Kinetics and dose-response of photosensitivity in cream psoralen plus ultraviolet A photochemotherapy: comparative in vivo studies after topical application of three standard preparations

BACKGROUND: Topical photochemotherapy with bath psoralen plus ultraviolet (UV) A irradiation (PUVA) has been developed to reduce possible side-effects of oral PUVA therapy. Although the efficacy of bath PUVA therapy appears to be similar to oral PUVA therapy, provision of bathing facilities has obvious economic, logistic and sanitary implications. Cream PUVA therapy has recently been developed as a variation of topical PUVA. OBJECTIVES: To understand the photobiological effects and to increase the safety and effectiveness of this novel topical PUVA therapy, we assessed the kinetics and dose-response of phototoxicity of 8-methoxypsoralen (8-MOP) cream in order to develop a treatment schedule for this treatment option. METHODS: Ninety-eight patients (63 men and 35 women) undergoing cream PUVA therapy were studied. The phototoxic properties of topically applied 8-MOP in three different water-in-oil creams as vehicles were assessed. In a dose-response study, four concentrations of 8-MOP cream (0.0006-0.005%) were used for determination of the minimal phototoxic dose (MPD). The kinetics of photosensitization were tested by determination of MPDs after different application times of 8-MOP cream (10, 20, 30 and 60 min). The persistence of phototoxicity was assessed by UVA exposure at defined time intervals after application of 8-MOP cream (0, 30, 60 and 120 min). RESULTS: The concentration required to produce sufficient but not undue photosensitization of the skin was 0.001% 8-MOP. The duration of application leading to the lowest MPD was 30 min. Greatest photosensitization was achieved when UVA irradiation was performed between 0 and 30 min after 8-MOP removal. These findings showed no significant difference between the three vehicles used. CONCLUSIONS: Based on our data we recommend application of 0.001% 8-MOP in a water-in-oil cream for 30 min. Irradiation with UVA should be performed within 30 min after removal of 8-MOP cream, as there is a rapid decrease in photosensitivity thereafter.     

Cream psoralen plus ultraviolet A therapy for granuloma annulare

BACKGROUND: Treatment modalities for granuloma annulare (GA) often remain unsatisfactory or can be accompanied by potentially hazardous side-effects. Psoralen plus ultraviolet (UV) A (PUVA) bath photochemotherapy has been reported to be highly effective in the treatment of GA. Another form of topical PUVA therapy, using 8-methoxypsoralen-containing cream or gel preparations, has been proven to be as effective as bath PUVA therapy in the treatment of palmoplantar dermatoses. OBJECTIVES: To assess the efficacy of cream PUVA photochemotherapy in patients with GA. METHODS: Five patients with GA were treated. The diagnosis was confirmed by pretreatment skin biopsies. Cream PUVA therapy was performed four times a week: the mean number of treatments was 26 (range 17-40) and mean cumulative UVA dose was 55.9 J cm-2 (range 18.2-109.2). RESULTS: Cream PUVA photochemotherapy induced significant clinical improvement (one patient) or clearance (four patients) of GA in all patients. Clearance was documented clinically and histopathologically. CONCLUSIONS: Cream PUVA phototherapy can be highly effective in patients affected by localized forms of GA.     

Treatment of genito-anal lesions in inflammatory skin diseases with PUVA cream photochemotherapy: an open pilot study in 12 patients

BACKGROUND: Localized skin lesions of the genito-anal region such as in lichen sclerosus et atrophicus or in lichen planus are a burden for many patients, and therapeutic efforts, including therapies with potentially hazardous side-effects, are often unsatisfactory. Recently, PUVA bath photochemotherapy has been proven highly effective in the treatment of various inflammatory skin diseases, including localized scleroderma. Another form of topical PUVA therapy, 8-methoxypsoralen-containing cream or gel preparations, has been proven to be as effective as PUVA bath therapy for palmoplantar dermatoses. OBJECTIVE: We evaluated the clinical effects of PUVA cream photochemotherapy in patients with genital lesions of inflammatory skin diseases. METHODS: Twelve patients with lichen sclerosus et atrophicus, lichen planus, vulvar eczema and pruritus vulvae were included in the study. PUVA cream therapy was performed up to 4 times a week. RESULTS: PUVA cream photochemotherapy induced a significant clinical improvement of genital lesions in most patients, as revealed by clinical examination. Clinical improvement (reduction in size of lesions of erythema, and/or of pruritus) was achieved in most patients after 10-20 treatments and was reduced in patients that had only received 5-15 treatments. Cumulative doses ranged between 4.5 and 180 J/cm(2); all patients tolerated PUVA cream phototherapy well without any side-effects. CONCLUSION: PUVA cream phototherapy represents a highly effective therapy that should be further investigated as an alternative treatment for patients with genital lesions of inflammatory skin diseases.     

