RU2265463C2 - METHOD FOR DIAGNOSTICS AND PHOTODYNAMIC THERAPY OF acne vulgaris - Google Patents

Abstract

FIELD: medicine, dermatovenerology.

SUBSTANCE: one should perform diagnostics with the help of fluorescence spectrums of affected sections. Section being of own intensive fluorescence should be irradiated with light at wave length being 630±10 nm and energy density 10-4500 J/sq. cm, sections which has no own intensive fluorescence should be applied with an applicator containing 2-20% solution of 5-aminolevulinic acid and after exposure and applicator's removal they should be irradiated with light at wave length being 630±10 nm and energy density of 10-4500 sq. cm. The flow of irradiation process should be controlled due to fixing fluorescence spectrums at affected skin sections before irradiation, after the use of applicator that contains 5-aminolevulinic acid, after irradiation, moreover, irradiation should be stopped at decreased concentration of porhyrins being below therapeutic values. The innovation decreases cutaneous fatty secretion, quantity and density of eruption.

EFFECT: higher accuracy and efficiency of diagnostics and therapy.

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Description

The present invention relates to dermatovenerology, and in particular to methods for the diagnosis and treatment of acne (acne vulgaris) using induced and endogenous fluorescence of porphyrins, and can find application in the clinic of skin diseases.

Forms of acne (acne vulgaris) that are resistant to local therapy or lead to the formation of nodes and scars require systemic treatment. Systemic acne therapy is carried out with antibiotics (drugs of the tetracycline group, erythromycin, clindamycin), vitamin A and its derivatives (tretionine, isotretionine, adafalene) and hormonal drugs.

Antibiotic therapy

As a rule, with systemic antibiotic therapy, tetracycline antibiotics are the drugs of choice. The effect of antibiotic therapy is achieved due to the antimicrobial and anti-inflammatory effects of the drugs. The course of treatment is usually 4-6 months and is always combined with local therapy with comedonolytic and antiseptic drugs. The disadvantages of antibiotic therapy include the risk of resistant forms of microorganisms. According to Eady et al. [Eady E.A., Jones C.E., Gandner K.J., Taylor J.P., Cove J.H., Cunliffe W.J. Tetracycline-resistant propionibacteria from acne patients are cross-resistant to doxycycline, but sensitive to minocycline // British journal of dermatology. 1993. V.128 (5), p. 566-560] about 60% of patients with acne had resistant strains of Propionibacterium acnes, about 1% of the strains were resistant to minocycline, but the BMD of the latter is constantly increasing. When prescribing antibiotics, the side effects of individual drugs should also be taken into account, in the case of tetracycline, this is candidiasis and photosensitivity.

Vitamin A and its derivatives

Isotretionine or 13-cis-retinoic acid is one of the most effective anti-acne drugs: acting on all mechanisms of pathogenesis, isotretionine reduces the size of the sebaceous glands and the pore colonization of P. acnes. The course of treatment is 16-20 weeks, the effect persists for a year. Adverse reactions - dry skin, alopecia, myalgia, hyperlipidemia, nosebleeds, intracranial hypertension, teratogenic effect.

Hormone therapy

It is carried out by estrogens, antiandrogens, hormonal contraceptives in combination with antiandrogens for the treatment of acne in women. Spironolactone and cyproterone acetate are used as antiandrogens. Spironolactone is also used for monotherapy of acne in men. The disadvantages of hormone therapy are the duration of treatment, the risk of harmonic imbalance, amenorrhea, alopecia. Long-term use of hormonal drugs should be under the control of an endocrinologist, gynecologist.

A known method of treating acne vulgaris using photodynamic therapy (PDT) acne vulgaris (WO 02/13788 A 61 K 9/00, 02/21/2002). This method of treatment consists in topical application of 5-aminolevulinic acid (5-ALA) to the skin, followed by light exposure, treatment is carried out cyclically at various time intervals. In general, the wavelength range used for therapy is in the range from 320 to 700 nm, preferably from 550 to 700 nm, and most preferably from 550 to 700 nm. In the General case, the range of energies acting on the skin surface is in the range from 1 to 200 J / cm ² , preferably from 25 to 200 J / cm ² , and most preferably about 100 J / cm ² . Obtaining fluorescence images was used to control the level of endogenous porphyrins, a decrease in the latter was one of the criteria for the effectiveness of PDT. The effectiveness of PDT was evaluated using histological studies and measuring the rate of sebum secretion. Fluorescence microscopy was used to localize the sites of predominant formation of protoporphyrin IX (PP IX), that is, to reveal the mechanism of the process. Significant improvement in skin condition was observed within 20 weeks after repeated exposure to ALA-PDT.

