Several cases of undesirable effects caused by methacrylate ultraviolet-curing nail polish for non-professional use.

BACKGROUND: Ultraviolet (UV)-curing nail polishes based on acrylates or methacrylates are currently also available for non-professional use. The Swedish Medical Products Agency recently prohibited one brand of UV-curing polish, because several consumers reported undesirable effects after using it. OBJECTIVES: To investigate whether consumers with undesirable effects after using the UV-curing nail polish that was later prohibited were contact allergic to the polish and its individual ingredients. MATERIALS/METHODS: Eight patients who had reported severe skin reactions after the use of the UV-curing polish were patch tested with two coatings of the nail polish and its ingredients at five dermatology departments in Sweden. RESULTS: All patients tested except one showed contact allergic reactions to one or several of the acrylate-based or methacrylate-based ingredients in the nail polish. CONCLUSIONS: The non-professional use of UV-curing nail polishes poses a risk of sensitization from acrylates and methacrylates.

Short-Term UVB Treatment or Intramuscular Cholecalciferol to Prevent Hypovitaminosis D After Gastric Bypass-a Randomized Clinical Trial.

BACKGROUND: Gastric bypass is increasingly used worldwide to treat morbidly obese patients with good results. However, several studies have reported low levels of vitamin D in spite of supplementation. In this randomized clinical trial, we have evaluated two principally different interventions, short-term UVB treatment or a single cholecalciferol injection, to prevent hypovitaminosis D. METHODS: Seventy-three patients, randomly treated by UVB (n = 26) or injection (n = 20), and compared to controls (n = 27), were followed for 6 months. Both interventions, 12 treatments of whole-body narrowband UVB and an intramuscular injection of 600,000 IU cholecalciferol, were given in December, when natural sunlight is limited. Blood samples for 25-OH-vitamin D (25[OH]D), intact PTH, calcium, and albumin were obtained at baseline, after 1 and 3 months, and after 6 months for the intervention groups. 25[OH]D was analyzed using a HPLC method. RESULTS: At baseline, 77.2 % of the patients had 25[OH]D <75 nmol/L. At 3 months, both UVB and cholecalciferol injection resulted in significantly higher 25[OH]D levels than controls (71.6 and 77.9 vs. 48.6 nmol/L, p < 0.05). The levels remained rather constant at 6 months (69.0 and 76.7 nmol/L, respectively); however, only injection therapy resulted in improved levels compared to baseline (55.7 nmol/L, p < 0.001). No toxic effects, nor significant changes in PTH or albumin-adjusted calcium, were seen. CONCLUSIONS: In this randomized trial, both interventions, UVB and cholecalciferol, given as an adjunct to oral supplementation in gastric bypass patients, increased the levels of 25[OH]D. Simplicity makes injection therapy suitable for maintaining vitamin D levels during the Nordic winter.

Patch testing with own cosmetics-- prospective study of testing and reporting of adverse effects to the Swedish Medical Products Agency.

BACKGROUND: The Swedish Medical Products Agency (MPA) provides a voluntary reporting system for adverse reactions to cosmetics. However, the reporting is sparse, and the products involved are sometimes difficult to identify. OBJECTIVES: To investigate how often patients referred for patch testing were tested with the cosmetic products that they had been using themselves, and to improve the reporting to the MPA by the use of photographic documentation of product labels. PATIENTS AND METHODS: Consecutive patients at five dermatology departments who were patch tested with their own cosmetics were included. Reports including protocols of positive patch test results for the patients' own cosmetics and photographs/photocopies of product labels were sent to the MPA. RESULTS: Three hundred and sixteen of 948 patients (33%) were tested with their own cosmetics, and 15% of these tested positive with one or more products. The number of reports was more than three times higher than in corresponding periods in earlier years. For 79% of the products, photographs/photocopies of the containers were submitted, and for 30%, batch numbers were submitted. CONCLUSIONS: For a substantial number of patients, their own cosmetics were suspected of causing adverse reactions and were therefore tested. During the study, the number of reports to the MPA tripled, and the relevant products were easier to identify.

Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris.

BACKGROUND: Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes. OBJECTIVE: The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected. METHODS AND FINDINGS: Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression. CONCLUSIONS: We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.

Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids.

In a previous study, 7-week treatment of normal human skin with two test moisturizers, Complex cream and Hydrocarbon cream, was shown to affect mRNA expression of certain genes involved in keratinocyte differentiation. Moreover, the treatment altered transepidermal water loss (TEWL) in opposite directions. In the present study, the mRNA expression of genes important for formation of barrier lipids, i.e., cholesterol, free fatty acids and ceramides, was examined. Treatment with Hydrocarbon cream, which increased TEWL, also elevated the gene expression of GBA, SPTLC2, SMPD1, ALOX12B, ALOXE3, and HMGCS1. In addition, the expression of PPARG was decreased. On the other hand, Complex cream, which decreased TEWL, induced only the expression of PPARG, although not confirmed at the protein level. Furthermore, in the untreated skin, a correlation between the mRNA expression of PPARG and ACACB, and TEWL was found, suggesting that these genes are important for the skin barrier homeostasis. The observed changes further demonstrate that long-term treatment with certain moisturizers may induce dysfunctional skin barrier, and as a consequence several signaling pathways are altered.

Sodium lauryl sulphate alters the mRNA expression of lipid-metabolizing enzymes and PPAR signalling in normal human skin in vivo.

Detergents irritate skin and affect skin barrier homeostasis. In this study, healthy skin was exposed to 1% sodium lauryl sulphate (SLS) in water for 24 h. Biopsies were taken 6 h to 8 days post exposure. Lipid patterns were stained in situ and real-time polymerase chain reaction (PCR) was used to examine mRNA expression of enzymes synthesizing barrier lipids, peroxisome proliferator-activated receptors (PPAR) and lipoxygenases. The lipid pattern was disorganized from 6 h to 3 days after SLS exposure. Concomitant changes in mRNA expression included: (i) reduction, followed by induction, of ceramide-generating beta-glucocerebrosidase, (ii) increase on day 1 of two other enzymes for ceramide biosynthesis and (iii) persistent reduction of acetyl-CoA carboxylase-B, a key enzyme in fatty acid synthesis. Surprisingly, the rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase, was unaltered. Among putative regulators of barrier lipids synthesis, PPARalpha and PPARgamma exhibited reduced mRNA expression, while PPARbeta/delta and LXRbeta were unaltered. Epidermal lipoxygenase-3, which may generate PPARalpha agonists, exhibited reduced expression. In conclusion, SLS induces reorganization of lipids in the stratum corneum, which play a role in detergents' destruction of the barrier. The changes in mRNA expression of enzymes involved in synthesizing barrier lipids are probably important for the restoration of the barrier.

Long-term treatment with moisturizers affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation.

In a recent study, we showed that long-term treatment with two different moisturizers affected TEWL in opposite directions. Therefore, we decided to examine the effect of these moisturizers on the cellular and molecular level. In a randomized controlled study on 20 volunteers, epidermal mRNA expression of genes essential for keratinocyte differentiation and desquamation after a 7-week treatment with two moisturizers was analyzed. Treatment with one test moisturizer increased gene expression of involucrin, transglutaminase 1, kallikrein 5, and kallikrein 7, while the other moisturizer affected only expression of cyclin-dependent kinase inhibitor 1A. Thus, moisturizers are able to modify the skin barrier function and change the mRNA expression of certain epidermal genes. Since the type of influence depends on the composition of the moisturizer, these should be tailored in accordance with the requirement of the barrier of each individual patient, which merits further investigations.

Photodynamic therapy with methyl aminolevulinate for prevention of new skin lesions in transplant recipients: a randomized study.

