What is pdt in dermatology?

The procedure, materials and method for photodynamic therapy are based on our experience.

Mordon, S.*, Martnez-Carpio, P.A.**, Vélez, M.**, Alves, R.

Professor of Medical Biophysics, Doctor of Physical Sciences. The University of Lille is in France. IMC Investilser is a company.

The Dermatologist is at the Hospital Universitario del Mar, Barcelona. Spain is a country. The Vilafortuny Medical Institute is in Tarragona, Spain. Hospital Central Funchal, Funchal, Portugal. Spain is a country.

The address is for correspondence.

There is aTRACT

Photodynamic therapy is used to treat a variety of conditions. It gets good results in cases of skin diseases.

There is little consensus on the application methodology, irradiation systems, and dosages of the photosensitizers and light sources that can be used. In this article we describe the materials and methods currently available and discuss some details that allow us to improve the results.

5 illustrative clinical cases of different diseases are presented.

Actinic keratosis, Basal cell carcinoma, Bowen's disease, and skin aging are some of the topics covered.

The code is 14.

There is aTRACT

Photo Dynamic Therapy is used in the treatment of skin diseases. The treatment of extended cutaneous cancer is one of the many medical applications of PDT. There is still no consensus on methods and energy dosage for photoactivation, despite the fact that the sensitizers and light sources are more and more varied. This study describes the current methods and material available and discusses how they can be improved.

There are five illustrative cases.

Key words are photodynamic therapy, photosensitizers, light sources, Actinic keratosis, Basal cell carcinoma, and Bowen's disease.

The code is 14-17-26.

The introduction

Photodynamic therapy is used to treat various dermatoesthetic conditions. The photosensitive compound that accumulates in the target cells is administered, and after a period of time called the incubation period, a light of a wavelength within the absorption spectrum of the photosensitizer can be seen.

The therapeutic effect can be obtained by the photoactivation of the sensitizing product in the pathological tissue, which leads to oxidative damage in a wide variety of cellular targets. The destruction of cancer or abnormal tissue can be accomplished by the synthesis of monatomic reactive oxygen and the damage caused by free radicals in the altered cells.

The ability of altered cells to capture and concentrate the photosensitizing agent makes it a non-invasive and selective treatment.

In the treatment of actinic keratoses, it is used successfully in the treatment of other skin diseases. There is more documentation on the efficacy and safety of the procedure as well as more knowledge of the biochemical and cellular mechanisms involved in it. Possibly, the indication of PDT in the treatment of cutaneous photoaging is the one that has gained the most popularity in recent years; some authors point out that, under optimized protocols, the results in this field could be superior to those obtained with intense pulsed light (IPL) therapy (2-7). The results achieved by both therapies are improved by the combination of the two.

The aim of this work is to present the characteristics of the photosensitizers and light sources available on the market and marketed for cutaneous PDT following the conditions of use proposed by the manufacturers and our personal experience on the results obtained.

There are photosensitizers.

The treatment outcome is dependent on the characteristics and particularities of the photosensitizer.

The characteristics that photosensitizers must have are stated by Stapleton and Rodes.

Photosensitizers that have shown efficacy in cutaneous PDT include 5-aminolevulinic acid (5-ALA), levulinic acid methyl ester ( MAL), hematoporphyrin derivatives, and meta-tetradidroxyphenylchlorin.

5-ALA and MAL have the advantage that they are more lipid-soluble. The lower the dose, the better the tissue penetration. Both compounds are considered optimal for clinical application, although other photosensitizing molecule are also available. Among them, hexylester 5-aminolevulinate (HAL) stands out, used in Urology and which, according to what has been observed, offers advantages for treating some skin cancers using PDT

5-ALA, MAL, and HAL are not effective photosensitizers by themselves, but are transformed into the main sensitizing agent after administration.

Although the peculiarities of the reaction and absorption of porphyrins against the extensive spectrum of wavelengths are known (Fig. 2), there are not enough studies that analyze the pharmacokinetics of these three compounds at the level of the production of the fluorescent pPIX that they generate, for Therefore, there is still no full consensus on which concentrations and under what conditions they should be applied. The manufacturing laboratories only give general recommendations for use.

Levulan® Kerastic contains 354mg of 5-ALA.

