Skip to main content
Log in

The Early Toxicology of Physostigmine

A Tale of Beans, Great Men and Egos

  • Review Article
  • Published:
Toxicological Reviews

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Table I
Table II
Table III
Table IV
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16

Similar content being viewed by others

References

  1. Waddell HM. Twenty-nine years in the West Indies and Central Africa: a review of missionary work and adventure. 1829–1858. London: T Nelson & Sons, 1863

    Google Scholar 

  2. Daniell WF. On the natives of Old Callebar, West Coast of Africa. Edinb N Philos J 1846; 40: 313–27

    Google Scholar 

  3. Rodin FH. Eserine: its history in the practice of ophthalmology. Am J Ophthalmol 1947; 30: 19–28

    PubMed  CAS  Google Scholar 

  4. Graham EJ. Seawolves: pirates and the Scots. Edinburgh: Birlinn Limited, 2005

    Google Scholar 

  5. Dickie W. Story of the mission in Old Calabar. Edinburgh: Offices of United Presbyterian Church, 1894

    Google Scholar 

  6. Jones GI. New introduction. In: Waddell HM, editor. Twenty-nine years in the West Indies and Central Africa: a review of missionary work and adventure 1829–1858. 2nd ed. London: Frank Cass & Co., 1970

    Google Scholar 

  7. Milne WG. Letter to JH Balfour. In: The John Hutton Balfour Correspondence [letter]. Edinburgh: Royal Botanic Garden, 1863, M215

    Google Scholar 

  8. Milne WG. Letter to J McNab. In: The John Hutton Balfour Correspondence [letter]. Edinburgh: Royal Botanic Garden, 1863, M216

    Google Scholar 

  9. Notes, queries and replies. Native use of the Calabar bean. Med Times Gaz 1864; 2: 293

  10. Dragstedt CA. Trial by ordeal. Q Bull Northwest Univ Med Sch 1945; 19: 137–41

    Google Scholar 

  11. Christison R. On the properties of the ordeal bean of Old Calabar, Western Africa. Edinb Med J 1855; 1: 193–204

    Google Scholar 

  12. Fraser TR. On the characters, actions, and therapeutical uses of the ordeal bean of Calabar (Physostigma venenosum, Balfour). Section I: history, employment as an ordeal, botanical characters etc. Edinb Med J 1863; 8: 36–56

    Google Scholar 

  13. Holmstedt BO. The ordeal bean of old Calabar: the pageant of Physostigmine venenosum in medicine. In: Swain T, editor. Plants in the development of modern medicine. Cambridge (MA): Harvard University Press, 1972: 303–60

    Google Scholar 

  14. United Presbyterian Church. Report of the missionary operations of the United Secession Church for 1846–7. Foreign operations. Old Calabar — West Africa. Missionary Record of the United Presbyterian Church 1847; 2: 91

    Google Scholar 

  15. Baillie Z. Letter to JH Balfour. In: The John Hutton Balfour Correspondence [letter]. Edinburgh: Royal Botanic Garden, 1860, B160

    Google Scholar 

  16. Balfour JH. Description of the plant which produces the ordeal bean of Calabar. Trans R Soc Edinb 1861; 22: 305–14

    Google Scholar 

  17. Watson E. On the physiological actions of the ordeal bean of Calabar, and on its antagonism to tetanus and strychnia-poisoning. Edinb Med J 1867; 12: 999–1024

    Google Scholar 

  18. Harley G. A brief account of the literary history, botanical characters, and their therapeutical properties of the ordeal bean of Old Calabar. BMJ 1863; 5: 262–5

    Article  Google Scholar 

  19. Fraser TR. An experimental research on the antagonism between the actions of physostigma and atropia. Trans R Soc Edinb 1872; 26: 529–618

    Google Scholar 

  20. London Hospital Medicine and Surgery. St Mary’s Hospital. Cases of mydriasis treated by the solution of Old Calabar bean, a new ophthalmic agent. Lancet 1863; 30: 604–5