BACKGROUND: Organ transplant recipients on long-term immunosuppressive therapy are at increased risk of non-melanoma skin lesions. Repeated field photodynamic therapy using topical methyl aminolevulinate (MAL) may have potential as a preventive treatment. METHODS: This open randomized, intrapatient, comparative, multicenter study included 81 transplant recipients with 889 lesions (90% actinic keratoses (AK)]. In each patient, the study treatment was initially administered to one 50 cm area on the face, scalp, neck, trunk, or extremities (n=476 lesions) twice (1 week apart), with additional single treatments at 3, 9, and 15 months. On each occasion, the area was debrided gently and MAL cream (160 mg/g) applied for 3 hr, before illumination with noncoherent red light (630 nm, 37 J/cm2). The control, 50 cm2 area (n=413 lesions) received lesion-specific treatment (83% cryotherapy) at baseline and 3, 9, and 15 months. Additionally, all visible lesions were given lesion-specific treatment 21 and 27 months in both treatment and control areas. RESULTS: At 3 months, MAL photodynamic therapy significantly reduced the occurrence of new lesions (65 vs. 103 lesions in the control area; P=0.01), mainly AK (46% reduction; 43 vs. 80; P=0.006). This effect was not significant at 27 months (253 vs. 312; P=0.06). Hypopigmentation, as assessed by the investigator, was less evident in the treatment than control areas (16% vs. 51% of patients; P<0.001) at 27 months. CONCLUSION: Our results suggest that repeated field photodynamic therapy using topical MAL may prevent new AK in transplant recipients although further studies are needed.

A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, double-blind, controlled trial.

BACKGROUND: New topical treatments in scalp psoriasis are needed because many current topical treatments are disliked by patients and associated with poor compliance. OBJECTIVE: To compare the efficacy and safety of once-daily, two-compound scalp formulation containing calcipotriene plus betamethasone dipropionate with the individual components in the same vehicle and the vehicle alone. METHODS: In this 8-week, multicenter, randomized, double-blind study, patients with scalp psoriasis were randomized to treatment with the two-compound scalp formulation (calcipotriene 50 microg/g plus betamethasone 0.5 mg/g, as dipropionate) (n = 541), betamethasone 0.5 mg/g (as dipropionate) in the same vehicle (n = 556), calcipotriene 50 microg/g in the same vehicle (n = 272), or vehicle alone (n = 136). RESULTS: More patients achieved "absent" or "very mild" disease at week 8 with the two-compound scalp formulation (71.2%) compared with betamethasone dipropionate in the same vehicle (64.0%, p = .011), calcipotriene in the same vehicle (36.8%, p < .0001), or the vehicle (22.8%, p < .0001). LIMITATIONS: Efficacy of the active comparators in the study has not been established in relation to calcipotriene and betamethasone formulations available for clinical use. CONCLUSION: Calcipotriene plus betamethasone dipropionate scalp formulation was more effective than either of the individual components or the vehicle alone.

Can the reporting of adverse skin reactions to cosmetics be improved? A prospective clinical study using a structured protocol.

BACKGROUND: The use of cosmetics is rising, and adverse reactions to these products are increasing. In Sweden, the Medical Products Agency (MPA) keeps a voluntary reporting system for such adverse reactions. However, the reporting is sparse, consisting almost only of cases with test-proven allergic contact dermatitis, thus under-reporting the more common irritant reactions. OBJECTIVE: The aim of the study was to try to improve the reporting system. PATIENTS AND METHODS: Dermatologists at 3 dermatology departments used a structured protocol during the clinical investigation of 151 consecutive patients reporting skin reactions to cosmetics. The protocol included symptoms, signs, affected body site, suspected products, and final diagnosis after patch testing. Based on clinical data and patch test results, a causality assessment for each product was made according to a protocol used at the MPA. RESULTS: Allergic contact dermatitis was found in 28% of the patients, and irritant reactions were equally common at 27%. CONCLUSIONS: Using this structured protocol, the cases of irritant dermatitis were also reported, and it is recommended that such a protocol is used as a standard to improve the reporting of adverse reactions to skin care products.

