From the jungle to the operating theatre

About curare and its medical applications

In the autumn of 1946, Robert Macintosh travelled to Spain invited by the Spanish National Research Council (CSIC). The announcement of his visit generated some stir in the national medical community because he came to present a novel technique that was revolutionising surgery. No one would be disappointed. For once, reality far exceeded expectations. There is no better proof of that than the British anaesthetist’s own diary. After the first of his presentations in Madrid, he wrote about the second case, a man with a large abdominal tumor, which happened to be a multiple hydatid cyst. He administered pentothal, light ether, and 15 mg of Tubarine. The resulting relaxation caused laughter and surprise, and the surgeon repeatedly raised the musculature to show the flabbiness. In his diary, he wrote: «Rather reminded me of natives with a new toy». The rest of his sessions in our country achieved identical success. These took place in operating theatres full of spectators eager to witness the unique event (Unzueta, Hervas, & Villar, 2000).

«In the beginning of the twentieth century, surgery was conditioned by postoperative infections and the need to use large doses of anaesthetics»

What was all the excitement about? To understand it, we need to look back to a time when doctors had far fewer weapons to improve our health. If we restrict ourselves to the field of surgery, this was conditioned by two serious drawbacks: postoperative infections and the need to use large doses of anaesthetics to achieve muscle relaxation, which sometimes produced cardiac arrhythmias and respiratory problems of diverse severity. Curiously enough, both obstacles disappeared almost at the same time. The first one, thanks to the discovery of antibiotics, with penicillin as the spearhead. The second one by means of the essential component of the technique shown by Macintosh, the Tubarine, whose brand name hid an unexpected origin. This astonishing muscle relaxant came from the tribal poison par excellence, the curare. Yes, curare, the great fear of the Spanish conquistadors in their forays into the Amazon and Orinoco basins. How did the main active ingredient of a substance that aroused a dreadful fear for centuries become a vital drug in surgery? Here is its story.

The active ingredient of curare, a poison used by the Amazon tribes, became for years a vital drug in surgery and to treat illnesses that involved muscle pains and contractions. Its unknown origin complicated for a long period of time the constant supply of tubocurarine, its active ingredient. This changed in 1938, when Richard Gill entered the Ecuatorian jungle for months and returned with 12 kg of curare made with the plant Chondrodendron tomentosum, from which it was possible to isolate the sufficient quantity of product to put it on the market. In the picture, samples of herbarium sheets of this plant collected in 1948 by Richard Gill years later, and preserved in the New York Botanical Garden. / The New York Botanical Garden

The poison

The Chronicles of the Indies are full of references to the use of poisoned arrows by the natives (Miguel & Vela, 1953). From the first one, the Decades of the New World by Peter Martyr d’Anghiera, who describes in his book: «[…] Ours were defeated; they killed Captain Ojeda’s second, Juan de la Cosa, who was the first one to collect gold in the sands of Urabá, and seventy soldiers fell, for the natives poisoned their arrows with the juice of a death-dealing herb […]». Reviews of this kind of confrontations can be found in most of the authors who narrated the conquest of America during the sixteenth century. Of course, many of them had other harmful substances as protagonists, because, as written by Gómez Suárez de Figueroa, better known as the Inca Garcilaso de la Vega, «[…] the Indians used various poisons to smear their arrows; some killed quickly and others slowly […]». Stories that talk about death with great pain, «raging with pain» according to the expression of the time, cannot refer to the use of curare, since its mechanism of action blocks the transmission of nerve impulses to muscles and leads to a torturous death by asphyxiation.

This fact prevents the English corsair Walter Raleigh from being the first to describe the effects of curare, as many Anglo-Saxon texts point out, since his travel chronicles allude to similar agonies in the miserable members of his crew wounded by an arrow. In that respect, we cannot point either to any of the Spanish conquerors, because the battles gave little choice to the exchange of information and, as a result, we will never know what poison in particular was used by the indigenous people in each case. For that reason, if we are to give a name to the first European who referred to this substance without any possibility of confusion, we need to advance several decades in time and get to a more peaceful time.

