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Wien Med Wochenschr DOI 10.1007/s10354-016-0481-y

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia The role played by two neglected protagonists Dimitri A Cozanitis

© Springer-Verlag Wien 2016

Summary In 1957, Professor Daniel Bovet received the Nobel Prize in Physiology or Medicine for his studies on various compounds including the muscle relaxants gallamine and succinylcholine that became very useful in anaesthesia. Textbooks credit Professor Bovet for the discovery of these drugs. However, although he indeed did discover their pharmacological character, the actual syntheses were made by Ernest Fourneau and Reid Hunt, respectively; sadly, these two scientists have largely been ignored. In this paper, a brief biography of Bovet is presented along with some of his more notable accomplishments. Particular emphasis has been placed on gallamine and succinylcholine along with their history. In an attempt to undo the “injustice” dealt to both Fourneau and Hunt, brief accounts of their history, story and character are provided. Keywords History of medicine · 20th century · Skeletal muscle relaxants · Gallamine · Succinylcholine

äußerst hilfreich sind. Fachbücher ehren Professor Bovet für die Entdeckung dieser Arzneimittel. Allerdings muss bemerkt werden, dass trotz der Tatsache, dass Professor Bovet ihren pharmakologischen Charakter entdeckt hat, die eigentlichen Zusammensetzungen von Ernest Fourneau bzw. Reid Hunt entwickelt wurden. Diese beiden Wissenschaftler wurden bisher leider größtenteils ignoriert. In diesem Dokument wird eine kurze Biographie Bovets zusammen mit seinen wichtigsten Errungenschaften aufgezeichnet. Besondere Schwerpunkte bilden Gallamin und Succinylcholin und ihre Geschichte. In einem Versuch, die „Ungerechtigkeit“, die sowohl Fourneau als auch Hunt angetan wurde, aufzuheben, wird ihnen ein kurzer Abriss ihrer Geschichte und ihres Charakters gewidmet. Schlüsselwörter Medizingeschichte · 20. Jahrhundert · Skeletale Muskelrelaxanzien · Gallamin · Succinylcholin

Daniel Bovet, Nobelpreisträger: Muskelrelaxanzien in der Anästhesie

Daniel Bovet (1907–1992)

Die Rolle zweier vernachlässigter Protagonisten

“For his discoveries relating to synthetic compounds that inhibit the action of certain body substances and especially their action on the vascular system and the skeletal muscles.” So states the citation for the 1957 Nobel Prize in Physiology or Medicine awarded to Professor Daniel Bovet (Fig. 1). Daniel Bovet was born in Neuchâtel, Switzerland, in 1907. He was the youngest of three sons and a daughter of Pierre Bovet, a deeply religious and celebrated professor of pedagogy at Geneva University, and Amy Babot, a school teacher. He began his career teaching philosophy for 9 years in Neuchâtel before being called to Geneva. The two new principles of education evolved each by Maria Montessori and Ovide Decroly interested Professor Bovet which he tested on his own

Zusammenfassung Professor Daniel Bovet erhielt 1957 den Nobelpreis für Physiologie oder Medizin für seine Studien zu verschiedenen Wirkstoffmischungen einschließlich der Muskelentspannungsmittel Gallamin und Succinylcholin, welche in der Anästhesie D. A. Cozanitis () Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, PO Box 340 (Haartmaninkatu 4), 00029 HUS Helsinki, Finland [email protected]

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Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

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Fig. 1 Professor Daniel Bovet. (With permission: Institut Pasteur/coll. Musée Pasteur)

children; the youngsters found the experience amusing. Whenever the professor felt that the small Daniel was being overly moody, he would sit him on a radiator and explain that the piping would drain the moodiness out of him [1]! During his early youth, Daniel Bovet became intensely interested in culturing mushrooms. When his parents felt that this had become more than just an ordinary affection, they sent him to visit relatives in France with the hope that the change might divert this passion. As a natural consequence, the mushrooms might well have influenced Bovet’s choice to study biology at Geneva University. He vowed that he would never study psychology but, 50 years on, in Sassari and Rome he did just that, interpreting this as a chromosomal relationship derived from his father. On completion of his studies in 1929, Bovet received his Doctor of Natural Science and then moved to Paris to join Ernest Fourneau as an assistant at the Pasteur Institute in his Laboratory of Therapeutic Chemistry. Whatever fate brought these two minds together would prove to be a most propitious coincidence for humanity.

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

Although women were generally rejected from medicine and science, Fourneau nourished no such prejudice. Many of his assistants were women who worked as pharmacologists or chemists. One was Filomena Nitti, who became Bovet’s wife (BovetNitti). An accomplished pharmacologist in her own right, she worked beside her husband, managed their home, performed secretarial tasks and raised their son, Daniel Pierre, who became a professor of Information Science at the University of Rome. Her father, Francesco Nitti, an Italian statesman, professor, economist, minister and writer, served several governments until the rise of Fascism when he was exiled to France. In Paris, during the war years, he provided for his family of four children entirely from the royalties for his books on economic issues. At war’s end, Nitti returned to Italy and again became active in government. When Bovet arrived at the Pasteur Institute, where he remained for 18 years, Fourneau was synthesising compounds to replace quinine, testing them on the canary and Java sparrow. Bovet’s baptism in chemotherapeutical research was with the molecule, 710 F (F for Fourneau), Rhodoquine®,1 in 1931 [2]. Bovet was a modest, quiet, kind and gentle person and his favourite relaxation, literature and gardening, certainly mirrored his personality. Throughout his lifetime, he carried with him the social problems that fell upon the underprivileged: “Our apprehension originates from the awareness that we are impotent against the priority of political and economic power”. Although the fixed smile he often displayed may have been linked to his shyness, his authentic one was of radiance, befitting his character. The young, Bovet taught, need not so much a protective shield that could eventually stifle their potential, but rather enriching experiences through which to grow and mature their ideas and their convictions. He believed that scientific research should aim at the acquisition of knowledge and its application for the sake of society. Although he was a person of great intellectual force, he expressed this principle not through abstract philosophical enunciations, but through his simple and straightforward behaviour which sprang from his nature. Bovet was a better listener than a speaker, so much so that at times he manifested a sort of modesty vis-à-vis the conclusions that he reached in his scientific research. He never created a school, but instead followed that of Fourneau [3]. The esteem that Bovet held for Fourneau is evinced in his Nobel Lecture where the sole name mentioned was that of Professor Fourneau whom Bovet hailed as, “my master”. Bovet had his little idiosyncrasies, e. g., he wore bow rather than straight ties. During the morning break, he sipped his coffee, of French–Italian blend, 1 The need for such drugs would become critical, especially for the Allied military forces when the Japanese conquered the Philippines and Java, the main sources of the bark of Cinchona sp.

