Botulinum toxin
Overview
Botulinum toxin is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 produced by the bacterium Clostridium botulinum
Clostridium botulinum
Clostridium botulinum is a Gram-positive, rod-shaped bacterium that produces several toxins. The best known are its neurotoxins, subdivided in types A-G, that cause the flaccid muscular paralysis seen in botulism. It is also the main paralytic agent in botox. C. botulinum is an anaerobic...

, and is considered the most powerful neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

 ever discovered. Botulinum toxin causes Botulism
Botulism
Botulism also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin which is metabolic waste produced under anaerobic conditions by the bacterium Clostridium botulinum, and affecting a wide range of mammals, birds and fish...

 poisoning, a serious and life-threatening illness in humans and animals. When introduced intravenously in monkeys, type A (Botox Cosmetic) of the toxin exhibits an LD50 of 40-56 ng, type C1 around 32 ng, type D 3200 ng, and type E 88 ng, rendering the above types some of the most powerful neurotoxins known.
Encyclopedia
Botulinum toxin is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 produced by the bacterium Clostridium botulinum
Clostridium botulinum
Clostridium botulinum is a Gram-positive, rod-shaped bacterium that produces several toxins. The best known are its neurotoxins, subdivided in types A-G, that cause the flaccid muscular paralysis seen in botulism. It is also the main paralytic agent in botox. C. botulinum is an anaerobic...

, and is considered the most powerful neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

 ever discovered. Botulinum toxin causes Botulism
Botulism
Botulism also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin which is metabolic waste produced under anaerobic conditions by the bacterium Clostridium botulinum, and affecting a wide range of mammals, birds and fish...

 poisoning, a serious and life-threatening illness in humans and animals. When introduced intravenously in monkeys, type A (Botox Cosmetic) of the toxin exhibits an LD50 of 40-56 ng, type C1 around 32 ng, type D 3200 ng, and type E 88 ng, rendering the above types some of the most powerful neurotoxins known. Popularly known by one of its trade names, Botox or Dysport or Xeomin, it is used for various cosmetic and medical procedures.

History

Justinus Kerner
Justinus Kerner
Justinus Andreas Christian Kerner was a German poet and medical writer.-Life:He was born at Ludwigsburg in Württemberg...

 described botulinum toxin as a "sausage poison" and "fatty poison", 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
Botulism
Botulism also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin which is metabolic waste produced under anaerobic conditions by the bacterium Clostridium botulinum, and affecting a wide range of mammals, birds and fish...

 (from Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

 botulus meaning "sausage"). In 1897, Emile van Ermengem
Émile van Ermengem
Émile Pierre-Marie van Ermengem was a Belgian bacteriologist who, in 1895, isolated Clostridium botulinum, the bacterium that causes botulism, from a piece of ham that had poisoned thirty four people....

 identified the bacterium Clostridium botulinum to be the producer of botulinum toxin. In 1928, P. Tessmer Snipe and Hermann Sommer for the first time purified the toxin. In 1949, Arnold Burgen's group discovered, through an elegant experiment, that botulinum toxin blocks neuromuscular transmission through decreased acetylcholine release.

Therapeutic research

In the late 1960s Alan Scott, M.D., a San Francisco ophthalmologist, and Edward Schantz were the first to work on a standardized botulinum toxin preparation for therapeutic purposes. By 1973, Scott (now at Smith-Kettlewell Institute
Smith-Kettlewell Institute
The Smith-Kettlewell Eye Research Institute in San Francisco was formed in 1959 by Arthur Jampolsky on the former campus of the Stanford Medical School.The current interim director of Smith-Kettlewell is Arthur Jampolsky.Major Work:...

) 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
Strabismus
Strabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...

 "crossed eyes", a condition in which the eyes are not properly aligned with each other, and "uncontrollable blinking" (blepharospasm
Blepharospasm
A blepharospasm , is any abnormal contraction or twitch of the eyelid....

). In 1993, Pasricha and colleagues showed that botulinum toxin could be used for the treatment of achalasia
Achalasia
Achalasia , also known as esophageal achalasia, achalasia cardiae, cardiospasm, and esophageal aperistalsis, is an esophageal motility disorder involving the smooth muscle layer of the esophagus and the lower esophageal sphincter...

, a spasm of the lower esophageal sphincter. In 1994 Bushara showed that botulinum toxin injections inhibit sweating. 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. Side effects 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 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.

In December 1989, Botox, manufactured by Allergan, Inc.
Allergan
Allergan, Inc., is a global specialty pharmaceutical company. Their product ranges include ophthalmic pharmaceuticals, dermatology products, and neurological products.-Profile:...

, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm
Hemifacial spasm
Hemifacial spasm or HFS is a neurological disorder in which blood vessels constrict the seventh cranial nerve and cause varying degrees of facial spasm, typically originating around the eye of the afflicted side of the face...

 in patients over 12 years old.

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. 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 glabella
Glabella
The glabella, in humans, is the space between the eyebrows and above the nose. It is slightly elevated, and joins the two superciliary ridges.-Etymology:The term is derived from the Latin glabellus, meaning smooth, as this area is usually hairless....

r frown lines in 1992.
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). 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.
The U.S. Food and Drug Administration approved an alternative product-safety testing method in response to increasing public concern that LD50
LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...

 testing was required for each batch sold in the market.

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
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....

 dysfunction, asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

, 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
Upper motor neuron
Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle...

 syndrome, for muscles with an impaired ability to effectively lengthen. Muscles affected by the Upper Motor Neuron Syndrome frequently are limited by weakness
Weakness
Weakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. 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...

, loss of reciprocal inhibition
Reciprocal inhibition
“ When the central nervous system sends a message to the agonist to contract, the tension in the antagonist is inhibited by impulses from motor neurons, and thus must simultaneously relax. This neural phenomenon is called reciprocal inhibition. This information can be used to ease the pain of an...

, decreased movement control and hypertonicity (including spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

). 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.

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. This was the first demonstration of non-muscular use of BTX-A. Bushara further showed the efficacy of botulinum toxin in treating hyperhidrosis
Hyperhidrosis
Hyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...

 (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
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

 on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.

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 headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

s. 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.

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
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...

 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.

Denaturing

Botulinum toxin is denatured
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...

 at temperatures greater than 60 °C (140 °F).

Sources

Botulism toxins are produced by these bacteria: Clostridium botulinum
Clostridium botulinum
Clostridium botulinum is a Gram-positive, rod-shaped bacterium that produces several toxins. The best known are its neurotoxins, subdivided in types A-G, that cause the flaccid muscular paralysis seen in botulism. It is also the main paralytic agent in botox. C. botulinum is an anaerobic...

, C. butyricum, C. baratii and C. argentinense.
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 twelve months old should not be fed honey. Honey is safe for persons one year of age and older.

Chemical overview and lethality

There are seven serologically distinct toxin types, designated A through G. Additionally, six of the seven 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
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

 to a 50-kDa light chain. This light chain is an enzyme (a protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...

, preventing vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

s from anchoring to the membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

 to release acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism
Botulism
Botulism also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin which is metabolic waste produced under anaerobic conditions by the bacterium Clostridium botulinum, and affecting a wide range of mammals, birds and fish...

, as opposed to the spastic paralysis seen in tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...

.

It is the most acutely toxic substance known, with a median lethal dose of about 1 ng/kg when introduced intravenously and 3 ng/kg when inhaled. This means that, depending on the method of introduction into the body, a mere 90–270 nanograms of botulinum toxin could be enough to kill an average 90 kg (200 lb) person, and four kilograms of the toxin, if evenly distributed, would be more than enough to kill the entire human population of the world.

Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) in an anaerobic environment
Hypoxia (environmental)
Hypoxia, or oxygen depletion, is a phenomenon that occurs in aquatic environments as dissolved oxygen becomes reduced in concentration to a point where it becomes detrimental to aquatic organisms living in the system...