Curare can be found, already in the eighteenth century, in one of the most striking social experiments of the Colonial Americas. The Spanish Crown had granted vast areas of barely explored jungle to the Society of Jesus, where they sought to create a New Jerusalem. For this purpose, they had tried to concentrate the Indians in settlements on the banks of the great rivers, called reductions. From that point, they organised a network of communities that tried to combine the Christian faith with some respect for native cultural values. It was not a perfect model, but, considering that outside of these missions the law of the slave traders prevailed, they could be considered an oasis of coexistence. We must not forget the estimable effort of learning languages and the indigenous ways of life that the Jesuits led to carry it out.

«Shamans were usually responsible of preparing the curare for the tribe, according to the recipes that were passed on orally»

The book The Orinoco illustrated and defended. Natural, civil and geographic history of this great river and its abundant branches was written in 1741 by Father Joseph Gumilla within this process of cultural immersion. The chapter «On the mortal poison called curare. Strange manners of fabricating it, and on its instantaneous activity» is the first reliable reference to this substance (Raviña, 2017). As a missionary who lived fifteen years in the basin of this river, Gumilla knew what he was talking about. This work contains several interesting notes. For example, he warns that curare «[…] has no taste or special acrimony: you can put it in your mouth, and swallow it without risk or danger; as long as neither the gums nor any other part of the mouth is wounded with blood […]». This curious circumstance, which allows people to ingest without fear the meat of the animals hunted with it, turned it into such a precious poison among Amazonian peoples of the time that the Jesuits used it to pay for their work on reductions and as a trade article in approaches to new tribes, which in turn increased their area of employment (Cipolleti, 1988).

Its production, however, always fell in indigenous hands and, in particular, in those of the shamans. They were usually responsible of preparing the curare for the tribe, according to the recipes that were passed on orally from generation to generation. All of them followed a similar procedure: the extraction of water from the starting materials and the subsequent concentration through heating the resulting mixture, until a substance with a semi-solid consistency could be spread in arrows or darts. They differed, however, in the ingredients they used. And not only because of the different cultural heritage of every tribe, but also due to the diversity of the natural environment around them. The flora of the Amazon is not uniformly distributed at all, and most species inhabit very specific areas.

On the left, an engraving from the time that shows the indigenous people with blowpipe, one of the methods used to shoot arrows impregnated with curare. On the right, preparation of arrows poisoned with curare. / Retrieved from Crevaux, J., & Lejanne, E. (1882). A travers la Nouvelle-Grenade et le Vénézuéla. Le Tour du Monde, 43(1114), 289–304 – Wellcome Library

These differences greatly complicated the answer to the question: «What is the origin of curare?». There were many European naturalists who attempted to answer this question and also many disputes they fought for their cause. Thus, for example, still in the Age of Enlightenment, we find that Hipólito Ruiz and José Pavón were responsible for the botanical expedition to the Viceroyalty of Peru promoted by the Spanish Crown. They identified the Chondrodendron tomentosum plant as the main source of this poison, while the German Alexander von Humboldt and the french Aimé Bonpland did the same with the liana Strychnos toxifera, which they discovered during their stay in the village of La Esmeralda, currently in Venezuela (Carod-Artal, 2012).

«The Chronicles of the Indies are full of references to the use of poisoned arrows by the natives»

Today we know that both sides were right. One of these two vegetables is always the key ingredient. The use of one or the other simply depends on the species occurring in the area in which it was prepared. It took decades to reach this conclusion, which meant that until well into the twentieth century, everything concerning this substance was surrounded by an exotic halo of mystery. Meanwhile, unable to find better criteria, samples arriving in Europe were listed by the their container. This is the origin of the so-called tube curares, curares in pumpkin, and curares in jar. These names refer to the three ways that the Amazonian villages had of storing their favourite hunting poison.

