{"title":"毒豆碱的早期毒理学:一个关于豆子、伟人和自负的故事。","authors":"Alex Proudfoot","doi":"10.2165/00139709-200625020-00004","DOIUrl":null,"url":null,"abstract":"<p><p>Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. It is salutary to realise that the doses and dosage frequency of atropine together with the endpoints that define they are adequate were formulated by Fraser and others a century and a half ago.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 2","pages":"99-138"},"PeriodicalIF":0.0000,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625020-00004","citationCount":"33","resultStr":"{\"title\":\"The early toxicology of physostigmine: a tale of beans, great men and egos.\",\"authors\":\"Alex Proudfoot\",\"doi\":\"10.2165/00139709-200625020-00004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. 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引用次数: 33
摘要
19世纪中期,来到尼日利亚东部省份老卡拉巴尔(Old Calabar)的欧洲游客不可避免地意识到,当地人相信当地植物的种子有一种力量,可以判断一个人是无辜的,还是犯了一些严重的轻罪。这些种子是一种以前不为人知的豆类,很快就被称为老卡拉巴的磨难豆。他们的政府在当地被称为“剁坚果”。1846年到达卡拉巴尔的传教士估计,坚果每年造成大约120人死亡,并记录了中毒过程。后一种信息和豆子的样本很快就传到了传教士的母教会苏格兰,这就解释了为什么豆豆中三种活性生物碱中最重要的一种,豆豆的早期毒理学与苏格兰(主要是爱丁堡)有如此强烈的联系。然而,直到1855年,许多医学科学家中的第一位,著名毒理学家罗伯特·克里斯汀森(Robert Christison)才调查了这种豆子的影响,他自己吃了一部分,并记录了中度(如果不是严重的话)后果。又过了6年,巴尔弗对豆类植物的全面植物学描述才出现。他将其命名为病耻菌。没过多久,下一次活动就开始了,这次活动引发了更多的国际关注。1863年,爱丁堡一位年轻的眼科医生阿盖尔·罗伯逊(Argyll Robertson)发表了一篇论文,宣布第一种缩小瞳孔的药物问世。这种药是从卡拉巴豆中提取的,阿盖尔·罗伯逊公开承认,他的医生朋友托马斯·弗雷泽(Thomas Fraser)曾提醒他注意这种药的不寻常特性。在接下来的几个月里,医学报刊上发表了大量关于豆类提取物眼科用途的文章;那些全身毒性更少。弗雷泽的博士论文于1862年提交给爱丁堡大学(University of Edinburgh),显然早于阿盖尔·罗伯逊(Argyll Robertson)与咖啡豆的关系。在阿盖尔·罗伯逊(Argyll Robertson)论文发表几周后,弗雷泽的博士论文变得普遍可用,这是第一个详细阐述咖啡豆提取物系统管理特征的论文。所有早期的咖啡豆研究人员面临的一个主要问题是如何最好地提取其活性成分,这一任务变得更加困难,因为生物测定是确定毒素是否被追踪的唯一方法。提取物的稳定性是一个不可避免的问题,其活性成分最终被称为physostigma或physostiming,以其母体植物的植物学名称命名。毒藻碱的毒性特征很快被详尽地记录下来,在动物和人类中都是如此。他们是如何调解的则完全是另一回事。弗雷泽坚持认为,肌肉麻痹是主要特征,是脊髓凹陷的结果,这种观点得到了普遍(但远非一致)的支持。在那些持保留意见的人中,哈利是最突出的。他的结论是,麻痹是次于运动神经末梢的影响,在乙酰胆碱、胆碱酯酶和胆碱酯酶抑制剂还没有被想象出来的时候,麻痹是最接近今天的知识的。关于豆子作用方式的意见分歧是意料之中的,因此没有得到解决也就不足为奇了。由于没有标准配方,所以所使用的药力会因研究者而异,实验动物的范围很大,而任何研究者使用的数量通常都是个位数,更容易获得的冷血动物似乎比温血动物对药力的毒性更不敏感,只有弗雷泽坚定地寻求答案;一般来说,其他人先涉足豆类研究,然后将注意力转移到其他地方。同样的问题也会困扰豆类研究的其他方面。虽然弗雷泽并没有像哈利那样接近蛇的碱的作用模式,但在蛇的碱和阿托品之间的拮抗作用方面,他是至高无上的。到这个时候,19世纪70年代已经来临,尽管治疗剂之间的拮抗作用的概念并不新鲜,但它几乎没有可靠的科学基础。这种情况即将改变;对抗变得激动人心和理性。弗雷泽坚定地认为,在生理层面上,肉毒杆菌碱和阿托品是相互拮抗的,这与他同时代的传统观念相反。仅凭这一点就足以让他在历史上占有一席之地,但他的贡献远不止于此。 与当时不同的是,他以严谨的科学态度进行研究,只对一个物种进行实验,尽可能确保动物体重相同,根据体重调整给药剂量,确定每种药物的最小致死剂量,然后评估它们的拮抗作用,采用单一的,无可争议的疗效终点,并进行足够数量的实验,以便在研究的统计力量至关重要的后来的时代显得有说服力。更重要的是,他用图形展示了他的结果。弗雷泽从未声称发现了肉毒杆菌碱和阿托品之间的拮抗作用。巴塞洛在1873年根据1869年的研究得出了结论。但他的数据很难证明这一点。如果有人能合理地获得这一特殊的科学桂冠,那就是1864年在布拉格工作的眼科医生涅梅切克。他在同一学科的同事Kleinwächter面临着治疗一个阿托品中毒的年轻人。了解到这两种药物对瞳孔的相反作用,Niemetschek建议卡拉巴豆提取物可能有用。Kleinwächter有勇气接受了这个建议,他的病人得到了显著的改善。显然,这些证据只是坊间传闻,但眼科医生是正确的,时至今日,毒豆油碱在抗胆碱能中毒的治疗中起着间歇性的作用。相反,用阿托品来治疗胆碱酯酶抑制剂中毒,其中第一个使用的是肉毒杆菌碱,这种方法更持久,至今仍是标准做法。认识到阿托品的剂量和剂量频率以及确定它们是否足够的终点是有益的,这是一个半世纪前由弗雷泽和其他人制定的。
The early toxicology of physostigmine: a tale of beans, great men and egos.
Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. It is salutary to realise that the doses and dosage frequency of atropine together with the endpoints that define they are adequate were formulated by Fraser and others a century and a half ago.