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Retinoids Used for Skin Renewal

The effect of the retinoids such as retinoic acid (vitamin A acid) and retinol (vitamin A alcohol) is complex. Retinoic acid became the first widely used product for skin renewal. Retinol is much weaker at skin renewal but may have potent actions on decreasing excessive breakdown of collagen and elastin in the skin, a process that become increasing excessive as we age.

Retinoic Acid (Tretinoin, Retin-A, Renova)

Retinoic acid or tretinoin is the acidic version of vitamin A or retinol. It is the only product that has been approved by FDA for reversing aging effects on skin, reducing wrinkles and mottled darkened spots and smoothing the skin.  It reduces skin oil by shrinking sebaceous glands and unclogs follicles, It also increases epidermal thickness and stimulates deposition of new collagen. Retinoic acid is sold under brand names such as Retin-A and Renova by Ortho Pharmaceutical Corp. of Raritan, N.J., a division of Johnson and Johnson. It is available by prescription only (Kligman 1989, Shalita 1990).

Skin Renewal Studies with Retinoic Acid

Typical strength of topical tretinoin creams is 0.025 - 0.1 percent. With tretinoin (Retin A, Renova) more is not necessarily better. One study has found that 0.025 percent tretinoin may be as effective as 0.05 or 0.1 percent, but with lower incidence of skin irritation. For people with sensitive skin, 0.025% may be the optimal strength. According to the studies, improvement on tretinoin (Retin A, Renova) may continue for up to a year of continued use.

Jonathan S. Weiss, M.D. and colleagues described a l6-week, double-blinded study of retinoic acid cream to treat sun-related skin aging in 30 patients. All 30 patients showed statistically significant improvements in sun-related skin damage on their retinoic acid-treated forearms, compared with forearms treated with a drug-free cream.  Improvement was also seen in l4 of the l5 patients who used tretinoin on their faces (Weiss, JS et al. 1988).

In double-blind controlled trials lasting up to 48 weeks, signs of improvement were observed in 68-79% of treated subjects (reduction in fine wrinkles and mottled hyperpigmentation, and smoothing of rough facial skin). Improvement was also seen in the group using the vehicle alone, but was judged to be only about half the improvement seen in the retinoic acid group. Patient self-evaluation correlated well with physician evaluation. Examination of skin biopsy specimens showed histologic improvement, including increased skin thickness and compaction and decreased pigment content (Olsen EA et al 1992, Weinstein et a. Arch Dermatol 1991).

The Irritation Problem with Retinoic Acid

Dermatologists tend to underplay the irritation effects of retinoic acid. Side effects from topical retinoic acid include mild to severe irritation, temporary peeling, redness, and blistering, and a permanent increase in sun sensitivity. The drug should not be used by persons receiving photosensitizing drugs (thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides).

The skin irritation is a major drawback with retinoic acid. It can can become very severe but should not be treated by cortisone or corticosteroids. Protect & Restore cream or CP Serum, described above, often effectively manages the irritation produced by retinoic acid.

Are New Retin-A Formulations Better?

Many new versions of retinoic acid are now appearing on the market and sold as great improvements over Retin-A. This is because the patents on Retin-A are expiring which will sharply drop the price. If retinoic acid becomes an OTC product available on the shelf in drugstore, the price will drop to $1 to $2 per tube. The new retinoic acid products appearing on the market are only marginally better (if at all) than the original Retin-A and are being introduced to keep a high price on the product.

Retinol (Vitamin A Alcohol)

This substance is ordinary vitamin A. Because pure retinol is unstable, the ester forms of vitamin A are used. These are molecules like retinyl palmitate and retinyl proprionate but they all work similarly. Cosmetic companies try to say different forms have very different actions but there is little basis for these claims.

Retinol is added to moisturizers or oils and serving as a humectant by attracting water to plump up the epidermis. A small amount of topical retinol also is converted in the skin to retinoic acid, the biologically active agent for skin. Retinol does markedly stimulate skin repair in immune-deficient rats and rabbits. Because the human immune system decreases in potency with age, retinol may help skin repair in humans over age 45 or when declines in immune system effectiveness first become significant.

Also, as mentioned above, retinol decreases excessive breakdown of collagen and elastin in the skin. However, it has long been established that excessive retinol on the skin can cause acne in younger persons. While there is no hard-and-fast age when retinol ceases to cause acne, in general, persons under 25 are more likely to develop retinol-produced acne, while in persons over 45, retinol appears to have very positive actions on skin renewal.

