Botulinum toxin
Botulinum toxin, or botulinum neurotoxin (commonly called botox), is a highly potent neurotoxic protein produced by the bacterium Clostridium botulinum and related species.[23] It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction, thus causing flaccid paralysis.[24] The toxin causes the disease botulism.[25] The toxin is also used commercially for medical and cosmetic purposes.[26][27] Botulinum toxin is an acetylcholine release inhibitor and a neuromuscular blocking agent.[1][22]
Clinical data
Botox, Myobloc, Jeuveau, others
BoNT, botox
abobotulinumtoxinA, daxibotulinumtoxinA, daxibotulinumtoxinA-lanm, evabotulinumtoxinA, incobotulinumtoxinA, letibotulinumtoxinA, letibotulinumtoxinA-wlbg,[1] onabotulinumtoxinA, prabotulinumtoxinA, relabotulinumtoxinA, rimabotulinumtoxinB
- Botulinum toxin A: 93384-43-1
- Botulinum toxin B: 93384-43-2
- Botulinum toxin A: none
- Botulinum toxin A: E211KPY694
- Botulinum toxin B: 0Y70779M1F
C6760H10447N1743O2010S32
149323.05 g·mol−1
The seven main types of botulinum toxin are named types A to G (A, B, C1, C2, D, E, F and G).[26][28] New types are occasionally found.[29][30] Types A and B are capable of causing disease in humans, and are also used commercially and medically.[31][32][33] Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals.[34]
Botulinum toxins are among the most potent toxins known to science.[35][36] Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food. The estimated human median lethal dose of type A toxin is 1.3–2.1 ng/kg intravenously or intramuscularly, 10–13 ng/kg when inhaled, or 1000 ng/kg when taken by mouth.[37]
Side effects[edit]
While botulinum toxin is generally considered safe in a clinical setting, serious side effects from its use can occur. Most commonly, botulinum toxin can be injected into the wrong muscle group or with time spread from the injection site, causing temporary paralysis of unintended muscles.[71]
Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis, however, and can also include headaches, flu-like symptoms, and allergic reactions.[72] Just as cosmetic treatments only last a number of months, paralysis side effects can have the same durations.[73] At least in some cases, these effects are reported to dissipate in the weeks after treatment.[74] Bruising at the site of injection is not a side effect of the toxin, but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days.[75] When injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods.[72] With continued high doses, the muscles can atrophy or lose strength; research has shown that those muscles rebuild after a break from Botox.[76]
Side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. In general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. These can arise from paralysis of critical muscle groups and can include arrhythmia, heart attack, and in some cases, seizures, respiratory arrest, and death.[72] Additionally, side effects common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.[72]
In response to the occurrence of these side effects, in 2008, the FDA notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy.[77] In 2009, the FDA announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site.[78][79][80][81] However, the clinical use of botulinum toxin A in cerebral palsy children has been proven to be safe with minimal side effects.[31][32] Additionally, the FDA announced name changes to several botulinum toxin products, to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were given the generic name of onabotulinumtoxinA, Myobloc as rimabotulinumtoxinB, and Dysport retained its generic name of abobotulinumtoxinA.[82][78] In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each.[83] A similar warning was issued by Health Canada in 2009, warning that botulinum toxin products can spread to other parts of the body.[84]
History[edit]
Initial descriptions and discovery of Clostridium botulinum[edit]
One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of Wildbad in what is now Baden-Württemberg, Germany. Thirteen people became sick and six died after eating pork stomach filled with blood sausage, a local delicacy. Additional cases of fatal food poisoning in Württemberg led the authorities to issue a public warning against consuming smoked blood sausages in 1802 and to collect case reports of "sausage poisoning".[96] Between 1817 and 1822, the German physician Justinus Kerner published the first complete description of the symptoms of botulism, based on extensive clinical observations and animal experiments. He concluded that the toxin develops in bad sausages under anaerobic conditions, is a biological substance, acts on the nervous system, and is lethal even in small amounts.[96] Kerner hypothesized that this "sausage toxin" could be used to treat a variety of diseases caused by an overactive nervous system, making him the first to suggest that it could be used therapeutically.[97] In 1870, the German physician Müller coined the term botulism to describe the disease caused by sausage poisoning, from the Latin word botulus, meaning 'sausage'.[97]
In 1895 Émile van Ermengem, a Belgian microbiologist, discovered what is now called Clostridium botulinum and confirmed that a toxin produced by the bacteria causes botulism.[98] On 14 December 1895, there was a large outbreak of botulism in the Belgian village of Ellezelles that occurred at a funeral where people ate pickled and smoked ham; three of them died. By examining the contaminated ham and performing autopsies on the people who died after eating it, van Ermengem isolated an anaerobic microorganism that he called Bacillus botulinus.[96] He also performed experiments on animals with ham extracts, isolated bacterial cultures, and toxins extracts from the bacteria. From these he concluded that the bacteria themselves do not cause foodborne botulism, but rather produce a toxin that causes the disease after it is ingested.[99] As a result of Kerner's and van Ermengem's research, it was thought that only contaminated meat or fish could cause botulism. This idea was refuted in 1904 when a botulism outbreak occurred in Darmstadt, Germany, because of canned white beans. In 1910, the German microbiologist J. Leuchs published a paper showing that the outbreaks in Ellezelles and Darmstadt were caused by different strains of Bacillus botulinus and that the toxins were serologically distinct.[96] In 1917, Bacillus botulinus was renamed Clostridium botulinum, as it was decided that term Bacillus should only refer to a group of aerobic microorganisms, while Clostridium would be only used to describe a group of anaerobic microorganisms.[98] In 1919, Georgina Burke used toxin-antitoxin reactions to identify two strains of Clostridium botulinum, which she designated A and B.[98]