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Curare ( or ; or ) is a common name for various
alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...
arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and
South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a considerably smaller portion in the Northern Hemisphere. It can also be described as the southern Subregion#Americas, subregion o ...
for hunting and for therapeutic purposes, curare only becomes active when it contaminates a wound or is introduced directly to the bloodstream; it is not active when ingested orally. Curare is prepared by boiling the bark of one of the dozens of plant sources, leaving a dark, heavy paste that can be applied to arrow or dart heads. These poisons cause weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by
asphyxia Asphyxia or asphyxiation is a condition of deficient supply of oxygen to the body which arises from abnormal breathing. Asphyxia causes generalized hypoxia, which affects all the tissues and organs, some more rapidly than others. There are m ...
tion due to
paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...
of the diaphragm. In medicine, curare has been used as a treatment for
tetanus Tetanus (), also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'' and characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually l ...
and
strychnine poisoning Strychnine poisoning is poisoning induced by strychnine. It can be fatal to humans and other animals and can occur by inhalation, swallowing or absorption through eyes or mouth. It produces some of the most dramatic and painful symptoms of any kno ...
and as a paralyzing agent for surgical procedures.


History

The word 'curare' is derived from , from the Carib language of the Macusi of Guyana. It has its origins in the Carib phrase "mawa cure" meaning of the Mawa vine, scientifically known as ''
Strychnos toxifera ''Strychnos toxifera'', called bush rope and devil doer, is a species of flowering plant in the genus ''Strychnos'', native to Costa Rica, Panama, Colombia, Ecuador, Venezuela, the Guianas, Brazil, Peru and Bolivia. It is the principal source of ...
''. Curare is also known among indigenous peoples as Ampi, Woorari, Woorara, Woorali, Wourali, Wouralia, Ourare, Ourari, Urare, Urari, and Uirary. The noun 'curare' is not to be confused with the Latin verb 'curare' ('to heal, cure, take care of').


Classification

In 1895, pharmacologist Rudolf Boehm sought to classify the various alkaloid poisons based on the containers used for their preparation. He believed curare could be categorized into three main types as seen below. However useful it appeared, it became rapidly outmoded. Richard Gill, a plant collector, found that the indigenous peoples began to use a variety of containers for their curare preparations, henceforth invalidating Boehm's basis of classification. * Tube or bamboo curare: Mainly composed of the toxin D-tubocurarine, this poison is found packed into hollow bamboo tubes. Tube curare is derived from Chondrodendron and other genera in the
Menispermaceae Menispermaceae (botanical Latin: 'moonseed family' from Greek ''mene'' 'crescent moon' and ''sperma'' 'seed') is a family (biology), family of flowering plants. The alkaloid tubocurarine, a neuromuscular blocker and the active ingredient in the ...
. According to their LD50 values, tube curare is thought to be the most toxic. * Pot curare: Mainly composed of alkaloid components protocurarine (the active ingredient), protocurine (a weak toxicity), and protocuridine (non-toxic) from both Menispermaceae and Loganiaceae/Strychnaceae. This subtype was originally found packed in
terra cotta Terracotta, also known as terra cotta or terra-cotta (; ; ), is a clay-based Vitrification#Ceramics, non-vitreous ceramicOED, "Terracotta""Terracotta" MFA Boston, "Cameo" database fired at relatively low temperatures. It is therefore a term used ...
pots. *
Calabash Calabash (; ''Lagenaria siceraria''), also known as bottle gourd, white-flowered gourd, long melon, birdhouse gourd, New Guinea bean, New Guinea butter bean, Tasmania bean, and opo squash, is a vine grown for its fruit. It can be either harvest ...
or
gourd Gourds include the fruits of some flowering plant species in the family Cucurbitaceae, particularly '' Cucurbita'' and '' Lagenaria''. The term refers to a number of species and subspecies, many with hard shells, and some without. Many gourds ha ...
curare: Mainly composed of CtoxiferineI, this poison, derived from Loganiaceae/Strychnaceae alone, was originally packed into hollow gourds. Manske also observed in his 1955 ''The Alkaloids'':
The results of the early re-1900work were very inaccurate because of the complexity and variation of the composition of the mixtures of alkaloids involved  ..these were impure, non-crystalline alkaloids  ..Almost all curare preparations were and are complex mixtures, and many of the physiological actions attributed to the early curarizing preparations were undoubtedly due to impurities, particularly to other alkaloids present. The curare preparations are now considered to be of two main types, those from Chondrodendron or other members of the Menispermaceae family and those from ''Strychnos'', a genus of the Loganiaceae now Strychnaceae family. Some preparations may contain alkaloids from both  ..and the majority have other secondary ingredients.


