“Botulinum toxin”的意思、由来-开放百科全书

Botulinum toxin (BTX) is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species.^[1] It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction and thus causes flaccid paralysis.^[2] Infection with the bacterium causes the disease botulism. The toxin is also used commercially in medicine, cosmetics and research.

Botulinum is the most acutely lethal toxin known, with an estimated human median lethal dose (LD₅₀) of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled.^[3] {{clarify |date=January 2019 |reason= Doesn't specify type as in source and why on earth is the oral lethal dose from the very same source omitted? Seems to me to be the by far most important one outside biological warfare.}}

There are eight types of botulinum toxin, named type A–H. Types A and B are capable of causing disease in humans, and are also used commercially and medically.^[4] Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals.^[5] Type H is considered the deadliest substance in the world{{snd}} an injection of only 2 ng can cause death to an adult.^[6] Botulinum toxin types A and B are used in medicine to treat various muscle spasms and diseases characterized by overactive muscle. Commercial forms are marketed under the brand names Botox and Dysport, among others.^[7]^[8]

Medical uses

Muscle spasticity

Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck,^[9] eyelid,^[10] vagina,^[11] limbs, jaw, and vocal cords.^[12] Similarly, botulinum toxin is used to relax clenching of muscles, including those of the oesophagus,^[13] jaw,^[14] lower urinary tract and bladder,^[15] or clenching of the anus which can exacerbate anal fissure.^[16] It may also be used for improper eye alignment.^[17] Botulinum toxin appears to be effective for refractory overactive bladder.^[18]

Other muscle disorders

Strabismus is caused by imbalances in the actions of muscles that rotate the eyes, and 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 it might seem that injection would then need to be repeated. However, muscles adapt to the lengths at which they are chronically held,^[19] so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect. If there is good binocular vision, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment.

In January 2014, botulinum toxin was approved by UK's Medicines and Healthcare Products Regulatory Agency (MHRA) for treatment of restricted ankle motion due to lower limb spasticity associated with stroke in adults.^[20]

On July 29, 2016, Food and Drug Administration (FDA), of the United States of America approved abobotulinumtoxinA for injection for the treatment of lower limb spasticity in pediatric patients two years of age and older.^[20] AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity. In the United States of America, the FDA approves the text of the labels of prescription medicines. The FDA approves which medical conditions the drug manufacturer may sell the drug for. However, those approved by the FDA to prescribe these drugs may freely prescribe them for any condition they wish, called off-label use. Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.^[22]

Excessive sweating

Khalaf Bushara and David Park were the first to demonstrate a nonmuscular use of BTX-A while treating patients with hemifacial spasm in England in 1993, showing that botulinum toxin injections inhibit sweating, and so are useful in treating hyperhidrosis (excessive sweating).^[21] BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating of unknown cause), which cannot be managed by topical agents.^[12]^[22]

Migraine

In 2010, the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache.^[23]

Cosmetics

In cosmetic applications, botulinum toxin is considered safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face.^[24] Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin.^[24] Smoothing of wrinkles is usually visible three days after treatment and is maximally visible two weeks following injection.^[24] The treated muscles gradually regain function, and generally return to their former appearance three to four months after treatment.^[24] Muscles can be treated repeatedly to maintain the smoothed appearance.^[24]

Other

Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating,^[22] neuropathic pain,^[25] and some allergy symptoms.^[12] In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain.^[26]

Side effects

While botulinum toxin is generally considered safe in a clinical setting, there can be serious side effects from its use. Most commonly, botulinum toxin can be injected into the wrong muscle group or spread from the injection site, causing paralysis of unintended muscles.

Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis however, and can also include headaches, flu-like symptoms, and allergic reactions.^[36] Just as cosmetic treatments only last a number of months, paralysis side-effects can have the same durations.{{citation needed|date=February 2015}} At least in some cases, these effects are reported to dissipate in the weeks after treatment.{{citation needed|date=February 2015}} 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.{{citation needed|date=February 2015}} 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.^[36]

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.^[36] Additionally, side effects which are common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.^[27]

In response to the occurrence of these side effects, in 2008 the U.S. Food and Drug Administration notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, they warned that 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.^[28] 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.^[41] Additionally, the FDA announced name changes to several botulinum toxin products, meant to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were renamed onabotulinumtoxinA, Myobloc was renamed rimabotulinumtoxinB, and Dysport name renamed abobotulinumtoxinA.^[29] In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each.^[43] A similar warning was issued by Health Canada in 2009, warning that botulinum toxin products can spread to other parts of the body.^[30]

Role in disease

Botulinum toxin produced by Clostridium botulinum is the cause of botulism.^[10] 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.^[31] 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.^[1]

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 which remains in the gut, enemas or induced vomiting may be used.^[32] For wound infections, infected material may be removed surgically.^[32] Botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. In severe cases, mechanical respiration may be used to support patients suffering from respiratory failure.^[32] The nerve damage heals over time, generally over weeks to months.^[5] With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced.^[32]

Two preparations of botulinum antitoxins are available for treatment of botulism. Trivalent (A,B,E) botulinum antitoxin is derived from equine sources using whole antibodies. The second antitoxin is Heptavalent (A,B,C,D,E,F,G) botulinum antitoxin, which is derived from equine antibodies which have been altered to make them less immunogenic. This antitoxin is effective against all known strains of botulism.

