Toxicological Reviews

, Volume 25, Issue 2, pp 99–138 | Cite as

The Early Toxicology of Physostigmine

A Tale of Beans, Great Men and Egos
  • Alex Proudfoot
Review Article

Abstract

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.

Keywords

Atropine Tetanus Active Principle Astigmatism Physostigmine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Although every effort has been made to make this review as comprehensive as possible, the lack of computerised databases for medical literature published prior to 1965 makes researching that era a paper trail that is all too readily a hit or miss affair, not least because of the incomplete (often only a surname) and frequently inaccurate referencing in use at the time. Almost certainly, therefore, relevant articles have escaped detection. That so many have been found is due to the unfailing helpfulness and enthusiasm of a number of people and agencies. Access to the Royal College of Physicians of Edinburgh’s copies of Index Medicus from its first appearance in 1879 was invaluable and the author is particularly grateful to Estela Dukan who produced, from the College’s extensive historic book collection or through inter-library arrangements, the more ancient papers on which this study is based including some the author would have requested had he known they existed! Bartholow’s article in The Clinic was particularly difficult to track down and the author is especially indebted to Dr EP Krenzelok who found its location and to Doris Haag of the library of the College of Nursing in the University of Ohio who speedily and generously provided a copy. Bartholow’s essay on atropine, too fragile to photocopy, was scanned then printed at the Wellcome Library for the History and Understanding of Medicine, London, thanks to Phoebe Harkins. Elizabeth Singh and Professor Kaufman searched out details of Bartholow’s connections with the Royal Medical Society of Edinburgh. Sarah Cage of the National Poisons Information Service (Birmingham Centre) obtained copies of recent literature and together with Joanna Rowe put the script into Reference Manager. Information on Watson was kindly provided by Carol Parry, archivist of the Royal College of Physicians and Surgeons of Glasgow, while Leonie Paterson, Archives Librarian at the Royal Botanic Garden, Edinburgh, was a mine of information on Balfour and his correspondence, and Murray. Waddell’s memoirs, the Missionary Record of the United Presbyterian Church of Scotland and Dickie’s account of the Calabar mission were consulted courtesy of the National Library of Scotland. Dr JA Vale and Professor MR Lee advised and encouraged during a long gestation.

No sources of funding were used to assist in the preparation of this manuscript. The author has no conflict of interest that are directly relevant to the content of this manuscript. The author was formerly Consultant Physician, Royal Infirmary of Edinburgh, and Director, Scottish Poisons Information Bureau, Edinburgh, UK.

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Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Alex Proudfoot
    • 1
  1. 1.Poisons Information Service (Birmingham Centre)City HospitalBirminghamUK

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