botulinum toxin botulinum toxin botulinum toxin, or botulinum neurotoxin (bont), is a neurotoxic protein produced by the bacterium clostridium botulinum and related species. it prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction, thus causing flaccid paralysis. the toxin causes the disease botulism. the toxin is also used commercially for medical and cosmetic purposes. botulinum toxin aribbon diagram of tertiary structure of bota (p0dpi1). pdb entry 3bta.clinical datatrade namesbotox, myobloc, jeuveau, othersother namesbont, abobotulinumtoxina, daxibotulinumtoxina, daxibotulinumtoxina-lanm, evabotulinumtoxina, incobotulinumtoxina, letibotulinumtoxina, onabotulinumtoxina, prabotulinumtoxina, relabotulinumtoxina, rimabotulinumtoxinbahfs/drugs.commonographmedlineplusa619021license data us dailymed: botulinum toxin pregnancycategory au: b3 routes ofadministrationintramuscular, subcutaneous, intradermalatc codem03ax01 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only eu: rx-only identifierscas number93384-43-1 ndrugbankdb00083 nchemspidernoneuniie211kpy694botulinum toxin: uc95nq339c ykeggd00783botulinum toxin: d08957echa infocard100.088.372 chemical and physical dataformulac6760h10447n1743o2010s32molar mass149323.05 g·mol−1 ny (what is this?) (verify) bontoxilysinidentifiersec no.3.4.24.69databasesintenzintenz viewbrendabrenda entryexpasynicezyme viewkeggkegg entrymetacycmetabolic pathwaypriamprofilepdb structuresrcsb pdb pdbe pdbsumgene ontologyamigo / quickgosearchpmcarticlespubmedarticlesncbiproteins the seven main types of botulinum toxin are named types a to g (a, b, c, d, e, f and g). new types are occasionally found. types a and b are capable of causing disease in humans, and are also used commercially and medically. types c–g are less common; types e and f can cause disease in humans, while the other types cause disease in other animals. botulinum toxins are among the most potent toxins known. intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food. the estimated human lethal dose of type a toxin is 1.3–2.1 ng/kg intravenously or intramuscularly, 10–13 ng/kg when inhaled, or 1000 ng/kg when taken by mouth. commercial forms are marketed under the brand names botox (onabotulinumtoxina), dysport/azzalure (abobotulinumtoxina), letybo (letibotulinumtoxina), myobloc (rimabotulinumtoxinb), xeomin/bocouture (incobotulinumtoxina), and jeuveau (prabotulinumtoxina). medical uses botulinum toxin is used to treat a number of therapeutic indications, many of which are not part of the approved drug label. muscle spasticity botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including cerebral palsy, post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck, eyelid, vagina, limbs, jaw, and vocal cords. similarly, botulinum toxin is used to relax the clenching of muscles, including those of the esophagus, jaw, lower urinary tract and bladder, or clenching of the anus which can exacerbate anal fissure. botulinum toxin appears to be effective for refractory overactive bladder. other muscle disorders strabismus, otherwise known as improper eye alignment, is caused by imbalances in the actions of muscles that rotate the eyes. this condition can sometimes be relieved by weakening a muscle that pulls too strongly, or pulls against one that has been weakened by disease or trauma. muscles weakened by toxin injection recover from paralysis after several months, so injection might seem to need to be repeated, but muscles adapt to the lengths at which they are chronically held, so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect. if binocular vision is good, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment. in january 2014, botulinum toxin was approved by uk's medicines and healthcare products regulatory agency for treatment of restricted ankle motion due to lower-limb spasticity associated with stroke in adults. in july 2016, the u.s. food and drug administration (fda) approved abobotulinumtoxina (dysport) for injection for the treatment of lower-limb spasticity in pediatric patients two years of age and older. abobotulinumtoxina is the first and only fda-approved botulinum toxin for the treatment of pediatric lower limb spasticity. in the u.s., the fda approves the text of the labels of prescription medicines and for which medical conditions the drug manufacturer may sell the drug. however, prescribers may freely prescribe them for any condition they wish, also known as off-label use. botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia. excessive sweating abobotulinumtoxina has been approved for the treatment of excessive underarm sweating of unknown cause, which cannot be managed by topical agents. migraine in 2010, the fda approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache. botulinum toxin for migraine is an effective treatment method for individuals who don’t find any oral medication helpful anymore. it works just like botulinum toxins for wrinkles reduction – blocks the nerve endings in the muscles and thus stops their contractions. cosmetic uses botulinum toxin being injected in the human face in cosmetic applications, botulinum toxin is considered relatively safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face. commercial forms are marketed under the brand names botox cosmetic/vistabel from allergan, dysport/azzalure from galderma and ipsen, xeomin/bocouture from merz, jeuveau/nuceiva from evolus, manufactured by daewoong in south korea. the effects of botulinum toxin injections for glabellar lines ('11's lines' between the eyes) typically last two to four months and in some cases, product-dependent, with some patients experiencing a longer duration of effect of up to 6 months or longer. injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin. smoothing of wrinkles is usually visible three to five days after injection, with maximum effect typically a week following injection. muscles can be treated repeatedly to maintain the smoothed appearance. daxibotulinumtoxina (daxxify) is used for the temporary improvement in the appearance of moderate to severe glabellar lines (eyebrows). daxibotulinumtoxina is an acetylcholine release inhibitor and neuromuscular blocking