Botulin toxin

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Botulin toxin, popularly sold under the brand name Botox®, is an incredibly potent neurotoxin that has found a variety of remarkable uses in modern medicine and biological warfare. It is also the most popular nonsurgical medical cosmetic treatment in the UK and USA.

Contents

Chemical Overview

Botulin toxin is the toxic compound produced by the bacterium Clostridium botulinum. It is a protease that breaks down one of the fusion proteins (docking proteins that anchor the vesicle to the membrane) that allow neurons to release acetylcholine at a neuromuscular junction. 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-kD light chain.

It is possibly the most 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. The spores are found in soil practically all over the earth, and if soil is included in a can or jar of poorly preserved food, the bacterium could grow and produce toxin.

History

The German physician and poet Justinus Kerner first developed the idea of a possible therapeutic use of botulinum toxin, which he called "sausage poison." In 1870, Muller (another German physician) coined the name botulism. The Latin form is botulus, which means 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 younger than 12 years. BTX-A received FDA approval for treatment of cervical dystonia on December 21, 2000. Finally 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). Although it has not been approved by the FDA for any other indications, the acceptance of BTX-A use for the treatment of spasticity and muscle pain disorders is growing, with approvals pending in many European countries.

Biological Warfare

Botulin toxin has always been considered an ideal agent for biological warfare since it oxidises rapidly on exposure to air, so an area attacked with a toxin 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 in "Operation Mongoose" in 1961, the CIA prepared some cigars of Fidel Castro's favorite brand which had been saturated with botulinum toxin, for the possibility of an assassination attempt. The cigars were never used, but when tested years later were still found to be effective. [1].

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 of toxin used therapeutically are considered impractical for use by terrorists because each vial has only an extremely small fraction of the lethal dose for humans. Another reason the toxin is considered impractical is that the bacterium in question is anaerobic (cannot survive in the presence of oxygen). This would make it extremely difficult for terrorists to produce enough of the toxin to launch a significant attack.

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 terrorist attacks used the nerve agent sarin instead, it being easier to disperse and faster acting.

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 4-6 months.

Alan Scott, a San Francisco opthamologist, 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 comsmetic 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. 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. The SNAP-25 protein is required for the release of neurotransmitter substances from the axon endings [2].

Botox, as a chemical weapon, has symptoms comparable to G-nerve agents such as Sarin . However, common first aid treatments, (namely the injection of atropine and 2-pam-chloride,)will INCREASE mortality by enhancing botox's mechanism of toxicity. Attacks involving botox 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.

External links

References

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