Method for treating the cases of intraocular tumors

FIELD: medicine.

SUBSTANCE: method involves introducing photosensitizer of photosense at a dose of 0.1-1.0 mg/kg of patient weight. Photodynamic therapy is applied in 48-72 h with laser radiation at wavelength of 675 nm after having introduced the photosense. Iradiation is carried out in transscleral way after having determined tumor base projection place over sclera in transillumination way. Exposure dose is equal to 80-800 mW/cm2 with cylindrical light guide set at a distance from sclera that laser radiation beam diameter overlaps tumor base diameter by 1-2 mm at its projection place on sclera.

EFFECT: enhanced effectiveness of treatment.

 

The present invention relates to ophthalmology, namely oftalmologii, and is intended for treatment of intraocular tumors.

Among tumors of the organ of vision intraocular tumors occupy the second place, second in frequency only to the eyelid neoplasms. Among intraocular tumors secrete retinal tumor and tumor vascular tract of the eye. They occur at almost any age. In childhood prevalent tumors of the retina. Basically they are represented by retinoblastoma. The lion's share of tumors of the adult population are tumors of the vascular tract neuroectodermal origin (pigmented and non-pigmented nevi and melanoma). Their smaller part is mesoderm origin (hemangioma) [Pačes A.I., Brovkin A.F., Zigangirov, Clinical Oncology organ of vision. - Moscow, Medicine. - 1980 - p.23].

The level of technology

Treatment of intraocular tumors are divided into two main types: conservative and liquidation.

For nearly 4 centuries only and no alternative method of treatment of intraocular tumors remained enucleation. However, over the last half century, thanks to the achievements of radiation medicine in the Arsenal of ophthalmology, new technology that not only destroy the tumor, but also preserve the eye is to the body. Among these technologies, the preference is given to those organomagnesium methods that have a selective effect, and therefore less traumatic for functionally important structures of the eye, is not involved in the neoplastic process. These methods are more promising for visual functions.

Today the most popular among organ-sparing treatments are radiation treatment: brachytherapy, laser photodestruction, thermotherapy, photodynamic therapy photosensitizers.

Each of these treatment methods has its advantages and disadvantages, as well as their indications and contraindications for their use.

Laser photodestruction (synonym: laser coagulation) as an independent method of treatment has very limited indications. It is produced when postequalization tumors of small size, when their thickness exceeds 1.5 mm, and the diameter does not exceed 12 mm [Guide oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-118]. A prerequisite for its implementation is the absolute transparency of the optical medium and maximum mydriasis, which allows full control during the procedure the laser photodestruction.

Laser photodestruction inside the eye tumors used argon (range radiation 488 nm), krypton (range radiation 568-647 nm) lasers. Exposure to a specified range of light absorption of light energy by the tissue structures of the eye - pigment epithelium of the retina and choroid, with subsequent transformation into heat energy. This type of impact causes the denaturation of the proteins that form the basis of the ability of tumor cells with their subsequent death [ibid]. The mechanism of tumor cell death: coagulation necrosis with subsequent cell-free sclerosis.

The disadvantages of the method are its limitations: it is not shown when the tumors thicker than 1.5 mm the Penetrating power of radiation in the specified spectral range of low waves. In addition, the effect in this mode is accompanied by the formation of dense coagulation film, which prevents further penetration of laser beams [Jalkh AE, Trempe CL, Nasrallah, et al Treatment of small choroidal melanomas with photocoagulation. // Ophthalmic Surg - 1988 - vol.19 - pp.738-742. Lanzetta P; Virgili G; Ferrari E; U. Menchini Diode laser photocoagulation of choroidal I // Int Ophthalmol. - 1995 - vol.96, No. 4 - pp.239-247].

Transscleral brachytherapy is one of the common ways of treatment of intraocular tumors. It is widely used by tumors of the Equatorial and postequalization localization. The method is based on short distance (contact) exposure on the basis of the tumor from one hundred the ons sclera various radioactive radiation sources. The radionuclide is placed on the matrix, located in the sealed stainless steel container having the shape of a spherical segment with a thickness of 1 mm, This design is called ophthalmoplegia. Ophthalmoplegia placed on the sclera (the place of the projection of the base of the tumor on the sclera), locking his special bow interrupted sutures.

Indications for brachytherapy are determined by the size of the tumor [Guide oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-134]. They are limited in the height of 5 mm and a maximum diameter of 14 mm Juxtapapillary tumors should not promenerat more than 3 mm, the radial size should not exceed 9.5 mm, and the meridional - no more than 1/3 (120°) the circumference of the optic nerve (optic nerve disc). Limitations in size when planning for brachytherapy due to two issues: first, the size and shape of modern applicators, maximally adapted to the size of the eyeball, secondly, the maximum area of exposure to the eye tissue, the excess of which is associated with complications that entail the loss of the eye. The type of applicator also depends on the thickness of the tumor. In the countries of the former USSR using ruthenium and strontium applicators. Abroad successfully used125I and60[Lommatzsch PK. Results after beta-irradiation ( 106EN/106Rh) ofchoroidal melanomas: 20 years' experience. // Br J Ophthalmology - 1986 - vol.70 - pp.844-851; Char CH, Castro JR, Quivey JM, et al. Uveal melanoma radiation:125I brachytherapy versus helium irradiation. // Ophthalmology.- 1989 - vol.96 - pp.1708-1715; Tjho-Heslinga R.E., J. Davelaar, Kemme H.M. Results of ruthenium irradiation of uveal melanomas: the Dutch experience. // Radiother Oncology. - 1999 - vol.53 - No. 2, pp.133-137].

The success of treatment is determined by exact calculation of the absorbed dose and not less accurate installation of the applicator over the tumor with overlapping its borders. The applicator is mounted in the zone of localization of the tumor after the preliminary marking its projection on the sclera. Boundary marking melanoma is performed using transpupillary diaphanoscopy on the operating table in terms of anesthesia and maximum drug-induced mydriasis. If it is impossible to define the boundaries of the tumor diaphanoscopy (in cases of amelanotic melanoma), use of Ophthalmoscope control [Manual oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-134].

