Reduc�on of Facial Redness with Resveratrol Added to Topical Product Containing Green Tea Polyphenols and Caffeine Sarah Y. Siu, Georgina M. Ferzli and Neil Brody The Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, NY, 11203University Hospital of Brooklyn Introduc�on Facial redness can occur in associa�on with a large number of medical problems. The most common causes of facial redness and rashes include inflammatory dermatoses, infec�ons, and connec�ve �ssue disorders. Rosacea is associated with flushing, erythema, telangiectasia, papules, and pustules. Its e�ology is unknown. Perioral ocular derma��s is an erythematous erup�on of unknown e�ology while atopic derma��s, an inflammatory skin disease, frequently affects the cheeks in infants and other facial areas in adults. Contact derma��s, seborrheic derma��s, psoriasis, celluli�s, discoid lupus erythematosus, dermatomyosi�s, and impe�go are also associated with facial redness *Tavadia 2003). Chronic sun damage, gene�c flusher-blusher, and acne are also frequently encountered. While redness is the final clinical manifesta�on, the pathophysiology leading to the redness may be quite varied. We refer to the common denominator in all of these as inflamma�on, and we now understand many molecules are involved in the inflammatory process. Many of the pathways of inflamma�on involve reac�ve oxygen species (ROS). It is probably true quenching ROS, should be considered an an�-inflammatory agent. Many topical formula�ons include an�oxidants to improve the an�oxidant capability of the skin (Berson 2008, Farris 2007, Palmer 2010). An an�oxidant that has received considerable a�en�on is resveratrol (3,5,4’-trihydroxys�lbene), a polyphenolic phytoalexin found in red wines, colored berries, and peanuts (Baxter 2007).The myriad of clinical benefits of resveratrol led to the hypothesis that the addi�on of this agent to a topical prepara�on containing green tea polyphenols and caffeine (both of which protect skin from UV injury [Elmets 2001, Heffernan 2009]) might be an even more effec�ve skin care product. The present study evaluated the ability of a resveratrol-enriched product containing green tea polyphenols and caffeine to reduce facial redness in human skin. Methods Stage 1. In a preliminary split-face study, 16 volunteers applied topical an�oxidant product containing green tea polyphenols and caffeine to one side of the face and the same product with resveratrol added to the other side of the face. Product was applied twice daily for 12 weeks. Both products were well tolerated. A�er 12 weeks subjects with facial redness showed a reduc�on in redness on the side treated with resveratrol-enriched product (data not shown). These results led to the present study in which subjects presen�ng with facial redness applied resveratrol-enriched product to the en�re face to evaluate the consistency of the apparent reduc�on in redness. Stage 2. Subjects (n = 16) presen�ng with facial redness applied the resveratrol-enriched product twice daily to the en�re face. Reduc�on in redness was evaluated and photographed at 2-week intervals for up to 9 weeks. Photography was obtained by Canfield Visia So�ware Version 5.2.0 2010-0503a. This unit has a mode that spectrally separates the red por�on of the image allowing enhanced ability to see changes in skin redness. Improvement was evaluated by nine trained staff members and 21 house staff residents on a scale of 1 to 9. The baseline score was assigned a value of 5 for each subject. Pos�reatment scores lower than 5 denoted redness reduc�on while scores above 5 indicated an increase in redness. Evaluators compared photographs taken before treatment and at 2-week intervals for up to 9 weeks. All subjects provided signed informed consent to treatment and photography. Results All subjects completed the study. Adverse effects were not observed in any subject. Data were analyzed by non-parametric sta�s�cs because the 9-point scale is not con�nuous and scoring data were not normally distributed as shown by the Shapiro-Wilk test. As shown in Figure 1, the collec�ve data show that median redness scores ranged from 2 to 6 and that most subjects (69%-99%) achieved a redness reduc�on of at least 1 score level at the end of their treatment period. Redness in the remaining subjects (0%-31%) either did not change (0%-19%) or increased by 1 score value (0%-19%). Discussion Overall, the results suggest that the treatment effect (i.e., reduc�on in facial redness) requires up to 6 weeks of treatment for most subjects. It is possible that subjects achieving redness reduc�on in 3 to 6 weeks may improve further. However, if redness has not been reduced a�er 6 weeks of treatment, it is unlikely that further treatment will reduce redness. Clinical examples are presented in Figures 2-4. Many topical formula�ons include an�oxidants. Common examples include the polyphenols (found in tea), vitamin C, vitamin E, silymarin, and soy isoflavones (Pinnell 2003). Interest in resveratrol became stronger when, in 1997, resveratrol was shown to have cancer chemopreventa�ve effects in tumor ini�a�on, promo�on, and progression stages in humans (Jang 1997). Resveratrol has since been shown to reduce intracellular hydrogen peroxide-upregulated ROS in human fibroblasts in vitro (Jagdeo 2010), modulate gene�c