Application of trisubstituted glycerol compounds for treatment of radiolesions

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to application for production of medication for prevention and/or treatment of radiolesion or lesion of trisubstituted glycerol compound, corresponding to formula where X is selected from phosphate and sulfate; R1 is selected from C16-C20alkyl, R2 is selected from C1-C3alkyl and C1-C3hydroxyalkyl, R3 is selected from hydrogen and C1-C3 alkyl, R4 is selected from C1-C3alkyl and C3-C6cycloalkyl, R5 is selected from hydrogen and methyl, or its enantiomer, or diastereomer, or pharmaceutically acceptable salt, and at least one pharmaceutically acceptable filling agent.

EFFECT: claimed is novel application of known compounds.

12 cl, 3 dwg, 5 ex, 5 tbl

 

The present invention relates to the use of compounds of tri-substituted glycerol or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the prevention and/or treatment of radiation injuries. In addition, the present invention relates to a relevant in vitro methods of prevention or treatment of radiation damage or lesions in one or more cells, comprising contacting these cells with the drug, as described in the present invention.

Exposure to radiation (such as x-rays, gamma rays and alpha or beta radiation) can cause damage to cells. Such damage can lead to cell death (e.g., through apoptosis) or may cause genetic changes in cells, leading to uncontrolled cell proliferation and, consequently, to the development and progression of tumors.

Although the impact of this radiation is in General undesirable effects carefully controlled doses of radiation is a common treatment for some cancers, such as leukemia, breast cancer, prostate cancer or colon cancer. The influence of radiation on the tumor can destroy cancer cells.

A common complication of radiation therapy is the exposure of normal tissues, surrounding the x-cancerous tissue. Such normal tissue is often damaged by radiation, which leads to unwanted radiation to defeat normal cells and tissues, which can have severe consequences for the treated patient.

You can be exposed to radiation and some other ways, including exposure to normal background radiation levels (such as cosmic radiation or radiation from those present on our planet natural isotopes) or increased environmental radioactivity (including occupational exposure of people in medical facilities or nuclear power plants, and exposure to x-rays in medical diagnosis). Another potential source of exposure to certain types of radiation is the accidental or intentional release of radioactive materials, for example, in the accident or the result of terrorist activity, for example in the use of radiological weapons such as the so-called "dirty nuclear bomb" (an explosive device designed to spread radioactive materials for contamination of the surrounding space).

The main form of protection from radiation damage is the avoidance of exposure to radiation. Protective materials capable of preventing the penetration of radiation from the body, can be used in cases where the known radiation source. For example, you can use protective lead aprons for blocking x-rays. You can use protective clothing to prevent contamination of the body with radioactive materials, and removal of radioactive materials can be used methods of cleaning.

Processing radioprotective chemicals is a way to prevent some types of radiation damage, such as DNA damage by free radicals (or other reactive particles)formed under the action of radiation.

Widely used radioprotective agent is amifostine, organic thiophosphate the prodrug (2-[(3-aminopropyl)amino]etention dihydrophosphate), which dephosphorylates in vivo alkaline phosphatase to the active thiol metabolite (see, for example, U.S. Patent 7073072, as well as international patent application WO 02/092103 and WO 02/062350). It is believed that selective protection of the non-cancerous tissue is due to the higher activity of alkaline phosphatase, a higher pH and permeability of blood vessels in normal tissues. Amifostine therapeutically used, among other things, to reduce the frequency of occurrence of induced neutropenia feverishly the on state, to reduce the cumulative renal toxicity caused by platinum-containing means, and to reduce the incidence of xerostomia in patients undergoing radiation therapy for the treatment of cancer of the head and neck. However, it was demonstrated that amifostine effective as a means of radiation protection only with the introduction shortly before exposure to radiation. Introduction after exposure to radiation does not provide a therapeutic effect. In addition, the introduction of amifostine or related tylnej compounds associated with severe harmful side effects such as systemic cytotoxicity and gastrointestinal incompatibility, such as nausea and vomiting.