Evaluation of the effectiveness of brachytherapy is carried out not earlier than 6 months when the first signs of the formation of chorioretinal scar around the tumor and regression (flattening) of the tumor site. It is considered brachytherapy effective if the observation period up to 12 months came regression to 50% of the initial tumor volume and clinical stabilization of the Oia process [ibid]. Incomplete regression of the tumor is possible relapses growth or tumor growth under scar [Karlsson UL, Augsburger JJ, Shields JA, et al. Reccurence of posterior uveal melanoma after 60Co episcleral plaque therapy. // Ophthalmology - 1989 - vol.96 - pp.382-388].

In the case of recurrence, growth, or incomplete regression, after a year or more earlier (but not earlier than 6 months after the first brachytherapy), possible re-brachytherapy. However, resources and tolerability of the sclera to the re-exposure is very limited. When the total radiation dose to the sclera, approaching 300 Gr, develops scleromalacia, which further attempts to save the hopeless eyes [Zaruba GD Radiotherapy of tumors of the eye. - Moscow. - 1982 - the Dissertation on competition of a scientific degree of the doctor of medical Sciences - page 343].

According to Russian authors to 60% of irradiated melanoma successfully regress to chorioretinal scar in terms of up to 1.5 years [ibid]. In General, the effectiveness of brachytherapy of malignant melanoma is 62.6-87%, according to different authors, with stabilization of the disease in 31% of cases, 5-year observation period [Pacher S, Stoller S, Lesser ML, et al. Long-term results of iodine 125 brachytherapy in the management of uveal melanoma. // Ophthalmology. - 1993 - vol.100 - pp.1547-1554; Lommatzsch PK. Results after beta-irradiation (106EN/106Rh) of choroidal melanomas: 20 years' experience. // Br J Ophthalmology - 1986 - vol.70 - pp.844-851; Char CH, Castro JR, Quivey JM, et al. Uveal melanoma radiation:125I brachytherapy versus helium irradiation. // Ophthalmology - 1989 - vol.96 - pp.1708 - 1715; Tjho-Heslinga R.E., J. Davelaar, Kemme H.M. Results of ruthenium irradiation of uveal melanomas: the Dutch experience. // Radiother Oncology. - 1999 - vol.53 - No. 2, pp.133-137].

Brachytherapy is fraught with a wide range of complications. Depending on the time of their development, they are divided into early and late. In addition, depending on the capabilities of carabellese, they are classified as reversible and irreversible. The early complications are iridotsiklity, increased intraocular pressure, exudative retinal detachment, detachment of the choroid, partial hemophthalmus. These States are avoided by using drug therapy. The use of anti-hypertensive, Mydriatics, anti-inflammatory drugs can cope in most cases [Guide oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-134].

In 44% of patients with juxtapapillary melanoma develops optic neuropathy with optic atrophy [Archer D, Gardiner T. Ionizing radiation and the retina. // Curr Opin Ophthalmol. - 1994. - Vol.5. - P.59-65]. With extensive radiation areas prequaternary and Equatorial localization after 1.5 years after brachytherapy in the background fully regressed tumors can develop ischemia of the retina, resulting in neovascular glaucoma [Kim MK, Char DH, Castro JL, et al. Neovascular glaucoma after helium ion irradiation for uveal melanoma. // Ophthalmology. - 1986. - Vol.93. - P. 189-193]. This state is upiraetsa normal antiglaucoma preparations and usually ends with enucleation after numerous attempts to resolve the hypertension. Short-term effect can be achieved using reapplication ciliary body [ibid].

Radiation cataract develops in a more long-term follow up [Seddon JM, Gragoudas ES, Egan KM, et al. Uveal melanomas near the optic disc or fovea, visual results after irradiation. // Ophthalmology. - 1987. - Vol.94. - P.354-361; Madreperla SA; Hungerford JL; Plowman PN. Choroidal hemangiomas: visual and anatomic results of treatment by photocoagulation or radiation therapy. // Ophthalmology. - 1997 - vol.104, No. 11 - pp.1773-1778; discussion 1779].

At high radiation doses on the surface of the sclera possible radiation necrosis with subsequent development of defects in the sclera, which shall be borne by the donor sclera.

Thus, the advantage of brachytherapy is the most efficient way compared to coagulation.

The disadvantages include: a strict limit on the size of the tumor, the restriction on the multiplicity of the use of the method, the long duration of rehabilitation and a wide range of these complications with a high probability of their development.

Thermotherapy is another radiation treatment of intraocular tumors, where the radiation source using infrared diode laser at a wavelength of 810 nm. The effect of thermotherapy based on a combination of volumetric hyperthermia of the tumor from 45 to 65° and coagulation intratumoral is Asadov. Thermotherapy is of two kinds - transpupillary and transcleral.

Transpupillary thermotherapy (TTT) is performed using diode lasers of different models (for example, OcuLight SLx, IRIS Medical instruments. Inc.) with a wavelength of 810 nm. The power of radiation exposure varies from 360 to 1000 mW, beam diameter ranges from 1.5 to 3 and 10 mm of the Specified parameters depend on the degree of pigmentation, size of tumor and its location. Exposure exposure ranges from 30 to 90 seconds [Robertson D.M. Buettner H., Transpupillary thermotherapy as primary treatment for small choroidal melanomas. // Trans Am Ophthalmol. Soc. - 1999 - vol.97 - pp.407-434]. When the directional effect of the diode laser the specified parameters within 60 seconds, the temperature in the zone of influence is increased up to 45-65° [Journee-de-Korver HG, Verburg-van der Marel EH, oosterhuis on JA, et al. Tumoricidal effect of hyperthermia by near infrared irradiation on pigmented hamster melanoma. // Lasers Light Ophthalmol. - 1992. - Vol.4. - P.175-180. Oosterhuis on JA, Journee-de-Korver HG, Kakebeeke-Kemme NM, Bleeker JC. Transpupillary thermotherapy in choroidal melanoma. // Arch Ophthalmol. - 1995. - Vol.13. - P.315-321].