Hunting uses

Curare was used as a paralyzing poison by many South American indigenous people. Since it was too expensive to be used in warfare, curare was mainly used for hunting. The prey was shot by arrows or
blowgun A blowgun (also called a blowpipe or blow tube) is a simple ranged weapon consisting of a long narrow tube for shooting light projectiles such as darts. It operates by having the projectile placed inside the pipe and using the force created by ...
darts dipped in curare, leading to asphyxiation owing to the inability of the victim's respiratory muscles to contract. In particular, the poison was used by the
Kalinago The Kalinago, also called Island Caribs or simply Caribs, are an Indigenous people of the Lesser Antilles in the Caribbean. They may have been related to the Mainland Caribs (Kalina) of South America, but they spoke an unrelated language know ...
, indigenous people of the
Lesser Antilles The Lesser Antilles is a group of islands in the Caribbean Sea, forming part of the West Indies in Caribbean, Caribbean region of the Americas. They are distinguished from the larger islands of the Greater Antilles to the west. They form an arc w ...
in the
Caribbean The Caribbean ( , ; ; ; ) is a region in the middle of the Americas centered around the Caribbean Sea in the Atlantic Ocean, North Atlantic Ocean, mostly overlapping with the West Indies. Bordered by North America to the north, Central America ...
, on the tips of their arrows. In addition, the Yagua people, indigenous to Colombia and northeastern Peru, commonly used these toxins via blowpipes to target prey 30 to 40 paces distant. Due to its popularity among the indigenous people as means of paralyzing prey, certain tribes would create
monopolies A monopoly (from Greek and ) is a market in which one person or company is the only supplier of a particular good or service. A monopoly is characterized by a lack of economic competition to produce a particular thing, a lack of viable sub ...
from curare production. Thus, curare became a symbol of wealth among the indigenous populations. In 1596, Sir
Walter Raleigh Sir Walter Raleigh (; – 29 October 1618) was an English statesman, soldier, writer and explorer. One of the most notable figures of the Elizabethan era, he played a leading part in English colonisation of North America, suppressed rebell ...
mentioned the arrow poison in his book '' Discovery of the Large, Rich, and Beautiful Empire of Guiana'' (which relates to his travels in
Trinidad Trinidad is the larger, more populous island of the Republic of Trinidad and Tobago, the country. The island lies off the northeastern coast of Venezuela and sits on the continental shelf of South America. It is the southernmost island in ...
and Guayana), though the poison he described was possibly not curare. In 1780, Abbe Felix Fontana discovered that it acted on the voluntary muscles rather than the nerves and the heart. In 1832,
Alexander von Humboldt Friedrich Wilhelm Heinrich Alexander von Humboldt (14 September 1769 – 6 May 1859) was a German polymath, geographer, natural history, naturalist, List of explorers, explorer, and proponent of Romanticism, Romantic philosophy and Romanticism ...
gave the first western account of how the toxin was prepared from plants by
Orinoco The Orinoco () is one of the longest rivers in South America at . Its drainage basin, sometimes known as the Orinoquia, covers approximately 1 million km2, with 65% of it in Venezuela and 35% in Colombia. It is the List of rivers by discharge, f ...
River natives.During 1811–1812, Sir Benjamin Collins Brody experimented with curare (''woorara''). He was the first to show that curare does not kill the animal and the recovery is complete if the animal's respiration is maintained artificially. In 1825,
Charles Waterton Charles Waterton (3 June 1782 – 27 May 1865) was an English naturalist, plantation overseer and explorer best known for his pioneering work regarding conservation. Family and religion Waterton was of a Roman Catholic landed gentry family de ...
described a classical experiment in which he kept a curarized
female An organism's sex is female ( symbol: ♀) if it produces the ovum (egg cell), the type of gamete (sex cell) that fuses with the male gamete (sperm cell) during sexual reproduction. A female has larger gametes than a male. Females and ...
donkey The donkey or ass is a domesticated equine. It derives from the African wild ass, ''Equus africanus'', and may be classified either as a subspecies thereof, ''Equus africanus asinus'', or as a separate species, ''Equus asinus''. It was domes ...
alive by
artificial respiration Artificial ventilation or respiration is when a machine assists in a metabolic process to exchange gases in the body by pulmonary ventilation, external respiration, and internal respiration. A machine called a ventilator provides the person air ...
with a bellows through a
tracheostomy Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision on the front of the neck to open a direct airway to the trachea. The resulting stoma (hole) can serve independently as an airway ...
. Waterton is also credited with bringing curare to Europe. Robert Hermann Schomburgk, who was a trained botanist, identified the vine as one of the genus ''
Strychnos ''Strychnos'' is a genus of flowering plants, belonging to the family Loganiaceae (sometimes Strychnaceae). The genus includes about 200 accepted species of trees and lianas. The genus is widely distributed around the world's tropics and is n ...
'' and gave it the now accepted name ''Strychnos toxifera''.