Mechanism of action

Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to nerves which use the neurotransmitter acetylcholine. Once bound to the nerve terminal, the neuron takes up the toxin into a vesicle by receptor-mediated endocytosis.^[34] As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin which triggers it to push across the vesicle membrane and into the cell cytoplasm.^[1] Once inside the cytoplasm, the toxin cleaves SNARE proteins, meaning that the acetylcholine vesicles can’t bind to the intracellular cell membrane,^[34] preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to paralysis.^[1]

The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases.^[12] 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.^[59] 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.^[1]^[59] The light chain is a 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 is unable to mediate fusion of vesicles with the host cell membrane, thus preventing the release of the neurotransmitter acetylcholine from axon endings.^[1] This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.^[1]

The seven toxin types (A-G) have different tertiary structures and sequence differences.^[59]^[35] While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members.^[33] 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).^[59]

History

In 1820, Justinus Kerner, a small-town German medical officer and romantic poet, gave the first complete description of clinical botulism based on extensive clinical observations of so-called “sausage poisoning”.^[36] Following experiments on animals and on himself, he concluded that the toxin acts by interrupting signal transmission in the somatic and autonomic motor systems, without affecting sensory signals or mental functions. He observed that the toxin develops under anaerobic conditions, and can be lethal in minute doses.^[37] His prescience in suggesting that the toxin might be used therapeutically earned him recognition as the pioneer of modern botulinum toxin therapy.^[38]

In 1895 (seventy-five years later), Émile van Ermengem, professor of bacteriology and a student of Robert Koch, correctly described Clostridium botulinum as the bacterial source of the toxin. Thirty-four attendees at a funeral were poisoned by eating partially salted ham, an extract of which was found to cause botulism-like paralysis in laboratory animals. Van Ermengem isolated and grew the bacterium, and described its toxin,^[39] which was later purified by P Tessmer Snipe and Hermann Sommer.^[40]

Food canning

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 prodigiously productive 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.

World War II

With the outbreak of World War II, weaponization of botulinum toxin was investigated at Fort Detrick in Maryland. Carl Lamanna and James Duff^[41] 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 generously provided it to the academic community.

The mechanism of botulinum toxin action – blocking the release from nerve endings of the neurotransmitter acetylcholine – was elucidated in the mid-1900s,^[42] and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.

Strabismus

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.^[43] 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 Drachman’s work with chicks at Johns Hopkins,^[44] Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles.^[45] 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,^[46] 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, patients who had come to rely on periodic injections became desperate. For 4 months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.^[79]

Based on data from thousands of patients collected by 240 investigators, Allergan received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and blepharospasm, using the trademark Botox.^[80] This was under the 1983 US Orphan Drug Act.^[47]

Cosmetics

Richard Clark, a plastic surgeon from Sacramento (CA), was the first to document a cosmetic use for botulinum toxin.^[82] He treated forehead asymmetry caused by left sided forehead nerve paralysis that occurred during a cosmetic facelift. Since the injured nerve could possibly regenerate by 24 months, a two-year waiting period was necessary before definitive surgical treatment could be done. Clark realized that botulinum toxin, which had been previously used only for cross eyed babies and facial tics, could also be injected to smooth the wrinkles of the right forehead to match her paralyzed left. He received FDA approval for this cosmetic application of the toxin and successfully treated the person and published the case study in 1989.^[82]

Marrying ophthalmology to dermatology, Jean and Alistair Carruthers observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines (“frown lines” between the eyebrows), thereby initiating the highly-popular cosmetic use of the toxin.^[48] Brin, and a group at Columbia University under Monte Keen made similar reports.^[85] In 2002, following clinical trials, the FDA approved Botox Cosmetic, botulinum A toxin to temporarily improve the appearance of moderate-to-severe glabellar lines.^[86] The FDA approved a fully in vitro assay for use in the stability and potency testing of Botox in response to increasing public concern that LD50 testing was required for each batch sold in the market.^[87]^[88]

Chronic pain

Society and culture

Economics

As of 2013, botulinum toxin injections are the most common cosmetic operation, with 6.3 million procedures in the United States, according to the American Society of Plastic Surgeons. Qualifications for Botox injectors vary by county, state and country. Botox cosmetic providers include dermatologists, plastic surgeons, aesthetic spa physicians, dentists, nurse practitioners, nurses and physician assistants.

The global market for botulinum toxin products, driven by their cosmetic applications, is forecast to reach $2.9 billion by 2018. The facial aesthetics market, of which they are a component, is forecast to reach $4.7 billion ($2 billion in the U.S.) in the same timeframe.^[52]

Bioterrorism

Botulinum toxin has been recognized as a potential agent for use in bioterrorism.^[53] It can be absorbed through the eyes, mucous membranes, respiratory tract, or non-intact skin.^[54]

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 and can be instantaneous.{{citation needed|date=February 2015}} Evidence suggests that nerve exposure (simulated by injection of atropine and pralidoxime) will increase mortality by enhancing botulinum toxin's mechanism of toxicity.{{Citation needed|date=February 2010}}

With regard to detection, current 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.{{citation needed|date=February 2015}} 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 patients.^[55]

The Japanese doomsday cult Aum Shinrikyo produced botulinum toxin and spread it as an aerosol in downtown Tokyo during the 1990s, but the attacks caused no fatalities.^[56]

During the early 1980s, the 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.^[57]

Brand names

Botulinum toxin A is marketed under the brand names Botox and Xeomin. Botulinum toxin B is marketed under the brand name Myobloc.