The initial indication for TTT served tumor thickness up to 5 mm, located in the posterior pole of the eye. In 30% of cases, a complete regression of the tumor (up to 3 mm) occurs within 3 months. Incomplete regression of therapy can be repeated to obtain a flat chorioretinal scar. In some cases, the regression of tumors in a single session TTT can last for a century is and observations [ibid]. The 13.3-18% of the tumor may be resistant to this method of treatment, as well as to any other radiotherapy, including brachytherapy [oosterhuis on JA, Journee de Korver HG, Kakebeeke Kemme HM, et al. Transpupillary thermotherapy in choroidal melanomas. // Arch Ophthalmology. - 1995 - vol.113 - pp.315-321].

The effectiveness of TTT is quite high. Thus, according to J..Shields, 94% of tumors (diameter of 7 mm and a thickness of 2.8 mm) completely regress. 2% of cases require repeated sessions TTT. 6% of cases are resistant to TTT and end with enucleation. Visual functions remain at the same level or improved in 58%, worse in 42%. The reduction of visual function due to macular tumor localization, vascular obstruction or secondary postradiation semiseria [J.A. Shields, Shields C.L, De Potter P, et al. Transpupillary thermotherapy in the management of choroidal melanoma. // Eye. - 1997 - vol.1 - pp.676-679].

Among the complications that can occur after TTT, allocate subretinal the choroidal neovascularization (6-13,8%), partial hemophthalmus (3.4%), local tractional retinal detachment (in 20% of cases), retinal detachment caused by errors made during TTT (perforation of the retina in the macular region, 1%), exudative neurosensory detachment, Vitrea [Balestrazzi, A., Blasi M.A. Retinal detachment due to macular hole after transpupillary thermotherapy of choroidal melanoma. // Retina. - 2001 - vol.21 - No.4 - pp.384-385], occlusion of the Central retinal vessels (20,6%), leading to loss of Central La is of [102]. Shields indicates that the risk of retinal traction is greatly increased when tumors extending from the macula in the temporal direction [J.A. Shields, Shields C.L, De Potter P, et al. Transpupillary thermotherapy in the management of choroidal melanoma. // Eye. - 1997 - vol.1 - pp.676-679]. TTT juxtapapillary melanomas is associated with a high risk of developing retinal neovascularization due to obstruction of the large retinal vascular arcades, is caused by exposure to radiation energy [ibid]. Kiratli leads as one of the complications TTT pigment dispersion in the vitreous body [Kiratli H., Bilgic S. Cal P. Intravitreal pigment dispersion as a complication of transpupillary thermotherapy of choroidal melanoma. // Retina. - 2000 - vol.20 No. 4 - pp.408-409]. Other authors indicate that multiple tumors TTT lead to calcification [Mosci C; Polizzi A, Zingirian m Transpupillary thermotherapy for circumscribed choroidal hemangiomas: first choice in therapy. // Eur J Ophthalmol. - 2001 - vol.11, No. 3 pp.316-318.

Thus, the advantages of TTT are as follows: non-invasive, relatively high efficiency, the possibility of holding sessions of exposure in the outpatient setting, the possibility of a replay session, the preservation of visual function.

Disadvantages can be considered: partial regression in some cases, a high frequency of recurrence of tumor growth, development of radiation resistance and the number of postradiation complications.

It is established that the effectiveness of TTT can be enhanced by typing various contra the exporting substances, accumulate in tumors and has a maximum absorption in the spectral wavelength range of the laser radiation. This scientific fact was the basis of infrared TTT.

Infrared TTT. It is known that the effectiveness of TTT densely pigmented tumors better than when amelanotic tumors of the choroid. In the literature there are pointing to the possibility of strengthening the effectiveness of TTT, thanks to the use of contrast - indocyanine green. Contrast is injected intravenously for 50-60 minutes until TTT [Kamal A; Watts AR; Rennie IG. Indocyanine green enhanced transpupillary thermotherapy of circumscribed choroidal haemangioma. // Eye. - 2000 - vol.14 No. 5 - pp.701-705. Journee-de Korver H., de Boer A.G. Infrared thermotherapy of amelanotic tumors. Abstract book of the International Congress of Ocular Oncology. - Amsterdam, the Netherlands, the - 2001 - pp.124]. Adjuvant potential of indocyanine green proved histomorphologically: increases the area and depth of necrosis induced by TTT.

Along with TTT, in which radiation is delivered through the pupillary aperture, increasingly in oftalmologii began to use transscleral thermotherapy (TST) using the same type of laser radiation, as in TTT. Irradiation is carried out using a special fiber that result in direct contact with the sclera, in the projection of the base of the tumor. Pre-mark the borders of the tumor on the sclera, are transillumination eyeball with protivopul is mportant side through the sclera or through the pupil.

The sclera makes the irradiation power up to 2500 mW, which is accompanied by a temperature increase to 44.5°on the surface of the sclera to reach the temperature at the boundary of the tumor-sclera - 60°C. When exposed in this mode necrosis covers up to 5 mm tumor thickness [Keunen J.E.E., oosterhuis on, Rem, A.I., Journee-de Korver H. Transcleral thermotherapy in choroidal melanoma: first results. // Abstract book of the International Congress of Ocular Oncology. - Amsterdam, the Netherlands, the - 2001 - pp.107]. Preliminary experimental data showed that the sclera maintains temperature exposure up to 60°C for 10 minutes without structural changes [ibid].

At the present stage of knowledge it is clear that tumors with well-developed vascular network, Anastasiya with short posterior ciliary arteries at the base of the node, difficult TTT. Features one TTT in this case is limited by the depth of 5 mm, and therefore, the tumor, which is well powered by anastomoses, located at the base retains a high probability of relapse growth after TTT.

Search for ophthalmooncologic new organ-sparing treatment suggests that the problem is far from being resolved.

