Method for applying photodynamic therapy and electrochemical destruction in choroid melanoma treatment

FIELD: medicine.

SUBSTANCE: method involves introducing photosensitizer in pharmaceutical water-soluble dosage form at a dose of 1.5-2.0 mg/kg * 0.7 during 40-60 min. Blood is concurrently exposed to laser radiation at a dose of 600-900 J/cm3. The wavelength is selected to match photosensitizer absorption maximum in the water-soluble dosage form. Chlorine row photosensitizer is introduced 3-3.5h later in liposome form at a dose of 1.5-2.0 mg/kg*0.3. 15 min later, laser radiation is applied all over the whole tumor perimeter in transpupillary mode with neighboring fields overlap by 5% of area with power density of 80-100 J/cm2. The wavelength is selected to match photosensitizer absorption maximum in the liposome form. Then the whole neoplasm surface is irradiated in transpupillary mode in laser radiation fields in circle moving from periphery to the center with neighboring fields overlap being equal to 5% of area. The wavelength is selected to match photosensitizer absorption maximum in the water-soluble dosage form. Power density of 80-100 J/cm2 in peripheral part is gradually increased when moving towards the center to 100-120 J/cm2. Two weeks later, localization is adjusted in diaphanoscopic transscleral way and electrochemical destruction of intraocular neoplasm is carried out with current intensity of 10-100 mA during 10-1 min.

EFFECT: enhanced effectiveness in achieving complete or partial tumor regress; reduced risk of metastatic complications.

4 cl

 

The invention relates to medicine, namely to ophthalmology, and can be used for the treatment of intraocular tumors of large size (according to the classification J.Sields, 1983).

In recent years, the principles of treatment of intraocular tumors has changed significantly. Replaced the radical surgical treatment or undue wait-and-see tactics came conservative methods, whose main objective is the complete destruction of the tumor while preserving the eyes as the body. Mandatory condition for the purpose of such techniques is a local effect on intraocular tumor with preservation of the healthy surrounding tissue. The leading role in this direction is photodynamic therapy (PDT). However, in the treatment of intraocular tumors of the large size of PDT is not efficient enough due to the limited penetration of laser radiation into the tumor tissue. In such cases, there is continued growth of the tumor, there is a need for multiple repeat sessions. Therefore, it becomes urgent to develop integrated methods of treatment, including a combination of photodynamic therapy with other techniques aimed at the destruction of tumor tissue.

There is a method of electrochemical degradation and photodynamic treatment nutrigen the x neoplasms (RF patent No. 2243755), including electrochemical destruction of tumors, intravenous administration of a photosensitizer (PS) and transpupillary laser irradiation of tumors. The disadvantage of this method is the difficulty accumulation of PS in tumor vessels due to their partial destruction in the process of electrochemical destruction, which complicates the conduct of a combined method.

The objective of the invention is to provide an efficient method of photodynamic therapy and electrochemical destruction of intraocular tumors.

The technical result is complete or partial regression of intraocular tumors, maintaining eye as the body, reducing the risk of metastasis. The technical result is achieved due to the fact that:

1. Applied photosensitizers (PS) chlorophyll-type high purity, low toxicity, have trapnest to cells with high mitotic activity, can accumulate in tumor cells, and even in small doses exhibit high photochemical activity during laser irradiation.

2. Enter FS chlorophyll-type in water-soluble form. This form has a higher trapnest to tumor cells.

3. Intravenous laser blood irradiation with simultaneous intravenous FS for 40-60 minutes (ICI is slightly PDT) causes in tumor cells enter the newly formed radical patterns that trigger apoptosis, in addition, the activation of the immune system, prevents hematogenous route of metastasis.

4. Conducting spectral-fluorescent diagnostics (CFD) allows you to determine whether there was a sufficient and necessary for conducting induced photochemical reactions accumulation of the photosensitizer in the tumor tissue compared with the surrounding.

5. Enter FS chlorophyll-type in liposomal form. The use of liposomal dosage form provides a high contrast accumulation of the photosensitizer in feeding the tumor choroidal and retinal vessels due to the mechanism of passive targeting of liposomes.

6. The sequence of the introduction of water-soluble and liposomal forms FS and the intervals of time between the introduction of the FS and IFD and the introduction of the FS laser irradiation are necessary and sufficient for accumulation of PS in tumor cells and blood vessels that feed the tumor, respectively.