The effect of another compound, 5-androstenediol, as a means of protection from irradiation has been studied in preclinical animal studies. It is reported that this compound improves survival in mice exposed to radiation, possibly by stimulating the production of neutrophils and other cells of the immune system, and thus prevents infection, a frequent cause of death of subjects affected by radiation. However, this connection is a rescue tool and does not counteract the pathogenic mechanism of irradiation, and does not protect other organs, besides the blood. It is not odorants use in humans.

How promising it may seem described preventive action protection from radiation, so modest are the results of attempts to develop treatment chemicals introduced after irradiation. Known attempts to treat damaged by radiation of nucleic acids by replacing the DNA or RNA. The first results of these studies, however, do not contribute to the further development of therapeutic concepts. Thus, the only remaining option is the treatment of indirect effects of cellular damage, such as impact on the failure of the bone marrow, which determines the clinical outcome after irradiation of the whole body in high doses. Secondary effects of damage to the bone marrow are infections caused by radiation and accompanied by fever, agranulocytosis, petechiae and profuse bleeding as a result of thrombocytopenia. In severe cases, these symptoms can lead to death. Therapy listed secondary effects of damage to the bone marrow includes treatment with antibiotics, as well as substitution therapy blood cells, which lack such as granulocytes and platelets. The last resort in cases of very high doses of radiation is a bone marrow transplant.

Bore is otra that level of intensive care for lethally irradiated victims can be very high, this therapy is only available to a limited number of patients in a small number of specialized clinics. In the event of a real nuclear disaster, most likely accompanied by the appearance of hundreds of heavily irradiated patients is complex, specialized treatment is not feasible. Intensive therapy using bone marrow transplantation can save people with irradiation of the whole body at the level of 10 Gy (gray). However, in the case of untreated or subjected to inadequate treatment of patients lethal dose is reduced to 3-4 Gr. Thus, an adequate therapeutic approach in this situation would be chemotherapy, which effectively improves the prognosis for Sredneuralsk irradiated people.

Connection tri-substituted glycerol, belonging to the class of synthetic alkyl-lysophospholipids with ether bridges, can be compounds-candidates for such radioprotective therapy. In preliminary analyses of some alkyl-lysophospholipid analogues demonstrated a beneficial effect on the cells after exposure to small doses of x-rays in mice (Berdel, W. et al. (1983) Radiation Res. 94, 166-170). However, this study says nothing about the distribution of other types of radiation, and the radiation doses are treatable. In addition, yet in order to sobratsa, can the alkyl-lysophospholipids counterparts both prevent and treat radiation injury or defeat.

It is known that synthetic alkyl-lysophospholipid with ether bridges have anti-cancer effects (summarized, for example, in Arthur, G., and Bittman, R. (1998) Biochim. Biophys. Acta 1390, 85-102; Jendrossek, V., and Handrick, R. (2003) Curr. Med. Chem. Anti-Canc. Agents 3, 343-353; Mollinedo, F. et al. (2004) Curr. Med. Chem. 11, 3163-3184). 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (also known as ET-18-OCH3 AR-121 or edelfosine) is considered the prototype of these lipids. 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine is a synthetic analogue of platelet activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), strong phospholipid activator and mediator of many leucocytes functions, including platelet aggregation, inflammation, and anaphylaxis. Unlike most conventional chemotherapeutic drugs data synthetic ether lipids do not act directly on cellular DNA, but act more on the lipid composition of cell membranes and/or intervene in various ways in signal transduction. Thus, the way their actions are not dependent on the availability of specific cell receptors and does not depend on cell cycle.

