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Botulinum toxin

January 01, 1970

Botulinum toxin, or botulinum neurotoxin (commonly called botox), is a highly potent neurotoxic protein produced by the bacterium Clostridium botulinum and related species.[23] It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction, thus causing flaccid paralysis.[24] The toxin causes the disease botulism.[25] The toxin is also used commercially for medical and cosmetic purposes.[26][27] Botulinum toxin is an acetylcholine release inhibitor and a neuromuscular blocking agent.[1][22]

Botulinum toxin A
Ribbon diagram of tertiary structure of BotA (P0DPI1). PDB entry 3BTA.
Clinical data
Trade namesBotox, Myobloc, Jeuveau, others
Other namesBoNT, botox
BiosimilarsabobotulinumtoxinA, daxibotulinumtoxinA, daxibotulinumtoxinA-lanm, evabotulinumtoxinA, incobotulinumtoxinA, letibotulinumtoxinA, letibotulinumtoxinA-wlbg,[1] onabotulinumtoxinA, prabotulinumtoxinA, relabotulinumtoxinA, rimabotulinumtoxinB
AHFS/Drugs.com
  • abobotulinumtoxinA Monograph
  • daxibotulinumtoxinA Monograph
  • incobotulinumtoxinA Monograph
  • onabotulinumtoxinA Monograph
  • prabotulinumtoxinA Monograph
  • rimabotulinumtoxinB Monograph
MedlinePlusa619021
License data
Pregnancy
category
Routes of
administration		Intramuscular, subcutaneous, intradermal
ATC code
Legal status
Legal status
Identifiers
CAS Number
  • Botulinum toxin A: 93384-43-1 N
  • Botulinum toxin B: 93384-43-2
DrugBank
  • Botulinum toxin A: DB00083 N
  • Botulinum toxin B: DB00042
ChemSpider
  • Botulinum toxin A: none
UNII
  • Botulinum toxin A: E211KPY694
  • Botulinum toxin B: 0Y70779M1F Y
KEGG
  • Botulinum toxin A: D00783
  • Botulinum toxin B: D08957
ECHA InfoCard100.088.372
Chemical and physical data
FormulaC6760H10447N1743O2010S32
Molar mass149323.05 g·mol−1
 NY (what is this?)  (verify)
Bontoxilysin
Identifiers
EC no.3.4.24.69
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

The seven main types of botulinum toxin are named types A to G (A, B, C1, C2, D, E, F and G).[26][28] New types are occasionally found.[29][30] Types A and B are capable of causing disease in humans, and are also used commercially and medically.[31][32][33] Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals.[34]

Botulinum toxins are among the most potent toxins known to science.[35][36] Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food. The estimated human median 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.[37]

Medical uses edit

Botulinum toxin is used to treat a number of therapeutic indications, many of which are not part of the approved drug label.[27]

Muscle spasticity edit

Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including cerebral palsy,[31][32] post-stroke spasticity,[38] post-spinal cord injury spasticity,[39] spasms of the head and neck,[40] eyelid,[25] vagina,[41] limbs, jaw, and vocal cords.[42] Similarly, botulinum toxin is used to relax the clenching of muscles, including those of the esophagus,[43] jaw,[44] lower urinary tract and bladder,[45] or clenching of the anus which can exacerbate anal fissure.[46] Botulinum toxin appears to be effective for refractory overactive bladder.[47]

Other muscle disorders edit

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,[48] so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect.[49]

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.[50][51]

In July 2016, the US 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.[52][53] AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity.[54] In the US, 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.[55] Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.[56]

Excessive sweating edit

AbobotulinumtoxinA has been approved for the treatment of axillary hyperhidrosis, which cannot be managed by topical agents.[42][57]

Migraine edit

In 2010, the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache.[58]However, the use of botulinum toxin injections for episodic migraine has not been approved by the FDA.[59][60]

Cosmetic uses edit

 
Botulinum toxin being injected in the human face

In cosmetic applications, botulinum toxin is considered relatively safe and effective[61] for reduction of facial wrinkles, especially in the uppermost third of the face.[62] 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.[63] 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 six months or longer.[62] Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin.[62] Smoothing of wrinkles is usually visible three to five days after injection, with maximum effect typically a week following injection.[62] Muscles can be treated repeatedly to maintain the smoothed appearance.[62]

DaxibotulinumtoxinA (Daxxify) was approved for medical use in the United States in September 2022.[22][64] It is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines (wrinkles between the eyebrows).[22][64][65] DaxibotulinumtoxinA is an acetylcholine release inhibitor and neuromuscular blocking agent.[22] The FDA approved daxibotulinumtoxinA based on evidence from two clinical trials (Studies GL-1 and GL-2), of 609 adults with moderate to severe glabellar lines.[64] The trials were conducted at 30 sites in the United States and Canada.[64] Both trials enrolled participants 18 to 75 years old with moderate to severe glabellar lines.[64] Participants received a single intramuscular injection of daxibotulinumtoxinA or placebo at five sites within the muscles between the eyebrows.[64] The most common side effects of daxibotulinumtoxinA are headache, drooping eyelids, and weakness of facial muscles.[64]

LetibotulinumtoxinA (Letybo) was approved for medical use in the United States in February 2024.[1][66] It is indicated to temporarily improve the appearance of moderate-to-severe glabellar lines.[1][67] The FDA approved letibotulinumtoxinA based on evidence from three clinical trials (BLESS I [NCT02677298], BLESS II [NCT02677805], and BLESS III [NCT03985982]) of 1,271 participants with moderate to severe wrinkles between the eyebrows for efficacy and safety assessment.[66] These trials were conducted at 31 sites in the United States and the European Union.[66] All three trials enrolled participants 18 to 75 years old with moderate to severe glabellar lines (wrinkles between the eyebrows).[66] Participants received a single intramuscular injection of letibotulinumtoxinA or placebo at five sites within the muscles between the eyebrows.[66] The most common side effects of letibotulinumtoxinA are headache, drooping of eyelid and brow, and twitching of eyelid.[66]

Other edit

Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating,[57] neuropathic pain,[68] and some allergy symptoms.[42] In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain.[69] Studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion.[70] The use of botulinum toxin A in children with cerebral palsy is safe in the upper and lower limb muscles.[31][32]

Side effects edit

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.[71]

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.[72] Just as cosmetic treatments only last a number of months, paralysis side effects can have the same durations.[73] At least in some cases, these effects are reported to dissipate in the weeks after treatment.[74] 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.[75] 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.[72] With continued high doses, the muscles can atrophy or lose strength; research has shown that those muscles rebuild after a break from Botox.[76]

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.[72] Additionally, side effects common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.[72]

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.[77] 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.[78][79][80][81] However, the clinical use of botulinum toxin A in cerebral palsy children has been proven to be safe with minimal side effects.[31][32] 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.[82][78] In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each.[83] A similar warning was issued by Health Canada in 2009, warning that botulinum toxin products can spread to other parts of the body.[84]

Role in disease edit

Main article: Botulism

Botulinum toxin produced by Clostridium botulinum (an anaerobic, gram-positive bacterium) is the cause of botulism.[25] 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.[85] 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.[23]

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.[86] For wound infections, infected material may be removed surgically.[86] 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 people with respiratory failure.[86] The nerve damage heals over time, generally over weeks to months.[87] With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced.[86]

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.[88][30]

Mechanism of action edit

 
Target molecules of botulinum neurotoxin (abbreviated BoNT) and tetanus neurotoxin (TeNT), toxins acting inside the axon terminal[89]

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.[90] 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.[23] Botulinum neurotoxins recognize distinct classes of receptors simultaneously (gangliosides, synaptotagmin and SV2).[91] 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,[90] preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to flaccid paralysis.[23][91]

