm
Hi and welcome to my webpage. I’m Lynsey Velasquez.
I have always dreamed of being a writer but never dreamed I’d make a career of it. In college, though, I aided a fellow student who needed help. She could not stop complimenting me . Word got around and someone asked me for to help them just a week later. This time they would compensate me for my work.
During the summer, I started doing research papers for students at the local college. It helped me have fun that summer and even funded some of my college tuition. Today, I still offer my writing skills to students.
Academic Writer – Lynsey Velasquez – Iseet-Papers Team
2019年12月24日于2:23 am
Hello All
Thanks for checking out my academic writing page . My name is Kaitlin Mcguire.
I have worked since high school in this niche. My passion for writing started at a young age. I wrote short stories as a child and eventually went on to work with my school newspaper.
This early tryst into news reporting eventually led me to academic writing. There is plenty of work for skilled writers. I specialize in dissertations , but have the skills to do all types of academic writing.
Reach out for more information about rates and a price quote. I’m looking forward to helping you.
2019年12月25日于1:16 pm
Hello and welcome to my blog . I’m Liam Scott.
I have always dreamed of being a book writer but never dreamed I’d make a career of it. In college, though, I aided a fellow student who needed help. She could not stop complimenting me . Word got around and someone asked me for to write their paper just a week later. This time they would pay me for my work.
During the summer, I started doing research papers for students at the local college. It helped me have fun that summer and even funded some of my college tuition. Today, I still offer my writing services to students.
Professional Writer – Liam Scott – Natalie Crawford Team
2019年12月27日于2:21 am
Hello All
Thanks for checking out my academic writing page . My name is Kaitlin Mcguire.
I have worked since high school in this niche. My passion for writing started at a young age. I wrote short stories as a child and eventually went on to work with my school newspaper.
This early tryst into news reporting eventually led me to academic writing. There is plenty of work for skilled writers. I specialize in dissertations , but have the skills to do all types of academic writing.
Reach out for more information about rates and a price quote. I’m looking forward to helping you.
Academic Writer – Kaitlin Mcguire – Mbkediadentalcollege Company
2019年12月27日于2:23 am
方舟子先生，对您非常佩服…
2019年12月31日于9:40 am
Hello All
Thanks for checking out my academic writing page . My name is Kaitlin Mcguire.
I have worked since high school in this niche. My passion for writing started at a young age. I wrote short stories as a child and eventually went on to work with my school newspaper.
This early tryst into news reporting eventually led me to academic writing. There is plenty of work for skilled writers. I specialize in dissertations , but have the skills to do all types of academic writing.
Reach out for more information about rates and a price quote. I’m looking forward to helping you.
Academic Writer – Kaitlin Mcguire – Mbkediadentalcollege Company.
2020年1月8日于1:24 am
方舟子先生，对您非常佩服… …
2020年1月8日于1:25 am
Hello All
Thanks for checking out my academic writing page . My name is Kaitlin Mcguire.
I have worked since high school in this niche. My passion for writing started at a young age. I wrote short stories as a child and eventually went on to work with my school newspaper.
This early tryst into news reporting eventually led me to academic writing. There is plenty of work for skilled writers. I specialize in dissertations , but have the skills to do all types of academic writing…
2020年5月12日于12:26 am
Welcome to my blog ,
I’m Lowrie.
If you’ve ever been too busy and couldn’t finish a research assignment , then you’ve come to the right place. I help students in all areas of the writing process . I can also write the assignment from start to finish.
My career as a scholarly writer started early in college . After learning that I was very able in the field of academic writing, I decided to take it up as a profession.
Talented Academic Writer- Lowrie- My Custom Essay Company
2020年6月17日于1:40 am
Hello, I’m Keiren.
Welcome to my website . I started writing in my early school years after a creative writing assignment for my English teacher. I did creative writing for a while before I thought about doing something else.
I had always loved doing non-fiction writing because I’m passionate about learning. When you combine writing talent with a love of learning, research paper writing only makes sense as a job.
I’m passionate about assisting the students of the future in their school career. When they get too busy, I am there to help.
Keiren – Professional Academic Writer - standrewspres.org Team