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Striving for subtle changes in toxin use

Say good-bye to the “frozen” face. Armed with an array of neurotoxins approved for cosmetic use by the U.S. Food and Drug Administration, dermatologists are honing their skills with the needle to induce subtle effects that allow their patients to look naturally younger and more refreshed, rather than immobilized. “The toxin world is exploding,” said Seth L. Matarasso, MD, clinical professor of dermatology at the University of California School of Medicine in San Francisco. “Historically, we just had one toxin. Now we have three FDA-approved injectable toxins, and potentially a topical toxin. Plus, the indications have dramatically expanded, so it’s a very exciting time to be in cosmetic medicine.” Inspired by publicity and word-of-mouth testimonials, patients are flocking to practitioners in pursuit of a more youthful appearance. According to the most recent survey of the American Society for Dermatologic Surgery, dermatologic surgeons performed 1.49 million neuromodulation procedures in 2012 — an impressive 24.4 percent increase over 2011. 

Off-label treatments expand

The three injectable neurotoxins most frequently used for cosmetic treatment are all botulinum toxin type A products: Botox (onabotulinumtoxinA), Dysport (abobotulinumtoxinA), and Xeomin (incobotulinumtoxinA), the most recently approved agent. “I use all three of the [botulinum toxin A agents], and I don’t really use them differently,” said Mark S. Nestor, MD, PhD, voluntary associate professor in the department of dermatology and cutaneous surgery at the University of Miami Miller School of Medicine. “They all work; it’s a matter of patient preference.” Often patients express a preference for Botox “because they know it, they’ve gotten good results, and they don’t want to change anything,” said Kimberly J. Butterwick, MD, a private practitioner in San Diego. “Others will agree to try Dysport or Xeomin because they’re a little less expensive. You can make a mistake with all three of them, and you can get beautiful results with all three of them.”

As dermatologists become more skilled at deploying these trusted agents against the signs of aging, they have ventured into new areas of the face and body and fine-tuned the ways in which they dilute and inject the neurotoxins. “The versatility of these toxins has really changed the face of aesthetic medicine,” Dr. Matarasso said. “We’re no longer just chasing lines, we’re helping to reshape the face and stave off aging.” While all three toxins are FDA-approved for use in the glabella, and Botox is approved for injection in “crow’s feet” wrinkles of the lateral canthus, dermatologists use the agents off-label to treat other areas of the face, as well as the neck and chest. [pagebreak]

“One key area people are talking about is the masseter muscle,” Dr. Matarasso noted. “Especially in the Asian population, it gets quite thick and can give a square-like appearance to the face. By injecting about 20 to 30 units of toxin per side, you can reduce the bulk or thickness of that muscle and give them a more pleasing, more defined face. It’s a really nice way to reshape a face.”

Susan H. Weinkle, MD, assistant clinical professor of dermatology at the University of South Florida, said she is now injecting inside the orbital rim. “Many Caucasians have asymmetry of their apertures — I actually have it myself — so if I put two units of botulinum toxin just beneath my tarsal plate, that changes the shape of the eye,” she said. “However, you can’t come too far down around the orbital rim beneath it, because then you hit the zygomaticus major and you make the cheek look dropped.”

Other sites

Dr. Nestor remarked that while experienced dermatologists have long been comfortable in treating the upper face with toxins, many are now moving to the lower face as well. “You can inject the upper nose for the bunny lines’ over the nasalis, the lower nose to lift it, and the depressor anguli oris (a muscle that causes the mouth to pull down),” he said. “We treat the platysmal bands on the neck, and we also treat the dcolletage area of the mid-chest for the fine lines there.” Practitioners should keep in mind the dichotomy of form vs. function as they move about the face, Dr. Matarasso warned. “In the upper half, if there’s a complication, it’s generally an aesthetic complication,” whereas in the lower half, “it’s not only a cosmetic problem, but is often a functional problem. Those muscles are less forgiving, and more associated with facial activity, so you may have a droopy lip, difficulty swallowing, difficulty clenching. My philosophy is a little bit is good, a lot is not necessarily better. The lower half of the face is more about paresis, not immobilization.” [pagebreak]

When less is more

“Many patients don’t want the frozen’ look, where you don’t move your face,” Dr. Nestor said. “Over time, dermatologists have begun to use less units of toxin to give a little bit of movement and a more natural look.” This can entail tweaking the dilution and/or the amount of fluid injected, as well as the number of injections, the experts said. “The focus now is really microdroplets or small aliquots of toxin for facial sculpting,” Dr. Weinkle said. In the perioral region, “I have lately been reconstituting my botulinum toxin so that normally I draw five units equals 0.1cc . Then I dilute it again with 0.1cc of saline so that each drop is a little more dilute, so it’s as though I reconstituted it with 4ccs instead of 2ccs. So now, 0.2 units equals 5 Botox. I’m thinning it out so that I can do a more microdroplet diffusion over the upper lip. First I start out with a little bit of filler into the fine lines and then add the Botox on top, and it just makes for a nice way to relax the muscle. We’ve been treating the upper lip with Botox before, that’s not anything new. But using a less concentrated dose, so that you can treat it over the whole upper lip like that with a microdroplet technique, I think allows for a more natural look,” she said. By injecting smaller aliquots in a microdroplet technique in the periorbital region, “you can inject superficially so that you don’t cause total muscle relaxation, you just relax part of those fibers. Now, the question we don’t know the answer to is, how does that affect the durability? If I put one unit in my crow’s feet area, will one unit last two months, or will it last three to four months like a four- to five-unit injection does into a muscle bundle? I think we’ll know that going forward.”

