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Biological Chemistry


Purpose: Typical Neuromuscular Modulator

by Lois Ember
June 20, 2005 | A version of this story appeared in Volume 83, Issue 25

Credit: Courtesy Of Joe Arndt And Raymond Stevens/Scripps Research Institute
Credit: Courtesy Of Joe Arndt And Raymond Stevens/Scripps Research Institute

If Botox was not exactly a household word before the last presidential campaign, it became one during it. For a brief period of time, the campaign's leitmotiv was whether one of the candidates was being injected with Botox to erase the frown lines from his well-lived-in face. He denied using it, but the publicity put this nonsurgical wrinkle eraser on the map.

Botox is the trade-marked name of Allergan's purified protein--botulinum toxin Type A--derived from the anaerobic bacterium Clostridium botulinum. According to the company, Botox has been approved in more than 75 countries to treat 20 different neurological disorders. In addition to its cosmetic application, the toxin has been used in the U.S. for about 15 years for a range of therapeutic applications, including the treatment of crossed eyes and excessive sweating.

Allergan spokeswoman Caroline Van Hove notes that Botox "ranks as the number one minimally invasive cosmetic procedure in the U.S., according to recent statistics from the American Society of Plastic Surgeons." But its therapeutic uses outweigh the cosmetic, accounting for about 60% of Allergan's worldwide sales of $705 million in 2004.

Type A is one of seven distinct botulinum toxins (identified by A-G) produced by different strains of the bacterium. Each toxin type produces a different immunologic response and is made by a different manufacturing process. In the U.K. and Europe, Ipsen markets a Type A toxin as Dysport that differs slightly from Botox. The only Type B toxin available is made by Solstice Neurosciences and is sold as Myobloc/Neurobloc. No other antigenic toxins are available for therapeutic use.

BOTULINUM TOXIN is a Dr. Jekyll/ Mr. Hyde molecule. It can kill--and indeed, in the 1940s was developed by the U.S. and other countries as a biological weapon. At much lower doses, it can temporarily alleviate, if not cure, neurological disorders. Though it has never been used as a weapon, it is the first biological toxin to be licensed for the treatment of human diseases.

Botulinum toxin is not easy to make into a weapon, yet many countries have tried because it is the most poisonous substance known. One gram of the crystalline form milled to the proper size for inhalation and evenly dispersed would kill more than 1 million people. Technical factors, however, make such dissemination difficult. Food-borne botulinum toxin would kill far fewer people but could terrorize a nation.

The toxin, a zinc proteinase, acts by preventing the release of the neurotransmitter acetylcholine from vesicles at the neuromuscular junction. As a proteinase, the toxin cleaves one or more of the fusion proteins by which the vesicles release acetylcholine. In the absence of acetylcholine, contraction of the muscle--or in some cases, the activity of a gland--is temporarily inhibited.

When used to treat medical disorders, tiny amounts of the highly purified toxin are injected directly into the targeted muscle or gland. Therapeutic blockage lasts from one to six months depending on the medical indication and the individual, but eventually the nerve endings recover and again begin to release acetylcholine. To maintain the therapeutic effect, another injection may be needed.

In addition to temporarily improving the appearance of facial frown lines, Botox has been licensed by the Food & Drug Administration for the treatment of some serious medical disorders: first in 1989 for blepharospasm or uncontrollable eye blinking that may lead to functional blindness, and strabismus, or crossed eyes. Then, in 2000, it was licensed for cervical dystonia, or involuntary neck muscle spasms that can cause abnormal postures of the head.

Botox was labeled for aesthetic use in 2002. And in 2004, FDA approved the use of Botox as a treatment for excessive underarm sweating, or hyperhidrosis, that cannot be managed with topical agents.

Van Hove says, "Allergan is currently investigating the use of Botox for the treatment of migraine headaches, overactive bladders, and adult spasticity." Outside the U.S., Botox is approved for the treatment of juvenile cerebral palsy and adult spasticity. In the U.S., physicians are already using the toxin for a variety of off-label--that is, non-FDA-approved--uses, including migraine headache, chronic low back pain, stroke, traumatic brain injury, and cerebral palsy.

Interestingly, in the late 18th century, Justinus Christian Kerner, an accomplished poet and an official physician in southern Germany, was the first to recognize the potential therapeutic uses of botulinum toxin. The toxin, produced under anaerobic conditions, is a potent food-borne poison that causes botulism.

An outbreak of botulism in southern Germany in 1815 among people who had eaten uncooked blood sausage led Kerner to publish two years later a precise description of botulism's symptoms--from blurred vision to progressive muscle weakness, culminating in respiratory failure. Although he was wrong about the cause--he believed it to be a fatty acid--he postulated that minute quantities of the disease-producing substance might be able to treat disorders of the nervous system.

It wasn't until 1897 that Pierre Emile van Ermengem, a Belgian professor of bacteriology, discovered the responsible bacterium. And what was once known as Kerner's disease was renamed botulism from the Latin botulus for sausage.

Botulinum toxin was isolated from the bacterium in the early 1900s. In the 1920s, Herman Sommer at the University of California, San Francisco, isolated botulinum toxin Type A as a stable acid precipitate. In 1946, Edward J. Schantz and colleagues at the University of Wisconsin purified Type A in crystalline form.

Botulinum Toxins

Other Names
◾ Botox
◾ botulin toxins
◾ botulinus toxins

◾ Seven serologically (immunologically) distinct types are known, designated A-G.

On the market

Type A is marketed by Allergan as Botox and by Ipsen as Dysport. Type A was first marketed by Oculinum Inc. as Oculinum in 1989; the company and product were acquired by Allergan in 1989. Type B is marketed by Solstice Neurosciences as Myobloc/ Neurobloc, which it acquired from Elan.

$705 million for Allergan in 2004

Did you know that botulinum toxin is the first biological toxin to be licensed for the treatment of human diseases?


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