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through a lump of sugar clenched between his teeth. If he asked his assistants to bring him four rats for an experiment and they hesitated by claiming that four would not meet statistical requirements, he would snarl, “just bring me four rats”. Bovet always began an experiment with precisely FOUR rats and only if needed would he increase the number—this crotchet was for bioethical and economic reasons [4]. Fourneau and Bovet embarked on a project to develop a drug that would antagonise histamine. Fourneau synthesised a series of phenolic ethers and with one of these, 883 F, gave the first indicative, albeit toxic, results when Bovet applied it to various organs of laboratory animals [5]. It was noted that 883 F could antagonise the hypertensive action of adrenaline. Besides, such compounds had sedative and analgesic qualities. Fourneau then developed antihistaminic compound 929 F. Bovet and Staub found it to protect guinea pigs from two lethal doses of histamine and so it became the first ever antihistaminic [6]. Staub continued her work with Fourneau’s compounds for her doctoral thesis. The phenolic substances were replaced by those having an ethylamine in their molecule but the problem of toxicity remained. In 1942, Bernard Halpern, realising the significance of antihistamines, seized the moment and reported his results with what became Antergen® [7]. Having shielded the guinea pigs from 75 lethal doses of histamine, Antergen evolved as the first feasible and marketable antihistamine. Two years later, Bovet described an improved compound, pyrilamine, Neo-Antergen®. On Christmas Day, 1932, the German investigator, Gerhard Domagk and his co-workers sensed that mice treated with a red azo dye were cured of a streptococcal infection. For greater certainty, it was only in February 1935 that they reported that the dye Prontosil possessed anti-infective properties. They wrongly believed that the portion of the molecular structure responsible for the colour was also active against microbes. Domagk was named winner of the 1939 Nobel Prize in Physiology or Medicine for his finding. In any case, the Nazi authorities barred Domagk from accepting the Prize. Finally, in 1945, he received his Nobel diploma and medal but the accompanying monetary reward had been forfeited. It should also be mentioned that dozens of drugs are derivatives of synthetic dyes. In 1935, Bovet gave mankind his decisive contribution—the “wonder drug” sulfanilamide which provided a cure for millions of patients. In a two-page article, he and his group identified, to their delight, the component of the Prontosil molecule that was undeniably responsible for its antibacterial activity [8]. This initial finding was confirmed a year later by Fourneau joined with Bovet and his associates [9]. With this, the German patent was pierced and sulfanilamide became freely available, as, e. g. Rhone-Poulenc’s benzyl-sulfamide, Septazine®. (In 1936, the son of President Franklin D.

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Roosevelt was healed of a streptococcal infection by this drug introduced in the U.S. as Prontylin. Another American president, Calvin Coolidge, was less fortunate when, in 1924, he lost his sixteen-year old son to a similar infection. The life of Winston Churchill, stricken with pneumonia while in Carthage in 1943, was saved by the sulfapyridine Dagénan®). But, because Domagk had earlier received the Nobel Prize for his discovery, accordingly, Bovet’s contribution is not featured in his Nobel citation. Fourneau provided Bovet with a seemingly endless stream of compounds to examine. Trials with synthetic sympatholytics, for instance, became the basis for antihypertensive drugs. Earlier, Bovet studied a series of barbiturate formulations and found one, 769 F, to be a desirable short-acting preparation for inducing intravenous anaesthesia [10]. Later he examined drugs produced by Fourneau that proved useful in treating such conditions as trypanosomiasis, thyrotoxicosis and anaphylaxis. Bovet’s Swiss citizenship shielded him from the tribulations arising from the German occupation of Paris. In 1945, Fourneau, as a result of his arrest and imprisonment, was obliged to leave the Institute and 2 years later, Bovet also departed. Now, however, Bovet found himself in a quandary as to what to do next. This was quickly and expediently solved by Domenico Marotta’s offer for him to move to Rome to create and lead the Laboratory of Chemical Therapeutics of the Istituto Superiore di Sanità, with facilities superior to those of the Pasteur. Needless to say, Bovet was given carte blanche. Marotta, a distinguished chemist with a charming personality possessed the qualities of an unrelenting administrator and politician. Under its Director, the Istituto gained international acclaim. Earlier, he recruited Enrico Fermi, the distinguished atomic physicist and subsequent Nobel Laureate. In 1948, using all his unique “skills”, Marotta convinced the German-born Russian Jew Ernst Boris Chain to leave Oxford for Rome. A biochemist with a flair for chemical engineering, Chain, together with Alexander Fleming and Howard Florey shared the 1945 Nobel Prize in Physiology or Medicine for their discovery of penicillin. Chain who had a rare disposition, arrived in Rome with his young bride, the biochemist Anne Beloff. There, he broadened his work on the chemistry and production of semisynthetic penicillins, penicillinaseresistant penicillins and acid stable penicillins which could be given orally [11]. The two Laureates and their wives published several papers together. Bovet selected Giovanni Battista Marini-Bettòlo to head the department of chemistry at the Istituto. Marini-Bettòlo was professor of chemistry in Rome before taking similar appointments in South America, in Santiago and Montevideo. During that time, he developed an interest in the alkaloidal chemistry of various species of Strychnos which proved to be a vital asset for Bovet’s curare research.

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

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Very early in his career, Bovet surmised the possible effects of compounds on the central nervous system believing that “the key to mental illness lies in chemistry”. He inspired Vicenzo Longo, an erstwhile student who later became his assistant, to carry the baton towards a new goal: “neuropharmacology”. Longo seized the challenge and using electroencephalography as his primary tool, became an authority in what is today psychoneuropharmacology. Longo’s doctoral thesis concerned curare and was made under the guidance of Bovet; later, he joined Bovet to study natural and synthetic curares. In 1817, the English physician and surgeon James Parkinson accurately described paralysis agitans in his paper “Essay on Shaking Palsy”. The Solaneceus drugs atropine, strophanthus and hyoscine, having antimuscarinic properties, provided the sole symptomatic remedy for the condition.2 The central effects of antihistamines captured Bovet’s attention and so he began to examine possible antiparkinson drugs. (Indeed, certain antihistamines were useful for treating symptoms of parkinsonism). This resulted in 1945 in 2987 RP (Rhone-Poulenc), Diparcol® becoming the first synthetic antimuscarinic. It and others similar to it, e. g. Parsidol®, proved more effective and having fewer adverse effects than the natural substances, became the bulwark for treating parkinsonism [13]. In 1961, this achievement became eclipsed when George Cotzias published his remarkable results with levodopa [14]. But, Bovet probably found the papers from the Semmelweis University of Medicine in Budapest more intriguing. There, Joseph Knoll (weighing 37 kg and unable to move when freed in Dachau by mostly black American soldiers) was involved with his “deprenyl” (selegiline) Eldepryl®, an antiparkinson drug without the serious side effects of levodopa [15] Knoll’s revolutionary ideas of “active focus”, “enhancer mechanisms” and “drives” undoubtedly pushed Bovet farther along the path of psychoneuropharmacology. The two became close friends and collaborators; one of Bovet’s eight doctorates (honoris causa) bestowed upon him was by the Semmelweis University of Medicine. In Rome, Bovet took Italian citizenship. Along with his team he placed emphasis on the central effects of drugs beginning with amphetamine and chlorpromazine. Later, his attention turned to curare and similar substances, the primary topics of this paper. Space, however, has been allotted here for a brief review of only some of Bovet’s other illuminating work so as to demonstrate its scope. Political schemes caused Bovet to leave the Istituto with great lament after 17 years in 1964. Even though certainly there were more illustrious institu-

