Botulinum toxin

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Botulinum toxin A
Botulinum toxin 3BTA.png
Clinical data
Legal status
  • US: Rx-Only
Routes IM (approved), SC, intradermal, into glands
Identifiers
CAS number 93384-43-1 YesY
ATC code M03AX01
DrugBank DB00083
Chemical data
Formula C6670H10290N1716O1983S32Zn 
Mol. mass 147,336.839 Da
 YesY (what is this?)  (verify)
Bontoxilysin
Identifiers
EC number 3.4.24.69
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Botulinum toxin is a protein and neurotoxin produced by the bacterium Clostridium botulinum.[1][2] It is the most acutely lethal toxin known, with an estimated human median lethal dose (LD-50) of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled.[3] Botulinum toxin (BTX) can cause botulism, a serious and life-threatening illness in humans and animals. Three forms of botulinum toxin type A (Botox, Dysport and Xeomin) and one form of botulinum toxin type B (MyoBloc) are available commercially for various cosmetic and medical procedures.

History[edit]

Justinus Kerner described botulinum toxin as a "sausage poison" and "fatty poison",[4] because the bacterium that produces the toxin often caused poisoning by growing in improperly handled or prepared meat products. It was Kerner, a physician, who first conceived a possible therapeutic use of botulinum toxin and coined the name botulism (from Latin botulus meaning "sausage"). In 1897, Emile van Ermengem found the producer of the botulin toxin was a bacterium, which he named Clostridium botulinum.[5] In 1928, P. Tessmer Snipe and Hermann Sommer for the first time purified the toxin.[6] In 1949, Arnold Burgen's group experimentally discovered that botulinum toxin blocks neuromuscular transmission through decreased acetylcholine release.[7]

Therapeutic research[edit]

In the late 1960s, Alan Scott, MD, a San Francisco ophthalmologist, and Edward Schantz were the first to work on a standardized botulinum toxin preparation for therapeutic purposes.[8] By 1973, Scott (now at Smith-Kettlewell Institute) used botulinum toxin type A (BTX-A) in monkey experiments, and, in 1980, he officially used BTX-A for the first time in humans to treat "crossed eyes" (strabismus), a condition in which the eyes are not properly aligned with each other, and "uncontrollable blinking" (blepharospasm). In 1993, Pasricha and colleagues showed botulinum toxin could be used for the treatment of achalasia, a spasm of the lower esophageal sphincter.[9] In 1994, Bushara showed botulinum toxin injections inhibit sweating.[10] This was the first demonstration of non-muscular use of BTX-A in humans.

Blepharospasm and strabismus[edit]

In the early 1980s, 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.[11] Side effects were deemed to be rare, mild and treatable.[12] 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.[13]

In December 1989, Botox, manufactured by Allergan, Inc., 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.[14]

Although it has not been approved for pediatric use, Botox has also been used for treating patients younger than 12 years of age, in particular children with infantile esotropia. Several studies which investigated the merits of using Botox for infantile esotropia yielded with different results; success rates similar to those of surgery have been reported in particular for small- to medium-angle esotropia.[15]

Cosmetic[edit]

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.[16] 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.[17] Similar effects had reportedly been observed by a number of independent groups (Brin, and the Columbia University group under Monte Keen.[18] 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).[19] Subsequently, cosmetic use of botulinum toxin type A has become widespread.[20] The results of Botox Cosmetic can last up to four months and may vary with each patient. [21] 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.[22] [23]

The global botox market is forecast to reach $2.9 billion by 2018.[24] The entire global market for facial aesthetics is forecast to reach $4.7 billion in 2018, of which the US is expected to contribute over $2 billion.

Upper motor neuron syndrome[edit]

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.[25] 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[edit]

While treating patients with hemifacial spasm at Southend Hospital in England in 1993, Khalaf Bushara and David Park were the first to show that botulinum toxin injections inhibit sweating.[10] This was the first demonstration of nonmuscular use of BTX-A. Bushara further showed the efficacy of botulinum toxin in treating hyperhidrosis (excessive sweating). BTX-A was later approved for the treatment of excessive underarm sweating. This is technically known as severe primary axillary hyperhidrosis – excessive underarm sweating with an unknown cause which cannot be managed by topical agents (see focal hyperhidrosis).

Cervical dystonia[edit]

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.[citation needed]

Chronic migraine[edit]

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, Inc. showing a very slight improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment.[26][27]

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[28] 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.[29]

Chemical overview[edit]

The eight serologically distinct toxin types are designated A to H. Additionally, six of the eight toxin types have subtypes with five subtypes of BoNT A having been described. The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain. This light chain is an enzyme (a protease) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism, as opposed to the spastic paralysis seen in tetanus.

