Botulinum toxin is a medication and a neurotoxic protein produced by the bacterium Clostridium botulinum, and is held to be the most toxic substance known to mankind[1][2] with an LD50 of roughly 0.005-0.05 µg/kg. Despite its deadly toxic effect, it is sometimes used in very small doses to treat muscle spasms.[citation needed].
History
Between 1817 and 1822, the German physician and poet Justinus Kerner described botulinum toxin as a "sausage poison" and "fatty poison",[3], as this bacterium often caused poisoning by growing in improperly handled or prepared meat products. It was Kerner who first conceived a possible therapeutic use of botulinum toxin. In 1870, Müller, another German physician, coined the name botulism. (In Latin, botulus means "sausage.") In 1897, Emile van Ermengem identified the bacterium Clostridium botulinum to be the producer of botulinum toxin.[4] In 1928, P. Tessmer Snipe and Hermann Sommer for the first time purified the toxin.[5] In 1949, Burgen's group discovered that botulinium toxin blocks neuromuscular transmission. In the late 1960s Allan Scott and Edward Schantz were the first to work on a standardized botulinum toxin preparation for therapeutic purposes.[6]
Other bacteria that produce botulinum toxin are Clostridium butyricum, C.baratii and C.argentinense.[7]
Botulinum toxin is neutralized at temperatures greater than 60 °C.[8] (140°F) 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, a condition in which the eyes are not properly aligned with each other. 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 ophthalmologist Jean Carruthers and dermatologist Alastair Carruthers, a husband-and-wife team working in Vancouver, Canada, although the effect had been observed by a number of independent groups (Brin, and the Columbia University group). 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. In June, 2009, its use for treating spasticity led a UK doctor to successfully treat an Australian man who had been confined to a wheelchair following a stroke 20 years ago.[9]
Botox is manufactured by Allergan Inc (U.S.) for both therapeutic as well as cosmetic use. Dysport is a therapeutic formulation of the type A toxin developed and manufactured in Ireland and which is licenced for the treatment of focal dystonias and certain cosmetic uses in many territories world wide. Lanzhou Institute (China), manufacturer of BTXA utilized its advanced technology to produce 50U and 100U type A toxin providing a choice of decision for physician. Neuronox is a new type A toxin manufactured by Medy-Tox Inc (South Korea).
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.
Chemical overview and lethality
There are seven serologically distinct toxin types, designated A through G. Additionally, 6 of the 7 toxin types have subtypes with 5 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 to a 50-kDa light chain. This light chain is an enzyme (a protease) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) 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 flaccid (sagging) paralysis of muscles in botulism, as opposed to the spastic paralysis seen in tetanus.
It is the most acutely toxic substance known, with a median lethal dose of about 1 ng/kg when introduced intravenously[10] and 3 ng/kg when inhaled[11]. 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.
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. It is the ingestion of preformed toxin that causes botulism, 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) prevents 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.[12] On the other hand, the spores which produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.[13] Fortunately, ingestion of the spores is safe, except in infants, as the highly oxygenated and highly acidic environment of the digestive system prevents the spores from growing and producing the botulinum toxin.
Medical uses
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 render the muscle unable to contract for up to a period of 3 to 4 months.[citation needed]
Alan Scott, a San Francisco ophthalmologist, first applied tiny doses of the toxin in a medicinal sense to treat 'crossed eyes' (strabismus) and 'uncontrollable blinking' (blepharospasm), but needed a partner to gain regulatory approval to market his discovery as a drug. Allergan renamed the drug Botox.
As of 2007, Botox injection is the most common cosmetic operation, with 4.6 million procedures in the United States, according to the American Society of Plastic Surgeons. Qualifications for Botox injectors vary by county, state and country. Botox Cosmetic providers include dermatologists, plastic surgeons, cosmetic physicians, nurses practitioners, nurses, physician assistants, and medical spas.