7. Following after the introduction of the FS transpupillary irradiation around the tumor and the tumor's edge around its entire perimeter of the laser radiation with the given parameters causes stasis of blood and photoinduced thrombosis of blood vessels that feed the tumor, eliminates the dissemination and migration of Oholibah cells.

8. Irradiation during PDT fields of laser radiation with neighbouring fields on 5% of the area provides uniformity of exposure.

9. Subsequent transpupillary irradiation (PDT) the entire surface of the tumor in a circle from the periphery to the center of the laser radiation with the given parameters cause the death of tumor cells to a depth of up to 4.6-4.8 mm, and also eliminates the dissemination and migration of tumor cells. Proof of the effectiveness of PDT at a depth of 4.6-4.8 mm in the treatment of intraocular tumors are the following data. Thirty-two new Zealand rabbits with pigmented melanomas of the choroid spent PDT (Kim RY; Nor LK; Foster BS; Gragoudas ES; Young LH. Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness // Ophthalmology. 1996 Dec; 103(12): 2029-36): intravenously injected FS at a dose of 1 mg/kg, after which transpupillary irradiated intraocular neoplasm. The dose of laser radiation ranged from 60 to 120 j/cm2. The results histomorphologically studies have confirmed the ability of PDT to destroy melanoma of the choroid thickness of 4.6 mm In an earlier similar study (Gonzales VH, Hu LK, Theodossiadis PG, et al. Photodynamic therapy of pigmented choroidal melanoma // Ophthalmol Vis Sci. 1995; 36: 871-878) was shown the efficacy of PDT in respect of pigmented malignant melanoma of the choroid thickness of 4.8 mm

10. Conducting electrochemical degradation after 2 weeks of PDT can access the e destruction of tumor tissue in the deeper layers of the tumor, the remaining intact after PDT.

The claimed technical result can be obtained only when using the entire set of techniques proposed method.

The method is as follows. Previously using the methods of ultrasonic diagnostics determine the localization and dimensions (thickness, radial or Meridian diameters) of intraocular tumors. In the cubital vein of one arm enter FS chlorophyll-type in water-soluble dosage form, for example Photolon, Radachlorin, photoditazine, dose rate of (1.5-2.0 mg/kg × 0,7) for 40-60 minutes, and simultaneously with the introduction of the FS in the cubital vein of the other hand hold the intravenous laser irradiation of blood (ILIB) with a wavelength corresponding to the maximum absorption of the photosensitizer in water-soluble form of light radiation, for example, 662 nm for FS chlorophyll-type, in the dose of 600-900 j/cm3through 3-3,5 hours after the start of the introduction of the Federal Assembly of conduct spectral-fluorescence detection (IFD) accumulation FS in intraocular tumors, and intravenous bolus injected FS chlorophyll-type in liposomal form, it may be, for example, trinacria salt of chlorin E6 (Photolon), or the photosensitizer comprising an alkaline salt 13-carboxy-17-[2-carboxyethyl]-15-carboxymethyl-17,18-TRANS-dihydro-3-vinyl-8-ethyl-2,7,12,18-t is trimethylphosphine (chlorin E6) in an amount of 80-90%, alkaline salt 13-carboxy-17-[2-carboxyethyl]-15-formyl-17,18-TRANS-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylpiperidine (purpurine 5) in an amount of 5-20%, and alkaline salt 13-carboxy-17-[2-carboxyethyl]-15-carboxy-17,18-TRANS-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylpiperidine (chlorin P6) - else (Radachlorin), or bis-N-methylglucamine salt chlorin E6 (photoditazine), dose rate of (1.5-2.0 mg/kg × 0.3) and 15 minutes after injection transpupillary irradiated around the tumor and the edge of the tumor around its perimeter fields of laser radiation with a diameter of 3.5-4 mm, the wavelength corresponding to maximum absorption of the photosensitizer in liposomal form of light radiation, for example, 670 nm for FS chlorophyll-type, when the energy density of 80-100 j/cm2with overlapping of adjacent fields on 5% of the area. Then transpupillary irradiate the entire surface of the neoplasm fields of laser radiation with a wavelength corresponding to maximum absorption of the photosensitizer in water-soluble form of light radiation, for example 662 nm for FS chlorophyll-type, and irradiation is carried out in a circle from the centre to the periphery when the energy density of 80-100 j/cm2when exposed at the periphery, with a gradual increase of energy density up to 100-120 j/cm2when irradiated in the center of the overlapping of adjacent fields at 5% p is Asadi.