Botulinum toxin is denatured at temperatures greater than 80 °C (176 °F).[30]

Sources[edit]

Botulism toxins are produced by the bacteria Clostridium botulinum, C. butyricum, C. baratii and C. argentinense.[31] Foodborne botulism can be transmitted through food that has not been heated correctly prior to being canned or food that was not cooked correctly from a can. Most infant botulism cases cannot be prevented because the bacteria that cause this disease are in soil and dust. The bacteria can be found inside homes on floors, carpet, and countertops even after cleaning. Honey can contain the bacteria that cause infant botulism, so children less than 12 months old should not be fed honey. Honey is safe for persons one year of age and older.[32]

Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) that provides an anaerobic environment, allowing the spores to germinate and grow. The growing bacteria produce toxin. It is the ingestion of toxin that causes botulism, not the ingestion of the spores or the vegetative bacteria. Infant and wound botulism both result from infection with spores, which subsequently germinate, resulting in production of toxin and the symptoms of botulism.

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. The toxin itself is rapidly destroyed by heat, such as in thorough cooking.[33] The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.[34]

Botulinum toxin can be absorbed from eyes, mucous membranes, respiratory tract or non-intact skin.[35]

Botulinum toxin has been recognized and feared as a potential bioterror weapon.[36]

Medical and cosmetic uses[edit]

Although botulinum toxin is a lethal, naturally occurring substance, it can be used as an effective and powerful medication.[37] Researchers discovered in the 1950s that injecting overactive muscles with minute quantities of botulinum toxin type-A would result in decreased muscle activity. Botulinum toxin type-A has this effect because it prevents the vesicle where the acetylcholine is stored from binding to the membrane where the neurotransmitter can be released. Botulinum toxin type-A thus blocks the release of acetylcholine by the neuron. This will effectively weaken the muscle for a period of three to four months.[38]

In cosmetic applications, a Botox injection, consisting of a small dose of botulinum toxin, can be used to prevent development of wrinkles by paralyzing facial muscles.[39] As of 2007, it is the most common cosmetic operation, with 4.6 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 wrinkle-preventing effect of Botox normally lasts about three to four months, but can last up to six months.[39] Following treatment, visible results of Botox Cosmetic are usually seen within 3–5 days, however it can take up to 2 weeks to see full results. [40]

In addition to its cosmetic applications, Botox is currently used in the treatment of spasms and dystonias, by weakening involved muscles, for the 60–70 day effective period of the drug.[41] The main conditions treated with botulinum toxin are:

  • Cervical dystonia (spasmodic torticollis) (a neuromuscular disorder involving the head and neck)[42]
  • Blepharospasm (excessive blinking)[43]
  • Severe primary axillary hyperhidrosis (excessive sweating / focal hyperhidrosis)[44][45]
  • Strabismus (squints)
  • Achalasia (failure of the lower oesophageal sphincter to relax)
  • Local intradermal injection of BTX-A is helpful in chronic focal neuropathies. The analgesic effects are not dependent on changes in muscle tone.[46]
  • Migraine and other headache disorders, although the evidence is conflicting in this indication[47]
  • Bruxism: by injecting the toxin into the muscles of mastication, such as the masseter

Other uses of botulinum toxin type A that are widely known but not specifically approved by the FDA (off-label uses) include treatment of:

Treatment and prevention of chronic headache[54] and chronic musculoskeletal pain[55] are emerging uses for botulinum toxin type A. In addition, Botox may aid in weight loss by increasing the gastric emptying time.[56]

Links to deaths[edit]

In September 2005, a paper published in the Journal of American Academy of Dermatology reported from the FDA saying that use of Botox has resulted in 28 deaths between 1989 and 2003, though none were attributed to cosmetic use.[57]

On February 8, 2008, the FDA announced Botox has "been linked in some cases to adverse reactions, including respiratory failure and death, following treatment of a variety of conditions using a wide range of doses", due to its ability to spread to areas distant from the site of the injection.[58] In April 2009, the FDA updated its mandatory boxed warning cautioning that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism.[59]

In January 2009, the Canadian government warned that Botox can have the adverse effect of spreading to other parts of the body, which could cause muscle weakness, swallowing difficulties, pneumonia, speech disorders and breathing problems.[60][61]

Side effects[edit]

Side effects, which are generally minor and temporary,[39] can be predicted from the mode of action (muscle paralysis) and chemical structure (protein) of the molecule, resulting, broadly speaking, in two major areas of side effects: paralysis of the wrong muscle group and allergic reaction. Bruising at the site of injection is a side effect not of the toxin, but rather the mode of administration. In cosmetic use, this can result in inappropriate facial expression, such as drooping eyelid,[39] double vision,[39] uneven smile, or loss of the ability to close eyes. This will wear off in around six weeks. Bruising is prevented by the clinician applying pressure to the injection site, but may still occur, and will last around seven to 11 days. When injecting the masseter muscle of the jaw, loss of muscle function will result in a loss or reduction of power to chew solid foods.[57] All cosmetic treatments are of limited duration, and can be as short as six weeks, but usually the effective period lasts from two to three months. At the extremely low doses used medicinally, botulinum toxin has a very low degree of human and animal toxicity.