, allowing the spores to germinate and grow. The growing (vegetative) bacteria produce toxin. It is the ingestion of preformed toxin that causes botulism
Botulism
Botulism also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin which is metabolic waste produced under anaerobic conditions by the bacterium Clostridium botulinum, and affecting a wide range of mammals, birds and fish...

, 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 and low pH levels. The toxin itself is rapidly destroyed by heat, such as in thorough cooking. On the other hand, the spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time. Fortunately, ingestion of the spores is safe, except in infants, as the highly oxygenated and highly acidic environment of an adult human digestive system prevents the spores from growing and producing the botulinum toxin.

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

Medical uses

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

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
Facial muscles
The facial muscles are a group of striated muscles innervated by the facial nerve that, among other things, control facial expression. These muscles are also called mimetic muscles.-Structure:...

. 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
American Society of Plastic Surgeons
The American Society of Plastic Surgeons 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 Physicians and Surgeons of Canada who perform Plastic and...

. 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 lasts for approximately three to four months, up to six months.

In addition to its cosmetic applications, Botox is currently used in the treatment of spasm
Spasm
In medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...

s and dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

s, by weakening involved muscles, for the 60-70 day effective period of the drug.
The main conditions treated with botulinum toxin are:
  • Cervical dystonia
    Dystonia
    Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

     (spasmodic torticollis
    Torticollis
    Torticollis, or wryneck, is a stiff neck associated with muscle spasm, classically causing lateral flexion contracture of the cervical spine musculature...

    ) (a neuromuscular disorder involving the head and neck)
  • Blepharospasm
    Blepharospasm
    A blepharospasm , is any abnormal contraction or twitch of the eyelid....

     (excessive blinking)
  • Severe primary axillary hyperhidrosis
    Hyperhidrosis
    Hyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...

     (excessive sweating)
  • Strabismus
    Strabismus
    Strabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...

     (Squints)
  • Achalasia
    Achalasia
    Achalasia , also known as esophageal achalasia, achalasia cardiae, cardiospasm, and esophageal aperistalsis, is an esophageal motility disorder involving the smooth muscle layer of the esophagus and the lower esophageal sphincter...

     (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.
  • Migraine
    Migraine
    Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...

     and other headache disorders, although the evidence is conflicting in this indication
  • Excessive sweating is a condition for the treatment of which FDA has approved the use of Botox.


Other uses of botulinum toxin type A that are widely known but not specifically approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (off-label uses) include treatment of:
  • Idiopathic and neurogenic detrusor overactivity,
  • Pediatric incontinence, incontinence due to overactive bladder, and incontinence due to neurogenic bladder
    Neurogenic bladder
    Neurogenic bladder refers to dysfunction of the urinary bladder due to disease of the central nervous system or peripheral nerves involved in the control of micturition .-Causes:...

    .
  • Anal fissure
    Anal fissure
    An anal fissure is a break or tear in the skin of the anal canal. Anal fissures may be noticed by bright red anal bleeding on the toilet paper, sometimes in the toilet. If acute they may cause severe periodic pain after defecation but with chronic fissures pain intensity is often less...

  • vaginismus
    Vaginismus
    Vaginismus, sometimes anglicized vaginism, is the German name for a condition which affects a woman's ability to engage in any form of vaginal penetration, including sexual intercourse, insertion of tampons and/or menstrual cups, and the penetration involved in gynecological examinations...

     To reduce the spasm of the vaginal muscles.
  • Movement disorders associated with injury or disease of the central nervous system
    Central nervous system
    The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

     including trauma, stroke
    Stroke
    A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

    , multiple sclerosis
    Multiple sclerosis
    Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

    , Parkinson's disease
    Parkinson's disease
    Parkinson's disease is a degenerative disorder of the central nervous system...

    , or cerebral palsy
    Cerebral palsy
    Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....