The disadvantage of this method is the insufficient development of methods for controlling PDT and evaluating treatment results, and the concentration of endogenous and ALA-induced porphyrins has not been quantified either. Significant disadvantages include the fact that the role of endogenous porphyrins as photosensitizers was not evaluated.

Closest to the proposed method (prototype) is the treatment method proposed by Y. Iton, Y. Ninomiya, S. Tajima, A. Ishibasi (Photodynamis therapy of acne vulgaris with topical 5-aminolaevulinic acid and incoherent light in Japanese patient // British journal of dermatology. 2001. V.144 (3), p. 575-579). An oil emulsion containing 20% 5-ALA hydrochloride was applied to the affected areas for 4 hours and covered with a light-tight dressing on top. Then, the treated areas were irradiated with nonmonochromatic visible light with a wavelength of 600-700 nm using a halogen light source. The radiation power density was 17 mW / cm ² , the radiation dose was 13 J / cm ² . In order to achieve the required radiation dose over an area of 100 cm ² , 13 minutes were required. After irradiation, the treated areas for 3 days were treated with a cream containing 0.12% betamethasone valerate. Patients were examined 1, 3, and 6 months after the procedure. To assess the condition of the skin, a standard certification system was used. Immediately after irradiation, the absence of PP IX fluorescence was monitored under a Wood lamp.

However, this method does not solve the problem of fluorescence diagnostics and monitoring the treatment process: the proposed diagnostic method using a Wood lamp does not allow to quantify the concentration of PP IX. This method, like the analogue, does not take into account the possibility of using endogenous porphyrins as photosensitizers. All this reduces the effectiveness of both diagnostics and PDT.

The present invention solves the problem of increasing the efficiency of fluorescence diagnosis and treatment of acne (acne vulgaris).

This problem is solved by the fact that in the method for the diagnosis and photodynamic therapy of acne using an endogenous or induced photosensitizer of a group of porphyrins, diagnostics are carried out using fluorescence spectra of the affected areas. An applicator containing 5-ALA is applied to areas that do not have intense intrinsic fluorescence, and after exposure and removal of the applicator, they are irradiated with light with a wavelength of 630 ± 10 nm, the energy density of the irradiating light is 10-4500 J / cm ² . The course of the irradiation process is monitored by recording the fluorescence spectra and obtaining fluorescence images of the affected areas.

This problem is also solved by the fact that for diagnosis, fluorescence images of affected skin areas are additionally used.

This problem is also solved by the fact that they conduct additional irradiation with light with a wavelength of 400-620 nm.

This problem is also solved by the fact that they conduct additional irradiation with light with a wavelength of 640-800 nm.

This problem is also solved by the fact that they conduct spot irradiation directly into the channel of the hair follicle with an energy density of 1200-4500 J / cm ² for a period of not more than 1 second.

This problem is also solved by the fact that they carry out spot irradiation with an energy density of 10-1200 J / cm ² .

This problem is also solved by the fact that they conduct diffuse irradiation with an energy density of 50-200 J / cm ² .

This problem is also solved by the fact that they conduct point or diffuse irradiation of the directly affected area of the skin.

This problem is also solved by using a 2-20% solution of 5-ALA.

This problem is also solved by the fact that the incubation time in the case of using 5-ALA is 1-3 hours.

The indicated interval of the energy density of the irradiating light is explained by the fact that at values lower than the lower limit it is impossible to obtain the necessary therapeutic effect. Exceeding the upper limit can lead to pain and burns.

The indicated range of concentrations of 5-ALA is explained by the fact that at values lower than the lower limit, it is impossible to obtain the necessary therapeutic effect. If the upper concentration limit is exceeded, discomfort in the patient may be associated with a burning sensation and tingling during exposure to the drug and the appearance of pain during irradiation. Exceeding the upper limit of 5-ALA concentrations can also lead to burns.