Other adverse events from cosmetic use include headaches, dysphagia, flu-like syndromes, blurred vision, dry mouth, fatigue, allergic reactions and swelling or redness at the injection site.[57][62]

A petition by Public Citizen to the FDA has requested regulatory action concerning the possible spread of botulinum toxin (Botox, Myobloc) from the site of injection to other parts of the body.[63]

Individuals who are pregnant, have egg allergies or a neuromuscular disorder are advised to avoid Botox.[39] Breastfeeding mothers should consult their doctors. While no data exists on the medical use of botulin A (botulinum toxin) during breastfeeding, one infant was safely breastfed during maternal botulism and no botulinum toxin was detectable in the mother's milk or infant. Since the doses used medically are far lower than those that cause botulism, the National Library of Medicine LactMed Drugs and Lactation Database suggests that no special precautions are required.[64]

Biochemical mechanism of toxicity[edit]

Target molecules of botulinum (BoNT) and tetanus (TeNT) toxins inside the axon terminal.[65]

The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon terminals. The toxin must get inside the axon terminals to cause paralysis. Following the attachment of the toxin heavy chain to proteins on the surface of axon terminals, the toxin can be taken into neurons by endocytosis. The light chain is able to cleave endocytotic vesicles and reach the cytoplasm. The light chain of the toxin has protease activity. The type A toxin proteolytically degrades the SNAP-25 protein, a type of SNARE protein. The SNAP-25 protein is required for vesicle fusion that releases neurotransmitters from the axon endings (in particular acetylcholine).[66] Botulinum toxin specifically cleaves these SNAREs, so prevents neurosecretory vesicles from docking/fusing with the nerve synapse plasma membrane and releasing their neurotransmitters.

Though it affects the nervous system, common nerve agent treatments (namely the injection of atropine and pralidoxime) will increase mortality by enhancing botulin toxin's mechanism of toxicity.[citation needed] Attacks involving botulinum toxin are distinguishable from those involving nerve agent in that NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a "positive" when a sample of the agent is tested. Furthermore, botulism symptoms develop relatively slowly, over several days compared to nerve agent effects, which can be instantaneous.

Treatment of botulinum poisoning[edit]

If the symptoms of botulism are diagnosed early, an equine antitoxin, use of enemas, and extracorporeal removal of the gut contents can be used to treat the food-borne illness. Wound infections can be treated surgically. Information regarding methods of safe canning, and public education about the disease are methods of prevention. Tests to detect botulism include a brain scan, a nerve conduction test, and a tensilon test for myasthenia gravis to differentiate botulism from other diseases that manifest in the same way. Electromyography can be used to differentiate myasthenia gravis and Guillain-Barré syndrome, diseases that botulism often mimics. Toxicity testing of serum specimens, wound tissue cultures, and toxicity testing, and stool specimen cultures are the best methods for identifying botulism. Laboratory tests of the patient's serum or stool, which are then injected into mice, are also indicative of botulism.[67] The faster way to detect botulinum toxin in people, though, is using the mass spectrometry technology, because it reduces testing time to three or four hours and at the same time it can identify the seven types of the toxin.[68]

The case fatality rate for botulinum poisoning between 1950 and 1996 was 15.5%, down from about 60% over the previous 50 years.[69] Death is generally secondary to respiratory failure due to paralysis of the respiratory muscles, so treatment consists of antitoxin administration and artificial ventilation until the neurotoxins are excreted or metabolised. If initiated on time, these treatments are quite effective, although antisera can not affect BoNT polypeptides that have already entered cells.[70] Occasionally, functional recovery may take several weeks to months or more.

Two primary botulinum antitoxins are available for treatment of botulism.

  • Trivalent (A,B,E) botulinum antitoxin is derived from equine sources using whole antibodies (Fab and Fc portions). This antitoxin is available from the local health department via the CDC in the USA.

Manufacturers[edit]

In the United States, Botox is manufactured by Allergan, Inc. for both therapeutic and cosmetic use (100-unit). In 2011, Allergan required less than one gram of raw botulinum toxin neurotoxin to "supply the world's requirements for 25 indications approved by Government agencies around the world".[72]

In the United States, Xeomin (manufactured in Germany by Merz) is available for both therapeutic and cosmetic use. Dysport, a therapeutic formulation of the type A toxin developed and manufactured in the United Kingdom, is licensed for the treatment of focal dystonias and certain cosmetic uses in the US and worldwide in 100-, 300- and 500-unit packages. Lanzhou Institute of Biological Products manufactures BTXA product, producing 50-unit and 100-unit type A toxin. BTXA is also known as Lantox, Prosigne in Global Market.[73] Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea, in 2009.[74] In America, Neuronox is also known as Siax. Solstice Neurosciences, LLC, a wholly owned subsidiary of US WorldMeds, LLC sells their product under the names Myobloc or Neurobloc, although it contains botulinum toxin type B, not the common type A found in Botox or Dysport.

See also[edit]

References[edit]

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