RU2345803C2 - Method of phototimmunotherapy using wave energy activated photosensitiser out of human body - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: PS is chlorophyll derivatives. PS is activated by light with oxygen, preliminary or in one stage introduced to organism using wave energy sources. Herewith radiation power is 0.1-20000 Wt, with dose 1-100000 J.

EFFECT: higher specificity of antibody response, suppression of pathological centre, activation of cell exchange processes, higher immune protection of organism in whole, improvement of life quality and tumour operability.

3 cl, 11 dwg, 1 tbl, 3 ex

Description

The invention relates to medicine and can be used to treat metabolic disorders, immunity, cardiovascular system, dermatological, infectious, parasitic, tumor, non-specific inflammatory and allergic diseases in adults and children.

Known methods for treating diseases using photodynamic therapy (Weishaupt KR, Dougherty T.O., Potter WR Purified hematoporphyrine derivative for diagnosis and treatment of tumors, and method, PCT, WO 84/01382, 1984, p.1-25), based on the combination of the phototoxic and / or photomodifying effect of the drug (toxic and / or modifying effect on the cell and tissue when it interacts with light) with the accumulation of the drug mainly in a pathologically altered cell or tissue. Photodynamic therapy also includes the action of laser radiation on blood cells in the presence of a photosensitizer (PS) (Proc. SPIE, 5973 (2005), OX-1-7, Photoditazine mediated chemosensitized blood photomodification. Advanced tumors treatment preliminary results. MLGelfond, DLVassiliev ) and antimicrobial photodynamic therapy (Laser medicine, 6 (1) (2002) 32-38. Antimicrobial photodynamic therapy. N.E. Vasiliev A.P. Ogirenko; Journal of Antimicrobal Chemotherapy. Photodynamic antimicrobial Chemotherapy. 42 (1998) 13- 28. M.Wainwright).

These methods according to the type of action are divided into phototoxic and photomodifying. Under the phototoxic effect, cell destruction and tissue necrosis occur due to direct contact of the photosensitizer, oxygen and light with tissue and blood cells (local action with a radius of about 20 nm for Photofrin II (ФII)). This radius is related to the lifetime of the active oxygen particle in the cellular environment (about 48 nanoseconds for FII), the type and concentration of PS (Phys. Med. Biol. 50 (2005) 2597-2616, Characterization of Photofrin photobleaching for singlet oxygen dose assessment during photodynamic therapy of MLL cells in vitro, Jonathan S. Dysart and Michael S. Patterson; J. Photochem. PhotobioL, B: Biol., 6 (1990), 343-344. On the diffusion length of singlet oxygen in cells and tissues. J . Moan). During the photomodifying action as a result of photochemomodification of cellular markers of pathological tissue, antigen-presenting cells and cells with tumor-specific memory are activated and an immune response is formed, sometimes accompanied by an active antitumor immune response that destroys tumors detected by the immune system far from the primary focus of the combined action of PS, oxygen and light (Proc. SPIE 4961 (2003) 1-9, Specific anti-tumor immune response with photodynamic therapy mediated by benzoporphyrin derivative and chlorin (e6), Ana P. Castano, Faten Gad, Touqir Zahra, Michael R. Hamblin).

During PDT, both mechanisms can be implemented simultaneously (Medical immunology. Immunological aspects of photodynamic therapy, 5-6 (2003) 507-518. N.E. Vasiliev, E.D. Danilenko, G.M.Sysoeva).

However, such methods of treatment require a single, and often multiple exposure to the light of the focus of the disease (for example, a tumor) or blood. For this, light must be brought to the focus of the disease. This, firstly, requires accurate knowledge of the location of the focal point of the disease, which is difficult even with highly developed diagnostics and requires sophisticated equipment (simultaneous use of ultrasound, computed tomography and NMR, blood tests and biopsies), therefore in modern oncology there is an acute problem of identifying primary tumors in the patient. Secondly, to summarize the light (except when the focus of the disease is located on the skin) it is necessary to use an endoscope or interstitial or intravascular invasion, which is associated with additional expensive equipment, a medical surgical hospital and inconvenience for the patient.

