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Botulinum toxin, or botulinum neurotoxin (BoNT), is a
neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central nervous system, central and/or peripheral nervous system. It occurs when exposure to a s ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...

protein
produced by the
bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

bacterium
''
Clostridium botulinum ''Clostridium botulinum'' is a Gram-positive bacteria, Gram-positive, Bacillus (shape), rod-shaped, Anaerobic organism, anaerobic, endospore, spore-forming, Motility, motile bacterium with the ability to produce the neurotoxin Botulinum toxin, b ...

Clostridium botulinum
'' and related species. It prevents the release of the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or mus ...
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts ...

acetylcholine
from
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, th ...
endings at the
neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

neuromuscular junction
, thus causing
flaccid paralysis Flaccid paralysis is a neurological condition characterized by weakness or paralysis and reduced muscle tone without other obvious cause (e.g., Physical trauma, trauma). This abnormal condition may be caused by disease or by trauma affecting the ...
. The toxin causes the disease
botulism Botulism is a rare and potentially fatal illness caused by botulinum toxin, a toxin produced by the bacterium ''Clostridium botulinum''. The disease begins with weakness, blurred vision, Fatigue (medical), feeling tired, and trouble speaking. Th ...
. The toxin is also used commercially for medical and cosmetic purposes. The seven main types of botulinum toxin are named types A to G (A, B, C1, C2, D, E, F and G). New types are occasionally found. Types A and B are capable of causing disease in humans, and are also used commercially and medically. Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals. Botulinum toxins are among the most potent toxins known. Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food. The estimated human
lethal dose In toxicology, the lethal dose (LD) is an indication of the lethal toxicity of a given substance or type of radiation. Because resistance varies from one individual to another, the "lethal dose" represents a dose (usually recorded as dose per kilog ...
of type A toxin is 1.3–2.1 ng/kg
intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
or intramuscularly, 10–13ng/kg when inhaled, or 1000ng/kg when taken by mouth. Commercial forms are marketed under the brand names Botox (onabotulinumtoxinA), Dysport/Azzalure (abobotulinumtoxinA), Letybo (letibotulinumtoxinA),https://www.tga.gov.au/resources/auspmd/letybo Myobloc (rimabotulinumtoxinB), Xeomin/Bocouture (incobotulinumtoxinA), and Jeuveau (prabotulinumtoxinA).


Medical uses

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


Muscle spasticity

Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including
cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, spasticity, stiff muscles, Paresis, weak muscles, and tremors. There may be p ...

cerebral palsy
, post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck,
eyelid An eyelid is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. The human eyeli ...
,
vagina In mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region o ...
, limbs, jaw, and
vocal cords In humans, vocal cords, also known as vocal folds or voice reeds, are folds of throat tissues that are key in creating sounds through vocalization. The size of vocal cords affects the pitch of voice. Open when breathing and vibrating for speec ...
. Similarly, botulinum toxin is used to relax the clenching of muscles, including those of the
esophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an Organ (anatomy), organ in vertebrates through which food passes, aided by Peristalsis, peristaltic contracti ...
, jaw, lower urinary tract and
bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
, or clenching of the anus which can exacerbate
anal fissure An anal fissure is a break or tear in the skin of the anal canal The anal canal is the part that connects the rectum to the anus, located below the level of the pelvic diaphragm. It is located within the anal triangle of the perineum, between ...
. Botulinum toxin appears to be effective for
refractory In materials science, a refractory material or refractory is a material that is resistant to Thermal decomposition, decomposition by heat, pressure, or chemical attack, and retains strength and form at high temperatures. Refractories are polycr ...

refractory
overactive bladder.


Other muscle disorders

Strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

Strabismus
, otherwise known as improper eye alignment, is caused by imbalances in the actions of muscles that rotate the eyes. This condition can sometimes be relieved by weakening a muscle that pulls too strongly, or pulls against one that has been weakened by disease or trauma. Muscles weakened by toxin injection recover from paralysis after several months, so injection might seem to need to be repeated, but muscles adapt to the lengths at which they are chronically held, so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect. If binocular vision is good, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment. In January 2014, botulinum toxin was approved by UK's
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health (United Kingdom), Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and ...
for treatment of restricted ankle motion due to lower-limb spasticity associated with stroke in adults. In July 2016, the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved abobotulinumtoxinA (Dysport) for injection for the treatment of lower-limb spasticity in pediatric patients two years of age and older. AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity. In the U.S., the FDA approves the text of the labels of prescription medicines and for which medical conditions the drug manufacturer may sell the drug. However, prescribers may freely prescribe them for any condition they wish, also known as
off-label use Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ...
. Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.


