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  • -present on curare, which is the most primitive type of muscle relaxant/NMB, and being the first of its kind, it is what began the wave of interest in utilizing this drug class clinically. it has an interesting past, many here might be familiar with its origins. I wanted to outline not only how this drug was discovered, but also the key players involved in making its recognition known, some hilights of the benchwork involved, and ultimately recognizing those who realized its potential use in the world of anesthesia. \n\n
  • - I like these quotes a lot, they provide the reasoning behind societies such as this exist, and how history provides a better understanding why we practice the way we do today.\n\n
  • - if we fast forward, relatively speaking, in time, this is a date of historic significance because it stands as the first use of curare in anesthesia. Prior to this time curare had seen other clinical uses which i’ll go into, but as far as neuromuscular blockers in anesthesia, Griffith gets most credit as the first.\n- this quote here was taken from the original medical chart\n
  • - from a plant source that is native to South America, numerous indian tribes by the 16th century were using extracts from these plants for hunting prey.\n- these are the two main plants researched by botanists and found to be the most commonly used species used to make curare, though additional strychnos and chondodendron species have been documented as well. There are roughly 50 species of strychnos found in the Americas.\n\n- geographically, it was the exploration of this diamond shape area in the 16th century, where first documentation of curare was noted. \n
  • - from a plant source that is native to South America, numerous indian tribes by the 16th century were using extracts from these plants for hunting prey.\n- these are the two main plants researched by botanists and found to be the most commonly used species used to make curare, though additional strychnos and chondodendron species have been documented as well. There are roughly 50 species of strychnos found in the Americas.\n\n- geographically, it was the exploration of this diamond shape area in the 16th century, where first documentation of curare was noted. \n
  • -not every indian arrow poison documented caused death in the same way. but in early literature that discusses arrow poisons it’s difficult to tell which are “true” curares in the sense that they cause death by muscle paralysis\n\n\n
  • - \n
  • - De Orbe Novo translates to “Concerning New World” - really the first written history of the new world. Takes us from expeditions of Christopher Columbus and covered a period of approximately 20 years. \n- Although first written hx of the new world, Martyr never left home! He met and entertained travelers and chronicled their stories.\n\n-Condamine was given special permission by the French Academy of Sciences to lead an expedition in 1735.\n- this was at the time, during the 17th and 18th centuries, Isaac Newton and other astronomers were arguing the shape of the earth. Hence the French Academy of the sciences sent one group along a meridian close to the equator (Condamine) and another near the north pole.\n\n- we’ll come back to these scientists and others in a little bit\n-if you think about it on a timeline, from the time Condamine brought samples back for study, it was another century before it was used to treat tetanus in a horse (we’ll get to that), and yet another century before it found its way into anesthesia!\n\n-there’s a time gap between these martyr and condamine!\n- de la Condamine (from Betcher journal) - after 1494, division of S. America between Spanish and Portuguese closed off the continent to explorers for the next 250 years. \n
  • - jump back to that italian entertainer to look at an early account of how curare was prepared\n-one Indian tribe apparently utilized old tribeswomen as the dedicated curare makers\n- this story of the old women had persisted for over 2 centuries after, story that added to the mythical qualities of curare, but was it really curare fumes that were causing these old women to nearly die? CO not known at the time.\n\n-another later account of the curare preparation was by Edward Bancoft, american physician lived in Guiana for a bit, while there studied the local environment, including a bit of the usage of curare. Later in life, he actually became a double agent spy for ben franklin during the american revolution!! He recorded the local ingredients used for its preparation, not exactly ingredients you might find at your local farmers market. Emphasized bark.\n\n(Herissant, scientist in 1750s who experimented with known curare sample, had similar experiences of feeling “sick at heart” from curare fumes (6), but unknown at the time was other chemicals such as CO that could have caused the reaction. It was in 1780 when Felix Fontana debunked the rumor of curare fumes causing symptoms - exposed pigeons to the fumes with no ill effect)\n
  • I apologize, I know this is already so many names to keep track of! There were truly a lot of individuals involved in the curare history.\n- Von Humboldt: couple important things here, he was allegedly first to personally witness the preparation of curare (normally sacred ritual). \n- also one of the first to identify the plant source, - Described in detail how the “maitre du poison”, or curare maker, creates the poison. Boiles and filters the bark of the Strychnos plant down to a molasses-like liquid... then tastes it to see if it was ready or not!\n\n- Schomburgk’s contribution was unique in that he insisted on having Indian guides show him the curare plant growing in the wild, something Humboldt and other explorers never saw. Not only identified Strychnos growing in the wild, also years later watched its preparation\n\n-(von Humboldt also denied that curare vapors caused any harm)\n
  • - recall De la condamine was the explorer set to measure the arc of the earths’ surface, first to bring samples of curare back, to University of Leyden in 1743\n-these two scientists marked the start of organized scientific research on curare\n-Brocklesby: its this observation that led the way to future scientists (Brodie) considering the idea of artificial respiration\n- I don’t really like thinking about this because we know now that muscle relaxants don’t double as analgesics.. the experiment provided crucial information, but if PETA was around they wouldn’t have been too happy...\n\n- Brodie: obtained curare from Bancroft who brought it back in 1776. confirmed Brocklesby’s work by observing in a guinea pig introduced to curare, after respirations ceased, the heart continued to beat at 70bpm. Took this further by artificially ventilating a cat. \n-At the time he didn’t realize the magnitude of how his research would apply to anesthesia, but in a sense this was pre-anesthesia era respiratory management!\n\n(-Herissant: basically killed a whole slurry of animals by introducing curare into small wounds. Described the death as painless but preceded by an almost universal palsy. Popular belief that sugar is antidote which he debunked.)\n(-Note: Felix Fontana (Italian), 1780, proved fumes were ineffective thus debunking the wives tale of the ‘old criminal ladies’. Didn’t include cuz original source is in Italian)\n
  • -Bernard: a medical school graduate who never practiced, became a physiologist. He learned about curare from his mentor Magendie, who used it for vivisection purposes. \n-because the muscle responded to a direct stimulus and not to indirect (nerve) stimulation, he concluded that the site of action must be in the junction between the muscle and nerve\n\n-Dale: followed up on Bernard years later, to fully understand the mechanism of the neuromuscular synapse, role of ACh, and mechanism of curare\n- this was the time the neuromuscular junction was just being discovered. Likely that Dale’s and others’ findings stimulated a whole area of research, things like mechanism of botulinum toxin and diseases like myasthenia gravis were on the way to being investigated.\n\n-(note on bernard source: couldnt obtain translated version of his original work so I cited this from a review book)\n
  • - due to the scientific discoveries in the first half of the 19th century, some physicians felt curare was ready for introduction into the clinical realm!\n- still something needed to be addressed: curare has yet to be standardized, so dosing properly is almost impossible\n\n-Sayre: as I was reading through the case report, I saw their first line approaches for treating tetanus: chloroform, cannabis, an injection of beef tea, brandy per rectum, an enema of soap suds and turpentine. Its clear they were pretty desperate for a new approach.\n(-I read in one book “death must have been a merciful release from both the disease and its treatment” (Sykes lib book p.122))\n\n-these two quotes were from an editorial page in the Lancet, spoke of the overall feeling of curare at the time, \n\n(-note: Spencer Wells also tried curare for tetanus in 3 gyn pts in 1859: 1 survived\n- other uses: noted from lib book p.123, not quoted\n-there appears to be a gap from after Spencer Well’s use to the 1930s, around the time standardization of curare was occurring)\n\n\n(-Successful treatment of tetanus years later: in 1947, years after Griffith had established curare use in anesthesia, two physicians successfully treated tetanus in an 18yo girl by administering d-tubocurarine and Intocostrin, in tandem with the iron lung and a tracheostomy to remove secretions. In 1952, two physicians used the newly introduced succinylcholine to treat tetanus in a 45yo woman, utilizing ventilation through a tracheostomy and a manual reservoir bag for several days (both sources in library book p.129-30). Takes it into 1954 with the development of Radcliffe ventilator (mechanical bellows using intermittent positive pressure instead of the neg pressure of an iron lung (tank ventilator))\n
  • -so at this point there was some much needed laboratory work isolate the active component of curare in hopes of maybe standardizing it and making it a safe, predictable drug.\n-these names bolded here were some of the chemists involved in doing just that.\n-so, what actually was the active component of curare?! \n\n- d-Tubocurarine was the isolate of chondodendron tomentosum! \n- we know tubocurarine in modern anesthesia as a long-acting nondepolarizing skeletal muscle relaxant, neat to now take this and trace it back to its roots in the hunting grounds of south american indians\n\n-King: he is given credit for identifying the structure of d-tubocurarine. This happened 5 years before ER Squibb came out with Intocostrin. \n\n\n(-Curare from strychnos species were not as studied or developed as the tubocurarine from chondodendron species.)\n(Wieland, in 1938-1940, isolated alkaloids from calabash/gourd curare and identified as derived from Strychnos toxifera)\n\n-Richard gill disproved - containers brought to Europe were not descriptive of the type or source of curare, rather chosen by whichever was on-hand at the time curare was made \n
  • - The next phase of development was transforming curare from a laboratory tool to a clinically useful and safe drug. Starts with Gill.\n\n- Dr. Freeman never before worked with curare but put the idea in Gill’s head that it might be worth a try\n- Gill, having made enough contacts in S. America that he might be able to bring back a good supply, got his expedition financed by a wealthy man, and during a remission of his disease in 1938, organized a 5 month expedition to collect vines of Chondodendron species. Seeked out the plants by having Indian tribesmen lead him to the plant in the wild. \n\n(3 facts about Gill:)\n1) recognized no two batches of curare that came out of the jungle were identical in potency or toxicity (25), and \n2) disproved Boehm’s thinking that a different kind of curare plant was in each of the 3 different containers (tube, pot, gourd), when in fact it was simply placed in the most accessible container (25)\n3)lengthy odyssey written in his book “white water and black magic”\n
  • - The next phase of development was transforming curare from a laboratory tool to a clinically useful and safe drug. Starts with Gill.\n\n- Dr. Freeman never before worked with curare but put the idea in Gill’s head that it might be worth a try\n- Gill, having made enough contacts in S. America that he might be able to bring back a good supply, got his expedition financed by a wealthy man, and during a remission of his disease in 1938, organized a 5 month expedition to collect vines of Chondodendron species. Seeked out the plants by having Indian tribesmen lead him to the plant in the wild. \n\n(3 facts about Gill:)\n1) recognized no two batches of curare that came out of the jungle were identical in potency or toxicity (25), and \n2) disproved Boehm’s thinking that a different kind of curare plant was in each of the 3 different containers (tube, pot, gourd), when in fact it was simply placed in the most accessible container (25)\n3)lengthy odyssey written in his book “white water and black magic”\n
  • - The next phase of development was transforming curare from a laboratory tool to a clinically useful and safe drug. Starts with Gill.\n\n- Dr. Freeman never before worked with curare but put the idea in Gill’s head that it might be worth a try\n- Gill, having made enough contacts in S. America that he might be able to bring back a good supply, got his expedition financed by a wealthy man, and during a remission of his disease in 1938, organized a 5 month expedition to collect vines of Chondodendron species. Seeked out the plants by having Indian tribesmen lead him to the plant in the wild. \n\n(3 facts about Gill:)\n1) recognized no two batches of curare that came out of the jungle were identical in potency or toxicity (25), and \n2) disproved Boehm’s thinking that a different kind of curare plant was in each of the 3 different containers (tube, pot, gourd), when in fact it was simply placed in the most accessible container (25)\n3)lengthy odyssey written in his book “white water and black magic”\n
  • - The next phase of development was transforming curare from a laboratory tool to a clinically useful and safe drug. Starts with Gill.\n\n- Dr. Freeman never before worked with curare but put the idea in Gill’s head that it might be worth a try\n- Gill, having made enough contacts in S. America that he might be able to bring back a good supply, got his expedition financed by a wealthy man, and during a remission of his disease in 1938, organized a 5 month expedition to collect vines of Chondodendron species. Seeked out the plants by having Indian tribesmen lead him to the plant in the wild. \n\n(3 facts about Gill:)\n1) recognized no two batches of curare that came out of the jungle were identical in potency or toxicity (25), and \n2) disproved Boehm’s thinking that a different kind of curare plant was in each of the 3 different containers (tube, pot, gourd), when in fact it was simply placed in the most accessible container (25)\n3)lengthy odyssey written in his book “white water and black magic”\n
  • - so where are we at now? Gill just delivered a huge supply of raw curare plant to a pharmaceutical company, and thanks to the work of several chemists, the chemical structure of d-tubocurarine was already known.\n- now it was up to ER Squibb to standardize and market curare\n\n
  • - finally we’ve reached the point where standardized curare has found its way into clinical medicine, and its from this point on that we start seeing a lot more successes in clinical medicine\n\n- Why bennett succeeded: \n1) developed standard dose that was enough to soften the convulsive seizure yet avoid respiratory depression.\n2) antidote prostigmine already discovered and in common use, always there as a backup\n\n\n- the 2 deaths were due to lack of airway knowledge, and lack of use of prostigmine.\n-Metrazol was a CNS stimulant\n(- though to be exact, Bennett obtained samples of crude curare from Gill in 1939, whereupon Dr. McIntyre of U of Nebraska first standardized the drug for his use. McIntyre established a physiologic dose for Bennett’s use. Bennett used for 5 months at 1/6 the lethal dose, thus had little problems with respiratory embarassment. It wasn’t until late 1939 that Gill’s samples were turned over to ER Squibb, where the rabbit head drop test was developed, and in late 1939 Intocostrin was released (24))\n\n
