Curare: The Flying Death*

The story of how the South American arrow poison, curare, was introduced into medical practice is one of the most fascinating stories in the history of pharmacology. The primitive use of curare is lost in the centuries-old culture of Indians living in the Amazon Basin. The first written historical account about curare was made by the Italian priest Pietro Martire d'Anghiera, who was attached to Queen Isabella's Spanish court. He chronicled the stories of homecoming explorers from the New World in his great book Rebus Oceanis et Novo Orbe published in 1516 (D'Anghiera 1516). De Orbe Novo contains many references to poisoned arrows and the preparation of curare. It is therefore certain that the Indians used poisoned arrows at the time the Spanish conquistadores reached the New World. However, the arrow and dart poisons were not curare as we understand the term now (Bisset 1992). Today, to the pharmacologists, curare is characterized by a non-depolarizing action at the neuromuscular junction causing relaxation of the skeletal muscle. To the anaesthetists, curare often simply refers to the alkaloid (+)-tubocurarine. The Indians used a blowgun (sarabatana) to deliver darts tipped with curare. The blowgun is basically a hollow tube of cane or wood, usually about 6 feet in length. A dart, wrapped at the proximal end with a wad of cotton, is introduced into one end of the tube, the cotton acting as a piston gasket. The distal end of the dart is impregnated with curare. At conquest times, the use of blowguns extended from northern Bolivia to central Mexico (Riley 1952). The Elizabethan explorer Sir Walter Ralegh penetrated deep into British Guiana in search of the fabulous city of Eldorado (Ralegh 1596). Contrary to popular belief, Sir Walter never described curare and was probably totally ignorant of its existence (Carman 1968). Furthermore, Ralegh did not bring arrow poison back to Europe (McIntyre 1947). Alexander von Humboldt was a great German scientist and explorer. He and Aimé Bonpland, a French surgeon and botanist, left Spain together in 1799 for the Americas. During the next five years, they travelled throughout all South America. The main focus of their journey was botany. Their botanical activities contributed substantially to our knowledge of the plant sources of the arrow poisons. Von Humboldt and Bonpland were the first scientifically trained persons to witness the actual preparation of curare in 1800 at Esmeralda at the Upper Orinoco (Humboldt 1807). They also learned about the poisons made by several other Indian tribes (Bisset 1992). Von Humboldt was the first investigator to distinguish between the toxic ingredients in curare and those added to confer the right consistency to the product. It was von Humboldt who brought curare back to Europe. The English Squire Charles Waterton was an excellent observer and recorder of nature although he had no formal scientific training as a naturalist. In 1812, Waterton made a “wandering” from Georgetown to the hinterland of British Guiana with the aim of investigating the origin and preparation of the Wourali (curare) poison (Waterton 1825). He demonstrated that artificial ventilation allowed for the total recovery of a she-ass poisoned by curare (Smith 1983). Waterton believed that curare might find use in medical therapeutics. The French physiologist Claude Bernard studied the action of curare. Using frogs, he carried out some experiments that were elegantly conceived and meticulously executed. On the basis of these experiments, Bernard concluded that curare acted peripherally at the neuromuscular junction (Bernard 1857). The studies paved the way for the first real clinical use of curare. The German surgeon Arthur Läwen was the first to use curare as a muscle relaxant during surgery (Läwen 1912). He obtained curare from the pharmacologist Rudolf Boehm at the University of Leipzig. However, the supply of curare was very limited, which prevented Läwen in continuing to use curare for muscular relaxation during surgery. In 1938, curare was in a unique position. Its mode of action was understood and it had been used in patients for more than one hundred years. Yet, predictable supply of curare was a barrier to further progress. There matters might have stood, if it had not been for Richard C. Gill, an American layman with a medical background (Humble 1982). Gill lived for several years in the Ecuadorian jungle. He became friendly with the local Indians and studied their use of the jungle pharmacopeia. He learned about curare and witnessed its preparation. In 1932, Gill became ill with multiple sclerosis. Two years later, he was almost totally paralyzed. His neurologist mentioned to him that his muscle spasms might be relieved, if only predictable supplies of curare were available (Humble 1982). It took Gill four years to retrain himself so that he could walk back into the jungle with the aid of a stick. In 1938, Gill led a large expedition to the Ecuadorian jungle (Gill 1940). He brought back to the United States 12 kg of crude curare together with curare specimens that were identified as Chondodendron tomentosum by Krukoff & Smith (1939) at the New York Botanical Garden. In 1939, McIntyre at the Department of Pharmacology, University of Nebraska standardized Gill's crude curare using mice. Subsequently, Holaday at the pharmaceutical firm E.R. Squibb & Sons devised a new assay for curare, the rabbit head-drop test (Betcher 1977). Wintersteiner & Dutcher (1943) at Squibb were the first to isolate (+)-tubocurarine from a single plant species, namely Chondodendron tomentosum. The psychiatrist A.E. Bennett at the University of Nebraska used metrazol in convulsive shock therapy of certain psychotic states (Bennett 1968). However, this treatment was associated with comprehensive spinal fractures and dislocations. In 1939, Bennett used Gill's standardized curare to prevent the traumatic complications of the metrazol convulsive treatment (Bennett 1940). In 1942, Griffith and Johnson at the Homeopathic Hospital in Montreal administered curare (Intocostrin) to 25 patients under light general anaesthesia (Griffith & Johnson 1942). Since ample supply of curare was now available, Griffith could continue the systematic use of curare in anaesthesia (Griffith 1945). The introduction of curare into anaesthetic practice by Griffith & Johnson (1942) caused profound changes in the efficacy and safety of anaesthesiology. It made possible the development of true balanced anaesthesia (Foldes 1993). Professor Dermot B. Taylor led the UCLA Phytopharmacological Expeditions (1957–1959) to the Peruvian jungle. The main aim of the expeditions was to collect medicinal plants, including those containing curare. The botanical identification was done by Professor Mildred Mathias, head of the UCLA Botanical Garden. The commercial collection and preparation of curare by Peruvian locals was observed. Knowledge of curare embraces geographic adventures and explorations, botany, chemistry, physiology and therapeutics. In other words, it epitomizes the most exacting of all biological sciences – Pharmacology (McIntyre 1973).

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