The patient in water-soluble and liposomal form is entered the same photosensitizer, and 70% of the total dose FS is introduced into a water soluble form, and 30% in liposomal.

All actions of the photosensitizer are dimmable, providing the impossibility of access to the premises to direct sunlight. This condition is well known and standard for sessions of PDT.

Liposomal form FS chlorophyll-type receive, for example, as follows. In a round bottom flask is mixed with 50 mg of egg phosphatidylcholine (AFH) and 7.5 mg of cholesterol (Hol), add 5 ml of chloroform, rinsed with argon or another inert gas, evaporated to constant weight on a rotary evaporator. Then dried for 10 h in a vacuum oil pump. Weighed. Add a solution of FC (5 mg/ml) to the film of lipids in the flask, shaken to all lipids were dispersibility (if necessary, read aloud in ULTRASONIC bath) frozen in liquid nitrogen, thawed at 40-60°C. Forced successively through filters with pores of 400 nm, 200 nm, 100 nm for 19 times. Put on a column Separate CL-4B, give 2 fractions: the fraction of free volume containing liposomes with incorporated FS, and the fraction not including FS. If necessary, the liposomal fraction FS concentrate (e.g., ultrafiltration).

After 2 weeks of tra is skleraina diaphanoscopy precise localization and dimensions of intraocular tumors. Then 2/3 of the thickness of the sclera above the intraocular neoplasm form a scleral pocket rectangular base from limb, formed through the bed is introduced into the structure of intraocular neoplasms multiple electrodes, for example from 2 to 4, is made of platinum, and, changing their polarity, conduct electrochemical destruction of intraocular tumors with amperage 10-100 mA during 10-1 minutes, respectively. The electrodes are removed, the superficial scleral flap return in place and fixed with interrupted sutures.

The invention is illustrated by the following examples.

Example 1. Patient H., 79 years. When surveyed in KF of IRTC "eye microsurgery" was diagnosed with melanoma of the choroid (MX) right eye (OD).

Ophthalmoscopically in ninananajna quadrant on average the periphery of the fundus of the right eye was determined by extensive, sharply prominere in the vitreous hearth gray-yellow, with indistinct borders. According to the ultrasonic B-scan size of the tumors was as follows: the diameter at the base is 12 to 14 mm; thickness at the top of tumor - 6,5 mm

The patient is treated under the proposed method.

In the cubital vein of one arm was introduced Photolon in dose rate of 1.5 mg/kg × 0,7 for 40 minutes, and at the same time with the introduction of the FS in the cubital vein of the other hand held nutrion the second laser blood irradiation with a wavelength of 662 nm at an irradiation dose of 900 j/cm 3. 3 hours after the beginning of the introduction of the FS conducted CFD and intravenous bolus has entered the same FS in liposomal form, dose rate of 1.5 mg/kg × 0,3. After 15 minutes after injection transpupillary irradiated around the tumor and the edge of the tumor around its perimeter fields of laser radiation with a diameter of 3.5 mm and a wavelength of 670 nm at a fluence of 80 j/cm2with overlapping of adjacent fields on 5% of the area. Then transpupillary irradiated the entire surface of the neoplasm fields of laser radiation with a wavelength of 662 nm, and the irradiation was carried out in a circle from the centre to the periphery when the energy density of 80 j/cm2when exposed at the periphery, with a gradual increase energy density of 100 j/cm2when irradiated in the center of the overlapping of adjacent fields on 5% of the area.

After 2 weeks transscleral diaphanoscopy said localization and dimensions of intraocular tumors. Then 2/3 of the thickness of the sclera above the intraocular neoplasm formed scleral pocket rectangular base from limb, formed through the bed introduced into the structure of intraocular neoplasms 2 electrode platinum. Spent the electrochemical degradation of intraocular tumors with rated current of 10 mA for 10 minutes, changing the polarity of the electrodes. The electrodes were removed, surface SC is erally flap returned to the place and recorded interrupted sutures.

During follow-up in terms of 3, 6 and 12 months after treatment, ophthalmoscopically and according to ultrasound B-scan, there was a gradual regression of tumors, 1.5 years on the site of the tumor was determined by extensive flat atrophic chorioretinal lesion with coarse pigmentation. Signs of recurrence MX and distant metastases in up to 1.5 years have been identified. Eyes saved as body.

Signs of recurrence of tumors and distant metastases in these terms were found. Eyes saved as body.