  • -Wright - gets much of the credit for the introduction of curare in anesthesia, not because of his personal use of it, but for realizing its potential and interesting others in its use\n- his way of thinking was if neuropsychiatrists like Bennett could use curare safely with no training in respiratory physiology, the anesthesiologist should be able to use it safely\n\n\n(- why not ether? problems documented of curare with ether, particularly in the dog)\n(- note: there were early trials of curare used in anesthesia that weren’t so well known at the time by those working with curare in the 1940s. I.e. Arthur Lawen, a Leipzig surgeon, tried small doses of curare to relax the muscles during closure of the abdomen, but didn’t have access to enough crude preparation to determine a dose. Later, FP De Caux, a London anaesthetist, administered crude curare in 1928 but didn’t publish findings (both mentioned in sykes book p.137-138)\n
  • -note Papper and Cullen both tried only with ether\n\n
  • - what made him the ideal candidate to successfully introduce curare into anesthesia?\n1) country doctor, little exposure to academic and laboratory medicine. Saw how expts on animals got Papper and Cullen’s way\n2) was originally a user of ethylene for anesthesia. published paper of 350 successful administrations (? problems of curare interacting with ether, as were the case in Papper and Cullen’s animal expts). Felt it was safe, non-irritating, non-toxic\n3) recognized tendency of cyclopropane to cause respiratory depression, for which he was an avid user of endotracheal intubation (already had the tools!)\n4) anything good coming out of curare use was certainly going to be well publicized\n5) in addition to all of these, was approached by Lewis Wright, who presented to him Bennett’s data on its safe use in convulsive therapy\n
  • - Jan 23, 1942: this is the quote brings it around full circle, its the quote i used on the beginning slide\n\n
  • - this initial use was followed by 25 more successful trials in surgery, and then published in a followup paper\n\n-Cullen: The exact site of neuromuscular interference by ether wasn’t clear at this time\n\n\n(- Cullen: was one of the 2 anesthetists who gave up using curare after appeared dangerous in an ether-anesthetized dog. Showed that curare caused more respiratory depression with ether anesthesia than with cyclopropane anesthesia. How did they prove this? Injected ACh into both cyclopropane and ether-anesthetized dogs, compared muscle contraction in both and found it markedly diminished in the ether dog. The exact site of neuromuscular interference by ether wasn’t clear at this time)\n
  • -Wright made the presentation on behalf of ER Squibb\n\n
  • - Scott Smith of Salt Lake City had given curare without anesthetics to babies believing they wouldn’t survive a general anesthetic. Wrongly concluded that since they didn’t move, curare also had an anesthetic effect.\n- In Scott Smith’s study of 1947, he wanted to solve the debate of whether or not curare had central depressing properties in addition to its peripheral muscle paralysis\n- hooked up to EEG and EKG and vitals, intubated; observations were made and at the point of complete paralysis, Smith was instructed to make mental note of all of his experiences\n- his graphic descriptions served to convince most anesthesiologists that curare didn’t produce unconsciousness!\n\n\n(- no anesthetic: in 1945 Whitacre and Fisher gave double the dose of Intocostrin without an anesthetic. 2/5 reported excruciating pain (sourced from sykes lib book).)\n
  • - Scott Smith of Salt Lake City had given curare without anesthetics to babies believing they wouldn’t survive a general anesthetic. Wrongly concluded that since they didn’t move, curare also had an anesthetic effect.\n- In Scott Smith’s study of 1947, he wanted to solve the debate of whether or not curare had central depressing properties in addition to its peripheral muscle paralysis\n- hooked up to EEG and EKG and vitals, intubated; observations were made and at the point of complete paralysis, Smith was instructed to make mental note of all of his experiences\n- his graphic descriptions served to convince most anesthesiologists that curare didn’t produce unconsciousness!\n\n\n(- no anesthetic: in 1945 Whitacre and Fisher gave double the dose of Intocostrin without an anesthetic. 2/5 reported excruciating pain (sourced from sykes lib book).)\n
  • - Scott Smith of Salt Lake City had given curare without anesthetics to babies believing they wouldn’t survive a general anesthetic. Wrongly concluded that since they didn’t move, curare also had an anesthetic effect.\n- In Scott Smith’s study of 1947, he wanted to solve the debate of whether or not curare had central depressing properties in addition to its peripheral muscle paralysis\n- hooked up to EEG and EKG and vitals, intubated; observations were made and at the point of complete paralysis, Smith was instructed to make mental note of all of his experiences\n- his graphic descriptions served to convince most anesthesiologists that curare didn’t produce unconsciousness!\n\n\n(- no anesthetic: in 1945 Whitacre and Fisher gave double the dose of Intocostrin without an anesthetic. 2/5 reported excruciating pain (sourced from sykes lib book).)\n
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  • - started as a laboratory tool, but was slow to be adapted to human use, primarily because of the inability to obtain purified, standardized preparation. Lack of a standard dosing means its dangerous and unpredictable\n\n- It took the work of scientists like Harold King to identify the structure of tubocurarine, Richard Gill made it readily available to pharmaceutical company ER Squibb, where it was ultimately sent into the clinical world as Intocostrin. \n- Abram Bennett showed the medical community that it could be safely used for convulsive shock therapy, which gave anesthesiologists like Lewis Wright and Harold Griffith the courage to apply its pharmacologic effects in the field of anesthesia.\n
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  • Curare Presentation

    1. 1. 400 YEARS IN THE MAKING: THE DISCOVERY OF CURARE AND ITS ROLE IN TRANSFORMING ANESTHESIA By: Adam Toth 3rd Year Medical Student Des Moines University
    2. 2. HISTORY“Without history a man’s soul is purblind, seeing only thethings which almost touch his eyes”. -Thomas Fuller, Holy andProfane State (1642)“When we travel we must know our present position,consult the map, and then plan the journey”. -John Thornton
    3. 3. FAST FORWARD IN TIMEJanuary 23, 1942: first successful trial ofcurare in anesthesia, using cyclopropanegas. Performed by Dr. Harold Griffith “. . . Intocostrin, Squibb (Curare) 3.5cc given intravenously in 1.5 minutes as operation started . . . after 5 minutes, another 1.5cc of Intocostrin given. Apparently complete relaxation of abdominal muscles resulted and continued for 20 minutes, during which time cyclopropane was lightened. At the end of this period, muscle tone returned, probably wearing off of curare effect. Cyclopropane was then increased in concentration, and anesthesia continued in the usual way. There was no demonstrable change in pulse, blood pressure or respiration” (1)
    4. 4. ORIGINS OF CURARE •Strychnos Toxifera•Strychnos Toxifera •Chondodendron Tomentosum Fig 1: map of river basins of the Amazon, Orinoco and Essequibo. (2)