Medical use

George Harley (1829–1896) showed in 1850 that curare (''wourali'') was effective for the treatment of
tetanus Tetanus (), also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'' and characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually l ...
and
strychnine Strychnine (, , American English, US chiefly ) is a highly toxicity, toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, ...
poisoning. In 1857,
Claude Bernard Claude Bernard (; 12 July 1813 – 10 February 1878) was a French physiologist. I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science". He originated the term ''milieu intérieur'' and the associated c ...
(1813–1878) published the results of his experiments in which he demonstrated that the mechanism of action of curare was a result of interference in the conduction of nerve impulses from the
motor nerve A motor nerve, or efferent nerve, is a nerve that contains exclusively efferent nerve fibers and transmits motor signals from the central nervous system (CNS) to the effector organs (muscles and glands), as opposed to sensory nerves, which transf ...
to the
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
, and that this interference occurred at the
neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...
. From 1887, the Burroughs Wellcome catalogue listed under its 'Tabloids' brand name,
grain A grain is a small, hard, dry fruit (caryopsis) – with or without an attached husk, hull layer – harvested for human or animal consumption. A grain crop is a grain-producing plant. The two main types of commercial grain crops are cereals and ...
(5.4mg) tablets of curare (price: 8shillings) for use in preparing a solution for hypodermic injection. In 1914, Henry Hallett Dale (1875–1968) described the physiological actions of
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
. After 25 years, he showed that acetylcholine is responsible for
neuromuscular transmission A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...
, which can be blocked by curare.The best known and historically most important toxin (because of its medical applications) is d-
tubocurarine Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic benzylisoquinoline alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxat ...
. It was isolated from the crude drug – from a museum sample of curare – in 1935 by Harold King of London, working in Sir Henry Dale's laboratory. King also established its chemical structure. Pascual Scannone, a Venezuelan anesthesiologist who trained and specialized in New York City, did extensive research on curare as a possible paralyzing agent for patients during surgical procedures. In 1942, he became the first person in Latin America to use curare during a medical procedure when he successfully performed a tracheal intubation in a patient to whom he administered curare for muscle paralysis at the El Algodonal Hospital in Caracas, Venezuela. After its introduction in 1942, curare/curare-derivatives became a widely used paralyzing agent during medical and surgical procedures. In medicine, curare has been superseded by a number of curare-like agents, such as pancuronium, which have a similar pharmacodynamic profile, but fewer side effects.


