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Toxiferine, also known as c-toxiferine I, is one of the most toxic plant
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 ...
s known. It is derived from several plant species, including ''
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 ...
. Historically, it has been used as an
arrow poison Arrow poisons are used to poison arrow heads or darts for the purposes of hunting and warfare. They have been used by indigenous peoples worldwide and are still in use in areas of South America, Africa and Asia. Notable examples are the poisons se ...
by indigenous peoples in South America for its neuromuscular blocking properties, allowing them to paralyze animals during hunting, but also possibly kill due to paralysis of the
respiratory muscles The muscles of respiration are the muscles that contribute to inhalation and exhalation, by aiding in the expansion and contraction of the thoracic cavity. The diaphragm and, to a lesser extent, the intercostal muscles drive respiration during ...
. Toxiferine functions as an
acetylcholine receptor An acetylcholine receptor (abbreviated AChR) or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptor ...
(AChR)
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.neostigmine Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...
. Toxiferine is the most important component in
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 ...
curare Curare ( or ; or ) is a common name for various alkaloid arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and South America for hunting and for therapeutic purposes, curare only ...
. Curare poisons contain many different toxins with similar properties of toxiferine. The most well known component of curare is
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 ...
. The paralysis caused by toxiferine is very similar to that caused by tubocurarine, however toxiferine is ~170 times as potent. The preparation of curare poisons involves complex rituals wherein the tribes extract toxins from various plants.


History

Curare Curare ( or ; or ) is a common name for various alkaloid arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and South America for hunting and for therapeutic purposes, curare only ...
was discovered in 1595, however toxiferine was only first isolated and characterized in 1941 by Wieland, Bähr and Witkop. They managed to produce only a couple micrograms of this compound as it is quite hard to isolate in large enough quantities to study. This is due to the complexity of curare as it is composed of many different
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 ...
s. In 1949 King was able to isolate 12 different types of toxiferines (I to XII). In 1951 some of these toxiferine types were analyzed for their
toxicological Toxicology is a scientific discipline (academia), discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnos ...
and
pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...
properties. These types were found to differ slightly in structure and their
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...
. Curares like
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 ...
were later used as
anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...
s in medical procedures, but were replaced in the 1960s by synthetic curare-like drugs like alcuronium,
pancuronium Pancuronium (trademarked as Pavulon) is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States. Mech ...
,
atracurium Atracurium besilate, also known as atracurium besylate, is a medication used in addition to other medications to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can also be used to help with endotracheal intubat ...
and
vecuronium Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal ...
. These drugs were safer to use as they had a shorter
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 ...
and less side effects. After the replacement of curares by these synthetic alternatives, research on toxiferine declined as it was hard to isolate from calabash curare and better alternatives to curares had been found thus decreasing the interest in researching this specific compound. However, curares as a whole have been (and still are) extensively researched.


Use/purpose

Toxiferine is most commonly known for its use as an
arrow poison Arrow poisons are used to poison arrow heads or darts for the purposes of hunting and warfare. They have been used by indigenous peoples worldwide and are still in use in areas of South America, Africa and Asia. Notable examples are the poisons se ...
alongside other
curare Curare ( or ; or ) is a common name for various alkaloid arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and South America for hunting and for therapeutic purposes, curare only ...
s by south american tribes. It is extracted from plants, like ''
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 ...
'' and ''
chondrodendron tomentosum ''Chondrodendron tomentosum'' is one of six accepted species in the small genus Chondrodendron, belonging to the Moonseed family Menispermaceae. It is a large tropical liana native to Central and South America. It contains highly toxic alkaloid ...
''. It is hard to extract in large quantities. It is very toxic however, so small quantities will suffice in paralyzing or killing animals while hunting. It could be used as an
anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...
in medical procedures, however it has a very long
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 ...
which doesn't make it suitable for such procedures. It is also unstable in solution, which further prevents its use in medical settings. Synthetic alternatives like alcuronium can and are still used in anesthetics due to their relatively shorter duration of action and fewer side effects.


Efficacy

Toxiferine is especially useful as an arrow poison because of its very minimal absorption through oral ingestion. Which is why it is safe to eat the animal after it has been shot with an arrow covered in toxiferine. It is also believed that because of its activity as muscle paralyzer, it can retain
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body. Glycogen functions as one of three regularly used forms ...
and ATP from releasing after death and by this delay
rigor mortis Rigor mortis (), or postmortem rigidity, is the fourth stage of death. It is one of the recognizable signs of death, characterized by stiffening of the limbs of the corpse caused by chemical changes in the muscles postmortem (mainly calcium ...
. This makes the meat more tender for longer and maintains its flavor.