Anticancer chemotherapy is usually aimed at slowing the growth or destruction of cancer cells, at the same time escaped the I side damage to surrounding cells and tissues. Consequently, the most effective anticancer funds are those funds that may selectively affect cancer cells while leaving normal cells relatively unaffected. It was shown that synthetic ether lipids have such an effect (see, for example, Magistrelli, A. et al. (1995) Drug. Metab. Dispos. 23, 113-118). It was suggested multiple mechanisms of action to explain the toxicity of essential lipids in cancerous cells, including the lack of such cells enzymes that chip off alkyl. The observed result in the inability to hydrolyze the ether lipids leads to their accumulation within the cell and subsequent damage to the lipid structure of cell membranes. Other possible mechanisms of action of essential lipids include effects on the levels of intracellular protein phosphorylation and disruption of cellular lipid metabolism. Normal cells usually possess the means to prevent or overcome the potentially toxic effects of essential lipids, while cancer cells do not have them.

To date synthetic ether lipids have been used to treat various types of tumors such as brain tumors or breast carcinoma (see, for example, German patent DE 2619686, as well as international patent stated the Ki WO 99/59599 and WO 00/01392 respectively).

Although the antitumor effects of these synthetic ether lipids has been experimentally confirmed in several animal tumor models, their clinical use is often hampered by systemic cytotoxic effects, including hemolysis, especially in the gastrointestinal tract, but also, among others, in the lungs, liver or kidneys. In 10-20% of patients who were treated with such solutions based on water and/or milk that contains essential lipids was observed severe gastrointestinal incompatibility corresponding to the III and IV degrees of toxicity who are associated with nausea, vomiting, diarrhea or higher (see, for example, Drings, P. et al. (1992) Onkologie 15, 375-382).

Thus, in addition to providing the desired pharmaceutical activity, there is a need in medicine, which provides an easy and convenient introduction. In particular, there remains a need in the remedy, which is suitable for preventing radiation damage or destruction prior to exposure to radiation and for the relief or treatment of radiation damage or destruction after exposure to radiation.

Accordingly, the present invention is the provision of medicines for the prevention and/or treatment of radiation damage or destruction, the region is giving these properties.

This goal is achieved by applying connection tri-substituted glycerol having the features of independent claim 1 for the production of the relevant medicinal product. Some preferred embodiments of the present invention are determined by the content of the dependent claims.

It has been unexpectedly discovered that compounds tri-substituted glycerol, such as 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine, which are known as anticancer funds also have a radioprotective effect on cells and tissue that provides effective prevention and/or treatment of radiation damage or destruction as a response to the impact of various types of radiation. Invented the drug provides the necessary efficiency, can be administered to the patient and does not show harmful side effects.

In the context of the present invention any specified numeric value is usually associated with an interval of accuracy, which, as is clear to a person skilled in the field of technology still provides the technical effect of a given characteristic. When used in this text, the deviation from the specified numeric value is within ±10%, and preferably ±5%.

In the first aspect of the present invention relates to the use of the connection is through the tri-substituted glycerol, corresponding to the formula (I)

or its enantiomer or diastereoisomer, or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for the prevention and/or treatment of radiation damage or destruction, where

X is selected from the group consisting of phosphate and sulfate;

R1selected from the group consisting of C16-C20Akilov;

R2selected from the group consisting of C1-C3Akilov and C1-C3hydroxyalkyl;

R3selected from the group consisting of hydrogen and C1-C3Akilov;

R4selected from the group consisting of C1-C3Akilov and C3-C6cycloalkyl;

and

R5selected from the group consisting of hydrogen and methyl.

Connection tri-substituted glycerol may be present in amorphous or crystalline form. The term "amorphous", when used in this text, refers to the solid phase, in which there is no long-range order in the arrangement of the atoms, i.e. non-crystalline material. In preferred versions of the present invention, the connection tri-substituted glycerol is present in crystalline form.

The terms "Cnalkyl, Cnhydroxyalkyl" and "Cncycloalkyl" PR is used in this text mean respectively an alkyl group, hydroxyalkyl group, or cycloalkyl group containing n carbon atoms. For example, the term "C18alkyl" refers to alkyl group containing 18 carbon atoms. Alkyl group or hydroxyalkyl group of the present invention can be straight or branched.