Treatment of severe recalcitrant dermatoses of the palms and soles with PUVA-bath versus PUVA-cream therapy

PUVA-bath therapy developed into a first line topical PUVA therapy, and gel and cream preparations have been described as alternative modes of topical 8-MOP application. Because bath-PUVA can be difficult to manage, topical PUVA therapy using 8-MOP gel or cream preparations may become an important alternative when treating localised skin diseases. However, controlled comparisons of efficacy with this alternative topical PUVA therapy are lacking. We therefore compared the efficacy of PUVA-cream therapy with PUVA-bath therapy in 12 patients with recalcitrant dermatoses of the palms and soles using a left/right trial design. These patients responded well to both treatment modalities, meaning that both could be used successfully to treat recalcitrant dermatoses of the palms and soles.     

PUVA-cream photochemotherapy for the treatment of localized scleroderma

BACKGROUND: The efforts to treat localized scleroderma, including therapies with potentially hazardous side effects, are often unsatisfactory. Recently, PUVA-bath photochemotherapy has been proven highly effective in the treatment of localized scleroderma. Another form of topical PUVA therapy, 8-methoxypsoralen (8-MOP) containing cream or gel preparations, has been proven to be as effective as PUVA-bath therapy for palmoplantar dermatoses. OBJECTIVE: We sought to assess the efficacy of PUVA-cream photochemotherapy in patients with localized scleroderma. METHODS: Four patients with localized scleroderma were included in the study. Diagnosis was confirmed by 20 MHz ultrasound assessment as well as pretreatment skin biopsy specimens from lesional skin. PUVA-cream therapy was performed 4 times a week; all patients received 30 treatments. RESULTS: PUVA-cream photochemotherapy induced significant clinical improvement or clearance of localized scleroderma in all patients. Clearance was documented by clinical features as well as by 20 MHz ultrasound and histopathologic analysis. CONCLUSION: PUVA-cream phototherapy can be highly effective in patients with localized scleroderma even if previous therapy was unsuccessful.     

A new psoralen-containing gel for topical PUVA therapy: development,and treatment results in patients with palmoplantar and plaque-type psoriasis,and hyperkeratotic eczema

Summary Topical photochemotherapy with psoralen and its derivatives 4.5′,8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP), with UVA irradiation, was evaluated with regard to minimum phototoxic dose, concentration, timing of UVA irradiation and systemic and local side-effects, in healthy volunteers. Psoralen (0.005%) in aqueous gel was found to be superior to TMP and 8-MOP in aqueous gel. No hyperpigmentation was seen after topical PUVA treatment with psoralen in aqueous gel. Patients with plaque-type psoriasis (n = 7), palmoplantar psoriasis (n = 7) and hyperkeratotic eczema (n = 2) were treated. Topical PUVA therapy was effective in most psoriasis patients, without the occurrence of local or systemic side-effects. Moreover, hyperkeratotic eczema patients who did not respond to conventional therapy showed partial remission. These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.     

