liposomes in combination with ultraviolet light therapy
Jaap de Leeuw, Nick van der Beek, Günther Maierhofer, Wolfgang-Dieter Neugebauer
European Journal of Dermatology 2003; 13: 474-477.
abstract
Vitiligo destroys the melanocytes in the epidermis; the inactive melanocytes in the outer root sheaths are not affected. Phosphatidylcholine liposomes are able to target molecules contained in them into the hair follicles. Khellin is activated by UVA and previous studies have shown that a combination of khellin and UVA (KUVA) can be effective in the treatment of vitiligo. The aim of this study was to determine in an open trial the efficacy and safety of treatment with khellin encapsulated in L-phenylalanine stabilized phosphatidylcholine liposomes in combination with UVA/
UVB light therapy(KPLUV) in74 subjects with vitiligo. After a mean treatment period of 12 months (range 10-14 months) 72% of the treated locations had a repigmentation response of 50% to 100%. Repigmentation of 75-100% was achieved on the face in 63%, the back in 59%, the arms in 58%, the trunk in 57%, the legs in 56% and on the hands in 4% of the patients.Side effects were not seen with KPLUV. The patients in the control group, only treated with UVA/B - light, hardly showed any repigmentation (Figure 2). This indicates that the exposure of the skin to UV light alone is not responsible for the results of KPLUV.
Introduction
Vitiligo, an acquired depigmention disorder affecting about 1% of the population,1, 2 may be a psychosocial disaster, particular in people with pigmented skin, especially in those countries where there is confusion of vitiligo with leprosy in the public mind.3 Vitiligo is histologically characterized by the absence of melanocytes in the epidermis.
Inactive melanocytes in the outer root sheaths of the hair follicles are not affected.
During the process of repigmentation, these inactive melanocytes proliferate and mature to an active condition as they migrate into the epidermis.4
Therapeutic approaches are aimed at reversing the progressive loss of melanocytes and reconstituting normal skin coloration, but none is uniformly effective and side effects may occur. Most common treatments are topical corticosteroids, systemic and topical PUVA, broad- and narrowband UVB, systemic and topical L-phenylalanine with UVA (PAUVA)5-9, systemic and topical khellin with UVA (KUVA).10-14 Surgical treatment is limited to small and stable vitiligo maculae.1
Khellin, a furanochromone with a chemical structure closely resembling that of the psoralen family, is activated by UVA (365 nm).10
Liposomes are small vesicles of membrane lipids. They can be used as microscopic carrier capsules for selective delivery of drugs into a specific disease site.
Phosphatidylcholine-based liposomes have a high potential for selectively targeting molecules contained in them into the hair follicles.15, 16, 17 Encapsulating khellin in phosphatidylcholine liposomes may enhance the penetration of khellin into the area of the inactive melanocytes in the hair follicle in order to provide optimal availability of khellin to stimulate the inactive melanocytes. L-phenylalanine is added to the formula in order to promote the stability of the solution. L-phenylalanine was also chosen because of its reputation to be effective, both orally and topically, together with UVA therapy in the treatment of vitiligo.8, 9 Schallreuter has suggested that oxidative stress plays a role in the pathomechanism of vitiligo18 and because L-phenylalanine has anti-oxidant properties this may be the way it works.19 The Arimed B light source has a UV spectrum approximating that of sunlight (approximately UVB 5% and UVA 95%). It can be argued that such a simulated sunlight source represents a more cautious approach to home therapy than conventional broad spectrum UVB therapy.20 The advantage of home therapy is that the high social and economic costs of hospital visits are reduced. The disadvantage of home therapy is that medical supervision is less frequent.
In this open, retrospective study the efficacy of topical treatment of vitiligo with khellin encapsulated in L-phenylalanine stabilized phosphatidylcholine liposomes in combination with ultraviolet light therapy (KPLUV) as home phototherapy is determined.
Subjects and methods
65 patients (50 females and 15 males) with vitiligo vulgaris and 9 patients (5 females and 4 males) with vitiligo universalis were included in the study. The average age was 43 years (range 12-75 years). Mean duration of vitiligo was 15 years (range 4-60 years). All patients had been treated before with topically applied
corticosteroids, 48 patients also with PUVA and 18 patients with broadband-UVB, without notable repigmentation. Exclusion criteria were phenylketonuria, pregnancy and breastfeeding, impaired hepatic and renal functions, malignant skin diseases, history of exposure to arsenates or ionizing radiation and photo-induced diseases.