Chemical structure

The various components of curare are organic compounds classified as either
isoquinoline Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a struc ...
or
indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...
alkaloids.
Tubocurarine Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic benzylisoquinoline alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxat ...
is one of the major active components in the South American dart poison. As an alkaloid, tubocurarine is a naturally occurring compound that consists of nitrogenous bases, although the chemical structure of alkaloids is highly variable. Tubocurarine and C toxiferine consist of a cyclic system with quaternary ammonium ions. On the other hand, while acetylcholine does not contain a cyclic system, it does contain a quaternary ammonium ion. Because of this shared moiety, curare alkaloids can bind readily to the active site of receptors for acetylcholine (ACh) at the neuromuscular junction, blocking nerve impulses from being sent to the skeletal muscles, effectively paralyzing the muscles of the body.


Pharmacological properties

Curare is an example of a non-depolarizing
muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
that blocks the nicotinic acetylcholine receptor (nAChR), one of the two types of acetylcholine (ACh) receptors, at the
neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...
. The main toxin of curare, d-tubocurarine, occupies the same position on the receptor as ACh with an equal or greater affinity, and elicits no response, making it a
competitive antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...
. The antidote for curare poisoning is an acetylcholinesterase (AChE) inhibitor (anti-cholinesterase), such as
physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and ...
or neostigmine. By blocking ACh degradation, AChE inhibitors raise the amount of ACh in the neuromuscular junction; the accumulated ACh will then correct for the effect of the curare by activating the receptors not blocked by toxin at a higher rate. The time of onset varies from within one minute (for tubocurarine in
intravenous administration Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
, penetrating a larger vein), to between 15 and 25 minutes (for intramuscular administration, where the substance is applied in muscle tissue). It is harmless if taken orally because curare compounds are too large and highly charged to pass through the lining of the digestive tract to be absorbed into the blood. For this reason, people can safely eat curare-poisoned prey, and it has no effect on its flavor.


Anesthesia

Isolated attempts to use curare during anesthesia date back to 1912 by Arthur Lawen of Leipzig, but curare came to anesthesia via
psychiatry Psychiatry is the medical specialty devoted to the diagnosis, treatment, and prevention of deleterious mental disorder, mental conditions. These include matters related to cognition, perceptions, Mood (psychology), mood, emotion, and behavior. ...
( electroplexy). In 1939 Abram Elting Bennett used it to modify
metrazol Pentylenetetrazol (PTZ), also known as pentylenetetrazole, pentetrazol (International Nonproprietary Name, INN), and pentamethylenetetrazol, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convulsions, as dis ...
induced convulsive therapy.
Muscle relaxants A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
are used in modern
anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...
for many reasons, such as providing optimal operating conditions and facilitating intubation of the trachea. Before muscle relaxants, anesthesiologists needed to use larger doses of the anesthetic agent, such as
ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...
,
chloroform Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and po ...
or
cyclopropane Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a triangular ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane ...
to achieve these aims. Such deep anesthesia risked killing patients who were elderly or had heart conditions. The source of curare in the Amazon was first researched by
Richard Evans Schultes Richard Evans Schultes (''SHULL-tees'';Jonathan Kandell ''The New York Times'', April 13, 2001, Accessed April 26, 2020. January 12, 1915 – April 10, 2001) was an American biologist, considered to be the father of modern ethnobotany. He is kno ...
in 1941. Since the 1930s, it was being used in hospitals as a muscle relaxant. He discovered that different types of curare called for as many as 15 ingredients, and in time helped to identify more than 70 species that produced the drug. In the 1940s, it was used on a few occasions during surgery as it was mistakenly thought to be an analgesic or anesthetic. The patients reported feeling the full intensity of the pain though they were not able to do anything about it since they were essentially paralyzed. On January 23, 1942, Harold Griffith and Enid Johnson gave a synthetic preparation of curare (Intercostrin/Intocostrin) to a patient undergoing an appendectomy (to supplement conventional anesthesia). Safer curare derivatives, such as rocuronium and pancuronium, have superseded d-tubocurarine for
anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...
during surgery. When used with
halothane Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. It can be used to induce or maintain anaesthesia. One of its benefits is that it does not increase the production of saliva, which can be particularly useful ...
d-tubocurarine can cause a profound fall in blood pressure in some patients as both the drugs are
ganglion blockers A ganglionic blocker (or ganglioplegic) is a type of medication that inhibits transmission between preganglionic and postganglionic neurons in the autonomic nervous system, often by acting as a nicotinic antagonist, nicotinic receptor antagonist. ...
. However, it is safer to use d-tubocurarine with
ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...
. In 1954, an article was published by Beecher and Todd suggesting that the use of muscle relaxants (drugs similar to curare) increased death due to anesthesia nearly sixfold., reprinted in This was refuted in 1956. Modern anesthetists have at their disposal a variety of muscle relaxants for use in anesthesia. The ability to produce muscle relaxation irrespective of sedation has permitted anesthetists to adjust the two effects independently and on the fly to ensure that their patients are safely unconscious and sufficiently relaxed to permit surgery. The use of neuromuscular blocking drugs carries with it the risk of anesthesia awareness.