It is indicated for the treatment of KA of minimal to moderate thickness and can also be used for other skin diseases. Only a qualified professional can apply the product. The recommended treatment is a single application.

It is recommended that at least 2 weeks or more elapse, but there are discrepancies on this point. Depending on the indication, we will proceed to irradiate with blue or red light of 409 or 635 nm. respectively, and as side effects the appearance of pruritus, painful sensation, erythema and edema is frequent.

The Metvix® cream contains 160mg/g of MAL. It is indicated for the treatment of KA on the face and scalp, in superficial and nodular BCC, and in Bowen's disease. Before applying the cream, the skin should be removed by rubbing the surface where they are located.

After applying the cream, the treated area is covered with a bandage for 3 hours before the light can be seen. One or two treatment sessions are usually required. Adverse effects include a burning sensation, the appearance of scabs and reddening of the skin.

Within 24 hours of light treatment, the sensation of pain and burning disappears. Patients with sensitivity to any of the components of the formula are at risk of having PDT.

Levulan® in the US and Metvix® in Europe are the most used photosensitizers. If the official acceptance of the FDA in the USA is taken into account, the indications, conditions of use and the applicable light sources are very limited. Most experts agree that the indications for photosensitizers in PDT are much more extensive than those listed in the Levulan® and Metvix® package inserts, and that the appropriate procedures and light sources may be different and obtain better results depending on the nature, extent and depth of the lesions.

The sensitizer HAL is activated with wavelength from 409 to .

Allumera, Ameluz and Alacare are three new sensitizing products that are beginning to be used successfully.

The material and method are related.

The method of application was summarized.

We can see the porphyrin form of the product in the UV or Wood's light, which allows us to see the distribution and objective definition of the lesions, which can be analyzed.

To adequately systematize the treatment, the following steps are needed.

The area to be treated is the cleaning of the area.

It is recommended that you use gentle spooning, microdermabrasion, or vigorous cleansing on very high KAs.

The photosensitizer can be applied.

Depending on the skin change, place an occlusive dressing for 30 minutes and 5 hours.

In some cases, such as skin aesthetic treatments, the occlusion can be replaced by the use of a sensitizing agent every 10 minutes. Adding an opaque protectant after application will prevent the product from reacting with light.

It is recommended to keep the occlusion times between 30 minutes and 5 hours when using ALA. ALA should be applied for one hour with 10-minute intervals, without the need to close the treatment area.

The occlusion is maintained for 3 hours in the case of using MAL.

The time is shorter for aesthetic treatments.

After this time, the dressing is removed by washing with water and non- aggressive soap.

The treatment is carried out with the system of coherent or non-coherent light that is chosen, following the doses indicated for each system.

Light sources.

The ideal light source for PDT needs to meet certain requirements.

The most effective wavelength for PDT after application of Levulan® or Metvix® is considered to be , but applicable wavelengths and illumination systems vary widely depending on pathology and experience of the optional light sources.

There is equipment specially designed for PDT on skin, such as the PDT 1200L Waldman® system (Herbert Waldmann GmbH & Co. KG Villingen-Schwenningen, Germany) equipped with a 2100W halogen lamp that, by mounting appropriate filters, allows light to be applied in a band between 580 at 740nm, with irradiations between 20 to 200 mW/cm2. The broadband blue light system from DUSA Pharmaceuticals, Inc is noteworthy.

It is important to remember that low doses of light can cause mild tissue damage that is easy to repair, while high doses can cause a lack of oxygen in the air, which can affect the efficacy of the treatment. Reducing the intensity can help to get better results.

There are indications.

While there is agreement on the efficacy of PDT in certain conditions, the question remains about the most appropriate wavelength and fluence to treat each type of condition. The visible light and sunlight emit wavelengths that are capable of exciting the PpIX generated by Levulan® and Metvix®.

The paper is not intended to give any details of each skin disorder that can be treated with PDT, but to highlight some of the more important aspects of the treatment. In our experience, there is enough support to design work protocols that allow a structured approach.

There are some types of cancer that can be treated with 5-ALA and MAL, such as superficial and nodular Basal cell carcinoma.

Good results can be obtained with a red light between 670 and 570nm.

Actinic Keratosis is a disease that can be treated with a PDT with 5-ALA or MAL. Good results can be obtained with one or two treatment sessions, with cure rates of 86% and 24% in the first year. The figures show that it's necessary to monitor the evolution of the lesions after treatment.