Skin barrier disruption by sodium lauryl sulfate-exposure alters the expressions of involucrin, transglutaminase 1, profilaggrin, and kallikreins during the repair phase in human skin in vivo.

Detergents are skin irritants affecting keratinocytes. In this study, healthy volunteers were exposed to water (vehicle) and 1% sodium lauryl sulfate (SLS) under occlusive patch tests for 24 hours. The messenger RNA (mRNA) expression of keratinocyte differentiation markers and of enzymes involved in corneodesmosome degradation was examined in skin biopsies (n=8) during the repair phase (6 hours to 7 days postexposure) using real-time reverse-transcription PCR. It was found that the expression of involucrin was increased at 6 hours, but then rapidly normalized. The expression of transglutaminase 1 exhibited a twofold increase after 24 hours in the SLS-exposed skin. Profilaggrin was decreased after 6 hours. Later (4-7 days), the expression in SLS-exposed areas was >50% above than in control areas. An increased and altered immunofluorescence pattern of involucrin, transglutaminase 1, and filaggrin was also found (n=4). At 6 hours post-SLS exposure, the mRNA expression of kallikrein-7 (KLK-7) and kallikrein-5 (KLK-5) was decreased by 50 and 75%, respectively, as compared with control and water-exposed areas. Thereafter, the expression pattern of KLK-7 and KLK-5 was normalized. Changes in protein expression of KLK-5 were also found. In conclusion, SLS-induced skin barrier defects induce altered mRNA expression of keratinocyte differentiation markers and enzymes degrading corneodesmosomes.

Detergents with different chemical properties induce variable degree of cytotoxicity and mRNA expression of lipid-metabolizing enzymes and differentiation markers in cultured keratinocytes.

The knowledge how detergents with different chemical properties influence epidermal keratinocytes is sparse. In the present study, the effects of five detergents were examined with respect to cell-toxicity and mRNA expression of key-enzymes in barrier lipid production and keratinocyte differentiation markers. First, the LD(50) for each detergent were determined. Secondly, keratinocytes were exposed to sub-toxic concentrations and the mRNA expression was analysed by real-time PCR after 24 h exposure to the detergents. SLS and CAPB induced a concentration-dependent increase in the expression of enzymes producing cholesterol and ceramides, while transcripts of enzymes producing fatty acids were unaffected. SLES and cocoglucoside increased the expression of certain enzymes involved in cholesterol and fatty acid synthesis while sodium cocoamphoacetate (SCAA) stimulated expression of transcripts involved in fatty acid synthesis. The expression of differentiation markers were increased by SLS, SLES and CAPB, while SCAA and cocoglucoside exhibited no effect. The present findings show that detergents have variable effects on lipid synthesis and keratinocyte differentiation, which could partly explain their barrier destruction potential in vivo.

Variations in the mRNA expression of inflammatory mediators, markers of differentiation and lipid-metabolizing enzymes caused by sodium lauryl sulphate in cultured human keratinocytes.

Detergents are well known irritants. Effects of the detergent sodium lauryl sulphate (SLS) on cell toxicity using the XTT assay and mRNA expression of inflammatory mediators, markers of keratinocyte differentiation and enzymes synthesizing barrier lipids using real-time PCR were studied in cultured differentiated keratinocytes. After exposure for 24 h to SLS concentrations at 0.002% or above, toxic effects were observed. When a lower SLS concentration (0.00075%) was used the mRNA expression of inflammatory mediators peaked around 4-8 h. The expression of enzymes involved in the synthesis of cholesterol, fatty acids and ceramides and markers of keratinocyte differentiation also increased but after 24 h. In cells exposed to 0.000125-0.0015% SLS, a concentration-dependent induction of the expression of inflammatory mediators was found after 4 h. Similar changes were found after 24 h for involucrin and enzymes involved in ceramide synthesis. The mRNA expression of HMG-CoA synthase and reductase, long-chain acyl-CoA synthase and transglutaminase also peaked after 24 h, but maximal induction was observed already at 0.00075% SLS. In conclusion, SLS induces an inflammatory response in keratinocytes and alters the mRNA expression of important barrier lipid enzymes and markers of keratinocyte differentiation, of possible importance for the irritant properties of SLS.