In the United States, botulinum toxin products are manufactured by a variety of companies, for both therapeutic and cosmetic use. A U.S. 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.^[58] 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 U.S. and other countries.^[59]

Besides the three primary U.S. manufacturers, there are numerous other botulinum toxin producers. Xeomin, manufactured in Germany by Merz, is also available for both therapeutic and cosmetic use in the U.S.^[60] Lanzhou Institute of Biological Products in China manufactures a BTX-A product; as of 2014 it was the only BTX-A approved in China.^[60] BTX-A is also sold as Lantox and Prosigne on the global market.^[61] Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea in 2009;^[62]

Toxin production

Botulism toxins are produced by bacteria of the genus Clostridium, namely Clostridium botulinum, C. butyricum, C. baratii and C. argentinense,^[63] which are widely distributed, including in soil and dust. As well, the bacteria can be found inside homes on floors, carpet, and countertops even after cleaning.{{citation needed|date=February 2015}} Some food products such as honey can contain amounts of the bacteria.{{citation needed|date=February 2015}}

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.{{citation needed|date=February 2015}} Critically, it is ingestion of toxin rather than spores or vegetative bacteria that causes botulism.{{citation needed|date=February 2015}} Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, and so is preventable.{{citation needed|date=February 2015}} Infant botulism cases arise chiefly as a result of environmental exposure and are therefore more difficult to prevent.{{citation needed|date=February 2015}} Infant botulism arising from consumption of honey can be prevented by eliminating honey from diets of children less than 12 months old.^[64]

Organism and toxin susceptibilities

Proper refrigeration at temperatures below 3 °C (38 °F) retards the growth of Clostridium botulinum. The organism is also susceptible to high salt, high oxygen, and low pH levels.^[5] The toxin itself is rapidly destroyed by heat, such as in thorough cooking.^[65] The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.^[66]

The botulinum toxin is denatured and thus deactivated at temperatures greater than {{convert|80|C|F}}.^[67] 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.^[68]^[69]

Research

Blepharospasm and strabismus

University-based ophthalmologists in the USA 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.^[70] Side effects in treatment of this condition were deemed to be rare, mild and treatable.^[71] The beneficial effects of the injection lasted only 4–6 months. Thus, blepharospasm patients required re-injection two or three times a year.

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. Patients became desperate, as supplies of Botox were gradually consumed, forcing him to abandon patients 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.^[72]

In December 1989, Botox was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.^[73]

Botox has not been approved for any pediatric use.^[59] It has, however, been used off-label by physicians for several conditions. including spastic conditions in pediatric patients with cerebral palsy, a therapeutic course that has resulted in patient deaths.^[59] In the case of treatment of infantile esotropia in patients younger than 12 years of age, several studies have yielded differing results.^[74]{{better source|date=February 2015}}

Cosmetic

The cosmetic effect of BTX-A on wrinkles was originally documented by a plastic surgeon from Sacramento, California, Richard Clark, and published in the journal Plastic and Reconstructive Surgery in 1989.^[75] Canadian husband and wife ophthalmologist and dermatologist physicians, JD and JA Carruthers, were the first to publish a study on BTX-A for the treatment of glabellar frown lines in 1992.^[48] Similar effects had reportedly been observed by a number of independent groups (Brin, and the Columbia University group under Monte Keen.^[76]) After formal trials, on April 12, 2002, 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).^[77] Subsequently, cosmetic use of botulinum toxin type A has become widespread.^[78] The results of Botox Cosmetic can last up to four months and may vary with each patient.^[79] The US Food and Drug Administration 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.^[80]^[81]

BTX-A has also been used in the treatment of gummy smiles,^[82]^[83] 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.^[84] 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).^[85]^[86]

Upper motor neuron syndrome

BTX-A is now a common treatment for muscles affected by the upper motor neuron syndrome (UMNS), such as cerebral palsy, 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.^[87] 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.

Sweating

Cervical dystonia

BTX-A is commonly used to treat cervical dystonia, but it can become ineffective after a time. Botulinum toxin type B (BTX-B) received FDA approval for treatment of cervical dystonia on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.^[60]

Chronic migraine

Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic migraines on October 15, 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 migraine sufferers undergoing the Botox treatment.^[88]^[89]

Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for patients with chronic migraine^[90] who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), "detoxification" of patients with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.^[91]

