More Information on Treatment of Facial Lines and Wrinkles

Botulinum Type A Neurotoxin (BoNT/A) is a neuromuscular blocking (paralyzing) agent produced by the bacterium Clostridium Botulinum. Before its first experimental use in monkeys in the late 1960's, and on humans for the treatment of strabismus ("crossed-eyes") in 1978, botulinum toxin was best known for causing a type of severe and often fatal food poisoning, botulism.

Although known since ancient times, the clinical symptoms of food-borne botulism were described in the early 19th century, and because this type of food poisoning was often seen after ingestion of spoiled sausages, it became known as botulism, after the Latin "Botulus", or sausage. Currently there are approximately 100 cases of food-borne botulism/yr. in the United States, with a 5% mortality with modern medical treatment.

Botulinum Type A neurotoxin (BoNT/A) was originally isolated at UCSF in 1928, and studied by the U.S. Government under the auspices of the Unversity of Wisconsin and National Academy of Sciences during and just after WWII at Camp Detrick, MD, as a biowarfare agent by a team led by Dr. Edward Schantz. Dr. Schantz, working at the University of Wisconsin, joined Dr. Alan Scott at the Smith-Kettlewell Eye Institute in San Francisco in the late 1960's to investigate the clinical use of BoNT/A as a selective paralyzing agent for strabismus in monkeys, and in 1970 formed the Oculinum Company. Preliminary clinical trials in humans with strabismus and blepharospasm, conditions which were formerly treatable only by surgery, were conducted in 1978, and a multicenter human trial to evaluate BoNT/A for the treatment of strabismus and blepharospasm with over 7000 patients was organized in 1982.

During the course of these clinical trials, patients injected with BoNT/A around the eyes and forehead noticed the smooth, relaxed appearance of the skin. Various investigators including Drs. Jean and Alistair Carruthers at the University of British Columbia and Drs. Andrew Blitzer and Mitchell Brin at Columbia Unversity began to consider the potential for cosmetic use of BoNT/A (the word "botox" is a contraction of "botulinum" and "toxin", originated at Columbia University in the 1980's), and the first published report by the Drs. Carruthers appeared in the literature in 1990.

In 1989, the US FDA granted approval to the Oculinum Company to market BoNT/A for the treatment of strabismus and blepharospam under the name Oculinum. Interestingly this relatively impure mix of bacterial proteins (often referred to as "Batch I") was the remaining orginal material prepared by Scott in 1978, and contained approximately 25ng of bacterial protein/100 U of BoNT/A activity.

In 1988, Allergan, Inc. acquired the rights to investigate other uses for BoNT/A, and in 1991 purchased the Oculinum Company, changing the name of its BoNT/A product from Oculinum to BOTOX^®. By the early to mid 90's the cosmetic uses of BoNT/A were becoming established with the medical community and the public, prompting the FDA to denounce the cosmetic use of BOTOX^® in a November 18, 1994 Federal Register notice as "an egregious example of promoting a potentially toxic biologic for cosmetic purposes". In 1997 Allergan was granted FDA approval for a new "batch" (referred to as "Batch II") of a more highly purified (5ng of bacterial protein/100U of BoNT/A activity) BoNT/A, which is currently being marketed in the U.S. Allergan received the indication for cervical dystonia in 2000, and on April 15, 2002, BOTOX^® Cosmetic was granted FDA approval for treatment of hyperkinetic glabellar lines.

In 2000, Myobloc^® (Botulinum B neurotoxin, BoNT/B) was approved by the U.S. Food and Drug Administration for the treatment of cervical dystonia (torticollis, "wry neck"). Its action and pharmacology are similar to that of Botulinum Type A neurotoxin, although it is antigenically distinct and acts a different location at the neuromuscular junction. Atlhough as effective as Type A toxin, Type B  toxin has a somewhat more rapid onset of action and shorter duration of effect, with a slighly higher incidence of adverse reactions such as dry mouth, visual disturbances, and dysphagia. Because Botulinum Type B neurotoxin is antigenically distinct from Type A, it remains effective in patients who have developed clinical "resiistance" to Type A toxin and is commonly used in this application.