Excellent results are achieved with a total dose of 105J/ cm2 with 16% MAL and red light.

The main component of porphyrins is coproporphyrin III. The synthesis of porphyrin increases when thebacteria are exposed to a wavelength of light that is blue. The formation of oxygen with a bactericidal effect is associated with the photoactivation of the porphyrins.

There are at least theoretical options for efficacy. For treatment, the light is illuminated with a visible polychromatic light or red light. After illumination for 15 minutes, the results have been obtained using 3-indole-acetic acid as a photosensitizer and green light. There is no previous literature for it.

In our experience, similar results are obtained with 8% MAL and red light for a total dose of 105J/ cm2.

Photoaging with 5-ALA or MAL proves to be effective. The same procedure makes it possible to treat both processes when photoaging is associated with KA.

There is good experience with the use of lasers and lamps. Good results have recently been described with MAL and 633nm LED red light using energies of 37J/cm2.

On the other hand, there are also documented studies on the efficacy of PDT in cases of psoriasis, actinic cheilitis, Paget's disease of the breast, scleroderma, lichen sclerosus and atrophic, type I herpes virus, sebaceous hyperplasia, viral warts, disseminated actinic porokeratosis. , cutaneous leishmaniasis and onychomycosis, among others (2,3).

There are cases of clinical nature.

A 76-year-old male is a phototype III farmer. He has head injuries that are random. The course has increased in number and severity, with bleeding and keratotic stacking in most of the lesions. MultipleBCC is the histological diagnosis. Despite the use of a hat and sun protection, the lesions continued to appear despite various treatments.

5-ALA was used for treatment with the PDT. Curettage was done with dry gauze to avoid any bleeding. After washing with soap and drying, the CO2 laser was passed quickly and systematically in fractional mode, which produced "perforations" in the skin that allowed the penetration of the sensitizer.

The time for the incubation was shortened by one hour. It was covered with a dressing and a cap. After this time, it was washed with soap and water and irradiated with an IPL lamp with a wavelength of between 980 and 400 nanometers, a spot size of . Exposure to any type of light for a week was recommended.

The control performed one year after the fall off of the scabs showed no reappearance of the lesions.

A 73-year-old male is a phototype III. He has a long-term head injury that has been increasing despite various treatments. His skin is very fragile.

The part of the lesion that is raised is easy to bleed from. Histology showed that the thickness of the skin was affected by the presence of abnormal cells and that it was a sign of squamous cell carcinoma or Bowen's disease.

We used the same protocol as in the previous case, but using 16% MAL (Metvix®) as a sensitizer for 3 hours, and then focused the beam to a diameter of 12 cm to cover the injury.

A total fluence of 54J and continuous laser emission at 1W of power were used to illuminate. One year after the treatment, there were no reappearances.

A 28-year-old woman, phototype IV/V, is suffering from moderate-severe acne and follicular reaction. She presents with a lot of redness in her face and no response to any of the treatments. 8% MAL was applied to the lesions.

It was irradiated with a 418 nm lamp after 30 minutes of incubation. The two sessions of 20 minutes each were performed in two separate batches, with a total dose of 48 J/ cm2 per session, separated by 3 weeks. After 6 months of follow-up, there were no reappearances except for isolated comedones that responded well to local treatment.

A 46-year-old woman is presenting advanced skin aging due to abuse of sun exposure. There are residual lines, scars, and wrinkling from various types of skin.

8% MAL was applied every 15 minutes for a period of 3 hours after the mechanical abrasion. Two treatments were carried out one month apart with a red light lamp, for 16 minutes each, for a dose of 105 J/ cm2.

A male is phototype III. The entire nose and cheeks are covered in a large, deep lump.

The tip, back and wings of the nose are affected by inflammation and reactivity. There are multiple telangectasias, facial erythroderma and formation of painful comedones.

We applied 16% MAL for one hour. After washing, we irradiated with a One session was held every 3 weeks.

The accessibility of the skin makes lighting techniques relatively simple and provides excellent cosmetic results, especially compared to surgery or cryotherapy in oncological pathology, which is why it is ideal in the treatment of skin lesions. This has led to an increase in the use of TF. The article reviews the most relevant aspects of our specialty. We have had professionals who have worked in this field in our country. In the first place, a review of the basic fundamentals of photodynamic treatment will be made; Subsequently, its clinical applications in dermatology will be exposed, both oncological and all those dermatological processes in which TF may play a role in its management, without forgetting its promising cosmetic application in the treatment of photoaging.