Depression

Premature ejaculation

See also

References

1. ^¹²³⁴⁵⁶{{cite journal | vauthors = Montecucco C, Molgó J | title = Botulinal neurotoxins: revival of an old killer | journal = Current Opinion in Pharmacology | volume = 5 | issue = 3 | pages = 274–79 | date = June 2005 | pmid = 15907915 | doi = 10.1016/j.coph.2004.12.006 }}
2. ^{{cite journal |last1=Figgitt |first1=David P. |last2=Noble |first2=Stuart |title=Botulinum Toxin B |journal=Drugs |date=2002 |volume=62 |issue=4 |pages=705–722 |doi=10.2165/00003495-200262040-00011|pmid=11893235 }}
3. ^{{cite journal | vauthors = Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, Lillibridge S, Osterholm MT, O'Toole T, Parker G, Perl TM, Russell PK, Swerdlow DL, Tonat K | title = Botulinum toxin as a biological weapon: medical and public health management | journal = JAMA | volume = 285 | issue = 8 | pages = 1059–70 | date = February 2001 | pmid = 11209178 | doi = 10.1001/jama.285.8.1059 }}
4. ^{{cite web|author1=American Society of Health-System Pharmacists|title=Botulinum Toxin Type A|url=https://www.drugs.com/monograph/botulinum-toxin-type-a.html|website=drugs.com|access-date=4 March 2015|date=October 27, 2011}}
5. ^¹²{{cite web|url=http://www.who.int/mediacentre/factsheets/fs270/en/ |title=Fact Sheet: Botulism |publisher=World Health Organization |access-date=4 October 2016}}
6. ^{{cite web | first = Chris | last = Weller | name-list-format = vanc | title = New Botulinum Toxin Deemed Deadliest Substance Ever: Sniffing 13-Billionths of a Gram Can Kill | date = 15 October 2013 | work = Medical Daily | url = http://www.medicaldaily.com/new-botulinum-toxin-deemed-deadliest-substance-ever-sniffing-13-billionths-gram-can-kill-259889}}
7. ^{{cite web |last1=Egan |first1=Matt | name-list-format = vanc |title=Botox maker bought for $66 billion in biggest deal of 2014 |url=http://money.cnn.com/2014/11/17/investing/allergan-actavis-merger-boom/ |website=cnn.com |date=17 November 2014}}
8. ^{{cite web|title=Actavis plc is now Allergan plc |url=http://www.actavis.com/NEWS/News/Thomson-Reuters/Actavis-plc-is-now-Allergan-plc|date=15 June 2015|work=Allergan|access-date=16 June 2015}}
9. ^{{cite web | url = http://www.mayoclinic.org/diseases-conditions/spasmodic-torticollis/basics/definition/con-20028215 | title=Cervical dystonia |publisher=Mayo Clinic |date=2014-01-28 |access-date=2015-10-14}}
10. ^¹{{cite journal | vauthors = Shukla HD, Sharma SK | title = Clostridium botulinum: a bug with beauty and weapon | journal = Critical Reviews in Microbiology | volume = 31 | issue = 1 | pages = 11–18 | year = 2005 | pmid = 15839401 | doi = 10.1080/10408410590912952 }}
11. ^{{cite journal | vauthors = Pacik PT | title = Botox treatment for vaginismus | journal = Plastic and Reconstructive Surgery | volume = 124 | issue = 6 | pages = 455e–56e | date = December 2009 | pmid = 19952618 | doi = 10.1097/PRS.0b013e3181bf7f11 }}
12. ^¹²³⁴{{cite journal | vauthors = Felber ES | title = Botulinum toxin in primary care medicine | journal = The Journal of the American Osteopathic Association | volume = 106 | issue = 10 | pages = 609–14 | date = October 2006 | pmid = 17122031 | url = http://jaoa.org/article.aspx?articleid=2093199 }}
13. ^{{cite journal | vauthors = Stavropoulos SN, Friedel D, Modayil R, Iqbal S, Grendell JH | title = Endoscopic approaches to treatment of achalasia | journal = Therapeutic Advances in Gastroenterology | volume = 6 | issue = 2 | pages = 115–35 | date = March 2013 | pmid = 23503707 | pmc = 3589133 | doi = 10.1177/1756283X12468039 }}
14. ^{{cite journal | vauthors = Long H, Liao Z, Wang Y, Liao L, Lai W | title = Efficacy of botulinum toxins on bruxism: an evidence-based review | journal = International Dental Journal | volume = 62 | issue = 1 | pages = 1–5 | date = February 2012 | pmid = 22251031 | doi = 10.1111/j.1875-595X.2011.00085.x }}
15. ^{{cite journal | vauthors = Mangera A, Andersson KE, Apostolidis A, Chapple C, Dasgupta P, Giannantoni A, Gravas S, Madersbacher S | title = Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA) | journal = European Urology | volume = 60 | issue = 4 | pages = 784–95 | date = October 2011 | pmid = 21782318 | doi = 10.1016/j.eururo.2011.07.001 }}
16. ^{{cite journal | vauthors = Trzciński R, Dziki A, Tchórzewski M | title = Injections of botulinum A toxin for the treatment of anal fissures | journal = The European Journal of Surgery = Acta Chirurgica | volume = 168 | issue = 12 | pages = 720–23 | year = 2002 | pmid = 15362583 | doi = 10.1080/11024150201680030 }}
17. ^{{cite journal | vauthors = Kowal L, Wong E, Yahalom C | title = Botulinum toxin in the treatment of strabismus. A review of its use and effects | journal = Disability and Rehabilitation | volume = 29 | issue = 23 | pages = 1823–31 | date = December 2007 | pmid = 18033607 | doi = 10.1080/09638280701568189 }}
18. ^{{cite journal | vauthors = Duthie JB, Vincent M, Herbison GP, Wilson DI, Wilson D | title = Botulinum toxin injections for adults with overactive bladder syndrome | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD005493 | date = December 2011 | pmid = 22161392 | doi = 10.1002/14651858.CD005493.pub3 }}
19. ^{{cite journal | vauthors = Scott AB | title = Change of eye muscle sarcomeres according to eye position | journal = Journal of Pediatric Ophthalmology and Strabismus | volume = 31 | issue = 2 | pages = 85–88 | year = 1994 | pmid = 8014792 }}