Excessive sweating

AbobotulinumtoxinA has been approved for the treatment of excessive underarm sweating of unknown cause, which cannot be managed by topical agents.


Migraine

In 2010, the FDA approved
intramuscular Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be p ...
botulinum toxin injections for
prophylactic Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
treatment of chronic
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

migraine
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe headaches. Headaches can occu ...

headache
.


Cosmetic Indications

In cosmetic applications, botulinum toxin is considered relatively safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face. Commercial forms are marketed under the brand names Botox Cosmetic/Vistabel from Allergan, Dysport/Azzalure from Galderma and
Ipsen Ipsen is a French biopharmaceutical company headquartered in Paris, France, with a focus on transformative medicines in three therapeutic areas: oncology, rare disease and neuroscience. Ipsen is one of the world’s top 15 biopharmaceutical com ...
, Xeomin/Bocouture from Merz, Jeuveau/Nuceiva from Evolus, manufactured by Daewoong in South Korea. The effects of botulinum toxin injections for glabellar lines ('11's lines' between the eyes) typically last two to four months and in some cases, product-dependent, with some patients experiencing a longer duration of effect of up to 6 months or longer. Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin. Smoothing of wrinkles is usually visible three to five days after injection, with maximum effect typically a week following injection. Muscles can be treated repeatedly to maintain the smoothed appearance. DaxibotulinumtoxinA (Daxxify) is used for the temporary improvement in the appearance of moderate to severe glabellar lines (eyebrows). DaxibotulinumtoxinA is an acetylcholine release inhibitor and neuromuscular blocking agent.


Other

Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating,
neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...
, and some
allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allerg ...
symptoms. In addition to these uses, botulinum toxin is being evaluated for use in treating
chronic pain Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between Acute (medicine), acute and Chronic condition, chronic pain is sometimes determined by the amount of time since onset. Two commonly ...
. Studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion. The use of botulinum toxin A in children with
cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, spasticity, stiff muscles, Paresis, weak muscles, and tremors. There may be p ...

cerebral palsy
is safe in the upper and lower limb muscles.


Side effects

While botulinum toxin is generally considered safe in a clinical setting, serious side effects from its use can occur. Most commonly, botulinum toxin can be injected into the wrong muscle group or with time spread from the injection site, causing temporary paralysis of unintended muscles. Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis, however, and can also include headaches, flu-like symptoms, and allergic reactions. Just as cosmetic treatments only last a number of months, paralysis side effects can have the same durations. At least in some cases, these effects are reported to dissipate in the weeks after treatment. Bruising at the site of injection is not a side effect of the toxin, but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days. When injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods. With continued high doses, the muscles can atrophy or lose strength; research has shown that those muscles rebuild after a break from Botox. Side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. In general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. These can arise from paralysis of critical muscle groups and can include
arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the Cardiac cycle, heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per mi ...
,
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Hemodynamics, blood flow decreases or stops to the coronary artery of the heart, causing ischemia, damage to the cardiac muscle, heart muscle. The most common symptom i ...

heart attack
, and in some cases, seizures, respiratory arrest, and death. Additionally, side effects common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes. In response to the occurrence of these side effects, in 2008, the FDA notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy. In 2009, the FDA announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site. However, the clinical use of botulinum toxin A in cerebral palsy children has been proven to be safe with minimal side effects. Additionally, the FDA announced name changes to several botulinum toxin products, to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were given the generic name of onabotulinumtoxinA, Myobloc as rimabotulinumtoxinB, and Dysport retained its generic name of abobotulinumtoxinA. In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each. A similar warning was issued by
Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary unit ...
in 2009, warning that botulinum toxin products can spread to other parts of the body.