As the closest to the proposed one, a method is also known, according to which any of the PSs - merocyanine 540, PII or naphthalimide - is activated with light outside the tube (ex vitro), then preactivated PS is added to the culture of herpes viruses or human immunodeficiency, or cancer cells of various lines, which leads to inactivation of viruses and inhibition of the proliferative activity of cancer cells by 70-90%. while 85% of normal human blood leukocytes survive (Eur J Cancer (1990) 26 (5), 551-553. Preactivation - a novel antitumour and antiviral approach. KSGulliya, T. Chanh, J. Newman, S. Pervaiz , JLMatthews). The role in the damaging effect in it is assigned to the tumor-specific metastable products of degradation of these PSs along with the products of oxidation of other molecules that are formed under the influence of light, and further light exposure is no longer required for the biological activity of PS to manifest.

The disadvantage of this method is its laboratory nature: until now there is no clinical technique for its use in humans for the reasons given below (The FASEB Journal (2001); 15 612-617. Reactive oxygen-dependent production of novel photochemotherapeutic agents. S. Pervaiz). The main disadvantage is that the proposed in the method of PS FII has a low tumor specificity both in cell cultures and in experiments on animal tumor carriers and in humans. In animals for model superficial forms of cancer, the ratio of accumulation in the tumor to normal tissue is 0.8 for the skin above the tumor. 1.1 for the skin around the tumor, and 2 for muscle tissue (Photochem. Photobiol. (1989) 50, 221-228. Distribution and elimination of Photon-in II in mice. DABellnier, Y.-K. Ho. RKPadney , JRMissert and TJDougherty). In people with various forms of cancer with localization in the abdominal cavity, the ratio of accumulation in the tumor to normal tissue is on average 1.6, the maximum is 2.3 (Clinical Cancer Research, 12, (2006) 5464-5470. Photofnn Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy (SMHahn, MEPutt, J. Metz, DBShin, E. Rickter, C. Menon, D. Smith, E. Glatstein, DLFraker and T.M. Busch). Merocyanine 540 is able to accumulate in the membrane and structures of cancer cells (Biochim Biophys Acta (2005) 1722 (1) 51-59. Merocyanine 540-sensitized photokilling of leukemia cells: role of post-irradiation chain peroxidation of plasma membrane lipids as revealed by nitric oxide protection. M. Zareba, M. Niziolek. W. Korytowski, AW Girotti), but as a dye for cytology, merocyanine 540 is not used in clinical medicine due to the high genotoxicity and phototoxicity for healthy tissues in vivo (Toxicol Lett (2000) 115, 53-61. Photocytotoxic and DNA damaging effect of temoporfin (mTHPC) and merocyanine 540 (MC540) on nasopharyngeal carcinoma cell. CMYow, NKMak, S. Szeto, JYChen, YLLee, NHCheung, DPHuang, AW Leung). Naphthalimide does not have tumor specificity.

These facts turn the mentioned method when used in humans into an analogue of traditional tumor chemotherapy, which does not differ in novelty.

An object of the present invention is to propose a method for remote and selective exposure of a tumor, infectious, parasitic, dermatological, immunological or allergic disease to a foci, a source of metabolic disorder or cardiovascular system suitable for clinical use.

Not all foci of diseases, such as tumors, can be treated with PDT due to the prevalence of the process or inaccessibility to laser exposure (for example, multiple metastases or metastases to the lymph nodes of the mediastinum or abdominal cavity). In addition, many patients, for various reasons, cannot be subjected to the classical methods of treatment - radiation, surgical or chemo-, antibiotic therapy. Doctors recommend only symptomatic treatment to such patients.

The problem is solved by creating a method that involves the introduction of FS previously or simultaneously with the introduction of the exposed wave energy in the presence of oxygen, moreover, chlorophyll derivatives containing, individually or together in one or several compounds that make up the composition, are used as PS: 15-carboxymethyl-, 3-vinyl-, 15-formyl-,

where R ₁ = oxygen atoms,

sulfur or NR,

R ₂ = R or -COOR,

R = hydrogen atom or alkyl

The objective of the present invention is also the achievement in the method of treatment of high reproducibility, simplicity, lack of toxicity for healthy organs, tissues and systems of the body, chemical stability of the preactivated form of PS for at least several days, the combination of physicochemical and biological properties of PS, which will ensure its effectiveness in therapy.

The present invention is fundamentally different from all known methods of exposure to the focus of the disease, the choice of chlorins as photosensitizers, and the impact of wave energy outside the human body (unlike, for example, intravascular and vascular exposure to light from a photosensitizer circulating in the blood ) With PDT, the combined action of oxygen, light, and PS occurs on a biological object, and in the present invention it is spaced apart in time (oxygen and wave energy act on PS, and then the oxidized form of PS on a remote biological object). By the type of action exerted on the body, this method can be attributed to photomodifying and increasing the specific recognizing functions of the immune system and is called “photoimmunotherapy” (FIT).