The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases.[42] 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.[92] The heavy chain contains domains with several functions; it has the domain responsible for binding specifically to presynaptic nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies.[23][92] The light chain is a M27-family zinc metalloprotease and is the active part of the toxin. It is translocated into the host cell cytoplasm where it cleaves the host protein SNAP-25, a member of the SNARE protein family, which is responsible for fusion. The cleaved SNAP-25 cannot mediate fusion of vesicles with the host cell membrane, thus preventing the release of the neurotransmitter acetylcholine from axon endings.[23] This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.[23]

The seven toxin serotypes (A–G) are traditionally separated by their antigenicity. They have different tertiary structures and sequence differences.[92][93] While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members.[89] The A, B, and E serotypes cause human botulism, with the activities of types A and B enduring longest in vivo (from several weeks to months).[92] Existing toxin types can recombine to create "hybrid" (mosaic, chimeric) types. Examples include BoNT/CD, BoNT/DC, and BoNT/FA, with the first letter indicating the light chain type and the latter indicating the heavy chain type.[94] BoNT/FA received considerable attention under the name "BoNT/H", as it was mistakenly thought it could not be neutralized by any existing antitoxin.[30]

Botulinum toxins are AB toxins and closely related to Anthrax toxin, Diphtheria toxin, and in particular tetanus toxin. The two are collectively known as Clostridium neurotoxins and the light chain is classified by MEROPS as family M27. Nonclassical types include BoNT/X (P0DPK1), which is toxic in mice and possibly in humans;[29] a BoNT/J (A0A242DI27) found in cow Enterococcus;[95] and a BoNT/Wo (A0A069CUU9) found in the rice-colonizing Weissella oryzae.[94]

History edit

Initial descriptions and discovery of Clostridium botulinum edit

One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of Wildbad in what is now Baden-Württemberg, Germany. Thirteen people became sick and six died after eating pork stomach filled with blood sausage, a local delicacy. Additional cases of fatal food poisoning in Württemberg led the authorities to issue a public warning against consuming smoked blood sausages in 1802 and to collect case reports of "sausage poisoning".[96] Between 1817 and 1822, the German physician Justinus Kerner published the first complete description of the symptoms of botulism, based on extensive clinical observations and animal experiments. He concluded that the toxin develops in bad sausages under anaerobic conditions, is a biological substance, acts on the nervous system, and is lethal even in small amounts.[96] Kerner hypothesized that this "sausage toxin" could be used to treat a variety of diseases caused by an overactive nervous system, making him the first to suggest that it could be used therapeutically.[97] In 1870, the German physician Müller coined the term botulism to describe the disease caused by sausage poisoning, from the Latin word botulus, meaning 'sausage'.[97]

In 1895 Émile van Ermengem, a Belgian microbiologist, discovered what is now called Clostridium botulinum and confirmed that a toxin produced by the bacteria causes botulism.[98] On 14 December 1895, there was a large outbreak of botulism in the Belgian village of Ellezelles that occurred at a funeral where people ate pickled and smoked ham; three of them died. By examining the contaminated ham and performing autopsies on the people who died after eating it, van Ermengem isolated an anaerobic microorganism that he called Bacillus botulinus.[96] He also performed experiments on animals with ham extracts, isolated bacterial cultures, and toxins extracts from the bacteria. From these he concluded that the bacteria themselves do not cause foodborne botulism, but rather produce a toxin that causes the disease after it is ingested.[99] As a result of Kerner's and van Ermengem's research, it was thought that only contaminated meat or fish could cause botulism. This idea was refuted in 1904 when a botulism outbreak occurred in Darmstadt, Germany, because of canned white beans. In 1910, the German microbiologist J. Leuchs published a paper showing that the outbreaks in Ellezelles and Darmstadt were caused by different strains of Bacillus botulinus and that the toxins were serologically distinct.[96] In 1917, Bacillus botulinus was renamed Clostridium botulinum, as it was decided that term Bacillus should only refer to a group of aerobic microorganisms, while Clostridium would be only used to describe a group of anaerobic microorganisms.[98] In 1919, Georgina Burke used toxin-antitoxin reactions to identify two strains of Clostridium botulinum, which she designated A and B.[98]

Food canning edit

Over the next three decades, 1895–1925, as food canning was approaching a billion-dollar-a-year industry, botulism was becoming a public health hazard. Karl Friedrich Meyer, a Swiss-American veterinary scientist, created a center at the Hooper Foundation in San Francisco, where he developed techniques for growing the organism and extracting the toxin, and conversely, for preventing organism growth and toxin production, and inactivating the toxin by heating. The California canning industry was thereby preserved.[100]

World War II edit

With the outbreak of World War II, weaponization of botulinum toxin was investigated at Fort Detrick in Maryland. Carl Lamanna and James Duff[101] developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army's Chemical Corps was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and provided it to the academic community.

The mechanism of botulinum toxin action – blocking the release of the neurotransmitter acetylcholine from nerve endings – was elucidated in the mid-20th century,[102] and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.

Strabismus edit

Ophthalmologists specializing in eye muscle disorders (strabismus) had developed the method of EMG-guided injection (using the electromyogram, the electrical signal from an activated muscle, to guide injection) of local anesthetics as a diagnostic technique for evaluating an individual muscle's contribution to an eye movement.[103] Because strabismus surgery frequently needed repeating, a search was undertaken for non-surgical, injection treatments using various anesthetics, alcohols, enzymes, enzyme blockers, and snake neurotoxins. Finally, inspired by Daniel B. Drachman's work with chicks at Johns Hopkins,[104] Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles.[105] The result was remarkable; a few picograms induced paralysis that was confined to the target muscle, long in duration, and without side effects.

After working out techniques for freeze-drying, buffering with albumin, and assuring sterility, potency, and safety, Scott applied to the FDA for investigational drug use, and began manufacturing botulinum type A neurotoxin in his San Francisco lab. He injected the first strabismus patients in 1977, reported its clinical utility in 1980,[106] and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum ("eye aligner").

In 1986, Oculinum Inc, Scott's micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, people who had come to rely on periodic injections became desperate. For four months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.[107]

Based on data from thousands of people collected by 240 investigators, Oculinum Inc (which was soon acquired by Allergan) received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and blepharospasm. Allergan then began using the trademark Botox.[108] This original approval was granted under the 1983 US Orphan Drug Act.[109]

Cosmetics edit

 
Doctor performing Botulinum toxin injection

The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped, and she constantly demonstrated deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that Botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with Botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report of the cosmetic use of Botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal Plastic and Reconstructive Surgery in 1989.[110] Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."[111]

Also in 1987, Jean and Alastair Carruthers, both doctors in Vancouver, British Columbia, observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines ("frown lines" between the eyebrows). Alastair Carruthers reported that others at the time also noticed these effects and discussed the cosmetic potential of botulinum toxin.[112] Unlike other investigators, the Carruthers did more than just talk about the possibility of using botulinum toxin cosmetically. They conducted a clinical study on otherwise normal individuals whose only concern was their eyebrow furrow. They performed their study between 1987 and 1989 and presented their results at the 1990 annual meeting of the American Society for Dermatologic Surgery. Their findings were subsequently published in 1992.[113]

Chronic pain edit

William J. Binder reported in 2000 that people who had cosmetic injections around the face reported relief from chronic headache.[114] This was initially thought to be an indirect effect of reduced muscle tension, but the toxin is now known to inhibit release of peripheral nociceptive neurotransmitters, suppressing the central pain processing systems responsible for migraine headache.[115][116]

Society and culture edit

Economics edit

As of 2018, botulinum toxin injections are the most common cosmetic operation, with 7.4 million procedures in the United States, according to the American Society of Plastic Surgeons.[117]

