Effects of tretinoin on photodamaged skin. A histologic study

The histologic effects of topical tretinoin therapy on photodamaged facial skin were investigated in two 24-week, double-blind, randomized, vehicle-controlled studies involving 533 subjects at eight US centers. Three concentrations of tretinoin (0.05%, 0.01%, and 0.001%) in a new emollient cream were studied. Pretherapy and posttherapy biopsy specimens from the periorbital (crow's foot) area were examined by conventional light microscopy and computerized image analysis. Four significant dose-dependent differences from vehicle were found in the tretinoin groups: increased epidermal thickness, increased granular layer thickness, decreased melanin content, and stratum corneum compaction. There was no significant difference between 0.001% tretinoin and the vehicle, and no obvious dermal changes were detected in any group. The four epidermal changes in tretinoin-treated skin establish the biologic activity of the new emollient cream formulation and may partially account for the clinical improvements in photodamage observed in the same group of subjects.     

Photodamage pilot study: a double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel

BACKGROUND: Tazarotene, a potent acetylenic retinoid for topical use, might be expected to benefit photodamaged skin, including improving the classical signs of fine wrinkles, mottled hyperpigmentation, and roughness. OBJECTIVE: Our purpose was to determine the efficacy and safety of tazarotene 0.1% gel in the treatment of photodamaged dorsal forearm skin. METHODS: Ten healthy female volunteers, aged 45 to 65 years, with moderately photodamaged forearm skin applied tazarotene 0.1% gel to one arm and vehicle gel to the other once daily for 12 weeks. The study was a double-blind, randomized, paired-comparison evaluation conducted at a single site. RESULTS: Tazarotene showed beneficial effects for several efficacy variables. It was more efficacious than vehicle in reducing skin roughness and fine wrinkling based on objective measurements. Tazarotene also corrected epidermal atrophy and atypia and improved skin hydration properties. CONCLUSION: In this 12-week pilot study tazarotene redressed abnormalities associated with photo-damaged skin.     

Tazarotene 0.1% cream versus tretinoin 0.05% emollient cream in the treatment of photodamaged facial skin: a multicenter, double-blind, randomized, parallel-group study.

OBJECTIVES: To compare the efficacy and tolerability of tazarotene 0.1% cream and tretinoin 0.05% emollient cream in the treatment of photodamaged facial skin. METHODS: Subjects were eligible to enroll in this multicenter, double-blind, randomized, parallel-group study if they had at least mild levels of facial fine wrinkling and mottled hyperpigmentation, and at least moderate levels of one of these. Subjects were randomly assigned to apply either tazarotene cream or tretinoin emollient cream to their faces once each evening for 24 weeks. RESULTS: A total of 173 subjects were enrolled, of whom 157 completed. All significant between-group differences in efficacy measures were in favor of tazarotene - for fine wrinkling at the study endpoint and, at earlier timepoints, for treatment success (> or =50% global improvement), and the overall integrated assessment of photodamage, mottled hyperpigmentation, and coarse wrinkling. Both products were comparable in terms of cosmetic acceptability and tolerability except that tazarotene was associated with a transiently higher incidence of a burning sensation on the skin (in the first week of treatment but not thereafter). CONCLUSIONS: Tazarotene 0.1% cream can offer superior efficacy over tretinoin 0.05% emollient cream in the treatment of facial photodamage, particularly with respect to the speed of improvement.     

Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized, vehicle-controlled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks.

OBJECTIVE: To assess the safety and efficacy of 4 concentrations of tazarotene cream in the treatment of facial photodamage. DESIGN: Prospective weekly multicenter, investigator-masked, randomized, parallel-group study. SETTING: University hospitals and clinical research centers. PATIENTS: Three hundred forty-nine subjects with facial photodamage. INTERVENTION: Daily topical application of tazarotene cream (0.01%, 0.025%, 0.05%, and 0.1%) compared with its vehicle and with 0.05% tretinoin emollient cream. RESULTS: Tazarotene cream and tretinoin cream significantly improved mottled hyperpigmentation and fine wrinkles. At week 24, treatment success rates based on global responses were 67% (39 of 58 subjects) with 0.1% tazarotene, 52% (30 of 58 subjects) with 0.05% tazarotene, 36% (21 of 58 subjects) with 0.025% tazarotene, 41% (24 of 59 subjects) with 0.01% tazarotene, 55% (32 of 58 subjects) with 0.05% tretinoin, and 22% (13 of 58 subjects) with vehicle. Local adverse events, although more frequent with tazarotene at higher concentrations, were generally mild to moderate. CONCLUSIONS: Tazarotene in a cream formulation is safe and is associated with positive changes in the treatment of photodamaged facial skin.     

Topical tretinoin for treatment of photodamaged skin. A multicenter study

The clinical and histologic effects of a new emollient cream formulation of topical tretinoin at concentrations of 0.05% and 0.01% were examined in 251 subjects with mild to moderate photodamaged facial skin in a randomized, double-blind, vehicle-controlled, multicenter study. Seventy-nine percent of the subjects who received 0.05% tretinoin for 24 weeks showed overall improvement in photodamaged skin compared with improvement in 48% of the vehicle-treated control subjects. Significant reductions were found in fine wrinkling, mottled hyperpigmentation, roughness, and laxity after 0.05% tretinoin therapy when compared with controls. In addition, histologic changes of increased epidermal thickness, decreased melanin content, and stratum corneum compaction provide independent evidence supporting clinical improvement. Side effects of erythema, peeling, and stinging were usually mild and well tolerated.     

A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin

The effects of myristyl nicotinate (MN), a nicotinic acid derivative designed to deliver nicotinic acid to skin without vasodilatation, on subjects with photodamaged skin have been studied. MN increased skin cell nicotinamide adenine dinucleotide (NAD) by 25% (P = 0.001) demonstrating effective delivery of nicotinic acid to skin. Relative to placebo, MN treatment of photodamaged facial skin increased stratum corneum thickness by approximately 70% (P = 0.0001) and increased epidermal thickness by approximately 20% (P = 0.001). In two separate studies, MN treatment increased rates of epidermal renewal by 6% (P = 0.003) to 11% (P = 0.001) and increased the minimal erythemal dose by 8.9 (P = 0.07) and 10% (P = 0.05) relative to placebo. MN treatment resulted in reductions in the rates of transepidermal water loss (TEWL) of approximately 20% relative to placebo on cheeks (P = 0.012) and arms (P = 0.017) of study subjects. Results of a tape stripping challenge before and after MN treatment demonstrated a significant correlation (P = 0.03) between increased skin NAD content and resistance to changes in TEWL for MN treated but not placebo subjects. Rates of TEWL changed more rapidly and to a greater extent in atopic subjects compared with normal subjects. The results indicate that MN enhances epidermal differentiation and barrier function in skin, suggesting that this method of nicotinic acid delivery may prove useful in limiting progression of actinic skin damage and possibly in treating other conditions involving skin barrier impairment.     

Tazarotene versus tazarotene plus hydroquinone in the treatment of photodamaged facial skin: a multicenter, double-blind, randomized study.

OBJECTIVES: To compare the efficacy and tolerability of tazarotene plus hydroquinone versus tazarotene alone in the treatment of facial photodamage. METHODS: Patients with facial mottled hyperpigmentation of at least moderate severity and an overall integrated assessment of photodamage score of at least moderate applied tazarotene 0.1% cream each evening and either hydroquinone 4% cream or placebo cream each morning for up to 24 weeks. RESULTS: Among 131 patients enrolled, 114/124 (92%) with exit data completed. Both regimens were highly effective in reducing photodamage, with tazarotene plus hydroquinone showing superiority over tazarotene alone for some efficacy measures. The incidence of >or=1-grade improvement from baseline (on a scale of none, minimal, mild, moderate, or severe) was significantly greater with tazarotene plus hydroquinone than with tazarotene alone for lentigines (weeks 12-24, por=50% global improvement was also significantly superior with the combination regimen as early as week 8 (p相似文献   

A pilot study to determine the effect of tazarotene gel 0.1% on steroid-induced epidermal atrophy