expression (Baxter 2007), inhibit inflammatory mediators (Baxter 2007), prevent skin cancer (Aziz 2005), exhibit an�prolifera�ve ac�vity in mul�ple forms of cancer (Athar 20078, Ding 2002), promote apoptosis in tumor cells (Delmas 2003), improve dermal wounds (Khanna 2002, Sen 2002, Khanna 2001), inhibit UVB-induced skin damage (Afaq 2003), and protect against LDL oxida�on (Brito 2003). Resveratrol has also been shown to have an�fungal and an�bacterial proper�es (Chan 2002) and to reduce levels of ROS in HaCaT kera�nocytes exposed to UVA light (Baxter 2007). Green tea polyphenols (GTPs) are an�oxidants shown in mice to protect against skin inflamma�on and tumorigenesis (Mukhtar 1994, Ka�yar 2000) and phototoxicity induced by psoralen plus UV-A radia�on (Zhao 1999). GTPs (catechins) include (—) epicatechin, (—) epicatechin-3-gallate, (—) epigallocatechin, and (—) epigallocatechin-3-gallate deriva�ves. When administered topically in mice, (-)-epigallocatechin-3-gallate protects against photocarcinogenesis (Gensler 1996) and is regarded as the most effec�ve catechin. Topical caffeine has been shown to protect against UV damage in mice by elimina�ng UV-damaged kera�nocytes (Koo 2007) and subsequently inhibi�ng skin cancer development. Topical caffeine has also been to inhibit forma�on of galactose cataracts (Varma 2010) and improve psoriasis vulgaris (Vali 2005). Exposure of the skin to UV radia�on induces inflammatory responses associated with a variety of skin disorders, including cancer. Regarded as early events in tumor promo�on, development, or both, inflammatory responses are characterized by erythema, edema, hyperplas�c responses, and increases in blood flow blood vessel permeability, and levels of COX-2 and prostaglandin. These responses are also associated with the induc�on of inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β) (Meeran 2009). It is useful to summarize mechanisms by which the combina�on product of the present study reduces facial redness and inflamma�on. Facial redness may occur in a variety of inflammatory dermatologic disorders and an effec�ve treatment of facial redness without the side effects of steroids would be useful (Oh 2010). Since the molecular targets of each component are not iden�cal, the components may act independently and synergis�cally to reduce cutaneous inflamma�on. Conclusion The skin product combina�on of resveratrol, green tea polyphenols, and caffeine reduces facial redness in most pa�ents a�er 3 to 6 weeks of con�nuous treatment and may provide further improvement with addi�onal treatment. Figure 2. Graph of 9 evaluators-natural photo data. A 75-year-old female (skin type 2) before treatment (le�) and 4 weeks a�er treatment with resveratrol-enriched product (right). Redness reduc�on was scored at 3. Figure 1. Median pos�reatment score vs. percentage of subjects for four sets of data. Baseline score was set at 5 for each subject. Pos�reatment scores less than 5 indicated reduced redness while scores greater than 5 denoted increased redness. Figure 3. Graph of 9 evaluators-redness photo data. A 72-year-old male (skin type 2) before treatment (le�) and 9 weeks a�er treatment with resveratrol-enriched product (right). Redness reduc�on was scored at 3. Figure 4. Graph of 21 evaluators-Natural photo data A 27-year-old female (skin type 1) )before treatment (le�) and 5 weeks a�er treatment with resveratrol-enriched product (right). Redness reduc�on was scored at 3. Figure 5. Graph of 21 evaluators- redness photo data. The possible role of treatment dura�on on facial redness reduc�on was also evaluated for each of the four data sets (Table 1). For the 3 to 6-week treatment period the propor�ons of subjects among the four data sets did not differ significantly by Pearson’s chi-square test (p = 0.1967). A similar result (p = 0.1059) was obtained when the 7 to 9 week treatment period data were compared. These results indicate that for each of the four sets of data, the distribu�on of subjects among median scores did not differ significantly within each of the two treatment periods. Table 1. Distribution of subjects among median scores for the 3 to 6 and 7 to 9- week treatment periods for each of the four data sets Median Score Weeks of Treatment 3 to 6 7 to 9 9 Nat 9 Red 21 Nat 21 Red 9 Nat 9 Red 21 Nat 21 Red 2 0 1 4 1 0 0 1 0 3 6 4 3 5 1 0 0 0 4 4 7 2 6 0 3 1 4 5 1 0 2 0 2 1 0 0 6 1 0 1 0 1 0 2 0 Х2 = 15.88, df = 12, p = 0.1967 (ns) Х2 = 18.33, df = 12, p = 0.1059 (ns) The distributions of subjects among the median scores for the 3 to 6-week treatment period were compared with those for the 7 to 9-week treatment period for each of the four data sets. As shown in Table 2, differences in proportions of subjects for the 3 to 6 and 7 to 9-week treatment durations did not achieve statistical significance for any of the four data sets. Table 2. Comparisons of distributions of subjects among median scores for the 3 to 6 and 7 to 9-week treatment periods Median Score 9* Nat 9* Red 21* Nat 21* Red 3-6† 7-9† 3-6† 7-9† 3-6† 7-9† 3-6† 7-9† 2 0 0 1 0 4 1 1 0 3 6 1 4 0 3 0 5 0 4 4 0 7 3 2 1 6 4 5 1 2 0 1 2 0 0 0 6 1 1 0 0 1 2 0 0 P = 0.1573 (ns) P = 0.1870 (ns) P = 0.3283 (ns) P = 0.2019 (ns) *No. of evaluators. † Weeks of treatment. Nat = natural photos; red = red images. FC17PosterTopixSiuReductionofFacialRedness.pdf