Botulinum

__Botulinum toxin__ (abbreviated either as BTX or BoNT) is produced by //Clostridium botulinum,// a gram-positive anaerobic bacterium. The clinical syndrome of botulism can occur following ingestion of contaminated food, from colonization of the infant gastrointestinal tract, or from a wound infection. BoNT is broken into 7 neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in animals. The various botulinum toxins possess individual potencies, and care is required to assure proper use and avoid __medication__ errors. Recent changes to the established drug names by the FDA were intended to reinforce these differences and prevent __medication__ errors. The products and their approved indications include the following: OnabotulinumtoxinA (__Botox__, __Botox__ Cosmetic)
 * Botox - Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm
 * Botox Cosmetic - Moderate-to-severe glabellar lines

AbobotulinumtoxinA (Dysport) - Cervical dystonia, moderate-to-severe glabellar lines

IncobotulinumtoxinA (Xeomin) - Cervical dystonia, blepharospasm

Rimabotulinumtoxin B (Myobloc) - Cervical dystonia

The BoNT molecule is synthesized as a __single__ chain (150 kD) and then cleaved to __form__ the dichain molecule with a disulfide bridge (see image below). The light chain (~50 kD - amino acids 1-448) acts as a zinc (Zn 2+ ) endopeptidase similar to tetanus toxin with proteolytic activity located at the N-terminal end (see image below). The heavy chain (~100 kD - amino acids 449-1280) provides cholinergic specificity and is responsible for binding the toxin to presynaptic receptors; it also promotes light-chain translocation across the endosomal membrane.  Proteolytic activity is located at the N-terminal end of the light chain of botulinum toxin type A. 

History
Justinus Kerner described botulinum toxin as a "sausage poison" and "fatty poison", [|[5]] 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 //otulus// meaning "sausage"). In 1897, Emile van Ermengem found the producer of the botulin toxin was a bacterium, which he named //Clostridium botulinum.// [|[6]] In 1928,P. Tessmer Snipe and Hermann Sommer for the first time purified the toxin. [|[7]] In 1949, Arnold Burgen's group discovered, through an elegant experiment, that botulinum toxin blocks neuromuscular transmission through decreased acetylcholine release. [|[8]]

Therapeutic research
In the late 1960s Alan Scott, M.D., a Sam Francisco ophtalmologist, and Edward Schantz were the first to work on a standardized botulinum toxin preparation for therapeutic purposes. [|[9]] 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 strabismus "crossed eyes", a condition in which the eyes are not properly aligned with each other, and "uncontrollable blinking" (blepharoapasm ). In 1993, Pasricha and colleagues showed that botulinum toxin could be used for the treatment of achalasia a spasm of the lower esophageal sphincter. [|[10]] In 1994 Bushara showed that botulinum toxin injections inhibit sweating. [|[11]] This was the first demonstration of non-muscular use of BTX-A in humans.

Blepharospasm and strabismus
In the early 1980s, university-based __ophthalmologists__ in the U.S.A. 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]. [|[12]] Side effects were deemed to be rare, mild and treatable. [|[13]] 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 micro-manufacturer 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. [|[14]] In December 1989, Botox, manufactured by [|Allergan, Inc.], was approved by the [|U.S. Food and Drug Administration] (FDA) for the treatment of strabismus, blepharospasm, and [|hemifacial spasm] in patients over 12 years old. [|[15]]

Cosmetic
The cosmetic effect of BTX-A on wrinkles was originally documented by a plastic surgeon from Sacramento, California, Dr. Richard Clark, and published in the journal // [|Plastic and Reconstructive Surgery] // in 1989. [|[16]] Canadian husband and wife ophthalmologist and dermatologist physicians Carruthers JD and Carruthers JA were the first to publish a study on BTX-A for the treatment of galbellar frown lines in 1992. [|[17]] Similar effects had reportedly been observed by a number of independent groups (Brin, and the Columbia University group). 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). [|[18]] Subsequently, cosmetic use of botulinum toxin type A has become widespread with many celebrities viewing it as less intrusive and/or artificial than other types of plastic surgery. The results of cosmetic procedures vary but can last up to eight months. [|[19]] The U.S. 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. [|[20]] [|[21]]

Muscle spasms
The acceptance of BTX-A use for the treatment of muscle pain disorders is growing, with approvals pending in many European countries. The efficacy of BTX-A in treating a variety of other medical conditions (including [|prostatic] dysfunction, [|asthma], and others) is an area of continued study.

Upper motor neuron syndrome
BTX-A is now a common treatment for muscles affected by the [|upper motor neuron] syndrome such as [|cerebral palsy], for muscles with an impaired ability to effectively [|lengthen]. Muscles affected by the Upper Motor Neuron Syndrome frequently are limited by [|weakness], loss of [|reciprocal inhibition] , decreased movement control and hypertonicity (including [|spasticity] ). Joint motion may be restricted by severe muscle imbalance related to the Upper Motor Neuron 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, and so improved ability to move and exercise. In June 2009, its use for treating hypertonic muscles helped an Australian man to walk again. He had required a wheelchair for mobility following a stroke 20 years prior. [|[22]]

Sweating
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. [|[11]] This was the first demonstration of non-muscular 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.

Cervical dystonia
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
OnabotulinumtoxinA (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. [|[23]][|[24]] Since then, several randomized control trials have shown Botulinum Toxin Type A to improve headache symptoms and quailty of life when used prophylactically for patients with chronic [|migraine][|[25]] who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), "detoxification" of patients with co-existing chronic daily headache due to medication overuse, no current history of other preventative headache medications. [|[26]]

Denaturing
Botulinum toxin is [|denatured] at temperatures greater than 80 °C (176 °F). [|[27]]

** Botulinum Rejuvenation **

Botulinum rejuvenation is a procedure that can erase years from the face or neck by reducing the appearance of lines and wrinkles. Because the injections are quick, side effects minimal, and the procedure does not generally require downtime, this is one of the most popular cosmetic procedures in the United States. **Signs of Aging Treated**  In some cases, a dermatologist may inject botulinum toxin into another area to help diminish signs of aging. Botulinum rejuvenation also may be used along with another cosmetic procedure to give you a more youthful appearance. 
 * Also Called**
 * Botox®
 * Botulinum toxin
 * Botulinum toxin type A
 * Botulinum toxin type B
 * Crow’s feet
 * Forehead lines
 * Frown lines between the eyebrows
 * Neck bands and lines