Photodynamic therapy using topically applied hypericin: comparative effect with methyl-aminolevulinic acid on UV induced skin tumours.

Photodynamic therapy (PDT) is a treatment option particularly well-suited for superficial (pre)malignant skin lesions due to the skin's accessibility to light. In the present study, the efficacy of topical hypericin-PDT was evaluated using a mouse model for actinic keratosis. For comparison, similar experiments were conducted with methyl-aminolevulinic acid (Me-ALA). Small skin tumours (1-2 mm) were induced in hairless mice by chronic UV irradiation. After topical application of hypericin (0.1% in gelcream for 24 h) or Me-ALA (Metvix® for 4 h), the lesional/non-lesional skin surface fluorescence ratio was determined and fluorescence microscopy was used to study the skin penetration of the photosensitizers. The antitumour activity of topical PDT (20 mW cm(-2), 40 J cm(-2)) was evaluated by measurement of the lesional diameters. Moreover, biopsies were taken at various time points after PDT for histological evaluation of the therapy. Our results demonstrate that after topical application of hypericin and Me-ALA, tumour selectivity is limited in mouse skin. The microscopic distribution of hypericin fluorescence showed an accumulation in the stratum corneum and low fluorescence levels in the rest of the lesions, whereas the distribution of PpIX in the skin was more homogenous. Topical hypericin-PDT was found to be less efficient (44% total lesional clearance) as compared to Me-ALA-PDT (80% total lesional clearance). Full lesional necrosis was observed in responsive lesions, and the atypical cells of actinic keratosis were replaced by normal keratinocytes 3 weeks later, both after hypericin-PDT and Me-ALA-PDT.

Photodermatology. Quo vadis? / Fotodermatología. Quo vadis?

El eritema no fue siempre un buen parámetro para valorar el daño solar y es más difícil de utilizar en fototipos más oscuros. Mientras que en el pasado la fotodermatología estaba centrada en la piel caucásica, el futuro puede ser completamente diferente. Además, el color de la piel no sólo tiene un papel protector, sino también una importancia social; este es otro factor a tener en cuenta. La fotodermatología y la clasificación de las fotodermatosis estarán más globalizadas en el futuro. Los desafíos para la fototerapia serán una reducción del tiempo de irradiación y del número de tratamientos y el desarrollo de fuentes de luz específicas para indicaciones concretas. Las fotopruebas deberán estandarizarse internacionalmente y esto dará lugar a la creciente necesidad de una Sociedad Internacional de Fotodermatología. Hasta ahora, la mayoría de los tratamientos han sido más bien sintomáticos. Hay también más razones para creer que otros tratamientos más activos puedan tener un papel en el futuro (AU)

Erythema was not always a good parameter for acute solar damage and is much more difficult to use in darker skin types. While in the past photodermatology was mainly focused on Caucasian skin, the future, therefore, could be completely different. In addition, skin colour has not only a protective importance but also a social importance. This is another factor that should be taken into account. Photodermatology and the classification of photodermatoses will also become more globalised in the future. Challenges for phototherapy will be a reduction of the irradiation time and the number of treatments, and the development of specific light sources for specific inrucations. Phototesting should be standardised on an international level and this will lead to a growing need for an International Society for Photodermatology. Until now, most treatments have been rather symptomatic. There are also more and more reasons to believe that more active treatments could play a role in the future (AU)

Photodermatology. Quo vadis?

Erythema was not always a good parameter for acute solar damage and is much more difficult to use in darker skin types. While in the past photodermatology was mainly focused on Caucasian skin, the future, therefore, could be completely different. In addition, skin colour has not only a protective importance but also a social importance. This is another factor that should be taken into account. Photodermatology and the classification of photodermatoses will also become more globalised in the future. Challenges for phototherapy will be a reduction of the irradiation time and the number of treatments, and the development of specific light sources for specific indications. Phototesting should be standardised on an international level and this will lead to a growing need for an International Society for Photodermatology. Until now, most treatments have been rather symptomatic. There are also more and more reasons to believe that more active treatments could play a role in the future.

Photosensitizing activity of hypericin and hypericin acetate after topical application on normal mouse skin.