Connection tri-substituted glycerol of the formula (I) have one or more centers of asymmetry and may therefore exist in the form of enantiomers or diastereoisomers. Thus, the drug described in this invention may contain one or more separate individual isomers (such as the L form and D form) or a mixture of isomers, preferably racemic mixture.

In some embodiments, execution of the present invention compounds of tri-substituted glycerol of the formula (I) are present in the medicinal product in the form of pharmaceutically acceptable salts. Such salts may include any pharmaceutically acceptable anion, "neutralizing the positive charge of the nitrogen (e.g., chloride, bromide or iodide), or any pharmaceutically acceptable cation, "neutralizing negative charge of the phosphate or sulfate fragment (for example, the cations of sodium or potassium).

In a particularly preferred embodiment of the present invention the pharmaceutical solid dosage form contains from the Association of the tri-substituted glycerol, corresponding to the formula (I), where X is a phosphate, R1represents -(CH2)17-CH3, R2represents CH3, R3represents H, R4represents -(CH2)2and R5represents CH3.

The drug of the present invention may be any pharmaceutical dosage form, which is therapeutically effective. Examples of such pharmaceutical dosage forms include tablets, pills, capsules, suspensions, emulsions, solutions for injection or infusion, tinctures, powders and the like.

Used in the present invention medicines contain at least one pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" as used in this text, means any substance used for pharmaceutical dosage forms, such as coating materials, film-forming materials, fillers, dezintegriruetsja tools, materials, modifying the release, carriers, diluents, binders and other additives all additives are well known in the art (see links below). Preferably used in the present invention, the filler including the et at least one filler, at least one binder, at least one dezintegriruetsja means, at least one means of controlling the flow, and at least one lubricating agent.

The drug can enter any parenteral or aparentally way. Methods of parenteral administration include, for example, methods of intradermal, subcutaneous, intramuscular or intravenous injections and infusions. Aparentally methods of introduction include, for example, oral administration or external application. In addition, the drug can be entered locally or systemically.

Preferably used in the present invention, the drug is a pharmaceutical dosage form suitable for oral administration. Particularly preferred dosage form is a solid dosage form. Examples of such dosage forms include, inter alia, tablets, pills, capsules, granules, pellets, powders, drugs, consisting of many particles (e.g., beads, granules or crystals) and pills. The standard dosage of drugs, consisting of many particles can be included in pharmaceutical solid dosage form, for example, by extrusion or molding into tablets or by placing demand the number inside gelatin capsules.

All of these solid dosage forms for oral administration, as well as methods for their preparation are well known in the art (see, for example, Gennaro, A.L. and Gennaro, A.R. (2000) Remington: The Science and Practice of Pharmacy, 20th Ed., Lippincott Williams & Wilkins, Philadelphia, PA; Ritschel, W.A. & Bauer-Brandl, A. (2002) Die Tablette: Handbuch der Entwicklung, Herstellung und Qualitätssicherung. Editio-Cantor Verlag, Aulendorf, Germany; Crowder, T.M. et al. (2003) A Guide to Pharmaceutical Particulate Science. Interpharm/CRC, Boca Raton, FL; Strieker, H. (2003) Arzneiformenentwicklung, Springer Verlag, Berlin, Germany; Niazi, S.K. (2004) Handbook of Pharmaceutical Manufacturing Formulations, CRC Press, Boca Raton, FL).

In preferred versions of the present invention the pharmaceutical solid dosage form selected from the group consisting of tablets, pills, capsules and granules, tablets are particularly preferred.

Solid dosage form preferably is an enteric dosage form. That is, the dosage form remains stable in the stomach, i.e. in an acidic environment with a pH in the range ≤2.5. This can be achieved by using a solid dosage form with a film membrane. For example, the invented formulation may be in the form of so-called film-coated tablets.

