Botulinum toxin

Botulinum toxin
Identifiers
CAS number 93384-43-1
ATC code M03AX01
PubChem CID 5485225
DrugBank DB00083
Chemical data
Formula C6760H10447N1743O2010S32 
Mol. mass 149.322,3223 kDa
Therapeutic considerations
Pregnancy cat.  ?
Legal status  ? (US)
Routes IM (approved),SC, intradermal, into glands

Botulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is known to be highly neurotoxic.[1][2] When introduced intravenously in monkeys, type A 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.[3] Popularly known by one of its trade names, Botox, botulinum toxin is now commonly used for various cosmetic and medical procedures.

Contents

History

Justinus Kerner described botulinum toxin as a "sausage poison" and "fatty poison",[4] as the bacteriu 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 (from Latin botulus meaning "sausage"). In 1897, Emile van Ermengem identified the bacterium Clostridium botulinum to be the producer of botulinum toxin.[5] In 1928, P. Tessmer Snipe and Hermann Sommer for the first time purified the toxin.[6] In 1949, Burgen's group discovered that botulinum toxin blocks neuromuscular transmission.

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.[7] By 1973, Scott (now at 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 "crossed eyes", a condition in which the eyes are not properly aligned with each other, and "uncontrollable blinking" (blepharospasm).

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.[8] Side effects were deemed to be rare, mild and treatable.[9] 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.[10]

In December 1989, BOTOX manufactured by Allergan, Inc., was approved by the U.S. Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.[11]

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.[12] 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 glabellar frown lines in 1992.[13] 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).[14] Subsequently, cosmetic use of botulinum toxin type A has become widespread with many celebrities, such as Kim Kardashian, viewing it as less intrusive and/or artificial than other types of plastic surgery.[15]

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 migraine headaches, prostatic dysfunction, asthma, 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 Syndrome, for muscles with an impaired ability to effectively lengthen. Muscles affected by the Upper Motor Neuron Syndrome frequently are limited by weakness, loss of reciprocal innervation, decreased movement control and spasticity. Joint motion may be restricted by severe muscle imbalance related to the Upper Motor Neuron Syndrome, when some muscles are markedly overactive. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, and so improved ability to exercise. In June 2009 its use for treating muscles with spasticity led a UK doctor to successfully help an Australian man who had required a wheelchair for mobility following a stroke 20 years prior to walk.[16]

Sweating

While treating patients with hemifacial spasm at Southend Hospital in England in 1993, Bushara and Park first showed that botulinum toxin injections inhibit sweating .[17] They further showed the efficacy of botulinum toxin in treating hyperhidrosis (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 on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.

Manufacturers

In the United States, BOTOX is manufactured by Allergan, Inc. 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.

Lanzhou Institute (China) manufactures a BTX-A product, producing 50U and 100U type A toxin.[18]

Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea, in 2009.[19]

Denaturing

Botulinum toxin is denatured at temperatures greater than 60°C (140°F).[20]

Sources

Botulism toxins are produced by these bacteria: Clostridium botulinum, C. butyricum, C. baratii and C. argentinense.[21]

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 disulphide 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[3] and 3 ng/kg when inhaled[22] 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.[23] On the other hand, the spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.[24] 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.[25] Intentional exposure to the toxin in a bioterrorism attack would most likely occur by poisoned food or water, or through breathing in the toxin.[26]

Medical uses

Although botulinum toxin is a lethal naturally occurring substance, it can be used as an effective and powerful medication.[27] 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.[28]

In cosmetics, a Botox injection, consisting of a small dose of botulinum toxin, can be used to prevent formation of wrinkles by paralyzing facial muscles.[29] 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. 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. The wrinkle preventing effect of Botox lasts for approximately three to four months,[29][30] up to six months.[30]

In addition to its cosmetic applications, Botox is currently used in the treatment e.g. spasms and dystonias, by weakening involved muscles, for the 60-70 day effective period of the drug.[31] The main conditions are:

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[42] and chronic musculoskeletal pain[43] 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.[44]

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.[45]

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.[46]

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.[47][48]

Several cases of death have been linked to the use of fake Botox,[49] one of the causes of death listed on the Spike TV show, "1000 Ways to Die".

Side effects

Side effects, which are generally minor and temporary,[29] 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,[29] double vision,[29] 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 7–10 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.[45] 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 three and eight months. At the extremely low doses used medicinally, botulinum toxin has a very low degree of toxicity.

Other adverse events from cosmetic use include headaches, dysphagia, flu-like syndromes, and allergic reactions.[45]

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

Individuals who are pregnant, have egg allergies or a neuromuscular disorder are advised to avoid Botox.[29]

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 shows that facial muscle paralysis has a selective effect on processing of emotional content.

