Histological effects of tazarotene 0.1% cream vs. vehicle on photodamaged skin: a 6-month, multicentre, double-blind, randomized, vehicle-controlled study in patients with photodamaged facial skin.

BACKGROUND: Topical tazarotene has been shown to offer efficacy in ameliorating multiple effects of photodamage. OBJECTIVES: To evaluate the histological effects of tazarotene cream on photodamaged skin. METHODS: In this multicentre, double-blind, randomized, vehicle-controlled study, 50 patients with photodamaged facial skin (at least mild fine wrinkling and mottled hyperpigmentation, with at least one of these being moderate) were randomized to apply tazarotene 0.1% cream or vehicle cream to their face, once daily for 24 weeks. RESULTS: Blinded assessments showed that tazarotene was less likely than vehicle to be associated with an increase in keratinocytic and melanocytic atypia, and more likely than vehicle to be associated with a reduction in atypia. Between-group comparisons in distribution of change from baseline categories of severity were in favour of tazarotene (P = 0.055 for keratinocytic atypia, P = 0.034 for melanocytic atypia, and P < 0.001 for the number of granular cell layers). Compared with vehicle, tazarotene was associated with an increase in epidermal polarity (P = 0.008) and epidermal thickness (P = 0.012), and a tendency for stratum corneum compaction. Tazarotene was also associated with widened intercellular spaces (reported as epidermal oedema) relative to vehicle (P < 0.001). CONCLUSIONS: Treatment of photodamaged skin with tazarotene is associated with an amelioration of keratinocytic and melanocytic atypia, an improvement in epidermal polarity, and an increase in epidermal thickness.

The combination formulation of clindamycin 1% plus benzoyl peroxide 5% versus 3 different formulations of topical clindamycin alone in the reduction of Propionibacterium acnes. An in vivo comparative study.

BACKGROUND: Isolates of Propionibacterium acnes resistant to one or more anti-acne antibiotics (most commonly erythromycin) are being increasingly reported, and the emergence of resistant strains can be associated with therapeutic failure of topical treatment. OBJECTIVE: Comparison of the in vivo effectiveness of the combination of clindamycin 1% plus benzoyl peroxide 5% in a gel formulation to that of each of 3 clindamycin 1% preparations (gel, lotion, and solution) with respect to reduction in counts of P. acnes cultured from the foreheads of healthy volunteers. METHODS: The effects of treatment with the 4 study drugs were compared in an open-label study. Cultures were collected before, after 1 week and after 2 weeks of treatment. RESULTS: Treatment with the combination formulation resulted in a 99.8% (> 2 logs) reduction in total propionibacterial numbers after 1 week of therapy compared with 30 to 62% (< 1 log) decreases for the different formulations of topical clindamycin alone. By the end of week 2, the combination had decreased P. acnes counts by more than 99.9% (> 3 logs) relative to reductions of from 88 to 95% (< or > 1 log) for the single agent formulations. CONCLUSIONS: Under the conditions of the present study, the combination of clindamycin 1% plus benzoyl peroxide 5% gel produced more rapid and highly significant reductions in P. acnes compared with formulations containing clindamycin alone.

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.

Photoreaction potential of orally administered levofloxacin in healthy subjects.

OBJECTIVE: To evaluate the photoreaction potential of levofloxacin on exposure to solar-simulating radiation. Solar-simulating is ultraviolet (UV) light, defined as UVA in the 320-400 nm range and UVB in the 290-320 nm range. DESIGN: In a single-center, double-blind, randomized study, 30 adults (20 men, 10 women) received oral levofloxacin (500 mg qd x 5 d) or placebo. At baseline photoexposure prior to drug administration, each subject was exposed to UVB light at 0.75, 1.0, and 2.0 times the minimal erythema dose and to UVA light (25 J/cm2). Photoexposure was repeated on day 5, two hours following final drug administration, and response was determined using both a photoreaction rating scale and investigator assessment. RESULTS: Using the photoreaction rating scale, following UVB exposure on day 5, no abnormal photoreactions were observed among levofloxacin recipients. UVA exposure was associated with mild reactions in 20 of 24 levofloxacin-treated and three of six placebo-treated subjects, with no associated symptoms. By investigator assessment, all subjects had a negative reaction to UVB photoexposure, and 10 of 24 levofloxacin-treated and three of six placebo-treated subjects had a photoreaction following UVA photoexposure. Dermal reactions were mild and similar for both treatment groups. No subject experienced an immediate wheal-and-flare reaction. There were no statistically significant differences between treatment groups for any of the comparisons. CONCLUSIONS: Levofloxacin has a low photosensitizing potential when administered to healthy subjects.

Use of topical corticosteroid pretreatment to reduce the incidence and severity of skin reactions associated with testosterone transdermal therapy.

Local skin reactions at the application site are the most common adverse events associated with the testosterone transdermal delivery (TTD) systems used to treat postpubertal hypogonadism in males. This open-label, controlled pilot study was conducted to determine whether topical pretreatment with triamcinolone acetonide 0.1% cream might be useful in reducing the incidence and/or severity of chronic skin irritation when used in healthy volunteers receiving TTD systems. Adult male volunteers wore three topical systems, which were applied to the upper back daily (Monday through Friday) for 6 weeks: (1) TTD with no pretreatment of application site; (2) TTD with pretreatment of application site using triamcinolone acetonide 0.1% cream; and (3) an inactive occlusive dressing (control). On Monday through Thursday, systems were removed 24 hours after application. Patches applied on Friday were worn continuously for 72 hours until their removal on Monday. Skin reactions were graded on a scale from 0 to 4 (0 = none, 4 = severe) and were assessed daily by research personnel, beginning at the time of system removal (assessment 1) and on the two subsequent clinic visits (assessments 2 and 3). All skin irritation scores of all subjects were totaled for each treatment regimen to obtain a cumulative score per treatment regimen. The cumulative scores were also analyzed by assessment time and study week (weeks 1-6). Eighty-two subjects were enrolled in the study, and 65 completed the 6-week treatment course. Mean age of subjects was 24 years (range, 18-69 years), and mean weight was 79.0 kg (range, 58.9-127.3 kg). All subjects were white males. At assessment 1, pretreatment with triamcinolone acetonide 0.1% cream (compared with no pretreatment) was associated more often with scores of 0 (no erythema), with comparable occurrences of mild skin irritation, and with fewer occurrences of moderate erythema. At all three assessments, more subjects had lower cumulative scores with pretreatment than without pretreatment. At every assessment and in each week of the study, total weekly cumulative skin irritation scores were also lower with pretreatment than without pretreatment. No adverse experiences other than skin irritation were reported. Results of this study suggest that in patients using TTD systems, the incidence and severity of skin irritation at application sites may be reduced through pretreatment with triamcinolone acetonide 0.1% cream.

The spectral dependence for UVA-induced cumulative damage in human skin.

The wavelength dependence for UVA-induced cumulative damage was investigated in human skin. Epidermal changes (stratum corneum thickening, viable epidermal thickening sunburn cell production), as well as dermal alterations (lysozyme deposition, inflammation), were used as indices of cumulative photoperturbation. UVA wavelengths between 320 nm and 345 nm were more effective than longer wavelengths (360-400 nm) in inducing viable epidermal thickening. Similarly, the shorter wavelengths (320-345 nm) elicited more sunburn cells, although these differences did not reach statistical significance. All UVA bands were equally effective in inducing the dermal markers. At equal fluences, wavelengths > 400 nm produced no measurable cutaneous alterations. These findings suggest that (i) chronic epidermal and dermal damages have different spectral dependence and (ii) the action spectrum for dermal damage in the UVA is broad, extending up to 400 nm, and is different from the acute erythema spectrum in humans.

Quantitative assessment of cumulative damage from repetitive exposures to suberythemogenic doses of UVA in human skin.

Daily exposures to relatively small suberythemogenic fluences of UVA (50-200 kJ/m2) for 8 days resulted in cumulative morphological skin alterations indicative of early tissue injury. Histologically, irradiated skin revealed epidermal hyperplasia, inflammation and deposition of lysozyme along the dermal elastic fiber network. Sunburn cells were also present within the epidermis. These changes were quantified by image analysis and were found to be related to the cumulative UVA fluence. A long UVA waveband (UVAI, 340-400 nm) was as effective as a broad UVA band (320-400 nm), suggesting that these changes are induced by longer UVA wavelengths.

Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin.

BACKGROUND: The skin is repeatedly exposed to solar UV radiation. Long-term photodamage is a consequence of cumulative UV radiation injury. Hence an examination of the repetitive effects of UV exposure is more likely to yield clues to the early alterations that lead to photoaged skin than a single exposure. OBJECTIVE: We examined the effects of repetitive low-dose UV irradiation on human skin with the aim of identifying UVA-induced effects that may have a different wavelength dependence than acute erythema. METHODS: Areas on the lower part of the back were each exposed to a suberythemal dose (0.5 minimal erythema dose [MED]) of solar simulated radiation (290 to 400 nm) and of UVA (320 to 400 nm) once daily, 5 days a week, for 28 doses. One site was also treated daily with a sunscreen having a sun protection factor of 22 and then exposed to 11 MEDs of solar simulated radiation for the same duration. Epidermal and dermal changes were analyzed and quantified by histochemical stains in combination with computer-assisted image analysis of tissue sections. RESULTS: At equal 0.5 MED doses, UVA induced greater cumulative changes than solar simulated radiation, as assessed by development of a greater cumulative erythema response in the first week of treatment, the presence of epidermal hyperplasia and stratum corneum thickening, depletion of Langerhans cells, dermal inflammatory infiltrates, and deposition of lysozyme on elastin fibers. These changes were not prevented by the sunscreen. A single short-term dose of UVA did not elicit these changes. CONCLUSION: These findings suggest that UVA may contribute significantly to long-term actinic damage and that the spectral dependence for cumulative damage does not parallel the action spectrum for acute injury (erythema) in human beings.

An ultraviolet radiation action spectrum for immediate pigment darkening.

The wavelength dependence for immediate pigment darkening (IPD) was investigated by exposing the midback skin of volunteers to a series of incremental fluences of narrow waveband radiation isolated by band-pass filters in the 310-400 nm region. The threshold IPD fluence for each waveband was determined by visual assessment of the skin responses immediately after each exposure. The action spectrum, constructed from the mean threshold fluences, was broad and extended from 320 nm to 400 nm with a peak at around 340 nm. No IPD could be evoked at 310 nm, even after erythemogenic fluences. The spectrum was similar in each of the three skin types investigated (III, IV, V). The broad nature of the action spectrum within the UVA region suggests that IPD may serve as an alternative endpoint for measuring photoprotection against these wavelengths.

Effects of topical ammonium lactate on cutaneous atrophy from a potent topical corticosteroid.

BACKGROUND: Topical corticosteroids produce atrophic changes in skin, including thinning of the epidermis and decrease in dermal ground substance. We observed that 12% ammonium lactate produced an increase in the thickness of epidermis and increased amounts of dermal glycosaminoglycans. OBJECTIVE: Our purpose was to determine whether 12% ammonium lactate could minimize cutaneous atrophy produced by a potent topical corticosteroid. METHODS: Clobetasol propionate, 12% ammonium lactate, and both agents were repetitively applied under occlusive patches as well as in open patches on the forearms of human volunteers for 3 to 4 weeks. Biopsy specimens were analyzed for thickness of the epidermis and dermal glycosaminoglycans by image analysis. RESULTS: Twelve percent ammonium lactate produced a significant sparing of atrophy in both the epidermis and dermis without any influence on the bioavailability or antiinflammatory properties of the corticosteroid. CONCLUSION: Twelve percent ammonium lactate may be useful in mitigating the adverse effects of corticosteroid on skin.

Determination of UVA protection factors by means of immediate pigment darkening in normal skin.

A method is described for screening potentially useful photoprotective agents against UVA radiation by the use of immediate pigment darkening as an end point. Threshold doses of immediate pigment darkening showed a log normal distribution and the response was found to obey dose-reciprocity at irradiance levels below 50 mW/cm2. With this procedure, several marketed sunscreens containing benzophenone-3 as the only UVA absorber were found to have poor UVA protection factors, whereas those containing combinations of benzophenone-3 and butyl methoxydibenzoyl methane or melanin were more effective. There was no correlation between the sun protection factor cited on the label and the calculated immediate pigment darkening-protection factor.

Reciprocity for solar simulators used in sunscreen testing.

Reciprocity for sunscreen solar protection factors (SPFs) and for delayed erythema was examined using a solar simulator equipped with neutral density filters to vary the beam intensity. Similar SPFs were obtained over a 15-fold intensity difference, using a sunscreen with a low (SPF-4) and a high (SPF-15) protection factor. Reciprocity was also observed for delayed erythema in unprotected skin.

Persistent light reactivity from systemic quinine.

A 41-year-old black female with psoriasis developed photosensitivity and a Koebner reaction while receiving phototherapy. She had been receiving oral quinine intermittently for muscle cramps. Photobiological evaluation revealed a strongly positive photopatch test to quinine sulfate and a marked persistent reduction in the minimal erythema dose to solar-simulated radiation in the uninvolved skin. There were no abnormal reactions to UVA. The photosensitivity is still present 3 years after the withdrawal of quinine. These features are similar to those observed previously in persistent light reactors to topical photosensitizers.

The photoprotective potential of the new superpotent sunscreens.

A sun protection factor (SPF)-15 and an SPF-30 sunscreen were compared with regard to their ability to prevent sunburn cell formation after the exposure of human skin to a standardized dose of solar-simulated radiation. The SPF-30 sunscreen provided a significantly superior degree of photoprotection and almost prevented sunburn cell induction. Because sunburn cells may be markers of ultraviolet radiation-induced damage to DNA, the new superpotent sunscreens should offer an advantage in the prevention of skin cancer and long-term actinic damage to skin.

Photosensitizing potential of certain nonsteroidal anti-inflammatory agents.

The nonsteroidal anti-inflammatory drugs (NSAIDs) have been repeatedly associated with photosensitivity reactions. The underlying mechanism however is not known, and the clinical features are not always consistent with either a phototoxic or a photoallergic mechanism. In this study, four NSAIDs were investigated for their phototoxicity potential in human volunteers using an oral dosing protocol. Phototoxicity, consisting of wheal-and-flare reactions following exposure to ultraviolet radiation, was demonstrated following the administration of naproxen and nabumetone, but was not seen in volunteers who received piroxicam, a drug reported to cause photosensitivity. Thus, although certain NSAIDs are potentially capable of producing phototoxicity reactions, others can presumably provoke clinical photosensitivity through other mechanisms.

Quantification of visible light-induced melanogenesis in human skin.

Exposure of normal skin to visible light (400-700 nm) resulted in the induction of immediate pigment darkening (IPD), immediate erythema and a persistent (delayed) tanning reaction. The intensity of pigmentation and time course of the reaction were monitored by measuring chromaticity coordinates. Both IPD and immediate erythema faded over a 24-h period but, unlike erythema, the pigmentation did not totally disappear and the residual tanning response remained unchanged for the rest of the 10-day observation period. The threshold dose for IPD with visible light was between 40 and 80 J/cm2, while the threshold dose for "persistent" pigmentation was greater than or equal to 80 J/cm2.

Wavelength dependence for DNA synthesis inhibition in hairless mouse epidermis.

Exposure of mammalian skin to ultraviolet radiation (UVR) results in a transient inhibition of scheduled DNA synthesis. The wavelength dependence for this response was investigated in the epidermis of albino hairless mice. Groups of animals were exposed to narrow wavebands of UVR (HPBW 6.6 nm) from a monochromator in the 260-335 nm range. A dose-dependent inhibition of DNA synthesis was observed following exposure to all test wavebands except that centered at 335 nm. An action spectrum constructed from dose-response regression lines showed peak effectiveness at 290 nm. This spectrum bears a close resemblance to published action spectra for the induction of pyrimidine dimers in vivo, suggesting that DNA is the primary chromophore for both events. The DNA synthesis inhibition spectrum bears little resemblance to a published therapeutic action spectrum for the clearing of psoriasis.

Comparison of sun protection factors obtained with a xenon solar simulator and an Ultravitalux lamp.

The influence of the type of UV source on the sun protection factor (SPF) was investigated in healthy volunteers with skin Types I to III. In an open-paired comparison, sunscreens with low, medium and high SPF were examined under identical test conditions using either a 150-watt xenon-arc solar simulator or a set of four 300-watt Osram Ultravitalux bulbs as the UV source. Despite wide differences in the spectral output of the two sources, both yielded similar mean SPF for each of the three test sunscreens. The only significant difference observed was with the FRG standard, for which a lower mean SPF (3.1) was obtained with the Ultravitalux lamps compared to the solar simulator (mean SPF 4.0). There were no differences between the calculated arithmetic and geometric means.

Comparison of methods for assessing photoprotection against ultraviolet A in vivo.

Photoprotection against ultraviolet A (UVA) by three sunscreens was evaluated in humans, with erythema and pigmentation used as end points in normal skin and in skin sensitized with 8-methoxypsoralen and anthracene. The test sunscreens were Parsol 1789 (2%), Eusolex 8020 (2%), and oxybenzone (3%). UVA was obtained from two filtered xenon-arc sources. UVA protection factors were found to be significantly higher in sensitized skin compared with normal skin. Both Parsol and Eusolex provided better and comparable photoprotection (approximately 3.0) than oxybenzone (approximately 2.0) in sensitized skin, regardless of whether 8-methoxypsoralen or anthracene was used. In normal unsensitized skin, Parsol 1789 and Eusolex 8020 were also comparable and provided slightly better photoprotection (approximately 1.8) than oxybenzone (approximately 1.4) when pigmentation was used as an end point. The three sunscreens, however, were similar in providing photoprotection against UVA-induced erythema. Protection factors obtained in artificially sensitized skin are probably not relevant to normal skin. It is concluded that pigmentation, either immediate or delayed, is a reproducible and useful end point for the routine assessment of photoprotection of normal skin against UVA.