Methods of obtaining coated dosage forms are also well defined in the art (see, for example, the above link). Also, specialist in the art will also know how to get the film sheath with certain properties, such as intersolubility coating film membrane that dissolve upon contact with body fluids, membrane controlled release membrane masking the taste or dezintegriruetsja shell. In a particularly preferred embodiment, the solid dosage form according to the present invention has intersolubility floor.

According to the present invention should be understood that the connection tri-substituted glycerol is present in the medicinal product in any amount effective to achieve the desired pharmacological effect when administered to the patient. An effective amount is usually chosen in accordance with several factors, such as age, weight and General condition of the patient, and a medical condition that needs to be cured, and identify different ways, for example, research on the effectiveness of the drug in the range of dosages, well-known and easily carried out by experts in the field of technology who know the essence of the present invention.

Usually the remedy described in the present invention, the number of connection tri-substituted glycerol of the formula (I) is less than 400 is g, preferably it is in the range from 30 to 250 mg, and most preferably in the range from 50 to 150 mg. In particularly preferred versions of the present invention, the number of connection tri-substituted glycerol of the formula (I) is 75 mg and 100 mg, respectively.

Enter the patient's daily dose of a compound tri-substituted glycerol is less than 1200 mg, usually less than 900 mg, preferably in the range from 30 to 600 mg, more preferably in the range of from 40 to 400 mg, and most preferably in the range of from 50 to 350 mg In private versions of the daily dose of 75, 100, 150, 200, 225 and 300 mg. Preferably, the daily dose of a compound tri-substituted glycerol is injected as a single dose, for example in the form of one to four tablets or capsules. However, it is also possible to introduce the connection of multiple doses, such as two or three separate doses, administered during the day, such as morning, afternoon and evening.

The drug of the present invention can be used for the prevention and/or treatment of radiation damage or destruction separately or in combination, at least one other drug containing at least one additional active ingredient. That is, in the scope of the present invention also includes the use of Lekarstvo the th means, contains the connection tri-substituted glycerol defined in the claims, together with at least one other drug that contains one or more different active ingredients, such as a means of chemotherapy or monoclonal antibodies.

The term "radiation damage or defeat" when used herein refers to any negative or harmful effects that exposure is obtained regardless of the dose and time of exposure, respectively - can have on cells, tissues, organs or organisms, leading to uncontrolled cell proliferation and/or differentiation and, consequently, to the development and progression of tumors. Examples of such radiation damage or lesions include, among other things, genetic changes in the cell (for example, mutation of DNA and/or RNA, the destruction of the DNA and/or RNA, chromosomal aberrations), and cell death (for example, programmed cell death/apoptosis).

In some embodiments, the performance of the present invention, radiation damage or failure caused by ionizing radiation. The term "ionizing radiation", when used in this text, mean corpuscular radiation or electromagnetic radiation, in which an individual particle/photon has sufficient quantity is the your energy to ionize an atom or molecule by complete removal of the electron from its orbit. If the individual particles do not have this amount of energy, even a large flow of particles actually unable to cause ionization. If ionization occurs at a significant scale, it can be very destructive to living tissue. Examples of corpuscular radiation, which is ionizing, can be a fast electrons, neutrons, ions, atoms or photons. Electromagnetic radiation can cause ionization if the energy of the photon or the frequency is high enough, and thus, the wavelength is small enough. The amount of energy needed varies depending on an ionisable molecules.

Preferably, the ionizing radiation is selected from the group consisting of neutron radiation, alpha radiation, beta radiation, gamma radiation and x-rays.