PUVA-gel vs. PUVA-bath therapy for severe recalcitrant palmoplantar dermatoses. A randomized, single-blinded prospective study

BACKGROUND/PURPOSE: In order to avoid unwanted effects of systemic psoralen and ultraviolet A (PUVA) therapy, various topical PUVA treatment modalities have been developed and are being increasingly used. However, up to now very few controlled studies comparing the therapeutic efficacy of different topical photochemotherapy modalities are available. Thus, the aim of our study was to compare the clinical efficacy of conventional PUVA-bath therapy to topical PUVA-gel therapy in patients with recalcitrant dermatoses of the palms and soles. METHODS: Twenty patients with severe palmoplantar dermatoses or localized psoriatic plaques were enrolled in our observer-blinded, randomized half-sided study. The treatment modalities compared were: (i) aqueous 8-methoxypsoralen (8-MOP)-containing gel plus broadband UVA irradiation (PUVA-gel therapy) and (ii) 8-MOP bath of the hands and/or feet plus broadband UVA (PUVA-bath therapy). RESULTS: On the body half, which was randomized to PUVA-gel therapy, the median Area and Severity Index for palmoplantar dermatoses (ASIppd) decreased from 28 (range 6-56) to 1.5 (range 1-37, P = 0.00) after a median 33 (13-49) irradiations compared with a reduction from 26.5 (range 6-52.5) to 1.5 (range 0-38, P = 0.00) for PUVA-bath therapy. Both improvements of ASIppd scores were found to be statistically significant, with no significant difference between PUVA-gel and PUVA-bath therapy. Severe phototoxic reactions such as strong erythema, blistering and/or pain were not observed in any patient. CONCLUSION: PUVA-gel therapy seems to be an effective therapeutic alternative to conventional PUVA-bath therapy in treating localized dermatoses of the palms and soles. The advantage of PUVA-gel therapy is reduced organizational efforts and expenses.     

Creme-PUVA-Photochemotherapie bei chronisch stationärer Psoriasis vulgaris

PUVA-bath therapy has developed into first line topical PUVA therapy in the treatment of psoriasis. Because of logistical and economic problems, bath PUVA may be difficult to administer. Recently, cream-PUVA therapy has been described as an alternative mode of topical therapy. We treated two patients with moderate plaque-type psoriasis with this new topical approach. 0,0006% 8-methoxypsoralen cream was applied for 1 hour, directly followed by increasing doses of UVA. The number of treatments needed for clearance were 34 and 40. The cumulative UVA dosages were 71.6 and 84 J/cm(2) respectively. Our data document that cream-PUVA therapy is an effective and safe variation of topical PUVA therapy, which may develop into first line photochemotherapy for patients with moderate plaque-type psoriasis.     

Lichen planus of the lower limbs: successful treatment with psoralen cream plus ultraviolet A photochemotherapy

Lichen planus (LP) classifies into different subtypes depending on morphology and localization. Localized LP of the lower limb (LPLL) manifests a great challenge due to persistent itching, therapeutic resistance and the risk to develop into SCC. We report two cases with LPLL refractory to standard topical therapy, which were successfully treated with psoralen cream plus UVA photochemotherapy (cream‐PUVA). We propose cream‐PUVA as an alternative therapeutic option effective for localized LP of the lower limbs.     

Comparison of localized high-dose UVA1 irradiation versus topical cream psoralen-UVA for treatment of chronic vesicular dyshidrotic eczema

BACKGROUND: Vesicular dyshidrotic palmoplantar eczema is a common disorder but treatment is difficult. Localized photochemotherapy (cream psoralen-UVA [PUVA]) has widely been used for therapy. Although the efficacy of cream PUVA therapy is well known, potential side effects may occur. Therefore, a more standardized safe and effective UV therapy should be carried out. OBJECTIVE: This study compared the effects of localized high-dose UVA1 irradiation versus topical cream PUVA for treatment of chronic vesicular dyshidrotic eczema. METHODS: On the basis of the assessment of the Dyshidrotic Area and Severity Index, the decrease of score points on the UVA1-treated side was compared with the decrease on the cream PUVA-treated side in 27 patients. In addition, analysis of serum markers was performed. RESULTS: Of 27 patients, 24 showed a good response to localized UVA1 irradiation or cream PUVA. Dyshidrotic Area and Severity Index scores significantly decreased on both sides and were reduced to half of the pretreatment values. No statistically significant differences between localized UVA1 irradiation or cream PUVA could be detected. CONCLUSION: This study demonstrates that localized UVA1 phototherapy is easy to perform and appears to be an effective and safe treatment for vesicular dyshidrotic eczema.     