The closest analogue of the invention. At the turn of XX-XXI centuries appeared and began to actively implemented a new method, called photodynamic therapy (PDT) of intraocular tumors. The essence of the method is that the patient enter the t photosensitizer (PS), which in a certain timeframe (they each FS) selectively accumulate in the tumor, however, creates a contrast ratio between the concentration of the drug in the pathological lesion and the surrounding healthy tissues of the eye. The difference in the concentration of the drug in the pathological lesion and surrounding normal tissue can focus effect exclusively in the tumor. Irradiated by the laser action on the wavelength in the maximum of the absorption spectrum of the used photosensitizer. Develops a cascade of photodynamic reactions, the main biological effect of which is destruction of the tumor. At the same time as photosensitizers can be used in a variety of natural and synthetic dyes [ed. Evangelos S. Gradoudas et al. Photodynamic therapy of ocular diseases. - Lippincott Williams Wilkins - USA - 2004 - p.272]. Irradiation is carried out traditionally transpupillary, that is, through the most advanced pupil.

The method is tested and has been used abroad in the treatment of intraocular tumors. The best results are associated with little pigmented tumors, which include amelanotic melanoma, osteomas and hemangioma of the choroid [Jurklies, Anastassiou G, S Ortmans, et al. "Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma." // Br J of Ophthalmology - 2003 - Vol.87 - P.84-89; Madreperla SA. "Choroidal I treated with photodynamic therapy using verteporfin." // Arch Ophhalmol. - 2001. - Vol.119 - N 11 - P.1606-1610; Porrini G. A. Giovannini et al // Photodynamic therapy of circumscribed choroidal approach. // Ophthalmology. - 2003. - Vol.110. - P.674-680; Battaglia Parodi M, Da Pozzo S, et al. Photodynamic therapy for choroidal neovascularization associated with choroidal osteoma. // Retina. - 2001. - Vol.21. - P.660-711].

PDT is used even in cases where TTT or brachytherapy is not shown or is obviously not effective. So, if a contraindication for use of brachytherapy or thermotherapy in hemangioma of the choroid is a serous retinal detachment, photodynamic therapy of such tumors proceeds favorably. During PDT, along with complete regression of hemangiomas, there is resorption of subretinal exudate. The effect persisted up to 18 months [Robertson DM. // Photodynamic therapy for choroidal approach associated with serous retinal detachment. Arch Ophthalmol. - 2002. - Vol.120. - P.1155-1161].

As the closest analogue we took PDT intraocular tumors with Visudyne. Vicodin used as filesystem, based on the calculation of the dose of 6 mg / m2the surface of the body. The drug was administered intravenously. Irradiated transpupillary on the laser, model Visulas 6905 (Carl Zeiss-Meditech AG, Jeud Germany) with a wavelength of 689 nm. For tumors greater than 2 mm in thickness, light dose radiation exposure was 100 j/cm2and the duration of the session - 186 sec, while tumors up to 2 mm, respectively, and 75 j/cm2and 125 seconds [Porrini G, Giovannini A, Amato G, loni A, Pantanetti M. // Photodynamic therapy of circumscribed choroidal approach. // Ophthalmology. - 2003. - Vol.110. - P.674-680].

As vidimus presents data the method is certainly effective, even in cases where brachytherapy or therapy cannot be used. The method has a number of indisputable advantages:

First, it is non-invasive.

Secondly, radiation sessions when geoeffective may be repeated.

Thirdly, PDT can be performed on an outpatient basis, which is more comfortable for the patient.

However, the method is not without disadvantages.

Serious disadvantages of PDT with Visudyne include a wide range of complications which can be classified as General or system and special ophthalmologic or local.

Among the local complications of PDT identified chemosis, iritis, cataract, Vitrea, detachment of the retina and choroid [Barr H, Kendall C, Reyes-Goddard J, Stone N. Clinical aspects of photodynamic therapy. // Sci Prog. - 2002. - Vol.85. - P.131-150; Holz, T. Exudative Complications After Photodynamic Therapy. // Arch Ophthalmol. - 2003. - Vol.121. - P.1649-1652].

Among the systemic effects observed cutaneous photosensitivity [Barbazetto IA, LeeTC, Rollins IS et al. Treatment of choroidal melanoma using photodynamic therapy. // Am. J Ophthalmol. - 2003. - Vol.135. - 898-899].

The method also has limited indications. It is established that the more pigmented tumor, the worse the efficiency and lower the depth of radiation penetration into tumor tissue, and therefore, a possible partial destruction of the tumor [Kim RY, Hu LK, Foster BS, et al. Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness. // Ophthalmology. - 1996. - Vol.103. - P.2029-2036 Gonzalez VH, Hu LK, Theodossiadis PC, et al. Photodynamic therapy of pigmented choroidal melanomas. // Invest Ophthalmol Vis Sci. - 1995. - Vol.36. - P.871-878]. A partial effect in the future is associated with recurrence of tumor growth, and hence, with repeated courses of PDT.

Our preliminary experimental studies have revealed the prospects of their application in oftalmologicheskiy problems.

The aim of our invention was to develop more effective treatment of intraocular tumors than our closest analogue, however, deprived of his shortcomings.

We suggested that one way to increase the effectiveness of PDT can be transscleral approach to laser exposure. The fact that tumors developing in the choroid, the original have expressed inlet or supply network of blood vessels located at the base. Impact through the pupil has only a partial effect. Better to take her power, causing photothrombosis lead to major vessels, and thus to cause tumor necrosis.

Choose the method of PDT with Visudyne with intraocular tumors the closest analogue of the invention, we have developed our own way of PDT is based on the use of domestic photosensitizer photosense and transscleral conducting laser irradiation.

The problem is solved by having photodynamics the th therapy by intravenous injection of photosensitizer dose of 0.1-1.0 mg/kg of body weight and exposure to laser radiation at a wavelength of 675 nm, the photosensitizer used photosense, and irradiation is carried out transscleral 48-72 hours after administration of the drug and determine where the projection of the base of the tumor on the sclera transilluminated by, is irradiated with the exposure dose 80-800 mW/cm2using a cylindrical waveguide, placing it at a distance from the sclera to the beam diameter of the laser radiation was blocked by 1-2 mm base diameter of the tumor at the site of its projection on the sclera.