Neutron radiation is usually called indirectly ionizing radiation. It is not ionizes the atoms in the same way as protons, photons and electrons, since neutrons have no charge. However, interaction with the neutrons are highly ionizing, for example, when the absorption of neutrons leads to gamma rays, and gamma rays then knocks out an electron from an atom or a nucleus departing sredstv the e interaction with a neutron, ionized and leads to more traditional subsequent ionization of other atoms. Since neutrons are not charged, they are more penetrating than alpha radiation (helium nuclei) and beta radiation (electrons or positrons). In some cases, they are more penetrating than gamma rays (electromagnetic radiation), which is difficult in materials with high atomic number.

X-rays are a type of electromagnetic radiation with a wavelength in the range of 10 to 0.01 nanometers, corresponding to frequencies in the range from 30 to 30000 PGC (1015Hz). X-rays are primarily used for diagnostic radiography and crystallography. X-rays are a form of ionizing radiation.

In the scope of the present invention radiation damage or loss that must be prevented and/or cured, may be the result of exposure to natural radiation and man-made radiation.

Radiation, in the context of the present invention, can be, and some other ways, including exposure to normal background radiation levels (such as cosmic radiation or radiation from those present on our planet natural isotopes) or increased environmental radioactivity (including professional who Noe irradiation of people in medical facilities or nuclear power plants, and exposure to x-rays in medical diagnosis, for example, computed tomography (CT). Another potential source of exposure to certain types of radiation is the accidental or intentional release of radioactive materials, for example, in the accident or the result of terrorist activity, for example in the use of radiological weapons such as the so-called "dirty nuclear bomb" (an explosive device designed to spread radioactive materials for contamination of the surrounding space).

In preferred versions of the present invention radiation damage or loss associated with cancer therapy, i.e. is the result of radiation therapy for cancer. In a particular embodiment, the present invention radiation damage or loss is associated with bone marrow transplantation in the treatment of cancer.

In a second aspect the present invention relates to the connection tri-substituted glycerol described in this text, intended for the prevention and/or treatment of radiation damage or destruction. In preferred versions of the radiation damage or loss due to cancer therapy or bone marrow transplantation during cancer therapy.

In the third aspect of the present is Britanie refers to the appropriate method of prevention and/or treatment of radiation damage or destruction, where this method includes the introduction of patient medicines described in this invention.

As noted above, the drug of the present invention it is possible to enter any parenteral or aparentally way. Preferably, the drug is administered orally. In addition, the drug is preferably possible to enter it in the form of a single dose, such as one tablet or capsule per day. However, you can also enter multiple drug doses, such as two or three separate doses, administered during the day. To prevent radiation damage or destruction, the drug is preferably administered before radiation exposure. However, you can also enter the drug during and/or after exposure to radiation.

In the fourth aspect of the present invention relates to methods of in vitro prevention of radiation damage or destruction and treatment or prevention of radiation damage or lesions in one or more cells, respectively, each method involves contacting one or more cells are exposed, with the medicinal product described in this invention. By the first method, the cells are in contact with the medicinal product to the effects of radiation.

Predpochtitel is but one or more cells are not cancer cells (i.e. non-oncogenic control cells), such as bone marrow cells.

The invention is additionally described by the following drawings and examples, which are intended for illustration only private embodiments of the present invention and should not be construed as in any way limit the present invention.

The materials used in the following tests, commercially available or can be easily obtained from commercially available materials by experts in the field of technology.

DRAWINGS

Figure 1 shows the radioprotective effect AT-OCH3 on the survival of mice. ET-OCH3 was administered as a single dose of 50 mg/kg of body weight of each of the 40 mice (20 control mice, 20 test mice). After 24 hours, 20 test mice were subjected to gamma radiation dose 7.9 Gy (gray) and 8.7 G, respectively. Survival was monitored for 30 days.

Figure 2 presents the radioprotective effect of ET-18-OCH3 (marked as "ALP") for the number of lymphocytes in mice. Mice were administered a single dose of 70 mg/kg ET-18-OCH3 (subcutaneous injection) for 24 hours prior to exposure to neutron radiation (radiation dose of 2.0 Gy). The number of lymphocytes on μl of blood is not exposed to processing (irradiated) control mice and powerhouse the Xia processing (test) mice was determined after 1, 3 and 10 days after irradiation.