The global market for botulinum toxin products, driven by their cosmetic applications, was forecast to reach $2.9 billion by 2018. The facial aesthetics market, of which they are a component, was forecast to reach $4.7 billion ($2 billion in the US) in the same timeframe.[118]

US market edit

In 2020, 4,401,536 botulinum toxin Type A procedures were administered.[119] In 2019 the botulinum toxin market made US$3.19 billion.[120]

Botox cost edit

Botox cost is generally determined by the number of units administered (avg. $10–30 per unit) or by the area ($200–1000) and depends on expertise of a physician, clinic location, number of units, and treatment complexity.[121]

Insurance edit

In the US, botox for medical purposes is usually covered by insurance if deemed medically necessary by a doctor and covers a plethora of medical problems including overactive bladder (OAB), urinary incontinence due to neurologic conditions, headaches and migraines, TMJ, spasticity in adults, cervical dystonia in adults, severe axillary hyperhidrosis (or other areas of the body), blepharospasm, upper or lower limb spasticity.[122][123]

Hyperhidrosis edit

Botox for excessive sweating is FDA approved.[71]

Cosmetic edit

Standard areas for aesthetics botox injections include facial and other areas that can form fine lines and wrinkles due to every day muscle contractions and/or facial expressions such as smiling, frowning, squinting, and raising eyebrows. These areas include the glabellar region between the eyebrows, horizontal lines on the forehead, crow's feet around the eyes, and even circular bands that form around the neck secondary to platysmal hyperactivity.[124]

Bioterrorism edit

Botulinum toxin has been recognized as a potential agent for use in bioterrorism.[125] It can be absorbed through the eyes, mucous membranes, respiratory tract, and non-intact skin.[126] The effects of botulinum toxin are different from those of nerve agents involved insofar in that botulism symptoms develop relatively slowly (over several days), while nerve agent effects are generally much more rapid. Evidence suggests that nerve exposure (simulated by injection of atropine and pralidoxime) will increase mortality by enhancing botulinum toxin's mechanism of toxicity.[127] With regard to detection, protocols using NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a "positive" when samples containing botulinum toxin are tested.[128] To confirm a diagnosis of botulinum toxin poisoning, therapeutically or to provide evidence in death investigations, botulinum toxin may be quantitated by immunoassay of human biological fluids; serum levels of 12–24 mouse LD50 units per milliliter have been detected in poisoned people.[129]

During the early 1980s, German and French newspapers reported that the police had raided a Baader-Meinhof gang safe house in Paris and had found a makeshift laboratory that contained flasks full of Clostridium botulinum, which makes botulinum toxin. Their reports were later found to be incorrect; no such lab was ever found.[130]

Brand names edit

Commercial forms are marketed under the brand names Botox (onabotulinumtoxinA),[18][82][131] Dysport/Azzalure (abobotulinumtoxinA),[82][132] Letybo (letibotulinumtoxinA),[1][2][133] Myobloc (rimabotulinumtoxinB),[20][82] Xeomin/Bocouture (incobotulinumtoxinA),[134] and Jeuveau (prabotulinumtoxinA).[135][63]

Botulinum toxin A is sold under the brand names Jeuveau, Botox, and Xeomin. Botulinum toxin B is sold under the brand name Myobloc.[20]

In the United States, botulinum toxin products are manufactured by a variety of companies, for both therapeutic and cosmetic use. A US supplier reported in its company materials in 2011 that it could "supply the world's requirements for 25 indications approved by Government agencies around the world" with less than one gram of raw botulinum toxin.[136] Myobloc or Neurobloc, a botulinum toxin type B product, is produced by Solstice Neurosciences, a subsidiary of US WorldMeds. AbobotulinumtoxinA), a therapeutic formulation of the type A toxin manufactured by Galderma in the United Kingdom, is licensed for the treatment of focal dystonias and certain cosmetic uses in the US and other countries.[83] LetibotulinumtoxinA (Letybo) was approved for medical use in the United States in February 2024.[1]

Besides the three primary US manufacturers, numerous other botulinum toxin producers are known. Xeomin, manufactured in Germany by Merz, is also available for both therapeutic and cosmetic use in the US.[137] Lanzhou Institute of Biological Products in China manufactures a botulinum toxin type-A product; as of 2014, it was the only botulinum toxin type-A approved in China.[137] Botulinum toxin type-A is also sold as Lantox and Prosigne on the global market.[138] Neuronox, a botulinum toxin type-A product, was introduced by Medy-Tox of South Korea in 2009.[139]

Toxin production edit

Botulism toxins are produced by bacteria of the genus Clostridium, namely C. botulinum, C. butyricum, C. baratii and C. argentinense,[140] which are widely distributed, including in soil and dust. Also, the bacteria can be found inside homes on floors, carpet, and countertops even after cleaning.[141] Complicating the problem is that the taxonomy for C. botulinum remains chaotic. The toxin has likely been horizontally transferred across lineages, contributing to the multi-species patten seen today.[142][143]

Food-borne botulism results, indirectly, from ingestion of food contaminated with Clostridium spores, where exposure to an anaerobic environment allows the spores to germinate, after which the bacteria can multiply and produce toxin.[141] Critically, ingestion of toxin rather than spores or vegetative bacteria causes botulism.[141] Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, so is preventable.[141] Infant botulism arising from consumption of honey or any other food that can carry these spores can be prevented by eliminating these foods from diets of children less than 12 months old.[144]

Organism and toxin susceptibilities edit

Proper refrigeration at temperatures below 4.4 °C (39.9 °F) slows the growth of C. botulinum.[145] The organism is also susceptible to high salt, high oxygen, and low pH levels.[34][failed verification] The toxin itself is rapidly destroyed by heat, such as in thorough cooking.[146] The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.[147]

The botulinum toxin is denatured and thus deactivated at temperatures greater than 85 °C (185 °F) for five minutes.[34] As a zinc metalloprotease (see below), the toxin's activity is also susceptible, post-exposure, to inhibition by protease inhibitors, e.g., zinc-coordinating hydroxamates.[92][148]

Research edit

Blepharospasm and strabismus edit

See also: Botulinum toxin therapy of strabismus

University-based ophthalmologists in the US and Canada further refined the use of botulinum toxin as a therapeutic agent. By 1985, a scientific protocol of injection sites and dosage had been empirically determined for treatment of blepharospasm and strabismus.[149] Side effects in treatment of this condition were deemed to be rare, mild and treatable.[150] The beneficial effects of the injection lasted only four to six months. Thus, blepharospasm patients required re-injection two or three times a year.[151]

In 1986, Scott's micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance. People became desperate, as supplies of Botox were gradually consumed, forcing him to abandon people who would have been due for their next injection. For a period of four months, American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.[107]

In December 1989, Botox was approved by the US FDA for the treatment of strabismus, blepharospasm, and hemifacial spasm in people over 12 years old.[108]

In the case of treatment of infantile esotropia in people younger than 12 years of age, several studies have yielded differing results.[56][152]

Cosmetic edit

The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped and she emoted with deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report on the cosmetic use of botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal Plastic and Reconstructive Surgery in 1989.[110] Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."[111]

J. D. and J. A. Carruthers also studied and reported in 1992 the use of botulinum toxin type-A as a cosmetic treatment.[78] They conducted a study of participants whose only concern was their glabellar forehead wrinkle or furrow. Study participants were otherwise normal. Sixteen of seventeen participants available for follow-up demonstrated a cosmetic improvement. This study was reported at a meeting in 1991. The study for the treatment of glabellar frown lines was published in 1992.[113] This result was subsequently confirmed by other groups (Brin, and the Columbia University group under Monte Keen[153]). The FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) in 2002 after extensive clinical trials.[154] Well before this, the cosmetic use of botulinum toxin type A became widespread.[155] The results of Botox Cosmetic can last up to four months and may vary with each patient.[156] The US Food and Drug Administration (FDA) approved an alternative product-safety testing method in response to increasing public concern that LD50 testing was required for each batch sold in the market.[157][158]

