Phototoxic effects of topical azelaic acid, benzoyl peroxide and adapalene were not detected when applied immediately before UVB to normal skin

ARTICLE

Auteur(s) : Salih ÇETINER, Turna ILKNUR, Şebnem ÖZKAN

Dokuz Eyll niversitesi Tip Fakltesi Dermatoloji Anabilim Dali Inciraltý, 35340, Izmir, Trkiye

Article accepted on 19/04/2004

Acne vulgaris is one of the most common skin diseases, seen primarily in adolescents, involving the pilosebaceous unit. The lesions in acne vulgaris are seen frequently on sun exposed areas such as the face [1, 2]. Sunburn is due to acute overexposure of ultraviolet irradiation. The doses of UVA required to produce erythema are approximately 1000 times greater than UVB but because natural sunlight contains 100 times more UVA than UVB, UVA represents only 10% of sunburn producing rays. Therefore, the relatively small UVB component of solar ultraviolet radiation accounts for the majority of sunburn reactions [3].

There are few studies which have investigated the interaction between topical agents and UVB penetration. In these studies, topical agents used for psoriasis treatment have usually been chosen since they could be used in conjunction with UVB therapy. Some studies have shown blocking effects of topical agents on UVB penetration [4-11]. However, the use of some lubricants applied prior to UVB treatment have been found to have enhancing effects on the penetration of light into psoriatic plaques [4, 12].

Since acne vulgaris is frequently localized on sun exposed areas, the enhancing effects of topical agents on UVB penetration are important. In this study, we tried to investigate whether azelaic acid, benzoyl peroxide and adapalene have either blocking or enhancing effects on UVB penetration.

Material and methods

In this single-blind study, phototesting was performed on 30 volunteers to determine the minimal erythema dose (MED) for UVB. This protocol was approved by the local ethics committee of the Dokuz Eyll University Faculty of Medicine. All participants were informed and consent forms were obtained. The patients were untanned and not taking any medication. Waldmann 8001 K (Waldmann Lichttecnik Gmbtt, Schwenningen, Germany) cabin was used for the light source of UVB.
The beginning doses of UVB phototesting were determined according to Fitzpatrick skin types: 2 volunteers had skin phototype II, 19 volunteers had skin phototype III, 8 volunteers had skin phototype IV, 1 volunteer had skin phototype V. The irradiated doses for UVB were up to 120 mJ/cm² for skin types I and II, 140 mJ/cm² for skin types III and IV and 200 mJ/cm² for skin type V [13]. MED values were determined by irradiating 4 cm² of uninvolved skin on the back of each patient at increments of 20 mJ/cm² in one row. In addition, seven parallel rows of skin were tested after application of different topical agents. The first rows were only irradiated by UVB without application of any topical agent to determine the MED. A thin (0.1 cc/25 cm²) and a thick (0.3 cc/25 cm²) layer of 20% azelaic acid cream (Skinoren cream^®), a thin (0.1 cc/25 cm²) and a thick (0.3 cc/25 cm²) layer of 5% benzoyl peroxide gel (5% Benzac AC gel^®), a thin (0.1 cc/25 cm²) and a thick (0.3 cc/25 cm²) layer of 0.1% adapalene gel (Differin gel^®) were applied respectively to the adjacent parallel rows. In each patient the rows of topical agent applications were exchanged. Then all the rows were irradiated with UVB at increments of 20 mJ/cm² immediately after the application of the agents without waiting. The results were evaluated after 24 hrs by a blinded investigator and MED values were determined (Fig. 1). Wilcoxon signed ranks test was used for statistical analysis. Bonferroni-corrected significance level of p < 0.0033 was considered to be statistically significant.

Results

The results of phototesting of all patients with pure UVB, with the application of thin and thick layers of azelaic acid cream, thin and thick layers of benzoyl peroxide gel and thin and thick layers of adapalene gel are shown in Table I.