  21. Nunneley T. On the Calabar bean: its action, preparations and use (continued). Lancet 1863; 31: 503–5

    Article  Google Scholar 

  22. Argyll Robertson D. On the Calabar bean as a new agent in ophthalmic medicine. Edinb Med J 1862; 8: 815–20

    Google Scholar 

  23. Fraser TR. On the moth of the esere, or ordeal-bean of Old Calabar. Ann Nat Hist 1864; 3: 389–93

    Google Scholar 

  24. Young D. Note on a case of poisoning by the Calabar bean. Edinb Med J 1864; 10: 192–3

    Google Scholar 

  25. Nunneley T. On the Calabar bean: its action, preparations and use. Lancet 1863; 24: 476–7

    Article  Google Scholar 

  26. Ogle JW. Observations on some of the effects of the application of the Calabar ‘ordeal bean’ to the eye. BMJ 1863; 13: 613–5

    Article  Google Scholar 

  27. Wells JS. Effects of the solution of the Calabar bean on the accommodation of the eye and on the pupil. Med Times Gaz 1863; 1: 500–3

    Google Scholar 

  28. Medical Societies. Royal Medical and Chirurgical Society. On the ordeal bean of Old Calabar; its action on the animal body compared with that of woorara and conia. Lancet 1863; 27: 717

    Google Scholar 

  29. Giraldès. De la fève de Calabar et de ses propriétés antimydriatiques. Bull Gen Ther 1863; 65: 34–5

    Google Scholar 

  30. Fraser TR. On the characters, actions, and therapeutical uses of the ordeal bean of Calabar (Physostigma venenosum, Balfour). Section III: preparations. Edinb Med J 1863; 8: 123–32

    Google Scholar 

  31. Evans JH. The recent cases of poisoning by Calabar bean. Med Times Gaz 1864; 15: 406–10

    Google Scholar 

  32. Lingen. Vergiftung durch Calabar-Bohne. St Petersburg Med Z 1864, 246

    Google Scholar 

  33. Kleinwächter. Beobachtung über die Wirkung des Calabar-Extracts gegen Atropin-Vergiftung. Berl Klin Wochenschr 1864; 1: 369–71

    Google Scholar 

  34. Liverpool Medical Institution. Reports of societies: the Calabar bean. BMJ 1863; 16: 521

    Google Scholar 

  35. Ogle JW. The Calabar bean paper and its effects upon the pupil of the eye. BMJ 1863; 27: 673

    Article  Google Scholar 

  36. Nunneley T. On the employment of the alkaloid of the Calabar bean in prolapsus of the iris. Lancet 1863; 18: 65

    Article  Google Scholar 

  37. Posner A. The discovery of miotics. Eye Ear Nose Throat Mon 1962; 41: 822–3

    Google Scholar 

  38. Fraser TR. On the characters, actions, and therapeutical uses of the ordeal bean of Calabar (Physostigma venenosum, Balfour). Section V: appendix. Experiments with the kernel of Physostigma venenosum. Edinb Med J 1863; 8: 235–48

    Google Scholar 

  39. Nunneley T. On the Calabar bean: its action, preparations and use (continued). Lancet 1863; 7: 530–3

    Article  Google Scholar 

  40. Nunneley T. On the Calabar bean: its action, preparations and use (continued). Lancet 1863; 21: 588–90

    Article  Google Scholar 

  41. Nunneley T. On the Calabar bean: its action, preparations and use (continued). Lancet 1863; 28: 616–8

    Article  Google Scholar 

  42. Bauer F. Einege Resultate von Versuchen über die Wirkung des Calabargiftes. Centralblatt für die medicinischen Wissenschaften 1866; 57: 577–81

    Google Scholar 

  43. Laschkewich W. Bemerkungen über die physiologische Wirkung der Calabar-Bohne (Physostigma venenosum). Virchows Arch Pathol Anat 1866; 35: 291–301

    Article  Google Scholar 

  44. Bartholow R. On atropia. Trans Am Med Assoc 1869; 20: 637–84

    Google Scholar 

  45. Harnack E, Witkowski L. Arbeiten aus dem Laboratorium für experimentelle Pharmakologie zu Strassburg. Pharmakologische Untersuchungen über das Physostigmin und Calabarin. Arch Exp Pathol Pharmakol 1876; V: 401–54

    Google Scholar 

  46. Fraser TR. On the characters, actions, and therapeutic uses of the ordeal bean of Calabar [dissertation]. Edinburgh: Oliver and Boyd, 1863