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 vesicle fusion that releases neurotransmitters from the axon endings (in particular Acetylcholine).[50] 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.

Treatment of botulinum poisoning

If the symptoms of botulism are diagnosed early, an equine antitoxin, use of enemas, and extracorporeal 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 and Guillain-Barré syndrome, 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.[51]

The case fatality rate for botulinum poisoning between 1950 and 1996 was 15.5%, down from approximately 60% over the previous 50 years.[52] 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.[53] Occasionally, functional recovery may take several weeks to months or more.

There are two primary Botulinum Antitoxins available for treatment of botulism.

See also

References

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  3. ↑ 3.0 3.1 Arnon, Stephen S.; Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, Lillibridge S, Osterholm MT, O'Toole T, Parker G, Perl TM, Russell PK, Swerdlow DL, Tonat K; Working Group on Civilian Biodefense. (21 February 2001). "Botulinum Toxin as a Biological Weapon: Medical and Public Health Management" (PDF, 0.5 MB). Journal of the American Medical Association 285 (8): 1059–1070. doi:10.1001/jama.285.8.1059. PMID 11209178. http://jama.ama-assn.org/cgi/reprint/285/8/1059.pdf. 
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  39. ↑ Akbar M, Abel R, Seyler TM, Gerner HJ, Möhring K (2007). "Repeated botulinum-A toxin injections in the treatment of myelodysplastic children and patients with spinal cord injuries with neurogenic bladder dysfunction.". BJU Int. 100 (3): 639–45. doi:10.1111/j.1464-410X.2007.06977.x. PMID 17532858. 
  40. ↑ Trzciński R, Dziki A, Tchórzewski M (2002). "Injections of botulinum A toxin for the treatment of anal fissures". The European journal of surgery = Acta chirurgica 168 (12): 720–3. PMID 15362583. 
  41. ↑ Pacik, PT Botox Treatment for Vaginismus Plast Reconst Surg vol 124: 455e-456e Dec. 2009
  42. ↑ Panicker JN, Muthane UB (2003). "Botulinum toxins: pharmacology and its current therapeutic evidence for use". Neurology India 51 (4): 455–60. PMID 14742921. http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2003;volume=51;issue=4;spage=455;epage=460;aulast=Muthane. 
  43. ↑ Charles PD (2004). "Botulinum neurotoxin serotype A: a clinical update on non-cosmetic uses". American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 61 (22 Suppl 6): S11–23. PMID 15598005. 
  44. ↑ Coskun H, Duran Y, Dilege E, Mihmanli M, Seymen H, Demirkol MO (2005). "Effect on gastric emptying and weight reduction of botulinum toxin-A injection into the gastric antral layer: an experimental study in the obese rat model". Obesity surgery : the official journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand 15 (8): 1137–43. doi:10.1381/0960892055002275. PMID 16197786. 
  45. ↑ 45.0 45.1 45.2 Coté TR, Mohan AK, Polder JA, Walton MK, Braun MM (September 2005). "Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases". J. Am. Acad. Dermatol. 53 (3): 407–15. doi:10.1016/j.jaad.2005.06.011. PMID 16112345. 
  46. ↑ FDA Notifies Public of Adverse Reactions Linked to Botox Use
  47. ↑ "Botox chemical may spread, Health Canada confirms". CBC News. 2009-01-13. http://www.cbc.ca/consumer/story/2009/01/13/botox.html. 
  48. ↑ http://www.google.com/hostednews/afp/article/ALeqM5jjXaXXB231Ty8J7Sbi8yeN0EH5tA
  49. ↑ Woman Dies From Fake Botox Injections
  50. ↑ Foran PG, Mohammed N, Lisk GO, et al. (2003). "Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons". J. Biol. Chem. 278 (2): 1363–71. doi:10.1074/jbc.M209821200. PMID 12381720. http://www.jbc.org/cgi/content/full/278/2/1363. 
  51. ↑ "Disease Listing, Botulism Manual, Additional Information". CDC Bacterial, Mycotic Diseases. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/botulism_manual.htm. Retrieved 2010-01-21. 
  52. ↑ "Disease Listing, Botulism Manual, Additional Information - CDC Bacterial, Mycotic Diseases". http://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/botulism_manual.htm. Retrieved 2007-08-14. 
  53. ↑ Turton, K., J. A. Chaddock, and K. R. Acharya. 2002. Botulinum and tetanus neurotoxins: structure, function and therapeutic utility. Trends in Biochemical Sciences 27:552-558.
  54. ↑ "FEMA". http://mmrs.fema.gov/news/publichealth/2006/aug/nph2006-08-03a.aspx. Retrieved 2007-08-14. 