The MED values detected after the application of thin and thick layers of azelaic acid cream, thin and thick layers of benzoyl peroxide gel and thin and thick layers of adapalene gel have not been found significantly different from the MED values after pure UVB (Wilcoxon signed ranks test, p > 0.0033). These results indicated that MED values were unaffected by azelaic acid cream, benzoyl peroxide gel and adapalene gel.
There was no statistically significant difference between the MED values of thin and thick applications of azelaic acid cream, between the MED values of thin and thick applications of benzoyl peroxide gel and between the MED values of thin and thick applications of adapalene gel. In addition the differences between the MED values after the applications of thin azelaic acid cream and thin benzoyl peroxide gel, thin azelaic acid cream and thin adapalene gel, thin benzoyl peroxide gel and thin adapalene gel, thick azelaic acid cream and thick benzoyl peroxide gel, thick azelaic acid cream and thick adapalene gel, thick benzoyl peroxide gel and thick adapalene gel were not found to be statistically significant. The results of the “Wilcoxon signed ranks test” of all the paired groups are shown in Table II.

Table II. Wilcoxon signed ranks test (p < 0.0033)

Discussion

Retinoids including tretinoin, isotretinoin, adapalene and tazarotene, azelaic acid, benzoyl peroxide, salicylic acid and antibiotics such as erythromycin, clindamycin and tetracycline are major topical agents for treating acne vulgaris. The lesions in acne vulgaris are frequently localized on sun exposed areas such as the face [1, 2]. Thus, the effects of these topical agents on UVB penetration can be important since they are used on sunlight exposed areas.
Products containing salicylic acid which is a keratolytic agent, can also be used for the treatment of acne vulgaris [1, 2]. The potential effects of salicylic acid at different concentrations (2, 3, 5, 6, 10, 20%) on UVB penetration have been investigated in several in vitro and in vivo studies. These studies have shown that salicylic acid blocked transmission of UVB light at all concentrations when applied prior to irradiation [4, 5, 7, 11]. In an in vivo study, Kristensen et al. [4] showed that salicylic acid had a dose-dependent inhibiting influence on UVB. In the same study, the duration of photoprotection after application of salicylic acid was found to be for at least 12 hrs, sometimes more than 24 hrs. According to these studies, salicylic acid can be used on sun exposed areas in day time since it had a blocking effect on UVB.
Jeanmougin and Civatte [14] investigated benzoyl peroxide phototoxicity by photoepidermotests after repeated applications. They found 10% benzoyl peroxide gel to be phototoxic in eight out of 18 subjects tested. On the other hand, we could not detect any phototoxic effect with 5% benzoyl peroxide gel when applied immediately before UVB. Two reasons might be responsible for this result. The difference might be because of the lower concentration of benzoyl peroxide (5%) used in our study and the possibility of phototoxicity for a substance in higher concentration is also higher. Also, in their study Jeanmougin and Civatte performed repeated applications of benzoyl peroxide while in our study we applied the substance only once before UVB.

In the literature, we could not find any study investigating the interaction between topical azelaic acid, adapalene and UVB. However, there were a few studies dealing with topical tretinoin and tazarotene belonging to synthetic retinoid family which can be used for acne vulgaris treatment [1, 2]. Kornreich et al. [7] measured the absorbance of tretinoin cream in different concentrations (0.025, 0.05, 0.1%) and 0.01% tretinoin gel between the wavelengths 260 to 400 nm, with an ex vivo technique. They found that tretinoin had substantial absorption in the UVA range. In addition they determined that the absorbance of tretinoin preparations was concentration-dependent, with higher values for more concentrated formulations. Smit et al. [15] evaluated the MED for UVB on 0.05% tretinoin cream in an in vivo study. They showed that topical treatment with 0.05% tretinoin cream for several days before UVB, did not change the MED. Hecker et al. [16] showed that while thin application of 0.1% tazarotene gel immediately before phototherapy had no significant effect on MED, thick application of the gel increased MED values slightly. They also reported that pretreatment with 0.1% tazarotene gel 3 times per week for 2 weeks before UVB had significantly reduced the MED. In our study, 0.1% adapalene gel both in thin and thick forms applied immediately before UVB did not show any significant effects on UVB.

In this study, we did not observe any blocking or enhancing effects of azelaic acid, benzoyl peroxide and adapalene on UVB penetration when applied immediately before UVB. On the other hand further studies examining the effects of UVB on skin pretreated with these topical agents for different periods in clinical trials is necessary. n

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