ISSN: 1545 9616 JDD - Jeanette Elliott Dermal Therapy · microdermabrasion and chemical peels 30 days before the study. The active group (n=22) used serum (Retriderm Serum; Biopelle,

JDDISSN: 1545 9616

TreaTmeNT of facIal PhoTodamage USINg a Novel

reTINol formUlaTIoN

Michael H. Gold MD, Leon H. Kircik MD, Vivian W. Bucay MD,

Monika G. Kiripolsky MD, and Julie A. Biron BS

J drugs in dermatol. 2013;12[5]:533-540.

May 2013 533 Volume 12 • Issue 5

Copyright © 2013 Original articles Journal of Drugs in Dermatology

special tOpic

treatment of Facial photodamage Using a novel retinol Formulation

Michael H. Gold MD,a,b Leon H. Kircik MD,c-e Vivian W. Bucay MD,f,g Monika G. Kiripolsky MD,h,i and Julie A. Biron BSca

aTennessee Clinical Research Center, Nashville, TN bDepartment of Medicine, Division of Dermatology, Vanderbilt University School of Medicine, Nashville, TN

cMount Sinai Medical Center, New York, NY dIndiana University School of Medicine, Indianapolis, IN

ePhysicians Skin Care, PLLC, Louisville, KY fPrivate Practice, San Antonio, TX

gUniversity of Texas Health Science Center, San Antonio, TX hPrivate Practice, San Diego, CA

iScripps Memorial Hospital, La Jolla, CA

Background: Photoaged skin is characterized by a variety of clinical, histologic, and biochemical features.Objective: To determine the efficacy of a new topical formulation of 1% retinol and the effects of this same formulation using a 0.5% retinol concentration to minimize irritation. Methods: Patients at 2 sites (n=6, n=5) with photodamaged skin applied a novel suspension of retinol (1%) daily to their faces for 8 to 12 weeks. Clinicians graded improvement in ultraviolet-induced features at 4 to 6 weeks and at 8 to 12 weeks. Positive results of the observational pilot study warranted a follow-up study on the low concentration. At a third site, females (n=30) with facial photodamage applied the same formulation with or without retinol (0.5%) daily for 8 weeks. Twenty-two subjects applied the test product and 8 applied vehicle according to a randomized, double-blinded, institutional review board–approved protocol. Improvements in photodamage features were graded at 4 and 8 weeks. Results: In the observational pilot study, most participants showed improvement in overall photodamage, crow’s feet, elasticity,wrinkles, brightness, and hyperpigmentation at 60 to 80 days. Improvements at 60 to 80 days were greater than at 30 to 46 days. In the low-concentration study with 0.5% retinol, improvements were modest, most likely due to the lower retinol concentration. Burning, pruritus, dryness, and erythema were minimal with the 0.5% retinol concentration. Conclusions: The topical formulation of 1% retinol improves photodamaged skin for at least 8 to 12 weeks. Although improvements with the 0.5% retinol were more modest, side effects such as burning, dryness, pruritus, and erythema during the 8-week study period were minimal. These encouraging results justify a longer-term study to determine whether topically applied 0.5% retinol can provide benefits comparable with those seen with topically applied 1% retinol.

J Drugs Dermatol. 2013;12(5):533-540.

abstract

intrOdUctiOn

r epeated exposure to solar ultraviolet (UV) radiation causes human skin to age prematurely (photoaging).1,2 Photoaged skin is characterized by a variety of clinical,

histologic, and biochemical features. Wrinkles, uneven pigmen-tation (including lentigines and ephelides), laxity, and a rough appearance are common.3,4 Histologic changes include disorga-nized collagen fibrils in the dermis, reduced levels of types I and III collagen precursors and cross-links, increased ratios of type III to type I collagen, and increased levels of elastin.4,5

All-trans retinoic acid (RA), or tretinoin, is the primary topical pharmaceutical used to improve the appearance of photoaged skin.2 RA induces expression of procollagen genes, which in turn likely upregulate production of procollagens I and III, resulting

in increased deposition of collagen fibrils.1 The beneficial effects of topical tretinoin on photodamaged skin have been described in detail by Kligman and colleagues.6 These authors also noted that skin irritation may occur during the first month of treatment, especially in young, fair-skinned patients.