Botulinum toxin type-A has also been used in the treatment of gummy smiles;[159] the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of gingiva.[160] Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the levator labii superioris (LLS), the levator labii superioris alaeque nasi muscle (LLSAN), and the zygomaticus minor (ZMi).[161][162]

Upper motor neuron syndrome edit

Botulinum toxin type-A is now a common treatment for muscles affected by the upper motor neuron syndrome (UMNS), such as cerebral palsy,[31] for muscles with an impaired ability to effectively lengthen. Muscles affected by UMNS frequently are limited by weakness, loss of reciprocal inhibition, decreased movement control, and hypertonicity (including spasticity). In January 2014, Botulinum toxin was approved by UK's Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults.[50] Joint motion may be restricted by severe muscle imbalance related to the syndrome, when some muscles are markedly hypertonic, and lack effective active lengthening. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, so improved ability to move and exercise.[31]

Sialorrhea edit

Sialorrhea is a condition where oral secretions are unable to be eliminated, causing pooling of saliva in the mouth. This condition can be caused by various neurological syndromes such as Bell's palsy, intellectual disability, and cerebral palsy. Injection of botulinum toxin type-A into salivary glands is useful in reducing the secretions.[163]

Cervical dystonia edit

Botulinum toxin type-A is used to treat cervical dystonia, but it can become ineffective after a time. Botulinum toxin type B received FDA approval for treatment of cervical dystonia in December 2000. Brand names for botulinum toxin type-B include Myobloc in the United States and Neurobloc in the European Union.[137]

Chronic migraine edit

See also: Migraine treatment § Botulinum Toxin (Botox)

Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic migraines on 15 October 2010. The toxin is injected into the head and neck to treat these chronic headaches. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for those with migraines undergoing the Botox treatment.[164][165]

Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for participants with chronic migraine[166] who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), "detoxification" of participants with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.[167]

Depression edit

See also: List of investigational antidepressants

A few small trials have found benefits in people with depression.[168][169] Research is based on the facial feedback hypothesis.[170]

Premature ejaculation edit

See also: List of investigational sexual dysfunction drugs

The drug for the treatment of premature ejaculation has been under development since August 2013, and is in Phase II trials.[169][171]

Role in the bacterial lifecycle edit

Botulinum toxin serves the bacterium by paralyzing muscles in the host organism. The paralysis of the Levator ani muscles slows Defecation and hence prevents the host organism from clearing the infection through Diarrhea. When a host is infected with Clostridium botulinum and exposed to its toxin, the toxin blocks the release of acetylcholine, a neurotransmitter responsible for muscle contraction, at the neuromuscular junction. This leads to flaccid paralysis, where the affected muscles become weak or paralyzed. As a result, the host's ability to respond to the infection via increased bowl movements is compromised, which aids the bacterium in establishing and maintaining the infection.

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Further reading edit

  • Carruthers JD, Fagien S, Joseph JH, Humphrey SD, Biesman BS, Gallagher CJ, et al. (January 2020). "DaxibotulinumtoxinA for Injection for the Treatment of Glabellar Lines: Results from Each of Two Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Studies (SAKURA 1 and SAKURA 2)". Plastic and Reconstructive Surgery. 145 (1): 45–58. doi:10.1097/PRS.0000000000006327. PMC 6940025. PMID 31609882.
  • Solish N, Carruthers J, Kaufman J, Rubio RG, Gross TM, Gallagher CJ (December 2021). "Overview of DaxibotulinumtoxinA for Injection: A Novel Formulation of Botulinum Toxin Type A". Drugs. 81 (18): 2091–2101. doi:10.1007/s40265-021-01631-w. PMC 8648634. PMID 34787840.

External links edit

  • Overview of all the structural information available in the PDB for UniProt: P0DPI1 (Botulinum neurotoxin type A) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: P10844 (Botulinum neurotoxin type B) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: A0A0X1KH89 (Bontoxilysin A) at the PDBe-KB.
  • "AbobotulinumtoxinA Injection". MedlinePlus.
  • "IncobotulinumtoxinA Injection". MedlinePlus.
  • "OnabotulinumtoxinA Injection". MedlinePlus.
  • "PrabotulinumtoxinA-xvfs Injection". MedlinePlus.
  • "RimabotulinumtoxinB Injection". MedlinePlus.