A consequence of this confusion is that the active ingredient of Chondrodendron tomentosum bears the name of tubocurarine. When the chemist Harold King first isolated this natural product in 1935, he did not know which plant it came from. All he knew was that the curare supplied to him by the Royal Pharmaceutical Society Museum was preserved in a bamboo cane (Raviña, 2017).

In 1942, the Canadian anaesthetist Harold Griffith first used tubocurarine as an anaesthetic in surgery. In the picture, bubbles of tubocurarine chloride of the trade brand Tubarine in their original box, from the company Burroughs Wellcome and Co. This brand would be used years later by the anaesthetist Robert Macintosh on his trip to Spain and would have an impact on the medical community. / The Board of Trustees of the Science Museum

Before this fact, however, there was another finding worth mentioning. It was led by Charles Waterton, the English landowner of a sugar cane plantation in British Guiana, now Guyana. He lived there for twenty years, during which he spent entire months in the jungles of the area dedicated to his great passion, the study of flora. As a result, he would gain a certain reputation as a naturalist, despite the fact that his Catholic status had prevented him from pursuing university studies in his country. His most significant contribution took place in 1814, when during one of his visits to his native land, together with doctor Benjamin Brodie, he carried out a key essay to clarify this poison’s mechanism of action. To this end, they inoculated curare samples he brought from Guyana in one of the legs of three donkeys. The first one, simply to test the power of the toxic, which was quickly evidenced because the donkey died in twelve minutes. The second survived a little longer, because they made a tourniquet on top of the cut and it continued grazing for an hour without showing any poisoning symptoms. Nevertheless, as soon as the ligature was removed, it followed the fate of the first animal. The luckiest donkey happened to be the third one. They made an incision in its trachea and breathed air with bellows until, after hours, it woke up, got up, and began to walk without symptoms of pain. It still lived another 25 years and became a small local celebrity (Birmingham, 1999).

The drug

With this experiment, Waterton and Brodie proved that curare kills by asphyxiation. As a powerful muscle relaxant, it causes temporary paralysis of the intercostal muscles and the diaphragm, whose participation is essential for breathing. The discovery completely changed the status of this substance, which went from being categorised as a poison to being considered a drug. Still, there was a major obstacle to overcome, the inability to keep a constant supply until its origin was clarified. And so, although the doctors began to prescribe it to treat various diseases that involve severe muscle pain and contractions, there was no way to adequately meet this demand until, already in the twentieth century, an unusual character came on the scene.

The name of the active ingredient of Chondrodendron tomentosum, the tubocurarine, has its origin in the bewilderment about the origin of the curare. Since the origin of the substance is unknown, the samples arriving in Europe are catalogued by the recipient containing them. From here, they sell the so-called tube curares, curares in pumpkin and curares in jar, which refer to the way in which the Amazonian peoples stored the poison. In the picture, pumpkin containers that kept curare coming from South America (left) and British Guiana, now Guyana (right). / Wellcome Library

Richard Gill’s personal journey is the basis for a novel (Betcher, 1977). Agent of the American Rubber Company, raised in Ecuador after the crash of 1929, the life of this American go-getter was completely altered when, in the early thirties of last century, he began to suffer frequent muscle spasms. This disease would force him to return to his country, where he was diagnosed with multiple sclerosis. However, he always blamed a horse fall he had suffered while living in South America as the cause of his condition. Either way, he had a severe disability and he was sometimes practically paralysed. He would only come out of this state after visiting a neurologist who recommended curare for his disease. This suggestion did not seem very practical when it came up against the usual lack of supplies of the substance, but it had the virtue of leading him to revolt against his misfortune in a heroic way.

