A review of photodynamic therapy in cutaneous leishmaniasis

We present a review of six clinical studies investigating the use of photodynamic therapy (PDT) using porphyrin precursors for the treatment of Old World cutaneous leishmaniasis (CL). Thirty-nine patients with a total of 77 lesions received PDT using a range of treatment schedules following topical application of aminolevulinic acid (ALA) or methyl-aminolevulinate (MAL). The tissue response to PDT is accompanied by a mild burning sensation, erythema and reversible hypo- and hyperpigmentation. Few mechanistic studies have addressed the principles underlying the use of PDT for CL. All six reviewed papers suggest that PDT with porphyrin precursors is relatively effective in treating CL. Data are still limited, and PDT cannot at this point be recommended in routine clinical practice. The mechanism of action of this promising therapeutic modality needs to investigated further and additional controlled trials need to be performed.     

Laser-mediated photodynamic therapy

Photodynamic therapy (PDT) has evolved since its inception at the beginning of the 20th century, when it was defined as an oxygen-dependent reaction between a photosensitizing dye and light. Photosensitizers and light sources have since been continually optimized for distinct applications and tissues. Systemic porphyrins, such as hematoporphyrin, were the first photosensitizers to be used, mostly to treat tumors. The first light sources used were broad-band, noncoherent lights, such as quartz, xenon, tungsten, or halogen lamps. The wavelengths of light chosen were based upon the absorption spectrum of porphyrins: blue because the largest peak is at 400 nm (the Soret band) and red because of its greater penetration depth but lesser absorption at 650 nm (a Q band). Systemic photosensitizers caused prolonged photosensitivity, and broad-band light sources had limitations and side effects. The development of topical photosensitizers, such as 5-aminolevulinic acid, and the advent of lasers in recent years have advanced PDT for cutaneous use. In the 1990s, red lasers were applied to PDT because of their increased skin penetration despite lesser absorption by porphyrins. Broad-band blue light and red light have been studied extensively, the former achieving Food and Drug Administration approval in combination with topical aminolevulinic acid for the treatment of actinic keratosis in 1997. These lasers and light sources caused significant side effects, such as discomfort, erythema, crusting, blistering, and dyspigmentation. The recent application of the long-pulsed pulsed dye laser (595 nm) after topical aminolevulinic acid greatly minimized side effects without compromising efficacy. Long-pulsed pulsed dye laser-mediated PDT has since been shown to be effective in treatment of actinic keratosis, actinic cheilitis, sebaceous hyperplasia, lichen sclerosus, and, most recently, acne vulgaris. Finally, intense pulsed light sources have been introduced to PDT for the treatment of photodamage and acne, offering advantages of versatility in wavelengths and applications.     

Photodynamic Therapy in Dermatology – an Update 2008

Photodynamic therapy (PDT) is used for the prevention and treatment of non‐melanoma skin cancer. Until recently, clinically approved indications have been restricted to actinic keratoses, nodular and superficial basal cell carcinoma, and – since 2006 – Bowen disease. However, the range of indications has been expanding continuously. PDT is also used for the treatment of non‐malignant conditions such as acne vulgaris and leishmaniasis, as well as for treating premature skin aging due to sun exposure. Here, PDT is used for the stimulation of immunomodulatory effects in contrast to the induction of necrosis and apoptosis as produced in the treatment of skin tumors. The porphyrin precursor 5‐aminolevulinic acid (ALA) or its methyl ester (MAL, so far the only approved formulation in Europe) is applied topically as photosensitizer to exclude systemic reactions. Possible light sources include lasers as well as incoherent light sources; irradiation with incoherent light sources is cheaper and more appropriate for large treatment areas. The main advantages of PDT in comparison to other treatment modalities are its excellent cosmetic results and its high remission rates despite low invasiveness.This article provides up‐to‐date information about PDT with focus on recently published studies.     

