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Curare is a poison obtained from different species of plants in South America, which was used in arrows by the natives. Its lethal paralyzing potential and mechanism of action began to be explored in the 19th century. In this article, we highlight the research on this poison and the fruitful exchanges between the Brazilian Emperor Dom Pedro II and the researchers João Baptista de Lacerda, Louis Couty and Alfred Vulpian who contributed to the development of experimental neurophysiology in Brazil. Vulpian found that curare does not affect the nerve itself, but acts between the nerves and the muscle, through a "ligand substance" - this Vulpian's pioneering concept is often wrongly attributed to Claude Bernard. These prestigious scientists contributed to the transnational circulation of knowledge that later yielded in the preparation of curare purified extract used for convulsive therapy and anesthesia., (© Société de Biologie, 2023.)

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'., (Copyright © 2020. Published by Elsevier Ltd.)

Between 1938 and 1951 erythroidine derivatives were seriously considered as alternatives to curare for the provision of muscle relaxation. This has been overlooked in the published history of anaesthesia. The first publication on the paralysing effect of an extract of Erythrina americana was in 1877, but this was in a Mexican journal, which was not widely read. Sixty years later erythroidine was isolated, and in 1938 it was first used clinically to treat spastic dystonia, preceding the use of Intocostrin for this purpose. By 1943 dihydro-β-erythroidine was prepared in crystalline form, which was equipotent with curarine and of acceptable duration; it was used in clinical anaesthesia in 1946. In the 1940s curare was presented in solutions with potency stated in units, determined by bioassay, which was a disadvantage compared with the straightforward mg of dihydro-β-erythroidine. However, by the early 1950s, improvement in the pharmaceutical presentation of d-tubocurarine and new neuromuscular blockers, displaced the erythroidines., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Francis Sibson (1814-1876) was a British physician and anatomist widely regarded as a true pioneer of the medical profession. He overcame a tragic and difficult childhood to become an avid educator at several medical schools and dedicated his life to research. For modern scientists, he is most remembered for describing Sibson's fascia, his experimental use of curare in the treatment of hydrophobia and tetanus, and his detailed description of the positions and movements of internal organs. He died on September 7, 1876 at the age of 62 from complications of an aortic aneurysm.

One of the most erroneous and repeated assertion in the history of pharmacology for anaesthetists is to say that "the curare was introduced in Europe by Sir Walter Raleigh under the name of ourari". On the contrary, the names to be reminded are: Lawrence Keymis for the first citation of the word ourari, José Gumilla for the word curare and the description of its effects, Charles-Marie de La Condamine for the import of the first known samples. The mistake was initiated by Alexander von Humboldt and developed by the physiologist Münter, a student of Johannes Müller, quoted by Claude Bernard. The repetition of this error was facilitated by the world diffusion of Claude Bernard's work.

Long lasting polemics about the mechanisms of the action of curare took place at the Société de Biologie over thirty years. After a period during which poisoning protocols were developed on various animal species, where Claude Bernard, Vulpian and their colleagues were involved, German electrophysiology combined its results with new histological data about motor end-plates, elaborating a theory in which young physiologists fought against Claude Bernard's views and finally managed to convince him. According to the new theory proposed by Vulpian, curare blocked transmission between end-plate and muscle. This first draft of the neurotransmission theory helps us to understand the rise of a novel physiology in the context of the school of Claude Bernard with a better integration of disciplines and a more prominent faith in reductionism and materialism.

"Curare and Claude BERNARD" is a well known set of physiology in several western scientific and medical communities. In using arrow poison curare as a tool of physiological anatomical approach, Bernard founded the experimental physiology of the nervous system. His famous experiments of using curare on frogs led to the observation of curare block in the myoneural junction of skeletal muscle. Bernard's achievements in curare research are recorded in full detail in his principal book of lectures, "Leçons sur les effets des substances toxiques et medicamenteuses (1857)". Nevertheless, Japanese physiological communities, attaching too much importance to German physiology between the end of the 19th century and the beginning of the 20th century, have mostly neglected the important work on curare done by Bernard, and the after-effect of this neglect is on-going in Japan. The aim of this article is to try to enlighten the communities with a small part of his lectures (i.e., arrow poison curare) described in "Leçons (1857)", which never reached us.