Fig. 2 In honour of Professor Bovet. (With permission: Office des Timbres, Principaute des Monaco)

tions, he was only tendered the chair of pharmacology at Sassari University on the island of Sardinia. The Bovets were not especially content with their new assignment yet they remained there for 5 years working exclusively in psychoneuropharmacology. Returning to Rome, Bovet served as director of the Laboratory of Psychobiology and Psychopharmacology at the National Research Council until 1975. There, he continued to study the genetic aspects of memory and learning in inbred mice. He concluded that in education, genetics played a more significant role than did the influence of one’s parents or the environment [1]. In 1971, he was named Professor of Psychopharmacology at the University of Rome; aged 75, this title was changed to Honorary Professor. Upon retiring [16], Bovet, with intense zeal, turned to the writing of his book Une chimie qui guérit (Chemistry that heals), i. e. the history of the discovery of sulfa drugs. With his wife as his devoted typist, this volume with its well over 300 pages appeared in 1989. Professor Bovet died of breast cancer on April 8, 1992, at the age of 85. A street in Buc, France, bears his name and he is featured on two postage stamps (Fig. 2). In 2005, the “Daniel Bovet Award for the Treatment and Prevention of Allergic Disease” was established in his honour.

Curare to gallamine—enter Bovet The sentence “The drug has a long and romantic history” floridly describes curare.3 Its source is the plant family, Menispermaceae, specifically Chondrodendron tomentosum and Strychnos toxifera. These are found in an immense region covering at least eight countries of Central and South America, in areas adjacent to the Amazon and Orinoco rivers and their tributaries. Only certain tribes are engaged in the preparation of curare—a closely guarded secret—whose techniques vary and may contain such bewildering substances as poisonous plants, teeth of animals, or fangs of snakes. Some tribes add thickening or hardening agents such as gum rubber to the concoction. The

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Berger describes a singular use of curare on patients with parkinsonism—for their spasticity, they received curare, 50 mg intramuscularly, either by the physician or themselves. An ampoule of edrophonium was kept on hand [12].

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

3 George B Koelle, Distinguished Professor of Pharmacology, University of Pennsylvania

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finished product is stored in special containers, e. g., bamboo tubes, earthen pots or hard-shells of certain fruit, and is smeared on the tips of arrows/spears or on branches near entry points of villages in an attempt to annihilate possible intruders. Curare is extracted from the bark and stems of the plant. It is brownish-black in colour with a licorice smell and extremely bitter in taste. Even a small breach of the skin by an object bearing curare may result in death. Curare is used for hunting of game, animals or birds; smaller amounts are used to stun, for instance, a bird if only its feathers are needed or an animal if one wishes to keep it as a pet. In addition, it is also used for warfare although some tribes avoid doing so lest evil spirits be aroused. The sale of curare became a source of income and it is also used in exchange for needed goods among tribes which are ignorant as to its preparation. In addition to spears and arrows, a blow-gun (sarabatana) can also be used to hurl the poison. This unique weapon, which is produced by a limited number of tribes, consists of two tubes, placed one within the other, made from different trees. The sarabatana may measure well over 2 meters and is used to propel specially designed wooden darts laced with curare. Particular strength and training is needed to fling it with the dart capable of reaching some 40 meters. The sarabatana is preferred to a gun because it acts noiselessly allowing several darts to be dispatched without frightening the entire group of birds or monkeys [12]. Between the 16th and 18th centuries, the interest in curare was stirred up by scores of explorers and naturalists among whom were such notables as Sir Walter Raleigh, Alexander von Humboldt, the Duke of York Charles Waterton, and Charles Maria de la Condamine; the last is credited not only with bringing curare but for introducing caoutchouc (gum rubber) to Europe. In 1948, Bovet spent several months in Brazil and so experienced for himself the fascinating adventure of curare. In 1959, he travelled again to Rio de Janeiro where he organised a week-long symposium of some 60 ethnographers, naturalists, pharmacologists, chemists, physiologists and clinicians who had a thorough knowledge of curare from the four corners of the globe. The event was sponsored, in part, by UNESCO. Bovet, along with his wife and Marini-Bettolo, published a volume of the proceedings of this conference [12]. Reading the chapters of this book, especially those dealing with the history of curare, truly becomes an epiphanic experience. An engrossing event was that involving a donkey in England injected with curare in her shoulder by two expatriates involved with curare. As could be expected, 10 minutes later, the mare stopped breathing and because of a feared fatal outcome, her trachea was cut open and a pair of bellows inserted therein to provide artificial respiration. The donkey survived the ordeal and after naming her Wouralia (curare) the

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experimenters sent her to a farm where she spent her remaining 25 years in luxury—being kept warm during winters, feeding on fine grass in summers and undertaking no tiring tasks. Her obituary appeared in a local newspaper [17]! A bizarre incident implicating curare was the assassination attempt on the British Foreign Minister David Lloyd George in January, 1917, by Alice Ann Wheeldon and her two daughters, all conscientious objects and unhappy with the political system. The plot involved a pharmacist amongst others who planned to fire a dart coated with curare at the Minister while on his golf course. The conspiracy was thwarted by an informant who penetrated the ring and as a result, the perpetrators were found and arrested and received stiff prison sentences. However, with the personal intervention of Lloyd George, they were soon released [18]. The French physiologists Claude Bernard and Francois Magendie were the first to experiment with crude curare. It was Bernard, however, whose work in 1857 on the ligated leg of a frog with the localisation of the curare block in the neuromuscular junction, who is best remembered. Again, it was Bernard who first spoke of the need of separating the active principle of curare from the extraneous matter. And yet, it was only in 1935 that the organic chemist Howard King, using a specimen of tube curare taken from the Pharmaceutical Society museum in London, isolated what he called d-tubocurarine and designated it as a bisquaternary ammonium molecule; this same structure was shown by Bovet in his Nobel Lecture. Nevertheless, in 1970, Everett and colleagues described the molecule as having but one quaternary ammonium atom, the other being tertiary in nature. Although King’s formula was inexact, it certainly did not hinder the development of synthetic molecules having curare-like activity. For example, the 14 Ångström unit distance between his two quaternary groups proved to be a crucial contribution. As it usually happens, the structural formula of a synthetic compound is considerably simpler than that of the alkaloid, which was also true with the curare substitutes. Bovet sought a synthetic curare and his first results appeared in 1946. He had most probably been influenced by the 3-page article in Anesthesiology by Harold R Griffith and George E Johnson of Montreal describing their experiences with d-tubocurarine in 25 patients. Fourneau, the “pharmacist”, and Bovet, the pharmacologist, or rather as he described himself a “chemical pharmacologist” once again strengthened their faculties to find a replacement for a basic natural substance. Using d-tubocurarine as his starting material, Fourneau designed molecules for various compounds which were sent to Bovet for pharmacological testing. According to Fourneau, hundreds of such formulations were created, but only a few would become clini-