We will end the review with different forms of non-invasive monitoring of the effectiveness.

There is a basic fundaMENTALS of photoDYNAMICTHERAPY.

The photosensitizer, light, and oxygen are required for TF. We will talk about each of the elements, focusing on the field of dermatology.

Photodynamic therapy uses photosensitizers

The effectiveness of the photodynamic treatment is dependent on the photosensitizer's qualities. It must have 2 characteristics: a) the ability to localize specifically in the tissue or cells to be treated; b) homogeneous distribution in the target tissue; c) high lipophilicity to diffuse through biological membranes; d) as short a time as possible between its administration and the maximum accumulation in said tissues; e) short half-life and rapid clearance from normal tissues; f) activation at wavelengths with optimal tissue penetration; g) high yield in the production of singlet oxygen (1O2), or in general of reactive oxygen species, and h) absence of toxicity in the dark.

Various photosensitizers have been used in the lab. Below is a description of the most widely used ones.

There are porphyrins.

They were the first substances used in the project. The use of Photofrin is approved in some countries for the treatment of bladder cancer, lung cancer, both in the early phase and palliatively, and in obstructive esophageal cancer 3. The photosensitizers have to be administered in a way that will accumulate in the stroma of the tumor.

Its slow clearance and cutaneous remanence make it hard for the patient to apply photoprotection for 3-6 weeks after its administration.

porphins.

Synthetic porphyrins have high photosensitizing power and can be used in tumors. The tumor stroma is preferentially affected by the activated 630-nanometer-longTPPS4 (tetra-sodium-meso-tetraphenylpor-phine-sulfonate).

In the treatment of a number of diseases, including actinic keratoses, common warts, and cutaneous T-cell lymphoma, it has been possible to use the product. The major limitation of the product is its toxicity.

porphycenos

The synthetic isomers of porphyrins are called porphycenes.

The porphycenes meet the main requirements to be useful in the area, and they produce 10 times more singlet oxygen than the hematoporphyrin derivative. The side chain could be modified to increase its photodynamic activity and accelerate cell growth.

The PC is made of phethalocyanines.

Natural porphyrins have a macrocyclic structure that is extended in the four pyrrole units by the benzoic rings, while the different pyrrole derivatives have a macrocyclic structure that is extended in the nitrogen atoms. The absorption peak of thalocyanines is between 650 and 700 nm, which allows them greater penetration into tissues than porphyrins 7. PCs produce a large amount of reactive oxygen species, and they reach the maximum concentration in the tumor tissue 3 hours after their IV administration.

They have minimal photosensitivity.

The treatment of lung cancer, Kaposi's sarcoma, and basal cell carcinoma is being evaluated with the help of Chloroaluminum phthalocyanine.

Chlorines are found in water.

Chlorins are a heterogeneous group of compounds. They have high extinction coefficients in the 650-nanometer range. The main application of the monoacid ring A benzoporphyrin derivative is the treatment of retinoblastoma.

N-aspartylchlorin e6 has a peak absorption wavelength of . The phase I clinical trial was carried out to demonstrate its efficacy in both basal cell and squamous cell carcinomas with just one treatment session.

The most promising photosensitizer within this group is ATX-S10 (Na), which has an absorption spectrum of 670 nm, which allows greater efficacy in deep lesions and is effective applied topically. After a 4-h period, good results have been obtained in the treatment of several diseases.

There is a substance called lu-Tex.

Lu-Tex are water-soluble compounds that are found in tumors and plaques.

Their maximum absorption spectrum is , and they are administered in a way that will cause their maximum accumulation in the tissues to be treated within 2–4 h. It is possible to successfully treat melanoma's metastases without damaging the surrounding skin.

-aminolevulinic acid.

ALA is the most widely used photosensitizer in the treatment of skin problems.

Kennedy et al 12 were the first to propose the idea of carrying out endogenous photosensitization of tumors. In this case, instead of administering the photosensitizer, ALA, is applied, which is preferentially converted into the active photosensitizer, Protoporphyrin IX (PpIX), by certain cells or tissues. ALA has an advantage over most photosensitizers which require IV administration, which is effective if administered topically or oral. The photosensitizer has been completely eliminated from the tissues after its administration.