Because of its ease of use, predictable results, and outstanding safety profile, Botulinum Type A neurotoxin complex (marketed by Allergan, Inc in the U.S. as BOTOX^® and BOTOX^® Cosmetic) has become a popular and valuable treatment for a number of medical conditions, including cerebral palsy, migraine, excess sweating, wry neck, back and facial spasms, as well as for the treatment of facial wrinkles.

How Botulinum Neurotoxins work: Botulinum neurotoxins work by blocking the nerve impulses which control muscle movement. When injected into muscle tissue, a flaccid paralysis results after about 3 days, and this paralysis can last anywhere from 3 to 8 months. When used for the treatment of dynamic facial lines, the therapuetic effect typically about 10-12 weeks for Botulinum Type A toxin and 6 weeks for Botulinum Type B toxin.

Botulinum toxin is prepared by laboratory fermentation of Clostridium Botulinum cultures. There are 7 antigentically distinct serotypes, A B C D E F G, but only Types A, B, E, F, and G are known to cause botulism in humans. All botulinum neurotoxins are zinc-dependent endopeptidases which act on the membranes involved in acetycholine release at the synaptic cleft, producing a flaccid paralysis of the muscle. Over time, new neuronal sprouts reinnervate the neuromuscular junction, and the orginal synaptic cleft neuron regenerates as well. The duration of denervation varies with the particular subtype of BoNT. Despite the prolonged flaccid paralysis, there has been no evidence of permanent degeneration or atrophy of the affected muscles, even with long-term repeated injections of Botulinum toxin. BoNT/A is the most widely used serotype because of it's long duration of action, stabiltiy, and relative ease of production and storage.

Pure botulinum toxin type A is generated as a 150kD single polypeptide chain, which is then "nicked" into a light chain (53kD) and heavy chain (97kD) held together by a disulfide bond. During synthesis, the bacteria produce associated proteins, including several 14-48kD hemagglutinins, and a large (130kD) non-hemagglutinizing protein. The function of these associated proteins is unclear, but they are not necessary for neurotoxic activity and have been associated with the production of "blocking" antibodies. This protein complex, with a total molecular weight of approximately 900kD, is diluted with human serum albumin, added to vials, lyophilized (freeze-dried), sealed, and marketed as BOTOX® (Botulinum Toxin Type A Neurotoxin Complex) and BOTOX® Cosmetic (Vistabel® in France).

Other BoNT/A preparations currently on the world market include Dysport^® (Ipsen, Inc., UK, to be marketed in the U.S as Reloxin^®, Ipsen, in late 2006), Linurase^® (Prollenium, Inc., Canada), and an assortment of preparations from Asia, including CBTX-A^® (Lanzhou Biological Products Institute, China), and Neuronox® (Medy-Tox, Inc., South Korea). Mentor Corporation plans to introduce a highly purified ( free of complexing proteins) "next generation" BoNT/A preparation, Puretox^®, currently in Phase II trials in the U.S., for the aesthetic market. A similar, highly purified BoNT/A (NT201, Xeomin^®) Merz Pharma) was introduced in Germany in July 2005. None of these products is currently licensed for importation into or approved for use in the US at this time.

Each 100 Unit vial of BOTOX^® contains 4.7ng of Botulinum Toxin Type A Neurotoxin Complex, 0.5mg of Human serum albuimin, and 0.9mg NaCl. 1 unit of purified toxin is defined as that amount which is lethal to 50% of female Swiss Webster mice. The lethal dose for humans is estimated to be about 1 ng/kg of the purified toxin, or 4 ng/kg of the Neurotoxin Complex, which translates to 40-50 U/kg, 3500 times the lethal dose for mice, or about 35 vials of BOTOX^®. Typically, only 20-50 units are used in treatment for facial lines, so there's a very wide margin of safety with proper administration.

