Editing Botulinum toxin (section)

==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]], 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".<ref name="Erbguth 2004">{{cite journal |vauthors = Erbguth FJ |title = Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin |journal = Movement Disorders |volume = 19 |issue = Supplement 8 |pages = S2–S6 |date = March 2004 |pmid = 15027048 |doi = 10.1002/mds.20003 |s2cid = 8190807 }}</ref> 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.<ref name="Erbguth 2004"/> 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.<ref name="Erbguth 1999">{{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 = 1850–1853 |date = November 1999 |pmid = 10563638 |doi = 10.1212/wnl.53.8.1850 |s2cid = 46559225 }}</ref> In 1870, the German physician Müller coined the term ''botulism'' to describe the disease caused by sausage poisoning, from the Latin word {{Lang|la|botulus}}, meaning 'sausage'.<ref name="Erbguth 1999"/>

In 1895, [[Émile van Ermengem]], a Belgian microbiologist, discovered what is now known as ''Clostridium botulinum'' and confirmed that a toxin produced by the bacteria causes botulism.<ref name="Monheit 2017">{{cite journal |vauthors = Monheit GD, Pickett A |title = AbobotulinumtoxinA: A 25-Year History |journal = Aesthetic Surgery Journal |volume = 37 |issue = suppl_1 |pages = S4–S11 |date = May 2017 |pmid = 28388718 |pmc = 5434488 |doi = 10.1093/asj/sjw284 }}</ref> 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''.<ref name="Erbguth 2004"/> 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 when ingested.<ref>{{cite journal |vauthors = Pellett S |title = Learning from the past: historical aspects of bacterial toxins as pharmaceuticals |journal = Current Opinion in Microbiology |volume = 15 |issue = 3 |pages = 292–299 |date = June 2012 |pmid = 22651975 |doi = 10.1016/j.mib.2012.05.005 }}</ref> 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 different strains of ''Bacillus botulinus'' caused the outbreaks in Ellezelles and Darmstad and that the toxins were serologically distinct.<ref name="Erbguth 2004"/> In 1917, ''Bacillus botulinus'' was renamed ''Clostridium botulinum'', as it was decided that the term ''Bacillus'' should refer to a group of aerobic microorganisms, while ''Clostridium'' would be used only to describe a group of anaerobic microorganisms.<ref name="Monheit 2017"/> In 1919, [[Georgina Burke]] used toxin-antitoxin reactions to identify two strains of ''Clostridium botulinum'', which she designated A and B.<ref name="Monheit 2017"/>

===Food canning===
{{more citations needed section|date=August 2018}}

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.<ref>{{cite web |date=24 June 2022 |title=Home Canning and Botulism |url=https://www.cdc.gov/foodsafety/communication/home-canning-and-botulism.html |access-date=3 August 2022 |archive-date=2 August 2022 |archive-url=https://web.archive.org/web/20220802021326/https://www.cdc.gov/foodsafety/communication/home-canning-and-botulism.html |url-status=live }}</ref>

===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<ref>{{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 = 613–614 |date = May 1946 |pmid = 21026141 |doi = 10.1126/science.103.2681.613 |bibcode = 1946Sci...103..613L }}</ref> developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army's [[Chemical Corps]] was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and provided it to the academic community.

The mechanism of botulinum toxin action – blocking the release of the neurotransmitter acetylcholine from nerve endings – was elucidated in the mid-20th century,<ref>{{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 }}</ref> 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.<ref>{{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 = 489–491 |date = May 1982 |pmid = 7099568 |doi = 10.1016/s0161-6420(82)34764-8 }}</ref> 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,<ref>{{cite journal |vauthors = Drachman DB |title = Atrophy of Skeletal Muscle in Chick Embryos Treated with Botulinum Toxin |journal = Science |volume = 145 |issue = 3633 |pages = 719–721 |date = August 1964 |pmid = 14163805 |doi = 10.1126/science.145.3633.719 |s2cid = 43093912 |bibcode = 1964Sci...145..719D }}</ref> [[Alan B. Scott]] and colleagues injected botulinum toxin into monkey extraocular muscles.<ref name="Scott_1973">{{cite journal |vauthors = Scott AB, Rosenbaum A, Collins CC |title = Pharmacologic weakening of extraocular muscles |journal = Investigative Ophthalmology |volume = 12 |issue = 12 |pages = 924–927 |date = December 1973 |pmid = 4203467 }}</ref> 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,<ref>{{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 = 1044–1049 |date = October 1980 |pmid = 7243198 |doi = 10.1016/s0161-6420(80)35127-0 |s2cid = 27341687 }}</ref> and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum ("eye aligner").