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cally acceptable, either because of an insufficient level of neuromuscular activity or because of the accompanying side effects (the smallest change in a molecule might well alter the mode of action of a drug). Bovet and his associates would first test each substance on intact animals such as the rat and the rabbit and later on isolated organs, e. g. muscle-nerve and intestine. Of vital importance was the “head drop” test, carried out on an unanaesthetised rabbit. Here, the amount of intermittent intravenously injected muscle relaxant required to produce temporary paralysis of the neck muscles was noted; this test remains the official bioassay of d-tubocurarine. The effect on arterial blood pressure was also recorded as indeed was the duration of paralysis and the amount of the drug that would be fatal to the animal. Artificial respiration was originally provided via a cannula but thereafter an “iron lung”, developed in the Istituto, was used. Atropine sulphate was given to block bronchial secretions. Bovet reflected, “The pharmacologist throws his die and entertains the hope of its falling on a winning number”. And metaphorically at least, that number was 2559, a pyrogallol derivative, “gallamin”, Flaxedil® produced and marketed by Rhone-Poulenc’s division, Spécia. Again, as Fourneau had declared, this did not materialise without trials and tribulations. The first propitious precursor of gallamine was code named 3381 F which was followed by compound 3565 F, being less toxic and with a duration of action that surpassed that of d-tubocurarine. Both are resorcin derivatives, with 3381 having diiodoethylate radicals while 3565 bears diiodomethylates in its structure. It was, however, 2559 that provided reproducibility, arterial blood pressure stability and no serious side effects, especially that of histamine release. In 1947, Bovet, Depierre and Lestrange published their results with this novel drug [19]. A year later, Pierre Huguenard presented his thesis at the University of Paris—the topic of his work being the “new French synthetic curare, 3697 RP”. On June 17, Huguenard along with Andre Boué reported the pertinent facts including those of the 127 patients engaged in the thesis work, given the drug during their surgery, to a meeting of the Société d’Anesthésie. In the discussion following this presentation, the result that no histamine was released, in contrast to tubocurarine, became particularly apparent [20]. Bovet proposed a classification of curariform substances based on the form of the molecule. Those compounds which are acetylcholine-competitive, such as d-tubocurarine and gallamine, have “thick” molecules which Bovet termed pachycurare (pachys = thick), while those which were acetylcholine-mimetic (depolarizing), e. g. decamethonium and succinylcholine, have a slender molecule and were designated leptocurare (leptos = slender). The advantage of this grouping is that it does not provide any inference as to the mode of action of the compound. After Bovet’s

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idea was presented in New York, Professor W. Paton, unquestionably the doyen of relaxant pharmacology, challenged this concept describing several shortcomings. In contrast, Professor D. Nachmansohn, himself an expert, found the definition credible. Bovet was absent from this meeting, with an alternate having read the paper [21]. Had he been present, the audience could well have witnessed a satisfying academic debate. A cursory view of the chapter written by Professor Bovet in the Proceedings illustrates the efforts made by others who were spurred on because of his discoveries to develop some eight other synthetic relaxants for use in clinical anaesthesia [12]. The relationship between the nature of the various molecules, that is, e. g. mono- or di-ammonium and aliphatic or aromatic and their pharmacological activity becomes clear. Without doubt, the contribution of neuromuscular blocking agents made anaesthesia safer. Adequate surgical conditions were thus provided with reduced amounts of anaesthetics.

Succinylcholine—having lain fallow The story of gallamine begins with curare and its most peculiar, long, colourful, exotic and tortuous past. Succinylcholine, on the other hand, with a history of neither glamour nor mystery would remain unrecognised for 40 years. In 1905, while in Professor Abel’s laboratory, Reid Hunt extracted acetylcholine from the adrenal medulla, and this unquestionably became his greatest feat. Acetylcholine had profound hypotensive activity, some 1000 times more than choline. Captivated by his finding, he began his studies on the effect of acetylcholine and then choline and its various analogues on blood pressure. One of these analogues was “succinyl cholin” which was first reported in 1906 by Hunt and his associate Taveau in a single sentence in the British Medical Journal [22]. Subsequently, they described in detail over 300 experiments with variable choline derivatives. The experiments were conducted on a rabbit or on a hare anaesthetised with chloral and urethane, and then given curare to prevent any possible respiratory “interference” [23]. The curare, however, concealed the effect of the intravenously administered succinylcholine on skeletal muscle, and so it escaped Reid Hunt’s attention. The skeletal muscle property of the compound remained unnoticed until 1949 when Bovet and his associates discovered its pharmacological attribute on the myoneural junction; it was initially designated “curare of short action” and later as “succinyl choline” [24]. The molecular configuration of succinylcholine resembles two molecules of acetylcholine being end to end. Accordingly, it is also known as diacetylcholine, in addition to succinyldicholine, and fits Bovet’s classification of a leptocurare.

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Unaware of Reid Hunt’s discovery of succinylcholine, in 1941 David Glick declared that he first prepared the compound [25]. In any case, he was the first to describe the hydrolysis of succinylcholine by an esterase which was confirmed by Bovet-Nitti. Glick was not alone in believing that he first discovered succinylcholine. (He earlier verified the presence of atropinesterase in some rabbits that enabled them to eat belladonna leaves without suffering toxic effects.) Unfortunately, the same would not have held true had this rabbit been eaten by humans! On delivering the fascinating Third Sarrazin lecture in 1979, the physiologist Frank C MacIntosh from McGill University spoke of his fumbled experience with succinylcholine many years earlier in England. Being ignorant of succinylcholine’s existence, he asked the professor of chemistry James Walker to create a compound having two molecules of acetylcholine stuck back to back, ten carbon atoms apart. Walker synthesized the molecule whose effect was extremely fleeting. MacIntosh rejected the effort saying, “Sorry, James, it’s too short acting to be useful” [26]. The initial products of hydrolysis of succinylcholine (preferably succinyldicholine) are succinylmonocholine + choline. Bovet described succinylmonocholine as lacking any relaxant property even though he did note a trace of “head drop”. It was later shown that indeed a slight degree of muscle relaxation does occur. Bovet’s interest in his “leptocurares” was shared by two groups in England: Barlow and Ing [27] as well as Paton and Zaimes were working with compounds having two quaternary nitrogen groups known as “the methonium series”. One of these, decamethonium bromide (C 10, Eulissin®), a depolarizing muscle relaxant, was tried first on the authors themselves [28]! In another compound of this series, hexamethonium chloride, being endowed with autonomic ganglionic blocking properties, became the first such hypotensive agent. Decamethonium was shorter acting than d-tubocurarine and in comparison, released only minute amounts of histamine. Unlike succinylcholine, its excretion was by the kidneys rather than undergoing hydrolysis, and it produced fewer fasciculations which merely affected the jaw and calf muscles; the outcome of fasciculations make the use of succinylcholine problematic. Churchill Davidson first affirmed that a small amount of d-tubocurarine given before succinylcholine would address this inadequacy [29]. On the other hand, Francis Foldes was of the opinion that these movements could be prevented simply by the administration technique. In 1952, the entry of succinylcholine into clinical usage was met with great enthusiasm by anaesthetists and surgeons. Here, at last, was a muscle relaxant having both a prompt onset and brevity of action that made it ideal for such procedures as tracheal intubation, orthopaedic reductions, electroconvulsive ther-