Dr. Nestor said he has been studying toxins in terms of “mathematical equivalence,” which means distributing the number of toxin molecules equally to receptors throughout the muscle. “What that affects is, number one, how many injection sites you’re doing and number two, the concentration of the toxin you’re injecting,” he explained. “And thirdly, the combination of the volume and distribution. That’s pushing more and more individuals to think about figuring out an ideal volume and increasing the number of injection sites — smaller amounts at more injection sites to spread this out more.” [pagebreak]

On the horizon: topical gels, cryomodulation

Even as they become more adept at utilizing the toxins currently on the market, dermatologists are looking to new agents in the pipeline to enhance their capabilities and, it is hoped, grow the market for cosmetic treatment with injectables. Revance Therapeutics, Inc. announced in an April 2013 news release that it had raised additional financing to support phase 3 trials of a botulinum toxin type A topical gel, now known as RT001, for treatment of crow’s feet. Intended for use in the physician’s office, the product is also in phase 2 testing for the topical treatment of hyperhidrosis and chronic migraine headache, the company said. Relying on information from a recent AAD presentation, Dr. Butterwick said the duration of RT001’s effects is about 90 days and predicted it would appeal to “needle-phobic” patients.

“I think this will be a very, very exciting new product for a couple of reasons,” said Mary P. Lupo, MD, clinical professor of dermatology at Tulane University School of Medicine. “We all know the number of people getting toxins are nowhere near the number of candidates for toxins. There is a huge, untapped market. I see this product increasing the awareness of what neuromodulation can do for the aging appearance of the face, and driving people into our offices who will be interested in getting this noninvasive, no-needle treatment. I’m curious to see how physicians will handle it; I think it’s obviously something that would be easily and more appropriately delegated to nurses and PAs.” Dr. Matarasso said he anticipates that the product’s greatest impact will be on patients with hyperhidrosis: “You can inject into axillary walls and have wonderful results, but if you have a patient who has hand and foot sweating, it’s very painful to inject these toxins, and we don’t have a lot of alternatives for these folks.” For cosmetic patients, “I think it will be a nice alternative, especially for people who just don’t want any needles in their face and don’t mind sitting in the office for 30 minutes with a cream on to get the same results.” 

Another product that can deliver toxins topically, Transdermal Corp.’s InParT (the name derives from Ionic Nano Particle Technology), is a passive delivery system that’s being tested with all of the approved neurotoxins, Dr. Nestor said. “We’ve done a number of studies with all the approved toxins showing significant promise at fairly low doses in the hyperhidrosis model,” he said. Theoretically, “the topicals would be more akin to the microinjection technique. It’s not to replace the injectable toxin,” Dr. Nestor explained. “It’s really to be used on the smaller muscle groups, around the eyes, maybe to improve the skin overall, or for sweating.” The Transdermal website describes InParT as a “technology that enables delivery and absorption of active compounds through the stratum corneum and throughout the skin and subcutaneous tissue without any cutaneous toxicity.” InParT is still “a couple of years” away from FDA approval, Dr. Nestor said, adding that it would likely be applied in the physician’s office. [pagebreak]

A new injectable agent now being tested, Mentor Corp.’s PurTox, is “a small molecule of botulinum toxin A, used in a one-to-one ratio with Botox,” Dr. Butterwick said. As principal investigator, she was unable to discuss the results of the studies but noted that in comparison to Botox, “it seems to be similar in effect and duration. It’s more competition, which is good, and it will hopefully decrease the price a little bit.”

Dr. Lupo cited another experimental technology that may increase the market: cryomodulaton, now being tested by MyoScience Inc. “The nerve is identified with a TENS unit, then a probe is inserted to temporarily freeze the nerve,” she said. “It probably will last about as long as Botox. This doesn’t involve any chemical at all, so it will appeal to those people who don’t want any toxins in their system.”

Cosmetic dermatologists are “on an evolving edge of looking at how we utilize the neuromodulators to perform facial sculpting,” Dr. Weinkle said. “I think what we’ve learned is that it’s nice to give a softer, more natural look, and that’s the direction we’re going.”

Editor’s note: Dr. Butterwick serves on the advisory board for Allergan, Merz, and Valeant. She is a principal investigator for Voluma (Allergan) and PurTox (Mentor). Dr. Lupo does research and work as speaker/trainer and is on the advisory board for Allergan; work as speaker/trainer and is on the advisory board for Medicis and Valeant; and is on the advisory board for Merz. Dr. Matarasso reported no conflicts. Dr. Nestor has received research grants and consults for Medicis and Galderma, and he consults for Ipsen and Transdermal. Dr. Weinkle is a consultant for Merz, Allergan, Valeant, and Galderma. 

 

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