Photoantimicrobials and PACT: what's in an abbreviation?

The use of a separate nomenclature for the application of photosensitisers to the oncological and infectious disease fields represents a sensible approach. There is commonality, of course, in that both utilise light activation and act via the local generation of reactive oxygen species, but the difference in cellular targets is so great that different designs are required to achieve proper selectivity for a clinical end use, whether in human or veterinary medicine. The following represents a personal view, and perhaps a clarification of terms, in what might be considered a major etymological dichotomy existing within photodynamic research, on the 20th anniversary of "PACT".

Lipid based nanocarriers system for topical delivery of photosensitizers.

Topical photodynamic therapy (PDT) is a non-invasive technique used in the treatment of malignant and non-malignant skin diseases. It offers great promise because of its simplicity, enhanced patient compliance, localisation of the photosensitizer, as well as the use of light and oxygen to achieve photocytotoxicity. Despite progress in photosensitizer-mediated topical PDT, its clinical application is limited by poor penetration of photosensitizers through the skin. Therefore, much effort has been made to develop nanocarriers that can tackle the challenges of conventional photosensitizer-mediated PDT for topical delivery. This review discusses recent data on the use of different types of lipid-based nanocarriers in delivering photosensitizer for topical PDT.

Evaluation of temperature change during antimicrobial photodynamic therapy with two different photosensitizers in dental caries.

INTRODUCTION: Many attempts have been made in elimination of bacteria in infected and demineralized dentin to not only provide efficient bactericidal potential, but to have minimal damage for tooth structure. The aim of this study was to assess the temperature change during aPDT with ICG and TBO compared with conventional Diode laser irradiation. MATERIALS AND METHODS: 48 premolar teeth which were selected for this study. A class I cavity was drilled in each teeth, with dimensions of 2mm width, 4mm length and depth of 2.5-3.5mm, providing a dentinal wall of approximately 0.5mm for pulp chamber. Then teeth were randomly allocated in 4 experimental groups (n=12); Group 1: TBO+LED, Group 2: ICG+Diode Laser, Group 3: Diode laser with output power of 0.5W, Group 4: Diode laser with output power of 1W. Thermocouple device was held by experimenter hand and the sensor was in pulp chamber of the teeth. Heat generated during irradiation was reported on LCD screen by NUX Plus software. Repeated measure ANOVA was used in order to compare the temperature before and after laser application. Tukey HSD was used to compare the results between groups. RESULTS: Temperature was risen for about 0.54±0.05°C for group 1, 1.67±0.14°C for group 2, 4.21±0.83°C for group 3, and 4. 50±0.32°C for group 4. The difference between group 1 & 2, 1 & 3 and 1 & 4 was significant (p<0.0001). CONCLUSION: According to results of this study, Diode (with or without photosensitizer- 0.5 and 1W) can be safely used as alternative approach for disinfection after caries removal in thermal point of view.

Comparative study of skin phototoxicity with three drugs by an in vivo mouse model.

Photosafety evaluation is becoming important during the drug development process in pharmaceutical companies. Both in vitro and in vivo test systems have been developed for the evaluation of phototoxic potential of chemicals. In the present study, we conducted an in vivo phototoxicity test using BALB/c mice. The mice were treated with sparfloxacin, lomefloxacin, or a quinoline derivative orally followed by the irradiation of simulated sunlight, and resulting phototoxic reactions of the ears were assessed. Sparfloxacin and lomefloxacin, but not the quinoline derivative, are well known to cause photoirritation in humans. All three drugs exhibited positive reaction in the 3T3 neutral red uptake phototoxicity test (3T3 NRU PT). In the in vivo test, sparfloxacin and lomefloxacin exhibited positive skin reaction in mice, but the quinoline derivative did not. The results of in vivo phototoxicity test in the mice coincided with phototoxic potential of these drugs in humans. The exposure levels of sparfloxacin or lomefloxacin at the minimum effective dose that exhibited phototoxic reaction in the mice were comparable with those in humans treated with the recommended therapeutic dose.

Photodynamic therapy: a targeted therapy in periodontics.

The oral cavity is colonized by a large number and highly diversified communities of micro-organisms. Bacterial biofilm present on tooth or root surface is a major cause of gingivitis and periodontitis. Chemical antimicrobial agents are widely used in prophylactic and therapeutic regimens for dental plaque related diseases, which are among the most common human infections. As these agents are difficult to maintain at therapeutic concentrations in the oral cavity and can be rendered ineffective by resistance development in target organisms, there is a need for an alternative antimicrobial approach. A novel approach, photodynamic therapy (PDT), could be a solution to these problems. Lethal photosensitization of many bacteria, both Gram positive and Gram negative was found in many studies. The advantage of this new approach includes rapid bacterial elimination, minimal chance of resistance development and safety of adjacent host tissue and normal microflora. Thus, the available knowledge of photodynamic therapy should encourage a more clinically oriented application of this technique.