    Google Scholar 

  47. ARC. Obituary. Thomas Richard Fraser. Edinb Med J 1920; 24: 125–6

    Google Scholar 

  48. Hay M. Obituary. Sir Thomas R Fraser, MD, FRS. Edinb Med J 1920; 24: 122–4

    Google Scholar 

  49. Fraser TR. On the physiological action of the Calabar bean (Physostigma venenosum Balf.). J Anat Physiol 1867: 332

    Google Scholar 

  50. Fraser TR. On the myotic action of the Calabar bean. Lancet 1863; 30: 619

    Article  Google Scholar 

  51. Argyll Robertson D. The myositic action of the Calabar bean. Lancet 1863; 13: 676

    Article  Google Scholar 

  52. Fraser TR. On the myotic action of the Calabar bean. Med Times Gaz 1863; 2: 605

    Google Scholar 

  53. Argyll Robertson D. The myositic action of the Calabar bean. Med Times Gaz 1863; 2: 632

    Google Scholar 

  54. Karczmar AG. History of the research with anticholinesterase agents. In: International encyclopedia of pharmacology and therapeutics. Oxford: Pergamon Press, 1970: 1–44

    Google Scholar 

  55. Salway AH. Chemical examination of Calabar beans. J Chem Soc 1911; 99: 2148–59

    Article  CAS  Google Scholar 

  56. Notes, queries and replies. The active principle of the Calabar bean. Med Times Gaz 1864; 1: 300

  57. Umbra N. Calabar bean. Med Times Gaz 1865; 1: 591

    Google Scholar 

  58. Polonovski M, Nitzberg C. Études sur les alcaloïdes de la fève de Calabar (II). La généserine nouvelle alcaloïde de la fève. Bull Soc Chim 1915; 17: 244–56

    CAS  Google Scholar 

  59. Takano S, Ogasawara K. Alkaloids of the Calabar bean. In: The alkaloids. New York: Academic Press,. 1989; 36: 225–51

    Google Scholar 

  60. Bartholow R. The antagonism between atropia and physostigmia. The Clinic 1873; 5: 61–3

    Google Scholar 

  61. Atack JR, Yu Q-S, Soncrant TT, et al. Comparative inhibitory effects of various physostigmine analogs against acetyl- and butyrylcholinesterases. J Pharmacol Exp Ther 1989; 249: 194–202

    PubMed  CAS  Google Scholar 

  62. Greig NH, Pei X-F, Soncrant TT, et al. Phenserine and ring C hetero-analogues: drug candidates for the treatment of Alzheimer’s disease. Med Res Rev 1995; 15: 3–31

    Article  PubMed  CAS  Google Scholar 

  63. Dale FJ, Robinson B. The synthesis and anti-acetylcholinesterase activities of (+)-physostigmine and (+)-physovenine. J Pharm Pharmacol 1970; 22: 889–96

    Article  PubMed  CAS  Google Scholar 

  64. Galli A, Renzi G, Grazzini E, et al. Reversible inhibition of acetylcholinesterase by eseroline, an opioid agonist structurally related to physostigmine (eserine) and morphine. Biochem Pharmacol 1982; 31: 1233–8

    Article  PubMed  CAS  Google Scholar 

  65. Argyll Robertson D. The effects of the Calabar bean. Med Times Gaz 1863; 1: 552

    Google Scholar 

  66. Argyll Robertson D. Note on the Calabar bean. Edinb Med J 1863; 8: 1115–9

    Google Scholar 

  67. Hemsworth BA, West GB. Anticholinesterase activity of some degradation products of physostigmine. J Pharm Sci 1970; 59: 118–20

    Article  PubMed  CAS  Google Scholar 

  68. Ogle JW. Calabar bean paper. BMJ 1863; 12: 308

    Article  Google Scholar 

  69. Spinney L. The killer bean of Calabar. New Scientist 2003; 28: 49–50

    Google Scholar 

  70. Seventeen children poisoned. BMJ 1871; 15: 73

  71. Reynalds GF. Two cases of poisoning I. By Calabar bean. J Trop Med 1899; Mar: 206–7

    Google Scholar 

  72. Campbell A. On a case of traumatic tetanus successfully treated with the ordeal bean of Calabar. Lancet 1867; 10: 157