January 01, 1970
botulinum, toxin, botulinum, neurotoxin, commonly, called, botox, highly, potent, neurotoxic, protein, produced, bacterium, clostridium, botulinum, related, species, prevents, release, neurotransmitter, acetylcholine, from, axon, endings, neuromuscular, juncti. Botulinum toxin or botulinum neurotoxin commonly called botox is a highly potent neurotoxic protein produced by the bacterium Clostridium botulinum and related species 23 It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction thus causing flaccid paralysis 24 The toxin causes the disease botulism 25 The toxin is also used commercially for medical and cosmetic purposes 26 27 Botulinum toxin is an acetylcholine release inhibitor and a neuromuscular blocking agent 1 22 Botulinum toxin ARibbon diagram of tertiary structure of BotA P0DPI1 PDB entry 3BTA Clinical dataTrade namesBotox Myobloc Jeuveau othersOther namesBoNT botoxBiosimilarsabobotulinumtoxinA daxibotulinumtoxinA daxibotulinumtoxinA lanm evabotulinumtoxinA incobotulinumtoxinA letibotulinumtoxinA letibotulinumtoxinA wlbg 1 onabotulinumtoxinA prabotulinumtoxinA relabotulinumtoxinA rimabotulinumtoxinBAHFS Drugs comabobotulinumtoxinA MonographdaxibotulinumtoxinA MonographincobotulinumtoxinA MonographonabotulinumtoxinA MonographprabotulinumtoxinA MonographrimabotulinumtoxinB MonographMedlinePlusa619021License dataUS DailyMed Botulinum toxinPregnancycategoryAU B3 2 3 Routes ofadministrationIntramuscular subcutaneous intradermalATC codeBotulinum toxin A M03AX01 WHO Legal statusLegal statusAU S4 Prescription only 2 3 5 6 7 8 CA only Schedule D 9 10 11 12 13 UK POM Prescription only 14 15 16 17 US WARNING 4 Rx only 18 19 20 21 22 1 EU Rx onlyIdentifiersCAS NumberBotulinum toxin A 93384 43 1 NBotulinum toxin B 93384 43 2DrugBankBotulinum toxin A DB00083 NBotulinum toxin B DB00042ChemSpiderBotulinum toxin A noneUNIIBotulinum toxin A E211KPY694Botulinum toxin B 0Y70779M1F YKEGGBotulinum toxin A D00783Botulinum toxin B D08957ECHA InfoCard100 088 372Chemical and physical dataFormulaC 6760H 10447N 1743O 2010S 32Molar mass149323 05 g mol 1 N Y 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 C1 C2 D E F and G 26 28 New types are occasionally found 29 30 Types A and B are capable of causing disease in humans and are also used commercially and medically 31 32 33 Types C G are less common types E and F can cause disease in humans while the other types cause disease in other animals 34 Botulinum toxins are among the most potent toxins known to science 35 36 Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food The estimated human median 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 37 Contents 1 Medical uses 1 1 Muscle spasticity 1 2 Other muscle disorders 1 3 Excessive sweating 1 4 Migraine 1 5 Cosmetic uses 1 6 Other 2 Side effects 3 Role in disease 4 Mechanism of action 5 History 5 1 Initial descriptions and discovery of Clostridium botulinum 5 2 Food canning 5 3 World War II 5 4 Strabismus 5 5 Cosmetics 5 6 Chronic pain 6 Society and culture 6 1 Economics 6 1 1 US market 6 1 2 Botox cost 6 1 3 Insurance 6 1 4 Hyperhidrosis 6 1 5 Cosmetic 6 2 Bioterrorism 6 3 Brand names 6 4 Toxin production 6 5 Organism and toxin susceptibilities 7 Research 7 1 Blepharospasm and strabismus 7 2 Cosmetic 7 3 Upper motor neuron syndrome 7 4 Sialorrhea 7 5 Cervical dystonia 7 6 Chronic migraine 7 7 Depression 7 8 Premature ejaculation 7 9 Role in the bacterial lifecycle 8 References 9 Further reading 10 External linksMedical uses editBotulinum toxin is used to treat a number of therapeutic indications many of which are not part of the approved drug label 27 Muscle spasticity edit Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement including cerebral palsy 31 32 post stroke spasticity 38 post spinal cord injury spasticity 39 spasms of the head and neck 40 eyelid 25 vagina 41 limbs jaw and vocal cords 42 Similarly botulinum toxin is used to relax the clenching of muscles including those of the esophagus 43 jaw 44 lower urinary tract and bladder 45 or clenching of the anus which can exacerbate anal fissure 46 Botulinum toxin appears to be effective for refractory overactive bladder 47 Other muscle disorders edit 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 48 so that if a paralyzed muscle is stretched by its antagonist it grows longer while the antagonist shortens yielding a permanent effect 49 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 50 51 In July 2016 the US 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 52 53 AbobotulinumtoxinA is the first and only FDA approved botulinum toxin for the treatment of pediatric lower limb spasticity 54 In the US 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 55 Botulinum toxins have been used off label for several pediatric conditions including infantile esotropia 56 Excessive sweating edit AbobotulinumtoxinA has been approved for the treatment of axillary hyperhidrosis which cannot be managed by topical agents 42 57 Migraine edit In 2010 the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache 58 However the use of botulinum toxin injections for episodic migraine has not been approved by the FDA 59 60 Cosmetic uses edit nbsp Botulinum toxin being injected in the human face In cosmetic applications botulinum toxin is considered relatively safe and effective 61 for reduction of facial wrinkles especially in the uppermost third of the face 62 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 63 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 six months or longer 62 Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles resulting in the smoothing of the overlying skin 62 Smoothing of wrinkles is usually visible three to five days after injection with maximum effect typically a week following injection 62 Muscles can be treated repeatedly to maintain the smoothed appearance 62 DaxibotulinumtoxinA Daxxify was approved for medical use in the United States in September 2022 22 64 It is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines wrinkles between the eyebrows 22 64 65 DaxibotulinumtoxinA is an acetylcholine release inhibitor and neuromuscular blocking agent 22 The FDA approved daxibotulinumtoxinA based on evidence from two clinical trials Studies GL 1 and GL 2 of 609 adults with moderate to severe glabellar lines 64 The trials were conducted at 30 sites in the United States and Canada 64 Both trials enrolled participants 18 to 75 years old with moderate to severe glabellar lines 64 Participants received a single intramuscular injection of daxibotulinumtoxinA or placebo at five sites within the muscles between the eyebrows 64 The most common side effects of daxibotulinumtoxinA are headache drooping eyelids and weakness of facial muscles 64 LetibotulinumtoxinA Letybo was approved for medical use in the United States in February 2024 1 66 It is indicated to temporarily improve the appearance of moderate to severe glabellar lines 1 67 The FDA approved letibotulinumtoxinA based on evidence from three clinical trials BLESS I NCT02677298 BLESS II NCT02677805 and BLESS III NCT03985982 of 1 271 participants with moderate to severe wrinkles between the eyebrows for efficacy and safety assessment 66 These trials were conducted at 31 sites in the United States and the European Union 66 All three trials enrolled participants 18 to 75 years old with moderate to severe glabellar lines wrinkles between the eyebrows 66 Participants received a single intramuscular injection of letibotulinumtoxinA or placebo at five sites within the muscles between the eyebrows 66 The most common side effects of letibotulinumtoxinA are headache drooping of eyelid and brow and twitching of eyelid 66 Other edit Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating 57 neuropathic pain 68 and some allergy symptoms 42 In addition to these uses botulinum toxin is being evaluated for use in treating chronic pain 69 Studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion 70 The use of botulinum toxin A in children with cerebral palsy is safe in the upper and lower limb muscles 31 32 Side effects editWhile 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 71 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 72 Just as cosmetic treatments only last a number of months paralysis side effects can have the same durations 73 At least in some cases these effects are reported to dissipate in the weeks after treatment 74 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 75 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 72 With continued high doses the muscles can atrophy or lose strength research has shown that those muscles rebuild after a break from Botox 76 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 72 Additionally side effects common in cosmetic use are also common in therapeutic use including trouble swallowing muscle weakness allergic reactions and flu like syndromes 72 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 77 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 78 79 80 81 However the clinical use of botulinum toxin A in cerebral palsy children has been proven to be safe with minimal side effects 31 32 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 82 78 In conjunction with this the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each 83 A similar warning was issued by Health Canada in 2009 warning that botulinum toxin products can spread to other parts of the body 84 Role in disease editMain article Botulism Botulinum toxin produced by Clostridium botulinum an anaerobic gram positive bacterium is the cause of botulism 25 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 85 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 23 Botulism can be difficult to diagnose as it may appear similar to diseases such as Guillain Barre 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 86 For wound infections infected material may be removed surgically 86 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 people with respiratory failure 86 The nerve damage heals over time generally over weeks to months 87 With proper treatment the case fatality rate for botulinum poisoning can be greatly reduced 86 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 88 30 Mechanism of action