Because of the skin irritation commonly associated with the use of topical RA, interest has emerged in another vitamin A deriva-tive, retinol, reported to have similar benefits to RA but with less skin irritation.7 Two groups8,9 have reported that topical retinol is metabolized to RA in the skin. Kang and colleagues10 and Varani et al11 described epidermal thickening, reduced levels of matrix me-talloproteinases, increased growth of fibroblasts, and increased collagen synthesis in human skin after retinol application.7

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Journal of Drugs in DermatologyMay 2013 • Volume 12 • Issue 5

M. H. Gold, L. H. Kircik, V. W. Bucay, et al.

or dermal filler/biostimulatory product or ablative laser treatment during the previous 6 months, use of topical medicated products on treatment areas during the study, recent excessive exposure of the face to UV radiation, a concomitant facial skin condition that might interfere with interpretation of study parameters, and re-cent (30-day) participation in any other research study.

Study DesignSubjects were instructed to discontinue use of topical antiaging facial products at least 1 week before the study and to avoid facial microdermabrasion and chemical peels 30 days before the study. The active group (n=22) used serum (Retriderm Serum; Biopelle, Inc), while the control group (n=8) used vehicle. Assignments were made in a randomized, double-blinded manner. Each sub-ject applied the product to her entire face once daily as described below. Treatment products were dispensed at the baseline visit and inspected at each follow-up visit. All subjects provided signed informed consent for treatment and study participation.

Each morning, test subjects applied a mild facial cleanser (Ceta-phil), rinsed and dried, and applied sunscreen (Neutrogena SPF 30) to the entire face. In the evening, subjects applied cleanser, rinsed and dried, applied test product, allowed to dry for at least 5 minutes, covered the entire face with a thin film of bland moisturizer (Cetaphil), and allowed to dry before retiring.

Control subjects followed the same protocol, except that vehi-cle was substituted for test product. Evaluations at the baseline, 4-week, and 8-week visits are presented in Table 1.

Improvements associated with topical retinol use may not be sole-ly attributed to the in vivo conversion of retinol to RA. An earlier study12 showed that the potency of retinol in inducing epidermal hyperplasia is approximately half that of RA. In a subsequent study, Connor and Smth13 treated hairless mice with either retinol or RA, attempting to identify the possible role of RA formation from retinol. Tissue and elimination studies of both agents led these authors to conclude that the difference in potency could not be explained by the in vivo conversion of retinol to RA, but rather by the lower tissue uptake of retinol compared with RA.

Retinol has been formulated in an oil-free, aqueous suspension to increase penetration into the skin. This topical formulation also includes collagen, elastin, and sodium hyaluronate to drive retinol metabolism to RA. The present report describes a small pilot study to determine the efficacy of this new topical formula-tion at 1% retinol, as well as a more extensive study to evaluate the effects of this same formulation at a lower concentration (0.5%), which may minimize skin irritation.

MetHOdsPilot Observational Study (1% Retinol)An open-label observational study was conducted at 2 sites (L.H.K., V.W.B.) to determine the efficacy of a suspension of retinol (1%) (Retriderm ULTRA; Biopelle, Inc, Ferndale, MI) for the topical treat-ment of photodamaged skin. Subjects (n=6, n=5, respectively) with wrinkles of grade 3 or higher on the Rao-Goldman wrinkle scale and overall photodamage of grade 3 or higher applied the retinol suspension once daily in the evening and sunscreen in the morn-ing for 8 weeks (V.W.B.) or 12 weeks (L.H.K.). Skin characteristics (cheek wrinkles, under-eye wrinkles, crow’s feet, forehead wrinkles, skin roughness, lack of skin brightness, mottled pigmentation, and overall photodamage) were measured at baseline (L.H.K., V.W.B.), 4 weeks (V.W.B.), 6 weeks (L.H.K.), 8 weeks (V.W.B.), and 12 weeks (L.H.K). Photographs were obtained at baseline and at 8 or 12 weeks. For simplicity in the analysis, the 4-week and 6-week findings were combined and the 8-week and 12-week data were combined. Sub-ject assessments were obtained at one site (V.W.B.). The results of this study warranted a follow-up low-concentration study.