In 1938, he was back in the Ecuadorian jungle. His goal: to acquire all the poison he could find. His mobility problems had not disappeared, but thanks to the invaluable help of the local indigenous people, he managed to withstand the harshness of the jungle for five months. He did not waste that time. He managed to collect twelve kilograms of curare made from the Chondrodendron tomentosum plant, which he delivered to the Squibb company once he returned to the United States. The company’s chemists extracted its active ingredient, which they identified as the well-known tubocurarine. The operation was a success, and enough product was isolated to release it to the market. The days of shortage of this drug were over.

«Curare kills by asphyxiation: as a powerful muscle relaxant, it causes temporary paralysis of the intercostal muscles and the diaphragm»

Gill’s audacity rewarded not only himself, who was able to have a remedy to alleviate his pains, but also all humankind. The sudden abundance of tubocurarine made it possible for doctors to explore its use in new applications. Soon, they discovered a therapeutic use that would become a turning point. This moment came at the beginning of 1942, when the Canadian anaesthetist Harold Griffith used it for the first time in a surgical procedure and achieved in a simple way a muscular relaxation that was unknown until that moment (Betcher, 1977). The virtues of this innovation were multiple: to facilitate the intubation of the patient, to decrease the dose of the main anaesthetic, and to improve the control of mechanical ventilation. Only the coincidence with the Second World War temporarily slowed its rapid spread throughout the world. For this reason, it was not until 1946 that one of the people who popularised this technique, Robert Macintosh, visited Spain. Robert Macintosh surprised the medical environment of this country thanks to this natural product.

Many naturalists tried to answer the question about the origin of curare, but it took decades until it was confirmed that the key ingredient was Chondrodendron tomentosum or Strychnos toxifera, depending on the presence of one plant or another in the local flora. On the left, botanical sheet of C. tomentosum, on the right, photograph of the plant in the New York Botanical Garden. / Welcome Library

Tubocurarine would revolutionise anaesthetic practice in the 1940s and 1950s, but it had a short reign. Soon, other drugs were designed with slight variations in their chemical structure that improved its performance, and they were gradually replaced it. They are still in use today, having become a common feature in operating theatres. Interestingly, the active ingredient of the other plant used as the main ingredient of curare, Strychnos toxifera, does not belong to this category. It was called toxiferine but its excessive power prevented its medical application. Something similar has happened with tribal poison coming from both compounds, because the art of hunting with blowpipe, of which it is an essential part, has practically disappeared. Despite having an obvious advantage over firearms – silence allows they to stealth their way close to the potential prey – these have relegated it to oblivion in the Amazon. There remains, however, the memory of a mythical substance that terrified several generations of European conquerors and explorers.

REFERENCES

Betcher, A. M. (1977). The civilizing of curare: A history of its development and introduction into anesthesiology. Anesthesia & Analgesia, 56(2), 305–319.

Birmingham, A. T. (1999). Waterton and Wouralia. British Journal of Pharmacology, 126(8), 1685–1689. doi: 10.1038/sj.bjp.0702409

Carod-Artal, F. J. (2012). Curares y timbós, venenos del Amazonas. Revista de Neurología, 55, 689–698.

Cipolleti, M. S. (1988). El tráfico del curare en la cuenca amazónica (Siglos xviii y xix). Anthropos, 83, 527–540.

Miguel, J., & Vela, R. (1953). Contribución española a la historia del curare. Hypnos, 1, 7–64.

Raviña, E. (2017). Las medicinas de la historia española en América. Santiago de Compostela: Servicio de publicaciones de la Universidad de Santiago de Compostela.

Unzueta, M. C., Hervás, C., & Villar, J. (2000). A new toy: La irrupción del curare en la anestesia española (1946). Revista Española de Anestesiología y Reanimación, 47, 343–351.

© Mètode 2018 - 99. Online only. Interlinked - Autumn 2018

Tenure-track professor at the Department of Organic and Inorganic Chemistry of the University of Alcalá (Madrid, Spain).

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