The maximum absorption peak is 410 nm and the minor one is around 630. Even though the first is less powerful than the first 14, we must use the second if we need to treat deeper than 2mm.

The heme synthesis pathway is present in the cells of the organisms that make ALA.

ALA is the first intermediate compound in the synthesis of porphyrins and is formed within the mitochondria through from glycine and succinyl-CoA through a reaction catalyzed by the enzyme ALA-synthase, which is located in the inner mitochondrial membrane and is the main regulator of pathway 16. ALA diffuses into the cytosol and after several enzymatic steps is transformed into coproporphyrinogen III, which again enters the mitochondria, where it is oxidized to form Protoporphyrinogen IX.

When losing 6 hydrogens, it becomes a tetrapyrrolic structure ready for the synthesis of the heme group.

There is a pathway for Heme synthesis. Solid arrows and dashed processes represent synthetic steps. The stimulatory and inhibitory signs are shown by the + and - signs.

The nucleus is dark grey, the mitochondria is light grey and the cytosol is white. Rtf: transferrinreceptor.

The heme biosynthetic pathway is regulated by the availability of the substrate and by a negative feedback system which directly affects the ALA synthase enzyme and also the transcription, translation, and transport of thisProtein within the mitochondria, thus regulating its own synthesis. The control of ALA is exceeded if it is administered in a way that causes an overproduction of porphyrins. The cells will become photosensitized due to theAccumulation of PpIX.

Since ALA increases its activity, the porphobilinogen deaminase has a regulatory role as well. The nuclear envelope, lysosomes, and mitochondria are all involved in the accumulation of PpIX.

The mechanism of ALA's absorption through the cell is mostly active transport through the membranes. The increase in permeability in the area with the corneum altered appears to contribute to the skin's ability to absorb the ALA.

However, ALA is a hydrophilic molecule, that is, it has low lipophilicity, so it poorly crosses biological barriers such as the cutaneous stratum corneum and, therefore, to reach clinically relevant levels of PpIX it is necessary to apply relatively high doses (ALA 20 %) and maintaining a long application time before lighting (4-8 h), sufficient for complete transformation and maximum accumulation of PpIX in the tissues to be treated 20.

The development of a derivative, specifically a methyl ester, 5-methyl aminolevulinate (MAL), was much more lipophilic than the previous one. The property gives it a high specificity.

MAL has a high specificity for cells with a ratio of 9:1, compared to ALA which has a ratio of 2:1 22.

The advantages of MAL over ALA include greater tissue penetration, increasing the production of intracellular PpIX, and obtaining superior photodynamic performance. There is evidence of stimulatory effects of MAL on the porphyrin pathway 24, as well as evidence that part of it is hydrolyzed by ALA, but there is also evidence that MAL is incorporated into the porphyrin synthetic pathway. The other clinical advantages offered by MAL over ALA are that it takes less time to apply to illuminate and that patients report less pain during illumination.

Light sources are used.

Any visible light source capable of penetrating enough tissue and with enough power can be used in the photofrequencies of the photosensitizer. We will focus on the most important aspects of the treatment of skin diseases.

Light penetration into tissues

Light penetration through the tumor thickness depends on the wavelength of the tissue to be treated and its characteristics. Penetration is influenced by a number of factors, including optical absorption, optical scattering, and the photosensitizing substance. The phenomenon has been called self-protection. The therapeutic window for skin diseases is between 600 and 1,200 nm.

The scattering and optical absorption are different for each tissue. Light penetration is about 1-2mm for a wavelength of 400-500 nm, between 5-10mm for 630 nm, and about twice as much for 700-850 nm. The light penetration is 1-2mm 26 due to the high scattering of light.

Light dosimetry.

The light source's power by the time gives us a dose of energy.

The intensity of the light in the tissue decreases with the distance traveled.

The amount of light that should be used in each case should be considered as to whether it will cause damage to the tissue or not.

It is necessary to adjust the light dose for each source. The effectiveness of photodynamic treatment could be improved by dividing the lighting, since it allows reoxygenation of the tissue in periods without light.

Most of the time, the light sources are used for skin care.

The lasers used in internal organs are more complicated than the lighting systems used in the skin.