A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp.

Photodynamic therapy (PDT) with topical methyl aminolevulinate (MAL) administered in two treatment sessions separated by 1 week is an effective treatment for actinic keratoses. This open prospective study compared the efficacy and safety of MAL-PDT given as a single treatment with two treatments of MAL-PDT 1 week apart. Two hundred and eleven patients with 413 thin to moderately thick actinic keratoses were randomized to either a single treatment with PDT using topical MAL (regimen I; n=105) or two treatments 1 week apart (regimen II; n=106). Each treatment involved surface debridement, application of Metvix cream (160 mg/g) for 3 h, followed by illumination with red light using a light-emitting diode system (peak wavelength 634+/-3 nm, light dose 37 J/cm2). Thirty-seven lesions (19%) with a non-complete response 3 months after a single treatment were re-treated. All patients were followed up 3 months after the last treatment. A total of 400 lesions, 198 initially treated once and 202 treated twice, were evaluable. Complete response rate for thin lesions after a single treatment was 93% (95% CI=87-97%), which was similar to 89% (82-96%) after repeated treatment. Response rates were lower after single treatment of thicker lesions (70% (60-78%) vs 84% (77-91%)), but improved after repeated treatment (88% (82-94%)). The conclusion of this study is that single treatment with topical MAL-PDT is effective for thin actinic keratosis lesions; however, repeated treatment is recommended for thicker or non-responding lesions.

Novel method for studying photolability of topical formulations: a case study of titanium dioxide stabilization of ketoprofen.

Sunlight may decompose active substances and excipients in pharmaceuticals. This may cause formulation problems as well as induce adverse skin reactions. The photodecomposition of topical preparations may occur on the skin surface, but also deeper in the skin after penetration of light into the viable tissues. The aim of the present study was to investigate whether microparticles of titanium dioxide could protect against photodecomposition using ketoprofen as a photolabile model substance. The results showed quality differences between titanium dioxide, where surface-coated particles were superior to pharmaceutical grades in reducing the degradation in vitro. The protective effect was also studied in humans. The skin was treated for 3 h with the gels and then exposed to ultraviolet (UV) light (11.7 J/cm2 UVA and 5.4 mJ/cm2 UVB). Layers of the stratum corneum were then removed by consecutive tape strippings and assayed for content of ketoprofen. The remaining amount was higher in the different stratum corneum compartments after treatment with a gel containing 4% coated titanium dioxide compared with a transparent gel. Thus, surface-coated microparticles of titanium dioxide may well be of clinical benefit in protecting photolabile drug substances against sunlight.

Bioequivalence determination of topical ketoprofen using a dermatopharmacokinetic approach and excised skin penetration.

Ketoprofen is a photolabile drug. The aim of the present study was to compare the bioavailability of ketoprofen in a photo-stabilised formulation with a gel without photoprotection using a new dermatopharmacokinetic tape-stripping model and an established ex vivo penetration method using human skin. Analyses of the stratum corneum showed that during the first 45 min about 12 microg/cm2 ketoprofen was absorbed into the skin from the formulations. The area under the ketoprofen content-time curve (AUC0-6 h) for the ratio photo-stabilised gel/transparent gel was 73% with a 90% confidence interval (CI) 65-83. The rate of penetration of ketoprofen through isolated skin was approximately 0.2 microg/cm2 h for both formulations. AUC0-36 h for the ratio was 84% with 90% CI 64-105. Thus, the two methods did not disagree in terms of relative efficacy of the two gels. However, the difference obtained in vivo was statistically significant, whereas no significant data arise from the ex vivo study. Comparing the amount of ketoprofen in the skin after 45 min with the amount penetrated through the excised skin during 36 h, suggests a change in the thermodynamic activity of ketoprofen during the exposure. A supersaturated formulation may well have been formed initially due to evaporation of ethanol.