edit nbsp Target molecules of botulinum neurotoxin abbreviated BoNT and tetanus neurotoxin TeNT toxins acting inside the axon terminal 89 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 90 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 23 Botulinum neurotoxins recognize distinct classes of receptors simultaneously gangliosides synaptotagmin and SV2 91 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 90 preventing the cell from releasing vesicles of neurotransmitter This stops nerve signaling leading to flaccid paralysis 23 91 The toxin itself is released from the bacterium as a single chain then becomes activated when cleaved by its own proteases 42 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 92 The heavy chain contains domains with several functions it has the domain responsible for binding specifically to presynaptic nerve terminals as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies 23 92 The light chain is a M27 family zinc metalloprotease and is the active part of the toxin It is translocated into the host cell cytoplasm where it cleaves the host protein SNAP 25 a member of the SNARE protein family which is responsible for fusion The cleaved SNAP 25 cannot mediate fusion of vesicles with the host cell membrane thus preventing the release of the neurotransmitter acetylcholine from axon endings 23 This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell 23 The seven toxin serotypes A G are traditionally separated by their antigenicity They have different tertiary structures and sequence differences 92 93 While the different toxin types all target members of the SNARE family different toxin types target different SNARE family members 89 The A B and E serotypes cause human botulism with the activities of types A and B enduring longest in vivo from several weeks to months 92 Existing toxin types can recombine to create hybrid mosaic chimeric types Examples include BoNT CD BoNT DC and BoNT FA with the first letter indicating the light chain type and the latter indicating the heavy chain type 94 BoNT FA received considerable attention under the name BoNT H as it was mistakenly thought it could not be neutralized by any existing antitoxin 30 Botulinum toxins are AB toxins and closely related to Anthrax toxin Diphtheria toxin and in particular tetanus toxin The two are collectively known as Clostridium neurotoxins and the light chain is classified by MEROPS as family M27 Nonclassical types include BoNT X P0DPK1 which is toxic in mice and possibly in humans 29 a BoNT J A0A242DI27 found in cow Enterococcus 95 and a BoNT Wo A0A069CUU9 found in the rice colonizing Weissella oryzae 94 History editInitial descriptions and discovery of Clostridium botulinum edit One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of Wildbad in what is now Baden Wurttemberg Germany Thirteen people became sick and six died after eating pork stomach filled with blood sausage a local delicacy Additional cases of fatal food poisoning in Wurttemberg led the authorities to issue a public warning against consuming smoked blood sausages in 1802 and to collect case reports of sausage poisoning 96 Between 1817 and 1822 the German physician Justinus Kerner published the first complete description of the symptoms of botulism based on extensive clinical observations and animal experiments He concluded that the toxin develops in bad sausages under anaerobic conditions is a biological substance acts on the nervous system and is lethal even in small amounts 96 Kerner hypothesized that this sausage toxin could be used to treat a variety of diseases caused by an overactive nervous system making him the first to suggest that it could be used therapeutically 97 In 1870 the German physician Muller coined the term botulism to describe the disease caused by sausage poisoning from the Latin word botulus meaning sausage 97 In 1895 Emile van Ermengem a Belgian microbiologist discovered what is now called Clostridium botulinum and confirmed that a toxin produced by the bacteria causes botulism 98 On 14 December 1895 there was a large outbreak of botulism in the Belgian village of Ellezelles that occurred at a funeral where people ate pickled and smoked ham three of them died By examining the contaminated ham and performing autopsies on the people who died after eating it van Ermengem isolated an anaerobic microorganism that he called Bacillus botulinus 96 He also performed experiments on animals with ham extracts isolated bacterial cultures and toxins extracts from the bacteria From these he concluded that the bacteria themselves do not cause foodborne botulism but rather produce a toxin that causes the disease after it is ingested 99 As a result of Kerner s and van Ermengem s research it was thought that only contaminated meat or fish could cause botulism This idea was refuted in 1904 when a botulism outbreak occurred in Darmstadt Germany because of canned white beans In 1910 the German microbiologist J Leuchs published a paper showing that the outbreaks in Ellezelles and Darmstadt were caused by different strains of Bacillus botulinus and that the toxins were serologically distinct 96 In 1917 Bacillus botulinus was renamed Clostridium botulinum as it was decided that term Bacillus should only refer to a group of aerobic microorganisms while Clostridium would be only used to describe a group of anaerobic microorganisms 98 In 1919 Georgina Burke used toxin antitoxin reactions to identify two strains of Clostridium botulinum which she designated A and B 98 Food canning edit This section needs additional citations for verification Please help improve this article by adding citations to reliable sources in this section Unsourced material may be challenged and removed August 2018 Learn how and when to remove this message Over the next three decades 1895 1925 as food canning was approaching a billion dollar a year industry botulism was becoming a public health hazard Karl Friedrich Meyer a Swiss American veterinary scientist created a center at the Hooper Foundation in San Francisco where he developed techniques for growing the organism and extracting the toxin and conversely for preventing organism growth and toxin production and inactivating the toxin by heating The California canning industry was thereby preserved 100 World War II edit With the outbreak of World War II weaponization of botulinum toxin was investigated at Fort Detrick in Maryland Carl Lamanna and James Duff 101 developed the concentration and crystallization techniques that Edward J Schantz used to create the first clinical product When the Army s Chemical Corps was disbanded Schantz moved to the Food Research Institute in Wisconsin where he manufactured toxin for experimental use and provided it to the academic community The mechanism of botulinum toxin action blocking the release of the neurotransmitter acetylcholine from nerve endings was elucidated in the mid 20th century 102 and remains an important research topic Nearly all toxin treatments are based on this effect in various body tissues Strabismus edit Ophthalmologists specializing in eye muscle disorders strabismus had developed the method of EMG guided injection using the electromyogram the electrical signal from an activated muscle to guide injection of local anesthetics as a diagnostic technique for evaluating an individual muscle s contribution to an eye movement 103 Because strabismus surgery frequently needed repeating a search was undertaken for non surgical injection treatments using various anesthetics alcohols enzymes enzyme blockers and snake neurotoxins Finally inspired by Daniel B Drachman s work with chicks at Johns Hopkins 104 Alan B Scott and colleagues injected botulinum toxin into monkey extraocular muscles 105 The result was remarkable a few picograms induced paralysis that was confined to the target muscle long in duration and without side effects After working out techniques for freeze drying buffering with albumin and assuring sterility potency and safety Scott applied to the FDA for investigational drug use and began manufacturing botulinum type A neurotoxin in his San Francisco lab He injected the first strabismus patients in 1977 reported its clinical utility in 1980 106 and had soon trained hundreds of ophthalmologists in EMG guided injection of the drug he named Oculinum eye aligner In 1986 Oculinum Inc Scott s micromanufacturer and distributor of botulinum toxin was unable to obtain product liability insurance and could no longer supply the drug As supplies became exhausted people who had come to rely on periodic injections became desperate For four months as liability issues were resolved American blepharospasm patients traveled to Canadian eye centers for their injections 107 Based on data from thousands of people collected by 240 investigators Oculinum Inc which was soon acquired by Allergan received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and blepharospasm Allergan then began using the trademark Botox 108 This original approval was granted under the 1983 US Orphan Drug Act 109 Cosmetics edit nbsp Doctor performing Botulinum toxin injection The effect of botulinum toxin type A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark MD a plastic surgeon from Sacramento California In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure This patient had desired to look better from her facelift but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped and she constantly demonstrated deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis Clark was aware that Botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with Botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same This study and case report of the cosmetic use of Botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal Plastic and Reconstructive Surgery in 1989 110 Editors of the journal of the American Society of Plastic Surgeons have clearly stated the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989 111 Also in 1987 Jean and Alastair Carruthers both doctors in Vancouver British Columbia observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines frown lines between the eyebrows Alastair Carruthers reported that others at the time also noticed these effects and discussed the