Low-Concentration Retinol (0.5%) StudySubjectsThirty females aged 36 to 63 years (median, 56 years) with Fitz-patrick skin types II or III were enrolled in this institutional review board–approved, placebo-controlled, randomized, single-center study (M.H.G., J.A.B.). Subjects had moderate to severe facial pho-todamage (scoring ≥3 on the Glogau scale) as well as moderate to severe facial wrinkles (scoring ≥3 on the Rao-Goldman scale). Exclusion criteria were pregnancy, uncontrolled systemic disease, hypersensitivity to components of study medication, topical use of a retinoid product during the previous 3 months, systemic steroid therapy during the previous 6 months, systemic retinoid therapy during the past year, facial use of botulinum toxin type A

TABLE 1.

Evaluations Performed by the Investigator, Subjects, or Both at Each Visit

Evaluation Baseline 4 Weeks 8 Weeks

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wrinkles, the percentage of improved patients was higher at 60 to 80 days than at 30 to 46 days. This suggests that improvement occurs rapidly, increases until at least 8 to 12 weeks, and might subsequently continue beyond 8 to 12 weeks.

Percentages of patients who improved by at least 1 grade in subject-assessed skin characteristics are shown in Figures 3 and 4. Percentages of improved patients ranged from 100% for skin suppleness to 25% for wrinkles. Skin irritation was report-ed by a few subjects (data not documented). Clinical examples are shown in Figures 5 to 7.

The data show that the the 1% retinol suspension improves skin characteristics of photodamage in the majority of par-ticipants. While no data regarding side effects were collected during these studies, there was an indication from patient com-ments that this could be an issue for a larger population. These encouraging results justified an additional study to evalutate the efficacy of a 0.5% retinol suspension for use over a short time (ie, 8 weeks) and to investigate the likelihood of skin irrita-tion at this lower concentration.

Data CollectionOverall photodamage was assessed using Glogau’s 4-point scale, in which 1 = minimal to no discoloration or wrinkling and no ac-tinic keratoses (AKs); 2 = wrinkling in skin with movement, slight lines near mouth and eyes, no AKs; 3 = visible wrinkles all the time, noticeable discolorations, visible AKs; and 4 = wrinkles through-out dynamic facial movement, gray or yellow skin discoloration, a history of skin cancer. Wrinkles were evaluated using the Rao-Gold-man 5-point scale, in which 1 = no wrinkles; 2 = shallow but visible wrinkles; 3 = moderately deep wrinkles; 4 = deep wrinkles with well-defined edges; and 5 = very deep wrinkles with redundant skin folds. Wrinkles and UV spots were evaluated by photogenerated scores (Visia; Canfield Scientific, Fairfield, NJ). Signs of photoaging (hyperpigmentation, telangiectasias, skin laxity, tactile roughness, AKs) were graded on a 5-point (1-5) scale. Burning, dryness, pruri-tus, and erythema were also graded on a 5-point (0-4) scale.

Global evaluation of response to treatment was graded by both the investigator and the subject, using the following scale: 0 = completely cleared; 1 = almost cleared (trace of signs, symp-toms); 2 = marked improvement (some signs, symptoms); 3 = moderate improvement (fair amount of signs, symptoms); 4 = mild improvement (distinct amount of signs, symptoms); 5 = no change from baseline; and 6 = worsening of signs, symptoms.

Facial skin quality (dryness, oiliness, texture, lines and wrinkles [periocular and perioral areas], cheek skin tightness, pigmenta-tion, thickness, general) was evaluated by subjects at each visit.

Statistical AnalysisNonparametric statistics were applied because numerical data were not continuous. The Mann-Whitney, Wilcoxon signed-rank, or χ2 test was used to test for significant differences. Fried-man’s test was used when baseline, 4-week, and 8-week data (3 groups) were compared within either the active product or vehicle group. The upper-limit cut-off level to determine statis-tical significance was P=.05. When multiple comparisons were made with baseline parameters, the Bonferroni correction was applied to the cut-off level. For example, if 2 comparisons were made with baseline, the corrected cut-off value was .05/2 = .025.