    5. 5. must take great care, as if it got into an open wound this also could prove fatal. In this period the source of the poison was hotly ORIGINS OF CURARE disputed. As we shall see later, this is not surprising as several different genera of plants would prove to be involved. Initially some authorities suggested that it came from ‘venomous apples’ which resembled the ‘muscadel pears’ of the Island of Sicily, Italy. These apples grew on •Strychnos Toxifera certain trees which were covered with many branches and leaves. It is possible here that these writers were describing Strychnos toxifera (see Schomburgk below and Figure 1). The fruit of Strychnos does indeed look like an apple although the plant is a rain jungle (forest) liana. The FIGURE 1 Strychnos toxifera. Bentham British explorer John Hawkins also mentions ‘apples’ which are ‘fair and red’ as a possible source of the poison.5 Negro, the other continuing as the main stre the Caribbean. The unusual link between the A In order to understand the geographical origin of the the Orinoco is now called the Casiquiare Cana arrow poison, we must now take a brief diversion into the its existence was denied for a considerable per complex topography of the river basins of the Amazon; It was first reported by d’Acuna in 1641 and s the Orinoco and the Essequibo (see Figure 2). The confirmed by de la Condamine (1742) a Amazon is considered to have its origins 2,300 miles from Humboldt (1800).2, 3 The latter collected cura the sea at the junction of two major rivers in Peru: the lianas) in this area (see Figure 2). Marañon and the Ucayali. One thousand miles downstream it is joined by another major river on its The Essequibo, 620 miles in length, runs thro northern bank, the Rio Negro. Guiana (now Guiana) and also empties into the In the upper reaches of this river lived the Ma•Strychnos Toxifera •Chondodendron Tomentosum The upper waters of the Orinoco river divide at a of Indians whose arrow poison came to be watershed near its source; one part flows south to join the one of the most potent available. It was in th HISTORY Fig 1: map of river basins of the Amazon, Orinoco and Essequibo. (2) FIGURE 2 The river basins of the Amazon, Orinoco and Essequibo
    6. 6. must take great care, as if it got into an open wound this also could prove fatal. In this period the source of the poison was hotly ORIGINS OF CURARE disputed. As we shall see later, this is not surprising as several different genera of plants would prove to be involved. Initially some authorities suggested that it came from ‘venomous apples’ which resembled the ‘muscadel pears’ of the Island of Sicily, Italy. These apples grew on •Strychnos Toxifera certain trees which were covered with many branches and leaves. It is possible here that these writers were describing Strychnos toxifera (see Schomburgk below and Figure 1). The fruit of Strychnos does indeed look like an apple although the plant is a rain jungle (forest) liana. The FIGURE 1 Strychnos toxifera. Bentham British explorer John Hawkins also mentions ‘apples’ which are ‘fair and red’ as a possible source of the poison.5 Negro, the other continuing as the main stre the Caribbean. The unusual link between the A In order to understand the geographical origin of the the Orinoco is now called the Casiquiare Cana arrow poison, we must now take a brief diversion into the its existence was denied for a considerable per complex topography of the river basins of the Amazon; It was first reported by d’Acuna in 1641 and s the Orinoco and the Essequibo (see Figure 2). The confirmed by de la Condamine (1742) a Amazon is considered to have its origins 2,300 miles from Humboldt (1800).2, 3 The latter collected cura the sea at the junction of two major rivers in Peru: the lianas) in this area (see Figure 2). Marañon and the Ucayali. One thousand miles downstream it is joined by another major river on its The Essequibo, 620 miles in length, runs thro northern bank, the Rio Negro. Guiana (now Guiana) and also empties into the In the upper reaches of this river lived the Ma •Strychnos Toxifera •Chondodendron Tomentosum The upper waters of the Orinoco river divide at a of Indians whose arrow poison came to be watershed near its source; one part flows south to join the one of the most potent available. It was in th• These plants are known as ‘lianas’, or vines, which grow attached to trees up to canopy level• Location: HISTORY • 3 primary areas where curare was investigated by explorers, between 1500-1700 • Upper Amazon, Orinoco and Essequibo river basins Fig 1: map of river basins of the Amazon, Orinoco and Essequibo. (2) FIGURE 2 The river basins of the Amazon, Orinoco and Essequibo
    7. 7. ORIGINS OF CURAREThe word ‘curare’: A generic term, indiscriminately describes many South American arrow poisons Scientific definition: arrow poison capable of producing death by muscle paralysis Origin of the term ‘curare’: derived from Indian word ‘uiraêry’ (3) uira = bird, eor = to kill variants of this word, including ‘curare’, come from attempts at Europeans to find phonetic equivalents in their languages
    8. 8. ORIGINS OF CURAREThe word ‘curare’: A generic term, indiscriminately describes many South American arrow poisons Scientific definition: arrow poison capable of producing death by muscle paralysis Origin of the term ‘curare’: derived from Indian word ‘uiraêry’ (3) uira = bird, eor = to kill variants of this word, including ‘curare’, come from attempts at Europeans to find phonetic equivalents in their languagesUses of Curare by South American Indians Prepared into a thick paste and coated onto arrow tips, which were used in either blowguns or bows to hunt and kill prey quickly Exerpt from Charles de la Condamine, French explorer: “The Yameos propel by the breath small arrows of wood to a distance of 30 to 40 paces and rarely miss their target . . . They cover the points of these little arrows . . . with a poison so active that, when it is fresh, it will kill in less than a minute any animal whose blood it has entered . . . We hardly ate anything killed in any other way than by these darts. There is no danger from this; the poison only kills if it enters the blood; but it is no less mortal to man than to animals.” (4)
    9. 9. ORIGINS OF CURARE
    10. 10. ORIGINS OF CURARESpanish Conquistadors of the 16th century told tales of South American Indians usingarrows tipped with a deadly poisonPeter Martyr d’Anghera Italian ‘gossip columnist’, author of De Orbe Novo (1516) Documents accounts of South American natives attacking and killing fellow Spaniard explorers with poisoned arrows, that “contained a kind of liquid which oozed out when the point broke” (5)
    11. 11. ORIGINS OF CURARESpanish Conquistadors of the 16th century told tales of South American Indians usingarrows tipped with a deadly poisonPeter Martyr d’Anghera Italian ‘gossip columnist’, author of De Orbe Novo (1516) Documents accounts of South American natives attacking and killing fellow Spaniard explorers with poisoned arrows, that “contained a kind of liquid which oozed out when the point broke” (5)Charles de la Condamine French naturalist and mathematician, sent on expeditions by L ’Academie Royale de Sciences to measure the arcs of the earth’s surface Spent 8 years making measurements, also led expeditions in Peru, where he witnessed Ticunas Indians prepare and use arrow poison (7) In 1743, credited as first to bring back samples of curare to Europe for study, at the University of Leyden (8,9) First scientists to study the samples: Richard Brocklesby (1747), Monsieur Herissant (1748)
    12. 12. ORIGINS OF CURARE: PREPARATIONPeter Martyr’s “De Orbe Novo”: “There are certain old women skilled in the art, who are shut in at certain times and furnished with the necessary materials; during two days these women watch and distil the ointment. As soon as it is finished the house is opened, and if the women are well and not found lying on the ground half dead from the fumes of the poison, they are severely punished, and the ointment is thrown away as being valueless; for the strength of the poison is such, that the mere odor of it, while compounding almost kills its makers” (6) Believed to be first written account of preparation of curare (3)
    13. 13. ORIGINS OF CURARE: PREPARATIONPeter Martyr’s “De Orbe Novo”: “There are certain old women skilled in the art, who are shut in at certain times and furnished with the necessary materials; during two days these women watch and distil the ointment. As soon as it is finished the house is opened, and if the women are well and not found lying on the ground half dead from the fumes of the poison, they are severely punished, and the ointment is thrown away as being valueless; for the strength of the poison is such, that the mere odor of it, while compounding almost kills its makers” (6) Believed to be first written account of preparation of curare (3)Edward Bancroft In his Essay in 1769, documented table of ingredients “Take the Bark of the Root of Woorara, six parts; used by the Accawau Indians of Guiana to make curare: Of the Bark of Warracobba coura, “The smallest quantity of this poison conveyed by a wound into the two parts; Of the Bark of the Roots of Coura- red blood vessels of an animal, causes it to expire in less than a napi, Baketi, and Hatchybaly, minute, without much apparent pain or uneasiness; though slight of each one part” (10) convulsions are sometimes seen near the instant of expiration.” (10)