20. ^{{Cite web|url=http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274|title=FDA Approved Drug Products – Dysport|last=|first=|date=|website=www.accessdata.fda.gov|publisher=U.S. Food and Drug Administration|access-date=2016-11-07}}
21. ^¹{{cite journal | vauthors = Bushara KO, Park DM | title = Botulinum toxin and sweating | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 57 | issue = 11 | pages = 1437–38 | date = November 1994 | pmid = 7964832 | pmc = 1073208 | doi = 10.1136/jnnp.57.11.1437 }}
22. ^¹²{{cite journal | vauthors = Eisenach JH, Atkinson JL, Fealey RD | title = Hyperhidrosis: evolving therapies for a well-established phenomenon | journal = Mayo Clinic Proceedings | volume = 80 | issue = 5 | pages = 657–66 | date = May 2005 | pmid = 15887434 | doi = 10.4065/80.5.657 }}
23. ^{{cite news|title=FDA Approves Botox to Treat Chronic Migraines|url=http://www.webmd.com/migraines-headaches/news/20101018/fda-approves-botox-to-treat-chronic-migraines#1|access-date=12 May 2017|work=WebMD}}
24. ^¹²³⁴{{cite journal | vauthors = Small R | title = Botulinum toxin injection for facial wrinkles | journal = American Family Physician | volume = 90 | issue = 3 | pages = 168–75 | date = August 2014 | pmid = 25077722 }}
25. ^{{cite journal | vauthors = Mittal SO, Safarpour D, Jabbari B | title = Botulinum Toxin Treatment of Neuropathic Pain | journal = Seminars in Neurology | volume = 36 | issue = 1 | pages = 73–83 | date = February 2016 | pmid = 26866499 | doi = 10.1055/s-0036-1571953 }}
26. ^{{cite journal | vauthors = Charles PD | title = Botulinum neurotoxin serotype A: a clinical update on non-cosmetic uses | journal = American Journal of Health-System Pharmacy | volume = 61 | issue = 22 Suppl 6 | pages = S11–23 | date = November 2004 | pmid = 15598005 | doi = 10.1093/ajhp/61.suppl_6.S11 }}
27. ^¹²³{{cite journal | vauthors = Coté TR, Mohan AK, Polder JA, Walton MK, Braun MM | title = Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases | journal = Journal of the American Academy of Dermatology | volume = 53 | issue = 3 | pages = 407–15 | date = September 2005 | pmid = 16112345 | doi = 10.1016/j.jaad.2005.06.011 }}
28. ^{{cite web|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116857.htm |title=FDA Notifies Public of Adverse Reactions Linked to Botox Use |website=Fda.gov |access-date=May 6, 2012 |date=8 February 2008}}
29. ^¹{{cite web|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm175013.htm |title=FDA Gives Update on Botulinum Toxin Safety Warnings; Established Names of Drugs Changed |website=FDA Press Announcement |date=August 3, 2009 |access-date=21 September 2016}}
30. ^{{Cite news|url=http://www.cbc.ca/consumer/story/2009/01/13/botox.html |work=CBC News |title=Botox chemical may spread, Health Canada confirms |date=January 13, 2009 |deadurl=yes | archiveurl = https://web.archive.org/web/20090221144310/http://www.cbc.ca/consumer/story/2009/01/13/botox.html |archivedate=21 February 2009 |df= }}
31. ^{{cite web|url=https://www.cdc.gov/botulism/definition.html |title=Kinds of Botulism |publisher=Centers for Disease Control and Prevention |access-date=4 October 2016}}
32. ^¹²³{{cite web|url=https://www.cdc.gov/botulism/testing-treatment.html |access-date=5 October 2016 |title=Botulism – Diagnosis and Treatment |publisher=Centers for Disease Control and Prevention}}
33. ^¹{{cite journal | vauthors = Barr JR, Moura H, Boyer AE, Woolfitt AR, Kalb SR, Pavlopoulos A, McWilliams LG, Schmidt JG, Martinez RA, Ashley DL | title = Botulinum neurotoxin detection and differentiation by mass spectrometry | journal = Emerging Infectious Diseases | volume = 11 | issue = 10 | pages = 1578–83 | date = October 2005 | pmid = 16318699 | pmc = 3366733 | doi = 10.3201/eid1110.041279 }}
34. ^¹{{cite journal |last1=Dressler |first1=D |last2=Saberi |first2=FA |last3=Barbosa |first3=ER |title=Botulinum toxin: mechanisms of action. |journal=Arquivos de Neuro-Psiquiatria |date=March 2005 |volume=63 |issue=1 |pages=180–5 |doi=10.1159/000083259 |pmid=15830090}}
35. ^{{cite book|last1=Hill|first1=Karen K|last2=Smith|first2=Theresa J|editor1-last=Rummel|editor1-first=Andreas|editor2-last=Binz|editor2-first=Thomas | name-list-format = vanc |title=Botulinum neurotoxins|journal=Current Topics in Microbiology and Immunology|volume=364|pages=1–20|date=2013|publisher=Springer|location=Heidelberg|isbn=978-3-642-33569-3|doi=10.1007/978-3-642-33570-9_1|pmid=23239346|chapter=Genetic Diversity Within Clostridium botulinum Serotypes, Botulinum Neurotoxin Gene Clusters and Toxin Subtypes}}
36. ^{{cite book | vauthors = Kerner J | year = 1820 | title = Neue Beobachtungen über die in Württemberg so häufig vorfallenden tödlichen Vergiftungen durch den Genuss geräucherter Würste. | location = Tübingen | publisher = Osiander}}
37. ^{{cite book | vauthors = Kerner J | year = 1822 | title = Das Fettgift oder die Fettsäure und ihre Wirkungen auf den thierischen Organismus, ein Beytrag zur Untersuchung des in verdorbenen Würsten giftig wirkenden Stoffes. | location = Stuttgart, Tübingen | publisher = Cotta | pages = 681–87 | oclc = 863571562 }}
38. ^{{cite journal | vauthors = Erbguth FJ, Naumann M | title = Historical aspects of botulinum toxin: Justinus Kerner (1786–1862) and the "sausage poison" | journal = Neurology | volume = 53 | issue = 8 | pages = 1850–53 | date = November 1999 | pmid = 10563638 | doi = 10.1212/wnl.53.8.1850 }}