BACKGROUND: Hypericin, originating from Hypericum perforatum, is a potent photosensitizer known to induce skin phototoxicity when given systemically. Previously, we have examined the penetration and distribution of hypericin and its acetate ester in the skin of hairless mice after topical application. OBJECTIVES: In this study, we assessed the time course and skin histopathology of the phototoxic response after a single topical application of hypericin and hypericin acetate, and subsequent irradiation. The amount of blood-borne photosensitizer and the skin clearance, as well the remaining photosensitizing capacity as a function of time, were evaluated. Furthermore, elicited phototoxic responses were compared with those after application of methyl aminolaevulinic acid (Me-ALA). METHODS: At different time points after topical application of hypericin (0.1-1%) and hypericin acetate (0.015-1.5%) onto mouse ears, penetration and retention of hypericin were assessed by fluorescence microscopy. After definite application times, the ears were irradiated (10 J cm(-2), 20 mW cm(-2)). Ear thickness measurements were conducted daily, and frequently ear samples were taken for histological analysis. RESULTS: Application of hypericin on mouse ears resulted only in limited phototoxicity, probably due to confined penetration into the epidermal layers. Extended penetration achieved by administration of hypericin acetate did give rise to a more severe and prolonged response after irradiation, characterized by intense erythema and ear swelling. Skin damage induced by 0.15% hypericin acetate application completely healed in 14 days without scar formation. After a single application of hypericin acetate, the residual photosensitizing capacity was found to decline quickly and was hardly detectable after 7 days. Under the experimental conditions used, hypericin acetate induced equal or more severe phototoxic responses compared with Me-ALA, depending on the concentration. CONCLUSIONS: Our results indicate that hypericin is an effective photosensitizer not only after systemic administration, but also after topical application, especially when applied as its precursor acetate ester. Moreover, our data provide some insights on safety limits and the time course of skin phototoxicity following hypericin and hypericin acetate application. These data will aid in developing protocols for future photodynamic therapy in the dermatological clinic.

Economic evaluation of methyl aminolaevulinate-based photodynamic therapy in the management of actinic keratosis and basal cell carcinoma.

BACKGROUND: Various effective therapeutic options are currently available for the treatment of actinic keratosis (AK) and basal cell carcinoma (BCC), but none is perfect. Poor cosmesis resulting from surgical procedures and skin irritation induced by topical agents remain significant problems. OBJECTIVES: To evaluate the cost-effectiveness of a recent approach, methyl aminolaevulinate-based photodynamic therapy (MAL-PDT; Metvix; Galderma, Lausanne, Switzerland) in AK and BCC. METHODS: A medical decision tree was developed for simulation of all possible outcomes associated with the medical decision to apply MAL-PDT or a comparator. The time horizon was 1 year for AK and 5 years for BCC. The comparators were cryotherapy in AK and excision surgery in BCC. Clinical data for the model were obtained from the literature. Data on medical management resulted from a Delphi panel performed among 12 Belgian dermatologists. Based on the model, the cost per full responder was calculated, whereby a responder was defined as a patient with all lesions clinically responding and showing an excellent cosmetic result. RESULTS: MAL-PDT is a more expensive treatment compared with cryotherapy for AK. However, the cost per full responder is comparable with cryotherapy (euro363 and euro379, respectively). Incremental cost per extra full responder is euro401. Incremental cost per full responder is euro469 for nodular BCC and euro251 for superficial BCC, both compared with excision surgery. CONCLUSIONS: The results suggest that MAL-PDT is a cost-effective intervention in AK taking a 1-year time horizon, if society is willing to pay euro1.50 per day of response, and that MAL-PDT is better value for money than excision in BCC, taking a 5-year time horizon.

Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis.