    14. 14. ORIGINS OF CURAREAlexander Von Humboldt Spent years 1799-1803 in South America as a plant collector First eyewitness account of the preparation of curare, by Indians of Esmeralda (11) Identified source of curare poison as the bark and part of the sapwood of the Strychnos family of lianas “One judged by the degree of bitterness whether the concentration by the fire had proceeded far enough . . . Curare is not dangerous unless it gains access to the blood; likewise, the vapor produced by heating is not harmful” (11)
    15. 15. ORIGINS OF CURAREAlexander Von Humboldt Spent years 1799-1803 in South America as a plant collector First eyewitness account of the preparation of curare, by Indians of Esmeralda (11) Identified source of curare poison as the bark and part of the sapwood of the Strychnos family of lianas “One judged by the degree of bitterness whether the concentration by the fire had proceeded far enough . . . Curare is not dangerous unless it gains access to the blood; likewise, the vapor produced by heating is not harmful” (11)Sir Robert Schomburgk 1841, led expedition into British Guiana, persuaded Indian guides to show them where curare plants grew and how to concoct the poison (12) Confirmed Humboldt’s suspicion that the curare plant “belongs to the genus Strychnos” “The mystery respecting the arrow-poison of the Indians, although not entirely cleared up, is in a great measure removed. Neither snake’s teeth nor stinging ants form the active principle, but the juice of a plant which we have described as Strychnos toxifera” (13)
    16. 16. EARLY LABORATORY EXPERIMENTATIONFirst to use samples of De la Condamine’s curare of the Ticunas Indians: Richard Brocklesby - In 1747, administered poison to a cat and found that the heart continued to beat for approximately 2 hours after its apparent death (9) Monsieur Herissant - In 1748, introduced poison to a variety of animals, from birds to horses. Confirmed curare only holds an effect if entered through bloodstream. Found that neither sugar nor sea salt is the antidote. (8)
    17. 17. EARLY LABORATORY EXPERIMENTATION First to use samples of De la Condamine’s curare of the Ticunas Indians: Richard Brocklesby - In 1747, administered poison to a cat and found that the heart continued to beat for approximately 2 hours after its apparent death (9) Monsieur Herissant - In 1748, introduced poison to a variety of animals, from birds to horses. Confirmed curare only holds an effect if entered through bloodstream. Found that neither sugar nor sea salt is the antidote. (8) First glimpse into potential role in anesthesia Sir Benjamin Brodie - physician and professor, who, in 1811-12, expanded upon the work of Brocklesby “Some woorara was inserted into a wound in a young cat ... In four minutes ... respiration entirely ceased, and the animal appeared to be dead; but the heart was still felt acting ... Lungs were artificially inflated about forty times in a minute ... At the end of another hour, [the cat] made spontaneous efforts to breathe twenty-two times in a minute. The artificial respiration was discontinued. She lay, as if in a state of profound sleep, for forty minutes, when she suddenly awoke, and walked away.” (14)Timeline of anesthesia: in the year of Brodie’s experimentation, Fanny Burney wrote “A Mastectomy: Letter to Esther Burney”- a personal narrative describing her agonizing surgical procedure before the introduction of anesthesia
    18. 18. EARLY LABORATORY EXPERIMENTATIONWhat is the site of action of curare? Claude Bernard, French physician turned physiologist Student of physiologist Francois Magendia, who had been using curare to keep animals still during experimentation (15) In 1842, Bernard injected curare into ligated limb of a frog; found that outside the ligature, muscle response to nerve stimuli were prevented, yet muscles still responded to direct stimulation Concluded that curare works by blocking conduction of nerve Fig. II: Apparatus for electrical stimulation of a nerve used by Claude Bernard to establish site of action of curare. impulse from the nerve to the muscle fiber (3,15) Cited from Anaesthesia and the Practice of Medicine: Historical Perspectives Timeline of anesthesia: in the year Claude Bernard identified curare’s mechanism of action, Crawford Long performed the first documented surgical procedure using ether to remove a neck tumor
    19. 19. EARLY LABORATORY EXPERIMENTATIONWhat is the site of action of curare? Claude Bernard, French physician turned physiologist Student of physiologist Francois Magendia, who had been using curare to keep animals still during experimentation (15) In 1842, Bernard injected curare into ligated limb of a frog; found that outside the ligature, muscle response to nerve stimuli were prevented, yet muscles still responded to direct stimulation Concluded that curare works by blocking conduction of nerve Fig. II: Apparatus for electrical stimulation of a nerve used by Claude Bernard to establish site of action of curare. impulse from the nerve to the muscle fiber (3,15) Cited from Anaesthesia and the Practice of Medicine: Historical Perspectives Timeline of anesthesia: in the year Claude Bernard identified curare’s mechanism of action, Crawford Long performed the first documented surgical procedure using ether to remove a neck tumor Sir Henry Dale Nobel Prize winner for Physiology in 1936 for his work on the chemical synapses of nervous impulse (16) Localized curare’s effect to motor endplate acetylcholine receptor Fig. III: (d) action of curare as a competitive antagonist of ACh receptors at the muscle endplate. Cited from Sultan Qaboos University “If the muscle was completely paralyzed . . . by curarine, stimulation of its motor nerve fibers Medical Library caused the usual output of acetylcholine, though the muscle remained completely passive”
    20. 20. EARLY LABORATORY EXPERIMENTATIONEarliest therapeutic use of curare was for control of tetanus: Prof. Sewell: recorded in 1835 as the first to treat tetanus successfully in two horses, utilizing curare and artificial respiration (17) Sayre and Burrall - surgeons at Bellevue Hospital in NY, first recorded administration of curare in 1858 to the wound of a patient with tetanus. Died of severe spasm. (18)
    21. 21. EARLY LABORATORY EXPERIMENTATIONEarliest therapeutic use of curare was for control of tetanus: Prof. Sewell: recorded in 1835 as the first to treat tetanus successfully in two horses, utilizing curare and artificial respiration (17) Sayre and Burrall - surgeons at Bellevue Hospital in NY, first recorded administration of curare in 1858 to the wound of a patient with tetanus. Died of severe spasm. (18)By 1859, there were 9 attempts and 7 failures of treating tetanus with curare (19) “Its chemical nature is not uniform, even its source is variable, and its energies are unequal in various specimens; the therapeutic action of curare is unreliable” “Experiments upon large animals have shown that after the tetanic spasms have ceased, perhaps controlled by . . . curare, death has followed apparently from paralysis of the organs of respiration. So that the surgeon has the satisfaction of thinking that if he saves his patient from the disease, he may kill him by the remedy”Other early clinical uses of curare involved treating spasms in strychnine poisoning, rabiesand epilepsy - few were successful
    22. 22. MUCH NEEDED STEPS TOWARD ISOLATING AND STANDARDIZING Origin of the drug name tubocurarine: In 1886, Boehm (25) believed that containers were fairly diagnostic of the type of curare found in them: gourd-curare, pot-curare, and tube-curare. - Note: this theory was later disproved by Richard Gill (21) All 3 sources contained active quaternary alkaloids, which he named “curarines”; thus from tube-curare came the name ‘tubocurarine’ (25) In 1928, Spath, Leithe and Ladeck (26) obtained sample of Boehm’s crystalline curine and traced it to the dried roots of Chondodendron tomentosum In 1935, Harold King (27) worked out the chemical structure of d- tubocurarine from a tube-curare sample provided by the museum of the Pharmaceutical Society In 1943, Wintersteiner and Dutcher (28) isolated d-tubocurarineFig VI: chemical structure ofd-tubocurarine from a crude sample of Chondodendron tomentosum.