The essence of the method lies in the fact that the FS before the introduction into the body is activated by radiation in the presence of oxygen, moreover, chlorophyll derivatives are used as the PS, containing individually or together, in one or several compounds of the group of 15-carboxymethyl-, 3-vinyl 15-formyl

where R ₁ = atoms

oxygen

sulfur or NR,

R ₂ = R or -COOR,

R = hydrogen atom or alkyl

and as radiation - wave energy with a power of 0.1-20000 W at a dose of 1-100000 J.

Besides. in the method, as an example of a composition from the above-mentioned FS, the drug “Radachlorin ^® ” (PX) containing chlorin e ₆ (13-carboxy-17- [2-carboxyethyl] -15-carboxymethyl-17,18-trans-dihydro-3 is used -Vinyl-8-ethyl-2,7,12,18-tetramethylporphyrin) (contains the groups 15-carboxymethyl-, 3-vinyl-)

in an amount of 80-90%, purpurin 5 (13-carboxy-17- [2-carboxyethyl] -15-formyl-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18- tetramethylporphyrin) (contains the group 15-formyl-)

in an amount of 5-20%, as well as purpurine 18-chlorin p ₆ (13-carboxy-17- [2-carboxyethyl] -15-carboxy-17,18-trans-dihydro-3-vinyl-8-ethyl-2, 7,12,18-tetramethylporphyrin)

in quantity - the rest, so that these components form the composition, and in dosage forms their salts with alkali metals and nitrogen-containing compounds can be used.

In addition, the method uses a medical laser "LAHTA-MILON ^® ", emitting wave energy with a wavelength of any (or two at a time) in a row 635, 662, 670, 690, 798, 808, 920, 960, 975, 1060, 1260, 1300, 1470, 1530, 1750 nm, power from 1 to 18 W in continuous mode or pulses from 1 to 1000 ms (with pauses from 1 to 1000 ms).

The specified method is implemented using standard medical equipment for irradiating FS (lasers, incandescent lamps, LED, fluorescent, gas-discharge lamps, sources of radio, magnetic and ultrasonic radiation, waveguides - quartz and others, both equipped and not equipped with cylindrical diffusers), for the introduction of activated FS into the human body (droppers, syringes, ultrasound and other inhalation devices).

In the method, chlorophyll derivatives are used due to their low toxicity (The use of lasers for the diagnosis and treatment of diseases. A scientific information digest - an appendix to the bulletin “Laser-inform” (2001) 3, 34-40. Assessment of the biological properties of new chlorine-type photosensitizers. A.V. Reshetnikov, A.V. Ivanov, O.Yu. Abakumova, A.T. Gradyushko, I.D. Zalevsky, A.V. Karmenyan, V.P. Laptev, N.P. Neugodova) and high selectivity of accumulation in the foci of pathological processes (tumors, abscesses, infected tissues, atherosclerotic b larvae, etc.) (Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy IX. - TJ Dougherty, ed., Vol. 3909, 131-137 (2000). One more PDT application of chlorin e ₆ . AVIvanov, AVReshetnickov, GVPonomarev). Namely, in tumor models of experimental animals with the introduction of a chlorophyll derivative at a dose of 20 mg / kg 0.5-5 hours after administration, the ratio of the concentration of chlorin in the tumor to the concentration in normal tissue ranged from 3 to 40, and for the skin and muscles, respectively 4 and 3, which exceeds the therapeutic index FII in a similar method of treatment, respectively, 3.6 and 2 times. In the treatment of skin cancer in humans, the fluorescence contrast of the accumulation of PX preparation containing chlorophyll derivatives at a dose of 1.2 mg / kg (tumor / skin) ranged from 3/1 to 6/1, which is higher than the therapeutic index II in the same way by the maximum possible value 2.6 times of treatment (Russian Biotherapeutic Journal (2004) 1, 77-82. Photodynamic therapy and fluorescence diagnostics with the photosensitizer Radachlorin ^® in patients with skin cancer. EG Vakulovskaya. A.V. Reshetnikov, I.D. .Zalevsky, Yu.V. Kemov; Current research on Laser Use in Oncology 2000-2004, AVIvano v, MAKazaryan, eds., Proceedings of SPIE (2005) 5973, 81-86. Photodynamic therapy and fluorescent diagnostics of head and neck cancer with second-generation photosensitizers. EGVakulovskaya). However, for the proposed method, it is fundamentally not so much a greater therapeutic relationship for PX as the absence of a significant affinity for it to the skin, mucous membranes and parenchymal organs, due to which it is eliminated from the body by 96% in 24 hours (while the remaining amount is retained by pathologically changed tissues up to 6 days). FII is removed from normal tissues within 2.5-3 months, and its activation during this period by daylight can lead to a systemic toxic effect on the patient's body.