The minimum dose of injected photosense was determined we empirically initially on experimental models of intraocular tumors in animals on the contrast ratio. This indicator, we were determined with the help of a special device designed for this purpose. It was called laser electron spectral installation for fluorescent diagnosis and monitoring of photodynamic therapy LESA-01-"BIOSPEC" GOST R 50460-92 (Registration certificate of Ministry of health of the Russian Federation No. 29/05020400/0617-00 from 27.07.2000).

Method of diagnosis based on:

the differences in the fluorescence intensity of healthy and tumor tissue when excited by laser radiation,

- selectivity of accumulation FS and the possibility of its detection by the characteristic fluorescence spectra.

The contrast ratio was not reached with 4.0 weenies Photosense below 0.1 mg/kg And at a dose of Photosense above 1.0 mg/kg of body weight developed skin toxicity. These data formed the basis of a fixed range of therapeutic doses of Photosense, which were subsequently transferred to the clinic.

Also empirically, we have found that only the contrast ratio allows for strictly dosed radiation, selectively directed the pathological focus in the eye. This uses the principle of maximum sustainable approach to functionally intact tissues of the eye. To achieve efficiency, the contrast ratio should not fall for the mark 4. This difference in accumulation of photosense evolves in time from 48 to 72 hours after the introduction of Photosense.

The dose of injected photosense as the exposure dose is determined by the size of intraocular tumors. The larger the tumor, the higher the required concentration of Photosense and the power of the laser exposure. Greater tumor array requires the use of large cumulative radiation doses.

However, it is found experimentally that a high single dose in excess of 800 mW/cm2associated with increased risk of cataract development, and at a dose of less than 80 mW/cm2the effects of PDT are not developing.

Irradiation is carried out transscleral after marking the boundaries of the tumor on the sclera tra is illuminationism by, focusing the laser radiation on the pathologic lesion using a special fiber. When this fiber have at such a distance from the impact zone, so that the light beam overlaps the base of the tumor at 1-2 mm.

High contrast ratio (>10), developing within a specified time, allows to give a total planned radiation dose simultaneously without much risk of damage to surrounding healthy tissues of the eye. This approach allows you to call photothrombosis of choriocapillaris trunk and feeder vessels located in the tumor bed.

Thus, our proposed method PDT intraocular tumors, as well as the way that we took for the nearest equivalent, consists of prior intravenous administration of a photosensitizer followed by laser exposure. However, our method differs substantially from its counterpart, namely, first, that as a photosensitizer, we propose to apply the photosense instead of Visudyne.

Secondly, we propose to PDT in strictly the established time intervals, in which due to a Deposit of Photosense in the tumor creates a high contrast pathological lesion in relation to surrounding healthy tissues of the eye. Photosense has the ability to selectively accumulate in the tumor is in a period of 48 to 72 hours after intravenous injection of the drug.

Thirdly, we offer during PDT delivery of radiation to implement transscleral from the base of the tumor.

PDT is performed on laser facility with a wavelength of 675 nm (the maximum of the absorption spectrum of Photosense).

The advantages of our proposed method, in our opinion, is the selectivity or strictly targeted delivery of radiation exposure in tumor tissue, representing the depot photosense. This allows you to minimize postradiation complications of PDT as chemosis, iritis, cataract, vitreitis, detachment of the retina and the choroid.

We have implemented our invention in practice, and received confirmation of its efficiency and ease of technical execution.

The technical result of the invention is the complete destruction of the tumor, located in the technically difficult to access the area in the eye.

The technical result is achieved through the strict application procedure: intravenous certain doses of photosensitizer Photosense in the range of 0.1-1.0 mg/kg of body weight, the PDT within strict timelines after 48-72 hours after administration of the Federal Assembly, as well as individual planning light doses of laser irradiation, depending on the size of the tumor, as well as due to the delivery of laser radiation at a wavelength of 675 n is transscleral from the base of the tumor.

The invention is carried out as follows.

At the first stage of intravenously injected photosensitizer photosense based doses of 0.1-1.0 mg/kg weight of the patient.

After 48 hours of intravenous Photosense conduct individual planning mode radiation exposure. The parameters of the radiation power is determined by the array of the tumor. The greater the thickness of the tumor, the stronger must be the radiation exposure. For tumors with a height of 2 mm is enough radiation capacity of 80 mW/cm2. Tumor height of 5 mm require more power, for example, 500 mW/cm2.

The patient is administered in endotracheal anaesthesia. On the operating table after exposure of the sclera from the conjunctiva in place of the proposed location of the tumor, conduct transscleral or transpupillary illumination to determine the exact boundaries of the projection of the base of the tumor on the sclera.

According to marking the boundaries of conduct PDT laser action of diode laser with a wavelength of 675 nm.

Radiation exposure exercise transscleral using a special optical fiber, forming a light beam with a spot diameter, the size of which capture 1-2 mm ring healthy tissue located outward from the marking of the boundaries of the projection of the base of the tumor on the sclera.

Example 1. Patient S., aged 65. Diagnosis: melanoma of the choroid (Art. T2N0M0)of the right eye. On the left eye of primary senile cataract. The original size of the tumor height was 3.0 mm, diameter 7 mm, the Patient entered the photosense the rate of 0.3 mg/kg of body weight. After 48 hours the patient in the operating conditions imposed in endotracheal anaesthesia. On the operating table after exposure of the sclera from the conjunctiva in place of the proposed location of the tumor, held transscleral illumination to determine the exact boundaries of the projection of the base of the tumor on the sclera. Spent the boundary marking the projection of the tumor on the sclera. They appear at a distance of 11 mm from the limbus in the sector of 5-7 hours. The posterior border of the tumor was located 20 mm from the limbus.

PDT spent transscleral, when this dose was 350 mW/cm2. The fiber was positioned so that the diameter of the light spot blocked the tumor to healthy tissue capture 1.5 mm around.