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apy and abdominal closure—all that without any apparent side effects. But then, Foldes reported several cases of prolonged apnoea following the injection of succinylcholine [30]. Over time this observation, albeit very rare, was reiterated by other anaesthetists who also presented its probable causes: excessive premedication, synergism with pethidine and/or thiopentone, acidaemia, hyperventilation and succinylcholine overdose; Foldes recommended doses from 10–30 mg. They revealed their attempts at correcting the problem: giving analeptics (nikethamide, picrotoxin), reducing ventilation, adding carbon dioxide into the ventilatory circuit, and the use of anticholinesterases (edrophonium, neostigmine). In these initial accounts, no mention was made concerning the hydrolysis of succinylcholine, or of the role of pseudocholinesterase. All this changed while an anaesthetic registrar in London was faced with apnoea of 40 minutes in a young Cypriot given succinylcholine 50 mg for a 5minute diagnostic procedure. When the patient’s pseudocholinesterase level was found to be low, his brother was also examined to determine whether hereditary factors might be implicated; the latter’s pseudocholinesterase was as well diminished [31]. (Earlier, there was an account of a soldier who totally lacked the enzyme.) Consanguinity played a possible role in two Eskimo children living in a secluded Alaskan community, isolated for generations, who presented reduced enzymatic activity. Another report described persons from a remote area in northern Kentucky having normal pseudocholinesterase values, but with a decidedly unique variety of the enzyme—one that hydrolysed succinylcholine at a greatly increased rate [32]. In 1965, Behring-Werke AG of Marburg produced a preparation of concentrated serum cholinesterase, Cholinesterase®, that proved effective for treating succinylcholine-induced apnoea (by the early 1970s, this was available in operating theatres throughout Finland). Until this time, pseudocholinesterase was only used as a test of liver function, reduced values being associated with liver disease or malnutrition. Genetic involvement in certain individuals’ response to, e. g. isoniazid and certain antimalarials, was already known. However, in 1959, the complexity and wide interest surrounding the splitting of succinylcholine served as impetus and became the keystone for a new discipline pharmacogenetics, defined as “The study of genetically determined variations in animal species that are revealed by the effects of drugs”. Vocational factors may influence the hydrolysis of succinylcholine. Individuals spraying insecticides containing an organophosphate anticholinesterase (e. g. malathion) on to fruit trees or other crops, can well absorb the chemical which irreversibly binds to

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pseudocholinesterase. As a result, such persons would require a longer time to hydrolyse succinylcholine. Bovet, true to his nature, did not stop with succinylcholine but continued his search for possible notable derivatives. Succinylcholine was a “methonium” because of its three methyl groups on each end of its molecule. By replacing one methyl group on each of the quaternary nitrogen groups with an ethyl group, the formulation became an “ethonium”; Bovet found that this, 306 I.S. (Istituto Superiore) had relaxant properties. Another compound, 362 I.S., suxethonium, Brevidil®, (May and Baker) was shorter acting than succinylcholine. First clinically used in Rome by the surgeon Valdone [33] and later by Scurr in London, its fasciculations were more pronounced than those of decamethonium while paralysis lasted some 2 minutes [34]. It enjoyed only limited success for it provided no real benefit over succinylcholine—nor for that fact has any other molecule been found to be more advantageous than the parent compound. Succinylcholine, like curare, also entered the crime scene. In 1966, in New Jersey, the anaesthetist, Carl Coppolino, who obviously was well informed about succinylcholine including its final products of hydrolysis into succinic acid and choline (which occur in the body), decided to get rid of his lover’s husband, a retired colonel, by having her inject the relaxant into his buttocks. At the last moment, she lost her nerve and thereafter the anaesthetist stepped in and smothered him with a pillow. After being found “not guilty”, he abandoned this mistress and with his wife moved to Florida where he began a new affair with a wealthy sweetheart whom he wished to marry. The wife, being a devout Catholic, refused to divorce him and so he injected her with succinylcholine into the buttocks. (The defence was able to show evidence of succinylmonocholine in the muscle where the needle had been thrust.) Although he engaged a brilliant lawyer, the court declared him guilty of first-degree murder and he was sentenced to life imprisonment. After having served 12 years, he was released on the grounds of “good behaviour” [35]. Succinylcholine has enjoyed many years of popularity. In spite of its side effects, there seems to be no other relaxant that approaches its efficaciousness. In any case, over time and with a measure of artful and designing modern marketing methods, it has been replaced, to a large extent, by newer nondepolarising drugs which without question, present their own problems. Still, one wonders if succinylcholine will ever completely disappear.

tual syntheses were the works of Ernest Fourneau and Reid Hunt, respectively. Fourneau, who wrote exclusively in French, has been neglected even in his own country [36]. Evidence for his discovery of gallamine lies in, firstly, the “F” (Fourneau) accompanying 2559 of the formulation’s code name, secondly, the patent granted for the synthesis of the molecule (French patent No. 951.134, April 11, 1949) and finally, the affirmation in the authoritative Merck Index as well as in Chemical Abstracts concerning its preparation. On the other hand, Hunt’s contribution was divulged in a single sentence 40 years before Bovet revealed its neuromuscular properties. Endeavouring to somehow amend the “injustice” dealt these men, brief sketches concerning their story, history and character follow.

Ernest François Auguste Fourneau (1872–1949) Ernest Fourneau (Fig. 3) was born in Biarritz in the French Basque region on October 4, 1872, the second of four children. The family was of Spanish descent by the name Hournau which, after immigrating to France, was changed to Fourneau. They were hote-

Two neglected protagonists Ostensibly, textbooks of anaesthesia and pharmacology maintain that Daniel Bovet discovered gallamine and succinylcholine. This gives the wrong impression for although Bovet, without question, disclosed the pharmacological aspects of these drugs, their ac-

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

Fig. 3 Professor Ernest Fourneau. (With permission: Institut Pasteur/coll. Musée Pasteur)