In the method, the power and doses of wave energy are proposed in the range of 0.1-20000 W, 1-100000 J. This is due to the fact that a power of less than 0.1 W makes the procedure too long, and powers above 20 kW are technically inaccessible and impossible currently use in a hospital setting. Doses of less than 1 J per dose of PS are not sufficient for its activation, and a dose of more than 100 kJ leads to photobleaching of PS and the loss of its properties.

The method provides chlorophyll derivatives containing individually or together in one or more compounds of the group 15-carboxymethyl-, 3-vinyl-, 15-formyl-,

where R ₁ = oxygen atoms,

sulfur or NR,

R ₂ = R or -COOR,

R = hydrogen atom or alkyl

It is known that the formation of singlet oxygen ( ¹ O ₂ ) requires the presence of PS molecules, with the help of which photon energy is transferred to oxygen molecules. It is also known that the effective PS of the formation of ¹ O ₂ are the main pigments of photosynthesis, for example, derivatives of chlorophylls. Singlet oxygen ( ¹ O ₂ ) is called electronically excited O ₂ molecules located at one of two singlet levels - log + and log. Thus, ¹ O ₂ differs from other reactive oxygen species (O ₂ ^- , HOO, OH radicals, or H ₂ O ₂ hydrogen peroxide) in that it requires only energy absorption without chemical modification of oxygen molecules. According to many studies, the lg - state ¹ O ₂ leads to peroxidase reactions. The groups mentioned in the method from the point of view of their chemical properties are capable of chemical transformations according to the schemes depicted in Figs. 1-4.

And then each of the four substances is able to attach a second oxygen molecule. This is demonstrated for a single substance by the circuit shown in FIG. 5. For other substances, the addition of the second oxygen molecule in the -CH = CH ₂ group proceeds similarly. This reaction is important for the subsequent intramolecular transfer of the reducing electron and the dismutation reaction with the release of singlet oxygen and hydrogen peroxide.

In this case, the p-electron molecular orbitals of the porphin core (18-π-electron aromatic system) stabilize superoxide anions formed as a result of the action of wave energy on the PS, leading to the chemical stability of the activated PS form for at least several days.

Peroxides formed under the influence of light and oxygen from the above groups, attached directly to the aromatic system of chlorophyll derivatives, stabilized by the presence of a porphin macrocycle and therefore long-lived, after being introduced into the human body, accumulate according to the property inherent in chlorin e ₆ derivatives in foci of tumor, infectious, parasitic, dermatological, immunological or allergic diseases, can carry an oxygen atom, a hydroxyl radical, or an electron like each other ha, and on the biomolecules of the membranes of pathologically altered cells (PIC) or microorganisms.

Singlet oxygen modified (oxidized) atomic groups of 15-carboxymethyl- and 3-vinyl-, 15-formyl- and 3-vinyl-,

where R ₁ = oxygen atoms,

sulfur or NR,

R ₂ = R or -COOR,

R = hydrogen atom or alkyl

and 3-vinyl-, connected to the aromatic core of porphin, during intermolecular (Figure 1-4) (or intramolecular - Figure 5) transfer of the reducing electron is capable of transformations similar to the known superoxide anion dismutation scheme, as a result of which the singlet can be released oxygen (which previously joined the chlorophyll derivative molecule during its activation by radiation) and hydrogen peroxide:

During the reaction of superoxide anion and hydrogen peroxide, a hydroxyl radical is formed:

which, when reacted with superoxide anion, forms singlet oxygen again:

Thus, the reaction products can be oxygen, water, hydroxide anion and singlet oxygen (which is second only to the hydroxyl radical in oxidizing ability).