In 1986, Oculinum Inc, Scott's micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, people who had come to rely on periodic injections became desperate. For four months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.<ref name="Boffey_1986" />

Based on data from thousands of people collected by 240 investigators, Oculinum Inc (which was soon acquired by Allergan) received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus (crossed eyes) and [[blepharospasm]] (uncontrollable blinking).<ref>{{cite web | vauthors = Soucheray S, Beusekom MV, Beusekom MV, Schnirring L | title = FDA approves cosmetic use of botulinum toxin | date = 2002-04-18 | work =  Center for Infectious Disease Research & Policy (CIDRAP) | publisher = University of Minnesota | url = https://www.cidrap.umn.edu/botulism/fda-approves-cosmetic-use-botulinum-toxin | access-date = 2025-05-01 }}</ref> Allergan then began using the trademark Botox.<ref name="alg" /> This original approval was granted under the [[Orphan Drug Act of 1983|1983 US Orphan Drug Act]].<ref name="pmid20036435">{{cite journal | vauthors = Wellman-Labadie O, Zhou Y | title = The US Orphan Drug Act: rare disease research stimulator or commercial opportunity? | journal = Health Policy | location = Amsterdam, Netherlands | volume = 95 | issue = 2–3 | pages = 216–228 | date = May 2010 | pmid = 20036435 | doi = 10.1016/j.healthpol.2009.12.001 }}</ref>

===Cosmetics===
[[File:Doctor performing Botox injection.jpg|thumb|Doctor performing Botulinum toxin injection]]
The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped, and she constantly demonstrated deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that Botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with Botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report of the cosmetic use of Botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal ''Plastic and Reconstructive Surgery'' in 1989.<ref name="Clark_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."<ref name="Rohrich_2003">{{cite journal |vauthors = Rohrich RJ, Janis JE, Fagien S, Stuzin JM |title = The cosmetic use of botulinum toxin |journal = Plastic and Reconstructive Surgery |volume = 112 |issue = 5 Suppl |pages = 177S–188S |date = October 2003 |pmid = 14504502 |doi = 10.1097/01.prs.0000082208.37239.5b }}</ref>

Also in 1987, Jean and Alastair Carruthers, both doctors in [[Vancouver|Vancouver, British Columbia]], observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines ("frown lines" between the eyebrows). Alastair Carruthers reported that others at the time also noticed these effects and discussed the cosmetic potential of botulinum toxin.<ref name="Carruthers A 2003">{{cite journal |vauthors = Carruthers A |title = History of the clinical use of botulinum toxin A and B |journal = Clinics in Dermatology |volume = 21 |issue = 6 |pages = 469–472 |date = Nov–Dec 2003 |pmid = 14759577 |doi = 10.1016/j.clindermatol.2003.11.003 }}</ref> Unlike other investigators, the Carruthers did more than just talk about the possibility of using botulinum toxin cosmetically. They conducted a clinical study on otherwise normal individuals whose only concern was their eyebrow furrow. They performed their study between 1987 and 1989 and presented their results at the 1990 annual meeting of the American Society for Dermatologic Surgery. Their findings were subsequently published in 1992.<ref name="Carruthers JD 19922">{{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 }}</ref>

===Chronic pain===

[[William J. Binder]] reported in 2000 that people who had cosmetic injections around the face reported relief from chronic headaches.<ref>{{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 = 669–676 |date = December 2000 |pmid = 11112955 |doi = 10.1067/mhn.2000.110960 |s2cid = 24406607 }}</ref> This was initially thought to be an indirect effect of reduced muscle tension; however, the toxin is now known to inhibit the release of peripheral nociceptive neurotransmitters, thereby suppressing the central pain processing systems responsible for [[migraine]] headaches.<ref>{{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 = 1736–1745 |date = April 2012 |pmid = 22535858 |doi = 10.1001/jama.2012.505 }}</ref><ref>{{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 = 4177–4192 |date = September 2014 |pmid = 24819339 |pmc = 4241086 |doi = 10.1111/bph.12763 }}</ref>