The history of curare is both curious and convoluted. A product of South American culture it emerged in the sixteenth century from the mists of antiquity at the same time as quinine, coca, and chocolate. Like quinine, at first came the extract but no plant, and later the plant but no chemical compound. It took more than 300 years and the efforts of many explorers and scientists to resolve the problem. These included Condamine, Humboldt, Brodie, Waterton, Bernard, Dale, Walker, and King. Finally, the pure compound d-tubocurarine was isolated from the liana Chondrodendron and synthesised. Its specific physiological action was blockade of the effect of acetylcholine at the neuro-muscular junction. Such a paralytic poison could be used to kill oneself or others. The bizarre plot to kill the Prime Minister, Lloyd George, during the First World War is described. Fortunately this nefarious plan was thwarted by the Secret Service!

In this paper we discuss some examples of ethnopharmacological research as it has been conducted during the last two centuries and look at the current role of this discipline in drug discovery (especially with respect to the American and European markets) and the further development of these phytotherapeutical resources for local use in the countries of origin (ethnopharmacology). Examples from 19th century research on curare (Humboldt and Bernard), from the 20th century on hallucinogenic mushrooms (Wasson), on Mexican Indian indigenous plants (our own research) and of current industry based research are used to illustrate the development of this discipline and to highlight the challenges for the future.

Through his visit to Spain in 1946, Robert R. Macintosh exercised considerable influence on the introduction and development of modern anesthesia in this country. This paper reviews the technical advances Mackintosh introduced and considers how his visit was one of the most important factors in unleashing the development of the profession here. Also reviewed are the other visits Mackintosh made in the course of his career. Those trips were less important, with the exception of a 1937 visit that inspired the design of the Oxford vaporizer, a technical concept based on simplicity, safety and the anesthesiologist's experience.

The introduction of curare for general anesthesia by Harold Griffith in 1942 was one of the most important moments in the development of anesthesiology. However, several years passed before curare came to be used in Spain. We review the early application of curare and the role played by Robert Macintosh, Professor of Anaesthesia at Oxford, in introducing the drug to Spain.

In France, a number of scientists from the fields of chemistry, physiology and surgery have been interested in anaesthesiology. Claude Bernard, who published in 1872 the most exhaustive studies on anaesthesia, was also interested from 1844 in drug curare. He created a methodology, studied pharmacology, including pharmacokinetics and demonstrated the specific action on motor nerves while muscle retained its irritability. It was however A. Vulpian who put forward the idea that curare does not affect the nerve itself but may act on a "linking substance" between nerve and muscle. In these times (1862), Rouget described the end apparatus at the nerve-muscle junction in a way which was finally accepted by German authors. Fifty years later, Couteaux achieved the microanatomic study of the end plate (1909). More recently (1972), Changeux and his team isolated the acetylcholine receptor from the electric organ of the torpedo fish.

1992 was the anniversary of Crawford Long's use of ether in 1842, and Griffith and Johnson's introduction of Intocostrin into anaesthetic practice in 1942. Harold Randall Griffith was born in Montreal in 1894 and died in 1985. He interrupted his medical studies to serve in the first world war and was awarded the Military Medal for gallantry at the battle of Vimy Ridge. Griffith qualified from McGill University in 1922. After spending a year studying homoeopathic medicine, he joined his father's general practice and became the anaesthetist to the Homoeopathic Hospital in Montreal. He succeeded his father as Medical Director of the hospital (now renamed the Queen Elizabeth Hospital) in 1936 and retired in 1966. Griffith was a superb clinical anaesthetist. He was an early advocate of detailed anaesthetic records, and was responsible for the introduction of both ethylene and cyclopropane into Canadian practice, later teaching himself to intubate under these two agents. Griffith was one of the first to be concerned with standards of patient care. He introduced postoperative recovery and intensive care units into Canadian practice and played a major role in postgraduate teaching. He was unstinting in his support of organisations designed to further the progress of anaesthesia and was the first President of the Canadian Anaesthetist's Society. He was one of those responsible for inaugurating the World Federation of Societies of Anaesthesiology and was President of the First World Congress of Anaesthesiology in 1955. It is remarkable that the introduction of curare into anaesthetic practice was delayed until 1942, since curare had been used in anaesthesia some 30 years previously. However, it was probably Griffith's confidence in his own clinical abilities which enabled him to seize the opportunity when it was offered.