Oxygen and singlet oxygen, further under certain conditions, can also lead to the formation of ozone and atomic oxygen:

These peroxides of both PS itself and substrates that are associated with it and also oxidize, turning into oxygen-containing radicals, can exist, according to chemiluminescence, from minutes to tens of hours and can be important factors of photoimmunotherapy (FIT), additional to the peroxides of PS accumulated in the outbreak.

Thus, on the shells of all PICs under the action of peroxides and other active forms of oxygen (total ROS), photochemomodification of the molecules responsible for the signal transmission and recognition function occurs, as a result of which the cells become recognizable for the body's immune system, which better recognizes and suppresses the pathological process. The death of the altered cells leads to a signal to the human stem cells, which are a kind of “storage” of the body, initiating the formation of new cells (for example, in the case of massive tissue damage). In place of the destroyed cells, new, healthy cells appear. At the same time, metabolic processes in the cells are activated, and the level of immune defense of the body as a whole rises. A similar effect is also on pathogenic microflora.

The action of PX does not appear at the gene level, which excludes genetic modifications. The lack of stimulation of the division of poorly differentiated (cancerous) cells has been additionally proved by animal experiments. This was also confirmed by immunological studies - the growth of the immunoregulatory index T4 / T8 and the growth of immunoglobulin A, which indicates an adequate completion of the immune response specifically to membrane-bound cell markers of destructible PICs (Rheological properties of blood in patients with lymphogranulomatosis during and after chemotherapy. Radachlorophyll effect. Materials. Materials 22 Symposium on Rheology of the Rheological Society named after G.V. Vinogradov, June 21-26, 2004, Valdai, page 41. A.V. Reshetnikov, N.A. Gorbunova, L.I. Ershova, Z.M .Likhovetskaya, T.A. Bal kina G.N.Kurbakova, M.L.Markova, N.N.Tsyba).

Along with increasing the specificity of the systemic (humoral) immune response, the action of the proposed method is also implemented at the level of suppression of the pathological focus by direct activation of blood mononuclear cells (macrophages). It is known that it is possible to stimulate macrophages by the action of 5-aminophthalhydrazide (Galavita), the stimulating action may be based on the mechanism of hyperproduction of the superoxide anion radical (Russian Biotherapeutic Journal (2005) 4/4, 44-49. In vivo and in vitro inducible effects Galavita on the chemiluminescent activity of blood mononuclear cells of cancer and non-cancer patients. A.F. Tsyb, M.A. Kaplan, V.N. Petrov, L.I. Krikunova, V.N. Medvedev, I.A.Smirnova), which is also one of the possible products of activation of PX by wave energy. Activated macrophages act on tumor and bacterial cells either cytotoxically or phagocytically. Their effect, however, as well as activated PS in the proposed method, is associated with the production of ROS, as well as interferon, interleukins, tumor necrosis factor, proteases, hydrolases, etc. (cited by ibid.).

The method can be used to treat cancer, improves the quality of life and in 33% of cases can increase the operability of the tumor (the condition of the patients after the procedure has improved significantly, which allowed surgical removal of the tumor).

The invention can be illustrated by the following examples. The drug “Radachlorin” was used, a solution for intravenous administration, 0.35% (Registration certificate No. LS-001868 of 08/04/2006). Shown in the method of FS are part of this drug either as the main components, or in the form of possible impurity compounds.

Example 1. Oncological diseases. The method is shown for:

1. Patients in the stage of cancer T3-T4 with contraindications to other methods of treatment or when recommended according to standard protocols only symptomatic treatment;

2. Combinations with classical PDT in order to enhance the effect;

3. Preoperative preparation for cancer of any localization and impossibility of classical PDT;

4. Post-operative ablastics.

PS at a dose of 0.5 mg / kg is diluted in 200.0 ml of physiological saline and is connected via a dropper to the patient's peripheral vein in a standard way. The drip rate is 40-60 drops / min. The time of drip administration is 40-60 minutes. Simultaneously with the start of drip administration, a sterile, single-use fiber is introduced into the lumen of the dropper by puncture of the needle cannula and the FS solution is activated by wave energy in the presence of oxygen.

It is also possible to activate directly in a bottle with a solution of FS with its subsequent injection or infusion introduction into the patient's body.

6 and 7 demonstrate the implementation of the method in this example.

Before, in 1-2 and 5-7 days after the above procedure, patients underwent laboratory clinical studies. The data in Table 1 demonstrate the effectiveness of the method, changes in biochemical and clinical laboratory parameters, indicating its safety for condition and transitivity. In full accordance with the concept of FS pharmacokinetics, there is an increase in hepatic transaminases for 1-2 days and normalization for 5-7 days, normalization of blood sugar, transient increase in bilirubin.