Lasers, non-coherent light lamps, and light-emitting diodes are some of the sources used to treat skin diseases.

Lasers allow the selection of the wavelength corresponding to the absorption spectrum of the photosensitizer and the precise application of light in a small area. One of the most widely used lasers is the argon dye laser, which emits continuous light that can be adjusted to the absorption properties of various photosensitizers.

The advantages of incoherent lights are that they can treat larger skin areas and be cheaper.

Light-emitting diodes, small Semiconductors with a narrow wavelength band of 20 to 50 nm, are one of the most widely used lamps in the world today.

There are few comparative studies between different light sources, but one showed an equivalent response to basal cell carcinoma with ALA using both a copper vapor laser and a broad-spectrum incandescent halogen lamp.

There is no single ideal lamp at the moment, so their choice must be made according to the clinical indication, number and size of the lesions to be treated, their flexibility, treatment time and cost.

Tissue destruction is caused by photodynamic therapy.

The photo-oxidation of biological materials in certain tissues is the basis for the term. The mechanism of photodynamic cell damage involves complex interactions between visible light photons, the local photosensitizer in the tissue to be treated, and various cellular repair processes

The combination of direct cell death, inflammation, and the host's immune response is what leads to the effectiveness of TF.

We will analyze the mechanism of action of TF at different levels, paying special attention to the mechanism of ALA and its derivatives.

Photochemistry

After light absorption, the photosensitizer is transformed from its ground state to an electronically excited and unstable state, with a half-life of 106 to109 s. The excited photosensitizer can emit light when it returns to its normal state. Another possibility is that the sensitizer in the triplet state interacts with the surrounding molecules giving rise to two types of photo-oxidative reaction: type I reaction by electron transfer, originating free oxygen radicals (ROS) (peroxides, superoxide anions and hydroxyl radicals). , which initiate chain reactions of free radicals 28 and type II reaction, mediated by energy transfer, giving rise to the formation of singlet oxygen and the return of the photosensitizer to its basal state 29. It seems that singlet oxygen is responsible for the tissue damage that occurs during the reactions.

If we take into account the diameter of a tumor cell, we can see that singlet oxygen has a short life of 0.04 s. It is a very reactive molecule that reacts quickly with many types of biomolecules, including cholesterol, histidine, and methionine.

During photobleaching 31, the photosensitizer is destroyed during exposure to light. This photobleaching is a mechanism of interruption of the photodynamic reaction which is important to restrict tissue damage from tumors and to eliminate residual skin photosensitivity. If photobleaching takes place before the threshold for tissue necrosis is reached, tissue damage won't occur.

There are targets of photodynamic therapy.

Direct damage to cells can be caused by phototoxic damage and indirect effects, which seem to play an important role in final tissue destruction.

Direct damage to targets.

The location of the photosensitizer at the time of photoactivation is related to the targets of photodynamic damage. The type of photosensitizer used and the type of cell are likely to affect the cytotoxicity.

The lysosomes are where porphyrins with cationic side chains are located, while the mitochondria is where more phototoxic porphyrins are located. The production of PpIX is concentrated in the mitochondria when we administer ALA. The primary photodynamic effects of PpIX being retained within the mitochondria are due to its low water solubility and high affinity for membrane lipids.

In tumors treated with ALA initial damage occurs in the cells of the tumor microvasculature 33.

The way in which photosensitizers are located in the mitochondria causes cell death, while the way in which they are located in the plasma causes necrosis with light.

The treatment protocol, the cell type and the energy state are all important. Cell death in the lab can be produced by either low or high doses of light. The light's incubation time seems to have an influence on that. The Zinc phthalocyanines (ZnPc) are located in the Golgi apparatus and less so in the plasma membrane after 2 h of incubation.

If illumination is done after 2 h, the most common form of cell death is necrosis, while if it is done after 24 h, it is due to apoptosis 36.

Various biochemical and microscopic changes are caused by TF.

The main targets of the reactive oxygen species produced in the photodynamic process 37 seem to be the lipid peroxidation and the inactivation of genes. The breakdown of the cellular respiratory chain 36 can be caused by the inactivation of the enzymes bound to the mitochondria, when photosensitizers are located in mitochondria. There is a decrease in the concentration of adenosine triphosphate. The increase in the permeability of the membranes makes it hard to transport certain substances.