  • Focal dystonia
    Dystonia
    Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

    s affecting the limbs, face, jaw, or vocal cords
  • TMJ
    Temporomandibular joint
    The temporomandibular joint is the joint of the jaw and is frequently referred to as TMJ. There are two TMJs, one on either side, working in unison. The name is derived from the two bones which form the joint: the upper temporal bone which is part of the cranium , and the lower jaw bone called the...

     pain disorders
  • Diabetic neuropathy
  • Wound healing
  • Excessive salivation
  • Vocal cord dysfunction
    Vocal cord dysfunction
    Vocal cord dysfunction is a condition that affects the vocal folds, commonly referred to as the vocal cords, which is characterized by full or partial vocal fold closure that usually occurs during inhalation for short periods of time; however, can occur during both inhalation and exhalation....

     (VCD) including spasmodic dysphonia and tremor
  • Reduction of the Masseter muscle for decreasing the apparent size of the lower jaw
    Jaw reduction
    Jaw reduction is a type of surgery in which the objective of treatment is to narrow the lower one-third of the face—particularly the contribution from the mandible and its muscular attachments. There are several techniques for treatment—including surgical and non surgical methods.-Facial...

  • Painful bladder syndrome,
  • Detrusor sphincter dyssynergia and benign prostatic hyperplasia,


Treatment and prevention of chronic headache and chronic musculoskeletal pain are emerging uses for botulinum toxin type A. In addition, there is evidence that Botox may aid in weight loss by increasing the gastric emptying time.

Links to deaths

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.

On February 8, 2008, the FDA announced that 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. 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.

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.

Several cases of death have been linked to the use of other chemicals as substitutes for Botox, one of the causes of death listed on the Spike TV
Spike TV
Spike is an American cable television channel. It launched on March 7, 1983 as The Nashville Network , a joint venture of WSM, Inc...

 show, 1000 Ways to Die
1000 Ways to Die
1000 Ways to Die is a docufiction anthology television series that premiered on May 14, 2008 on Spike. The program recreates unusual supposed deaths and debunked urban legends and includes interviews with experts who describe the science behind each death...

.

Also, in 2001, US President George W. Bush, his Secretary of State Colin Powell, National Security Advisor Condoleeza Rice, and Chief of Staff Andy Card were all thought to have been exposed to the toxin. It turned out to be a false alarm.

Side effects

Side effects, which are generally minor and temporary, 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, double vision, 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 7–11 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. All cosmetic treatments are of limited duration, and can be as short a period 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 toxicity.

Other adverse events from cosmetic use include headaches, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

, flu-like syndromes, blurred vision, dry mouth, fatigue, allergic reactions and swelling or redness at the injection site.

There has been a petition by Public Citizen
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts:Public Citizen...

 to the FDA requesting regulatory action concerning the possible spread of botulinum toxin (Botox, Myobloc) from the site of injection to other parts of the body.

Individuals who are pregnant, have egg allergies or a neuromuscular disorder are advised to avoid Botox.

A recent experimental study suggests that cosmetic use of botulinum toxin for treatment of glabellar lines affects human cognition. Havas and colleagues (Havas, Glenberg, Gutowski, Lucarelli, & Davidson, 2010) asked participants to read emotional (angry, sad, happy) sentences before and two weeks after botox injections in the corrugator supercilii muscle used in frowning. Reading times for angry and sad sentences were longer after botox injection than before injection, while reading times for happy sentences were unchanged. This finding suggests that facial muscle paralysis has a selective effect on processing of emotional content.

As published in Forbes and originally published in the journal Social Psychology and Personality Science, Botox takes away or dampens the emotional feelings in a particular situation. That may be due to less interaction between facial muscle movement and brain.
According to David Neal, a psychology professor at the University of Southern California, “if muscular signals from the face to the brain are dampened, you’re less able to read emotions.”

Biochemical mechanism of toxicity

]
The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

 terminals. The toxin must get inside the axon terminals in order 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
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...

. The light chain is able to cleave endocytotic vesicles and reach the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

. The light chain of the toxin has protease activity. The type A toxin proteolytically degrades the SNAP-25 protein
SNAP-25
Synaptosomal-associated protein 25 is a protein that in humans is encoded by the SNAP25 gene. The SNAP-25 protein is a component of the SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the...