    23. 23. MUCH NEEDED STEPS TOWARDISOLATING AND STANDARDIZING
    24. 24. MUCH NEEDED STEPS TOWARD ISOLATING AND STANDARDIZINGRichard Gill - In the 1930s, took the historicalknowledge of curare and guided it into modern clinical use. Background: Worked for the American Rubber Company in 1927; moved to Ecuador after 1929 stock market crash, where he raised coffee, cacao and vegetables (20)
    25. 25. MUCH NEEDED STEPS TOWARD ISOLATING AND STANDARDIZINGRichard Gill - In the 1930s, took the historicalknowledge of curare and guided it into modern clinical use. Background: Worked for the American Rubber Company in 1927; moved to Ecuador after 1929 stock market crash, where he raised coffee, cacao and vegetables (20) Developed neurological symptoms in 1932; diagnosed with multiple sclerosis by Dr. Walter Freeman, who expressed interest in trying curare to treat his illness
    26. 26. MUCH NEEDED STEPS TOWARD ISOLATING AND STANDARDIZING 312 AND . ANESTHESIA ANALGESIA. Current Researches VOL.56, No. 2, MARCH-APRIL, . 19Richard Gill - In the 1930s, took the historicalknowledge of curare and guided it into modern clinical use. Background: Worked for the American Rubber Company in 1927; moved to Ecuador after 1929 stock market crash, where he raised coffee, cacao and vegetables (20) Developed neurological symptoms in 1932; diagnosed with multiple sclerosis by Dr. Walter Freeman, who FIG3. Richard Gill collecting curare in the jungle. expressed interest in trying curare to treat his illness of a form of curare. IV:was also theGilltified specimencurare (26) toment source Fig It Richard collecting of chondodendron first authenticated variety of curare.24 sum.26 Harold King, working in Britain National Institute for Medical Research When Gill returned to the United States In 1938, Gill organized anat expeditionoffrom Ecuador into the end of 1938, he had with him several crates containing a total 25 pounds of 1935, first isolated and determined t chemical formula of the pure alkaloid, whi he named d-tubocurarine chloride.27 Ho prepared curare. To his dismay, he found ever, he was unable to identify the type the jungle, spent 5 months collectingcurare plant and their investigation of the vines identified as that the chemists at Merck had dropped plant or species the alkaloid had come fro although it pointed to the genus chond were now studying an entirely different dendron as the probable source of the acti Chondodendron Tomentosum (21) had curarelikeanproperties from plant which had which they isolated alkaloid they ingredient of the crude curare. called erythroidine. Gill next offered his cu- Meanwhile, an orthopaedic surgeo rare, in May 1939, to E. R. Squibb and Michael Burman, who in the 1930s was Sons, who contracted to buy Gill’s product member of the Medical Staff of the Hosp and subject it to laboratory investigation. tal for Joint Diseases, became interested 1934 in the use of curare for patients wi Gill’s plants were identified as chondo- spastic paralysis.28 He came across the wo dendron tomentosum by the Squibb chem- of Ranyard West29 in the course of his ow ists, among who was Horace Holaday, father investigations. Between 1931 and 193 of Duncan Holaday, the anesthesiologist. West had investigated the action of cura He devised the rabbit head-drop test, still on paralytic rigidity in man.2g Burman r in use today to assay the strength of puri- ceived a supply of curare from the Mer fied curare.25 No one as yet knew what the Institute of Therapeutic Research in Ra active ingredient was. Holaday named the way, New Jersey, and began his study
    27. 27. MUCH NEEDED STEPS TOWARD ISOLATING AND STANDARDIZING 312 AND . ANESTHESIA ANALGESIA. Current Researches VOL.56, No. 2, MARCH-APRIL, . 19Richard Gill - In the 1930s, took the historicalknowledge of curare and guided it into modern clinical use. Background: Worked for the American Rubber Company in 1927; moved to Ecuador after 1929 stock market crash, where he raised coffee, cacao and vegetables (20) Developed neurological symptoms in 1932; diagnosed with multiple sclerosis by Dr. Walter Freeman, who FIG3. Richard Gill collecting curare in the jungle. expressed interest in trying curare to treat his illness of a form of curare. IV:was also theGilltified specimencurare (26) toment source Fig It Richard collecting of chondodendron first authenticated variety of curare.24 sum.26 Harold King, working in Britain National Institute for Medical Research When Gill returned to the United States In 1938, Gill organized anat expeditionoffrom Ecuador into the end of 1938, he had with him several crates containing a total 25 pounds of 1935, first isolated and determined t chemical formula of the pure alkaloid, whi he named d-tubocurarine chloride.27 Ho prepared curare. To his dismay, he found ever, he was unable to identify the type the jungle, spent 5 months collectingcurare plant and their investigation of the vines identified as that the chemists at Merck had dropped plant or species the alkaloid had come fro although it pointed to the genus chond were now studying an entirely different dendron as the probable source of the acti Chondodendron Tomentosum (21) had curarelikeanproperties from plant which had which they isolated alkaloid they ingredient of the crude curare. called erythroidine. Gill next offered his cu- Meanwhile, an orthopaedic surgeo rare, in May 1939, to E. R. Squibb and Michael Burman, who in the 1930s was Sons, who contracted to buy Gill’s product member of the Medical Staff of the Hosp Offered his curare samples to pharmaceutical company and subject it to laboratory investigation. tal for Joint Diseases, became interested 1934 in the use of curare for patients wi Gill’s plants were identified as chondo- spastic paralysis.28 He came across the wo E.R. Squibb in 1939, who ists, among who was Horace Holaday, father agreed to buy his entire supply dendron tomentosum by the Squibb chem- of Ranyard West29 in the course of his ow investigations. Between 1931 and 193 of Duncan Holaday, the anesthesiologist. West had investigated the action of cura He devised the rabbit head-drop test, still on paralytic rigidity in man.2g Burman r in use today to assay the strength of puri- ceived a supply of curare from the Mer fied curare.25 No one as yet knew what the Institute of Therapeutic Research in Ra active ingredient was. Holaday named the way, New Jersey, and began his study
    28. 28. MUCH NEEDED STEPS TOWARD ISOLATING AND STANDARDIZINGHorace Holaday, E.R. Squibb chemist He and others identified Gill’s plants as Chondodendron Tomentosum Isolated d-tubocurarine and gave the trade name “Intocostrin” in 1939 Developed “Rabbit Head-Drop Test” to standardize strength of purified curare (22) Determines the relative potency of sample curare preparations against a standard dose of Intocostrin (d-tubocurarine chloride) (23) Endpoint is relaxation of rabbit neck muscles to the point that the animal’s head cannot be moved in response to physical stimulus Fig. V: rabbit head-drop assay. Endpoint visualized, where rabbit is unable to raise its head. Original image from E.R. Squibb institute. (22)
    29. 29. INTRODUCTION OF INTOCOSTRIN INTO PSYCHIATRYBackground: Abram Elting Bennett, a neuropsychiatrist of Omaha, Nebraska, had been using convulsive shock therapy to treat depression; mid-1930s (24) Convulsions produced by pentylenetetrazole (Metrazol) were associated with 17% incidence of dislocation and 43-51% incidence of compressive spinal fractures Bennett used standardized preparations of Gill’s crude curare in 1939, provided first from A.R. McIntyre then from pharmaceutical company E.R. Squibb By 1940, Bennett had established standard doses of Intocostrin to be used in tandem with Metrazol for shock therapy, and performed 1,000 successful treatments By 1941, over 30,000 treatments reported with only 2 deaths
    30. 30. ALAS, D-TUBOCURARINE IN ANESTHESIA4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.Wright, E.M. Papper, Stuart C. Cullen, and Harold R. GriffithTimeline of anesthesia: by 1847, John Snow begins to use ether anesthesia for major surgeries at St. George’s Hospitalin London Lewis H. Wright Anesthesiologist associated with E.R. Squibb, envisioned potential of curare in anesthesia Intrigued by Bennett’s presentation of curare use in shock therapy at an AMA conference in 1940 (29) “Between 1930-1935, many new anesthetic agents had been introduced which did not produce good and adequate relaxation . . . I mentioned this use of curare to many of my anesthesiologist friends. Most of them thought I was crazy; that this Indian arrow poison to be used in the operating room was really far from a modern scientific approach” Felt strongly that anesthetic agents of the time - cyclopropane, ethylene and IV barbiturates - could be augmented by the addition of curare
    31. 31. ALAS, D-TUBOCURARINE IN ANESTHESIA 4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H. Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith E.M. Papper, Stuart Cullen and Harold Griffith were the first recipients of curare from Wright Failed uses by Papper and Cullen in 1940 (20) E.M. Papper, anesthesiologist in NY, administered Intocostrin to a small number of ether-anesthetized cats - all died from apparent asthma attack. Later gave to 2 patients under ether anesthesia, spent the night resuscitating with a breathing bag; felt curare was too dangerous from a respiratory standpoint Stuart Cullen, NY anesthesiologist who, similar to Papper, gave Intocostrin to several dogs anesthetized with ether; witnessed respiratory and asphyxial convulsions, and was discouraged from applying to humans
    32. 32. ALAS, D-TUBOCURARINE IN ANESTHESIA 4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H. Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith Howard Griffith - country doctor in Montreal, worked as general practitioner and part time anesthetist What made him the ideal candidate for introducing curare into anesthesia? 1) Little exposure to academic and laboratory medicine, which was a roadblock for Papper and Cullen 2) Avid user of cyclopropane anesthesia - between 1933 and 1942 had published 14 articles mostly on cyclopropane use (30) 3) Aware of risk of respiratory depression with cyclopropane, and was avid user of endotracheal intubation 4) Able to effectively publish his experiences and observations
    33. 33. ALAS, D-TUBOCURARINE IN ANESTHESIA 4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H. Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith January 23, 1942: first successful trial of curare in anesthesia, using cyclopropane gas. Performed by Dr. Harold Griffith “. . . Intocostrin, Squibb (Curare) 3.5cc given intravenously in 1.5 minutes as operation started . . . after 5 minutes, another 1.5cc of Intocostrin given. Apparently complete relaxation of abdominal muscles resulted and continued for 20 minutes, during which time cyclopropane was lightened. At the end of this period, muscle tone returned, probably wearing off of curare effect. Cyclopropane was then increased in concentration, and anesthesia continued in the usual way. There was no demonstrable change in pulse, blood pressure or respiration” (1)
    34. 34. ALAS, D-TUBOCURARINE IN ANESTHESIA 4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H. Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith Griffith releases preliminary report of 25 patients who received Intocostrin with cyclopropane anesthesia (31)
    35. 35. ALAS, D-TUBOCURARINE IN ANESTHESIA 4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H. Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith Griffith releases preliminary report of 25 patients who received Intocostrin with cyclopropane anesthesia (31) Follow-up from Stuart Cullen After acknowledging Griffith’s success with Intocostrin in 1942, Cullen followed suit and reported 131 cases of using curare for abdominal wall relaxation during inhalation anesthesia (32) Addressed his initial failure of curare in ether-anesthetized dogs: Showed that ether, sodium thiopental and tribromethanol all have ‘curariform’ actions, with ether having the greatest (33)
    36. 36. ALAS, D-TUBOCURARINE IN ANESTHESIA 4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H. Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith 318 ANESTHESIA AND ANALGESIA . . Current Researches VQL.56, No. 2, MARCH-APRIL, . 1977 FIG8. Presentation of the plaque a t the 10th Anniversary of the introduction of curare into clinical Griffith accepting plaque at Queen Elizabeth Hospital, anesthesia. marking 10th anniversaryTranslation byPd’A:Mainutt. New York, GPin of Martyr FA De of curareLatin). 3. first use Orbe Novo (1516 Put- nam’s Sons, 1912, vol 1, p 75 anesthesia (20) AR: Curare: Its History, Nature, 4. McIntyre and Clinical Use. Chicago, University of Chicago Press, 1947 5. Thomas KB: Curare: Its History and Usage. London, Pitman Medical Publishing Company Ltd, Quoted by Lewis Wright: “this use of curare was the beginning of a chain of events 1964, p 24 resulting in benefit to more than 10,000,000 1960 Anaesthesia.patients inHundred throughout the Ltd, 6. Sykes WS: Essays on the First Years surgical Edinburgh, ES Livingstone of a year world”111, p 649. Sir Walter: ofHAKLUYT’s Rich and vol 7. (20) Raleigh, Discovery the Large, Voyages, Beautiful Empire of Guiana (Imprinted in London by Robert Robinson, 1596). Reprinted for the HAKLUYT Society, London, 1868
    37. 37. D-TUBOCURARINE IN ANESTHESIAPersonal accounts of the effects of d-tubocurarine:
    38. 38. D-TUBOCURARINE IN ANESTHESIAPersonal accounts of the effects of d-tubocurarine:Helen Barnes, London anesthetist, 1943 Wanting to test if curare would relax laryngeal muscles enough to facilitate tracheal intubation, had 2 colleagues give her IV Intocostrin: (34) “My sensations were dramatic. I feel that I experienced the sufferings of a patient with myasthenia gravis. At once my vision became blurred and I almost ‘blacked out’ ... Ptosis was also very oppressive, and was accompanied by extreme prostration, fatigue, a sense of impending death, and a transient sensation of constriction in the throat”
    39. 39. D-TUBOCURARINE IN ANESTHESIAPersonal accounts of the effects of d-tubocurarine:Helen Barnes, London anesthetist, 1943 Wanting to test if curare would relax laryngeal muscles enough to facilitate tracheal intubation, had 2 colleagues give her IV Intocostrin: (34) “My sensations were dramatic. I feel that I experienced the sufferings of a patient with myasthenia gravis. At once my vision became blurred and I almost ‘blacked out’ ... Ptosis was also very oppressive, and was accompanied by extreme prostration, fatigue, a sense of impending death, and a transient sensation of constriction in the throat”Some physicians believed that if you increased the dose of Intocostrin for surgery, noanesthetic would be necessary
    40. 40. D-TUBOCURARINE IN ANESTHESIAPersonal accounts of the effects of d-tubocurarine:Helen Barnes, London anesthetist, 1943 Wanting to test if curare would relax laryngeal muscles enough to facilitate tracheal intubation, had 2 colleagues give her IV Intocostrin: (34) “My sensations were dramatic. I feel that I experienced the sufferings of a patient with myasthenia gravis. At once my vision became blurred and I almost ‘blacked out’ ... Ptosis was also very oppressive, and was accompanied by extreme prostration, fatigue, a sense of impending death, and a transient sensation of constriction in the throat”Some physicians believed that if you increased the dose of Intocostrin for surgery, noanesthetic would be necessaryScott Smith, anesthetist of Salt Lake City, 1947 Offered himself as an experimental subject to evaluate whether curare has any central depressing properties. His remarks were recorded: (35) “[He] can distinguish heat from cold, sharp from dull and can feel pain pinprick . . . Ability to signal by slight movement [of] left eyebrow almost gone. [He] indicates ... that he is perfectly conscious and that his sensorium is unimpaired”
    41. 41. IN CONCLUSIONThe discovery of curare marks the beginning of the history ofneuromuscular blocking agentsCurare is a “drug with a long and romantic history” (36), taking over 400 yearsto transform it from a mysterious Indian arrow poison into a clinically usefuldrugd-tubocurarine introduced into surgical anesthesia in the 1940s, where itremained until slowly replaced by suxamethonium in the 1950s, thenatracurium, pancuronium and vecuronium in the 1980s.