Evaluation of time-dependent response to psoralen plus UVA (PUVA) treatment with topical 8-methoxypsoralen (8-MOP) gel in palmoplantar dermatoses

BACKGROUND: Topical psoralen plus UVA (PUVA) is an effective treatment for localized forms of eczema, psoriasis, and palmoplantar pustulosis, which avoids some of the undesirable side-effects of systemic psoralens. Aims In this study, the efficacy of topical PUVA treatment with 8-methoxypsoralen (8-MOP) gel was compared with placebo plus UVA in chronic recurrent palmoplantar dermatoses. METHODS: Twenty-two patients with palmoplantar disease (11 with psoriasis vulgaris, six with eczema, and five with pustulosis) were enrolled in the study. The study design was a left-right comparison: one hand or foot was treated with 8-MOP 0.01% gel plus UVA, whilst the contralateral hand or foot received placebo and UVA for 6 weeks. Twenty minutes after application of the gel, both sides were exposed to UVA. The treatment regimen was three times a week, and the UVA dose was increased weekly by 20%. RESULTS: A comparison of the pre- and post-treatment scores with regard to the severity of the clinical picture and the infiltration of plaques showed a significant decrease (from 7.5 +/- 2.0 to 2.5 +/- 2.1 and from 2.0 +/- 0.7 to 0.3 +/- 0.5, respectively) in the sites treated with 8-MOP gel compared with placebo after 6 weeks. CONCLUSION: The results of the study indicate that at least 18 courses of local PUVA within 6 weeks, with a cumulative dose of 87 J/cm(2), are required to induce a significant decrease in the disease severity and an improvement in the infiltration of plaques due to 8-MOP gel at a concentration of 0.01% when treating chronic recurrent palmoplantar dermatoses.     

5-Methoxypsoralen (Bergapten) in photochemotherapy of psoriasis

5-Methoxypsoralen (5-MOP, Bergapten) was evaluated as a potential photosensitizing drug in oral photochemotherapy of psoriasis. Treatment results indicate that (1) 5-MOP is as effective as, and in high doses more effective than, 8-methoxypsoralen in clearing psoriatic lesions; (2) therapeutic doses of 5-MOP do not lead to erythema; the acute side-effects of 8-MOP PUVA therapy--erythema, blistering, pruritus--are thus avoided; (3) even high doses of 5-MOP are not followed by nausea. 5-MOP PUVA therapy thus represents a real alternative to 8-MOP PUVA, its advantages over 8-MOP PUVA being greater safety and patient acceptance.     

Alopecia areata treatment with a phototoxic dose of UVA and topical 8-methoxypsoralen

Twenty-five patients with alopecia totalis (AT) or alopecia universalis and 124 patients with alopecia areata (AA) were treated with photochemotherapy, combining topical 8-methoxypsoralen (8-MOP) with UV irradiation of the scalp at a phototoxic dose. The mean energy required was 15 J/cm2 for AA and 42 J/cm2 for AT. Ninety-four patients had multiple bald patches and 12 with AT had complete or > 50% hair regrowth. Positive treatment results did not seem to depend on the age of onset or the duration of the disease. Few side-effects of topical psoralens plus UVA (PUVA) treatment were noted, except a for few days of slight erythema caused by the high dose of UV.     

New aspects in uv and photochemotherapy

Recent data show that from a pharmacological point of view topical (cream or bath) PUVA therapy is superior to systemic PUVA. Due to a significant reduction of side effects compared to systemic PUVA, bath PUVA has now started to replace oral PUVA therapy. Narrowband UVB has proved to be superior to broadband UVB in the treatment of psoriasis and is effective for a number of dermatoses such as vitilgo, atopic dermatitis and polymorphic light eruption. UVA1 phototherapy is highly effective in the treatment of moderate to severe atopic dermatitis and sclerosing diseases of the skin. Data dealing with UVA1 phototherapy for other indications are still preliminary. High-dose UVA1 is has been widely replaced by medium-dose UVA1, as a number of studies have shown similar therapeutic efficacy of both dose regimens.     