The exposure time with 5-ALA is determined by the time required for penetration of 5-ALA into epithelial cells, hair follicles, and subsequent metabolization along the porphyrin pathway until PP IX is formed. The exposure time depends on the individual properties of the skin and the concentration of 5-ALA.

In accordance with the proposed method of treatment and diagnosis, immediately before PDT, diagnostics are carried out using fluorescence spectra and / or images of the affected areas in fluorescence light. At high concentrations of endogenous porphyrins in the affected areas, point or diffuse irradiation of directly affected skin is performed.

An applicator containing 5-ALA is applied to areas that do not have intense intrinsic fluorescence, and after exposure and removal of the applicator, they are irradiated point and / or diffuse with light with a wavelength of 400-800 nm, the energy density of the irradiating light is 10-4500 J / cm ² s the possible use of additional means of exposure, providing an increase in the content of the photosensitizer in the affected areas. As a similar effect, infrared light can be used. The course of the irradiation process is monitored by recording the fluorescence spectra and obtaining fluorescence images of the affected areas.

The proposed method is illustrated by the following examples.

Example 1

Patient Sh., 22 years old, with a diagnosis of acne 4 degrees, localization - face, neck, behind the ear region, a spectral analysis of the skin was performed, as a result of which it was found that certain elements of the rash have a pronounced intrinsic fluorescence. On figa spectrum No. 3 corresponds to the fluorescence of endogenous porphyrins in the affected area of the skin before irradiation. The concentration of endogenous porphyrins at this point allows you to evaluate the diagram (figb), spectrum No. 3 corresponds to column No. 3. In the marked areas with high fluorescence of endogenous porphyrins, spot irradiation was performed with light with a wavelength of 630 ± 10 nm and an energy density of 1200 J / cm ² . Point irradiation was carried out with a semiconductor laser with a wavelength of 630 nm. Spectrum No. 2 (FIG. 1A) corresponds to fluorescence of endogenous porphyrins at the marked point on the affected area of the skin after irradiation. Column No. 2 in the diagram (FIG. 1B) allows us to estimate the concentration of endogenous porphyrins at a given point after irradiation. When comparing spectra Nos. 2 and 3, and the corresponding columns in the diagram, it is seen that, as a result of irradiation, the concentration of intrinsic porphyrins decreased by approximately 2 times and is outside the lower limit of the therapeutic value interval, which was determined based on the practice of PDT. Therefore, further irradiation will not contribute to the achievement of the therapeutic effect.

For comparison, the fluorescence spectrum of normal skin is shown, where the fluorescence of endogenous porphyrins is also low (Fig. 1A, spectrum No. 1), it corresponds to column No. 1 in the diagram (Fig. 1B), so further irradiation will not contribute to the therapeutic effect.

After that, an applicator moistened with a 15% 5-ALA solution was applied to the remaining affected areas of the face skin that did not have high fluorescence of endogenous porphyrins. The applicator was covered with a moisture-proof dressing and kept on the skin for 2 hours, then the applicator was removed and the accumulation of PP IX was monitored spectrally and using fluorescence images. Figure 2A (spectrum No. 6) shows the fluorescence of ALA-induced PP IX after 2 hours exposure with an applicator containing 5-ALA, column No. 6 in the diagram (Fig.2B). For comparison, FIG. 2A shows spectrum No. 2 corresponding to fluorescence of ALA-induced PP IX after 2 hours exposure with an applicator containing 5-ALA on healthy skin (column No. 2, FIG. 2B). When comparing spectra Nos. 6 and 2, and the corresponding columns in the diagram reflecting the concentration of PP IX, a high contrast accumulation of ALA-induced PP IX in the affected areas of the skin is seen compared to healthy tissue.

The treated areas were irradiated diffusely with light with a wavelength of 630 ± 10 nm and an energy density of 200 J / cm ² and point light with a wavelength of 630 ± 10 nm and an energy density of 550 J / cm ² to reduce the concentration level of PP IX below therapeutic values. A sequential decrease in the concentration of ALA-induced PP IX during the irradiation process is demonstrated by spectra Nos. 5 and 3, showing fluorescence of ALA-induced PP IX in the affected areas of the skin after irradiation for 30 sec and 1 min, respectively.

Thus, the spectral method made it possible to quantify the concentration of endogenous porphyrins or PP IX. Fluorescence spectra were recorded on a LESA-01-BIOSPEC setup (Patent No.RU 2169590 7, A 61 N 5/06, publication date 06/27/2001).