    42. 42. TIMELINE OF EVENTS16th century: tales of Spanish conquistadors witnessing South American Indians hunt and attack with poison-tippedarrows1740s: Charles de la Condamine brings samples of curare to Europe to the University of Leyden. Two scientists, Brocklesbyand Herissant, conduct animal experiments with the samples, observe heart continues to beat after animal’s apparentdeath1800: Von Humboldt first eyewitness of curare preparation, identified plant source as Strychnos1811: Benjamin Brodie administers curare to a cat and keeps alive with artificial respiration1838: William Sewell, veterinarian, used curare to treat tetanus in two horses but failed1842: Claude Bernard identified site of action of curare as the myoneural junction1858: First clinical use of curare by Sayres and Burrall for treating tetanus1930s: Richard Gill, sparked by thought that curare might help treat his multiple sclerosis, collected ChondodendronTomentosum vines and gave to company E.R. Squibb for analysis and standardization1935: Harold King identifies chemical structure of d-tubocurarine from a crude sample of tube curare1939: E.R. Squibb releases Intocostrin, purified d-tubocurarine from Gill’s Chondodendron samples. A.H. Holadaydevelops rabbit-head-drop test to standardize the drug.1940: Bennett reports first large scale tests of curare in humans, over 1000 successful Metrazol shock therapy treatmentsusing standard doses of Intocostrin. Lewis Wright envisions potential of d-tubocurarine for muscle relaxation in surgicalanesthesia. EM Papper and Stuart Cullen discouraged by their use of Intocostrin in ether-anesthetized animals.1942: January 23rd, Harold Griffith first to use Intocostrin with surgical anesthesia, for an appendectomy
    43. 43. BIBLIOGRAPHY1. Griffith HR. The evolution of the use of curare in anesthesiology. Annals of the New York Academy of Science, 54:493-97, 1951.2. Lee MR. Curare: The South American Arrow Poison. The Journal of the Royal College of Physicians of Edinburgh 2005;35(i):83-92.3. Mcintyre AR. Curare: Its History, Nature and Clinical Use. Chicago: University of Chicago Press, 1947.4. De La Condamine CM. Relation Abregee d’un Voyage fait dans l’Interieur de l’Amerique Meridionale. Memoires de l’Academie des Sciences; 62:391-492, 1745.5. Martyr Pd’A. De orbe novo (1516 Latin). Translation by Francis Augustus MacNutt (New York: G. P. Putnam’s Sons, 1912), 1:75.6. ------. Ibid., 2: 385-86.7. De La Condamine CM. Relation Abregee d’un Voyage fait dans l’Interieur de l’Amerique Meridionale. Memoires de l’Academie des Sciences; 62:391-492, 1745.8. Herissant M. Experiments made on a great number of living animals with the poison of Lamas and Ticunas. Translation by Thomas S. Stack, M.D., Phil. Tr. Roy. Soc., London, 37:51-92, 1751.9. Brocklesby RA. Letter to the President of the Royal Society concerning the Indian poison, sent over from M. de la Condamine. Philosophical Transactions of the Royal Society of London 1747;44(ii):408.10. Bancroft E. An essay on the natural history of Guiana and South America (London: T. Beckel & P.A. DeHont, 1769), p.286.
    44. 44. BIBLIOGRAPHY11. Humboldt AV, Bonpland A. Voyage aux régions équinoxiales du nouveau continent. Translation by A.R. McIntyre, in Curare: Its History, Nature and Clinical Use. 5:ii, 1807.12. Schomburgk R. On the urari, the arrow poison of the Indians of Guiana; with a description of the Plant from which it is extracted. Ann. & Mag. Nat. Hist., 7:409, 1841.13. Schomburgk R. Ralegh’s discovery of Guiana (London: Hakluyt Society, 1848), p.71n.14. Brodie Sir BC. Further experiments and observations on the actions of poisons on the animal systems. Philos Trans 102: 207-8, 1812.15. Sykes K, Bunker J. Anesthesia and the Practice of Medicine: Historical Perspectives. London: Royal Society of Medicine Press Ltd, 2007.16. Dale H. Some Recent Extensions of the Chemical Transmission of the Effects of Nerve Impulses. The Nobel Prize in Physiology or Medicine 1936. Nobel Lecture 1936.17. Travers B. A further inquiry concerning constitutional irritation and the pathology of the nervous system. London: Longman, Hurst, Rees, 1835; p.308-309.18. Sayre LA, Burrall FA. Two cases of traumatic tetanus. New York Journal of Medicine, 4:250-253, 1858.19. Editorial: Curare in tetanus. Lancet, 74:595-597, 1859.20. Betcher AM. The civilizing of curare: a history of its development and introduction into anesthesiology. Anesthesia and Analgesia, 56:305-319, 1977.
    45. 45. BIBLIOGRAPHY21. Gill RC. Curare: misconceptions regarding the discovery and development of the present form of the drug. Anesthesiology, 7:14-24, 194622. McIntyre AR. Historical background, early use and development of muscle relaxants. Anesthesiology, 20:409-415, 1959.23. Varney RF, Linegar CR and Holaday HA. The assay of curare by the rabbit “head-drop” method. JPET, 97:72-83, 1949.24. Bennett AE. How ‘Indian arrow poison’ curare became a useful drug. Anesthesiology, 28:467-470, 1967.25. Boehm R. Chemische Studien über das Curare. Translation by A.R. McIntyre, in Curare: Its History, Nature and Clinical Use. (Leipzib, 1886), p.176.26. Spath E, Leithe W, and Ladeck F. Curare alkaloids. I. Constitution of curine, Ber. d. deutsche Chem., 61:1698-1709, 1928.27. King H. Curare alkaloids. I. Tubocurarine, J. Chem. Soc., p.1381-89, 1935.28. Wintersteiner O, Dutcher JD. Curare alkaloids from Chondodendron tomentosum. Science, 97:467-70, 1943.29. Portion of an interview with Lewis H. Wright taped by David A. Davis, MD, Duke University, Durham, North Carolina. Reproduced from Betcher AM, The civilizing of curare: a history of its development and introduction into anesthesiology.30. Griffith HR. Cyclopropane anesthesia: a clinical record of 350 administrations. Can Med Assoc J, 31:157-160, 1934.
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