After 2 months there was a regression of the tumor size reduction to 1.0 mm in height. After 3 months on the former site of the tumor formed flat chorioretinal scar.

All patients treated by our method, developed positive clinical effect in the form of full or partial regression of the tumor. Complications are not checked.

Thus, the proposed method for the treatment of intraocular tumors is quite effective, can be used in the practice of oftalmol the gods.

A method for the treatment of intraocular tumors, consisting in conducting photodynamic therapy by intravenous administration of a photosensitizer followed by laser irradiation, characterized in that the photosensitizer is used photosense dose of 0.1-1.0 mg/kg weight of the patient is irradiated in 48-72 hours from the moment of introduction of Photosense at a wavelength of 675 nm with exposure dose 80-800 mW/cm2while the delivery of radiation is carried out after determining the place of projection of the tumor on the sclera and marking its borders transscleral with cylindrical light guide, placing it at a distance from the sclera to the diameter of the beam of laser radiation focused on the sclera, were blocked for 1-2 mm diameter tumor in her projection.



 

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FIELD: medicine.

SUBSTANCE: method involves mixing patient liquor with 3 ml of 10% albumin solution, with chemopreparation and incubating. Then, the mixture is introduced via catheter into subarchnoid space. Repeated introduction is carried out 7 days later.

EFFECT: alleviated intracranial hypertension phenomena in cases of endolumbal drugs introduction; reduced risk of toxic complications.

FIELD: medicine.

SUBSTANCE: method involves introducing water-soluble chemopreparation as a course in lymphotropic way. Riva-Rocci apparatus cuff is applied to lower part of femur and pressure of 40 mm of mercury column is created. 20 ml of chymotrypsin dissolved in 0.5% Novocain solution is subcutaneously introduced into the middle area of lateral shank surface 30 min later. Water-soluble chemopreparations are slowly subcutaneously introduced 0.5 cm below the chymotrypsin injection place in 5-7 min as single dose. The cuff is left in swollen state for 2 h. After having taken off the cuff, 50 ml of 0.5% Novocain solution is subcutaneously introduced into the place of previous water-soluble chemopreparations injection. Then the lower extremity is dressed with elastic bandage. The lymphotropic water-soluble chemopreparations introduction procedure is carried out once a day combined with standard chemotherapy course. Detralex is daily given to the patient on the background of the chemotherapy course at a dose of 2 pills twice a day combined with subcutaneous Fraxiparin injections introduced at a dose of 0.3 ml once a day.

EFFECT: avoided surgical intervention; increased antitumor effectiveness; reduced risk of recurrences, metastases and toxic complications.

5 dwg

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating metastatic hepatic disorder in patients with malignant neoplasms. The method of regional polychemotherapy (RPCT) concentrates upon catheterization of proper hepatic artery (PHA) through gastro-omental artery to fulfill intra-arterial RPCT. Moreover, additionally after PHA catheterization it is necessary to catheterize an umbilical vein (UV) due to fulfilling arterio-venous shunting. For this purpose, one should connect catheters introduced into UV and PHA, with the help of a T-joint valve appliance (TVA); before carrying out RPCT it is important to conduct hepatic arterialization due to directing the blood from PHA through UV into the liver by setting TVA valves in position being open for PHA and UV; for carrying out RPCT one should locate TVA valves in position being open for introducing chemopreparations out of the system with a dosing tank of medicinal substances into PHA to carry out the infusion of chemopreparations. Seances for alternating hepatic arterialization and RPCT should be fulfilled daily once a day during the whole course of therapy. The innovation enables to simultaneously increase the concentration of chemopreparations in metastatic hepatic foci, detoxication hepatic function and sensitivity of tumor cells to chemopreparations as a result of additional preliminary oxygenation of hepatocytes.

EFFECT: higher efficiency of therapy.

1 cl, 6 dwg, 1 ex

FIELD: medicine, prophylactic oncology, pharmacy.

SUBSTANCE: invention proposes an agent belonging to class of nonsteroid anti-inflammatory preparations, namely, associate comprising 2[(2,6-dichlorophenyl)amino]-benzene acetic acid, inosine and N-methylglucosamine. In oral administration this associate inhibits effectively origination and development of malignant and benign tumors of brain, spinal cord, kidneys, breast, esophagus, forestomach, uterus cervix and vagina induced by chemical carcinogens in laboratory animals. Invention provides preparing the preparation possessing the more expressed anti-carcinogenic activity and lesser toxic ulcerous effect.

EFFECT: improved and valuable medicinal properties of agent.

5 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves taking blood sample into sterile flask in the amount of 150 ml before and after funiculo-orchectomy. Plasma and formed elements are separated by means of centrifuging. Plasma is taken and 300 mg Bleocin and 1000 mg Cyclophosphane are dissolved in a portion of it. Platinum preparation is added to the plasma and formed elements remaining in the flask in the amount of 75-100 mg/m2. When completely dissolved, the produced solutions are incubated in thermostat at 37°C during 40 min. Endolymphatic infusion of preparations on patient autoplasma is carried out into lymphatic vessel of foot back on the side where tumor process takes place, and intravenous autohemochemotherapy with platinum preparations are sequentially carried out under hyperhydration and forced diuresis conditions.

EFFECT: concentrated purposeful action upon primary testicular carcinoma and metastases into retroperitoneal lymph nodes; reduced risk of toxic complications.

FIELD: medicine, oncology.

SUBSTANCE: in patients with prognostically unfavorable laryngeal and pharyngeal cancer therapy should be started with carrying out chemotherapy with preparations that enhance radiation action. Local hyperthermia should be conducted twice weekly at the background of radiation therapy. Moreover, during hyperthermal days a single focal dosage corresponds to 4 Gy - 2 Gyx2 at 4-h-long interval. The innovation enables to increase efficiency in treating patients with cerebral and cervical squamous cell cancer stage III-IV, improve viability values in this category of patients, decrease toxicity and improve therapeutic results at acceptable increase of topical radiation alterations and hematological toxicity.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine.