Mechanism of action

Toxiferine I competes with
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 ...
, a
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
, for binding to the
nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...
s on the post-synaptic membrane of 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 ...
. By binding to these receptors, toxiferine I prevents acetylcholine from attaching to them. This inhibition blocks the ion channels associated with these receptors from opening, thereby preventing the influx of
sodium ions Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...
into the muscle cell. The prevention of sodium influx leads to an inhibition of
depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...
of the post-synaptic membrane, which is a necessary step for
muscle contraction Muscle contraction is the activation of Tension (physics), tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in musc ...
. Without depolarization, the muscle fiber cannot generate an
action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
, resulting in muscle paralysis. Toxiferine I is a potent
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.acetylcholine receptor An acetylcholine receptor (abbreviated AChR) or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptor ...
s, but especially potent for muscle-type nAChR:


Binding

Similar to alcuronium, toxiferine is classified as a non-depolarizing neuromuscular-blocking drug. These are drugs that inhibit
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
by
competitive inhibition Competitive inhibition is interruption of a chemistry, chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for molecular binding, binding or chemical bond, bonding. Any metabolism, metabolic or c ...
of in this case mainly muscle-type nAChRs. Toxiferine though binds 17 times stronger to muscle-type nAChRs than its pharmacological analogue alcuronium. The
quaternary ammonium salt In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, ...
that toxiferine and its analogues share with
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 ...
is thought to be the reason for the binding affinity to the AChRs. The exact reason for the especially high binding affinity of toxiferine to for example muscle-type nAChRs is unknown. There have been attempts at understanding the exact binding of toxiferine in nAChRs, but the models are dated.


Reversing the mechanism

Neostigmine Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...
is known to be effective at reversing the competitive inhibition of toxiferine and its analogues. Neostigmine works by inhibiting acetylcholinesterase, increasing the acetylcholine concentrations so it can compete more with the non-depolarizing neuromuscular-blocking drug. By this toxiferine can be freed into the circulation for excretion.


Chemistry


Structure

Toxiferine I is an
indole alkaloid Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known differ ...
derived from
tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...
. It has a dimeric structure with each
monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...
containing a
quaternary ammonium salt In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, ...
. The parent structure, without counter ions, has the molecular formula C40H46N4O22+, while the dichloride salt has the molecular formula C40H46N4O2Cl2. Alkaloids are naturally occurring compounds that are basic and contain at least one nitrogen atom. Toxiferine is classified as a dimeric bisindole alkaloid because it is symmetrically constructed from two identical monomeric units, each containing an indole ring.


Analogues

A dozen different types of toxiferine were found to exist (designated as toxiferine I to XII), but the different structures of toxiferine II till XII have not been studied in great detail. Toxiferine does have multiple analogues which are researched extensively. Some of these include: bisnortoxiferine, caracurine V and alcuronium. Caracurine V is, like toxiferine, another naturally occurring curare toxin from the strychnos toxifera. Caracurine V, unlike the other analogues, has a closed ring formed between the
hydroxyl groups In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
and the middle ring. Though the main difference between the analogues are the side groups attached to the positive nitrogen atom, also called the
quaternary ammonium ion In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, or ...
. The main target of toxiferine and its analogues are
acetylcholine receptor An acetylcholine receptor (abbreviated AChR) or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptor ...
s. It is this quaternary ammonium ion that both toxiferine and its analogues share with
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 ...
that gives them their specific affinity for these receptors. The difference in hydroxyl side groups together with most importantly the quaternary ammonium side groups is believed to cause the variability in
receptor affinity In chemistry, biochemistry, and pharmacology, a dissociation constant (''K''D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a Complex ...
and
metabolic activity Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
and with this a variability in the toxic properties of these analogues. From this it can be concluded that the side groups of toxiferine, mainly those attached to the quaternary ammonium have large effect over its reactivity and affinity, but to this day no research exists that can reliably explain the structural reactivity of toxiferine.