, a type of SNARE protein. The SNAP-25 protein is required for vesicle fusion
Vesicle fusion
Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis at the porosome...

 that releases neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s from the axon endings (in particular Acetylcholine). Botulinum toxin specifically cleaves these SNAREs, and so prevents neuro-secretory 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
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...

 and 2-pam-chloride) will increase mortality by enhancing botulin toxin's mechanism of toxicity. 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

If the symptoms of botulism are diagnosed early, an equine antitoxin, use of enemas, and extracorporeal
Extracorporeal
An extracorporeal medical procedure is a medical procedure which is performed outside the body.-Circulatory procedures:A procedure in which blood is taken from a patient's circulation to have a process applied to it before it is returned to the circulation...

 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, nerve conduction test, and a tensilon test for myasthenia gravis in order to differentiate botulism from other diseases that manifest in the same way. Electromyography (EMG) can be utilized to differentiate myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...

 and Guillain-Barré syndrome
Guillain-Barré syndrome
Guillain–Barré syndrome , sometimes called Landry's paralysis, is an acute inflammatory demyelinating polyneuropathy , a disorder affecting the peripheral nervous system. Ascending paralysis, weakness beginning in the feet and hands and migrating towards the trunk, is the most typical symptom...

, 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 idientifying botulism. Laboratory tests of the patient's serum or stool, which are then injected into mice are also indicative of botulism. But the faster way to detect botulinum toxin in people 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.

The case fatality rate for botulinum poisoning between 1950 and 1996 was 15.5%, down from approximately 60% over the previous 50 years. 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. Occasionally, functional recovery may take several weeks to months or more.

There are two primary Botulinum Antitoxins available for treatment of botulism.
  • Trivalent
    Valence (chemistry)
    In chemistry, valence, also known as valency or valence number, is a measure of the number of bonds formed by an atom of a given element. "Valence" can be defined as the number of valence bonds...

     (A,B,E) Botulinum Antitoxin
    Antitoxin
    An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

     is derived from equine sources utilizing whole antibodies (Fab & Fc portions). This antitoxin
    Antitoxin
    An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

     is available from the local health department via the CDC in the USA.

  • The second antitoxin
    Antitoxin
    An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

     is Heptavalent (A,B,C,D,E,F,G) Botulinum Antitoxin
    Antitoxin
    An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

    , which is derived from "despeciated" equine IgG antibodies, which have had the Fc portion cleaved off leaving the F(ab')2 portions. This is a less immunogenic antitoxin
    Antitoxin
    An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

     that is effective against all known strains of botulism where not contraindicated. This is available from the United States Army. On June 1, 2006 the United States Department of Health and Human Services awarded a $363 million contract with Cangene Corporation for 200,000 doses of Heptavalent Botulinum Antitoxin
    Antitoxin
    An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

     over five years for delivery into the Strategic National Stockpile
    Strategic National Stockpile
    The Strategic National Stockpile is the United States' national repository of antibiotics, vaccines, chemical antidotes, antitoxins and other critical medical equipment and supplies...

     beginning in 2007.

Manufacturers

In the United States, BOTOX is manufactured by Allergan, Inc. for both therapeutic and cosmetic use (100Unit). In the United States, Xeomin (manufactured in Germany by Merz
Merz Pharma
Merz Pharma GmbH & Co. KGaA is an international healthcare company specializing in the research, development and marketing of pharmaceuticals for the treatment of neurological and psychiatric diseases...

) is available for both therapeutic and cosmetic use.

Dysport, a therapeutic formulation of the type A toxin developed and manufactured in Ireland, is licensed for the treatment of focal dystonias and certain cosmetic uses in the US and worldwide in 100, 300 and 500 Units. Lanzhou Institute (China) manufactures a BTX-A product, producing 50U and 100U type A toxin. Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea, in 2009. Merz manufactures the toxin and sells it under the trade name Xeomin. Solstice Neurosciences sells their product under the names Myobloc or Neurobloc, although it contains Botulinum Toxin Type B, not the common Type A found in Botox.

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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