Role in disease

Botulinum toxin produced by ''Clostridium botulinum'' is the cause of botulism. Humans most commonly ingest the toxin from eating improperly canned foods in which ''C. botulinum'' has grown. However, the toxin can also be introduced through an infected wound. In infants, the bacteria can sometimes grow in the intestines and produce botulinum toxin within the intestine and can cause a condition known as floppy baby syndrome. In all cases, the toxin can then spread, blocking nerves and muscle function. In severe cases, the toxin can block nerves controlling the respiratory system or heart, resulting in death. Botulism can be difficult to diagnose, as it may appear similar to diseases such as
Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a rapid-onset Paralysis, muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or ...
,
myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision ...
, and
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

stroke
. Other tests, such as brain scan and spinal fluid examination, may help to rule out other causes. If the symptoms of botulism are diagnosed early, various treatments can be administered. In an effort to remove contaminated food that remains in the gut, enemas or induced vomiting may be used. For wound infections, infected material may be removed surgically. Botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. In severe cases, mechanical respiration may be used to support patients with respiratory failure. The nerve damage heals over time, generally over weeks to months. With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced. Two preparations of botulinum antitoxins are available for treatment of botulism. Trivalent (serotypes A, B, E) botulinum
antitoxin An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacterium, bacteria in response to toxin exposure. Although they are most effective in neutralizing toxins, the ...
is derived from equine sources using whole
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform ...

antibodies
. The second antitoxin is heptavalent botulinum antitoxin (serotypes A, B, C, D, E, F, G), which is derived from equine antibodies that have been altered to make them less immunogenic. This antitoxin is effective against all main strains of botulism.


Mechanism of action

Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to presynaptic surface of
neurons A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
that use the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts ...

acetylcholine
. Once bound to the nerve terminal, the neuron the toxin into a
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
by receptor-mediated
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, an ...

endocytosis
. As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin that triggers it to push across the vesicle membrane and into the cell
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryote, eukaryotic Cell (biology), cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear envelope, nuc ...
. Botulinum neurotoxins recognize distinct classes of receptors simultaneously (
ganglioside A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. N-acetylneuraminic acid, ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative ...
s, synaptotagmin and SV2). Once inside the cytoplasm, the toxin cleaves SNARE proteins (proteins that mediate vesicle fusion, with their target membrane bound compartments) meaning that the acetylcholine vesicles cannot bind to the intracellular cell membrane, preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to paralysis. The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases. The active form consists of a two-chain
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...

protein
composed of a 100-
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a Non-SI units mentioned in the SI, non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an chemical bond, unbound neutral atom of carbon-12 in its ...
heavy chain
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called Protein, proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapepti ...
joined via
disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
to a 50-kDa light chain polypeptide. The heavy chain contains domains with several functions; it has the domain responsible for binding specifically to nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies. 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 Synaptosomal-Associated Protein, 25kDa (SNAP-25) is a Target Soluble NSF (''N''-ethylmaleimide-sensitive factor) Attachment Protein Receptor (SNARE (protein), t-SNARE) protein encoded by the ''SNAP25'' gene found on chromosome 20p12.2 in humans. ...
, 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 A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or mus ...
acetylcholine from axon endings. This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell. The seven toxin serotypes (A–G) are traditionally separated by their antigenicity. They have different tertiary structures and sequence differences. While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members. 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). 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. BoNT/FA received considerable attention under the name "BoNT/H", as it was mistakenly thought it could not be neutralized by any existing antitoxin. Botulinum toxins are closely related to
tetanus toxin Tetanus toxin (TeNT) is an extremely potent neurotoxin produced by the vegetative cell of ''Clostridium tetani'' in Hypoxia (environmental), anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment ...
; the two are collectively known as ''Clostridium'' neurotoxins and the light chain is classified by
MEROPS MEROPS is an online database An online database is a database In computing, a database is an organized collection of Data (computing), data stored and accessed electronically. Small databases can be stored on a file system, while large databa ...
a
family M27
Nonclassical types include BoNT/X (), which is toxic in mice and possibly in humans; a BoNT/J () found in cow ''
Enterococcus ''Enterococcus'' is a large genus of lactic acid bacteria of the Phylum (biology), phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococcus, diplococci) or short chains, and are difficult to distinguish from S ...
''; and a BoNT/Wo () found in the rice-colonizing '' Weissella oryzae''.