After PDT for 3-7 days, peeling (exfoliation) was observed in the treated areas and the formation of a necrotic crust at the points of radiation exposure. The fluorescence spectra in these skin areas corresponded to the picture of necrosis (figa, spectrum No. 4).

Two types of control over the treatment process were used - spectral analysis and obtaining two-dimensional fluorescence images of affected skin areas. Fluorescence images of areas with increased accumulation of endogenous or ALA-induced porphyrins were obtained using a light source based on a metal halide lamp MHR-100, BLV (Germany) with a wavelength of λ in the range of 400-430 nm and a narrow-band filter A = 635 ± 5, 700 ± 5 nm. The figure 3 shows examples of two-dimensional fluorescence images of the affected skin in the behind-the-ear region (Fig. 3A) and on the chin (Fig. 3B) of patient Sh., Obtained after 2-hour exposure with an applicator containing 5-ALA and removal of the applicator.

Diagnostics and control were carried out at all the main stages of PDT.

Spectroscopic studies of the skin were performed before PDT, the next day and one week after the PDT session. The rate of sebum secretion was measured before and after the course of treatment. The course of treatment included 3-5 PDT procedures carried out with an interval of one week.

Photodynamic therapy caused temporary acne-like folliculitis. Sebum secretion stopped for 2 weeks and remained lowered compared to baseline for 6 months. The number and density of rashes sharply decreased. Immediately after PDT, hyperemia and edema were observed, which persisted for 3 days.

The result of PDT is shown in figure 4, showing the condition of the patient's skin on the chin before treatment (figa) and after treatment (figv).

Example 2

Patient M, 19 years old, with a diagnosis of acne 4 degrees (acne conglobata), localization - cheeks, forehead, chin, was performed spectral analysis of the skin according to the method of Example 1, which showed a high level of accumulation of endogenous porphyrins. After that, point irradiation of individual elements of inflammation was performed with light with a wavelength of 630 ± 10 nm and an energy density of 700 J / cm ² . An applicator with a 20% solution of 5-aminolevulinic acid was applied to the affected areas of the facial skin that did not have intense intrinsic fluorescence. The applicator was covered with a moisture-proof dressing and kept on the skin for 1 hour, then the applicator was removed and individual large inflammation elements were irradiated with spot light with a wavelength of 630 ± 10 nm and an energy density of 650 J / cm ² to reduce the concentration level of PP IX below therapeutic values, and then the entire affected area was irradiated diffusely with light with a wavelength of 630 ± 10 nm and an energy density of 130 J / cm ² until the PP IX concentration level decreased below therapeutic values. PDT control was carried out according to the method of Example 1.

Sebum secretion stopped for 1.5 weeks and remained lowered compared to baseline for 4 months. The number and density of rashes decreased. Immediately after PDT, hyperemia and edema were observed, which persisted for 4 days.

Example 3

Patient T., 21 years old, second-degree acne (acne comedonica, acne papulopustular), localization - cheeks and forehead, back. Fluorescence images and spectra of the affected skin areas were obtained according to the method of Example 1, as a result, it was noted that the concentration of endogenous porphyrins is below the level of therapeutic values. An applicator with a 2% solution of 5-aminolevulinic acid was applied to the affected areas. The applicator was kept on the skin for 1 hour, then it was removed and individual elements of the inflammation were irradiated with spot light with a wavelength of 630 ± 10 nm and an energy density of 10 J / cm ² to reduce the concentration level of PP IX below therapeutic values, and then the entire affected area was irradiated diffusely with light with a wavelength of 630 nm and an energy density of 50 J / cm until the PP IX concentration level is lower than therapeutic values, and then additional irradiation with light with a wavelength of 425 ± 10 nm was performed using a metal halide-based light source Oh lamp MHR-100, BLV (Germany). PDT control was carried out according to the method of Example 1.

Sebum secretion stopped for 2 weeks and remained lowered compared to baseline for 6 months. The number and density of rashes decreased. Immediately after PDT, hyperemia was observed, which persisted for 2 days.