The influence of the vehicle on the synthesis of porphyrins after topical application of 5-aminolaevulinic acid. Implications in cutaneous photodynamic sensitization

BACKGROUND: The optimal vehicle to ensure adequate penetration of 5-aminolaevulinic acid (ALA) for its use in photodynamic therapy (PDT) of skin lesions has not been determined. OBJECTIVES: We aimed to study the effects of ALA in various vehicle formulations [saline lotion with and without dimethylsulphoxide (DMSO), cream, liposomes and vaseline] after topical application in a murine subcutaneous adenocarcinoma model. METHODS: The effect of DMSO on porphyrin synthesis and ALA penetration through the skin was studied by measuring the uptake of 14C label from ALA, ALA and porphobilinogen accumulation, and some haem enzyme activities. The tissue distribution and kinetics of porphyrin synthesis after topical application of ALA entrapped in large multilamellar liposomes was also determined. RESULTS: ALA in saline lotion, alone or with 10% DMSO, proved to be the most efficient vehicle for tumour porphyrin accumulation (mean +/- SD 1.75 +/- 0.25 and 2.09 +/- 0.39 microg g-1, respectively), whereas cream and liposomes induced lower levels and identical porphyrin accumulation (0.60 microg g-1). Using ALA + DMSO saline lotion, a higher porphyrin accumulation was found in skin overlying the tumour tissue and in the first 2 mm of tumour, probably due to increased ALA penetration, or greater interconversion to porphyrins, or greater retention of ALA and/or porphyrins. CONCLUSIONS: These findings reinforce the importance of the vehicle in topical ALA-based PDT, and explain the mechanism of action of DMSO in enhancing protoporphyrin IX biosynthesis in superficial lesions.     

Efficacy of photodynamic therapy with topical 5‐aminolevulinic acid using intense pulsed light for Bowen’s disease

Photodynamic therapy (PDT) with topical 5‐aminolevulinic acid (ALA) is reported to be an effective and safe treatment for superficial non‐melanoma skin cancers. We have developed an photodynamic therapy with topical δ‐aminolevulinic acid (ALA‐PDT) protocol using intense pulsed light (IPL) for treating Bowen’s disease (BD). Three patients diagnosed with BD by skin biopsy were recruited in this study. They received IPL treatment after 3 h of occlusive dressing with application of ALA. This protocol was repeated every 2 weeks for a total of five sessions. The treated areas did not show any signs of BD for more than 1 year; therefore, it appeared that the affected areas showed improvement in all the patients. No patients withdrew from the study because of side‐effects. ALA‐PDT with IPL as a light source is well tolerated by patients and is beneficial for treating BD.     

δ-氨基酮戊酸光动力学疗法治疗皮肤病的研究进展

δ-氨基酮戊酸光动力学疗法是一种非创伤性局部治疗技术,可特异性杀死病变细胞.近年研究表明,该疗法对靶细胞某些生物学特征的影响是重要作用机制之一.除非色素细胞性皮肤恶性肿瘤外,δ-氨基酮戊酸光动力学疗法的适应症逐渐扩展至癌前病变、病毒疣、痤疮、结缔组织病、光化性疾病等范围.升高温度、促溶剂、金属离子螫合物、电离子导入、脂质体载体等因素可促进其疗效.     

Photodynamic therapy in dermatology

Photodynamic therapy (PDT) is a modern therapy modality, based upon the application of a photosensitizing agent like aminolevulinic acid, a physiological precursor of porphyrins, onto the tissue followed by illumination with light of the visible wavelength spectrum. During this oxygen‐dependent reaction, reactive oxygen species (ROS) are generated that have immunomodulatory or cytotoxic effects. PDT shows excellent cosmetic results especially for its key indication in dermatology – the treatment of non‐melanoma skin cancer. The associated pain and the low tissue penetration are the most frequent limiting factors of PDT. We review basic principles and recent developments in photosensitizers and light sources. Key oncological and non‐oncological indications are presented as well.     

Treatment of superficial basal cell carcinoma by topical photodynamic therapy with fractionated 5‐aminolaevulinic acid 20% vs. two‐stage topical methyl aminolaevulinate: results of a randomized controlled trial