SUBSTANCE: method involves administering Wobenzyme combined with brachytherapy with radiomodification and transpupillary thermotherapy or combined with isolated transpupillary thermotherapy. When combined with brachytherapy with radiomodification, Wobenzyme is given 2 days before brachytherapy at a dose of 3 pills 3 times a day with the exception of 8 h before fixation and removal of β-applicator. Next to it, Wobenzyme is given at a dose of 4-6 pills 3 times a day during 3 months. Then, the dose is reduced by 2 pills every month at the fourth, fifth and sixth months. Adjuvant transpupillary thermotherapy is carried out 6 months later after brachytherapy. Wobenzyme is given at a dose of 2-3 pills 3 times a day 2 days before transpupillary thermotherapy. Then, the dose is 4-6 pills 3 times a day during 2 months with following dose reduction by 3 pills every month to prophylactic dose of 1 pill a day. When carrying out isolated transpupillary thermotherapy, Wobenzyme is given in the same mode that it was the case when carrying out adjuvant transpupillary thermotherapy after brachytherapy. To prevent metastasis occurrence, Wobenzyme administration is continued at a dose of 1 pill 7 days every month during the first year and at a dose of 1 pill 3 days every month during the second observation year.

EFFECT: accelerated resorption processes; reduced risk of radiation treatment complications.

FIELD: oncology.

SUBSTANCE: treatment consists in performing 2-4 courses of preoperative chemotherapy with 2-weak intervals between courses, each course comprising intravenous administration of methotrexate in dose 40 mg/m2 on first or eighth day and intramuscular cyclophosphanin dose 100 mg/m2 during 14 days, while introducing additionally oral Xeloda in dose 1000 mg/m2 twice a day on the first to fourteenth days.

EFFECT: achieved complete regression of tumor focus owing to high selectivity of Xeloda preparation diminishing toxic effect of chemotherapy.

3 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel C-2'-methylated derivatives of paclitaxel of the formula (I): wherein R represents trifluoromethyl group, phenyl, 2-furyl, 2-thienyl; R1 represents tert.-butoxycarbonyl or benzoyl group; R2 represents hydroxy-group; R3 means hydrogen atom or in common with R2 forms residue of cyclic carbonate of the formula: under condition that when R3 means hydrogen atom then R is not phenyl. Also, invention relates to a pharmaceutical composition based on thereof and using for preparing medicinal agents possessing an antitumor activity. Invention provides preparing novel derivatives of paclitaxel that possess antitumor activity.

EFFECT: valuable medicinal property of derivatives and pharmaceutical composition.

4 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to derivatives of camptothecin of the general formula (I): wherein R1 represents alkyl or their pharmaceutically acceptable salts. Compounds of the formula (I) are intermediate compounds used in synthesis of camptothecin derivatives that possess anticancer activity.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 ex

FIELD: medicine, in particular, oncology and urology, possible use for treatment of surface cancer of urinary bladder.

SUBSTANCE: in accordance to method, tumor is irradiated by laser with output power 0,5-2 Wt with wave length 662 nm and light energy of 300-600 J/cm2 during 10-30 minutes in presence of specified photosensitizer injected intravenously in volume of 0,8-1 mg/kg. Then a silicon vessel is inserted into urinary bladder with fibro-optical filament with cylindrical diffuser positioned therein. Vessel is filled with distilled water and laser irradiation of whole mucous tunic of urinary bladder by light energy at 30-40 J/cm2 is continued during 40-60 minutes.

EFFECT: possible decrease of frequency of relapses and collateral reactions.

1 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out transpupillary irradiation of melanoma with low intensity laser radiation of wavelength 633 nm at a dose of 2.5 J or wavelength of 890 nm at a dose of 1.2 J. Photosensitizer of chlorine row is intravenously injected in water-soluble pharmaceutical dosage form at a dose of (0.8-1.1 mg/kgx0.7) during 10 min. 1 h later after having introduced the photosensitizer, spectral fluorescent diagnosis is carried out. Melanoma fluorescence being detected on the background of surrounding tissues, The same photosensitizer is intravenously introduced in liposomal form as bolus injection at a dose of (0.8-1.1 mg/kgx0.3). Tumor edge is transpupillary irradiated allover its perimeter field-by-field with laser at 670 nm wavelength with power density equal to 60-80 J/cm2 with neighboring fields overlapping by 5% of area, 10-15 min later after the injection. Then, the whole neoplasm surface is exposed to laser radiation of wavelength 662 nm and power density equal to 100-120 J/cm2 with neighboring fields overlapping by 5% of area. Irradiation is carried out moving in circle from periphery to the center.

EFFECT: dosed treatment sessions; making blood vessel feeding the tumor empty; enhanced effectiveness in killing tumor cells and stopping tumor growth; reduced recurrence risk.

FIELD: medicine.

SUBSTANCE: method involves translimbally exposing anterior chamber neovascularization angle projection zone to low intensity laser radiation field-by-field at wavelength of 633 nm at a dose of 2.5 J or at wavelength of 890 nm at a dose of 1.2 J. Water-soluble chlorine row photosensitizer dosage form is intravenously introduced at a bolus dose of 0.8-1.1 mg/kg. Newly formed blood vessels are exposed to radiation in 15-20 min after having accomplished photosensitizer introduction, field-by-field with diameter not greater than 3 mm and wavelength corresponding to maximum luminous flow absorption by the photosensitizer. Power density is equal to 50-80 J/cm2. Irradiation is applied with neighboring fields overlap by 5% of area. The laser field covers anterior chamber angle structures and iris root zone. Irradiation zone is not to exceed 180° per one session along anterior chamber angle length. The treatment is completely repeated in 2-3 weeks in the zone remaining intact during the first session.

EFFECT: dosed action; reduced risk of traumatic complications; stable ophthalmotone and anterior chamber angle neovascularization regress.

FIELD: medicine, possible use in oncology for treatment of metastasis of tumors of any aetiology, in particular, ophthalmo-oncology after enucleation of eye because of tumor.