BACKGROUND: Repeated applications of a corticosteroid can induce epidermal atrophy. This study was performed to investigate whether the adjunctive use of tazarotene gel 0.1% might help to minimize the development of steroid-induced epidermal atrophy. METHODS: Each of 24 healthy volunteers received the following six treatments (applied 6 days per week for 4 weeks), which were randomized to each of six sites on their forearms: no treatment, tazarotene vehicle, tazarotene vehicle + tazarotene gel 0.1%, diflorasone diacetate 0.05% ointment, diflorasone diacetate 0.05% ointment + tazarotene vehicle, or diflorasone diacetate 0.05% ointment + tazarotene gel 0.1%. RESULTS: The mean epidermal thickness was increased by 20% (NS) and 62% (P < or = 0.0005) after applications of tazarotene vehicle and tazarotene gel 0.1%, respectively. Application of diflorasone diacetate reduced the mean epidermal thickness by 43% (P < or = 0.0005). Concomitant application of tazarotene gel 0.1% with diflorasone diacetate did not entirely prevent atrophy, but was shown to ameliorate 37% of the epidermal atrophy induced by diflorasone diacetate alone (P < or = 0.003 compared with steroid monotherapy). CONCLUSIONS: Tazarotene gel 0.1% significantly reduces epidermal atrophy induced by diflorasone diacetate 0.05% ointment.     

Tazarotene cream for postinflammatory hyperpigmentation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study

Previous investigations have reported the efficacy of tazarotene 0.1% cream for the treatment of dyschromia associated with photoaging and for acne vulgaris. The present investigation assessed tazarotene 0.1% cream for the treatment of postinflammatory hyperpigmentation (PIH) in a double-blind, randomized, vehicle-controlled study of 74 patients from darker racial ethnic groups who had acne. Once-daily application of tazarotene cream was shown to be effective against PIH, achieving significantly greater reductions compared with vehicle in overall disease severity and in the intensity and area of hyperpigmentation within 18 weeks (P< or =.05). Mean levels of erythema, burning, and peeling were no more than trace in both groups throughout the study, and mean levels of dryness were no more than mild in both groups. In our study, tazarotene cream was effective and well tolerated in the treatment of PIH in patients with darker skin.     

Long-Term Efficacy and Safety of Tretinoin Emollient Cream 0.05% in the Treatment of Photodamaged Facial Skin

Background: Long-term (>1 year) placebo-controlled studies of tretinoin in the treatment of photodamaged skin have not been conducted. Recently, we conducted a 2-year placebo-controlled study of tretinoin emollient cream 0.05%, including histopathologic assessment of safety and analysis of markers of collagen deposition. Objective: The objective of the study was to determine the long-term safety and efficacy of tretinoin emollient cream 0.05% in the treatment of moderate to severe facial photodamage. Methods: A total of 204 subjects were treated with tretinoin or placebo (vehicle emollient cream) applied to the entire face once a day for up to 2 years. Clinical and histologic effects were assessed at regularly scheduled clinic visits. Results: Treatment with tretinoin resulted in significantly greater improvement relative to placebo in clinical signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness), overall photodamage severity, and investigator’s global assessment of clinical response (p < 0.05). Histologic evaluation showed no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on stratum corneum following treatment with tretinoin compared with placebo. Immunohistochemistry studies, conducted at three study centers, showed a significant increase relative to placebo in facial procollagen 1C terminal, a marker for procollagen synthesis, at month 12 (p = 0.0074). Conclusion: Long-term treatment with tretinoin emollient cream 0.05% is safe and effective in subjects with moderate to severe facial photodamage.     

The effects of an estrogen and glycolic acid cream on the facial skin of postmenopausal women: a randomized histologic study

A prospective, randomized, double-blind study was conducted to determine if estradiol and glycolic acid creams produced a significant reversal of epidermal and dermal markers of aging and if the cumulative effect of the creams was greater than either alone. Sixty-five patients applied a cream containing 0.01% estradiol or 15% glycolic acid, alone or in combination, to one side of the face, and a vehicle cream to the opposite side, for 6 months. A 2-mm punch biopsy was obtained from the hairline of each patient and processed for analysis. The estradiol treatment produced a 23% increase in epidermal thickness (P = .00458); the glycolic acid, a 27% increase (P = .00467); and the combination, a 38% increase (P = .000181). All groups showed a statistically significant improvement in reversing markers (rete peg pattern, epidermal thickness) of skin aging. Although not statistically significant (P = .1), a cumulative effect was seen when estradiol and glycolic acid creams were used in combination.     

Tazarotene 0.1% cream versus tretinoin 0.05% emollient cream in the treatment of photodamaged facial skin: a multicenter,double‐blind,randomized, parallel‐group study

OBJECTIVES: To compare the efficacy and tolerability of tazarotene 0.1% cream and tretinoin 0.05% emollient cream in the treatment of photodamaged facial skin.