39. ^{{cite journal | vauthors = van Ermengem E | title = Classics in infectious diseases. A new anaerobic bacillus and its relation to botulism. E. van Ermengem. Originally published as "Ueber einen neuen anaëroben Bacillus und seine Beziehungen zum Botulismus" in Zeitschrift für Hygiene und Infektionskrankheiten 26: 1–56, 1897 | language = German | journal = Reviews of Infectious Diseases | volume = 1 | issue = 4 | pages = 701–19 | date = 1979 | pmid = 399378 | authorlink = Émile van Ermengem }} Original {{doi|10.1007/BF02220526}}
40. ^{{Cite journal | last1 = Snipe | first1 = P. Tessmer | last2 = Sommer | first2 = H. | name-list-format = vanc | date = August 1928 | title = Studies on Botulinus Toxin: 3. Acid Precipitation of Botulinus Toxin|journal = The Journal of Infectious Diseases|volume = 43|issue = 2|pages = 152–60|jstor = 30083772|doi = 10.1093/infdis/43.2.152}}
41. ^{{cite journal | vauthors = Lamanna C, McElroy OE, Eklund HW | title = The purification and crystallization of Clostridium botulinum type A toxin | journal = Science | volume = 103 | issue = 2681 | pages = 613–14 | date = May 1946 | pmid = 21026141 | doi = 10.1126/science.103.2681.613 | bibcode = 1946Sci...103..613L }}
42. ^{{cite journal | vauthors = Burgen AS, Dickens F, Zatman LJ | title = The action of botulinum toxin on the neuro-muscular junction | journal = The Journal of Physiology | volume = 109 | issue = 1–2 | pages = 10–24 | date = August 1949 | pmid = 15394302 | pmc = 1392572 | doi = 10.1113/jphysiol.1949.sp004364 }}
43. ^{{cite journal | vauthors = Magoon E, Cruciger M, Scott AB, Jampolsky A | title = Diagnostic injection of Xylocaine into extraocular muscles | journal = Ophthalmology | volume = 89 | issue = 5 | pages = 489–91 | date = May 1982 | pmid = 7099568 | doi = 10.1016/s0161-6420(82)34764-8 }}
44. ^{{cite journal | vauthors = Drachman DB | title = Atrophy of skeletal muscle in chick embryos treated with botulinum toxin | journal = Science | volume = 145 | issue = 3633 | pages = 719–21 | date = August 1964 | pmid = 14163805 | doi = 10.1126/science.145.3633.719 | bibcode = 1964Sci...145..719D }}
45. ^{{cite journal | vauthors = Scott AB, Rosenbaum A, Collins CC | title = Pharmacologic weakening of extraocular muscles | journal = Investigative Ophthalmology | volume = 12 | issue = 12 | pages = 924–27 | date = December 1973 | pmid = 4203467 }}
46. ^{{cite journal | vauthors = Scott AB | title = Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery | journal = Ophthalmology | volume = 87 | issue = 10 | pages = 1044–49 | date = October 1980 | pmid = 7243198 | doi = 10.1016/s0161-6420(80)35127-0 }}
47. ^{{cite journal | vauthors = Wellman-Labadie O, Zhou Y | title = The US Orphan Drug Act: rare disease research stimulator or commercial opportunity? | journal = Health Policy | volume = 95 | issue = 2–3 | pages = 216–28 | date = May 2010 | pmid = 20036435 | doi = 10.1016/j.healthpol.2009.12.001 }}
48. ^¹{{cite journal | vauthors = Carruthers JD, Carruthers JA | title = Treatment of glabellar frown lines with C. botulinum-A exotoxin | journal = The Journal of Dermatologic Surgery and Oncology | volume = 18 | issue = 1 | pages = 17–21 | date = January 1992 | pmid = 1740562 | doi = 10.1111/j.1524-4725.1992.tb03295.x }}
49. ^{{cite journal | vauthors = Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM | title = Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study | journal = Otolaryngology–Head and Neck Surgery | volume = 123 | issue = 6 | pages = 669–76 | date = December 2000 | pmid = 11112955 | doi = 10.1067/mhn.2000.110960 }}
50. ^{{cite journal | vauthors = Jackson JL, Kuriyama A, Hayashino Y | title = Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis | journal = JAMA | volume = 307 | issue = 16 | pages = 1736–45 | date = April 2012 | pmid = 22535858 | doi = 10.1001/jama.2012.505 }}
51. ^{{cite journal | vauthors = Ramachandran R, Yaksh TL | title = Therapeutic use of botulinum toxin in migraine: mechanisms of action | journal = British Journal of Pharmacology | volume = 171 | issue = 18 | pages = 4177–92 | date = September 2014 | pmid = 24819339 | pmc = 4241086 | doi = 10.1111/bph.12763 }}
52. ^{{cite web |url= http://www.companiesandmarkets.com/News/Healthcare-and-Medical/The-global-botox-market-forecast-to-reach-2-9-billion-by-2018/NI2991 |title= The global botox market forecast to reach $2.9 billion by 2018 |date= May 10, 2012 |access-date= October 5, 2012 |first1= Paul |last1= Chapman |archive-url= https://web.archive.org/web/20120806230249/http://www.companiesandmarkets.com/News/Healthcare-and-Medical/The-global-botox-market-forecast-to-reach-2-9-billion-by-2018/NI2991# |archive-date= 2012-08-06 |dead-url= yes |df= }}
53. ^{{cite web | last1 = Koirala | first1 = Janak | last2 =Basnet | first2 = Sangita | name-list-format = vanc | date = July 14, 2004 | title = Botulism, Botulinum Toxin, and Bioterrorism: Review and Update | work = Medscape | publisher = Cliggott Publishing | url = http://www.medscape.com/viewarticle/482812 | access-date = July 14, 2010}}
54. ^Clostridium botulinum – Public Health Agency of Canada. Phac-aspc.gc.ca (April 19, 2011). Retrieved on May 6, 2012.
55. ^{{cite book | author = Baselt RC | title = Disposition of toxic drugs and chemicals in man | year = 2014 | publisher = Biomedical Publications | location = Seal Beach, Ca. | isbn = 978-0-9626523-9-4 | pages = 260–61 }}
56. ^http://www.emsworld.com/article/10324792/botulinum-toxin-a-bioterrorism-weapon
57. ^{{cite book|last1=McAdams|first1=David|last2=Kornblet|first2=Sarah|editor1-last=Pilch|editor1-first=Richard F.|editor2-last=Zilinskas|editor2-first=Raymond A. | name-list-format = vanc | title = Encyclopedia of Bioterrorism Defense|date=15 July 2011|publisher=Wiley-Liss|isbn=978-0-471-68678-1|chapter=Baader-Meinhof Group (OR Baader-Meinhof Gang|doi=10.1002/0471686786.ebd0012.pub2}}