The study included 21 patients with various forms of malignant tumors. All patients are shown symptomatic treatment with oncologists for various reasons.

FS was activated with light previously or simultaneously with its introduction into the body by a wave energy source - a laser - with a power of 0.1-20000 W, at a dose of 1-100000 J in the presence of atmospheric oxygen:

Patients 1-3: FS were activated with a laser with a wavelength of 662 nm for chlorin with groups of atoms of 15-carboxymethyl- and 3-vinyl- (chlorin e ₆ ) with a power of 0.1 W at a dose of 1 J in a dropper.

Patients 4-6: FS was activated with a laser with a wavelength of 665 nm for chlorin with groups of 15-formyl- and 3-vinyl- (purpurin 5) atoms with a power of 2 W at a dose of 5000 J / ml in a vial of the drug.

Patient C. Diagnosis Benefits for the patient Effect Condition after nephroectomy of the left kidney for hypernephroma, Relapse of hypernephroma TSNxMx damage to the vertebral body and legs of the diaphragm surgical treatment not shown a 2/3 decrease in adrenal gland formation Partial (figure 10)

Patients 7-9: PS was activated with a laser with a wavelength of 635 nm with a power of 1 W at a dose of 1000 J for chlorins with groups of 3-vinyl and

where R ₁ = oxygen atoms,

sulfur or NR,

R ₂ = R or -COOR,

R = hydrogen atom or alkyl

Patient T. Diagnosis Benefits for the patient Effect nephroectomy 5 years before the procedure, moderately differentiated cancer of the right kidney T ₄ N ₂ M ₁ no tumor growth for 2 months stabilization

Patients 10-12: FS was activated by a laser with a wavelength of 2500-4200 nm with pulses of 0.5 μs length for the Radachlorin composition, with a pulse power of 10,000 W (pause 3 μs, total duration of energy exposure 100 μs, duration of the entire activation process 0 , 7 s) at a dose of 1 J.

Patients 13-15: FS was activated by a laser with a wavelength of 5000-6000 nm with pulses of 0.5 μs length for the Radachlorin composition, with a pulse power of 20,000 W (pause 3 μs, total duration of energy exposure 5 s, duration of the entire activation process 35 c) at a dose of 100,000 J.

Patients 16-18: PS was activated with a laser with a wavelength of 662 nm for chlorin with groups of 15-carboxymethyl- and 3-vinyl- (chlorin e ₆ ) atoms with a power of 2.5 W at a dose of 25,000 J (continuous radiation for 10,000 s).

Patient G. Diagnosis Benefits for the patient Effect condition after removal of the mammary gland on the right and polychemotherapy, pleurisy, metastasis in the lymph nodes of the neck, adenocarcinoma T ₂ N ₁ M ₁ 50% reduction in exudation after 1 day: it was 200 ml per day, it became 50-60 ml per day palliative

Patients 19-21: FS was activated with a laser with a wavelength of 1750 nm for the composition "Radachlorin", with a power of 1 W at a dose of 5000 J (pulse 1 s, pause 1 s, activation time 5000 s, exposure time 10000 s).

Patient T. Diagnosis Benefits for the patient Effect rectosigmoid cancer moderately differentiated adenocarcinoma T ₃ N ₂ Mx after 1 month, a decrease in education by 20% partial

Table 1 of the effects of the application of the method in 21 patients demonstrates the presence of an incomplete effect in 33% of cases (tumor reduction by more than 50%) and a partial effect in 38% of cases (tumor reduction by less than 50%). Thus, in 71% of cases, a positive clinical effect was obtained (improved quality of life) in patients who, in accordance with the general condition and standards of treatment of cancer, only "symptomatic treatment" (that is, no treatment). In 33% of cases, the procedure allowed the clinical condition of the patients to be so improved that they underwent surgical radical removal of the tumor.

The procedure has no complications, is well tolerated.

The results were documented by radiographs, photographs, ultrasound data, medical records.

Example 2. Tuberculosis. FS was activated by a laser with a wavelength of 662 nm s for the Radachlorin composition, with a wave radiation power of 2 W at a dose of 1000 J in the presence of atmospheric oxygen. Fig. 8 shows an implementation of the method in this example.