History


Initial descriptions and discovery of ''Clostridium botulinum''

One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of Wildbad in what is now
Baden-Württemberg Baden-Württemberg (; ), commonly shortened to BW or BaWü, is a states of Germany, German state () in Southwest Germany, east of the Rhine, which forms the southern part of Germany's western border with France. With more than 11.07 million inha ...
, Germany. Thirteen people became sick and six died after eating pork stomach filled with
blood sausage A blood sausage is a sausage filled with blood as food, blood that is cooked or dried and mixed with a filler until it is thick enough to solidify when cooled. Most commonly, the blood of pigs, sheep, lamb, cow, chicken, or goose is used. In E ...
, 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". 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. 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. 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". 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. 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''. 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. 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 Darmstadt () is a city in the States of Germany, state of Hesse in Germany, located in the southern part of the Frankfurt Rhine Main Area, Rhine-Main-Area (Frankfurt Metropolitan Region). Darmstadt has around 160,000 inhabitants, making it th ...

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. 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. In 1919, Georgina Burke used toxin-antitoxin reactions to identify two strains of ''Clostridium botulinum'', which she designated A and B.


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 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 Fort Detrick () is a United States Army Futures Command installation located in Frederick, Maryland. Historically, Fort Detrick was the center of the United States biological weapons program, U.S. biological weapons program from 1943 to 1969. Sin ...
in Maryland. Carl Lamanna and James Duff developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army's
Chemical Corps The Chemical Corps is the branch of the United States Army tasked with defending against chemical weapon, chemical, biological agent, biological, radiological weapon, radiological, and nuclear weapon, nuclear (Chemical, biological, radiological, a ...
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, 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 Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

strabismus
) had developed the method of EMG-guided injection (using the
electromyogram Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an medical instrument, instrument called an electromyograph to produce a record called an electromyog ...

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. 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, Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles. 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 Albumin is a protein family, family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-solubility, soluble, moderately soluble in concentrated salt solutions, and experience h ...
, 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, 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 four months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections. Based on data from thousands of patients 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 Blepharospasm is any abnormal contraction of the orbicularis oculi muscle. The condition should be distinguished from the more common, and milder, involuntary quivering of an eyelid, known as myokymia, or fasciculation. In most cases, blepharosp ...
. Allergan then began using the trademark Botox. This original approval was granted under the 1983 US Orphan Drug Act.


Cosmetics

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. 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." Jean and Alastair 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). Alastair Carruthers reported that others at the time also noticed these effects and discussed the cosmetic potential of botulinum toxin. 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 during 1987-1989 and presented their results at the 1990 annual meeting of the American Society for Dermatologic Surgery. Their findings were subsequently published in 1992.


Chronic pain

William J. Binder reported in 2000, that patients who had cosmetic injections around the face reported relief from chronic headache. 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 Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

migraine
headache.


Society and culture


Economics

, 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 The American Society of Plastic Surgeons (ASPS) is the largest plastic surgery specialty organization in the world. Founded in 1931, the society is composed of surgeons certified by the American Board of Plastic Surgery or by the Royal College of ...
. 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, 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 U.S.) in the same timeframe. ;Global Market: In 2019, 6,271,488 Botulinum Toxin procedures were administered worldwide. The Global Botulinum Toxin market size was US$4.83 billion in 2019 and is projected to reach US$7.71 billion by 2027. ;US Market: In 2020, 4,401,536 Botulinum Toxin Type A procedures were administered. In 2019 the botulinum Toxin market made US$3.19 billion. ;Botox cost: Botox cost is generally determined by the number of units administered (avg. $10.00 - $30.00 per unit) or by the area ($200–1000) and depends on expertise of a physician, clinic location, number of units, and treatment complexity. ;Insurance: Botox for medical purposes is usually covered by insurance if deemed medically necessary by your doctor and covers a plethora of medical problems including overactive bladder (OAB), urinary incontinence due to neurologic conditions, headaches and migraines, TMJ, spasticity in adult patients, cervical dystonia in adult patients, severe axillary hyperhidrosis (or other areas of the body), blepharospasm, upper or lower limb spasticity. ;Migraines: For migraine induced headaches the FDA-recommended dosage is 155 units and costs between $300 to $600 per treatment out of pocket when covered by insurance. ;Hyperhidrosis: Botox for excessive sweating is FDA approved. ;Cosmetic: 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.


