Botulin toxin, popularly sold under the brand name Botox, is an exceptionally potent neurotoxin that has found a variety of remarkable uses in modern medicine. It is also the most popular nonsurgical medical cosmetic treatment in the UK and USA.
Botulinum (botulinus) toxin is the toxic compound produced by the bacterium Clostridium botulinum. The names Botox and Dysport are trade names and should not be used generically to describe the neurotoxins produced by Clostridia species. There are seven serologically distinct toxin types, designated A through G; 3 subtypes of A have been described. The toxins incorporate an enzyme (a protease) that attacks one of the fusion proteins 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 paralysis of muscles in botulism. The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulphide bond to a 50-kDa light chain.
It is possibly the most acutely toxic substance known, with a lethal dose of about 200-300 pg/kg, meaning that somewhat over a hundred grams could kill every human living on the earth (for perspective, the rat poison Strychnine, often described as highly toxic, has an LD50 of 1 mg/kg, or 1 billion pg/kg). It is also remarkably easy to come by: Clostridium spores are found in soil practically all over the earth. Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) where the environment is anaerobic, allowing the spores to germinate and grow. The growing (vegetative) bacteria produce toxin; ingestion of preformed toxin causes botulism, not ingestion of the spores or vegetative organism. Infant (intestinal) and wound botulism both result from infection with spores which subsequently germinate, resulting in production of toxin and the symptoms of botulism.
The German physician and poet Justinus Kerner called botulinum toxin "sausage poison", as this bacterium often causes poisoning cases by growing in badly-handled made-up meat items. He first developed the idea of a possible therapeutic use of botulinum toxin. In 1870, Muller (another German physician) coined the name botulism, from Latin botulus = "sausage". In 1895, Emile Van Ermengem first isolated the bacterium Clostridium botulinum. In 1944, Edward Schantz cultured Clostridium botulinum and isolated the toxin, and, in 1949, Burgen's group discovered that botulinum toxin blocks neuromuscular transmission. Throughout the 1950s, the toxin was used experimentally in the medical cosmetic treatment of politicians. Then actor-turned-politician Ronald Reagan is rumoured to be one of the earliest patients of this microexpression-concealing procedure.
By 1973, Alan B Scott, MD, of Smith-Kettlewell Eye Research 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. In December 1989, BTX-A (BOTOX) was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients aged older than 12 years. The cosmetic effect of BTX-A was initially described by the Carruthers, a dermatologist/ophthalmologist husband and wife team although the effect had been observed by a number of independent groups. BTX-A received FDA approval for treatment of cervical dystonia on December 21, 2000. On April 15, 2002, the FDA announced the approval of botulinum toxin type A (BOTOX Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). BTX-A has also been approved for the treatment of excessive underarm sweating. The acceptance of BTX-A use for the treatment of spasticity and muscle pain disorders is growing, with approvals pending in many European countries and studies on headaches (including migraine), prostatic symptoms, asthma, obesity and many other possible indications are ongoing.
Dysport is a therapeutic formulation of the type A toxin developed and manufactured in the UK and which is licenced for the treatment of focal dystonias and certain cosmetic uses in many territories world wide.
Botulin toxin has always been considered an inferior agent for chemical warfare since it degrades rapidly on exposure to air, and therefore an area attacked with the toxic aerosol would be safe to enter within a day or so. There are no documented cases of the toxin's actually being used in warfare; however, it was probably used in the Operation Anthropoid to kill top Nazi Reinhard Heydrich () and in "Operation Mongoose" in 1961, the CIA saturated some cigars, of Fidel Castro's favorite brand, with botulinum toxin for a possible assassination attempt. The cigars were never used, but when tested years later were found still effective. .
There has been concern over the use of botulin toxin as a terrorist weapon, but it appears not to be ideal for this purpose. The vials used therapeutically are considered impractical as weapons because each vial contains only an extremely small fraction of the lethal dose. Nor is home-growing very viable; the bacterium in question is anaerobic and grows poorly in the presence of oxygen. This would make it difficult for terrorists to produce the toxin in bulk.
The toxin's properties did not escape the attention of the Aum Supreme Truth cult in Japan, who had set up a plant for bulk production of this agent, though their assassination and other attacks used the nerve agent sarin instead, because of its easy dispersal and faster-acting properties.
Researchers discovered in the 1950s that injecting overactive muscles with minute quantities of botulinum toxin type A decreased muscle activity by blocking the release of acetylcholine at the neuromuscular junction, thereby rendering the muscle unable to contract for a period of 4 to 6 months.
Alan Scott, a San Francisco ophthalmologist, first applied tiny doses of the toxin in a medicinal sense to treat crossed eyes and uncontrollable blinking, but a partner was needed to gain regulatory approval to market his discovery as a drug. Allergan, Inc., a small pharmaceutical company that focused on prescription eye therapies and contact lens products, bought the rights to the drug in 1988 and quickly received FDA approval in 1989. Allergan renamed the drug Botox.
Cosmetic benefits of Botox were quickly realized when the frown lines between the eyebrows appeared to soften following treatment for eye muscle disorders. The increased potential of Botox as a cosmetic treatment led to clinical trials and subsequent FDA approval in April 2002.
Currently, Botox is finding enormous additional potential in several therapeutic areas including the treatment of migraine headaches, cervical dystonia (a neuromuscular disorder involving the head and neck), blepharospasm (involuntary contraction of the eye muscles), and severe primary axillary hyperhidrosis (excessive sweating). Other uses of botulinum toxin type A that are widely known but not approved by FDA include urinary incontinence, anal fissure, spastic disorders associated with injury or disease of the central nervous system including trauma, stroke, multiple sclerosis, or cerebral palsy and focal dystonias affecting the limbs, face, jaw, or vocal cords. It is also used off label for the treatment of TMJ, but a side effect in some patients is a jaw left too weak to chew solid food for about 3 months after the injection. 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.
Chemical mechanism of toxicity
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 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. The light chain is able to leave 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 the release of neurotransmitter substances from the axon endings . Botulin toxin specifically cleave these SNAREs, and so prevent neuro-secretory vesicles from docking/fusing with the nerve synapse plasma membrane and releaseing their neurotransmitters.
Though it affects the nervous system, common nerve agent treatments (namely the injection of atropine and 2-pam-chloride) will increase mortality by enhancing botulin toxin's mechanism of toxicity. Attacks involving botulin 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.
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