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Neuromodulator, cosmeceutical product options expanding


Noteworthy products under development include modified neuromodulators that can function as carrier molecules, as well as a promising wrinkle- and redness-reducing cosmeceutical, experts say.

Las Vegas - Intriguing dermatological products under development or relatively new to the U.S. market include topical and other modified botulinum toxin options, plus new cosmeceutical preparations for the skin and hair, according to experts at Cosmetic Surgery Forum, held here.

Among eagerly awaited topical neuromodulators, the closest to Food and Drug Administration approval is RT001 (Revance), followed by ANT-1207 (Anterios), says Erin Gilbert, M.D., Ph.D., assistant professor of dermatology at SUNY Downstate Medical Center, New York. ANT-1207 is currently in phase 2b. Indications being pursued include lateral canthal lines, hyperhidrosis and acne. RT001 is in phase 3 studies for lateral canthal lines, according to Revance.

To penetrate the stratum corneum, both products use protein carriers. Specifically, she says, RT001 uses TransMTS technology, which she describes as “a straight protein with specific receptor domains that’s non-covalently bound through its positive charge to the negatively charged neuromodulator molecule.”

Related: Topically applied neurotoxin addresses wrinkles without needles

There were initials doubts about this approach, Dr. Gilbert says.

“But it works. The clinical trial data have exceeded most people’s expectations,” she says.

Another promising approach has involved liposomal delivery, Dr. Gilbert says. In a preclinical study regarding chemically induced bladder hyperactivity, liposome-encapsulated onabotulinumtoxinA achieved greater decreases in the post-treatment inflammatory reaction and resulted in a lower level of intact SNAP-25 protein (Chuang YC, Tyagi P, Huang CC, et al. J Urol. 2009;182(2):786-792).

AbobotulinumtoxinA’s mechanism of action involves cleaving SNAP-25, Dr. Gilbert notes. This study is of interest, she says, because it means that the liposomally delivered neuromodulator had more efficient uptake and metabolism than did standard onabotulinumtoxinA. Additionally, the liposome-treated rats showed decreased release of calcitonin gene-related peptide, a phenomenon seen in neuroinflammation, she says.


Next: Experimental approaches to neuromodulator delivery



Neuromodulator delivery

Other experimental approaches being evaluated for neuromodulator delivery include chimeric molecules and fusion proteins, according to Dr. Gilbert. For example, “Pep-1 is a small transfection protein that has been added to the end of the onabotulinumtoxinA molecule,” she says. One study showed that this approach enhanced epidermal penetration of the toxin when sprayed onto mouse skin (Kim DW, Kim SY, An JJ, et al. J Biochem Mol Biol. 2006;39(5):642-647).

Conversely, Dr. Gilbert says using an onabotulinumtoxinA primary molecule carrier domain may one day enable botulinum toxin to be used in oral drug delivery.

“This is extremely interesting, and an area that we should keep our eyes on because it has such far-reaching implications,” she says.

In much the same way that polylysine allows drugs to be used for DNA therapy, modified botulinum toxin could function as a carrier for gene therapy, pain relief and other indications, according to Dr. Gilbert.

“We know that botulinum toxin is the most toxic molecule to humans,” Dr. Gilbert says. “It enters cell membranes and exerts its effects at very low concentrations.”

Accordingly, she says researchers have long been examining its potential use as a carrier for vaccines and many other medical therapies.

“This is an example of how botulinum toxin could be used in the medical community overall,” she says.

Related: Botulinum toxin has therapeutic potential in rosacea and psoriasis

Overall, “Transcytosis is the final frontier. Whether you’re using a liposomal approach or a receptor-mediated binding effect, you still have to get across the cell membrane.”


Next: Cosmeceutical products in development



Cosmeceutical creations

Among products under development, Intense Defense Serum (IDS, Episciences) reduced fine wrinkles by 50 percent after one week of use in a manufacturer-sponsored trial, says Carl Thornfeldt, M.D. He is a private practitioner in Fruitland, Idaho, and founder and CEO of Episciences. This finding was highly statistically superior to one comparator - a multiple growth factor product - and another vitamin C and antioxidant combination serum, he says.