cosmetic potential of botulinum toxin 112 Unlike other investigators the Carruthers did more than just talk about the possibility of using botulinum toxin cosmetically They conducted a clinical study on otherwise normal individuals whose only concern was their eyebrow furrow They performed their study between 1987 and 1989 and presented their results at the 1990 annual meeting of the American Society for Dermatologic Surgery Their findings were subsequently published in 1992 113 Chronic pain edit William J Binder reported in 2000 that people who had cosmetic injections around the face reported relief from chronic headache 114 This was initially thought to be an indirect effect of reduced muscle tension but the toxin is now known to inhibit release of peripheral nociceptive neurotransmitters suppressing the central pain processing systems responsible for migraine headache 115 116 Society and culture editEconomics edit This article needs to be updated Please help update this article to reflect recent events or newly available information October 2017 As of 2018 update botulinum toxin injections are the most common cosmetic operation with 7 4 million procedures in the United States according to the American Society of Plastic Surgeons 117 The global market for botulinum toxin products driven by their cosmetic applications was forecast to reach 2 9 billion by 2018 The facial aesthetics market of which they are a component was forecast to reach 4 7 billion 2 billion in the US in the same timeframe 118 US market edit In 2020 4 401 536 botulinum toxin Type A procedures were administered 119 In 2019 the botulinum toxin market made US 3 19 billion 120 Botox cost edit Botox cost is generally determined by the number of units administered avg 10 30 per unit or by the area 200 1000 and depends on expertise of a physician clinic location number of units and treatment complexity 121 Insurance edit In the US botox for medical purposes is usually covered by insurance if deemed medically necessary by a doctor and covers a plethora of medical problems including overactive bladder OAB urinary incontinence due to neurologic conditions headaches and migraines TMJ spasticity in adults cervical dystonia in adults severe axillary hyperhidrosis or other areas of the body blepharospasm upper or lower limb spasticity 122 123 Hyperhidrosis edit Botox for excessive sweating is FDA approved 71 Cosmetic edit Standard areas for aesthetics botox injections include facial and other areas that can form fine lines and wrinkles due to every day muscle contractions and or facial expressions such as smiling frowning squinting and raising eyebrows These areas include the glabellar region between the eyebrows horizontal lines on the forehead crow s feet around the eyes and even circular bands that form around the neck secondary to platysmal hyperactivity 124 Bioterrorism edit Botulinum toxin has been recognized as a potential agent for use in bioterrorism 125 It can be absorbed through the eyes mucous membranes respiratory tract and non intact skin 126 The effects of botulinum toxin are different from those of nerve agents involved insofar in that botulism symptoms develop relatively slowly over several days while nerve agent effects are generally much more rapid Evidence suggests that nerve exposure simulated by injection of atropine and pralidoxime will increase mortality by enhancing botulinum toxin s mechanism of toxicity 127 With regard to detection protocols using NBC detection equipment such as M 8 paper or the ICAM will not indicate a positive when samples containing botulinum toxin are tested 128 To confirm a diagnosis of botulinum toxin poisoning therapeutically or to provide evidence in death investigations botulinum toxin may be quantitated by immunoassay of human biological fluids serum levels of 12 24 mouse LD50 units per milliliter have been detected in poisoned people 129 During the early 1980s German and French newspapers reported that the police had raided a Baader Meinhof gang safe house in Paris and had found a makeshift laboratory that contained flasks full of Clostridium botulinum which makes botulinum toxin Their reports were later found to be incorrect no such lab was ever found 130 Brand names edit The examples and perspective in this article deal primarily with the United States and do not represent a worldwide view of the subject You may improve this article discuss the issue on the talk page or create a new article as appropriate April 2017 Learn how and when to remove this message Commercial forms are marketed under the brand names Botox onabotulinumtoxinA 18 82 131 Dysport Azzalure abobotulinumtoxinA 82 132 Letybo letibotulinumtoxinA 1 2 133 Myobloc rimabotulinumtoxinB 20 82 Xeomin Bocouture incobotulinumtoxinA 134 and Jeuveau prabotulinumtoxinA 135 63 Botulinum toxin A is sold under the brand names Jeuveau Botox and Xeomin Botulinum toxin B is sold under the brand name Myobloc 20 In the United States botulinum toxin products are manufactured by a variety of companies for both therapeutic and cosmetic use A US supplier reported in its company materials in 2011 that it could supply the world s requirements for 25 indications approved by Government agencies around the world with less than one gram of raw botulinum toxin 136 Myobloc or Neurobloc a botulinum toxin type B product is produced by Solstice Neurosciences a subsidiary of US WorldMeds AbobotulinumtoxinA a therapeutic formulation of the type A toxin manufactured by Galderma in the United Kingdom is licensed for the treatment of focal dystonias and certain cosmetic uses in the US and other countries 83 LetibotulinumtoxinA Letybo was approved for medical use in the United States in February 2024 1 Besides the three primary US manufacturers numerous other botulinum toxin producers are known Xeomin manufactured in Germany by Merz is also available for both therapeutic and cosmetic use in the US 137 Lanzhou Institute of Biological Products in China manufactures a botulinum toxin type A product as of 2014 it was the only botulinum toxin type A approved in China 137 Botulinum toxin type A is also sold as Lantox and Prosigne on the global market 138 Neuronox a botulinum toxin type A product was introduced by Medy Tox of South Korea in 2009 139 Toxin production edit Botulism toxins are produced by bacteria of the genus Clostridium namely C botulinum C butyricum C baratii and C argentinense 140 which are widely distributed including in soil and dust Also the bacteria can be found inside homes on floors carpet and countertops even after cleaning 141 Complicating the problem is that the taxonomy for C botulinum remains chaotic The toxin has likely been horizontally transferred across lineages contributing to the multi species patten seen today 142 143 Food borne botulism results indirectly from ingestion of food contaminated with Clostridium spores where exposure to an anaerobic environment allows the spores to germinate after which the bacteria can multiply and produce toxin 141 Critically ingestion of toxin rather than spores or vegetative bacteria causes botulism 141 Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening so is preventable 141 Infant botulism arising from consumption of honey or any other food that can carry these spores can be prevented by eliminating these foods from diets of children less than 12 months old 144 Organism and toxin susceptibilities edit This section needs expansion with modern content and referencing on antibiotic susceptibilities You can help by adding to it February 2015 Proper refrigeration at temperatures below 4 4 C 39 9 F slows the growth of C botulinum 145 The organism is also susceptible to high salt high oxygen and low pH levels 34 failed verification The toxin itself is rapidly destroyed by heat such as in thorough cooking 146 The spores that produce the toxin are heat tolerant and will survive boiling water for an extended period of time 147 The botulinum toxin is denatured and thus deactivated at temperatures greater than 85 C 185 F for five minutes 34 As a zinc metalloprotease see below the toxin s activity is also susceptible post exposure to inhibition by protease inhibitors e g zinc coordinating hydroxamates 92 148 Research editBlepharospasm and strabismus edit See also Botulinum toxin therapy of strabismus University based ophthalmologists in the US and Canada further refined the use of botulinum toxin as a therapeutic agent By 1985 a scientific protocol of injection sites and dosage had been empirically determined for treatment of blepharospasm and strabismus 149 Side effects in treatment of this condition were deemed to be rare mild and treatable 150 The beneficial effects of the injection lasted only four to six months Thus blepharospasm patients required re injection two or three times a year 151 In 1986 Scott s micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance People became desperate as supplies of Botox were gradually consumed forcing him to abandon people who would have been due for their next injection For a period of four months American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved 107 In December 1989 Botox was approved by the US FDA for the treatment of strabismus blepharospasm and hemifacial spasm in people over 12 years old 108 In the case of treatment of infantile esotropia in people younger than 12 years of age several studies have yielded differing results 56 152 Cosmetic edit The effect of botulinum toxin type A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark MD a plastic surgeon from Sacramento California In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure This patient had desired to look better from her facelift but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped and she emoted with deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis Clark was aware that botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same This study and case report on the cosmetic use of botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal Plastic and Reconstructive Surgery in 1989 110 Editors of the journal of the American Society of Plastic Surgeons have clearly stated the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989 111 J D and J A Carruthers also studied