Fragrance material review on benzyl salicylate.

A toxicologic and dermatologic review of benzyl salicylate when used as a fragrance ingredient is presented.

Fragrance material review on methyl ionone (mixture of isomers).

A toxicologic and dermatologic review of methyl ionone when used as a fragrance ingredient is presented.

[Photodynamic therapy in localised prostate cancer]. / Terapia fotodinámica en el cáncer de próstata localizado.

Photodynamic therapy is based on the administration of an energy source in form of light of a specific wavelength, on a previously photosensitized tissue by a chemical compound, in the presence of oxygen, so that the great deal of free radicals and oxygen derivatives generated (hydroxyl compounds) produces necrosis of the treated tissue. Technique improvement during the last years has allowed its recent development as a therapeutic method for localised prostate cancer. At present, several clinical trials are ongoing in patients with organ-confined prostate cancer both as a first line and salvage treatment. There is no risk either of cancer dissemination in surrounding tissues or accumulative pharmaco-toxicity. Therefore, the technique can be repeated as often as needed and can be administered on a previously irradiated tissue. The literature review shows that photodynamic treatment will become a therapeutic option for patients with prostate cancer in the very near future.

Assessment of the phototoxic hazard of some essential oils using modified 3T3 neutral red uptake assay.

When substances are developed in the aim to be a constituent of personal care products, and to be applied on the skin, it is necessary to carry out an assessment of potential phototoxic hazard. Phototoxicity is skin reaction caused by concurrent topical or systemic exposure to specific molecule and ultraviolet radiation. Most phototoxic compounds absorb energy particularly from UVA light leading to the generation of activated derivatives which can induce cellular damage. This type of adverse cutaneous response can be reproduced in vitro using different models of phototoxicity such as the validated 3T3 Neutral Red Uptake (NRU) phototoxicity assay. In the present study we utilised two different cell lines (the murine fibroblastic cell line 3T3 and the rabbit cornea derived cell line SIRC) to compare the photo-irritation potential of a strong phototoxic compound, chlorpromazine, to a weaker composite, such as 8-methoxypsoralen and Bergamot oil. After comparison of the different systems, five other essential oils were tested with both cell lines. Cellular damage was evaluated by the NRU cytotoxicity test or by MTT conversion test.

Photosensitizing effect of some nonsteroidal antiinflammatory drugs on natural and artificial membranes: dependence on phospholipid composition.

Previous studies have clarified the molecular mechanism of photosensitization on red blood cell membranes induced by some drugs belonging to the class of nonsteroidal antiinflammatory drugs: ketoprofen, naproxen, and diflunisal. This process involves the participation of photodegradation products, free radicals, and reactive oxygen species. The aim of the present paper is to investigate the photohemolytic process using red blood cells of mammalian species, with different membrane phospholipid compositions. Human and bovine red blood cell membranes were selectively enriched with phosphatidylcholine and sphingomyelin. For this purpose, a new approach for phospholipid investigation was undertaken. Moreover, the phototoxic effect was tested with liposomes at different phospholipid compositions. A structure-function relationship between the erythrocyte membrane phospholipid composition and the photohemolytic process induced by the sensitizers can be proposed. Indeed, the different contents of the photoperoxidable double bond and the variable architecture of the membrane bilayer, due to the different phosphatidylcholine and sphingomyelin contents, strongly influence the resistance of the cell to an osmotic shock induced by photogenerated transient species or by the lytic activity of drug photoproducts. The higher content of sphingomyelin, its asymmetric disposition at the outer surface of membrane bilayers, the high level of saturated acyl fatty chains, and the presence of photoperoxidable trans double bonds in the hydrophilic region greatly decrease the fluidity of bilayers and enhance the resistance of the membrane to phototoxic damage. On the other hand, an increase in the content of phosphatidylcholine, which is rich in species with unsaturated acyl fatty chains, decreases the membrane resistance, because these latter can be easily oxidized by drug-photogenerated reactive oxygen species.

High throughput screening (HTS) for phototoxicity hazard using the in vitro 3T3 neutral red uptake assay.