Example 2. Patience P., 74 years of age. Diagnosis at admission: melanoma of the choroid (MX) left eye (OS).

Localization of tumor - paracentral region with distribution to the equator in vernaison side; the size of the tumors, according to the ultrasonic B-scan: base width of 12 mm, length 16 mm, the size of prominence - 8.0 mm at the apex of the tumor.

The patient treated by the proposed method.

In the cubital vein of one arm was introduced photoditazine in dose rate of 2.0 mg/kg × 0,7 within 60 minutes, and at the same time with the introduction of the FS in the cubital vein of the other hand held intravenous laser blood irradiation with a wavelength of 662 nm at an irradiation dose of 600 j/cm3. After 3.5 hours after the start of the introduction of the FS conducted CFD and intravenous bolus which were the same FS in liposomal form in a dose rate of 2.0 mg/kg × 0,3. After 15 minutes after injection transpupillary irradiated around the tumor and the edge of the tumor around its perimeter fields of laser radiation with a diameter of 4 mm with a wavelength of 670 nm at a fluence of 100 j/cm2with overlapping of adjacent fields on 5% of the area. Then transpupillary irradiated the entire surface of the neoplasm fields of laser radiation with a wavelength of 662 nm, and the irradiation was carried out in a circle from the centre to the periphery when the energy density of 100 j/cm2when exposed at the periphery, with a gradual increase energy density of up to 120 j/cm2when irradiated in the center of the overlapping of adjacent fields on 5% of the area.

After 2 weeks transscleral diaphanoscopy said localization and dimensions of intraocular tumors. Then 2/3 of the thickness of the sclera above the intraocular neoplasm formed scleral pocket rectangular base from limb, formed through the bed introduced into the structure of intraocular tumors 4 electrode platinum. Spent the electrochemical degradation of intraocular tumors with rated current 100 mA for 1 minute, changing the polarity of the electrodes. The electrodes were removed, the superficial scleral flap was returned to the place and recorded interrupted sutures.

When the control ultrasonic B-scan of the right eye on reoperations period observed regression of tumors, a decreasing value of prominence tumor - to 4.0 mm to 3 months, and up to 2.5 mm to 6 months. In a long-term observation period (1.5 years) was noted further flattening of education with the formation of chorioretinal scar, according to the location of melanoma of the choroid.

Under the proposed method treated 6 patients with melanoma of the choroid. As FS used Photolon, Radachlorin, photoditazine in water-soluble and liposomal forms. Electrochemical degradation was performed with electrodes of platinum or iridium, or rhodium with amperage 10, 30, 40, 60, 80, 100 mA for 10, 8, 7, 5, 3, 1 minutes, respectively. In all cases has been made of the claimed technical result.

Thus, the inventive method can achieve a complete or partial regression of intraocular tumors, keep the eye as the organ to ensure the absence of metastasis.

1. The method of photodynamic therapy and electrochemical degradation of melanoma of the choroid, including electrochemical destruction of intraocular tumors, intravenous administration of a photosensitizer (PS) chlorophyll-type and transpupillary laser irradiation of tumors, characterized in that in the cubital vein of one arm enter FS in water-soluble dosage form dose at the rate of 1.5-2.0 mg/kg × 0.7 photosensitizer within 40-60 min, and simultaneously with the introduction of the FS in the cubital vein of the other hand hold the intravenous laser blood irradiation with a wavelength corresponding to the maximum absorption of the photosensitizer in water-soluble form of light radiation, the radiation dose of 600-900 j/cm3through 3-3,5 hours after the beginning of the introduction of the FS intravenous bolus injected FS chlorophyll-type in liposomal form, dose rate of 1.5-2.0 mg/kg × 0.3 photosensitizer, and a water-soluble and liposomal form is administered the same drug, and 15 min after injection transpupillary irradiated around the tumor and the edge of the tumor around its perimeter fields of laser radiation with a wavelength corresponding to maximum absorption of the photosensitizer in liposomal form of light radiation, the energy density of 80-100 j/cm2with overlapping of adjacent fields at the 5% area, then transpupillary irradiate the entire surface of the neoplasm fields of laser radiation with a wavelength corresponding to maximum absorption of the photosensitizer in water-soluble form of light radiation, and irradiation is carried out in a circle from the centre to the periphery when the energy density of 80-100 j/cm2when exposed at the periphery, with a gradual increase of energy density up to 100-120 j/cm2when irradiated in the center, overlapping the adjacent field is 5% of the area after 2 weeks transscleral diaphanoscopy precise localization and dimensions of intraocular tumors, enter into the structure of intraocular neoplasms multiple electrodes and, changing their polarity, conduct electrochemical destruction of intraocular tumors with amperage 10-100 mA during 10-1 min, respectively, the electrodes are removed.

