Botulinum toxin is a medication and a neurotoxic protein produced by the bacterium Clostridium botulinum. It is the most toxic protein known with an LD50 of roughly 0.005-0.05 µg/kg. Despite this, it is used in minute doses, in some parts of the world, to treat muscle spasms. It is sold commercially under the brand names Botox, Dysport, Myobloc, Neurobloc and Xeomin for this purpose. Botox Cosmetic and Vistabel are available for cosmetic treatment. The terms Botox (Cosmetic), Vistabel, Dysport, Myobloc, Neurobloc and Xeomin are trade names and are not used generically to describe the neurotoxins produced by C. botulinum.

History

Between 1817 and 1822, the German physician and poet Justinus Kerner described botulinum toxin, using the terms “sausage poison” and or “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 botulinium toxin. In 1870, Müller coined the name botulism, from Latin botulus = “sausage”. In 1897, Emile van Ermengem identified the bacterium Clostridium botulinum to be the producer of botulinum toxin.[4]In 1928 Snipe and Hermann Sommer for the first time purified the toxin. 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.[5]

Other bacteria that produce botulinum toxin, are Clostridium butyricum, C.baratii and C.argentinense.[6]

Botulinum toxin is neutralized at temperatures greater than 60 °C.[7] (140°F) By 1973, Alan B Scott, MD, of Smith-Kettlewell Institute used botulinium 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 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.

Botox is manufactured by Allergan Inc (U.S.) for both therapeutic as well as cosmetic use. The formulation is best stored at cold temperature of 2-8 degrees Celsius. 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. Neuronox is a new type A toxin manufactured by Medy-Tox Inc (South Korea).

Botulinium 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 & lethality

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 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 opposite 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 (intravenously).[8]

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 ingestion of the spores or vegetative organism.

Proper refrigeration at temperatures below 3 °C (38 °F) prevents the growth of Clostridium botulinum. Clostridium botulinum is also susceptible to high salt and low ph levels.

Infant (intestinal) and wound botulism both result from infection with spores which subsequently germinate, resulting in production of toxin and the symptoms of botulism.

Toxin itself is rapidly destroyed by heat, such as in thorough cooking.[9] However, the spores which produce the toxin are heat-tolerant and will survive boiling at 100 degrees Celsius for an extended period of time.[10]