Bioterrorism

Botulinum toxin has been recognized as a potential agent for use in
bioterrorism Bioterrorism is terrorism involving the intentional release or dissemination of biological agents. These agents are bacteria, viruses, insects, fungi, and/or toxins, and may be in a naturally occurring or a human-modified form, in much the same ...
. It can be absorbed through the eyes, mucous membranes, respiratory tract, and non-intact skin. 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 Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of bradycardia, slow heart rate, and to decrease saliva production during surgery. It is typic ...

atropine
and pralidoxime) will increase mortality by enhancing botulinum toxin's mechanism of toxicity. 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. 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. Japanese doomsday cult
Aum Shinrikyo , formerly , is a Japanese doomsday cult founded by Shoko Asahara in 1987. It carried out the deadly Tokyo subway sarin attack in 1995 and was found to have been responsible for the Matsumoto sarin attack the previous year. The group says tha ...
produced botulinum toxin and spread it as an aerosol in downtown
Tokyo Tokyo (; ja, 東京, , ), officially the Tokyo Metropolis ( ja, 東京都, label=none, ), is the capital and List of cities in Japan, largest city of Japan. Formerly known as Edo, its metropolitan area () is the most populous in the world, ...

Tokyo
during the 1990s, but the attacks caused no fatalities. 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 ''Clostridium botulinum'' is a Gram-positive bacteria, Gram-positive, Bacillus (shape), rod-shaped, Anaerobic organism, anaerobic, endospore, spore-forming, Motility, motile bacterium with the ability to produce the neurotoxin Botulinum toxin, b ...

Clostridium botulinum
'', which makes botulinum toxin. Their reports were later found to be incorrect; no such lab was ever found.


Brand names

Botulinum toxin A is sold under the brand names Jeuveau, Botox, and Xeomin. Botulinum toxin B is sold 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. 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. Besides the three primary U.S. 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 U.S. Lanzhou Institute of Biological Products in
China China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's List of countries and dependencies by population, most populous country, with a Population of China, population exceeding 1.4 billion, slig ...

China
manufactures a botulinum toxin type-A product; as of 2014, it was the only botulinum toxin type-A approved in China. Botulinum toxin type-A is also sold as Lantox and Prosigne on the global market. Neuronox, a botulinum toxin type-A product, was introduced by Medy-Tox Inc. of South Korea in 2009.


Toxin production

Botulism toxins are produced by bacteria of the genus ''Clostridium,'' namely ''C. botulinum'', '' C. butyricum'', '' C. baratii'' and '' C. argentinense,'' 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. 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. Critically, ingestion of toxin rather than spores or vegetative bacteria causes
botulism Botulism is a rare and potentially fatal illness caused by botulinum toxin, a toxin produced by the bacterium ''Clostridium botulinum''. The disease begins with weakness, blurred vision, Fatigue (medical), feeling tired, and trouble speaking. Th ...
. Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, so is preventable. 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.


Organism and toxin susceptibilities

Proper refrigeration at temperatures below slows the growth of ''C. botulinum''. The organism is also susceptible to high salt, high oxygen, and low pH levels. The toxin itself is rapidly destroyed by heat, such as in thorough cooking. The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time. The botulinum toxin is denatured and thus deactivated at temperatures greater than for five minutes. As a zinc metalloprotease (see below), the toxin's activity is also susceptible, post-exposure, to by protease inhibitors, e.g., zinc-coordinating hydroxamates.


Research


Blepharospasm and 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. Side effects in treatment of this condition were deemed to be rare, mild and treatable. 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. In December 1989, Botox was approved by the U.S. FDA for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old. In the case of treatment of infantile esotropia in patients younger than 12 years of age, several studies have yielded differing results.