The long-term result of treatment was inhibition of the development of pulmonary fibrosis, which was revealed during a 3-year follow-up compared with the control group of patients and that was expressed in the absence of a decrease in the main indicators of the function of external respiration.

Example 3. Psoriasis. Oral administration of PS activated by wave radiation. The photostim dietary supplement (Registration certificate of the Ministry of Health of the Russian Federation No. 005730.Р.643.04.2003), which is a glycerol solution of a chlorophyll derivative containing together in one compound the groups 3-vinyl-, 15-carboxymethyl-, was used as the FS. This FS solution was activated in a bottle by wave radiation of an Elan diode lamp with a wavelength of 664 nm in the presence of air oxygen with a power density of 12 mW / cm ² (distance 25 cm) for 3600 s (light dose 43.2 J). The patient took activated FS in 5 ml for 20 days. After 10 days of administration, a decrease in infiltration and blanching of psoriatic papules and plaques was noted. After 1 month, there was a decrease in the infiltration of psoriatic papules and plaques, a decrease in peeling and the appearance of Voronov's pseudoatrophic corolla on the periphery, which indicates a positive trend against the background of the conservative treatment (Fig. 11).

Table 1. The effectiveness of the method with the intravenous administration of FS with the simultaneous activation of FS by wave energy. before 1-3 day 5-7 day red blood cells 4.58 + 0.14 4.63 + 0.14 4.68 + 0.2 hemoglobin 119.43 + 4.0 115.38 + 4.2 119.71 + 5.4 white blood cells 10.24 + 1.0 11.74 + 1.28 8.85 + 0.67 ESR 29.76 + 3.11 27.69 + 3.2 26.18 + 4.03 Sugar 5.41 + 0.22 4.19 + 0.3 4.28 + 0.4 Bilirub commonly 10.12 + 0.9 12.27 + 0.98 13.06 + 0.64 direct bilirub 1.14 + 0.19 1.77 + 0.42 1.38 + 0.24 ALT 0.22 + 0.03 0.29 + 0.2 0.19 + 0.01 ACT 0.19 + 0.02 0.7 + 0.08 0.22 + 0.04 urea 4.96 + 0.27 4.96 + 0.49 4.43 + 0.55 total protein 70.53 + 1.1 70.24 + 1.14 71.56 + 1.12 albumin 33.70 + 0.7 32.37 + 0.87 33.85 + 0.92 EFFECT Total incomplete partial without is unknown 21 7 8 3 3 33% 38% fourteen% fourteen%

Claims (3)

1. A method of treatment with a photosensitizer (PS) capable of being activated by light outside the human body, characterized in that chlorophyll derivatives are used as PS, containing individually or together, in one or more compounds making up the composition, groups 15-carboxymethyl-, 3- vinyl, 15-formyl,

where R ₁ = atoms of oxygen, sulfur or NR,
R ₂ = R or -COOR,
R = hydrogen atom or alkyl,
and activation of PS with light is carried out in the presence of oxygen previously or simultaneously with its introduction into the body by sources of wave energy with a power of 0.1-20000 W, at a dose of 1-100000 J. 2. The method according to claim 1, characterized in that as the FS use the drug "Radachlorin®" containing chlorin e ₆ (13-carboxy-17- [2-carboxyethyl] -15-carboxymethyl-17,18-trans- dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylporphyrin) (contains the groups 15-carboxymethyl-, 3-vinyl-)

in an amount of 80-90%, purpurin 5 (13-carboxy-17- [2-carboxyethyl] -15-formyl-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18- tetramethylporphyrin) (contains the group 15-formyl-)

in an amount of 5-20%, as well as purpurine 18-chlorin p ₆ (13-carboxy-17- [2-carboxyethyl] -15-carboxy-17,18-trans-dihydro-3-vinyl-8-ethyl-2, 7,12,18-tetramethylporphyrin)

in quantity - the rest so that these components form a composition, and in dosage forms their salts with alkali metals and nitrogen-containing compounds can be used. 3. The method according to claim 1, characterized in that as the source of wave energy use a medical laser "LAHTA-MILON®", emitting energy of any wavelength (or two at a time) in a row 635, 662, 670, 690, 798 , 808, 920, 960, 975, 1060, 1260, 1300, 1470, 1530, 1750 nm, power from 1 to 18 W in continuous mode or pulses from 1 to 1000 ms (with pauses from 1 to 1000 ms).

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