Figure 3 presents the radioprotective effect of ET-18-ONS (marked as "ALP") for the number of granulocytes in mice. The experiment was carried out by a method similar to that described in figure 2.

EXAMPLES

The effectiveness of 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (hereinafter referred to as "ET-18-OCH3) as radioprotective tools in the treatment of acute radiation injury caused (medium)lethal doses of irradiation were analyzed by determining its effect on the survival rates of mice and hematological syndrome radiation damage as a response to the impact of various types of radiation.

Example 1: Efficiency AT-OCH3 in response to exposure to x-rays

A single dose of 25 mg/kg ET-18-OCH3 simultaneously injected intravenously 25 mice 12 hours after exposure to x-ray radiation dose of 650 cGy (centigray). Killed only one of the 25 exposed to processing mice compared with 6 out of 25 mice in the control group.

After intravenous administration of 25 mg/kg ET-OCH3 6 hours and 12 hours after x-ray irradiation, respectively, the following results were obtained (table 1). The Chi-squared distribution presents for all positive values. The Chi-square was used to compare the results to, for example, avisa treatment of animals compared to control animals.

Table 1
Levels of survival of irradiated x-rays mice after the injection of 2×25 mg/kg ET-OCH3 6 hours and 12 hours after irradiation, respectively.
The dose of x-ray radiation (cGy)Mortality/Survival of Control animalsMortality/Survival Subjected to processing animalsChi2p
6504/262/280.740.402
70019/113/2517.03<0.001
75027/314/1613.02<0.001
80030/022/89.230.002

LD50/30x-ray irradiation increased with 688.1±38.6 to 749±37.1 cGy for podvergavshikhsya animals compared to not exposed to processing of the control animals. Caused by x-ray radiation lethality exposed to processing in mice was delayed compared with the control mice.

After oral administration of 25 mg/kg ET-ONS after 6 hours and 24 hours after exposure to x-ray radiation dose x-ray irradiation of 700 cGy killed 2 of 25 exposed to processing animals compared with 7 out of 25 control animals.

Example 2: Efficiency AT-OCH3 in response to exposure to neutron radiation

Mice were irradiated using a generator van de Graaff neutrons with 3-8 MeV. Used in subsequent analyses of the dose was 400, 410 and 420 cGy for each third of the exposed treated and control mice, respectively. A single dose of 50 mg/kg ET-OCH3 was administered to half of the mice by subcutaneous injection. The results obtained are presented in Table 2.

From the presented results we can conclude that treatment with a single dose ET-OCH3 should be implemented as soon as possible after neutron irradiation. As therapeutic experiments were carried out in the range of doses at which prevails hematological syndrome radiation damage, it is important to determine therapeutic effect of the drug on the blood (hematopoietic system). From this Table the s 3 it becomes clear what E-OCH3 significantly increases the concentration of leukocytes and granulocytes in the peripheral blood during the period of time during which died irradiated mice (day 10-15 after irradiation).

Example 3: Efficiency AT-OCH3 before applying gamma radiation

Effect of prophylactic treatment of a connection ET-OCH3 on the survival of irradiated gamma rays mice are summarized in Table 4.