2. The method according to claim 1, characterized in that the diameter of the laser radiation field is 3.5-4 mm.

3. The method according to claim 2, characterized in that the electrodes are introduced into the structure of intraocular tumors transscleral.

4. The method according to claim 3, characterized in that the number of electrodes is 2 to 4.



 

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1 tbl, 1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves intramuscular administration of galavite in the dose 0.1 g, once per a day for 5 days, but from 6 to 10 days - every other day, and gentamycin also in the dose 80 mg, 3 times per a day for 7 days, and bifidum - liquid bacteriophage of 791 series of production of firm "Vektor" in the dose one-half flask, 2 times per a day, one-half hour before eating, and wobenzym is given in the dose 5 tablets, 3 times per a day for 3 weeks and then in the dose 3 tablets, 3 times per a day for 3 weeks. Method provides eliminating the main clinical symptoms of these diseases based on transient suppression of hyperactivity of lipopolysaccharides of cell membrane, decreasing level of TNF-α, IL-1 and other anti-inflammatory cytokines in increasing activity of microbiocid system of neutrophile granulocytes. Invention can be used in treatment of uveitis of obscure or viral etiology.

EFFECT: improved method of treatment.

3 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzo[g]quinoline of the formula (I): as a free base or acid-additive salt used in treatment of glaucoma and myopia, and to a method for their synthesis and a pharmaceutical composition. In compound of the formula (I) each A and B means hydrogen atom (H); X means -CH2; Y means sulfur atom (S); R1 means H or (C1-C4)-alkyl wherein this compound can be in form of a free base or acid-additive salt. Method for synthesis of compound of the formula (I) by claim 1 or its salt involves the conversion step of alkoxy-group in compound of the formula (II): wherein A, B, X, Y and R1 have values given in claim 1; R3 means (C1-C4)-alkyl to hydroxy-group, and conversion of synthesized compounds of the formula (I) to free base or its acid-additive salt.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzo[g]quinoline of the formula (I): as a free base or acid-additive salt used in treatment of glaucoma and myopia, and to a method for their synthesis and a pharmaceutical composition. In compound of the formula (I) each A and B means hydrogen atom (H); X means -CH2; Y means sulfur atom (S); R1 means H or (C1-C4)-alkyl wherein this compound can be in form of a free base or acid-additive salt. Method for synthesis of compound of the formula (I) by claim 1 or its salt involves the conversion step of alkoxy-group in compound of the formula (II): wherein A, B, X, Y and R1 have values given in claim 1; R3 means (C1-C4)-alkyl to hydroxy-group, and conversion of synthesized compounds of the formula (I) to free base or its acid-additive salt.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 ex

FIELD: medicinal plants, chemical technology.

SUBSTANCE: method involves extraction of milled licorice (Glycyrrhiza uralensis, Fischer) roots with 0.5% aqueous solution of NH4OH. The total triterpene acids of extract are precipitated with concentrated H2SO4 followed by extraction of total triterpene acids with 1% solution of H2SO4 in acetone, precipitation of glycyrrhizic acid triammonium salt with 25% solution of NH4OH and its conversion to monoammonium salt by re-crystallization from glacial CH3COOH and purification of the latter by re-crystallization from 85% ethanol. Invention provides enhanced yield of the end product.

EFFECT: improved preparing method, enhanced yield.

1 dwg, 1 ex

FIELD: medicine, ophthalmology, endocrinology.

SUBSTANCE: method involves instillation of 0.1% indocollir solution into conjunctival cavity in the dose 1 drop, 4 times per a day 7-10 days before carrying out the laser coagulation and for 7-10 days after the coagulation procedure. Immediately before laser coagulation indicollir solution is instilled 4 times with interval for 15 min, and immediately after laser coagulation indocollir solution is instilled one time. Method provides improving visual functions in this pathology based on recovery of impaired hemo-ophthalmic barrier owing to the power anti-inflammatory and analgesic effect of indocollir. Invention can be used in treatment of patients with edematous form of diabetic maculoretinopathy.

EFFECT: enhanced effectiveness of treatment.

2 cl, 2 ex

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