Methoxsalen

Oral Aminolevulinic Acid Induces Protoporphyrin IX Fluorescence in Psoriatic Plaques and Peripheral Blood Cells^(par)

ABSTRACT

Photodynamic therapy (PDT) with topical aminolevulinic acid (ALA) has been shown in previous studies to improve psoriasis. However, topical ALA-PDT may not be practical for the treatment of extensive disease. In order to overcome this limitation we have explored the potential use of oral ALA administration in psoriatic patients. Twelve patients with plaque psoriasis received a single oral ALA dose of 10, 20 or 30 mg/kg followed by measurement of protoporphyrin IX (PpIX) fluorescence in the skin and circulating blood cells. Skin PpIX levels were determined over time after ALA administration by the quantification of the 635 nm PpIX emission peak with in vivo fluorescence spectroscopy under 442 nm laser excitation. Administration of ALA at 20 and 30 mg/kg induced preferential accumulation of PpIX in psoriatic as opposed to adjacent normal skin. Peak fluorescence intensity in psoriatic and normal skin occurred between 3 and 5 h after the administration of 20 and 30 mg/kg, respectively. Ratios of up to 10 for PpIX fluorescence between psoriatic versus normal skin were obtained at the 30 mg/kg dose of ALA. Visible PpIX fluorescence was also observed on normal facial skin, and nonspecific skin photosensitivity occurred only in patients who received the 20 or 30 mg/kg doses. PpIX fluorescence intensity was measured in circulating blood cells by flow cytometry. PpIX fluorescence was higher in monocytes and neutrophils as compared to CD4+ and CD8+ T lymphocytes. PpIX levels in these cells were higher in patients who received higher ALA doses and peaked between 4 and 8 h after administration of ALA. There was only a modest increase in PpIX levels in circulating CD4+ and CD8+ T lymphocytes. In conclusion oral administration of ALA induced preferential accumulation of PpIX in psoriatic plaques as compared to adjacent normal skin suggesting

that PDT with oral ALA should be further explored for the treatment of psoriasis.

^^Abbreviations: ALA, aminolevulinic acid; ALT, alanine amino transaminase; AP, alkaline phosphatase; AST, aspartate amino transaminase; FITC, fluorescein isothiocyanate; GGT, y-glutamyl transferase; LDH, lactate dehydrogenase; MPD, minimal phototoxic dose; PDT, photodynamic therapy; PE, phycoerythrin; PpIX, protoporphyrin IX; PUVA, psoralen and ultraviolet A.

INTRODUCTION

Photodynamic therapy (PDT)^^ is a therapeutic modality that combines the sequential administration of a photosensitizer followed by its activation by light. Psoriasis is a common skin disorder characterized by elevated, erythematous and scaly plaques. Psoriasis can be improved by psoralen and ultraviolet A (PUVA) therapy; however, PUVA therapy is carcinogenic and has been associated with an increased risk of developing skin cancer (1,2). Clinical improvement in psoriatic plaques has been reported following PDT with intravenous photosensitizers such as hematoporphyrin derivative (3), porfimer sodium, verteporfin (benzoporphyrin derivative) (4) and tin-protoporphyrin (5). Aminolevulinic acid (ALA) is a photosensitizer precursor that is metabolized in vivo by cells to protoporphyrin IX (PpIX) which in turn can be activated for PDT by visible light. Topical PDT with ALA has been shown to improve and even clear selected psoriatic plaques after activation with red light (6,7). However, topical ALA is associated with a number of limitations, including inhomogeneous penetration of ALA through the stratum corneum as well as impracticality of treating larger skin surfaces such as in extensive psoriasis. In order to circumvent these limitations we have investigated oral administration of ALA to psoriatic patients. The objectives of this initial study were to evaluate PpIX accumulation in the skin and peripheral blood cells of psoriatic patients after oral ALA in order to determine the pharmacokinetic profile for eventual drug and light dosimetry and timing.

In conclusion, oral administration of ALA to psoriatic patients induced a preferential accumulation of PpIX in psoriatic plaques as compared to adjacent normal skin. Knowledge gained with this study suggests that for further development in the treatment of psoriasis lower oral ALA doses such as 10 or 20 mg/kg should be selected particularly if multiple drug and light exposures are involved. The elevated level of PpIX fluorescence observed on the face also suggests that if whole body exposures are to be performed the face should be covered. The preferential accumulation of PpIX in psoriatic skin suggests that oral ALA-PDT should be further explored for the treatment of psoriasis.

Acknowledgements-We would like to thank Mike Gagel, Sharon Kim and Gilles Viau for their assistance. The help and comments of Drs. Stuart Marcus and Allyn Golub in designing the protocol are greatly appreciated. Expert technical assistance in flow cytometry experiments was provided by Jinghai Sun and Denise McDougal. Dr. Ralph Durand gave helpful advice on the flow cytometry procedure. This study was funded by a research grant from DUSA Pharmaceuticals.

(par)Posted on the website on 10 May 2001.

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Robert Bissonnette1, Haishan Zeng2, David I. McLean1, Mladen Korbelik2 and Harvey Lui*1

1Division of Dermatology, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada and 2Department of Cancer Imaging, British Columbia Cancer Agency, Vancouver Hospital & Health Sciences Centre and University of British Columbia, British Columbia, Canada

Received 11 December 2000; accepted 30 April 2001

*To whom correspondence should be addressed at: Division of Dermatology, University of British Columbia, 835 West 10th Avenue, Vancouver, British Columbia, Canada VSZ 4E8. Fax: 604-873-- 9919; e-mail: hlui@interchange.ubc.ca

^This work was presented in an abstract form at the 7th International Photodynamic Therapy Association meeting, Nantes, 1998.

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