Example 4

Patient S., 17 years old, fourth-degree acne (acne papulopustular, acne conglobata), localization of the cheeks and forehead, spectroscopic examination of the skin was carried out according to the method of Example 1, which showed a high level of accumulation of endogenous porphyrins. After that, point irradiation of individual elements of inflammation was carried out directly into the hair follicle channel with light with a wavelength of 630 ± 10 nm and an energy density of 4,500 J / cm ² , the irradiation time was 0.5 sec. Then, an applicator with a 5% solution of 5-aminolevulinic acid was applied to the remaining affected areas. The applicator was kept on the skin for 1.5 hours, then the applicator was removed and the treated areas were irradiated with diffuse light with a wavelength of 630 ± 10 nm and an energy density of 170 J / cm ² until the concentration of PP IX decreased below the level of therapeutic values. During exposure to the drug, the skin was irradiated with a light source based on a metal halide lamp MHR-100, BLV (Germany) with light with a wavelength of 780 ± 10 nm. PDT control was carried out according to the method of Example 1.

After treatment, the release of sebum stopped for 2 weeks and remained lower than the initial level for 4 months. The number and density of rashes decreased. Immediately after PDT, hyperemia and edema were observed, which persisted for 3 days. Within a day after PDT, the opening of a clogged funnel of the hair follicle was observed and the purulent contents of the pustule were released outside, which subsequently dried up with the formation of a crust.

Example 5

Patient A., 28 years old, fourth-degree acne (acne papulopustular, acne conglobata), localization - face, back, spectroscopic examination of the skin was carried out according to the method of Example 1, which revealed a high level of accumulation of endogenous porphyrins. Then, point irradiation of individual elements of the inflammation on the back was carried out directly into the hair follicle channel with light with a wavelength of 630 ± 10 nm nm and an energy density of 2700 J / cm ² , the irradiation time was 0.7 seconds, and after that diffuse irradiation of the entire affected area with light was carried out with a wavelength of 630 ± 10 nm and an energy density of 180 J / cm ² to lower the level of concentration of endogenous porphyrins below the level of therapeutic values. PDT control was carried out according to the method of Example 1.

Sebum secretion stopped for 1.5 weeks and remained lowered compared to baseline for 2 months. The number and density of rashes decreased. Immediately after PDT, hyperemia and edema were observed in the areas of point irradiation, which persisted for 2 days. Within 2 days after PDT, the opening of a clogged funnel of the hair follicle was observed and the purulent contents of the pustule were released outside, which subsequently dried up with the formation of a crust.

Thus, the proposed method provides high efficiency for the treatment of acne (acne vulgaris) due to spectral fluorescence diagnostics and monitoring of the treatment process.

Claims (9)

1. A method for the diagnosis and photodynamic therapy of acne (acne vulgaris) using an endogenous or induced photosensitizer of a group of porphyrins, which consists in diagnosing with the fluorescence spectra of the affected areas, areas with intense intrinsic fluorescence are irradiated with light with a wavelength of 630 ± 10 nm and an energy density of 10-4500 J / cm ² , on areas that do not have intense intrinsic fluorescence, apply an applicator containing a 2-20% solution of 5-aminolevulinic acid, and After exposure and removal of the applicator, they are irradiated with light with a wavelength of 630 ± 10 nm and an energy density of 10-4500 J / cm ² , the course of the irradiation process is monitored by recording the fluorescence spectra in the affected areas of the skin before irradiation, after applying an applicator containing 5-aminolevulinic acid, after irradiation, and irradiation was stopped with a decrease in the concentration of porphyrins below therapeutic values. 2. The method according to claim 1, characterized in that for the diagnosis additionally use fluorescence images of the affected areas of the skin. 3. The method according to claim 1, characterized in that they conduct additional irradiation with light with a wavelength of 400-620 nm. 4. The method according to claim 1, characterized in that they conduct additional irradiation with light with a wavelength of 640-800 nm. 5. The method according to claim 1, characterized in that the point irradiation is carried out directly into the channel of the hair follicle with an energy density of 1200-4500 J / cm ² for a period of not more than 1 s. 6. The method according to claim 1, characterized in that the point irradiation is carried out with an energy density of 10-1200 J / cm ² . 7. The method according to claim 1, characterized in that the diffuse irradiation is carried out with an energy density of 50-200 J / cm ² . 8. The method according to claim 1, characterized in that the point or diffuse irradiation is carried out directly on the affected area of the skin. 9. The method according to claim 1, characterized in that the incubation time in the case of using 5-aminolevulinic acid is 1-3 hours

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