The use of retinol in skin cream is safe if used in moderation. A skin cream with 0.1% retinol would contain 500 units of retinol per gram of cream. For example, if you used 2 grams of such a cream per day, and if all the retinol were taken into your body, this would only be 1,000 units of vitamin A daily. The daily safe dose of retinol is 10,000 units but liver damage has been reported at 21,600 units per day.

Controlled Damage for Increasing Skin Turnover

Skin cell turnover can be increased by controlled skin damage. This damage then triggers skin repair and renewal. Mild damage is usually termed "skin exfoliation" to differentiate this method from more vigorous medical methods performed by physicians such as chemical peels.

Stage 1. Induction of skin damage.

Stage 2. Skin Healing Phase.

Following damage, skin healing progresses must proceed at rapid pace to get good skin repair and avoid scars. To aid the skin renewal process, the stage of skin damage is often followed by the use of skin regeneration accelerators that are described above.

Stage 3. Concurrent Cosmetic Surgery

Skin renewal techniques are often combined with cosmetic surgery such as a facelift and focused liposuction. For example, for the front of the face, skin renewal techniques such as chemical peels or laser resurfacing work well to tighten the skin and remove blemishes. However, excessive skin sagging on the sides of the face often requires an additional partial facelift. Also, as we age, fat deposits increase in various areas such as under the eyes and under the chin. Liposuction techniques are used to remove fat from selected areas of the face to achieve a better overall result. An overview of cosmetic surgery techniques is given in the next chapter of this book.

Skin Exfoliating Methods

Hydroxy Acids

Hydroxy acids are one of the best of the skin renewal approaches. They are naturally occurring, non-toxic substances found in the  human body, fruits, wine, milk and sugarcane, to name a few sources. Scientifically, these chemicals are known as alpha keto/carboxylic acids or beta keto/carboxylic acids. They are more commonly known as alpha hydroxy acids, or AHAs and betahydroxy acids, or BHAs. The AHAs and BHAs help retain moisture in very dry skin, as well as helping reduce fine lines and uneven color of sun-damaged skin. They often lighten "age" spots.

Part of their effect is decreasing the "glue" that holds dead cells on the surface of the skin.  Hydroxy acids reduce the thickness of the hyperkeratotic stratum corneum by reducing corneocyte cohesion in lower levels of the stratum corneum. This induces epidermolysis, which triggers an increase in cell renewal. This helps the dead cells to slough off (desquamation), speeds skin turnover, and brings to the surface a layer of smoother, softer skin.

Of the AHAs, glycolic acid, which comes from sugarcane, is generally regarded as the best for skin renewal. Mixtures of several different AHAs have no advantage. Glycolic acid speeds the turnover of the skin cells resulting in a smoother texture and healthier appearance. It usually takes about eight weeks of regular use to see a significant improvement in the skin. Glycolic acid can be combined with other bleaching agents that are used in the treatment of dark spots on skin. Products containing hydroxy acids include cleansers, moisturizers, toners, masks, age-spot removers, and other preparations.

Types of AHAs and BHAs

AHAs include:      glycolic acid - The most popular AHA
                            lactic acid
                            malic acid
                            citric acid
                            glycolic acid + ammonium glycolate
                            alpha-hydroxyethanoic acid + ammonium alpha-hydroxyethanoate
                            alpha-hydroxyoctanoic acid
                            alpha-hydroxycaprylic acid
                            hydroxycaprylic acid
                            mixed fruit acid
                            tri-alpha hydroxy fruit acids
                            triple fruit acid
                            sugar cane extract
                            alpha hydroxy and botanical complex

BHAs include:             Salicylic acid
                            Citric acid

Effective and Ineffective AHA Creams

Research of Eugene J. Van Scott M.D. and R. J. Yu Ph.D. opened the modern era of AHA use. In 1976 they reported that glycolic acid, in specially designed formulations, helped in the treating of a scaling skin disease (ichtyosis) and in 1988 they founded NeoStrata, a company where they continue to develop novel methods for the treatment of skin problems.