resUltsPilot Observational StudyOne subject was lost to follow-up because of a surgical emer-gency unrelated to the study. The percentage of participants who achieved at least 1-grade improvement from baseline at 30 to 46 days (4-6 weeks) and at 60 to 80 days (8-12 weeks) for each skin characteristic is shown in Figures 1 and 2. At 60 to 80 days, the percentage of improved patients was 100% for overall photodamage, crow’s feet, and lack of elasticity; 90% for cheek wrinkles and lack of brightness; 80% for mottled hyperpigmen-tation; 70% for under-eye wrinkles and forehead wrinkles; and 40% for skin roughness. For all characteristics except under-eye

FigurE 1. Percentage of subjects who achieved at least 1-grade improvement from baseline at 30 to 46 days and at 60 to 80 days for investigator-assessed skin characteristics.

FigurE 2. Percentage of subjects who achieved at least 1-grade improvement from baseline at 30 to 46 days and at 60 to 80 days in investigator-assessed skin characteristics.

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Differences from baseline were calculated by subtracting base-line values from posttreatment values for each treatment group. Differences between active product and vehicle values were tested for significance by either the Mann Whitney or χ2 test. The P values at week 4 and week 8 are shown in Table 3.

FigurE 3. Patient assessments. Percentage of subjects who achieved at least 1-grade improvement from baseline at 60 to 80 days.

FigurE 6. A 69-year-old female before (left) and after (right) 8 weeks of treatment with retinol (1%) suspension. Photographs courtesy of Vivian W. Bucay MD.

FigurE 7. A 57-year-old female before (left) and after (right) 8 weeks of treatment with retinol (1%) suspension. Photographs courtesy of Vivian W. Bucay MD.

FigurE 5. A 58-year-old female before (left) and after (right) treatment with retinol (1%) for 12 weeks. Photographs courtesy of Leon H. Kircik MD.

FigurE 4. Patient assessments. Percentage of subjects who achieved at least 1-grade improvement from baseline at 60 to 80 days.

Low-Concentration Retinol StudyBaseline ComparisonsAll subjects completed the study. Subject ages and baseline val-ues of each skin characteristic for active product and vehicle were compared and tested for significant differences. The results show that except for the moist/dry parameter, baseline characteristics do not differ significantly between the 2 groups (Table 2).

Intergroup ComparisonsAssessments of each skin characteristic were compared be-tween the active product and vehicle groups at weeks 4 and 8.

TABLE 2.

Baseline Assessments, Active Product Compared With Vehicle

Characteristic P Value

Agea 0.3837 General evaluation of facea .8982 Visia white lighta .0743 Visia UVa .3345 Glogaua .0973 Signs of photodamageb

Hyperpigmentation 1.000 Telangiectasias .4987 Skin Laxity .2105 Tactile roughness .3740 Actinic keratoses .3067 Facial skin qualityb

Moist/Dry .0365c Oiliness .7568 Texture .5241 Eye wrinkles .4727 Mouth wrinkles .5211 Cheek skin .3383 Pigment .7795 Skin thickness .7967 Overall .5309aMann-Whitney test. bχ2 test. cSignificant.

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Differences between the 2 treatment groups were not significant for general evaluation of the face, Visia White light (wrinkles), Visia UV (spots), and the Glogau analysis. Differences were significant for hyperpigmentation and AKs at 8 weeks (P=.0096 and .0041, re-spectively), cheek skin at 4 weeks (P=.0251), and overall response to treatment at 8 weeks (P=.0261). In these 4 categories, the active product performance was superior to that of the vehicle.

Intragroup ComparisonsThe actual grade values (as opposed to values obtained by subtracting baseline values from posttreatment values) were compared with baseline within each of the 2 treatment groups (Table 4). Unlike the previous comparisons, in which active product and vehicle groups were compared directly, these comparisons were all within a single treatment group. Fried-man’s test was used when baseline, 4-week, and 8-week data (3 time points) were compared within either the active product

or vehicle group. The Wilcoxon signed-rank test was used when either the 4-week or 8-week values (2 time points) were com-pared with baseline within a single treatment group.