agent. other botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating, neuropathic pain, and some allergy symptoms. in addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain. studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion. the use of botulinum toxin a in children with cerebral palsy is safe in the upper and lower limb muscles. side effects while botulinum toxin is generally considered safe in a clinical setting, serious side effects from its use can occur. most commonly, botulinum toxin can be injected into the wrong muscle group or with time spread from the injection site, causing temporary paralysis of unintended muscles. side effects from cosmetic use generally result from unintended paralysis of facial muscles. these include partial facial paralysis, muscle weakness, and trouble swallowing. side effects are not limited to direct paralysis, however, and can also include headaches, flu-like symptoms, and allergic reactions. just as cosmetic treatments only last a number of months, paralysis side effects can have the same durations. at least in some cases, these effects are reported to dissipate in the weeks after treatment. bruising at the site of injection is not a side effect of the toxin, but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days. when injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods. with continued high doses, the muscles can atrophy or lose strength; research has shown that those muscles rebuild after a break from botox. side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. in general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. these can arise from paralysis of critical muscle groups and can include arrhythmia, heart attack, and in some cases, seizures, respiratory arrest, and death. additionally, side effects common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes. in response to the occurrence of these side effects, in 2008, the fda notified the public of the potential dangers of the botulinum toxin as a therapeutic. namely, the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy. in 2009, the fda announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site. however, the clinical use of botulinum toxin a in cerebral palsy children has been proven to be safe with minimal side effects. additionally, the fda announced name changes to several botulinum toxin products, to emphasize that the products are not interchangeable and require different doses for proper use. botox and botox cosmetic were given the generic name of onabotulinumtoxina, myobloc as rimabotulinumtoxinb, and dysport retained its generic name of abobotulinumtoxina. in conjunction with this, the fda issued a communication to health care professionals reiterating the new drug names and the approved uses for each. a similar warning was issued by health canada in 2009, warning that botulinum toxin products can spread to other parts of the body. role in disease main article: botulism botulinum toxin produced by clostridium botulinum is the cause of botulism. humans most commonly ingest the toxin from eating improperly canned foods in which c. botulinum has grown. however, the toxin can also be introduced through an infected wound. in infants, the bacteria can sometimes grow in the intestines and produce botulinum toxin within the intestine and can cause a condition known as floppy baby syndrome. in all cases, the toxin can then spread, blocking nerves and muscle function. in severe cases, the toxin can block nerves controlling the respiratory system or heart, resulting in death. botulism can be difficult to diagnose, as it may appear similar to diseases such as guillain–barré syndrome, myasthenia gravis, and stroke. other tests, such as brain scan and spinal fluid examination, may help to rule out other causes. if the symptoms of botulism are diagnosed early, various treatments can be administered. in an effort to remove contaminated food that remains in the gut, enemas or induced vomiting may be used. for wound infections, infected material may be removed surgically. botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. in severe cases, mechanical respiration may be used to support patients with respiratory failure. the nerve damage heals over time, generally over weeks to months. with proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced. two preparations of botulinum antitoxins are available for treatment of botulism. trivalent (serotypes a, b, e) botulinum antitoxin is derived from equine sources using whole antibodies. the second antitoxin is heptavalent botulinum antitoxin (serotypes a, b, c, d, e, f, g), which is derived from equine antibodies that have been altered to make them less immunogenic. this antitoxin is effective against all main strains of botulism. mechanism of action target molecules of botulinum neurotoxin (abbreviated bont) and tetanus neurotoxin (tent), toxins acting inside the axon terminal botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. first, the toxin binds specifically to presynaptic surface of neurons that use the neurotransmitter acetylcholine. once bound to the nerve terminal, the neuron takes up the toxin into a vesicle by receptor-mediated endocytosis. as the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin that triggers it to push across the vesicle membrane and into the cell cytoplasm. botulinum neurotoxins recognize distinct classes of receptors simultaneously (gangliosides, synaptotagmin and sv2). once inside the cytoplasm, the toxin cleaves snare proteins (proteins that mediate vesicle fusion, with their target membrane bound compartments) meaning that the acetylcholine vesicles cannot bind to the intracellular cell membrane, preventing the cell from releasing vesicles of neurotransmitter. this stops nerve signaling, leading to flaccid paralysis. the toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases. the active form consists of a two-chain protein composed of a 100-kda heavy chain polypeptide joined via disulfide bond to a 50-kda light chain polypeptide. the heavy chain contains domains with several functions; it has the domain responsible for binding specifically to presynaptic nerve terminals, as well as the