Plant sources

There are dozens of plants from which isoquinoline and indole alkaloids with curarizing effects can be isolated, and which were utilized by indigenous tribes of Central and South America for the production of arrow poisons. Among them are: In family
Menispermaceae Menispermaceae (botanical Latin: 'moonseed family' from Greek ''mene'' 'crescent moon' and ''sperma'' 'seed') is a family (biology), family of flowering plants. The alkaloid tubocurarine, a neuromuscular blocker and the active ingredient in the ...
: * Genus '' Chondrodendron'' notably '' C. tomentosum'' * Genus '' Curarea'', species '' C. toxicofera'' and '' C. tecunarum'' * Genus '' Sciadotenia toxifera'' * Genus '' Telitoxicum'' * Genus '' Abuta'' * Genus '' Caryomene'' * Genus ''
Anomospermum ''Anomospermum'' is a genus of flowering plants in the family Menispermaceae. It consists of five species from tropical America, ranging from Nicaragua to southern Brazil.Orthomene'' * Genus '' Cissampelos, section L. (Cocculeae) of genus Other families: * several species of the genus ''
Strychnos ''Strychnos'' is a genus of flowering plants, belonging to the family Loganiaceae (sometimes Strychnaceae). The genus includes about 200 accepted species of trees and lianas. The genus is widely distributed around the world's tropics and is n ...
'' of family Loganiaceae including '' S. toxifera'', '' S. guianensis'', '' S. castelnaei'', '' S. usambarensis'' * a plant in the subfamily
Aroideae Aroideae is a subfamily of flowering plants in the family (biology), family Araceae. It is the largest subfamily in Araceae and consists of about 72 genera, and 2,300 species. Many Aroideae have spiny pollen grains without a sporopollenin outer e ...
of family
Araceae The Araceae are a family of monocotyledonous flowering plants in which flowers are borne on a type of inflorescence called a spadix. The spadix is usually accompanied by, and sometimes partially enclosed in, a spathe (or leaf-like bract). Also ...
called taja * at least three members of the genus '' Artanthe'' of family
Piperaceae The Piperaceae (), also known as the pepper family, are a large family (biology), family of flowering plants. The group contains roughly 3,600 currently accepted species in five genera. The vast majority of species can be found within the two mai ...
* ''
Paullinia cururu ''Paullinia'' is a genus of Flowering plant, flowering shrubs, small trees and lianas in the Sapindus, soapberry family, Sapindaceae and typical of tribe Paullinieae. It is native to Tropics, tropical South America, Central America and the Carib ...
'' in the family
Sapindaceae The Sapindaceae are a family (biology), family of flowering plants in the order Sapindales known as the soapberry family. It contains 138 genera and 1,858 accepted species. Examples include Aesculus, horse chestnut, maples, ackee and lychee. The ...
Some plants in the family
Aristolochiaceae The Aristolochiaceae () are a family, the birthwort family, of flowering plants with seven genera and about 400 known species belonging to the order Piperales. The type genus is '' Aristolochia'' L. Description They are mostly perennial, her ...
have also been reported as sources. Alkaloids with curare-like activity are present in plants of the fabaceous genus ''
Erythrina ''Erythrina'' is a genus of plants in the pea family, Fabaceae. It contains about 130 species, which are distributed in tropical and subtropical regions worldwide. They are trees, with the larger species growing up to in height. These species ...
''.