Photodynamic therapy (PDT) is a frequently used treatment for a type of skin cancer called superficial basal cell carcinoma (sBCC). It works by using a cream called a porphyrin precursor, which is applied to the affected skin area and covered with a dressing. After several hours and after removing the occlusive dressing, the area is irradiated with intense visible light which causes the death of cancer cells. There are two porphyrin precursors available in the Netherlands, 5‐aminolevulinic acid 20% (ALA) and methylaminolevulinic acid (MAL). In conventional MAL PDT, skin receives one illumination (treatment with light) which is repeated one week later. In the case of ALA, skin receives two different illuminations, two hours apart. This is called fractionated ALA‐PDT. In this study, from the Netherlands, we investigated whether this fractionated ALA‐PDT is superior to conventional MAL‐PDT. 162 patients were randomly assigned to one of two groups. 82 patients were treated with fractionated ALA‐PDT and 80 patients with conventional MAL‐PDT. After 12 months a total of 6 treatment failures (recurrence of the sBCC) occurred after ALA‐PDT and 13 after MAL‐PDT. Although there were twice as many treatment failures in the MAL‐PDT group, this difference was not statistically significant. Secondly, we investigated pain scores in both treatment groups because PDT is known to cause a severe burning sensation. We found that ALA‐PDT resulted in more pain and side effects, such as erythema (skin redness, like sunburn), wounds/erosions and vesicles (small blisters) compared to MAL‐PDT. In conclusion, there is a trend toward better efficacy of ALA‐PDT compared to MAL‐PDT for the treatment of sBCC, although the difference was not significant.     

Photodynamic therapy for dermatologic conditions in the pediatric population: a literature review

Photodynamic therapy (PDT), using topical aminolevulinic acid (ALA), has been used for years to treat a variety of dermatologic conditions, including actinic keratosis, superficial basal cell carcinoma, and in situ squamous cell carcinoma. While there is a wide range of neoplastic and non‐neoplastic skin diseases for which ALA‐PDT is used in adults, there is a knowledge gap when it comes to its use in children. This review highlights what is currently known regarding the use and efficacy of this therapy in the pediatric population. A PubMed search was conducted to identify studies including pediatric patients undergoing monotherapy PDT with topical aminolevulinate (published 2005–2016). Twenty pediatric articles were identified. ALA‐PDT has been used successfully in children to reduce the number and size of basal cell tumors, inflammatory acne lesions, plantar warts, and linear porokeratoses. ALA ‐ PDT may be an attractive alternative to surgery for children with basal cell nevus syndrome, or to conventional destructive and/or topical methods used for plantar warts or linear porokeratoses. PDT can be considered for inflammatory acne when topical treatments have failed and systemic medications are not an option. Pain associated with treatment and insurance coverage may be a barrier to use.     

Therapeutic and immune effects of 5‐aminolevulinic acid photodynamic therapy on UVB‐induced squamous cell carcinomas in hairless mice

The therapeutic effects of 5‐aminolevulinic acid (ALA)‐mediated photodynamic therapy (PDT) on cutaneous squamous cell carcinoma (SCC) are not fully understood, and the usefulness of topical PDT in the treatment of SCC is still debatable. The most interesting aspect in SCC PDT is perhaps its potential in inducing antitumor immune responses. In this study, cutaneous SCCs were established by UVB irradiation of hairless mice and treated with multiple ALA PDT. Immunohistochemistry assays showed that ALA PDT could induce quick apoptosis, overexpression of TNFα and marked increases in DCs, CD4⁺ and CD8⁺ cells in tumor interstitium and subcutaneous connective tissues. However, a complete response was only achieved for small SCCs. The clinical value of ALA PDT‐induced specific antitumor immune responses in long‐term control of SCCs deserves further study.     

Photodynamic therapy in a teenage girl with xeroderma pigmentosum type C

Despite aggressive sun protection, most individuals with xeroderma pigmentosum (XP) develop cutaneous neoplasia, including actinic keratoses. We describe the case of a 16-year-old girl with XP type C treated safely with photodynamic therapy (PDT). Although there is little if any evidence in the literature supporting the use of aminolevulinic acid PDT in individuals with XP, they may be the ideal candidates for PDT treatment because the profound post-treatment photosensitivity and strict post-therapy sun avoidance necessitated by PDT treatment is already part of the everyday lifestyle of people with XP.     

Photodynamic therapy: a review of the literature and image documentation

Photodynamic therapy (PDT) consists of a chemical reaction activated by light energy that is used to selectively destroy tissue. The reaction requires a photosensitizer in the target tissue, a light source and oxygen. The most extensively studied photosensitizing agents for PDT are 5-aminolevulinic acid for the treatment of actinic keratosis and methyl-aminolevulinate, which has been approved for the treatment of actinic keratosis, basal cell carcinoma and Bowen's disease. The light sources used in photodynamic therapy should emit light at wavelengths within the absorption spectrum of the photosensitizer used in PDT treatment. Light emitting diode (LED) lamps are indicated for the photodynamic treatment of nonmelanoma skin cancer. PDT should be considered as a therapeutic option, particularly in the case of patients with superficial, multiple or disseminated lesions and for immunosuppressed patients. More recently, PDT has been indicated for a wide range of dermatological conditions such as photo-damaged skin, acne, hidradenitis, scleroderma, psoriasis, warts and leishmaniosis, among others. This article provides an extensive review of photodynamic therapy, its mechanisms, indications and results.     