Indications for treatment: Botulinum Toxin injections are used cosmetically for the treatment of facial lines and wrinkles which are caused by excessive movement of the underlying muscles. Lines and wrinkles from sagging skin will not be improved by treatment with Botulinum Toxin !

The most commonly treated areas include frown lines, "surprise" or forehead lines, crows feet or "laugh lines", and occasionally lip lines and neck bands. In these areas, excessive contraction of the muscles below the skin cause it to wrinkle and eventually "crease". The facial expressions caused by these particular muscle actions are generally regarded as undesirable and are not missed when they are absent. "Crease" lines on the skin that do not disappear when stretched out will be improved, but not completely removed by Botulinum Toxin injections, and may need treatment by other methods (see below).

Patients with neuromuscular disorders such as myesthenia gravis should not be treated with Botulinum neurotoxins. True allergic reactions to Botulinum neurotoxins have not been observed. No side effects from Botulinum Toxin injections have been reported when pregnant or nursing women have been inadvertently treated, although safety during pregnancy or lactation has not been firmly established. Certain medications, such as quinine or calcium channel blockers, can increase the effect of Botulinum neurotoxins.

Facial areas most commonly treated with Botulinum Neurotoxins. Treatment can be performed where movement is causing lines, but where the movement won't be missed

Duration of action: Botulinum toxin Type A causes a flaccid paralysis of the injected muscles, which lasts from 10-12 weeks. During that time, collagen remodels beneath the wrinkle line, and as a result, tends to "fill in" those lines cause by the former movement of the now-paralyzed muscle. This effect becomes more apparent with repeated injections, and in many cases, the lines actually will disappear over time.

This "filling in" effect accounts for some of the stories regarding the variability about how long BOTOX^® "lasts". Patients (and physicians!!) need to keep in mind that the goal is to minimize the appearance of lines caused by movement, not to maintain a "frozen face" or to keep the injected muscles paralysed. Experience with thousands of patient has shown that the vast majority of patients using Botulinum Toxin injections on a regular basis will only need treatment every 4-6 months to maintain the effacement of the dynamic lines.

Preparation and Treatment: BOTOX^® and BOTOX^® Cosmetic (Botulinum Type A Neurotoxin Complex) is supplied in 100 unit vials, which must be kept frozen until used. After reconstitution with saline, the manufacturer recommends that the toxin be used within 4 hours, although activity remains for upt to 30 days if the leftover solution is properly refrigerated. Because treatment for facial lines typically uses 20-40 units, each vial can be used for 2 patients, with a bit left over for "touch-up" injections a few days later. Many doctors designate "Botox Days" dedicated to BOTOX^® injections. Myobloc is supplied as an injectable solution in vials of 2500, 5000, or 10000 units. The units of BOTOX® and Myobloc are NOT equivalent; 1 unit of BOTOX^® is equivalent to 30-50 units of Myobloc.

Small quanitities of the toxin are injected directly into the muscles to be treated using a tiny needle and a calibrated syringe. Each injection contains 3-6 units of BOTOX^® or 100-300 units of Myobloc Although the injections may be mildly uncomfortable, local or topical anesthetic is almost never needed.

Patients can resume normal activity the same day, although vigorous rubbing or kneading the injected areas should be avoided for at least 8 hours. Contrary to what was formerly thought, the position of the patient during or after properly performed preparation or injection of BOTOX® or Myobloc does not influence the area or intensity of the injection's effect.

Immediately after treatment, movement of the injected muscles not only assists in diffusing the Botulinum Toxin molecules throughout and across fascial planes, but the electrical activity at the neuromuscular junction facilitates binding of the larger botulinum toxin protein subunit to the cell membrane. The new "third generation" botulinum toxins, free of complexing protiens, seem to act somewhat more quicky than current preparations.

Other uses for Botulinum Neurotoxins: Botulinum neurotoxin therapy is currently being studied for a variety of conditions in which muscular hyperactivity or spasm plays a significant role, including: