Topical Application Of 5-aminolevulinic Acid Research Articles

In Vivo Quantification of the Effectiveness of Topical Low-Dose Photodynamic Therapy in Wound Healing Using Two-Photon Microscopy.

The effect of low-dose photodynamic therapy on in vivo wound healing with topical application of 5-aminolevulinic acid and methylene blue was investigated using an animal model for two laser radiation doses (1 and 4 J/cm2). A second-harmonic-generation-to-auto-fluorescence aging index of the dermis (SAAID) was analyzed by two-photon microscopy. SAAID measured at 60–80 μm depths was shown to be a suitable quantitative parameter to monitor wound healing. A comparison of SAAID in healthy and wound tissues during phototherapy showed that both light doses were effective for wound healing; however, healing was better at a dose of 4 J/cm2.

Effects of pretreatment with calcipotriol on protoporphyrin IX content in the normal epithelium of nude mice after topical application of aminolevulinic acid

Objective To evaluate the effect of pretreatment with calcipotriol on protoporphyrin IX (PpIX) content in the normal epithelium of nude mice after topical application of aminolevulinic acid (ALA) . Methods A total of 36 BALB/C nude mice were randomly and equally divided into 2 groups: calcipotriol + ALA group topically pretreated with calcipotriol ointment for 3 days followed by topical application of ALA, and ALA group topically treated with ALA alone. At 2, 3, 4, 5, 6 and 7 hours after ALA application, 3 mice in each group were sacrificed separately, and skin tissues were obtained from the experimental region in the back of mice. A fluorospectrophotometer was used to detect the PpIX content in the normal epithelial tissue of the nude mice, and an inverted fluorescence phase-contrast microscope to observe the fluorescence intensity and distribution of PpIX in the frozen sections of epithelial tissues. Results During 2 - 8 hours after topical application of ALA, the content of PpIX in the skin tissues of nude mice in the two groups gradually increased over time. Correlation analysis revealed no correlations between the PpIX content in the ALA group and the treatment duration (r = 0.451, P = 0.369) , while the PpIX content in the calcipotriol + ALA group was strongly correlated with the treatment duration (r = 0.913, P = 0.011) . The PpIX content in the ALA group reached a peak at 5 hours [ (461.24 ± 43.45) ng/g tissues], while the PpIX content in the calcipotriol + ALA group peaked at 6 hours [ (668.88 ± 42.46) ng/g tissues]. At 2, 3, 4, 5, 6 and 7 hours after ALA application, the PpIX content was significantly higher in the calcipotriol + ALA group than in the ALA group (P < 0.05 or 0.01) . Frozen-section examination showed that PpIX was diffusely distributed in the epidermis and dermis of the nude mice, and the fluorescence intensity of PpIX was higher in the calcipotriol + ALA group than in the ALA group at 5, 6 and 7 hours after ALA application. Conclusion Pretreatment with calcipotriol can increase the content of PpIX in the normal epidermis and dermis of nude mice after topical application of ALA, which provides a theoretical basis for the clinical application of calcipotriol as a local synergist of ALA-PDT. Key words: Photochemotherapy; Cholecalciferol; Aminolevulinic acid; Protoporphyrins; Disease models, animal; Calcipotriol

Rheological characterization and permeation behavior of poloxamer 407-based systems containing 5-aminolevulinic acid for potential application in photodynamic therapy

Topical application of 5-aminolevulinic acid (ALA) in photodynamic therapy is of great interest because of avoiding systemic side effects with such an easy way of application. However, due to ALA's high polarity its dermal bioavailability is rather limited and thus, permeation enhancement of this active is of major interest in research. In a previous study, a semisolid poloxamer 407-based (POX), five-component system ("thermogel") was developed for permeation enhancement of ALA across isolated human stratum corneum. In the present study, five-component systems of systematically varied compositions were investigated both rheologically and in terms of permeation enhancement. The five-component systems contained water, a fixed combination of 1:1 of isopropyl alcohol (IPA) and dimethyl isosorbide (DMIS) and a fixed ratio of 4:1 of POX to propylene glycol dicaprylocaprate (MIG). Rheological characterization showed that complex viscosity depended on IPA/DMIS and POX/MIG content. The gelation temperature (GT) was strongly influenced by interactions between MIG, IPA and DMIS. Regarding permeation behavior, several systems showing better permeation fluxes than the original "thermogel" were identified. Surprisingly, permeation flux did not inversely correlate with the complex viscosity, showing that permeation behavior may depend on a variety of further physicochemical characteristics including individual composition and microstructure of the respective formulation.

Topical application of 5-aminolevulinic acid followed by 595-nm pulsed dye laser irradiation for the treatment of recalcitrant port-wine stains: A primary study

Objective: To evaluate the effectiveness and safety of topical application of 5-aminolevulinic acid (ALA) followed by pulsed dye laser (PDL) irradiation for the treatment of recalcitrant port-wine stain (PWS). Methods: Thirty-five patients (19 females and 16 males) with recalcitrant PWS were treated with topical application of 20% ALA and then irradiated with a 595-nm PDL (energy density of 6.5–9.0 J/cm2 and pulse duration of 6 or 10 ms) at 6–8 weeks intervals. Clinical improvement of lesions was evaluated by comparing photographs of lesions at baseline and 2 months after the last treatment. Results: Topical ALA spreading followed by irradiation with a 595-nm PDL improved PWS in 21 out of 35 patients who were previously recalcitrant to PDL treatment alone. Side effects were limited to transient erythema, vesicle formation, edema and mild purpura with no obvious subsequent scarring or undesirable pigment changes. Conclusion: The topical application of ALA followed by irradiation with a 595-nm PDL is an effective and safe treatment for PWS recalcitrant to PDL therapy alone.

A randomized clinical comparative study of cryotherapy plus photodynamic therapy vs. cryotherapy in the treatment of multiple condylomata acuminata

Cryotherapy cannot destroy subclinical human papillomavirus-infected cells of condylomata acuminata (CA). The topical application of aminolevulinic acid (ALA) results in a shallow penetration depth in CA lesions (1). To compare the efficacy and safety of cryotherapy plus ALA-photodynamic therapy (PDT) with cryotherapy in the treatment of multiple CA. Eighty patients with multiple CA received cryotherapy plus ALA-PDT (n=40) or cryotherapy plus placebo-PDT (n=40). After cryotherapy, a 20% ALA or a placebo solution was applied to the CA area 3 h before illumination with red light (635 nm, 100 mW/cm(2) , 100 J/cm2). The treatment was repeated 7 days after the first treatment if the lesions were not completely resolved. The complete response rate, recurrence rate and adverse effects in the two groups were analyzed. After two treatments, the complete response rates in the combined group (cryotherapy plus ALA-PDT) and cryotherapy group were 32.4% (36/111) and 32.6% (43/132) in the anal area (P>0.05), 100% (32/32) and 54.5% (18/33) in the urethral meatus (P<0.05), and 94.2% (129/137) and 50.5% (56/111) in the external genitals (P<0.05), respectively. The recurrence rates in the combined group and cryotherapy group were 24.3% (27/111) and 31.1% (41/132) in the anal area (P>0.05), 9.4% (3/32) and 39.4% (13/33) in the urethral meatus (P<0.05), and 3.6% (5/137) and 31.5% (35/111) in the external genitals (P<0.05), respectively. The adverse effects in each group included mild to moderate pain, edema, erosion and hypopigmentation, without any infection, ulcers, scarring or urethral malformations. Cryotherapy plus ALA-PDT is a more effective regimen for the treatment of multiple CA compared with cryotherapy alone.

The Efficacy of Photodynamic Diagnosis in Defining the Lateral Border Between a Tumor and a Tumor-Free Area During Mohs Micrographic Surgery

Photodynamic diagnosis (PDD) is a preoperative procedure that simplifies Mohs micrographic surgery (MMS) by allowing more accurate demarcation of neoplastic lesions involving the skin. After topical application of aminolevulinic acid (ALA), protoporphyrin IX (PpIX) is selectively induced in neoplastic cells with a high tumor-to-surrounding tissue ratio and can be visualized after excitation using a Wood's lamp. To evaluate the efficacy of PpIX fluorescence images in accurately determining the boundaries of tumors during MMS. A retrospective evaluation of biopsy-proven basal cell carcinoma (BCC; n=163), squamous cell carcinoma (SCC; n=51), and Bowen's disease (n=8) in 222 patients treated with MMS was conducted. In the PDD group, 20% ALA ointment was applied 6 hours before the surgery, and then the boundaries were mapped based on the red fluorescence of the Wood's lamp in the operating room. Each of the PDD (n=142) and non-PDD (n=80) groups was surgically staged and compared. The average number of stages was 1.59, with more in the PDD group (1.66) than the non-PDD group (1.44) (p=.05). The average number of stages was 1.77 in the PDD group and 1.50 in the non-PDD group (p=.06) for BCC, was 1.40 in the PDD group and 1.37 in the non-PDD group (p=.90) for SCC, and 1.25 in the PDD group and 1.00 in the non-PDD group (p=.36) for Bowen's disease. In previous studies, the fluorescence of induced porphyrins was effective in detecting and delineating neoplastic skin areas, but, in the present study, PDD did not support surgical efficacy during MMS.

CLINICAL RESPONSES TO TOPICAL PHOTODYNAMIC THERAPY OF ACTINIC KERATOSES, BOWEN'S DISEASE AND NON-ONCOLOGICAL DISEASES IN JAPAN

Background: Photodynamic therapy (PDT) is a novel noninvasive dermatological therapy that has been used together with topical application of 5-aminolevulinic acid (ALA) to treat non-melanoma skin cancers and non-oncological diseases. Multicenter randomized controlled studies have now demonstrated high efficacy of PDT in actinic keratoses and Bowen’s disease. However, it seemed possible that topical PDT would be less effective in brown-skinned individuals, including Japanese, than in white Caucasians.Aim: Establish a standard treatment modality of ALA-PDT in Japanese patients in order to evaluate and improve the effects of PDT in the treatment of actinic keratoses and Bowen’s disease.Materials: A total of 152 lesions of actinic keratoses and 48 lesions of Bowen’s disease in Japanese patients were treated with ALA-PDT using our protocol.Methods: Lesions were treated in three sessions, one week apart, with 50J/cm2 irradiation in each session for a total dose of 150J/cm2 in actinic keratoses, and 100J/cm2 irradiation in each session for a total dose of 300J/cm2 in Bowen’s disease.Results: We achieved overall complete response rates of 81.6% (124/152 lesions) in total actinic keratoses, especially 87.2% (109/125 lesions) for lesions on the face/scalp, and 75.0 % (36/48 lesions) in Bowen’s disease, especially 88.9% (8/9 lesions) for lesions on the trunk. We have also treated non-oncological diseases, such as recalcitrant warts, cutaneous sarcoidosis and other diseases with ALA-PDT with satisfactory outcomes.Conclusions: The ALA-PDT according to our protocol was very successful in the treatment of Japanese patients with actinic keratoses or Bowen’s disease. A therapeutical benefit of PDT is evident in inflammatory and other dermatoses.

Photodynamic therapy using topically applied 5-aminolevulinic acid for treatment of cervical cancer

Objective: The purpose of this study was to investigate the treatment effects of a topical application of 5-aminolevulinic acid (5-ALA) for photodynamic therapy (PDT) to treat cervical cancer. Methods: We first investigated the effects of 5-ALA cream according to application time. And to find the effective 5-ALA concentration and the distribution times in vivo, 20% 5-ALA cream was topically applied to the tumor of the nude mouse. We then observed the distribution of 5-ALA via fluorescence measurement with using a 532 nm diode laser. 25 nude mice were divided into Control, ALA, Laser, and PDT group. To evaluate the PDT effect at cancer lesion, we applied 20% 5-ALA cream to the tumor by the same method, and the PDT was done by using a 632 nm diode laser at the time of the peak level of fluorescence. We checked the changes of the volume of cancer for 30 days, and then biopsy was done. Results: The effective post-irradiation time after topical ALA application was 9 hours. In the PDT group, 40% (4/10) of the mice showed decreased tumor size. Conclusion: The maximum PpIX fluorescence at 9 hours after local applicationof 5-ALA cream was checked. And PDT group did not show any statistical difference than control group in the growth of tumor size than control group. However responding cases (4/10) of PDT group showed the meaningful decrease of tumor size than control group (P

Fluorescence diagnostics of skin tumors using 5-aminolevulinic acid and its methyl ester

The incidence of malignant skin tumors is rapidly increasing. Early diagnosis, determining the margins of the tumor, is extremely important to achieve good treatment results. We investigated fluorescence of protoporphyrin IX in skin carcinomas. The study aimed to compare the effectiveness of topical 5-aminolevulinic acid and methyl-aminolevulinate in determining the exact margins of skin tumors. Fluorescence measurements were performed in 126 patients with malignant, premalignant, and benign skin lesions for detection of the margins of squamous cell carcinoma and basal cell carcinoma. 5-Aminolevulinic acid or its methyl ester was applied to the skin lesion for 2-4 h, and the data of evaluated protoporphyrin IX fluorescence were correlated with the data of morphological tissue examination. Malignant tissue shows a specific red fluorescence when illuminated with blue-violet light, whereas no fluorescence was observed in normal skin. In 30% of cases, the delineation of neoplastic lesions excited by 5-aminolevulinic acid was slightly weaker than using methyl-aminolevulinate. A sensitivity of 95.4% and a specificity of 88.6% as well as positive and negative predictive values of 86.1% and 96.3%, respectively, were obtained. Fluorescence diagnostics can be used for complete visualization of malignant skin lesions after topical application of 5-aminolevulinic acid or methyl aminolevulinate. It has been shown to be highly effective in the diagnostics of malignant superficial skin lesion. This method is applicable for detecting early superficial tumors, margins of tumors, and follow-up after therapy. Topical application of methyl aminolevulinate is slightly superior to 5-aminolevulinic acid in detection of lesion margins.

Depth Profile of Protoporphyrin IX Fluorescence in an Amelanotic Mouse Melanoma Model

Protoporphyrin IX (PpIX) fluorescence was measured at different depths in a subcutaneous amelanotic melanoma model (LOX) in mice. PpIX was induced by topical application of 5-aminolevulinic acid (ALA) and two of its derivatives, the methylester (MAL) and hexylester (HAL) onto the normal skin covering the tumor. The PpIX fluorescence intensity on the surface of the tumors was the highest for HAL, followed by ALA and MAL. Using equimolar concentrations (0.5 mmol g(-1)), HAL induced nearly twice as much fluorescence as ALA did. The depth profile of PpIX fluorescence was measured at different layers of the tumor, which was carefully sliced and controlled in situ ex vivo. The PpIX fluorescence was mainly localized within the upper 2 mm of the tissue for ALA and within 1 mm for MAL and HAL. There were no significant differences in the shape of the fluorescence excitation spectra, but the long wavelength excitation peak (633 nm) was so weak that these results are unreliable for depth estimation. When considering the low fluorescence intensity (around 5% of the intensity at the tumor surface), the actual penetration depth of HAL was comparable to that of ALA. The fluorescence after topical application of ALA and HAL was significantly above the background level down to a depth of around 6 mm, and there were traces of PpIX fluorescence even at the tumor base (10 mm). The fluorescence after topical application of MAL was detectable down to 1 mm. In the depth of 2-6 mm, the fluorescence was slightly higher for HAL than for ALA. Using the estimated diffusion coefficients for topically applied ALA (0.16 +/- 0.03 mm(2) h(-1)), MAL (0.045 +/- 0.005 mm(2) h(-1)) and HAL (0.037 +/- 0.003 mm(2) h(-1)), the behavior of the drugs after different application times could be estimated in this tumor model.

Photodynamic Therapy for the Treatment of Cutaneous Neoplasia, Inflammatory Disorders, and Photoaging

Photodynamic therapy (PDT) has demonstrated high efficacy, minimal side effects, and improved cosmetic outcome when used for the treatment of actinic keratoses (AK), basal cell carcinoma (BCC), squamous cell carcinoma, and photoaging. To review the literature on the use of PDT in dermatologic surgery using MEDLINE. Published clinical studies using PDT in the treatment of AKs yield overall efficacy rates ranging from 50% to 71% with one treatment to as high as 88% to 90% with two or more treatments. For superficial BCC, initial clearance rates were 76% to 97%, and for Bowen's disease, initial clearance rates ranged from 72% to 94% overall. The use of PDT for photorejuvenation is a relatively new application of this technology, which has shown promise in improving the appearance of fine lines, pigmentary variation, and telangiectasias. The advantages of photodynamic therapy include the capacity for noninvasive targeted therapy through topical application of aminolevulinic acid and methyl aminolevulinic acid, with outstanding cosmetic results. Although the theory behind the use of chemical photosensitizers and ultraviolet light to treat a wide variety of skin disorders is straightforward, the practical application of this technology is evolving. Additional research into the precise mechanisms of action for specific photosensitizers and optimal light sources will be highly beneficial to the advancement of this technology.

Aminolevulinic acid (ALA)-assisted photodynamic diagnosis of subclinical and latent HPV infection of external genital region

The relatively high recurrence rate of genital warts can be attributed to the unsuccessful elimination of viruses in areas of subclinical and latent infection. Therefore, the identification and treatment of the subclinical and latent infection is a key to reduce the recurrence. The goal of this study is to investigate the usefulness of 5-aminolevulinic acid (ALA)-assisted in situ fluorescence diagnosis of subclinical lesion and latent HPV infection. A total of 30 patients with histologically confirmed genital warts (condylomata acuminata) were subjected to topical application of ALA, acetic acid test, histopathologic examination and HPV DNA subtyping. Topical application of ALA was performed by applying 20% ALA cream to the lesion plus 2-cm margin for 2h followed by fluorescence examination. Correlations between histopathologic examination, aceto-whitening test, HPV DNA subtyping and fluorescence were examined. All warty lesions and subclinical lesions (n=25) showed red fluorescence and harbored HPV DNA (HPV6 or 11). Latent HPV infections at 0.5-2 cm away from the warty lesion also showed red fluorescence. Nonspecific fluorescence was associated with mucosa, inflammatory infiltration and erosive lesion. ALA-assisted photodynamic diagnosis could be employed for the detection of the lesion and subclinical lesion of genital warts. It is also useful in detecting latent HPV infection.

Comparison of ALA- and ALA hexyl-ester-induced PpIX depth distribution in human skin carcinoma

Photodynamic therapy (PDT) based on the use of photoactivable porphyrins, such as protoporphyrin IX (PpIX), induced by the topical application of amino-levulinic acid (ALA) or its derivatives, ALA methyl-ester (m-ALA), is a treatment for superficial basal cell carcinoma (BCC), with complete response rates of over 80%. However, in the case of deep, nodular-ulcerative lesions, the complete response rates are lower, possibly related to a lower bioavailability of PpIX. Previous in vitro skin permeation studies demonstrated an increased penetration of amino-levulinic acid hexyl-ester (h-ALA) over ALA. In this study, we tested the validity of this approach in vivo on human BCCs. An emulsion containing 20% ALA (w/w) and preparations of h-ALA at different concentrations were applied topically to the normal skin of Caucasian volunteers to compare the PpIX fluorescence intensities with an optical fiber-based spectrofluorometer. In addition, the PpIX depth distribution and fluorescence intensity in 26 BCCs were investigated by fluorescence microscopy following topical application of 20% ALA and 1% h-ALA. We found that, for application times up to 24 h, h-ALA is identical to ALA as a PpIX precursor with respect to PpIX fluorescence intensity, depth of penetration, and distribution in basal cell carcinoma, but has the added advantage that much smaller h-ALA concentrations can be used (up to a factor 13). We observed a non-homogenous distribution in BCCs with both precursors, independent of the histological type and depth of invasion in the dermis.

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.

Split-face study of facial rejuvenation for fine-line wrinkles using pulsed dye laser with or without topical application of aminolevulinic acid

Split-face study of facial rejuvenation for fine-line wrinkles using pulsed dye laser with or without topical application of aminolevulinic acid

Editorial Comment on: Photodynamic Diagnosis in Urology: State-of-the-Art

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Systemic Component of Protoporphyrin IX Production in Nude Mouse Skin upon Topical Application of Aminolevulinic Acid Depends on the Application Conditions¶

Topical application of 5-aminolevulinic acid (ALA) for protoporphyrin IX (PpIX)–based photodynamic therapy of skin cancer is generally considered not to induce systemic side effects because PpIX is supposed to be formed locally. However, earlier studies with topically applied ALA have revealed that in mice PpIX is not only produced in the application area but also in other organs including skin outside the application area, whereas esterified ALA does not. From these results, it was concluded that it is not redistribution of circulating PpIX that causes the fluorescence distant from the ALA application site, but rather, local PpIX production induced by circulating ALA. In the present study we investigate the effects of the ALA concentration in the cream, the application time, the presence of a penetration enhancer, the presence of the stratum corneum and esterification of ALA on the PpIX production in nude mouse skin outside the area where ALA is applied. For this purpose, ALA and ALA hexyl ester (ALAHE) were applied to one flank, and the PpIX fluorescence was measured in the contralateral flank. During a 24 h application of ALA, PpIX was produced in the contralateral flank. No PpIX could be detected in the contralateral flank after ALA application times ranging from 1 to 60 min. Tape-stripping the skin prior to short-term ALA application, but not the addition of a penetration enhancer, resulted in PpIX production in the contralateral flank. When ALAHE was applied, no PpIX fluorescence was measured in the contralateral flank under any application condition. The results suggest that the systemic component of PpIX production outside the ALA application area plays a minor or no role in relevant clinical situations, when the duration of ALA (ester) application is relatively short and a penetration enhancer is possibly added.

Topical Application of 5-Aminolevulinic Acid and its Methylester, Hexylester and Octylester Derivatives: Considerations for Dosimetry in Mouse Skin Model¶

Topical Application of 5-Aminolevulinic Acid and its Methylester, Hexylester and Octylester Derivatives: Considerations for Dosimetry in Mouse Skin Model¶

Temperature Effect on Accumulation of Protoporphyrin IX After Topical Application of 5-Aminolevulinic Acid and its Methylester and Hexylester Derivatives in Normal Mouse Skin¶

Temperature Effect on Accumulation of Protoporphyrin IX After Topical Application of 5-Aminolevulinic Acid and its Methylester and Hexylester Derivatives in Normal Mouse Skin¶

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.