Further studies by them indicated a use for hydroxy acids in skin renewal - however, their work was ignored by the skin care industry until the 1990s when alpha and beta hydroxy acids began to be incorporated into skin care products (Van Scott and Yu 1989). Later, Stiller et al conducted large-scale, placebo-controlled studies with AHAs and found they reversed premature aging caused by sun exposure (Stiller et al 1996).  Their use was soon extended to chemical peels (Dial 1990).

Alpha hydroxy acids (AHA's) are one of the safest methods of skin renewal. Their effectiveness depends on the type and concentration of the AHA, its pH (acidity), and other ingredients in the product. AHAs become effective at concentrations of about 7% to 8% with a pH of 3.5 to 4.0. Many AHA-containing cosmetic products have very little skin renewal effects because the AHA concentrations are too low and the pH is too high. There is little evidence that concentrations below 5% have beneficial actions on skin.

Skin improvements should be apparent after four weeks of AHA treatment, but AHA therapy also helps maintain skin health and is normally continued indefinitely.

Chemical peels with stronger AHA's (40-70%) speed the process, but skin rebuilding induced by a 70% AHA chemical peel (which is costly and may cause scarring) in 3 months can be duplicated by a 7% AHA cream in 9 months.

AHAs are marketed for a variety of purposes: to smooth fine lines and surface wrinkles, to improve skin texture and tone, to unblock and cleanse pores, to improve oily skin or acne, and to improve skin condition in general. In reality, they do increase the turnover of skin cells and enhance the rebuilding of collagen and elastin plus improve the internal moisture-holding properties of GAGs and proteoglycans. With long term use, AHAs alleviate fine to moderate wrinkles, and remove many skin lesions such as weathered skin, freckling, blotchy pigmentation, sun damage, age spots, mild acne scars, benign overgrowths of skin, and flat warts. They appear to work by causing an increased skin peeling of the lesion plus an irritation around the lesion. In time the lesion becomes smaller and is replaced by normal healthy skin.

Hydroxy acids are helpful in treating oily and acne-prone skin. Persons with these conditions often see dramatic results. Blackheads, white heads and acne breakouts are caused when the hair follicles clog and trap sebum in the follicle. Removing the upper layer of skin promotes natural sebum flow to the skin.

Long Term Low Dose AHAs as Good as Short Term Chemical Peels

Reports by various skin researchers strongly suggest that long term use of AHAs give results similar to chemical peels. The key to skin renewal is a process where (1) the skin is irritated or slightly damaged by exfoliating agents (alpha hydroxy acids, beta-hydroxy acids, retinoic acid, or mildly burned by by laser re-surfacing). This is followed by (2) a natural rebuilding of the skin that removes imperfections, rebuilds collagen and elastin fibers that tighten skin, and increases the amount of glycosamoinoglycans. The stronger the exfoliation or skin damage, the stronger is the skin rebuilding action. Unfortunately, strong exfoliation causes strong skin irritation with itching, burning, and pain.
 

 Alpha Hydroxy Acid ( 7-8%, Ph=3.8 ) Effects on Skin

Effects in 3 months	Effects in 9 months
Softer smoother skin Increased moisturization	Softer smoother skin Increased moisturization Increased glycosaminoglycans Strong rebuilding of collagen, and elastin Pigment more uniform Skin imperfections reduced

Safety of Hydroxy Acids and Cautions

AHAs increase sun sensitivity by 13% on average but in some persons by as much as 50%. For a 50% increase in sun sensitivity, a hydroxy acid formulated with a sun protection factor of 2 would eliminate the added sun sensitivity. AHAs with concentrations of 20% or higher are skin peels (see below) and should be applied by a dermatologist or trained cosmetologists at salons.

AHAs also may increase the penetration of other chemicals used on the skin. These include vitamins, antibiotics, Retin-A, benzoyl peroxide, resorcinol, and other dermatological medications. One should be aware of this possible interaction when using AHAs along with other skin treatments.

By 1997, The US Food and Drug Administration (FDA) had received about 100 reports of adverse effects with AHAs ranging from mild irritation and stinging to blistering and burns. The FDA advises you to test any product that contains an AHA on a small area of skin before applying it to a large area. If you you experience skin irritation or prolonged stinging, you should stop using the product and consult your physician.

The Cosmetic Ingredient Review Panel of the Cosmetic, Toiletry, and Fragrance Association concluded in December 1996 that AHAs are "safe for use in cosmetic products at concentrations less than or equal to 10 percent, at final formulation pHs greater than or equal to 3.5, when formulated to avoid increasing the skin's sensitivity to the sun, or when directions for use include the daily use of sun protection." For salon use products, the panel said that the products are "safe for use at concentrations less than or equal to 30 percent, at final formulation pHs greater than or equal to 3.0, in products designed for brief, discontinuous use followed by thorough rinsing from the skin, when applied by trained professionals, and when application is accompanied by directions for the daily use of sun protection."

Are Beta Hydroxy Acids Better?

BHAs include salicylic and citric. Some research suggests that BHAs, especially salicylic acid, may be more effective in exfoliating the lower dermal skin layers and may be less irritating. Synthetic salicylic acid has long been in dermatology for treating adult acne and removing corns on feet.  Salicylic acid is lipid soluble and hence penetrates the fatty sebum produced by sebaceous glands, eliminates acne causing bacteria, and reduces the clogging of infected pores and acne.

A leading dermatologist, Dr. Albert Kligman, believes that BHAs, in particular salicylic acid are better than AHAs for anti-aging and for skin exfoliation. Professor Kligman is well known in  dermatology for his research on the anti-aging actions of retinoic acid (Retin-A). Results from Dr. Kligman's laboratory found that the outermost stratum corneum layer is renewed after applications of salicylic acid.

Other Proven Skin Renewal Products

Alpha Lipoic Acid

Alpha lipoic acid is a molecule that functions in fat metabolism. It is also a key anti-oxidant that is both lipid and water soluble. Its anti-oxidant properties give it some anti-inflammation qualities. While most aging effects are due to innate genetic programs, some aging effects are due to the generation of free radicals within the cell which activate a cellular messenger called nuclear factor kappa-B. Nuclear factor kappa-B then enters the nucleus of the cell and causes the DNA to produce proteins that can cause cellular damage. Alpha lipoic acid (and other anti-oxidants) can block the development of nuclear factor kappa-B and protect the cell from damage. Alpha lipoic acid also acts synergistically with other anti-oxidants such as vitamin E and vitamin C.

In animal studies, alpha lipoic acid has remarkable success in blocking the development of degenerative diseases. It is the most effective protective anti-oxidant supplement.

Alpha lipoic acid also helps aging cells increase their energy production. This enhances their ability to repair cellular damage and expel cellular waste products. Because of this action, alpha lipoic acid, as a 1% lotion, has been used as a skin treatment for aged skin.

Prof. Nicholas Perricone (to the left), author of "The Wrinkle Cure" (Rodale Press, about $18 and highly recommended), is a research dermatologist with Yale University who has designed a line of skin cosmeceuticals (Nicholas Perricone, M.D. Cosmeceuticals). He also has conducted studies on alpha lipoic acid and found it has skin renewal properties and can diminish scarring that has been caused by acne after approximately 6-8 weeks of use. He sells a version of alpha lipoic acid for skin renewal (2 oz. / $85.00) from a website at http://nvperriconemd.com and in many high end stores. Even if you use topical alpha lipoic acid on your skin, you should still supplement with an oral dose of about 30 to 100 mgs alpha lipoic acid taken along with your vitamins.

Kinerase/Kinetin - Copper Peptides Proven Better

Kinerase/Kinetin (N6-furfuryladenine) is an essential growth factor that retards senescence of plants and delays age-related changes in cultured human skin cells. An independent 48-week clinical study, begun in October 1996 at the Univ. of California at Irvine (under the direction of Gerald D. Weinstein, M.D., an authority in the area of photoaging and photodamaged-skin treatment), N6-furfuryladenine was found to be safe and effective in partially reversing the clinical signs of photodamaged facial skin during extended use. It was effective in reducing the appearance of fine lines and wrinkles, blotchy hyperpigmentation, telangiectasia and tactile skin roughness.  The UC Irvine data were similar to the clinical efficacy results reported in a published study of Renova (Olsen et al 1997). In contrast to Renova, however, Kinetin did not cause any clinical signs or subjective symptoms of irritation.  Renova (0.05% tretinoin (retinoic acid) emollient cream) is the first prescription cream proven to diminish fine lines and wrinkles.

Paula Begoin (In: The Cosmetic Counter, March 1999) has pointed out that, while Kinerase/Kinetin is said to be as good as Renova, only 16% of women were pleased with the results in one Renova study and even less in another. Furthermore, in the Renova study more than two-thirds of the women thought the results were mediocre or nonexistent.