The bubbles and ballooned structures can be seen a few hours after death 38, after the arrest of cell division and after the formation of a new cell.

According to Dougherty et al 35, the low potential to cause DNA damage is due to the fact that most photosensitizers accumulate in the cell nucleus.

It can be deduced from this that there is a low potential for TF to induce cancer. There is a delay in the S phase of the cell cycle and a decrease in the expression of genes that are involved in cell proliferation in the case of TF with ALA.

The effects are indirect. There is regulation of the growth of blood vessels. The vasculature appears to be the most critical target of indirect photodamage. The damage to the endothelium is caused by direct TF-induced damage. However, this effect is absolutely dependent on the photosensitizer used, since, for example, TF with Photofrin increases the formation of vascular endothelial growth factor (VEGF) and leads to vasoconstriction, thrombus formation, and tumor destruction by necrosis, while phthalocyanines induce the outflow of the contents of the vessels 41.

The matrix is regulated. The expression of metalloproteinases (MPP) 1, 3, 8 and 9 has been observed to increase with the use of photofrin.

On the one hand, the action on MMPs can help stop the spread of tumors, and on the other, it can help the result of the test.

The effect of the immune system on TF. The anti-tumor effects of the treatment of solid tumors with TF. The anti-tumor activity of inflammatory cells and the specific immune reaction against the tumor are facts.

The release of arachidonic acid 36 is caused by the rapid activation of membranous phospholipases, which is caused by photooxidative lesions of the membranes. The release of potent inflammatory mediators will be stimulated by this. The porphyrin photosensitizers 35 have been used to demonstrate the production of interleukins, tumor necrosis factor a, and G-CSF.

Inflammation signals will initiate a recruitment of neutrophils, which will cause vessel damage and destroy tumors. The arrival of mast cells, powerful mediators of the inflammatory response, together with the former constitute the non-specific immune effector response. Monocytes and macrophages attend, clearing tumor cell remnants, processing tumor-specific antigens, and presenting them in the context of major histocompatibility complex type II (MHC II) class molecules. The production of tumor-specific cytotoxic T lymphocyte clones 42 can be achieved by the recognition of tumor-specific epitopes by CD4 lymphocytes. The synthesis of immune cells with memory will be an advantage over other tumor therapies, such as radiotherapy or surgery, because it will induce a specific systemic immune response against the tumors.

There are someICAL applications of photoDYNAMIC THERAPY with -AMINOLEVULINIC ACID.

Kennedy and his colleagues successfully treated 80 basal cell carcinomas with the use of TF and ALA in 1990. Since then, publications on skin cancer and precancer treatments using MAL and ALA have increased. The British group of photodermatology 26 has published guidelines for applying for and establishing treatment protocols for MAL 22, which were made possible by these studies. The clinical procedures for the two photosensitizers will be discussed later.

The procedure of photodynamic therapy.

An O/W (oil/water) emulsion of ALA is prepared and applied to the lesion to be treated, covering it with an opaque dressing to protect it from light. The most widely used concentration of ALA is 20% and the application time is from 3-6 h, although times between 3 and 12 h have been used.

The only indication approved in the United States is actinic keratosis, which can be treated with a 20% ALA solution and light after 14 h. The lamp used in this country is of blue light at 417 nm and a dose of 10 J/ cm 2 Red light lamps with an approximate wavelength of 630 nm are needed to guarantee greater penetration if deeper lesions are to be treated.

5-ALA is also marketed in our country.

5-ALA is marketed in Europe at a maximum concentration of 160. Actinic keratoses and basal cell carcinoma are the approved indications. The treatment procedure consists of: a) scraping of the lesion, eliminating hyperkeratosis and crusts or reducing the tumor in the case of nodular basal cell carcinoma; b) application in occlusive cure of the MAL in the lesion, 1 mm thick and 1 cm around, leaving it incubated for 3 h; c) clean the area with serum and exposure to a red light (630 nm) administering a dose of 75 J/cm 2 , one of the most widely used light sources being the diode lamp (fig. 2).

Table 3 shows the 10-step clinical procedure to be followed to perform a skin exam. The response to treatment is assessed at 3 months.

The MAL application procedure is shown in the figure. The lamp has Aktilite®.