and reported in 1992 the use of botulinum toxin type A as a cosmetic treatment 78 They conducted a study of participants whose only concern was their glabellar forehead wrinkle or furrow Study participants were otherwise normal Sixteen of seventeen participants available for follow up demonstrated a cosmetic improvement This study was reported at a meeting in 1991 The study for the treatment of glabellar frown lines was published in 1992 113 This result was subsequently confirmed by other groups Brin and the Columbia University group under Monte Keen 153 The FDA announced regulatory approval of botulinum toxin type A Botox Cosmetic to temporarily improve the appearance of moderate to severe frown lines between the eyebrows glabellar lines in 2002 after extensive clinical trials 154 Well before this the cosmetic use of botulinum toxin type A became widespread 155 The results of Botox Cosmetic can last up to four months and may vary with each patient 156 The US Food and Drug Administration FDA approved an alternative product safety testing method in response to increasing public concern that LD50 testing was required for each batch sold in the market 157 158 Botulinum toxin type A has also been used in the treatment of gummy smiles 159 the material is injected into the hyperactive muscles of upper lip which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of gingiva 160 Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose the levator labii superioris LLS the levator labii superioris alaeque nasi muscle LLSAN and the zygomaticus minor ZMi 161 162 Upper motor neuron syndrome edit Botulinum toxin type A is now a common treatment for muscles affected by the upper motor neuron syndrome UMNS such as cerebral palsy 31 for muscles with an impaired ability to effectively lengthen Muscles affected by UMNS frequently are limited by weakness loss of reciprocal inhibition decreased movement control and hypertonicity including spasticity In January 2014 Botulinum toxin was approved by UK s Medicines and Healthcare products Regulatory Agency MHRA for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults 50 Joint motion may be restricted by severe muscle imbalance related to the syndrome when some muscles are markedly hypertonic and lack effective active lengthening Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion so improved ability to move and exercise 31 Sialorrhea edit Sialorrhea is a condition where oral secretions are unable to be eliminated causing pooling of saliva in the mouth This condition can be caused by various neurological syndromes such as Bell s palsy intellectual disability and cerebral palsy Injection of botulinum toxin type A into salivary glands is useful in reducing the secretions 163 Cervical dystonia edit Botulinum toxin type A is used to treat cervical dystonia but it can become ineffective after a time Botulinum toxin type B received FDA approval for treatment of cervical dystonia in December 2000 Brand names for botulinum toxin type B include Myobloc in the United States and Neurobloc in the European Union 137 Chronic migraine edit See also Migraine treatment Botulinum Toxin Botox Onabotulinumtoxin A trade name Botox received FDA approval for treatment of chronic migraines on 15 October 2010 The toxin is injected into the head and neck to treat these chronic headaches Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for those with migraines undergoing the Botox treatment 164 165 Since then several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for participants with chronic migraine 166 who exhibit headache characteristics consistent with pressure perceived from outside source shorter total duration of chronic migraines lt 30 years detoxification of participants with coexisting chronic daily headache due to medication overuse and no current history of other preventive headache medications 167 Depression edit See also List of investigational antidepressants A few small trials have found benefits in people with depression 168 169 Research is based on the facial feedback hypothesis 170 Premature ejaculation edit See also List of investigational sexual dysfunction drugs The drug for the treatment of premature ejaculation has been under development since August 2013 and is in Phase II trials 169 171 Role in the bacterial lifecycle edit This section does not cite any sources Please help improve this section by adding citations to reliable sources Unsourced material may be challenged and removed March 2024 Learn how and when to remove this message Botulinum toxin serves the bacterium by paralyzing muscles in the host organism The paralysis of the Levator ani muscles slows Defecation and hence prevents the host organism from clearing the infection through Diarrhea When a host is infected with Clostridium botulinum and exposed to its toxin the toxin blocks the release of acetylcholine a neurotransmitter responsible for muscle contraction at the neuromuscular junction This leads to flaccid paralysis where the affected muscles become weak or paralyzed As a result the host s ability to respond to the infection via increased bowl movements is compromised which aids the bacterium in establishing and maintaining the infection References edit a b c d e f g Letybo letibotulinumtoxinA wlbg for injection for intramuscular use PDF Archived PDF from the original on 2 March 2024 Retrieved 2 March 2024 a b c Letybo Therapeutic Goods Administration TGA Archived from the original on 18 December 2022 Retrieved 18 December 2022 a b Nuceiva Therapeutic Goods Administration TGA 10 February 2023 Retrieved 8 April 2023 FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 October 2023 Nuceiva PPD Australia Pty Ltd Therapeutic Goods Administration TGA 16 February 2023 Archived from the original on 18 March 2023 Retrieved 8 April 2023 Nuceiva prabotulinumtoxinA 100 Units Powder for Solution for Injection vial 381094 Therapeutic Goods Administration TGA 26 January 2023 Archived from the original on 8 April 2023 Retrieved 8 April 2023 Prescription medicines registration of new chemical entities in Australia 2014 Therapeutic Goods Administration TGA 21 June 2022 Archived from the original on 10 April 2023 Retrieved 10 April 2023 Archived copy Archived from the original on 31 March 2024 Retrieved 31 March 2024 a href Template Cite web html title Template Cite web cite web a CS1 maint archived copy as title link Regulatory Decision Summary Botox Health Canada 23 October 2014 Archived from the original on 12 June 2022 Retrieved 12 June 2022 Regulatory Decision Summary Nuceiva Health Canada 23 October 2014 Archived from the original on 7 June 2022 Retrieved 11 June 2022 Regulatory Decision Summary for Xeomin Drug and Health Products Portal 15 March 2022 Retrieved 1 April 2024 Regulatory Decision Summary for Botox Drug and Health Products Portal 7 February 2024 Archived from the original on 2 April 2024 Retrieved 2 April 2024 Health Canada New Drug Authorizations 2016 Highlights Health Canada 14 March 2017 Archived from the original on 7 April 2024 Retrieved 7 April 2024 Azzalure Summary of Product Characteristics SmPC emc 16 August 2022 Archived from the original on 18 December 2022 Retrieved 18 December 2022 Alluzience 200 Speywood units ml solution for injection Summary of Product Characteristics 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this source which is in the public domain Watkins T 15 October 2010 FDA approves Botox as migraine preventative CNN Archived from the original on 27 July 2020 Retrieved 16 October 2010 Dodick DW Turkel CC DeGryse RE Aurora SK Silberstein SD Lipton RB et al June 2010 OnabotulinumtoxinA for treatment of chronic migraine pooled results from the double blind randomized placebo controlled phases of the PREEMPT clinical program Headache 50 6 921 936 doi 10 1111 j 1526 4610 2010 01678 x PMID 20487038 S2CID 9621285 Ashkenazi A March 2010 Botulinum toxin type a for chronic migraine Current Neurology and Neuroscience Reports 10 2 140 146 doi 10 1007 s11910 010 0087 5 PMID 20425239 S2CID 32191932 Magid M Keeling BH Reichenberg JS November 2015 Neurotoxins Expanding Uses of Neuromodulators in Medicine Major Depressive Disorder Plastic and Reconstructive Surgery 136 5 Suppl 111S 119S doi 10 1097 PRS 0000000000001733 PMID 26441090 S2CID 24196194 a b Onabotulinum toxin A Allergan AdisInsight Archived from the original on 30 October 2017 Retrieved 5 September 2017 Finzi E Rosenthal NE May 2014 Treatment of depression with onabotulinumtoxinA a randomized double blind placebo controlled trial Journal of Psychiatric Research 52 1 6 doi 10 1016 j jpsychires 2013 11 006 PMID 24345483 Clinical trial number NCT01917006 for An Exploratory Study of the Safety and Efficacy of Botox for the Treatment of Premature Ejaculation at ClinicalTrials govFurther reading editCarruthers JD Fagien S Joseph JH Humphrey SD Biesman BS Gallagher CJ et al January 2020 DaxibotulinumtoxinA for Injection for the Treatment of Glabellar Lines Results from Each of Two Multicenter Randomized Double Blind Placebo Controlled Phase 3 Studies SAKURA 1 and SAKURA 2 Plastic and Reconstructive Surgery 145 1 45 58 doi 10 1097 PRS 0000000000006327 PMC 6940025 PMID 31609882 Solish N Carruthers J Kaufman J Rubio RG Gross TM Gallagher CJ December 2021 Overview of DaxibotulinumtoxinA for Injection A Novel Formulation of Botulinum Toxin Type A Drugs 81 18 2091 2101 doi 10 1007 s40265 021 01631 w PMC 8648634 PMID 34787840 External links editOverview of all the structural information available in the PDB for UniProt P0DPI1 Botulinum neurotoxin type A at the PDBe KB Overview of all the structural information available in the PDB for UniProt P10844 Botulinum neurotoxin type B at the PDBe KB Overview of all the structural information available in the PDB for UniProt A0A0X1KH89 Bontoxilysin A at the PDBe KB AbobotulinumtoxinA Injection MedlinePlus IncobotulinumtoxinA Injection MedlinePlus OnabotulinumtoxinA Injection MedlinePlus PrabotulinumtoxinA xvfs Injection MedlinePlus RimabotulinumtoxinB Injection MedlinePlus Portals nbsp Biology nbsp Medicine Retrieved from https en wikipedia org w index php title Botulinum toxin amp oldid 1222817948, wikipedia, wiki, book, books, library,

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