    Article  Google Scholar 

  73. Alexander W. Two cases of tetanus. Glasgow Med J 1868; 1: 40–51

    Google Scholar 

  74. Keyworth JW. Case of strychnia poisoning. Glasgow Med J 1868; 1: 54–6

    Google Scholar 

  75. Ashmead G. Poisoning by strychnia treated with Calabar bean. Edinb Med J 1872; 18: 235–6

    Google Scholar 

  76. Ringer S. A successful case of traumatic tetanus treated by large doses of Calabar bean. Practitioner 1874; 13: 338–47

    Google Scholar 

  77. Watson E. Two cases of traumatic tetanus successfully treated with the ordeal bean of Calabar. Lancet 1867; 2: 265–7

    Article  Google Scholar 

  78. Harley G. La fève du Calabar. J Anat 1864, 152

    Google Scholar 

  79. Gaddum JH. The pharmacologists of Edinburgh. Annu Rev Pharmacol 1962; 2: 1–10

    Article  CAS  Google Scholar 

  80. Nickalls RWD, Nickalls EA. The first use of physostigmine in the treatment of atropine poisoning: a translation of Kleinwachter’s paper entitled ‘Observations on the effect of Calabar bean extract as an antidote to atropine poisoning’. Anaesthesia 1988; 43: 776–9

    Article  PubMed  CAS  Google Scholar 

  81. The week. The recent case of fatal poisoning by the Calabar bean. Med Times Gaz 1864; 2: 283

    Google Scholar 

  82. Hudson JQA. Remarks on the physiological action and therapeutic uses of Physostigma venenosum, or the ordeal bean of Calabar. South Med Rec 1873; 3: 705–21

    Google Scholar 

  83. Carson J. On the physiological action of the Calabar bean. Am J Med Sci 1868; Apr: 502–10

    Google Scholar 

  84. Gubler A, Labbée E. De l’antidotisme ou de l’antagonisme thérapeutique. Bull Gen Ther 1873; 84: 510–22

    Google Scholar 

  85. MacLaurin HN. Remarks on a case of heightened reflex action treated by Calabar bean. Edinb Med J 1865; 11: 318–23

    Google Scholar 

  86. Fraser TR. On atropia as a physiological antidote to the poisonous effects of physostigma. Practitioner 1870; 4: 65–72

    Google Scholar 

  87. Fraser TR. The antagonism between the actions of active substances (concluded): limits to the antagonism between atropia and physostigma. BMJ 1872; 2: 485–7

    Article  PubMed  CAS  Google Scholar 

  88. Fraser TR. The antagonism between the actions of active substances. BMJ 1872; 26: 457–9

    Article  Google Scholar 

  89. Bourneville DM. De l’emploi de la fève de Calabar dans le traitement du tetanus. Paris, 1867

    Google Scholar 

  90. Fraser TR. Preliminary note on the antagonism between the actions of Physostigma (Calabar bean) and Belladonna. Proc R Soc Edinb 1870; 6: 586–90

    Google Scholar 

  91. Gubler A. De l’antagonisme thérapeutique et spécialment de l’antidotisme réciproque de la belladonne et de la fève du Calabar. J Pharm Chim 1872; 16: 448–55

    Google Scholar 

  92. Gubler A, Labbée E. De l’antidotisme ou de l’antagonisme thérapeutique (suite et fin). Bull Gen Ther 1873; 84: 556–64

    Google Scholar 

  93. Bennett JH. Report of the British Medical Association to investigate the antagonsim of medicines II: antagonism between sulphate of atropia and calabar bean. BMJ 1874; 10: 464–6

    Google Scholar 

  94. Bartholow R. Note on atropia and its physiological antagonists. Practitioner 1870; 5: 27–33

    Google Scholar 

  95. Jones TW. On an important new application of the Calabar bean. Practitioner 1869; 3: 160–3

    Google Scholar 

  96. Progress of the Medical Sciences. Materia medica and pharmacy: antagonistic effects of Calabar bean and atropia. Am J Med Sci 1865; Apr: 472