SUBSTANCE: in accordance to method, photosensitizer of chlorine line in dose of 0,7-0,8 mg/kg is injected intravenously into pronator vein of one arm, and in pronator vein of other arm, intravenous laser irradiation of blood is performed with wave length matching light radiation absorption maximum for photosensitizer, in irradiation dose of 600-850 J/cm3. Injection of photosensitizer and intravenous laser irradiation of blood is performed simultaneously for 30-50 minutes, then in 3-4 days method is repeated fully. If repeated metastatic focuses appear, up to 6 treatment sessions are performed. In case of presence of superficially positioned metastatic focuses at first stage of treatment, irradiation of superficially positioned metastatic focuses is performed, injecting low intensity laser radiation in dose of 0,15-0,20 J through skin.

EFFECT: full or partial regression of development of small metastatic focuses and inhibition of growth of large metastatic focuses of any localization, significantly decreased relapse risk, increased probability of survival and extended lifespan of patients.

3 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to surgery methods of treatment. Method involves insertion of gel into wound representing a photosensitizing agent comprising 0.5-1.5% of chlorin E6 glucamine salt followed by carrying out treatment of wound by laser in continuous regimen at wavelength 660 nm, energy density supplied to wound 30-40 J/cm2 and power density 0.8-1.0 Wt/cm2. Method provides simplifying, acceleration and enhancing effectiveness of treatment based on using the optimal density of radiation powder. Invention can be used in treatment of spacious suppurative diseases of soft tissues.

EFFECT: improved method of treatment.

3 ex

FIELD: medicine, in particular photosensitizing agents for antimicrobial photodynamic therapy.

SUBSTANCE: invention relates to new photosensitizing agents for antimicrobial photodynamic therapy namely cationic phthalocyanines of general formula MPc(CH2X)nCln, wherein Pc is phthalocyanine rest C32H16N8; M is Zn, AlY; n = 6-8; X is Y is Cl, OH, OSO3H. Claimed agents is characterized by wide range of antimicrobial activity. Single complex action of nontoxic in darkness micromolar (up to 2.0 muM) concentration thereof and low dose of red irradiation make it possible to produce high inactivation levels (up to 97-99 %) both gram-negative bacteria and yeast fungi of genus Candida.

EFFECT: improved agents for treatment of various severe complications of inflammation diseases.

3 dwg, 13 ex, 2 tbl

FIELD: medicine, in particular photosensitizing agents for photodynamic therapy.

SUBSTANCE: invention relates to quaternary phthalocyanines of general formula MPc(CH2X)nCln, wherein Pc is phthalocyanine rest C32H16N8; M is Zn, AlY; n = 6-8; X is Y is Cl, OH, OSO3H, useful as photosensitizing agents in photodynamic therapy having high photoinduced activity in vivo and in vitro.

EFFECT: new class of effective photosensitizing agents useful in treatment of various tumors by photodynamic therapy.

1 dwg, 8 ex

FIELD: medicine, oncology, pharmacology.

SUBSTANCE: invention relates to methods for preparing biologically active substances. Method for preparing a photosensitizer involves treatment of spirulina preliminary dried by lyophilization method in methanol for preparing a precipitate containing chlorin e6 followed by its washing out, suspending and repeated centrifugation. Prepared precipitate is dissolved in aqueous solution of N-methyl-D-glucamine, pH value is brought about to 7.75-8.20, then 510-520 ml of apyrogenic water is added to obtain the optical density of solution 200-210 U at 654 nm and pH = 9.0 followed by filtration of solution through filter with pores size 0.22 mmc and polyvinylpyrrolidone of molecular mass from 9600 to 11500 Da is added. Prepared photosensitizer for photodynamic therapy comprises chlorin e6 in the amount 98%, not less, N-methyl-D-glucamine in the mole ratio = 1:2 and polyvinylpyrrolidone of molecular mass from 9600 to 11500 Da wherein chlorin e6 has the following structural formula: . Invention provides the development of a new medicinal formulation possessing the more effective therapeutic properties for treatment of different oncological diseases by methods of photodynamic therapy based on the higher content of chlorin e6. Invention can be used for preparing a water-soluble form of highly purified chlorin e6 that can be used as a photosensitizer in photodynamic therapy of cancer and other neoplasm of different genesis.

EFFECT: improved preparing method, valuable medicinal properties of agent.

5 cl, 8 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: method involves covering ectocervix with Photodithazine photosensibilizer produced on the basis of glycamine chlorine salt E6 with active substance concentration being equal to 0.3-0.5% and holding it for 2 h. Laser radiation treatment is applied in continuous mode at wavelength of 660 nm and energy density of 80-200 J/cm2 supplied to wound during 8-20 min.

EFFECT: enhanced effectiveness of treatment; reduced risk of allergic response and adverse side effects.

FIELD: medicine.

SUBSTANCE: method involves introducing photosensibilizer into wound and exposing it to laser radiation. Photodithazine gel is applied as photosensibilizer based on glycamine chlorine salt E6 Photodithazine with active substance concentration of 0.5-1.5%. Laser radiation treatment is applied in continuous mode at wavelength of 660 nm and energy density of 30-40 J/cm2 supplied to wound and power density of 0.8-0.1 W/cm2.

EFFECT: enhanced effectiveness of treatment.

FIELD: medicine.

SUBSTANCE: method involves separating flap from corneal stroma stromal bed and one that projecting beyond the flap edge. The stromal bed is washed, the flap is wetted and laid to its place. Flap folds are eliminated by mechanically removing epithelium from the surface by means of blade instrument. The epithelium removal starts from flap pedicle base in moving over the center towards the opposite edge. Then the whole flap is sequentially cleared from epithelium making movements in perpendicular to fold direction sector-by-sector beginning from sector having folds moving from the center in radial direction. The flap is hold with the instrument at the opposite side. The folds are smoothed with blunt instrument. Soft contact lens is laid over cornea.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications and infection occurrence; returned vision acuity.

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