In developing IDS, “We asked, what do the skin cells actually use for normal metabolism and function? When we perform a lot of procedures and apply many products to the skin, we are asking that skin to perform in a certain way - and assuming that the skin cell has the ability to do it,” he says.

For normal function, basic science research has revealed that the skin requires three different forms of vitamin A, Dr. Thornfeldt says. Although medical literature focuses on L-ascorbic acid, he trained with Dr. Linus Pauling, who discovered vitamin C at Oregon State University, he says.

“The complete vitamin C activity comes from dehydroascorbic acid. You need both dehydroascorbic and L-ascorbic acids together in a complete ratio to produce a vitamin C antioxidant effect,” he says.

IDS also has demonstrated the ability to reduce redness in eight weeks, Dr. Thornfeldt says. Unlike other anti-erythema products, “We’re not working with vasoconstrictors - we’re working with the natural nutrients that all skin cells need, including inflammatory and regulatory cells, to function optimally,” he says.


Next: Novel cosmeceuticals on the market



On the market

Regarding already available cosmeceuticals, Jeanine Downie, M.D., says the novel skin brightener Lytera (SkinMedica) reduces melanocyte activation and transfer to keratinocytes and reduces melanocyte synthesis while also removing epidermal melanin.

“It contains a lipid-soluble form of vitamin C, which works very well, plus essential peptides, niacinamide, retinol and licorice,” she says. As such, “It helps to even out the skin tone.” Dr. Downie is a dermatologist in private practice in Montclair, N.J.

As an antioxidant, “Niacinamide is useful for reducing the inflammation we see with many melasma patients.” One of Dr. Downie’s patients, a cook, has very reactive skin, particularly on the upper lip, due to the steam to which she is exposed daily.

“She can’t tolerate hydroquinone at all. But she loves the niacinamide in this product,” she says.

Related: Niacinamide eases rosacea inflammation

Combined with chemical peels and Fraxel (Solta) resurfacing, Lytera has significantly reduced the patient’s melasma, Dr. Downie says.

“Because niacinamide helps to maintain the moisture levels,” she adds, “it helps reduce excess sebum production, which can lead to more inflammation for some people.”

Because the cream can dry the skin initially, she has patients start applying it three times weekly, then every other night, and eventually Monday through Friday, if not nightly. Combined with TNS Essential Serum (SkinCeuticals), Dr. Downie says, “I find it fantastic for keeping my melasma at bay.”

Next: A patented cosmetic ingredient




Renewnt (Makucell) is a selective synthetic modulator of the WNT signaling pathway.

“It discourages skin stem cells from differentiating. It’s not an antioxidant, growth factor, vitamin, botanical, retinoid or glycolic acid. It’s a patented cosmetic ingredient” used in separate products for brightening, hydrating, decreasing oxidative stress and increasing skin firmness, she says.

Renewnt downregulates pro-opiomelanocortin (POMC) and upregulates the melanocortin receptor, Dr. Downie says. Additionally, “Gene expression analysis has shown measurable upregulation of genes associated with skin structural proteins, with simultaneous downregulation of inflammatory genes.”

Internal studies suggest that treatment with Renewnt may reverse gene-expression changes associated with aging and skin lentigines, she adds. If a patient has irregular pigmentation associated with aging skin and lentigines, however, “It does not work as fast as Lytera. And in New Jersey, patients want everything yesterday.”

Regarding the oral hair-growth supplement Viviscal (Lifes2good), Dr. Downie says, “Americans spend more than $3.5 billion yearly in attempts to combat hair loss. And there’s a growing preference toward natural solutions.” In this area, she says Viviscal Professional has drug-free ingredients and seven clinical trials showing it reduces hair loss and promotes growth of existing hair.

Its key ingredient, AminoMar Marine Complex, provides essential proteins to nourish thinning hair and encourage growth of existing hair, said Dr. Downie. Other ingredients include biotin, which helps the body metabolize carbohydrates, fats and amino acids (important building blocks of protein), and an apple extract (procyanidin B2) that encourages hair growth and thickness during the anagen phase, she adds.

Disclosures: Dr. Gilbert is a consultant to Allergan and Merz Aesthetics. Dr. Downie performed the clinical trials for Lytera (SkinMedica) and is a consultant for Allergan, Valeant and Merz. Dr. Thornfeldt is a shareholder in Episciences.

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