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liers and in 1885 built the majestic 150-room Hotel Victoria in Biarritz whose clients included members of royal houses as well as scholars, artists and writers. The young Ernest was brought up in this grand environment and received a genteel education with little left out. His secondary education was completed in Bayonne. During his youth at the Hotel Victoria, Fourneau learned to paint both in water colours and in oil. He also played the piano, though not particularly well, but in any case, he enjoyed these hobbies with friends throughout his life [37]. Fate would play a paramount role when Fourneau befriended the brothers Moreau, Charles and Felix. Charles, who was 10 years older than Fourneau, distinguished himself in chemistry and pharmacy (a street in Paris carries his name) and encouraged him to consider a scientific career. Fourneau followed this advice and entered a 3-year apprenticeship in a pharmacy owned by Felix. Work in the pharmacy was from 7 a.m. until 10 or even 11 p.m.; the first 2 hours of the morning were usually spent dusting bottles; he often carried out this task on his knees. The tenure fulfilled a prerequisite for entrance into the École de Pharmacie in Paris. In early March, 1899, Fourneau completed the 3-year course and so qualified as a pharmacien. He then spent a year with Charles Moreau familarising himself with various methods of organic chemistry. Thereafter, he lived 6 months in romantic Heidelberg enjoying a nonchalant life and improving his German. Fourneau stayed in Germany for another 3 years working under four eminent professors of chemistry, two of whom later received the Nobel Prize in Chemistry (Emil Fischer, Berlin, 1902 and Richard Willstätter,4 Munich, 1915). In his autobiography, Willsätter praised Fourneau and other young Frenchmen who came to him, not only for their unparalleled passion in their scientific work, but for their burning patriotism as well. When Fourneau returned to France, he set out on a mission to raise the level of pharmaceutical research to that of Germany. Nevertheless, sadly, in 1944, malicious individuals questioned his patriotism and accused him of collaborating with the enemy. This cruel allegation resulted in his serving a 4-month jail sentence. He was released from prison through the intervention of friends, colleagues and various national societies; Fourneau was finally exonerated in 1948 [37]. A digression is made here to portray the undisputed position that German scientists held in chemistry and pharmacy. In America, Eli Lilly, nee’ Lillja, (Swedish) and Company was earning millions of dollars annually from the sale of their “Sussus Alterans” as a cure for syphilis (also called the “French” or “Bad” disease). This secret panacea which had been used by the Creek

Indians in Alabama to treat the malady contained the botanicals “queen’s delight”, “pokeroot”, “prickly ash”, “burdock root” and “bamboo brier”. Physicians and patients, however, misinterpreted its effectiveness. The natural course of syphilis contains intervals of quiescence throughout its progression. Evidently, “these periods of deceptive calm” were looked upon as a certain sign of cure. Another example of a Lilly “money maker” was “Pil Damiana” , promoted “for mental overwork or enfeebled condition of the general system”, in addition to being “a powerful, permanent, and determined aphrodisiac”. The American market was flooded with nostrums bearing such catchy names as “Weak Manhood” and “Piso’s Consumption Cure” [38]. In contrast, in Germany during the same period, von Behring and Ehrlich (both Nobel Prize laureates) had discovered antidiphtheria and antitetanus sera. In 1910, Ehrlich’s arsenical “606”, Salvarsan® (the first ever chemotherapeutic agent), was found to be effective for treating syphilis. The population of the Nyanja tribe in the German colony of Cameroon had decreased from 12,000 to 609 individuals due to the trypanosomiasis epidemic; the advent of “Bayer 205” finally halted the scourge. Fritz Hoffman had discovered synthetic (methyl) rubber, and guaranteed pure reagents, labeled “pro analysi” became available, as did Bayer’s Aspirin®. Credible scientific research was stagnant in the U.S. as well as in Great Britain, Japan and other countries. In any case, there was an insatiable demand for German goods. A serious problem arose during the Great War—America, still neutral in 1916, urgently needed German products, but the British naval blockade of the North Atlantic made shipping perilous. In order to circumvent this, crates of Merck goods, in some instances, were sent to America aboard U-boats (German submarines) [39]! In 1903, on his return from Germany, Fourneau was named director of pharmaceutical research at the Poulenc Laboratories, which today form part of the colossus Sanofi. The desire to create a local anaesthetic free of the toxic effects of cocaine was accomplished when he discovered his first synthetic drug to which he added his name to the suffix -aine, calling it “Fourneaucaine”. Soon after, Fourneau decided that this sounded “ridiculous”. Consequently, he anglicised his name to Stove and christened it, Stovaine® [40].5 Affectionately, his colleagues began calling him, “Monsieur Stove”. The surgeon Paul Reclus, experienced with local anaesthesia, initiated the first clinical trial of Stovaine by comparing it to cocaine [41]. Happily free of the side effects ascribed to cocaine, Stovaine became an immediate success. In 1904, it was presented in a conference in Berlin with over 100 pa-

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5 A pleasing revelation concerning Stovaine surfaced in Stedman’s Medical Dictionary (18th ed.) where Stovainization is defined as: “The induction of spinal anaesthesia by subarachnoid injections of Stovaine”.

Willstätter was a Jew who, in spite of his scientific achievements, was not spared Hitler’s persecution and so with heaviness of heart, left his native land in 1939, for a village close to Locarno in Switzerland.

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pers extolling its efficacy. For this achievement, Bayer offered Fourneau an outstanding contract for work in their research laboratory. Being fervently patriotic, however, Fourneau could not be persuaded and so declined the proposal. Some years later, Fourneau again alluded to his “English” name by designating his pentavalent arsenical, Stovarsol® . Stovarsol, the first arsenical to be orally administered for curing syphilis, also proved efficacious in the treatment of trypanosomiasis and yaws. The fellowship between Fourneau and Reclus continued after their connexion with Stovaine. Reclus introduced Fourneau to the family of a surgical colleague Paul Segond, whose younger daughter Claudie interested Fourneau. Within 3 years, Claudie became Fourneau’s wife and they had 3 children. One of their 2 sons, Jean-Pierre, became a pharmacist and worked alongside his father at the Pasteur Institute. Later on he wrote highly detailed biographies of his father; much of the information in this text is derived from one such account [37]. Fourneau was very sociable and had a cheerful disposition although during his work he could be scrupulous, strict and disagreeable. At times, he allowed his coworkers to publish work in their names and without including him. Fourneau regarded himself simply as a “pharmacist”. In 1903, he formed La Molecule, whose members included pharmacists, chemists and later, pharmaceutical industrialists. They met frequently for several years to discuss topics of mutual interest as well as their scientific research. In 1911, Émile Roux, the director of the Pasteur Institute, commissioned Fourneau to establish France’s first laboratory of chemotherapy. Fourneau accepted the offer and remained its director for 30 years, until the age of 74 when he retired; Tiffeneau, his brotherin-law and colleague, succeeded him. Without question, during the 30 years at the Institute, Fourneau created more substances than any other pharmaceutical chemist. His exceptional ability and perseverance along with his perspicacity in relating pharmacological activity to molecular structure made him masterful in synthesizing organic compounds. In addition to those substances mentioned earlier, Fourneau created, among others, the hypnotic Quietol®, the anti-malarial Rhodoquine, synthetic ephedrine, the antibacterial sulphone and the antileprotic dapsone. Chlorpromazine, meprobamate, and propanolol are examples of drugs developed from molecules that Fourneau introduced. His final discovery was 2559 F (gallamine) [42]. As fate had it, Fourneau’s first and last syntheses would involve the field of anaesthesia. At one time, the Fourneaus were living with their three children in the Paris suburb of Gif-sur-Yvette. Their house was infested with mice. One day, Fourneau brought home from his laboratory his splendiferous cat who, endowed with a hefty appetite, would surely put an end to this problem. Alas, it turned out

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

to be a fiasco—the cat had become so used to peacefully living with Fourneau’s laboratory animals, it had lost its predatory trait. The outcome was this: the cat simply endured the mice whose population merely increased [43]. People south of the Sahara were being wasted by trypanosomiasis. Efforts either to rid the region of the tsetse fly or to move the entire populations to unaffected areas proved ineffective. In 1916, Bayer scientists produced Bayer 205, Germanin®, a nonmetallic drug which would end this plague. It was given intramuscularly or intravenously (at times using rain water). The existence of the drug was kept secret while Bayer enjoyed the monopoly and the profits. So valuable was Germanin that the Germans offered it in exchange for the Cameroons! This bedeviled Fourneau who was determined to decipher the mystery. Eventually he triumphed with the discovery of the same substance, 309 F, Maronyl®, thus ending the hold. In 1917, Fourneau was invited to the School of Pharmacy in Madrid for a 3-month residency. There he gave a series of 14 lectures as well as practical instruction in the synthesis of organic compounds. In 1921, he published these facts in a most interesting and novel small book, “the writing of which was a labour of love”, in Spanish and French and later in English [44], German and Russian. It includes such topics as the setting up of laboratory apparatus and the determination of nicotine content of tobacco. He was bestowed a doctorate honoris causa during his visit to Madrid in 1934. Life in Paris under the German occupation was as trying for Fourneau as for any Frenchman. Although he had access to an automobile, he instead walked or used his bicycle. In any case, in 1942, he again traveled to Madrid. The journey was marred by incidents that left him virtually penniless when he arrived there. During his travel, the French authorities confiscated most of his money and later he was even forced to sell his gold watch, which he had taken in place of his everyday one, at an absurdly low price, so that he finally could arrive to Madrid. The purpose of the trip was to intervene in the detainment of a colleague charged for activities against the Franco regime; Fourneau’s efforts saved him from imprisonment and even possible execution [37]. After Fourneau retired from the Institute in 1945, his faithful friends at Rhone-Poulenc established a research laboratory for him. He remained active for 3 years until shortly before his death. When the old gentleman felt that his end was near, he asked to be moved to his beloved house in Ascain in the Basque region. There he died peacefully of monocytic leukaemia and was buried next to his wife. Today, a street in Ascain and another in Biarritz bear his name.

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Reid Hunt (1870–1948) On May 20, 1870, Reid Hunt was born at Martinsville in Ohio (population in 1870: 264) to a family belonging to the Religious Society of Friends (Quakers).The central point of this persuasion is the Inner Light. It is vital to point out that Hunt’s, or as he is usually known, “Reid Hunt”, faith would undoubtedly influence his unique personality and character. Friends hold to such values as integrity, truthfulness, peace, simplicity and tolerance; or, perhaps in the words of their founder George Fox, “Be still and cool in thine own mind and spirit”. Reid Hunt (Fig. 4) was the younger son of Milton, a banker, and Sarah, a teacher. Drawn to science early by the village pharmacist, Charles H. Irwin, Hunt completed his secondary education at the age of 16 after which he was admitted to the second year at Wilmington College (a Quaker institution). The following year, Hunt moved to Ohio University and read botany and Virgil’s Aeneid for one term. Thereafter, he completed his studies at Johns Hopkins University and received his A.B. degree in 1890. Subsequently, Reid Hunt began his medical studies in Bonn, only to return to America where he began working towards his doctorate degree in physiology at Johns Hopkins and

Fig. 4 Professor Reid Hunt. (Harvard Medical Library in the Francis A. Countway Library of Medicine)

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at the same time attending the College of Physicians and Surgeons in Baltimore. In 1896, he received both his Ph.D. and M.D. degrees [45]. After spending a year at Columbia University’s Department of Physiology, Hunt returned to Johns Hopkins where he joined the Department of Pharmacology, led by John Jacob Abel. Abel first isolated “epinephrin” and is today regarded as the dean of American pharmacology. An incident that would remain indelible for Reid Hunt took place in 1899, during his second trip to Upper Egypt and the Sudan; the then Tutor in Physiology, along with two associates from the Zoology Department of Columbia University, went in search of the primordial fish Polypterus bichir6 (Fig. 5) that inhabits that region of the Nile. The expedition was funded by Charles H. Senff, Vice President of the American Sugar Refining Company. Their aim was to find the evolutional position of this strange creature. The journey was hampered by military activity that subsequently ended in the Anglo-Egyptian condominium of the Sudan. But the war was only a prelude to the ill fortune that would befall the explorers; all three were taken ill with typhoid fever that proved fatal to Nathan R. Harrington, aged 28, leader of the mission [46]. With a military escort and the Almighty, Hunt was left to move the other survivor Francis B. Sumner across the desert to a place of shelter. But, the fish they were seeking remained undetected. It was found 5 years later in The Gambia, by the Englishman John S. Budgett, who soon afterwards died of blackwater fever as a complication of Plasmodium falciparum malaria, aged 32. While studying the effect of acetylcholine on blood pressure, Hunt errored by presuming that this response of acetylcholine resulted from a negative inotropic activity, rather than to peripheral vasodilatation. Earlier in his career, he investigated the innervation of the heart of the opossum, lobster and calf, being particularly interested in the simultaneous stimulation of the vagus and sympathetic nerves. As said earlier, in Hunt’s experimental procedure, the animals received curare before succinylcholine thus eclipsing any possible visual activity on skeletal muscle. In any case, at that time (ca. 1911), anaesthesia was solely of the volatile agent variety and thus it is highly unlikely that Hunt could envisage any link between it and his succinylcholine. (His other interest then was iodine and the thyroid gland.) The same would apply to Glick who was engaged with his esterases. However, it was indeed a sad day for MacIntosh who dismissed succinylcholine as “use-

6 Polypterus bichir was mistakenly believed to be a lungfish and a link between fishes and amphibians. Coloured greenish-yellowbrown, it has 13–18 dorsal finlets. The lower jaw is longer than the upper jaw. It is covered by scales of enamel, crawls with its fins and swims like an eel. Basking in the mud, it jumps from the water to gasp air into its air sacs. The adult male is some 75 cm long and weighs about 2.5 kg

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Fig. 5 Polypterus bichir (dorsal and lateral views). (Courtesy: Dr. Sumaia Abukashawa, Department of Zoology, Khartoum University)

less” because of its “evanescent” action! Fortune, however, was kinder to Bovet and his colleagues who, being aware of exactly what they were looking for, finally removed succinylcholine from the shelf where for decades it had gathered dust and offered it to anaesthesia. Succinylcholine was not the only substance developed by Hunt whose therapeutic value remained hidden. β-methylacetylcholine became the second analogue that suffered a similar fate. Its medicinal properties were only detected some 20 years later in 1933 by Starr et al. [47]. Marketed as Mecholyl®, methacholine, having parasympathetic activity, became useful in the treatment of peripheral vascular disease, urinary bladder retention and paroxysmal tachycardia. It provided relief in arthritis when applied locally using the technique of iontophoresis. Hunt travelled to Frankfurt in 1902 where he studied at Paul Ehrlich’s Institute for Experimental Therapy for 2 years. This participation incited in him the nexus of chemical compounds to physiological activity; the principle became the foundation of his research throughout his career. On completion of his stay with Ehrlich, which for him was the happiest and most rewarding period of his career, Hunt became Chief of the Pharmacological Division in the Hygiene Laboratory of the U.S. Public Health Service where he remained for almost 10 years. The toxicology of ethanol and methanol (1907, especially valuable during the prohibition era in America), the demonstration of thyroid hormone in human blood, the effect of diet on thyroid function, his “acetonitrile reaction” (1909) and the choline experiments (1911) became some of his most noteworthy attainments of that period. In 1913, Reid Hunt became the first professor of pharmacology at Harvard University. He was not particularly eager to take the position as it involved teaching which he disliked intensely. Hunt was erudite yet cautious, absolutely sincere, gentle, unpretentious and modest, but he was also extremely shy and a poor