The efficacy of localized PUVA therapy for chronic hand and foot dermatoses

The response to treatment of all patients enrolled over an 18-month period for localized oral or topical psoralen photochemotherapy (PUVA) of chronic hand and foot dermatoses was retrospectively reviewed. There were broadly similar success rates for the two groups for complete clearance: 61.5% (eight of 13 patients who completed therapy)—oral PUVA, 47.8% (11 of 23 patients who completed therapy)—topical PUVA, and for significant improvement: 23.1% (three of 13 patients)—oral PUVA, 30.4% (seven of 23 patients)—topical PUVA; there were no significant differences in response when diagnostic subgroupings of the hand dermatoses were taken into account. The mean number of treatments (22 for oral PUVA and 24 for topical), treatment durations (122 and 129 days), maximum UVA doses (11.2 and 12.3J/cm²) and to a lesser extent cumulative UVA doses (189.3 and 237.0 J/ cm²) for the therapies were similar in the two groups; adverse effects were minimal for both treatment protocols. However, at least five of the eight patients in the oral PUVA group and five of the 11 in the topical group who cleared completely relapsed after a mean 86 (range 19.245) and 174 (range 23-596) days, respectively. These findings are in broad agreement with those of previous studies. Therefore to avoid generalized photo-sensitivity and a higher likelihood of adverse effects with systemic therapy, as well as a possible slower relapse rate, topical therapy seems preferable.     

Treatment of palmoplantar psoriasis with monochromatic excimer light (308-nm) versus cream PUVA

Palmoplantar psoriasis is a chronic disease, which is very resistant to treatment and often leads to severe disabilities. Photochemotherapy employing psoralens combined with UVA irradiation (PUVA) is a well-accepted therapy for palmoplantar psoriasis. Its topical application (bath PUVA; cream PUVA) avoids the typical side effects of orally applied psoralens. We compared the efficacy of cream PUVA therapy with monochromatic excimer light therapy, a treatment modality employing 308-nm UVB radiation generated by a new kind of light source. Ten patients with psoriasis of the palms and soles were randomly assigned to receive cream PUVA on one side and 308-nm UVB on the contralateral side. Based on the psoriasis area and severity index (PASI) score, clinical assessment was carried out before and 5 weeks after the beginning of the study. At the end of the treatment period both test groups showed a remarkable PASI score reduction (308-nm UVB, 63.57%; cream PUVA, 64.64%). No relevant adverse effects were observed, except for mild irritation in a few patients. After a 12-week follow-up, a relapse of the disease was only observed in one patient. Thus, mono-chromatic excimer light cleared palmoplantar psoriasis as rapidly as cream PUVA. In contrast to cream PUVA, monochromatic excimer light therapy is not associated with prior drug application. This might lead to a lower incidence of adverse reactions and better compliance. Therefore, monochromatic excimer light therapy seems to be a useful new therapeutic option for palmoplantar psoriasis.     

Initial photochemotherapy of psoriasis with orally administered 8-methoxypsoralen and longwave ultraviolet light ''PUVA)

One hundred and seven patients with psoriasis underwent initial PUVA therapy. Complete clearance was obtained in 52.3% of the patients, incomplete in 40.2% while 7.5% of the patients did not respond at all. The non-responders to the regular PUVA treatment regime (0.5 mg 8-MOP/kg body-weight) were given an increased 8-MOP (8-methoxypsoralen) dose schedule (0.6 mg 8-MOP/kg body weight) and in 90.9% of these patients their lesions cleared after 35 PUVA exposures. However, a small percentage (9.1%) of the non-responders to the normal dose schedule did not want to continue the increased 8-MOP dose schedule because of persistent nausea. For this reason they were given regular PUVA therapy and they reacted well, but only after fifty-five exposures. Irrespective of the complete or incomplete clearance of psoriasis the patients remained in remission for a mean period of about 5 1/2 months. During the remission period the patients were advised to use a tar preparation or topical corticosteroids in the event of minor exacerbations.     