Biosynthesis

Toxiferine is an indole alkaloid. Indole alkaloids are the largest among the alkaloids. They are primarily synthesized using
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
. The dimeric subunits of toxiferine bear high similarity to
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, ...
and may be a related product of its biosynthesis. Especially the intermediate
Wieland-Gumlich aldehyde The so-called Wieland-Gumlich aldehyde (6) is an indoline derived by chemical degradation from strychnine. This compound is of some commercial interest as a chemical intermediate. It was first synthesized in 4 steps from strychnine (1) by Walter ...
is very similar to the dimeric subunits of toxiferine, though this lacks the quaternary ammonium ion. The biosynthesis of strychnine was solved in 2022. It is also possible to artificially synthesise strychnine. The exact biosynthetic and possible artificial ways to synthesise toxiferine are not known. It is believed though that toxiferine may be biosynthetically derived from the
monoterpenoid Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen funct ...
indole alkaloid
strictosidine Strictosidine is a natural chemical compound and is classified as a glucoalkaloid and a vinca alkaloid. It is formed by the Pictet–Spengler condensation reaction of tryptamine with secologanin, catalyzed by the enzyme strictosidine synthase. ...
. Strictosidine in turn is derived from the alkaloid
tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...
and the terpene
secologanin Secologanin is a secoiridoid monoterpene synthesized from geranyl pyrophosphate in the mevalonate pathway. Secologanin then proceeds with dopamine or tryptamine to form ipecac and terpene indole alkaloids, respectively. Biosynthesis Secologa ...
through the action of
strictosidine synthase Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction: :3-α(''S'')-strictosidine + H2O = tryptamine ...
.


ADME

This describes the
ADME ADME is the four-letter abbreviation (acronym) for absorption (pharmacokinetics), ''absorption'', distribution (pharmacology), ''distribution'', ''metabolism'', and ''excretion'', and is mainly used in fields such as pharmacokinetics and pharmacol ...
of toxiferine.


Absorption

Toxiferine is known to enter the body in two different ways: either
orally The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...
by ingestion or
intravenously 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 ...
while applied to a sharp tip for killing purposes. When orally ingested, toxiferine is only absorbed minimally into the plasma and is not known to be dangerous even though it has a very high potency. Intravenous absorption is thus the only way of effective administration.


Distribution

The distribution of toxiferine has been researched in
rats Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' (pack rats), '' Bandicota'' (bandicoot ...
. Toxiferine distributes through the body in a way that is similar to other non-depolarizing curare alkaloids. Toxiferine is a highly
water soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...
substance and because of this also generally not
lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...
. Toxiferine does not easily pass the blood-brain barrier. It is mostly retained in motor endplates and the
sciatic nerve The sciatic nerve, also called the ischiadic nerve, is a large nerve in humans and other vertebrate animals. It is the largest branch of the sacral plexus and runs alongside the hip joint and down the right lower limb. It is the longest and widest ...
where it binds to specific receptors. It was also found that toxiferine is distributed to tissues with a high acidic
mucopolysaccharide Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosacchari ...
content like
intervertebral disc An intervertebral disc (British English), also spelled intervertebral disk (American English), lies between adjacent vertebrae in the vertebral column. Each disc forms a fibrocartilaginous joint (a symphysis), to allow slight movement of the ver ...
s and
cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
of the ribs. Alkaloids are known to have affinity for such polysaccharides at acidic extracellular pH.


Metabolism

Toxiferine does not have any known
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...
s. This may be due to its low lipophilicity. Bis-quaternary nitrogen compounds like toxiferine have shown to be dependent on their lipophilicity to be transported to sites in the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
. The liver, which is the main site of metabolic activity, can thus not or hardly be reached. When comparing the metabolic activity of toxiferine to that of maybe its most important analogue alcuronium, it is observed that the
allylic In organic chemistry, an allyl group is a substituent with the structural formula . It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, . In 1844, Theodor Wertheim isolat ...
side chains of alcuronium make it more potent for
biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected ...
than toxiferine with its
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
side chains. This makes 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 toxiferine significantly longer when compared to alcuronium.


Excretion

Toxiferine is mainly excreted in the
urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
even though elimination of toxiferine by the
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
is very poor relative to its analogue alcuronium. Toxiferine has a strong receptor affinity, which together with the poor excretion makes it accumulate in the body rapidly after repeated administration. This is another reason why toxiferine has an especially long duration of action in the body.


Toxicological data

The effects of toxiferine have been studied in multiple organisms like
rhesus monkeys The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies split between two groups, the Chinese-derived and the Indian-derived. Generally brown or ...
,
guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy ( ), is a species of rodent belonging to the genus ''Cavia'', family Caviidae. Animal fancy, Breeders tend to use the name "cavy" for the ani ...
s and
mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
by
intravenous 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 ...
(IV) and
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
(IM) injections of different doses of toxiferine. The data on rhesus monkeys likely resembles human effects more closely. It has to be said that the duration of paralysis varies a lot between different individual monkeys and doses. It could be as short as 6 minutes but also as long as 85 minutes. In mice the LD100 was determined to be 23 μg/kg with a duration of paralysis around 12 minutes.


References

{{Nicotinic acetylcholine receptor modulators Indole alkaloids Nicotinic antagonists Quaternary ammonium compounds Neuromuscular blockers Neurotoxins Plant toxins