The patients were instructed to apply twice a day, in the morning and half an hour prior to the UVA therapy, a spray containing khellin in a concentration of 0.005%
encapsulated in phosphatidylcholine liposomes, stabilized with L-phenylalanine 0.1%. The light source (Arimed B Cosmedico, Stuttgart, Germany) has a spectrum from 295 to 400 nm and peak emissions at 317 and 356 nm. The phototreatment schedule started with one minute daily 5 times a week raising the exposure time by one minute every week until the erythematic dose was reached. The treatment was continued with the suberythema dose. The exposure time was never more than l5 minutes. The light source was given to the patients for treatment at home as a panel and not as a booth in order to save space, so that patients with vitiligo on the frontal and dorsal parts of the body underwent two exposures. As soon as a marked improvement was achieved, the treatment schedule was reduced from 5 times a week to 3 times a week.
This study is a case-study and not a placebo-controlled, randomized study. The control group consisting of 30 patients used the same UVA/B light source (Arimed B Cosmedico), with the same photo treatment schedule, but not in combination with the application of the khellin and phenylalanine containing liposomal solution. The liposomal vehicle of the spray has an absorption spectrum from 190- to 210-nm.
This is out of the range of the emission spectrum of the used UVA/B light source, excluding the need to use the vehicle in the control group. Photographs (Fotofinder, TeachScreen Software GmbH, Germany) of the subjects were taken at the beginning of the therapy and than once every two months for one year. The extent of repigmentation was recorded by visual comparison of the successive photographs, making use of planimetry.
The before-and-after evaluation was performed by 2 experienced clinicians, who did not know whether the patients were treated with UVA/B light therapy in combination with topical liposomal solutions (study group) or with UVA/B as monotherapy (control group).
Results
After a mean treatment period of 12 months (range 10 to 14 months) 72% of treated locations had a repigmentation response of 50% to 100%. The repigmentation was not equal for different parts of the body. Repigmentation of more than 50% was achieved on the face in 79%, the trunk in 73%, the arms in 76%, the legs in 70%, and on the hands in 65%. Repigmentation of 75%-100% was achieved in the face
in 63%, the arms in 58%, the trunk in 73%, the legs in 56% and the hands in 4%
(Figure1). Surprisingly eight out of the nine patients (88%) with vitiligo universalis showed a repigmentation of more than 75%. The patients in the control group treated with only Uvlight (Arimed B), without the use of the khellin spray, hardly showed any repigmentation (Figure 2).
Mean cummulative annual Joules doses of UVA 679 J/cm2 and of UVB 25.9 J/cm2 (table 1).
Discussion
The treatment of vitiligo can be frustrating to patients and doctors. A standard modality that cures every patient does not yet exist.1, 2 Topical corticosteroids, topical- and systemic PUVA, broad- and narrow-band UVB light therapy are the most common methods, although they are not always effective and side effects may limit the therapeutic options.5-9 Narrow-band UVB is effective in the treatment of vitiligo. An overall repigmentation of 75% in 53% of the patients and a stabilization of the disease in 80% has been seen.21 But not all investigators came to the same conclusion.22 Surgical treatment is limited to small and stable vitiligo maculae.1 The results of systemic khellin in combination with UVA11-14 are comparable to the rates reported from psoralen phototherapy.1 The major advantage of khellin is that it does not induce phototoxic skin erythema and it does not induce detectable DNA mutations in contrast to PUVA.11,12 Ortel et al. studied the effect of oral khellin in combination with UVA light in 26 patients. A repigmentation of more than 70%
was achieved in 41 % of the patients who had received 100 to 200 treatments.
A mild elevation of liver transaminases was observed in 28% of the patients on oral treatment. Of three patients who were treated with topical khellin and UVA, two patients had a repigmentation of only 30%.12 In our study with topically administered khellin in liposomes, a repigmentation between 50% and 100% was seen in 72% of the patients. Hofer et al. performed a study to assess the effectiveness and short-term and long-term safety of oral khellin plus UVA light therapy (KUVA) in patients with vitiligo. Of 17 patients, 41 % had a response of more than 70% repigmentation after a mean of 194 treatments. Short term side effects were episodes of nausea in 29% of the patients, elevated liver enzymes in 7% and gastritis in 7% of the patients.
Long-term side effects have not been seen, no skin cancer or actinic damage of vitiliginous skin was found in any patient. Their data indicate that KUVA seems to be safe as well as effective for vitiligo, provided treatment is administered long enough.13 Orecchia et al. concluded from their study that topically applied khellin is effective in the treatment of vitiligo, but that the results are vehicle dependant.14 A potential concern is the hepatotoxic side effect of khellin. The low active ingredient concentration of 0.005% khellin in the topically applied spray would tend to exclude