BACKGROUND: As psoriasis patients often require continuous treatment optimal therapy has to provide efficacy and a good safety profile over the long term. OBJECTIVES: The aim of this multicentre study was to assess the efficacy, safety and tolerability of tacalcitol (4 microg g(-1)) ointment (Curatoderm, Hermal, Reinbek, Germany) applied once daily over a treatment period of 18 months. PATIENTS AND METHODS: Efficacy parameters were Psoriasis Area Severity Index (PASI), based on summed scores of erythema, infiltration and scaling and total body surface involvement (TBI). Safety assessment included serum levels of calcium, parathyroid hormone, calcitonin, 1,25-dihydroxy vitamin D3 (calcitriol); urinary calcium, creatinine, calcium/creatinine ratio in spot and 24-h urine and urinary alpha(1)-microglobulin. A group of 304 patients with chronic plaque psoriasis, covering between 7% and 20% of the body surface area was included for the initial treatment phase of 3 months. Of the 257 patients who completed the initial 3 months, 197 patients continued in a second treatment phase of 15 months. RESULTS: Tacalcitol treatment proved to be effective in reducing the severity of psoriasis and maintained therapeutic response over the study period. The median PASI fell from 9.5 to 4 .6 at month 3 and to 3.25 at month 18 (P < 0.0001). The median improvement in TBI was 30% at month 3 and 50% at month 18. In no patient was there any relevant disturbance of calcium homeostasis. There were no significant changes in mean values of serum calcium, parathyroid hormone and calcitriol. Additionally no significant changes in 24-h urinary excretion evaluation were observed. There was no correlation between levels of serum calcium or urinary calcium and amount of tacalcitol ointment used, even in the patients requiring the largest amounts of ointment (up to 13 g day(-1) and up to 20% of body area affected). Treatment was generally well tolerated and there were no serious or unexpected adverse events reported. However, discontinuation of treatment as a result of skin irritation was seen in 5.9% of patients. The greatest frequency of cutaneous side-effects occurred during initial treatment and the incidence decreased markedly as the treatment was well-tolerated with continued use. CONCLUSIONS: Tacalcitol ointment once daily was demonstrated to be efficacious, safe and well tolerated in the long-term control of plaque psoriasis in patients with up to 20% body surface involvement.

Phototherapy of photodermatoses.

Phototherapy and photochemotherapy (PUVA therapy) have revolutionized the treatment of many photodermatoses and can offer photosensitive patients an improved quality of life. This is especially the case for polymorphic light eruption, chronic actinic dermatitis, erythropoietic protoporphyria and solar urticaria.

The diagnosis of photosensitivity.

Many photosensitive patients are seen for consultation when they have no lesions, so a detailed history is important. The differential diagnosis is based on the age at which the symptoms first occurred. The striking symptoms and signs are discussed, and advice is given on which additional investigations are necessary and when phototesting must be performed. Guidelines are also given for the performance of phototesting with simple light sources.

Photo(chemo)therapy in private practice in Belgium, France and The Netherlands.

Photo(chemo)therapy is used widely, and ultraviolet (UV) sources, protocols and indications are numerous. A survey was carried out to examine how photo(chemo)therapy is employed in private practice and to determine whether safety guidelines are respected. A questionnaire survey sent to Belgian, French and Dutch dermatologists generated 593 useful responses. UV sources, doses of UV and 8-methoxypsoralen (8-MOP), as well as the frequency of the treatment, were all different in the three countries. UV starting doses were rarely chosen according to the minimal phototoxic dose (MPD) or to the minimal erythema dose (MED). Total cumulative UV doses were not always determined. Maintenance PUVA therapy for psoriasis was still performed by 15 to 40% of dermatologists in the respective countries. Another striking fact was that genital protection is not universal. On the other hand, the irradiance of tubes is checked regularly, and contraindications are respected. Despite the availability of guidelines, clinicians seem to be inconstant in their assessment of the carcinogenic risk of UV radiation.

Skin photosensitization with topical hypericin in hairless mice.

Hypericin, a naturally occurring photosensitizer, exhibits interesting in vitro photobiological activities, which suggest that the compound is a potential antipsoriatic agent. In this study, the possibility of hypericin penetrating the skin in photo-active concentrations has been studied. Hypericin is incorporated in either emulsifying ointment supplemented with solketal (hypericin content: 0.05%) or in polyethylene glycol (PEG) ointment (hypericin content: 0.5%) and applied to the skin of hairless mice for 4 h. After removing excess ointment, the mice are then irradiated with different light doses using a 500 W halogen lamp. As a positive control, intraperitoneally (i.p.) administered hypericin (10 and 40 mg/kg) has also been tested. Erythema, desquamation and erosions are demonstrated in the mice treated with hypericin in emulsifying ointment with solketal using a light dose of at least 4.5 J/cm2. In general, these reactions correlate well with those of i.p. administered hypericin (40 mg/kg), indicating that hypericin incorporated in emulsifying ointment with solketal is well absorbed by the skin of the mice. However, for the i.p. administered hypericin (40 mg/kg), we could not evaluate phototoxic reactions in the group of animals that received a light dose of 108 J/cm2, as they all died 12-24 h after irradiation, indicating extreme photosensitization with systemic hypericin at higher light doses. On the contrary, there is no measurable skin photosensitivity induced by hypericin when incorporated in PEG ointment or when 10 mg/kg hypericin is i.p. administered. Our results show that hypericin incorporated in a suitable vehicle can be delivered to the skin in photo-active concentrations. Using a vehicle such as emulsifying ointment with solketal, it will be possible to explore the photo-activity of hypericin in the treatment of psoriasis and other skin diseases.