58. ^{{cite web |url=http://www.allergan.com/assets/pdf/2011AnnualReport.pdf |title=2011 Allergan Annual Report |publisher=Allergan |access-date=May 3, 2012}} See PDF p. 7.
59. ^¹²³{{cite web|title=Information for Healthcare Professionals: OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc)|url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm|website=fda.gov|publisher=Food and Drug Administration|access-date=1 September 2015}}
60. ^¹²{{cite journal | vauthors = Walker TJ, Dayan SH | title = Comparison and overview of currently available neurotoxins | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 7 | issue = 2 | pages = 31–39 | date = February 2014 | pmid = 24587850 | pmc = 3935649 }}
61. ^{{cite web | title = Botulinum Toxin Type A | publisher = Hugh Source (International) Limited | url = http://www.btxa.com/ | access-date = July 14, 2010}}
62. ^{{cite news | last = Petrou | first = Ilya | name-list-format = vanc | date = Spring 2009 | title = Medy-Tox Introduces Neuronox to the Botulinum Toxin Arena | newspaper = The European Aesthetic Guide | url = http://www.miinews.com/pdf/MedyTox_Ed_EAGsp09v2_022809.pdf | format = PDF | access-date = 2009-12-09 | archive-url = https://web.archive.org/web/20130320010107/http://www.miinews.com/pdf/MedyTox_Ed_EAGsp09v2_022809.pdf# | archive-date = 2013-03-20 | dead-url = yes | df = }}
63. ^{{cite journal | vauthors = Schantz EJ, Johnson EA | title = Properties and use of botulinum toxin and other microbial neurotoxins in medicine | journal = Microbiological Reviews | volume = 56 | issue = 1 | pages = 80–99 | date = March 1992 | pmid = 1579114 | pmc = 372855 }}
64. ^[https://www.cdc.gov/nczved/divisions/dfbmd/diseases/botulism/ Botulism, General Information – NCZVED]. Cdc.gov. Retrieved on May 6, 2012.
65. ^{{cite journal | vauthors = Licciardello JJ, Nickerson JT, Ribich CA, Goldblith SA | title = Thermal inactivation of type E botulinum toxin | journal = Applied Microbiology | volume = 15 | issue = 2 | pages = 249–56 | date = March 1967 | pmid = 5339838 | pmc = 546888 }}
66. ^{{cite journal | vauthors = Setlow P | title = I will survive: DNA protection in bacterial spores | journal = Trends in Microbiology | volume = 15 | issue = 4 | pages = 172–80 | date = April 2007 | pmid = 17336071 | doi = 10.1016/j.tim.2007.02.004 }}
67. ^{{Cite book | last1 = Jay | first1 = James M. | last2 = Loessner | first2 = Martin J. | last3 = Golden | first3 = David A. | name-list-format = vanc | year = 2005 | title = Modern Food Microbiology: Seventh Edition | publisher = Springer | location = New York | chapter = Chapter 24: Food Poisoning Caused by Gram-Positive Sporeforming Bacteria | page = 581 | isbn = 978-0-387-23180-8 }}
68. ^¹²³⁴{{cite journal | vauthors = Li B, Peet NP, Butler MM, Burnett JC, Moir DT, Bowlin TL | title = Small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication | journal = Molecules | volume = 16 | issue = 1 | pages = 202–20 | date = December 2010 | pmid = 21193845 | pmc = 6259422 | doi = 10.3390/molecules16010202 }}
69. ^{{cite journal | vauthors = Capková K, Salzameda NT, Janda KD | title = Investigations into small molecule non-peptidic inhibitors of the botulinum neurotoxins | journal = Toxicon | volume = 54 | issue = 5 | pages = 575–82 | date = October 2009 | pmid = 19327377 | pmc = 2730986 | doi = 10.1016/j.toxicon.2009.03.016 }}
70. ^{{cite journal | vauthors = Flanders M, Tischler A, Wise J, Williams F, Beneish R, Auger N | title = Injection of type A botulinum toxin into extraocular muscles for correction of strabismus | journal = Canadian Journal of Ophthalmology | volume = 22 | issue = 4 | pages = 212–17 | date = June 1987 | pmid = 3607594 }}
71. ^{{cite journal | vauthors = | title = Botulinum toxin therapy of eye muscle disorders. Safety and effectiveness. American Academy of Ophthalmology | journal = Ophthalmology | volume = Suppl | pages = 37–41 | date = September 1989 | pmid = 2779991 | doi = 10.1016/s0161-6420(89)32989-7 }}
72. ^¹{{Cite news | last = Boffey | first = Philip M. | date = October 14, 1986 | title = Loss Of Drug Relegates Many To Blindness Again | work = The New York Times | url = https://www.nytimes.com/1986/10/14/science/loss-of-drug-relegates-many-to-blindness-again.html | access-date = July 14, 2010}}
73. ^¹{{cite web | author = United States Department of Health and Human Services | date = April 30, 2009 | title = Re: Docket No. FDA-2008-P-0061 | publisher = Food and Drug Administration | url = http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/UCM143989.pdf | access-date = July 26, 2010}}
74. ^¹{{cite web | last1 = Ocampo | first1 = Vicente Victor D | last2 = Foster | first2 = C Stephen | name-list-format = vanc | url = http://emedicine.medscape.com/article/1198876-treatment#showall | title = Infantile Esotropia Treatment & Management | publisher = Medscape | date = May 30, 2012 | access-date = April 6, 2014}}
75. ^¹²{{cite journal | vauthors = Clark RP, Berris CE | title = Botulinum toxin: a treatment for facial asymmetry caused by facial nerve paralysis | journal = Plastic and Reconstructive Surgery | volume = 84 | issue = 2 | pages = 353–55 | date = August 1989 | pmid = 2748749 | doi = 10.1097/01.prs.0000205566.47797.8d }}