For the general facial evaluation, baseline, 4-week, and 8-week assessments were compared using Friedman’s test and were found to differ significantly (P=.0012). To locate more precisely the differences within these 3 subgroups, the 4-week and 8 week data were compared separately to baseline by the Wil-coxon signed-rank test. Since both comparisons were with baseline the Bonferroni correction was applied to obtain a new cut-off level of .025.

As shown in Table 4, the 8-week general evaluation of the face was significantly improved as compared with baseline in sub-jects treated with active product (P=.0010), but not for those subjects treated with vehicle (P=.2500). Improvements in hyper-pigmentation, telangiectasias, skin laxity, tactile roughness, and AKs were observed in subjects treated with active product, with 4-week and 8-week assessments of improvement being statisti-cally significantly when compared with corresponding baseline values. This was not the case for these same skin characteristics in patients using vehicle. These results suggest that the active product appears to improve all 5 skin characteristics over the treatment period, whereas the vehicle alone does not. These results are in conflict with those of Table 3, in which active prod-uct and vehicle were compared directly with each other by the χ2 test. Hyperpigmentation and AKs improved significantly at 8 weeks but not at 4 weeks when active product was used.

These conflicting results may be due to the different number of patients assigned to the active product group (n=22) compared with the vehicle group (n=8), as well as to differences in sensitivity between the χ2 and the Wilcoxon signed-rank tests. Nonetheless, at the very least there appears to be a trend in improvement in hyperpigmentation, telangiectasias, skin laxity, tactile roughness, and AKs when active product is used but not when vehicle is used. Improvements in hyperpigmentation as well as in AKs with active product are apparent at 8 weeks by both statistical approaches.

SymptomsBurning, dryness, itching, and redness are tabulated in Tables 5 and 6. These data demonstrate that these symptoms are neg-ligible in most cases. Dryness was moderate at 4 weeks in a single vehicle subject and at 8 weeks in a single subject treated with the active product.

Response to TreatmentInvestigator-assessed response to treatment was generally mild (grade 4) to moderate (grade 3) at both 4 weeks and 8 weeks for both treatment groups (Table 7). Differences between the 2 treatment groups (active vs vehicle) were not significant at 4 weeks and at 8 weeks by the Mann-Whitney test. Visual inspec-

TABLE 3.

Differences From Baseline, Active Product vs Vehicle

CharacteristicWeek 4 Week 8

P Value P Value

General evaluation of face .1369 .2217Visia white light (wrinkles) .0912 .2909 Visia UV (spots) .8510 .1446 Glogau .1635 .8964 Signs of photodamage Hyperpigmentation .2750 .0096c Telangiectasias .6074 .6691 Skin laxity .1852 .1188 Tactile roughness .2187 .0914 Actinic keratoses .0709 .0041c Symptoms Burning — .7455a Dryness — .1618a Itching — .5659a Redness — .5872a Response to treatment (investigator) .3884b .9244,b .5385a

Facial skin quality Moist/Dry .6051 .3215 Oiliness .2001 .8834 Texture .1488 .3379 Eye wrinkles .0564 .1038 Mouth wrinkles .7766 .1604 Cheek skin .0251a .1825 Pigment .6612 .4184 Skin thickness .2993 .5844 Overall .1042 .0577 Response to treatment (subject) .1086b .0261b,c, .1365a

aDifference from week 4. bGraded response.cSignificant.

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TABLE 4.

P Values of Comparisons With Baseline Within Each Treatment Group

ParameterBaseline vs 4 Weeks vs 8 Weeks Baseline vs 4 Weeks Baseline vs 8 Weeks

Active Vehicle Active Vehicle Active Vehicle

General evaluation of face .0012a .6065 .0391 1.000 .0010a .5000 Visia white light .6286 .0498 .7502 .3750 .7680 .3125 Visia UV .4046 .5818 .3683 .9375 .1870 .3750 Glogau .0663 .2636 .2500 .5000 .0625 .5000 Signs of photodamage Hyperpigmentation <.000a .0681 <.000a .2500 <.0001a .0625 Telangiectasias .0069a .1738 .0107a .2500 .0137a .6250 Skin laxity <.0001a .1738 <.0001a .2500 <.0001a .2500 Tactile roughness <.0001a .2122 .0001a .6250 <.0001a .0938 Actinic keratoses <.0001a .6514 .0034a .8125 <.0001a .8125 aSignificant.