External links

Skeletal muscle relaxants (M03)
Peripherally acting
(primarily antinicotinic,
NMJ block)
Non-depolarizing
Curare alkaloids
Alcuronium · Dimethyltubocurarine · Tubocurarine
4° ammonium agents

ultra-short duration: Gantacurium

short duration: Mivacurium  · Chandonium

intermediate duration: Atracurium  · Cisatracurium  · Fazadinium  · Rocuronium  · Vecuronium

long duration: Doxacurium · Dimethyltubocurarine · Pancuronium · Pipecuronium  · Laudexium  · Gallamine

unsorted: Hexafluronium (Hexafluorenium)
Depolarizing

Choline derivatives: Suxamethonium (Succinylcholine)

Polyalkylene derivatives: Hexamethonium
Botulinum toxin
Centrally acting
Carbamic acid esters
Carisoprodol · Febarbamate · Meprobamate · Methocarbamol · Phenprobamate · Styramate · Tybamate
Bentazepam · Diazepam · Lorazepam · Nitrazepam · Tetrazepam
Anticholinergics (Antimuscarinics)
Cyclobenzaprine · Orphenadrine
Other
Baclofen · Chlormezanone · Chlorphenesin • Chlorzoxazone · Donepezil · Eperisone · Flopropione · Mephenesin · Mephenoxalone · Metaxalone · Phenyramidol · Pridinol · Promoxolane · Quinine · Thiocolchicoside · Tizanidine · Tolperisone · Trazadone
Directly acting
Dantrolene

: MUS, DF+DRCT

anat (h/n, u, t/d, a/p, l)/phys/hist

noco(m, s, c)/cong(d)/tumr, sysi/, injr

proc, drug (M1A/3)
Toxins (enterotoxin/neurotoxin/hemotoxin/cardiotoxin/phototoxin)
Bacterial toxins
Exotoxin
Gram positive
Bacilli

Clostridium: tetani (Tetanospasmin) · perfringens (Alpha toxin, Enterotoxin) · difficile (A, B) · botulinum (Botox)

other: Anthrax toxin · Listeriolysin O
Cocci
Streptolysin · Leukocidin (Panton-Valentine leukocidin) · Staphylococcus (Staphylococcus aureus alpha/beta/delta, Exfoliatin, Toxic shock syndrome toxin, SEB)
Cord factor · Diphtheria toxin
Shiga toxin · Verotoxin/shiga-like toxin (E. coli) · E. coli heat-stable enterotoxin/enterotoxin · Cholera toxin · Pertussis toxin · Pseudomonas exotoxin · Extracellular adenylate cyclase
By mechanism
type I (Superantigen) · type II (Pore forming toxins) · type III (AB toxin/AB5)
Endotoxin
Lipopolysaccharide (Lipid A) · Bacillus thuringiensis delta endotoxin
Virulence factor
Clumping factor A · Fibronectin binding protein A
Mycotoxins
Aflatoxin · Amatoxin (alpha-amanitin, beta-amanitin, gamma-amanitin, epsilon-amanitin) · Citrinin · Cytochalasin · Ergotamine · Fumonisin (Fumonisin B1, Fumonisin B2) · Gliotoxin · Ibotenic acid · Muscimol · Ochratoxin · Patulin · Phalloidin · Sterigmatocystin · Trichothecene · Vomitoxin · Zeranol · Zearalenone
Invertebrates
arthropod: scorpion: Charybdotoxin, Maurotoxin, Agitoxin, Margatoxin, Slotoxin, Scyllatoxin, Hefutoxin, Lq2, Birtoxin, Bestoxin, BmKAEP  · spider: Latrotoxin (Alpha-latrotoxin) · Stromatoxin · PhTx3
mollusca: Conotoxin · Eledoisin · Onchidal · Saxitoxin · Tetrodotoxin
Vertebrates

fish: Ciguatera · Tetrodotoxin

amphibian: (+)-Allopumiliotoxin 267A · Batrachotoxin · Bufotoxins (Arenobufagin, Bufotalin, Bufotenin · Cinobufagin, Marinobufagin) · Epibatidine · Histrionicotoxin · Pumiliotoxin 251D · Tarichatoxin

reptile/snake venom: Bungarotoxin (Alpha-Bungarotoxin, Beta-Bungarotoxin) · Calciseptine · Taicatoxin · Calcicludine · Cardiotoxin III
note: some toxins are produced by lower species and pass through intermediate species

: TOX

gen / txn

pto

ant