Solar urticaria. A report of 25 cases and difficulties in phototesting.

BACKGROUND: Solar urticaria is a rare photosensitive disease, and its differential diagnosis with respect to polymorphous light eruption is sometimes difficult. We report our experience with 25 cases of solar urticaria and discuss the pitfalls in phototesting such patients. OBSERVATION: The most important locations in this patient series are the V of the neck and the arms, which are similar to those of polymorphous light eruption. In all of the patients, however, the lesions appeared within 30 minutes of sun exposure or phototesting and disappeared within 24 hours. Notably, 12 (48%) of the patients had a history of atopy. Phototesting helps confirm the diagnosis, but, in some patients, this was difficult. CONCLUSIONS: A negative phototest result from a single light source does not necessarily exclude a diagnosis of solar urticaria. In patients in whom phototesting elicits negative reactions, other light sources should be used, and, if the phototest result is still negative, a provocative test with natural sunlight should be done. Histamine1-receptor antihistamines are a useful first-line therapy, although more severely affected persons may require prophylactic courses of phototherapy or photochemotherapy. The main problem is maintenance treatment.

Photo(chemo)therapy and general management of erythropoietic protoporphyria.

Erythropoietic protoporphyria is an autosomal dominant or autosomal recessive photodermatosis characterized by a deficiency of the enzyme ferrochelatase. The diagnosis is based on the very typical complaints of burning and pain on sun exposure and on increased protoporphyrin concentration in the red blood cells, the plasma and the feces. Different treatment modalities have been proposed. The treatment of choice has always been beta-carotene. For severe cases, PUVA treatment can be given three times a week until a total UVA dose of 120-200 J/cm2. In younger children, UVB phototherapy can be used if beta-carotene gives unsatisfactory therapeutic results. The irradiations are given four times a week until a total dose of 1-1.5 J/cm2 is reached.

Chronic actinic dermatitis.

Chronic actinic dermatitis (CAD) is one of the most frequently encountered photodermatoses in patients older than 50 years of age. It is characterized by persistent redness of the face and other exposed areas. CAD can become so severe that even nonexposed parts of the body develop eczematous lesions and the disease persists during winter. The diagnosis must be confirmed by phototests that show a broad action spectrum with low threshold doses. CAD must be differentiated from photocontact allergy and airborne dermatitis. The histopathologic features in the early stages are comparable to contact dermatitis, whereas in the later stages they may be those of pseudolymphoma. The most popular treatments are azathioprine and PUVA.

The relative importance of the components used for ultraviolet A protection in broad-spectrum sunscreens.

The need for effective ultraviolet A (UVA) protection is increasing. Broad-spectrum sunscreens are being used to protect the skin against aging and in the treatment of photodermatoses, where UVA protection can be vital. They are also used by patients taking photosensitizing drugs, such as 8-methoxypsoralen, to protect their skin against solar UVA. This raises the question of what components in broad-spectrum sunscreens are the most necessary for optimal UVA protection. In the present study, the components that can be used are compared and evaluated using an animal method with the inhibition of skin edema induced by 8-methoxypsoralen plus UVA as the biological end point. The results of this method indicate that powders do not provide any significant UVA protection. This could be due to the use of 8-methoxypsoralen in the test so that particularly the shorter UVA range is evaluated. Powders reflect mainly the longer UVA wavelengths. The UVA protection as measured with this method seems to be similar for the benzophenone derivative and for the dibenzoylmethane derivative. The UVA protection factors obtained are compared with those obtained in human skin using phototoxic erythema and UVA-induced tanning as parameters.