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Botulinum toxin

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Botulin toxin is a neurotoxic protein produced by the bacterium clostridium botulinum. Though it is highly toxic, it is used in minute doses as a cosmetic treatment in some parts of the world, and it is sold commercially under the brand names Botox® and Dysport® for this purpose. The terms Botox and Dysport are trade names and are not used generically to describe the neurotoxins produced by Clostridia species.

History

The German physician and poet Justinus Kerner called botulinum toxin "sausage poison", as this bacterium often causes poisoning cases by growing in badly handled prepared meat products. He first conceived 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 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 over 12 years old. 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. 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.

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.

Medical uses

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 needed a partner 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 received FDA approval in 1989. Allergan renamed the drug Botox.

Cosmetically desirable effects of Botox were quickly discovered thereafter when the frown lines between the eyebrows were observed to soften following treatment for eye muscle disorders, leading to clinical trials and subsequent FDA approval for cosmetic use in April 2002. As of 2006, botox injection is the most common cosmetic operation in the United States.

Besides its cosmetic application, Botox is used in the treatment of

  • migraine headaches
  • cervical dystonia (a neuromuscular disorder involving the head and neck)
  • blepharospasm (involuntary contraction of the eye muscles)
  • severe primary axillary hyperhidrosis (excessive sweating)

Other uses of botulinum toxin type A that are widely known but not specifically approved by FDA include:

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.

A side effect in some patients is a jaw left too weak to chew solid food for about 3 months after the injection. In addition, the cosmetic treatment generally wears off after 6 months.

Chemical overview

There are seven serologically distinct toxin types, designated A through G; 3 subtypes of A have been described. The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulphide bond to a 50-kDa light chain. This light chain is 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. 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 on 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) in an anaerobic environment, 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.

Chemical warfare

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 actually being used in warfare; however, it was probably used in the Operation Anthropoid to kill top Nazi Reinhard Heydrich ([1]) and in "Operation Mongoose", where 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. [2].

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.

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 [3]. Botulin toxin specifically cleave these SNAREs, and so prevent 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 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.

Mini Botox

Mini Botox products include various creams and gels that contain special agents, which help the skin to regenerate and make it firmer and younger. Most of these Mini Botox preparations comprise of the main substances, such as antioxidants, vitamins, natural fruit acids, DMEA, and carnauba wax. Antioxidative agents help to prevent the destructive action of free radicals. These agents repair and stop disruption of the skin cells. Another component, natural fruit acids, maintain the important moisture balance in the skin, which make the skin firmer. DMEA, known as 2-dimethyl-amino-ethanol, is also one of the components of Mini Botox creams. The action of this agent is to make the skin muscles firmer and activate distribution in the skin. Carnauba wax on the other hand is used to fill in the lines in order for the face to look younger.

References

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