8-Methoxypsoralen Serum Levels in Poor Responders to Photochemotherapy

8-Methoxypsoralen (8-MOP) serum levels of psoriatic patients poorly responsive to photochemotherapy (PUVA) treatment (problem cases) were determined by the HPLC method with 11 single blood probes over 8 hours. Abnormally low or deviated serum levels were found in 7 of 11 PUVA problem patients. There was a great interindividually different first-pass effect for 8-MOP in dependence on the galenic formulation of the 8-MOP brand; therefore, the change to another 8-MOP brand with a modern galenic formulation led only to a slight increase of serum levels, and consequently an increase in the 8-MOP dosage was necessary. It is important to be cautious at this point because patients may show an unproportional increase of 8-MOP serum levels due to the individually limited capacity of biotransformation. The studies of the authors reaffirm the necessity of the determination of 8-MOP serum levels in problem cases of PUVA therapy.     

Plasma levels of 8-methoxypsoralen following PUVA-bath photochemotherapy

Administration of 8-methoxypsoralen (8-MOP) in a dilute bath water solution is an effective therapeutic alternative to oral PUVA therapy, avoiding systemic side effects, offering better bioavailability of the psoralen and requiring much smaller amounts of UVA for induction of therapeutic effects. To obtain exact data about the percutaneous absorption of 8-MOP during a psoralen bath, the plasma levels of the drug were determined in 26 patients with different skin diseases by a reverse high-performance liquid chromatographic method. Fifteen patients receiving oral PUVA therapy (0.8 mg 8-MOP/kg body weight) served as a positive control group. Bath solutions were prepared by diluting 15 ml of 0.5% stock solution of 8-MOP in 150 l of bath water (0.5 mg/l, 37°C). Blood samples were drawn from patients 5, 30, 60, 120 and 180 min after the bath. In the oral PUVA group, blood samples were obtained 1½ h after administration of the drug. In 23 of 26 patients, 8-MOP levels were undetectable in every blood sample. After 30 min, two patients showed detectable levels of 8-MOP (5 ng/ml, 7 ng/ml), while 60 min after the PUVA bath 8-MOP was detectable in only one volunteer (5 ng/ml). In patients receiving oral 8-MOP therapy, serum levels varied between 45 and 360 ng/ml 1½ h after drug administration. Our data confirm extremely low 8-MOP levels resulting from 8-MOP bath water treatments and provide confirmation of the absence of systemic side effects in patients who are undergoing PUVA-bath therapy.     

Liver cytochrome P450 CYP1A2 is markedly inhibited by systemic but not by bath PUVA in dermatological patients

BACKGROUND: Methoxsalen (8-MOP) may cause important pharmacokinetic drug interactions as it has been shown to inhibit and/or induce several drug-metabolizing enzymes in vitro, in animal models and in humans. OBJECTIVES: In order to assess the clinical importance of acute and chronic 8-MOP effects on the liver cytochrome P-450 enzyme CYP1A2 in vivo, we measured caffeine clearance in dermatological patients before the onset of systemic or bath psoralen + ultraviolet A radiation (PUVA) (8-MOP + UVA) therapy, on the first day and after 1 week of treatment. METHODS: Data from four patients with systemic PUVA and seven patients with bath PUVA were available (age range 23-71 years, five women and six men). RESULTS: For all of the patients, individual pre-PUVA caffeine clearance values were above the lower limit of previously assessed reference ranges. Systemic PUVA markedly decreased caffeine clearance by factors of 0.17 [90% confidence interval (CI) 0.07-0.42] on the first day and 0.14 (90% CI 0.05-0.36) after 1 week of treatment, respectively, and values thus dropped below the reference ranges. In contrast, bath PUVA had no obvious effect on pre-PUVA clearance values as the latter changed by factors of 1.00 (90% CI 0.81-1.23) and 1.05 (90% CI 0.75-1.49) on the first day and after 1 week of treatment, respectively. CONCLUSIONS: Systemic PUVA causes pronounced inhibition of liver CYP1A2, while bath PUVA has no such effect. The extent of interaction makes a dose adjustment for most CYP1A2 substrates such as theophylline mandatory in patients undergoing systemic PUVA.