Are adverse skin reactions to cosmetics underestimated in the clinical assessment of contact dermatitis? A prospective study among 1075 patients attending Swedish patch test clinics.

It is known that cosmetics and skin care products can cause adverse skin reactions. However, the frequency of adverse reactions reported to the Medical Product Agency (MPA) in Sweden is low. The purpose of the present study was to evaluate the occurrence of adverse skin reactions to cosmetics among patients referred for standard patch testing owing to suspected contact dermatitis in general, most frequently hand eczema. Consecutive patients at four patch test clinics in Sweden were invited to participate; 1075 were included. Of these, 47.3% (54.2% women and 30.8% men) reported current or previous adverse skin reactions to cosmetics and skin care products. This group showed significantly more positive patch test reactions, a higher prevalence of atopic dermatitis and the dermatitis was more frequently located in the face and neck region. Our results show that patients referred for standard patch testing have--or have had--a large proportion of self-reported adverse reactions to cosmetics or skin care products. We conclude that among patients with suspected contact dermatitis, adverse reactions to cosmetics can be a more important aetiological and/or complicating factor than is commonly acknowledged and that the reporting of such reactions to the MPA probably can be improved.

Enhanced epidermal ultraviolet responses in chronically sun-exposed skin are dependent on previous sun exposure.

The p53 protein plays a key role in protecting cells from acquiring manifest mutations by inducing cell cycle arrest or apoptosis. The mechanisms for differences in epidermal responses to ultraviolet irradiation are unclear, although they have been shown to be related to both genetic events and environmental factors. In this study, we compared epidermal ultraviolet responses in chronically sun-exposed and non-sun-exposed skin using immunohistochemistry with antibodies recognizing thymine dimers and p53 protein. Six healthy volunteers were subjected to both artificial ultraviolet irradiation and natural sunlight, with and without photoprotection. A smaller number of thymine dimer-positive keratinocytes were detected 24 h after ultraviolet exposure in chronically sun-exposed skin compared to non-sun-exposed skin. Further, the p53 response was more variable in chronically sun-exposed skin. A significant correlation between total ultraviolet dose and number of p53-immunoreactive keratinocytes was found after natural sun exposure. Our findings suggest that repair of DNA damage is more efficient in chronically sun-exposed skin than in non-sun-exposed skin.

Similar UV responses are seen in a skin organ culture as in human skin in vivo.

Ultraviolet radiation (UVR) plays an important role in the development of non-melanoma skin cancer. Most tumors develop in chronically sun-exposed skin, most often in cosmetically sensitive locations, where in vivo experiments may be difficult to perform. In this study, we describe a skin organ culture model with preserved normal morphology and intact response to UVR. Skin explants from chronically sun-exposed and non-sun-exposed skin were irradiated with artificial UVA+UVB with and without topical sunscreen. UV-induced DNA damage, epidermal p53 response and repair kinetics were analyzed using immunohistochemistry. Four hours after UV-irradiation epidermal keratinocytes showed a strong immunoreactivity for thymine-dimers. Gradual repair during an incubation time resulted in few residual thymine-dimers after 48 h. Repair appeared to be more efficient in chronically sun-exposed skin compared with non-sun-exposed skin. There was also an accumulation of p53 protein in epidermal keratinocytes, peaking at 4-24 h after irradiation. Large interindividual differences with respect to formation and repair of thymine-dimers as well as induction and duration of the p53 response were observed. Skin explants treated with topical sunscreen prior to UV-irradiation showed a clear reduction of thymine-dimers and p53 expression. The epidermal UV-responses and repair kinetics in organ-cultured skin were similar to what was found in vivo. Our data suggest that organ-cultured skin provides a valuable tool for studies of UV-induced epidermal responses in chronically sun-exposed skin.