76. ^¹{{cite journal | vauthors = Keen M, Kopelman JE, Aviv JE, Binder W, Brin M, Blitzer A | title = Botulinum toxin A: a novel method to remove periorbital wrinkles | journal = Facial Plastic Surgery | volume = 10 | issue = 2 | pages = 141–46 | date = April 1994 | pmid = 7995530 | doi = 10.1055/s-2008-1064563 }}
77. ^¹{{cite web | date = October 29, 2009 | title = Botulinum Toxin Type A Product Approval Information – Licensing Action 4/12/02 | publisher = Food and Drug Administration | url = http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm | access-date = July 26, 2010}}
78. ^{{cite journal |doi=10.1509/jm.10.0406 |title=How Doppelgänger Brand Images Influence the Market Creation Process: Longitudinal Insights from the Rise of Botox Cosmetic |year=2012 |last1=Giesler |first1=Markus | name-list-format = vanc |journal=Journal of Marketing |volume=76 |issue=6 |pages=55–68}}
79. ^{{cite web | date = January 22, 2014 | title = BOTOX Cosmetic (onabotulinumtoxinA) Product Information | publisher=Allergan | url=http://www.botox.com/}}
80. ^¹{{cite web | date = June 24, 2011 | title = Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX and BOTOX Cosmetic (onabotulinumtoxinA) | publisher = Allergan | url = http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 | access-date = June 26, 2011 | deadurl = yes | archiveurl = https://web.archive.org/web/20110626185759/http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 | archivedate = June 26, 2011 | df = }}
81. ^¹{{cite web | date = April 12, 2008 | title = In U.S., Few Alternatives To Testing On Animals | work = Washington Post | url = https://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html | access-date = June 26, 2011}}
82. ^{{cite journal | vauthors = Nayyar P, Kumar P, Nayyar PV, Singh A | title = BOTOX: Broadening the Horizon of Dentistry | journal = Journal of Clinical and Diagnostic Research : JCDR | volume = 8 | issue = 12 | pages = ZE25–9 | date = December 2014 | pmid = 25654058 | pmc = 4316364 | doi = 10.7860/JCDR/2014/11624.5341 }}
83. ^{{cite journal | vauthors = Al-Fouzan AF, Mokeem LS, Al-Saqat RT, Alfalah MA, Alharbi MA, Al-Samary AE | title = Botulinum Toxin for the Treatment of Gummv Smile | journal = The Journal of Contemporary Dental Practice | volume = 18 | issue = 6 | pages = 474–478 | date = June 2017 | pmid = 28621277 | doi = 10.5005/jp-journals-10024-2068| url = }}
84. ^{{cite journal | vauthors = Hwang WS, Hur MS, Hu KS, Song WC, Koh KS, Baik HS, Kim ST, Kim HJ, Lee KJ | title = Surface anatomy of the lip elevator muscles for the treatment of gummy smile using botulinum toxin | journal = The Angle Orthodontist | volume = 79 | issue = 1 | pages = 70–7 | date = January 2009 | pmid = 19123705 | doi = 10.2319/091407-437.1 | url = }}
85. ^{{cite journal | vauthors = Gracco A, Tracey S | title = Botox and the gummy smile | journal = Progress in Orthodontics | volume = 11 | issue = 1 | pages = 76–82 | date = May 2010 | pmid = 20529632 | doi = 10.1016/j.pio.2010.04.004 }}
86. ^{{cite journal | vauthors = Mazzuco R, Hexsel D | title = Gummy smile and botulinum toxin: a new approach based on the gingival exposure area | journal = Journal of the American Academy of Dermatology | volume = 63 | issue = 6 | pages = 1042–51 | date = December 2010 | pmid = 21093661 | doi = 10.1016/j.jaad.2010.02.053 }}
87. ^¹UK Approves New Botox Use {{Webarchive|url=https://web.archive.org/web/20140222135115/http://www.dddmag.com/news/2014/02/uk-approves-new-botox-use?et_cid=3751256&et_rid=657808477&type=cta# |date=2014-02-22 }}. dddmag.com. February 4, 2014
88. ^{{Cite news | last = Walsh | first = Sandy | name-list-format = vanc | date = October 15, 2010 | title = FDA approves Botox to treat chronic migraine | newspaper = FDA Press Releases | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm | access-date = October 15, 2010}}
89. ^{{Cite news | last = Watkins | first = Tom | name-list-format = vanc | date = October 15, 2010 | title = FDA approves Botox as migraine preventative | newspaper = CNN (US) | url = http://us.cnn.com/2010/HEALTH/10/15/migraines.botox/index.html}}
90. ^{{cite journal | vauthors = Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, Diener HC, Brin MF | title = OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program | journal = Headache | volume = 50 | issue = 6 | pages = 921–36 | date = June 2010 | pmid = 20487038 | doi = 10.1111/j.1526-4610.2010.01678.x }}
91. ^{{cite journal | vauthors = Ashkenazi A | title = Botulinum toxin type a for chronic migraine | journal = Current Neurology and Neuroscience Reports | volume = 10 | issue = 2 | pages = 140–46 | date = March 2010 | pmid = 20425239 | doi = 10.1007/s11910-010-0087-5 }}
92. ^{{cite journal | vauthors = Magid M, Keeling BH, Reichenberg JS | title = Neurotoxins: Expanding Uses of Neuromodulators in Medicine – Major Depressive Disorder | journal = Plastic and Reconstructive Surgery | volume = 136 | issue = 5 Suppl | pages = 111S–19S | date = November 2015 | pmid = 26441090 | doi = 10.1097/PRS.0000000000001733 }}
93. ^¹http://adisinsight.springer.com/drugs/800008810

Medical uses

Muscle spasticity

Other muscle disorders

Excessive sweating

Migraine

Cosmetics

Other

Side effects

Role in disease

Mechanism of action

History

Food canning

World War II

Strabismus

Cosmetics

Chronic pain

Society and culture

Economics

Bioterrorism

Brand names

Toxin production

Organism and toxin susceptibilities

Research

Blepharospasm and strabismus

Cosmetic

Upper motor neuron syndrome

Sweating

Cervical dystonia

Chronic migraine

Depression

Premature ejaculation

See also

References

External links