METHODS: Subjects were eligible to enroll in this multicenter, double‐blind, randomized, parallel‐group study if they had at least mild levels of facial fine wrinkling and mottled hyperpigmentation, and at least moderate levels of one of these. Subjects were randomly assigned to apply either tazarotene cream or tretinoin emollient cream to their faces once each evening for 24 weeks.

RESULTS: A total of 173 subjects were enrolled, of whom 157 completed. All significant between‐group differences in efficacy measures were in favor of tazarotene – for fine wrinkling at the study endpoint and, at earlier timepoints, for treatment success (≥50% global improvement), and the overall integrated assessment of photodamage, mottled hyperpigmentation, and coarse wrinkling. Both products were comparable in terms of cosmetic acceptability and tolerability except that tazarotene was associated with a transiently higher incidence of a burning sensation on the skin (in the first week of treatment but not thereafter).

CONCLUSIONS: Tazarotene 0.1% cream can offer superior efficacy over tretinoin 0.05% emollient cream in the treatment of facial photodamage, particularly with respect to the speed of improvement.     

Is melanocyte density our last hope? Comparison of histologic features of photodamaged skin and melanoma in situ after staged surgical excision with concurrent scouting biopsies

Differentiating melanocytic hyperplasia (MH) on photodamaged skin from junctional lentiginous melanocytic proliferations (JLMP), early evolving melanoma in situ (MIS), or the periphery of a lesion of MIS on staged excision can be challenging. Although previous cross‐sectional studies have elucidated important criteria for distinguishing MH on photodamaged skin from more concerning lesions, this study highlights a technique to treat JLMP and MIS with staged mapped excision and baseline scouting biopsies of adjacent nonlesional photodamaged skin to assist in determination of surgical margin clearance. Additionally, we compare the lesional and photodamaged control biopsies from the same patient to evaluate relevant histologic criteria that may be used to distinguish MH in photodamaged skin from JLMP/MIS, while minimizing confounding factors. There was a statistically significant difference (P ≤ 0.05) found for melanocyte density, irregular melanocyte distribution, melanocyte clustering, follicular infundibulum involvement, and nesting. However, criteria such as nesting, epithelioid cells and melanocyte clustering were seen in both photodamaged skin and MIS. These findings underscore the fact that histologic features of photodamaged skin can overlap with the histopathological features of MIS. Of all of the criteria evaluated, melanocytic density was the most objective histologic criterion and did not show overlap between the sun‐damaged and JLMP/MIS groups.     

The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study

BACKGROUND: SDZ ASM 981 is a selective inhibitor of inflammatory cytokines released from T lymphocytes and mast cells, which has been developed for the treatment of inflammatory skin diseases. OBJECTIVES: In the present study, the atrophogenic potential of SDZ ASM 981 1% cream in humans was compared with that of medium and highly potent topical steroids, and vehicle. METHODS: Four different preparations, SDZ ASM 981 1% cream, the corresponding vehicle of SDZ ASM 981 1% cream, betamethasone-17-valerate 0.1% cream and triamcinolone acetonide 0.1% cream, were applied to the volar aspect of the forearms of 16 healthy volunteers, twice daily, 6 days a week, for 4 weeks. Skin thickness was evaluated by ultrasound examination, clinical signs of atrophy by stereomicroscopy, and epidermal thickness was assessed by histology. RESULTS: Both topical corticosteroids induced a significant reduction in skin thickness, as compared with SDZ ASM 981 1% cream and vehicle, which were shown to be equivalent. The difference in skin thickness (measured by ultrasound examination) between patients treated with SDZ ASM 981 1% cream and those receiving either of the two topical steroids was significant from day 8 onwards. Histological analysis performed at day 29 showed significant epidermal thinning with topical steroids compared with SDZ ASM 981 1% cream or the vehicle. Conclusion The lack of atrophogenic properties of SDZ ASM 981 1% cream in this short-term study demonstrates its potential as long-term treatment for inflammatory skin diseases, thus overcoming a major drawback of topical steroids. This may also be important for the treatment of children, and sensitive areas of skin, such as the face and skin-folds.     