Testing for phototoxic hazard is usually carried out for product ingredients intended for use on skin, which may be exposed to sunlight. Unilever currently uses the validated in vitro 3T3 Neutral Red Uptake phototoxicity test (NRU PT). This protocol involves 2-3 experiments, each taking 3 days to perform. One person can test up to seven test materials plus positive control at any one time, requiring approximately 0.5 g test material. Higher throughput is required where libraries of potential actives are being generated and screening for potential phototoxicants is required. A proposed HTS protocol would use the NRU PT, but only one concentration (10 microg/ml) in a single experiment. The validity of the HTS protocol was investigated by a retrospective examination of data from 86 materials previously tested. Phototoxic hazard predictions made using the conventional NRU PT were compared with those obtained if only data at 10 microg/ml were considered. A majority of 73 materials (84.9%) gave agreement in predictions between the two protocols; for 13 materials (15.1%) the assessments did not agree. There were no false positives; however, there were some false negatives, i.e., predicted as phototoxic from the conventional assay, but non-phototoxic at 10 microg/ml. As this protocol is intended for screening purposes only it is considered that this would be acceptable at this stage in material selection. One person could screen 128 test materials in 3 days, requiring <1 mg test material, giving a substantial increase in productivity. Any material selected for further development and inclusion in a formulation may require further confirmatory testing, e.g. using a human skin model assay for phototoxicity.

Tumor PO(2) changes during photodynamic therapy depend upon photosensitizer type and time after injection.

In this study, the vascular and tissue oxygen changes induced by photodynamic therapy in the RIF-1 tumor were examined, using electron paramagnetic resonance (EPR) oximetry. Two photosensitizers, including verteporfin (BPD-MA in a lipid-based formulation) and aminolevulinic acid-induced protoporphyrin IX (ALA-PPIX), were investigated with optical irradiation, sufficient to induce sub-curative damage in the tumor tissue, and the transient changes in PO(2) and vascular perfusion were examined. A large increase in tissue oxygenation (from 3 up to 9.5 mmHg) was observed when treated with ALA-PPIX based photodynamic therapy, which lasted during the treatment and a small residual increase that returned back to baseline levels by 48 h after treatment. With verteporfin-based photodynamic therapy, one group of animals was irradiated 15 min after injection and exhibited a small decrease in oxygenation relative to pre-irradiation levels. The second group was irradiated at 3 h after injection and exhibited a large increase in the average PO(2), (from 3 to 15 mmHg) by the end of the treatment. These observations indicate that photodynamic therapy significantly increases tissue PO(2) under certain treatment conditions, with the potential cause being either increased local blood flow or decreased local oxygen metabolic consumption due to cellular damage.

Validation successes: chemicals.

The ECVAM validation concept, which was defined at two validation workshops held in Amden (Switzerland) in 1990 and 1994, and which takes into account the essential elements of prevalidation and biostatistically defined prediction models, has been officially accepted by European Union (EU) Member States and by the Federal regulatory agencies of the USA and the OECD. The ECVAM validation concept was introduced into the ongoing ECVAM/COLIPA validation study of in vitro phototoxicity tests, which ended successfully in 1998. The 3T3 neutral red uptake in vitro phototoxicity test was the first experimentally validated in vitro toxicity test recommended for regulatory purposes by the ECVAM Scientific Advisory Committee (ESAC). It was accepted by the EU into the legislation for chemicals in the year 2000. From 1996 to 1998, two in vitro skin corrosivity tests were successfully validated by ECVAM, and they were also officially accepted into the EU regulations for chemicals in the year 2000. Meanwhile, in 2002, the OECD Test Guidelines Programme is considering the worldwide acceptance of the validated in vitro phototoxicity and corrosivity tests. Finally, from 1997 to 2000, an ECVAM validation study on three in vitro embryotoxicity tests was successfully completed. Therefore, the three in vitro embryotoxicity tests, the whole embryo culture (WEC) test on rat embryos, the micromass (MM) test on limb bud cells of mouse embryos, and the embryonic stem cell test (EST) including a permanent embryonic mouse stem cell line, are considered for routine use in laboratories of the European pharmaceutical and chemicals industries.

Photosensitizer delivery for photodynamic therapy of choroidal neovascularization.

The present review examines the importance of improving photosensitizer delivery for choroidal neovascularization (CNV) in light of the clinical impact of photodynamic therapy (PDT) for CNV. An overview of the classes of available photosensitizers is provided and the properties governing photosensitizer uptake and circulation in serum are discussed. Current delivery systems, for example liposomal formulations as well as the use of the promising strategy of antibody targeted delivery as a strategy to improve PDT selectivity and efficiency for CNV treatment are described. A summary of the work using Verteporfin, tin ethyl purpurin and Lu-Tex--photosensitizers currently in clinical trials for CNV--is given.

Clinical and preclinical photodynamic therapy.

Photodynamic therapy (PDT) is a treatment modality that utilizes a photosensitizing drug activated by laser generated light, and is proving effective for oncologic and nononcologic applications. This report provides an overview of photosensitizers, photochemistry, photobiology, and the lasers involved in photodynamic therapy. Clinical and preclinical PDT studies involving Photofrin and various second generation photosensitizers are reviewed.