The main advantages of TF with ALA or MAL are that it is not an invasive treatment, it is quite well tolerated by patients, several lesions can be treated in the same session, the treatment can be performed as many times as necessary, and the cosmetic results they are excellent regardless of the size of the lesion treated 43.

The lack of histological confirmation of tumor healing and pain during illumination is the main downside.

Treatments for skin cancer and pre-cancer.

In the last few years, there have been many studies showing the efficacy, safety, comfort, and excellent cosmetic results of TF. Treatments for skin cancer and pre cancer are the majority of studies. Since there are multiple studies that support its efficacy and safety, the only approved indications in Europe for the use of TF are non-hypertrophic actinic keratoses and non-morphein basal cell carcinoma.

Actinic keratoses are one of the best indications for TF.

The healing rates of these lesions range from 80% to 100% using ALA in a concentration of 20% 19. The group treated with TF 46 had actinic keratoses on the back of the hands, but treatment comfort and patient tolerance were better than the group treated with a single session of ALA. A randomized study compared the efficacy of a single session of TF with MAL versus cryotherapy in non-hypertrophic actinic tumors located on the face. The results in the first group were better than the results in the second group.

The treatment of actinic keratoses and better cosmetic results were found by using two cycles of TF with MAL. In a study in the US, the efficacy of FT with MAL was shown to be more effective than placebo, and it was shown that more than 90 percent of the patients treated with TF 49 had excellent results. A study shows that the healing rate of actinic keratoses can be increased by using two sessions of TF with ALA, compared to a single session.

Fig. 3.--Multiple actinic keratoses before (A) and after two sessions with a one-week interval (B and C) of TF with methylaminolevulinate (Metvix®) and a total dose of 37 J/cm 2 of red light (630 nm) (Aktilite® lamp).

There are studies that show the usefulness of TF, even though it isn't currently approved for the treatment of Bowen's disease.

One study compared the efficacy of the two drugs in the treatment of a disease. After 12 months of follow-up, the cure rates dropped to 22% and 22%, respectively, although the initial cure rate was still higher than the group that was treated with 5-fluorouracil. The group treated with 75% cure was found to be more effective than the group treated with 50% cure. The group that was treated with the treatment had less pain. The percentage of cures rose to 80% if this treatment was applied twice, after it was concluded that 60 percent of the lesions that were treated only once with TF obtained a cure.

The patients' tolerance was good and the results were good.

There are few studies on the use of TF in the treatment of cancer.

According to different publications, the cure rates for superficial squamous cell carcinomas range from 67 to 92% with ALA. The cure rates are from 0 to 67% 19 when the cancer is treated. More studies are needed to be able to consider the efficacy of the treatment.

Regarding the use of TF for the treatment of basal cell carcinoma, its indication for MAL has recently been approved in Europe, both for superficial and nodular basal cell carcinoma, although the latter previously requires reduction of the tumor mass until it is the same. adjacent skin surface so that the MAL can penetrate well (fig. 4). The efficacy of FT with MAL was compared by Rhodes and his colleagues.

Response rates were 98% in those treated by surgery versus 91% in the group treated with TF. The rates dropped to 96 and 83% after a year. The difference between one and two treatments is compared in a work. The cure percentages were higher in the group that was treated with a single cycle than in the group that was treated with two sessions.

After 6 months of treatment with two sessions of MAL and lighting with an Aktilite® lamp,Basal cell carcinoma can be treated.

There are isolated cases of a good response to ALA in cutaneous T-cell lymphomas.

Experimental animals have not provided good results when it comes to studies on the effectiveness of TF with ALA in killing melanoma cells. The main problem is that the absorption of light with porphyrins is less effective than the absorption of light with melanin. The results of the treatment of melanoma have been provided by the higher optical extinction coefficients of phachocyanines.

There are non-oncological applications of photodynamic therapy in the skin.

It is useful in the treatment of inflammatory skin diseases.

Depending on the dose and type of light applied, the cytotoxic effects result in tumor destruction and the immunomodulatory effects result in improvement of the disorders.

It has been shown that it can be effective in inflammatory diseases such asPsoriasis andAcne, as well as in viral diseases such as condylomas or common warts.

There are many patients treated with TF who have been diagnosed with a number of diseases. There are some isolated cases of diseases.

There is a promising experience with the non-oncological dermatoses that will be reviewed.

Psoriasis is a disease.