Before the advent of curare, muscular relaxation essential for upper abdominal and intrathoracic surgery adequate operating conditions, could only be provided by deep ether or cyclopropane anaesthesia. The required depth of anaesthesia frequently caused severe cardiovascular depression, metabolic and respiratory acidosis and alteration of kidney and liver function. Ether, and especially cyclopropane sensitized the heart to the development of arrhythmias and the danger of explosion was never far away. For fear of anaesthetic mortality essential, life saving operations were often abandoned in poor risk patients. The administration of anaesthesia was more an art, mastered by relatively few, than a science that could be taught to many. It is a tribute to the early masters of anaesthesiology that they were able to carry their patients through the dangers associated with the provision of anaesthesia for major surgical procedures, with relatively low morbidity and mortality. The introduction of curare into anaesthetic practice, by Griffith and Johnson, in 1942, caused profound changes in the efficacy and safety of anaesthesiology. It made possible the development of true balanced anaesthesia, and the elimination of the explosive inhalation anaesthetics and the profound metabolic disturbances associated with their use. The concept of "inoperability," due to severe pathology or extremes of age became obsolete. It would be hard to envisage how open heart, organ transplant and radical brain and cranio-facial surgery could have developed without muscle relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

The introduction of curare into clinical anaesthesia by Griffith and Johnson in 1942 contributed to the termination of the era where anaesthesia was a reversible intoxication rather than the result of controlled drug action. Curare allowed general anaesthesia to be reduced to a lighter level, thereby conferring a significant safety factor to the patient. Both the shortage in supply of crude curare and its variable composition led the search for synthetic curare analogues conferring well defined pharmacodynamic and pharmacokinetic properties. Based on the chemical structure of tubocurarine which has been known since 1935 the efforts concentrated on bisquaternary ammonium compounds. Gallamine was the only synthetic curare analogue to contain three quaternary ammonium groups. This drug had significant undesired vagolytic effects. In 1951 succinylbischoline appeared to be the ideal muscle relaxant, particularly with respect to its fast onset and short duration of action. The disadvantages of its depolarising mechanism of action which were appreciated during the years to follow prevented the concept of depolarising neuromuscular blockade to be pursued further. With other muscle relaxants, including curare itself, histamine release, vagal blockade and ganglionic blockade were undesired effects to be eliminated in future compounds. Improved understanding of structure-activity relationships turned out to be an indispensable tool for future research. This in turn required more elaborate methods in chemical analysis, in electrophysiology of the motor endplate, and in ultrastructural research. As a result, alcuronium and pancuronium became available in the late sixties and early seventies. Both muscle relaxants had a non-depolarising mechanism of action with reduced side effects relative to curare. From now on better techniques for pharmacodynamic and pharmacokinetic research became available resulting in research activity with particular emphasis in this field. Researchers became aware that new muscle relaxants should be designed for larger volumes of distribution and more rapid biodegradation than those currently available. Concurrently, anaesthesia techniques had changed in a way to use intubation and mechanical ventilation as a routine procedure. The risk of intraoperative hypoventilation and hypoxemia was eliminated, yet, due to the lack of adequate monitoring techniques the slow recovery from curare, alcuronium or pancuronium neuromuscular blockade was hardly appreciated.(ABSTRACT TRUNCATED AT 400 WORDS)

Curare was used in the 19th century in England by a wide variety of scientists, physicians and veterinarians. Their experiments indicated many of the properties of the drug, but its clinical usage remained very limited and was reserved for cases of tetanus, hydrophobia and strychnine poisoning. Griffith and Johnson are usually credited with the introduction of curare into clinical anaesthesia in 1942, but a Dr F.P. de Caux working at the North Middlesex Hospital, London, in 1928 utilised curare in a series of seven patients. His work was not widely publicized and this contribution to anaesthetic history has been overlooked by subsequent authors.