Immunosuppressive effects of photodynamic therapy by topical aminolevulinic acid

Photodynamic therapy (PDT) has been used for inflammatory skin disorders as well as superficial skin cancers such as solar keratosis and Bowen's disease. Whether PDT with topical application of aminolevulinic acid (ALA) and exposure to visible light has a similar immunosuppressive action to ultraviolet phototherapy was investigated using a murine contact hypersensitivity (CHS) model. The number of epidermal Langerhans cells (LC) was decreased with their morphological changes 1 day after PDT with the minimal level at 5 days and gradual recovery thereafter. Conversely, the number of CD11c(+) I-A(+) cells was significantly increased in the draining lymph nodes after PDT. This suggests that LC moved from PDT-treated skin, resulting in the decrement of epidermal LC and migration to lymph nodes. CHS response to DNFB applied on the PDT-treated skin with 20% ALA and 40 J/cm(2) visible light was significantly suppressed (local immunosuppression). When mice were treated with 80 J/cm(2) of PDT, CHS response to the antigen applied on untreated distant skin was also significantly suppressed (systemic immunosuppression). The locally or systemically immunosuppressed mice by PDT were attempted to sensitize again with DNFB on non-treated skin, but elicitation responses were significantly suppressed. However, these mice were able to be sensitized with another hapten, oxasolone. Thus, a hapten-specific immunological unresponsiveness (tolerance) was induced in mice by topical ALA-PDT. These findings suggest that PDT has a potential immunological contribution to clinical efficacy for inflammatory diseases identical to ultraviolet phototherapies.     

Photodynamic therapy: treatment of choice for actinic cheilitis?

ABSTRACT: The major therapeutic approaches (5‐fluorouracil, imiquimod, vermilionectomy, and CO₂ Laser ablation) for actinic cheilitis are aimed at avoiding and preventing a malignant transformation into invasive squamous cell carcinoma via destruction/removal of the damaged epithelium. Recently, photodynamic therapy (PDT) has been introduced as a therapeutic modality for epithelial skin tumors, with good efficacy/safety profile and good cosmetic results. Regarding actinic cheilitis, PDT could be considered a new therapeutic option? The target of our study was to evaluate the efficacy and tolerability of PDT in actinic cheilitis, using a methyl‐ester of aminolevulinic acid (MAL) as topical photosensitizing agent and controlled the effects of the therapy for a 30‐month follow‐up period. MAL‐PDT seems to be the ideal treatment for actinic cheilitis and other actinic keratosis, especially on exposed parts such as the face, joining tolerability and clinical efficacy with an excellent cosmetic outcome.     

Photodynamic therapy: current evidence and applications in dermatology

Photodynamic therapy (PDT) involves the activation of a photosensitizing drug, which preferentially localizes to diseased skin, by irradiation with light to cause selective cytotoxic damage. Since its discovery in the early 20th century and the development of topical photosensitizers 2 decades ago, PDT is increasingly being used in dermatology for a wide range of neoplastic, inflammatory, and infectious cutaneous conditions. Topical 5-aminolevulinic acid and methyl aminolevulinic acid, the most commonly used agents in PDT, have received Food and Drug Administration approval for the treatment of actinic keratoses, and many second-generation photosensitizers are under investigation. Compared with conventional therapies, PDT has the advantage of being noninvasive and capable of field treatment. It is also associated with quicker recovery periods and excellent cosmetic results. Because of these benefits, PDT is being evaluated as a potential treatment option for many dermatologic conditions and has been shown to be effective for certain nonmelanoma skin cancers. Although research is still limited, PDT might also have a therapeutic benefit for cutaneous T-cell lymphoma, acne, psoriasis, leishmaniasis, and warts, among others. This article is a review of the clinical applications of PDT in dermatology and summarizes the current evidence in literature describing its efficacy, safety, and cosmetic outcome.     