TABLE 5.

Severity of Symptoms at 4 Weeks

GradeBurning Dryness Itching Redness

Active Vehicle Active Vehicle Active Vehicle Active Vehicle

0 20 6 19 6 22 7 20 71 1 1 1 0 0 0 2 0

2 1 0 2 0 0 0 0 0

3 0 0 0 1 0 0 0 04 0 0 0 0 0 0 0 0

TABLE 6.

Severity of Symptoms at 8 Weeks

GradeBurning Dryness Itching Redness

Active Vehicle Active Vehicle Active Vehicle Active Vehicle

0 22 8 19 7 21 8 21 71 0 0 2 0 0 0 0 1

2 0 0 0 1 1 0 1 0

3 0 0 1 0 0 0 0 04 0 0 0 0 0 0 0 0

TABLE 7.

Response to Treatment (Investigator)

Grade4 Weeks 8 Weeks

Active Vehicle Active Vehicle

0 0 0 0 01 0 0 0 0

2 1 0 1 0

3 9 1 9 3

4 10 4 10 4

5 2 2 2 1

tion reveals, however, that at 4 weeks, moderate improvement occurs in 9/22 (41%) and marked improvement occurs in 1 (4%) of the active subjects; moderate improvement is observed in

only 1/7 (14%) of vehicle subjects. At 8 weeks, the respective values are 45%, 4%, and 38%. Although more vehicle subjects show mild improvement at 8 weeks than at 4 weeks, both the percentage of improved subjects and the degree of improve-ment are greater in the active group at both time points.

Subject-assessed response to treatment was generally mild (grade 4) to moderate (grade 3) at both 4 weeks and 8 weeks for both treatment groups (Table 8). Differences between the 2 treatment groups were not significant at 4 weeks and at 8 weeks by the Mann-Whitney test. Visual inspection reveals, however, that at 4 weeks, mild to moderate improvement oc-curs in 4/22 (18%) of active subjects and in none of vehicle subjects, although marked improvement occurs in 1/7 (14%) of vehicle subjects. At 8 weeks, 12/22 (54%) of active subjects

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show at least moderate improvement compared with 25% of vehicle subjects. Although more vehicle subjects show mild improvement at 8 weeks than at 4 weeks, the percentage of improved subjects and the degree of improvement are greater in the active group at both time points.

Both investigator- and subject-assessed responses to treatment suggest a trend in which more subjects improve with active product than with vehicle, although the difference between the 2 groups did not achieve statistical significance. Clinical exam-ples are shown in Figures 8 to 10.

discUssiOnThis is the first report to demonstrate (1) the efficacy of 1% reti-nol in a proprietary formulation designed to improve delivery of retinol to photodamaged skin and (2) the efficacy and safety of this same formulation at a concentration of 0.5% retinol. The pilot study shows that the commercially available prod-uct (1% retinol) improves crow’s feet, elasticity, wrinkles of the cheek, under-eye, and forehead, brightness, mottled hyperpig-mentation, and skin roughness for up to 8 to 12 weeks. In the subsequent study using the same formulation but at a lower concentration of retinol 0.5%, more modest efficacy was ob-served, perhaps because the concentration of active product was reduced and the study period was limited to 8 weeks.

In the study of 0.5% retinol, when active product and vehicle were compared directly, active product performance was significantly superior to that of vehicle in improving hyperpig-mentation and AKs at 8 weeks (P=.0096 and .0041, respectively), cheek skin at 4 weeks (P=.0251), and subject-evaluated response to treatment at 8 weeks (P=.0261). Treatment group responses did not differ significantly with respect to telangiectasias, skin laxity, and tactile roughness, moist/dry, oiliness, texture, wrin-kles (eye and mouth), pigment, skin thickness, and overall. Within-group comparisons to baseline, however, were differ-ent. The 8-week general evaluation of the face was significantly superior to baseline in subjects treated with active product (P=.0010), but not for subjects treated with vehicle (P=.2500). Visia White light (wrinkles), Visia UV (spots), and Glogau data at 4 weeks and 8 weeks did not differ significantly from base-

line. For hyperpigmentation, telangiectasias, skin laxity, tactile roughness, and AKs of subjects treated with active product, the 4-week and 8-week assessed improvements were significantly significant when compared with those at baseline. These same skin parameters at 4 weeks and 8 weeks did not differ signifi-cantly from baseline in the vehicle group. Burning, dryness, itching, and redness were generally negligible in both treat-ment groups. Improvement with treatment was generally mild to moderate at both 4 weeks and 8 weeks for both treatment groups. Responses between the 2 treatment groups did not dif-fer significantly at 4 weeks and at 8 weeks.