Although Botulinum toxin is a lethal naturally occurring substance, when carefully isolated and purified, it can be used as an effective and powerful medication.[14]
In addition to its cosmetic applications, Botox is currently used in the treatment of:
- Cervical dystonia (spasmodic torticollis) (a neuromuscular disorder involving the head and neck)[15]
- Blepharospasm (excessive blinking)[16]
- Severe primary axillary hyperhidrosis (excessive sweating)[17]
- Achalasia (failure of the lower oesophageal sphincter to relax)
- Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone.[18]
- Migraine and other headache disorders, although the evidence is conflicting in this indication[19]
Other uses of botulinum toxin type A that are widely known but not specifically approved by FDA (off-label uses) include treatment of:
Treatment and prevention of chronic headache[24] and chronic musculoskeletal pain[25] 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.[26]
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.[27]
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 to the site of the injection.[28]
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.[29][30]
Several cases of death have been linked to the use of fake Botox.[31]
Side effects
Side effects 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 means that the client will complain of inappropriate facial expression such as drooping eyelid, uneven smile, or loss of the ability to close eyes. This will wear off in around 6 weeks. Bruising is prevented by the clinician applying pressure to the injection site, but may still occur, and will last around 7 – 10 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 one sees an effective period of between 3 and 8 months. At the extremely low doses used medicinally, botulinum toxin has a very low degree of toxicity.
Reported adverse events from cosmetic use includes headaches, focal facial paralysis, muscle weakness, dysphagia, flu-like syndromes, and allergic reactions.[27]
There has been a petition by 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 (HRG Publication #1834): Public Citizen
Biochemical mechanism of toxicity
Target molecules of botulinum (BoNT) and tetanus (TeNT) toxins inside the axon terminal.
[1]
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 cleave 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 neurotransmitters from the axon endings.[32] 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 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.
Documented outbreaks
Bon Vivant incident
On July 2, 1971, the U.S. Food and Drug Administration (FDA) released a public warning after learning that a New York man had died and his wife had become seriously ill due to botulism after eating a can of Bon Vivant vichyssoise soup. The company began a recall of the 6,444 cans of vichyssoise soup made in the same batch as the can known to be contaminated. The FDA discovered that the company’s processing practices raised questions not only about these lots of the vichyssoise, but also about all other products packed by the company. The effectiveness check of the recall had revealed a number of swollen or otherwise suspect cans among Bon Vivant’s other products, so FDA extended the recall to include all Bon Vivant products. The FDA shut down the company’s Newark, New Jersey plant on July 7, 1971. Only five cans of Bon Vivant soup were found to be contaminated with the botulin toxin, all in the initial batch of vichyssoise recalled and part of the first 324 cans tested. The ordeal destroyed public confidence in the company’s products and the Bon Vivant name. Bon Vivant filed for bankruptcy within a month of the announcement of the recall.[33]
Treatment of botulinum poisoning
The case fatality rate for botulinum poisoning between 1950 and 1996 was 15.5%, down from approximately 60% over the previous 50 years.[34] 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.[35] Occasionally, functional recovery may take several weeks to months.
There are two primary Botulinum Antitoxins available for treatment of botulism.
- Trivalent (A,B,E) Botulinum Antitoxin is derived from equine sources utilizing whole antibodies (Fab & Fc portions). This antitoxin is available from the local health department via the CDC in the USA.
- The second antitoxin is Heptavalent (A,B,C,D,E,F,G) Botulinum Antitoxin 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 that is effective against all known strains of botulism where not contraindicated. This is available from the US Army. On June 1, 2006 the US Department of Health and Human Services awarded a $363 million contract with Cangene Corporation for 200,000 doses of Heptavalent Botulinum Antitoxin over five years for delivery into the Strategic National Stockpile beginning in 2007.[36].
See also
References
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- ^ FDA Notifies Public of Adverse Reactions Linked to Botox Use
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- ^ "An Examination of FDA’s Recall Authority". Harvard Law School. http://leda.law.harvard.edu/leda/data/729/Curatolo05.html. Retrieved 2007-09-25. "The incident did not take a toll only on the company, however. Bon Vivant did not have adequate records and controls of production lots and distribution in order to trace the products quickly. The company also did not have the finances or manpower necessary to run a successful recall program. As a result, the FDA had to seize all the Bon Vivant soup throughout the country, more than a million cans in all. FDA said the seizure occupied 125 man years of FDA time, enough for 2,000 ordinary factory inspections for preventive purposes."
- ^ "Disease Listing, Botulism Manual, Additional Information". http://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/botulism_manual.htm. Retrieved 2007-08-14.
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External links