Toxicity

Administration must be
parenteral In pharmacology and toxicology, a route of administration is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...
, as gastro-intestinal absorption is ineffective. The toxicity of curare alkaloids in humans has not been systematically established, but it is considered highly toxic and slow-acting, with a lowest reported
lethal dose In toxicology, the lethal dose (LD) is an indication of the lethal toxicity of a given substance or type of radiation. Because resistance varies from one individual to another, the "lethal dose" represents a dose (usually recorded as dose per kilog ...
of 375 μg/kg (unknown route of administration). For animals, the
median lethal dose In toxicology, the median lethal dose, LD50 (abbreviation for " lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose re ...
of tubocurarine is: * 1200 μg/kg (dog, intravenous) * 140 μg/kg (mouse, intravenous) * 1300 μg/kg (rabbit, intravenous) * 3200 μg/kg (mouse, intraperitoneal) * 500 μg/kg (mouse, subcutaneous) * 2700 μg/kg (rabbit, subcutaneous) * 270 mg/kg (rabbit, oral) Death can be prevented by
artificial ventilation Artificial ventilation or respiration is when a machine assists in a metabolic process to exchange gases in the body by pulmonary ventilation, external respiration, and internal respiration. A machine called a ventilator provides the person air ...
until curare subsides and muscle function is regained, in which case no permanent effects of poisoning occur.


Preparation

In 1807,
Alexander von Humboldt Friedrich Wilhelm Heinrich Alexander von Humboldt (14 September 1769 – 6 May 1859) was a German polymath, geographer, natural history, naturalist, List of explorers, explorer, and proponent of Romanticism, Romantic philosophy and Romanticism ...
provided the first eye-witness account of curare preparation. A mixture of young bark scrapings of the ''Strychnos'' plant, other cleaned plant parts, and occasionally snake venom is boiled in water for two days. This liquid is then strained and evaporated to create a dark, heavy, viscid paste that would be tested for its potency later. This curare paste was described to be very bitter in taste. In 1938, Richard Gill and his expedition collected samples of processed curare and described its method of traditional preparation; one of the plant species used at that time was '' Chondrodendron tomentosum''.


Adjuvants

Various irritating herbs, stinging insects, poisonous worms, and various parts of amphibians and reptiles are added to the preparation. Some of these accelerate the onset of action or increase the toxicity; others prevent the wound from healing or blood from coagulating.