A review of skin ageing and its medical therapy

Intrinsic (chronological) skin ageing is characterized hy atrophy of the skin with loss of elasticity and slowed metabolic activity. The superposition of environmental damage, particularly exposure to ultraviolet radiation (photodamage). on the intrinsic ageinj; process results, at least initially, in a hypcrtrophic repair response, with a thickened epidermis and increased melanogenesis. Even more striking changes occur in the dcrmis: massive elastosis (deposition of abnormal elastic libres). collagen degenerafion. and twisted, dilated microvasculature. ReguUir use of a sunscreen alone appears to allow some repair as well as protection from further photodamage. Topical tretinoin has been shown fo partially reverse the clinical and histological changes induced by the combination of sunlight exposure and chronological ageing. A formulation of tretinoin in an emollient cream (Retinova? Renova®). developed speciiically for the treatment of photodamaged skin, has heen extensively investigated in multifenlre. double-blind trials and has been shown to produce significant improvement within 4–6 months of daily use, compared witb vehicle alone, as part of a regimen including sun protection and moisturizer use. Histological changes in the epidermis and dermis noted after 12 months suggest tretinoin repairs photodamage by reconstitution of the rete pegs, repair of kcratinocyte ultrastructural damage, more even distribution of melanocytcs and melanin pigment, deposition of new papillary dermal collagen, and Improvements in vasculature. Alpha-hydroxy acids (AHAs) have also been widely used for therapy of photodamaged skin, and these compotinds have been reported lo normalize hyperkeratlnization and increase viable epidermal thickness and dermal glycosaminoglycans content. The single randomized controlled study now available appears to substantiate AHA efficacy and safety. In summary, recent work has substantially elucidated the ageing processes that alTect the skin and has demonstrated that many of tbe unwanted changes can be improved by topical therapy.     

TOPICAL TRETINOIN IMPROVES THE APPEARANCE OF PHOTO DAMAGED SKIN

A multicentre clinical trial has been conducted to assess the efficacy and safety of tretinoin 0.05% cream (Retin-A®) in the treatment of photodamaged Australian skin. Subjects with cutaneous facial photodamage were randomised to treatment with tretinoin (62) or vehicle (63) cream. After an initial two week run-in, all subjects applied the cream to the face, neck and left forearm/hand, once nightly for 24 weeks. Changes in clinical signs of photodamage and parameters of cutaneous irritation were assessed by investigators using a 7 point scale, whilst changes in signs of photodamage were rated by subjects using a 5 point scale. Changes in skin biopsies and silicone skin surface replicas were also assessed. Significant improvements in skin wrinkles, mottled hyperpigmentation, laxity, lentigines and roughness of tretinoin treated subjects were noted by investigators. Subjects receiving tretinoin noted significant improvements in skin wrinkles, tightness, colour and pores. Improvement in overall severity of photodamage was significantly greater for tretinoin treated subjects and was progressive over the study period. Histological findings included a significant increase in mean epidermal thickness. Significant topographical changes were not detected in skin surface replica sets. Cutaneous irritation, the most common side effect, was usually mild and transient. We conclude that tretinoin 0.05% cream significantly improved the appearance of photodamaged skin.     

Clinical panel assessment of photodamaged skin treated with isotretinoin using photographs.

BACKGROUND AND DESIGN--Evaluation of the treatment of photodamaged skin requires adequate efficacy criteria. This study tested the ability of five independent dermatologists to distinguish the effect of topical treatment with isotretinoin cream (0.05% for 3 months, then 0.1% for 6 months) in 326 patients compared with vehicle for 9 months in 325 patients using high-quality, reproducible photographic slides. Panelists were blinded to the patient's identity, treatment group, and time of the photograph (baseline or end of treatment). A computer randomly projected the baseline photograph to one side of a split screen and the end-of-treatment photograph to the other. OBSERVATIONS--Isotretinoin was significantly better than vehicle for overall appearance, fine wrinkles, and discrete pigmentation by multivariate analysis of the combined results for all panelists. Univariate analysis for each panelist also indicated statistically significant superiority of isotretinoin over vehicle for overall appearance (four panelists), fine wrinkles (five panelists), and discrete pigmentation (three panelists). CONCLUSION--The clinical panel detected significantly better improvement in photodamaged-skin treated with isotretinoin than in such skin treated with vehicle. The panel provided an independent assessment of the effects of treatment uninfluenced by physical findings during treatment or information provided by the patients treated.     

Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone

Idebenone is an antioxidant lower molecular weight analogue of coenzyme Q10. Previously, idebenone was shown to be a very effective antioxidant in its ability to protect against cell damage from oxidative stress in a variety of biochemical, cell biological, and in vivo methods, including its ability to suppress sunburn cell (SBC) formation in living skin. However, no clinical studies have been previously conducted to establish the efficacy of idebenone in a topical skincare formulation for the treatment of photodamaged skin. In this nonvehicle control study, 0.5% and 1.0% idebenone commercial formulations were evaluated in a clinical trial for topical safety and efficacy in photodamaged skin. Forty-one female subjects, aged 30-65, with moderate photodamaged skin were randomized to use a blind labelled (either 0.5% or 1.0% idebenone in otherwise identical lotion bases) skincare preparation twice daily for six weeks. Blinded expert grader assessments for skin roughness/dryness, fine lines/wrinkles, and global improvement in photodamage were performed at baseline, three weeks and six weeks. Electrical conductance readings for skin surface hydration and 35 mm digital photography were made at baseline after six weeks. Punch biopsies were taken from randomly selected subjects, baseline and after six weeks, and stained for certain antibodies (interleukin IL-6, interleukin IL-1b, matrixmetalloproteinase MMP-1, collagen I) using immunofluorescence microscopy. After six weeks' use of the 1.0% idebenone formula, a 26% reduction in skin roughness/dryness was observed, a 37% increase in skin hydration, a 29% reduction in fine lines/wrinkles, and a 33% improvement in overall global assessment of photodamaged skin. For the 0.5% idebenone formulation, a 23% reduction in skin roughness/dryness was observed, a 37% increase in skin hydration, a 27% reduction in fine lines/wrinkles, and a 30% improvement in overall global assessment of photodamaged skin. The immunofluorescence staining revealed a decrease in IL-1b, IL-6, and MMP-1 and an increase in collagen I for both concentrations.     

Tretinoin cream 0.02% for the treatment of photodamaged facial skin: a review of 2 double-blind clinical studies

In extensive clinical studies and practical use since its US Food and Drug Administration approval in 1995, tretinoin emollient cream 0.05% has been shown to be safe and effective in the treatment of fine facial wrinkles, mottled hyperpigmentation, and skin roughness. To provide additional prescribing flexibility for various patient needs, a new lower concentration formulation, tretinoin cream 0.02% was chosen for further development. Two multicenter, randomized, double-blind, vehicle-controlled clinical., studies were conducted to evaluate the safety and efficacy of the lower concentration tretinoin formulation in the treatment of moderate-to-severe facial photodamage. Results indicate statistically significant improvement in fine wrinkling, coarse wrinkling, and yellowing with the use of tretinoin cream 0.02% at week-24 end point, compared with placebo. Therapy with tretinoin cream 0.02% was well tolerated overall and demonstrated a favorable safety profile. Both studies demonstrated that tretinoin cream 0.02% is safe and effective for the treatment of moderate-to-severe photodamaged facial skin.     

Tretinoin microsphere gel 0.1% for photodamaged facial skin: a placebo-controlled trial

Tretinoin microsphere gel (TMG) 0. 1% was evaluated as a treatment of photodamaged skin. The study included a 6-month, randomized, double-blinded, placebo-controlled phase and an additional 6-month open-label phase during which all subjects received TMG 0. 1%. Forty-five subjects with moderate to severe photodamaged facial skin applied study gel topically to the face once nightly (22 subjects received TMG 0.1% and 23 subjects received placebo). At 6 months, TMG 0. 1% was found to be superior to placebo in improving overall severity of photodamage (P=.0003) and in the investigator's global assessment of clinical response (P<.0001). Statistically significant improvement relative to placebo was observed in fine wrinkling (P<.0001), mottled hyperpigmentation (P=.0002), yellowing/ sallowness (P<.0001), and lentigines (P=.0054). The improvements observed after 6 months of open-label therapy were consistent with the results observed in TMG 0. 1%-treated subjects during double-blinded treatment. Most signs and symptoms of cutaneous irritation were mild throughout the treatment period. At one month, a higher proportion of subjects in the TMG 0. 1% group relative to the placebo group experienced an increase in severity of cutaneous irritation. After 6 months, the difference between treatment groups was statistically significant only for peeling (P=.001) and dryness (P=.007).