  97. Hudson J. Case of belladonna-poisoning cured with physostigma. BMJ 1881; 11: 918

    Google Scholar 

  98. Grattan N. On a case of belladonna poisoning treated with pilocarpin. Lancet 1881; 11:951

    Article  Google Scholar 

  99. Kauders J. Pilocarpine als Antidot gegen Atropin. Wien Med Wochenschr 1881; 45: 1253–8

    Google Scholar 

  100. Empoisonnement par le belladone, guérison par l’emploi de la fève de Calabar. Bull Gen Ther 1869; 83: 561

  101. Empoisonnement par le belladone, guérison par l’emploi de la fève de Calabar. Gaz Med Paris 1869; 9: 550

  102. Fraser TR. On the employment of Physostigma (Calabar bean) in the treatment of tetanus and chorea. Practitioner 1868; 1: 76–88

    Google Scholar 

  103. White J. Case of strychnia-poisoning, and recovery under treatment with Calabar bean and chloroform. Glasgow Med J 1871; 3: 488–90

    Google Scholar 

  104. Smith MW. Strychnia poisoning; two cases treated by Calabar bean. Ohio Med Rec 1879; 4: 145–56

    Google Scholar 

  105. Pal J. Physostigmine ein Gegengift des Curare. Centralbl Physiol 1900; 14: 255–8

    Google Scholar 

  106. Nickalls RWD, Nickalls EA. The first reversal of curare: a translation of Pal’s original paper, ‘Physostigmine, an antidote to curare’. Anaesthesia 1985; 40: 572–5

    Article  PubMed  CAS  Google Scholar 

  107. Fenwick W. Calabar bean in tetanus. Glasgow Med J 1869; 1: 300–5

    Google Scholar 

  108. Coote H. Tetanus in which the Calabar bean was freely administered. Lancet 1864; 26: 348–9

    Article  Google Scholar 

  109. Tétanos spontané. Emploi simultané de la medication sudorifique et de la fève du Calabar. Guérison. Bull Gen Ther 1864; 67: 79–86

  110. Westminster Hospital. Traumatic tetanus treated with Calabar bean; death; autopsy. Lancet 1868; 10: 480

    Google Scholar 

  111. Reports of Societies. Clinical Society of London. BMJ 1869; 6: 224

  112. Répertoire Médical. Revue des Journaux. Tétanos traumatique traité par la fève de Calabar. Insuccès. Bull Gen Ther 1868; 64: 427

  113. Ridout CV. Traumatic tetanus treated by the tincture of the Calabar bean. Lancet 1868; 31: 567

    Article  Google Scholar 

  114. McEwan J. Report on a case of tetanus treated with calabar bean. Glasgow Med J 1874; 6: 478–85

    Google Scholar 

  115. Episcopal Hospital. Case of severe traumatic tetanus, resulting favorably under the use of calabar bean. Philadelphia Med Times 1871; 16: 138

    Google Scholar 

  116. Watson E. Additional case of tetanus, with remarks. Glasgow Med J 1868; 1: 56

    Google Scholar 

  117. Macarthur AJ. Case of traumatic tetanus: recovery under the use of the Calabar bean. Edinb Med J 1869; 14: 989–93

    Google Scholar 

  118. Heath C. A fatal case of tetanus treated by Calabar bean. Practitioner 1870; 5: 275–7

    Google Scholar 

  119. Cunningham J. Case of traumatic tetanus successfully treated by Calabar bean. BMJ 1874; 4: 450

    Article  Google Scholar 

  120. Répertoire Médical. Revue des Journaux. De l’emploi de la fève de Calabar dans le tétanos des nouveau-nés. Bull Gen Ther 1869; 77: 564–5

  121. Alexander W. Two cases of tetanus. Glasgow Med J 1868; 1: 40–51

    Google Scholar 

  122. Jalland WH. Treatment of tetanus by Calabar bean. BMJ 1874; 11: 79–80

    Google Scholar 

  123. Calabar bean in tetanus. BMJ 1872; 22: 679

  124. Lebensohn JE. The first miotic. Am J Ophthalmol 1963; 55: 657–9

    PubMed  CAS  Google Scholar 

  125. Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet 1934; I: 1200–1

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Proudfoot, A. The Early Toxicology of Physostigmine. Toxicol Rev 25, 99–138 (2006). https://doi.org/10.2165/00139709-200625020-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00139709-200625020-00004

Keywords

Navigation