Daniel Bovet, Nobelist: muscle relaxants in anaesthesia

teacher; medical students found his lectures perplexing. In any case, Reid Hunt also became involved with other issues: he believed that medical research in the U.S. was, “conspicuously backward . . . with the discovery of drugs” and he envied Germany’s position in pharmaceutical development. (These thoughts were aligned with Fourneau’s.) He encouraged the formation of nonhabit forming opiates and local anaesthetics so as to replace opium and cocaine and later, became one of the original members of the Committee on Drug Addiction. Hunt was a strong advocate of measures against nostrums; the gullible public was easily swayed by the advertisements and testimonials in the lay press [39]. Abel, with the Swiss-born brilliant investigator in chemotherapy Carl Voegtlin and Hunt founded the American Society for Pharmacology and Experimental Therapeutics with Hunt serving as its first Secretary. (Membership was denied to those pharmacologists engaged with the pharmaceutical industry or in clinical medicine.) Reid Hunt was named Chairman of the Council of Pharmacy and Chemistry and served as president of the U.S. Pharmacopoeial Convention, vigorously encouraging drug standards. In recognition of these efforts, he was called to the Permanent Standards Committee of the League of Nations Health Committee. He was active also in the problems of gas warfare [45]. Reid Hunt married Mary Lillie Taylor but they had no children. His wife played a great part in his life that was otherwise unassumingly devoted to his work. He travelled widely and spent a year as Visiting Professor in Peking. This “tall kind gentleman without any prejudice” died in Boston on March 7, 1948, after a long illness. Acknowledgements I am most grateful to the following: Professor Daniel Pierre Bovet for inviting me to his apartment in Rome and giving details of his father; Professor Marcel

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Bickel, Department of Medical History, University of Bern, for guidance during our many meetings in Zurich; Philippe Galanopoulos, Curator, BIU Santé, Paris, for the days spent with me in the literature search. I wish to thank the professors of anaesthesia: Richard SJ Clarke, Belfast, Gottfried Benad, Rostock and Klaus Olkkola, Helsinki, for reading the manuscript. The paper is in memory of those who taught me at the Faculty of Medicine, Alexandria University. Conflict of interest D.A. Cozanitis declares that he has no competing interests.

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20. Huguenard P, Boué A. Un nouvel curarisant français de synthèse – le RP3697. Communication faite à la Séance de la Société d’ Anesthésie du 17 juin 1948. 21. Bovet D. Some aspects of the relationship between the chemical constitution and curare-like activity. Ann N Y Acad Sci. 1951;54:407–37. 22. Hunt R, de Traveau RM. On the physiological action of certain cholin functions derivatives and new methods for detecting cholin. BMJ. 1906;:1788–91. 23. Hunt R, Traveau R de M. The effects of a number of derivatives of cholin and analogous compounds on blood pressure. Public Health and Marine Hospital Service of U.S. Public Health Hospital. U.S. Hygienic Laboratory Bull. No. 73; 1911. 24. Bovet D, Bovet-Nitti F, Guarino S, Longo VG, Marotta M. Proprietà farmacodinamiche di alcuni derivati della succinilcolina dotati di azione curarica. Rend Ist Super Sanita. 1949;12:106–37. 25. Glick D. Some additional observations on the specificity of cholinesterase. J Biol Chem. 1941;137:357–62. 26. MacIntosh FC. Third Sarrazin lecture. Quebec: Centre d’Arts d’Orford; 1979. 27. BarlowRB, Ing HR. Curare-likeaction of polymethylenebisquaternary ammonium salts. Nature. 1948;161:718. 28. Organe GSW, Paton WDM, Zaimes EJ. Bistrimethylammonium decane and pentrane (C10 and C5) in man. Lancet. 1949;1:21–3. 29. Churchill DH. Suxamethonium (Succinylcholine) chloride and muscle pain. BMJ. 1954;1:74. 30. Foldes F. Prolonged respiratory paralysis after succinylcholine. BMJ. 1952;I:1352. 31. Forbat A, Lehmann H, Silk F. Prolonged apnoea following injection of succinyldicholine. Lancet. 1953;II:1067–8. 32. Dorkins HR. Suxamethonium – the development of a modern drug from 1906 to the present day. Med Hist. 1982;26:145–68. 33. Valdoni P. Osservazioni clinche sull’impiego del curarizzante 362. I S Rend Ist Supersanità. 1944;12:255–62. 34. Scurr CF. A relaxant of very short action. BMJ. 1951;2:831–2. 35. Tracing the intraceable. Time. 1967; 89:34 36. Rousseau P. Un bienfaiteur de l’humanité ignoré et vaincu: Ernest Fourneau. Notre Temps. 1968;4:35–8. 37. Fourneau J-P. Ernest Fourneau, fondateur de la chimie thérapeutique française : feuillets d’album. Rev Hist Pharm (Paris). 1987;275:335–55. 38. Adams SH. The great American fraud. Collier’s. 1908;7(29):14–5. 39. Bernschneider-Reif S, Huber WT, Possehl I. Was der Mench thun kann. . . History of the pharmaceutical and chemical company Merck. Darmstadt: Merck KGaA; 2002. 40. Fourneau E. Un nouvel anesthésique: la stovaine. J Pharm Chim. 1904;20:108–9. 41. Reclus P. L’analgésie locale par la stovaine. Bull Acad Med. 1904;52:7–11. 42. Fourneau E, Janot M-M. Les curares. II. – Aperçu sur la chimie des curares et de quelques substances curarisantes. Ann Pharm Fr. 1949;7:353–68. 43. Fougére P. Grands Pharmaciens. Paris: Buchet-Chastel; 1956. 44. Fourneau E. Organic medicaments and their preparation. Philadelphia: P. Blakiston’s Son; 1925. 45. Marshall EK Jr. Reid Hunt: 1870–1948. Nat Acad Sci Biogr Mem. 1951;26:25–41. 46. Harrington NR. dead: was the leader of Columbia University’s expedition to the Nile. The New York Times. 1899 Aug 12. 47. Starr I Jr, Elsom KA, Reisinger JA, Richards AN. Acetyl-ßmethylcholin. I. The action on normal persons. Am J Med Sci. 1933;186:313–23. Daniel Bovet, Nobelist: muscle relaxants in anaesthesia