Cosmetic

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 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. 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." JD and JA Carruthers also studied and reported in 1992 the use of botulinum toxin type-A as a cosmetic treatment.They conducted a study of patients whose only concern was their glabellar forehead wrinkle or furrow. Study participants were otherwise normal. Sixteen of seventeen patients available for follow-up demonstrated a cosmetic improvement. This study was reported at a meeting in 1991. The study for the treatment of
glabella The glabella, in humans, is the area of skin between the eyebrows and above the Human nose, nose. The term also refers to the underlying bone that is slightly depressed, and joins the two brow ridges. It is a cephalometric analysis#Cephalometric ...
r frown lines was published in 1992. This result was subsequently confirmed by other groups (Brin, and the Columbia University group under Monte Keen). 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. Well before this, the cosmetic use of botulinum toxin type A became widespread. The results of Botox Cosmetic can last up to four months and may vary with each patient. The US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved an alternative product-safety testing method in response to increasing public concern that
LD50 In toxicology, the median lethal dose, LD50 (abbreviation for " lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance ...
testing was required for each batch sold in the market. Botulinum toxin type-A has also been used in the treatment of gummy smiles, 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 The gums or gingiva (plural: ''gingivae'') consist of the mucosal tissue that lies over the mandible and maxilla inside the mouth. Gum health and disease can have an effect on general health. Structure The gums are part of the soft tissue ...
. 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 The levator labii superioris (pl. ''levatores labii superioris'', also called quadratus labii superioris, pl. ''quadrati labii superioris'') is a muscle of the human body used in facial expression. It is a broad sheet, the origin of which extends ...

levator labii superioris
(LLS), the levator labii superioris alaeque nasi muscle (LLSAN), and the
zygomaticus minor The zygomaticus minor muscle is a muscle Skeletal muscles (commonly referred to as muscles) are Organ (biology), organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeleta ...
(ZMi).


Upper motor neuron syndrome

Botulinum toxin type-A is now a common treatment for muscles affected by the
upper motor neuron Upper motor neurons (UMNs) is a term introduced by William Gowers (neurologist), William Gowers in 1886. They are found in the cerebral cortex and brainstem and carry information down to activate interneurons and lower motor neurons, which in tu ...
syndrome (UMNS), such as
cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, spasticity, stiff muscles, Paresis, weak muscles, and tremors. There may be p ...

cerebral palsy
, for muscles with an impaired ability to effectively lengthen. Muscles affected by UMNS frequently are limited by
weakness Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...
, loss of reciprocal inhibition, decreased movement control, and hypertonicity (including
spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscle ...
). In January 2014, Botulinum toxin was approved by UK's
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health (United Kingdom), Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and ...
(MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults.UK Approves New Botox Use
. dddmag.com. 4 February 2014
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.


Sialorrhea

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 Bell's palsy is a type of facial nerve paralysis, facial paralysis that results in a temporary inability to control the facial muscles on the affected side of the face. In most cases, the weakness is temporary and significantly improves over wee ...
, intellectual disability, and cerebral palsy. Injection of botulinum toxin type-A into salivary glands is useful in reducing the secretions.


Cervical dystonia

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 Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements ma ...
in December 2000. Brand names for botulinum toxin type-B include Myobloc in the United States and Neurobloc in the European Union.


Chronic migraine

Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

migraine
s 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. 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 Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

migraine
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.


Depression

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


Premature ejaculation

The drug for the treatment of
premature ejaculation Premature ejaculation (PE) occurs when a man Ejaculation, expels semen (and most likely experiences orgasm) soon after beginning Human sexual activity, sexual activity, and with minimal penile stimulation. It has also been called ''early ejaculat ...
has been under development since 7 August 2013, and is in Phase II of the FDA trials.


References


Further reading

* *


External links


BotDB: extensive resources on BoNT structures, inhibitors, kinetics, and literature
* * * * * * * * * * *

''
The New York Times ''The New York Times'' (''the Times'', ''NYT'', or the Gray Lady) is a daily newspaper based in New York City with a worldwide readership reported in 2020 to comprise a declining 840,000 paid print subscribers, and a growing 6 million paid d ...

The New York Times
'' {{DEFAULTSORT:Botulinum Toxin AbbVie brands Acetylcholine release inhibitors Bacterial toxins Biological toxin weapons Botulism EC 3.4.24 Muscle relaxants Neurotoxins Peripherally selective drugs Plastic surgery Protein domains