The choice to use retinol in the present study was based on sever-al considerations. Antille and colleagues14 studied the penetration and metabolism of topical retinol, RA, retinyl palmitate (RP), and retinal (retinaldehyde) in human skin explants. Twenty-four hours after applying a retinol-containing cream, the retinol and retinyl

TABLE 8.

Response to Treatment (Subjects)

Grade4 Weeks 8 Weeks

Active Vehicle Active Vehicle

0 0 0 0 01 0 0 1 1

2 0 1 2 0

3 4 0 9 1

4 16 4 10 3

5 2 2 0 3

FigurE 8. A 50-year-old female before (left) and after (right) 8 weeks of treatment with retinol (0.5%) suspension. Photographs courtesy of Michael H. Gold MD.

FigurE 9. A 42-year-old female before (left) and after (right) 8 weeks of treatment with retinol (0.5%) suspension. Photographs courtesy of Michael H. Gold MD.

FigurE 10. Visia brown spot analysis of a 41-year-old female before (left) and after (right) 8 weeks of treatment with retinol (0.5%) suspen-sion. Photographs courtesy of Michael H. Gold MD.

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ester content of skin had increased 100-fold and 5-fold, respec-tively. Duell and colleagues9 compared retinoidal effects of retinol, retinaldehyde, and RP in human skin and evaluated the effects of occlusion during contact with skin. The retinoid effect in these ex-periments was the induction of retinoic acid 4-hydroxylase activity. Each retinoid was in a prototypic vehicle of ethanol, propylene gly-col, and antioxidant. When using this vehicle, the authors found that the penetration of unoccluded retinol was greater than that of unoccluded RA, and that the retinoid effects of retinol were greater than those of RA, even though retinol is a weaker retinoid that RA. This study shows the importance of skin penetration on the ability of a retinoid formulation to exert its retinoid effects. In the present study, retinol was applied to photodamaged skin and shown in both studies to provide clinical benefit, even at the lower retinol concentration of 0.5%. These results may be explained by improved penetration of retinol into photodamaged skin.

Limitations of the present study are the short study period, as well as the small number of subjects in both the pilot study and the vehicle treatment arm of the subsequent 0.5% retinol study. Future studies should further explore the use of 0.5% retinol and should include a larger number of subjects with varying severities of photodamage. Future studies should also consider following subjects for longer than 8 weeks. Finally, the addition of histologic tissue analysis could elucidate interactions among the skin retinoids (eg, retinol and retinyl ester) in the skin after application of the less-concentrated active product.

cOnclUsiOnDaily application of this topical 1% retinol formulation improves photodamaged skin for at least 8 to 12 weeks. Although improve-ments with the 0.5% retinol were more modest, side effects such as burning, dryness, itching, and redness during the 8-week study pe-riod were minimal. These encouraging results justify a longer-term study to determine whether 0.5% retinol would provide benefits comparable with those of 1% retinol while reducing side effects.

disclOsUresThis study was funded by Biopelle, Inc. L.H.K. has been an inves-tigator, speaker, and consultant for Biopelle and Ferndale. M.H.G., V.W.B., M.G.K., J.A.B. have no financial interest in Biopelle, Inc.

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aUtHOr cOrrespOndence

Michael H. Gold MD E-mail:................…….........…[email protected]

"This is the first report to demonstrate (1) the efficacy of 1% retinol in a proprietary formulation designed to improve delivery of retinol to photodamaged skin and (2) the efficacy and safety of this same formulation at a concentration of 0.5% retinol."

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ISSN: 1545 9616 JDD - Jeanette Elliott Dermal Therapy · microdermabrasion and chemical peels 30 days before the study. The active group (n=22) used serum (Retriderm Serum; Biopelle,