This product was developed for skin care by Senetek Inc., a company that develops products for reversing effects of human aging. N6-furfuryladenine for skin care is marketed by ICN Corporation as Kinerase and as a more expensive version called Kinetin by Osmotics Corporation, but both versions are similar. The product typically sells for about $70 for a 2 ounce bottle. What to expect from N6-furfuryladenine products? Some improvement in skin appearance.

Kinerase(TM) and Kinetin(TM) are based on a plant chemical called Furfuryladenine. In one published clinical study, such creams have been shown to improve skin texture, reduces blotchiness, and reduce fine wrinkles while being non-irritating. However, their effects are not as fast of effective as copper peptide creams. This comparison is from product literature supplied by the Procyte Corporation entitled "NEOVA - Copper Peptide Therapies".
 

Vitamin C Serums and Patches

Vitamin C based creams were researched and introduced in 1992 by Prof. of Dermatology Sheldon Pinnell, M.D. (Photograph to the left) of the Duke University Medical Center, Durham, North Carolina, who has researched the relationship between vitamin-C (L-ascorbic acid) and collagen. Vitamin C is critical in the cross-linking of collagen using an enzyme called Lysyl Hydroxylase. Pinnell was instrumental in the development of Cellex-C and later founded Skinceuticals.

Prof. Pinnell has published studies showing that vitamin C, applied according to his instructions, does improve the quality of collagen in the skin but this is only one aspect of skin health and beauty. Moreover, published studies on positive effects of vitamin C on the skin are very scanty. And if these effects were more significant, vitamin C products would be used clinically on slow healing wounds and skin ulcers where inadequate collagen synthesis is a serious problem.

Dr. Pinnell has stated that to get positive effects on the skin's collagen with vitamin C, the vitamin C must be at least 10% in solution and at a low pH of 2.5 or lower. He also states that only vitamin C (L-ascorbic acid) is effective and that many vitamin C derivatives used in cosmetics such as esters and analogs of ascorbic acid cannot be absorbed by the skin and converted into active vitamin C in any meaningful amount. Such unsatisfactory derivatives include ascorbic acid sulfate, ascorbic acid magnesium phosphate, ascorbyl stearate, ascorbyl palmitate and ascorbyl dipalmitate.

However, despite the emphasis on vitamin C and collagen production, in the only comparison study between vitamin C and copper-peptides, the copper-peptides were more potent than vitamin C on improving collagen production (Abulghani et al 1998).  It should be also remembered that copper-peptides have many other positive effects on skin besides effects on collagen production.

So expect a positive effect of vitamin C on skin if you stick to Pinnell's formulas which are available from a company he founded called Skinceuticals, which can be found on the Internet. Many other companies sell various solutions and vitamin C patches, but few are formulated according to Pinnell's recipe.

Caution: Do not mix vitamin C products with copper-peptide skin regeneration creams. The copper breaks down the vitamin C. If you wish to use both, use them on alternate days.

Kligman, AM 1989 - Guidelines for the use of topical tretinoin (Retin-A) for photoaged skin. Journal of the American Academy of Dermatology 21:650-654

Olsen EA et al 1992 - J Am Acad Dermatol 26:215-224

Olsen et al 1997 - Tretinoin emollient cream for photodamaged skin: Results of 48-week, multicenter, double-blind studies, Journal of the American Academy of Dermatology, August 1997

Perricone and Dinardo 1996  - Dermatol Surg 1996;22: 435-437

Pruijn FB, Schoonen WG, Joenje H, Inactivation of mitochondrial metabolism by hyperoxia-induced oxidative stress. Ann N Y Acad Sci 663: 453-455 (Nov 21 1992)

Shalita, A 1990 - Retin-A for wrinkles: daily use preferred. Skin Allergy News:21:1

Stiller et al 1996 - Stiller, MJ et al. (1996) Topical 8% glycolic acid and 8% lactic acid creams for the treatment of photodamaged skin. Archives of Dermatology 132:631-636).

Van Scott and Yu 1989 - Van Scott, EJ and RJ Yu,  Alpha hydroxy acids: procedures for its use in clinical practice, Cutis 43:222-228, 1989.

Weinstein GD et al 1991 - Arch Dermatol 1991;127:659-665

Weiss, JS et al. 1988 - Topical tretinoin improves photoaged skin. Journal of the American Medical Association. 259:527-532

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