Diagnosis and management of curare poisoning

Curare poisoning can be indicated by typical signs of
neuromuscular-blocking drug Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcho ...
s such as paralysis including respiration but not directly affecting the heart. Curare poisoning can be managed by
artificial respiration Artificial ventilation or respiration is when a machine assists in a metabolic process to exchange gases in the body by pulmonary ventilation, external respiration, and internal respiration. A machine called a ventilator provides the person air ...
such as
mouth-to-mouth resuscitation Mouth-to-mouth resuscitation, a form of artificial ventilation, is the act of assisting or stimulating respiration in which a rescuer presses their mouth against that of the victim and blows air into the person's lungs. Artificial respiration ...
. In a study of 29 army volunteers that were paralyzed with curare, artificial respiration managed to keep
oxygen saturation Oxygen saturation (symbol SO2) is a relative measure of the concentration of oxygen that is Dissolution (chemistry), dissolved or carried in a given medium as a proportion of the maximal concentration that can be dissolved in that medium at the g ...
always above 85%, a level at which there is no evidence of
altered state of consciousness An altered state of consciousness (ASC), also called an altered state of mind, altered mental status (AMS) or mind alteration, is any condition which is significantly different from a normal waking state. It describes induced changes in one's me ...
. Yet, curare poisoning mimics total locked-in syndrome in that there is paralysis of every voluntarily controlled muscle in the body (including the eyes), making it practically impossible for the victim to confirm consciousness while paralyzed. Spontaneous breathing is resumed after the end of the
duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...
of curare, which is generally between 30 minutesFor therapeutic dose of tubocurarine by shorter limit as given in: and 8 hours, depending on the variant of the toxin and dosage.
Cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
is not directly affected by curare, but if more than four to six minutes has passed since respiratory cessation the cardiac muscle may stop functioning due to oxygen deprivation, making
cardiopulmonary resuscitation Cardiopulmonary resuscitation (CPR) is an emergency procedure used during Cardiac arrest, cardiac or Respiratory arrest, respiratory arrest that involves chest compressions, often combined with artificial ventilation, to preserve brain function ...
including chest compressions necessary.


Chemical antidote

Since tubocurarine and the other components of curare bind reversibly to the ACh receptors, treatment for curare poisoning involves adding an acetylcholinesterase (AChE) inhibitor, which will stop the destruction of acetylcholine so that it can compete with curare. This can be done by administration of acetylcholinesterase (AChE) inhibitors such as pyridostigmine, neostigmine,
physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and ...
, and edrophonium. Acetylcholinesterase is an enzyme used to break down the acetylcholine (ACh) neurotransmitter left over in motor neuron
synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
s. The aforementioned inhibitors, termed "anticurare" drugs, reversibly bind to the enzyme's active site, prohibiting its ability to bind to its original target, ACh. By blocking ACh degradation, AChE inhibitors can effectively raise the amount of ACh present in the neuromuscular junction. The accumulated ACh will then correct for the effect of the curare by activating the receptors not blocked by toxin at a higher rate, restoring activity to the motor neurons and bodily movement.


Gallery

File:Abuta selloana.jpg, ''Abuta selloana''. Certain species in the menispermaceous genus '' Abuta''—particularly the Colombian species '' A. imene''—have sometimes been used in the preparation of curare. File:Anomospermum schomburgkii.jpg, ''Anomospermum schomburgkii''. Certain species in the genus ''
Anomospermum ''Anomospermum'' is a genus of flowering plants in the family Menispermaceae. It consists of five species from tropical America, ranging from Nicaragua to southern Brazil.Cissampelos'' have been employed in the preparation of curare.


See also

* Arrow poison, what curare was originally used for *
Poison dart frog Poison dart frog (also known as dart-poison frog, poison frog or formerly known as poison arrow frog) is the common name of a group of frogs in the family Dendrobatidae which are native to tropical Central and South America. These species are ...
, another source of arrow poison *
Strychnine Strychnine (, , American English, US chiefly ) is a highly toxicity, toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, ...
, a related alkaloid poison that occurs in some of the same plants as curare


References


Further reading

* * – contains papers and records pertaining to Griffith's introduction of curare into
anesthesiology Anesthesiology, anaesthesiology or anaesthesia is the medical specialty concerned with the total perioperative medicine, perioperative care of patients before, during and after surgery. It encompasses anesthesia, intensive care medicine, critica ...
* * * * * {{Authority control Muscle relaxants Neuromuscular blockers Neurotoxins Nicotinic antagonists Plant toxins