5-氨基酮戊酸光动力学疗法在皮肤科的应用进展

探讨5-氨基酮戊酸（ALA）光动力学疗法（PDT）治疗皮肤病的作用原理及应用范围，为临床合理使用ALA—PDT提供参考依据。对近lO余年来文献报道的有关PDT研究进展及其临床应用的文献进行总结和分析，综述ALA．PDT治疗各类皮肤病的作用原理和机制，以及ALA．PDT治疗皮肤病的范围，所引起的不良反应。PDT对皮肤肿瘤、红斑鳞屑性皮肤病、人乳头瘤病毒（HPV）感染性皮肤病、痤疮、鲜红斑痣等均有良好的临床效果，不良反应相对较小，在皮肤科有很大的应用前景。     

Systemic photodynamic therapy with aminolevulinic acid induces apoptosis in lesional T lymphocytes of psoriatic plaques

Photodynamic therapy (PDT) is a recently approved treatment modality that involves the sequential administration of a photosensitizer or its precursor and light to generate singlet oxygen for treating diseased tissue. The use of topical aminolevulinic acid (ALA) and blue light for nonhypertrophic actinic keratoses currently represents the only approved dermatologic application for PDT in the U.S.A. ALA is a photosensitizer precursor that is metabolized by cells into protoporphyrin IX (PpIX), which can be subsequently activated by visible light. PDT with topical ALA has been shown to improve psoriasis, but post-treatment hyperpigmentation as well as inconsistent clinical responses despite repeated PDT sessions have limited the development of this treatment approach for psoriasis. Furthermore the use of topical PDT photosensitizers becomes somewhat impractical for treating larger body surface areas in patients with extensive psoriasis. We have recently shown that oral administration of ALA induces preferential accumulation of PpIX in psoriatic plaques. The objectives of this study were to evaluate the effects of PDT with blue light on psoriatic plaques after systemic ALA administration as well as to determine whether systemic ALA-PDT induces apoptosis in lesional T lymphocytes. It has been suggested that induction of apoptosis in lesional T lymphocytes may be indicative of longer remission time following treatment of psoriasis.     

Topical ALA-photodynamic therapy for the treatment of acne vulgaris

Topical aminolevulinic acid is converted into a potent photosensitizer, protoporphyrin, in human hair follicles and sebaceous glands. Photodynamic therapy with topical aminolevulinic acid was tested for the treatment of acne vulgaris, in an open-label prospective human study. Each of 22 subjects with acne on the back was treated in four sites with aminolevulinic acid plus red light, aminolevulinic acid alone, light alone, and untreated control. Half of the subjects were treated once; half were treated four times. Twenty percent topical aminolevulinic acid was applied with 3 h occlusion, and 150 J per cm2 broad-band light (550-700 nm) was given. Sebum excretion rate and auto-fluorescence from follicular bacteria were measured before, and 2, 3, 10, and 20 wk after, treatment. Histologic changes and protoporphyrin synthesis in pilosebaceous units were observed from skin biopsies. Aminolevulinic acid plus red light caused a transient acne-like folliculitis. Sebum excretion was eliminated for several weeks, and decreased for 20 wk after photodynamic therapy; multiple treatments caused greater suppression of sebum. Bacterial porphyrin fluorescence was also suppressed by photodynamic therapy. On histology, sebaceous glands showed acute damage and were smaller 20 wk after photodynamic therapy. There was clinical and statistically significant clearance of inflammatory acne by aminolevulinic acid plus red light, for at least 20 wk after multiple treatments and 10 wk after a single treatment. Transient hyperpigmentation, superficial exfoliation, and crusting were observed, which cleared without scarring. Topical aminolevulinic acid plus red light is an effective treatment of acne vulgaris, associated with significant side-effects. Aminolevulinic acid plus red light causes phototoxicity to sebaceous follicles, prolonged suppression of sebaceous gland function, and apparent decrease in follicular bacteria after photodynamic therapy. Potentially, aminolevulinic acid plus red light may be useful for some patients with acne.     

A case of pediatric lymphomatoid papulosis treated with photodynamic therapy and narrowband ultraviolet B

We report a case of a 13-year-old boy with extensive lymphomatoid papulosis (LyP) involving his elbows, forearms, proximal thighs, and right hip, with treatment-resistant nodules on his right forearm. He was treated with full-body narrowband ultraviolet B and targeted photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA). After two months, there was complete resolution of the right forearm nodules. Due to its minimal toxicity, PDT offers unique advantages and may be considered for pediatric LyP patients with symptomatic, localized disease resistant to conventional treatments.