Table 4
The survival rate of mice after gamma irradiation and injection of a single dose ET-OCH3 at different points in time before or after irradiation (BP), respectively. The Chi-square was used to map exposed to processing animals compared to control animals.
Dose (cGy)Processing E-OCH3SurvivalMortalityChi2p
750-11 (55%)9 (45%)
75030 the g/kg; BP17 (94%)1 (6%)7.600.006
775-020(100%)
77540 mg/kg; BP8 (40%)12 (60%)10.000.002
800-035 (100%)
80040 mg/kg; BP25(71%)10(29%)3889<0.001
77550 mg/kg; 2 h15(75%)5 (25%)
80050 mg/kg; 2 h17(85%)3 (15%)
750 -10(50%)10 (50%)
75050 mg/kg; 1 d20(100%)013.33<0.001
77550 mg/kg; 1 d18(90%)2(10%)
790-2(10%)18(90%)
79050 mg/kg; 1 d18(90%)2 (10%)25.60<0.001
830-1 (5%)19(95%)
83050 mg/kg; 1 d17(85%)3 (15%)25.85<0.001
870 -020(100%)
87050 mg/kg; 1 d13 (65%)7 (35%)19.260.001

Thus, treatment of mice with compound ET-OCH3 resulted in a significant radioprotective effect, which was almost the same with the introduction of E-OCH3 24 hours or shortly before irradiation. This differs from the usual radioprotection means, which is expressed only with the introduction of radioprotective funds directly before irradiation. With the introduction of E-OCH3 one day before irradiation dose LD50/30gamma radiation was increased from 7.47 G (not exposed to processing of irradiated control animals) to 8.98 G (cooked on irradiated mouse) (defined probit analysis). The effect of EM 18-OCH3 on the survival of mice with two different doses of irradiation are presented in figure 1.

Example 4: Efficiency AT-OCH3 to exposure to neutron radiation

The effect of ET-18-OCH3 to the effects of various doses of neutron radiation on the levels of survival of mice are summarized in Table 5.

Table 5
The effect IT-OCH3, introduced subcutaneously 1 day before neutron irradiation. The Chi-square was used to map exposed to processing animals compared to control animals.
Dose (cGy)ProcessingSurvivalMortalityChi2p
425-015 (100%)
42550 mg/kg4 (27%)11 (73%)4.610.032
450-8 (28%)21 (72%)
45050 mg/kg22 (73%)8 (26%)12.35<0.001
475- 20 (100%)
47550 mg/kg6 (24%)19 (76%)5.540.019
425-015 (100%)
42570 mg/kg5 (33%)10 (67%)6.000.014
450-1 (7%)14 (93%)
45070 mg/kg3 (20%)12 (80%)1.150.283

Example 5: Effect E-OCH3 on the level of leukocytes in the blood count (hemogram)

After injection of 50 mg/kg and 70 mg/kg ET-18-OCH3, respectively, and the effects of neutron irradiation reduced the number of leukocytes (lymphocytes and granulocytes) increased slightly compared with not under ergasies processing control animals (not statistically significant; 5 experiments, n=90).

However, since 3 days after exposure processing by the connection of ET-18-OCH3 led to the increase in the number of leukocytes (lymphocytes and granulocytes), which became significant at day 7 (4 experiment; n=30, p<0.003). There was not a statistically significant difference between the introduction of 50 mg/kg and 70 mg/kg ET-OCH3. Radioprotective effects ET-OCH3 on the number of lymphocytes and granulocytes in mice are presented in figure 2 and Figure 3, respectively.

Despite a significant increase caused by the introduction ET-ONS, when Sredneuralsk doses, the number of cells remains low, averaging about one-tenth of normal values, while the number of leukocytes in the exposed treatment of animals shows a significantly larger variance than the deviation of the control animals. So, at 7-10 days after exposure exposed to processing animals can be classified into two groups, one of which is the number of leukocytes virtually unchanged compared with the control group. These mice usually died for 10-14 days after exposure. The respective shares of leucocytes fractions were variable, but in General, the number of leukocytes and granulocytes was significantly increased.

The present invention illustratively described in this paper can be applied to practices which, in the absence of any element or elements, restrictions or limitations, not specifically described in this text. For example, the terms "comprising", "including", "containing", etc. should be understood broadly and without limitation. Also used in this text, the terms and expressions have been used as terms of description and not of limitation, and the use of such terms and expressions does not imply the exclusion of any equivalents of the above described signs or portions thereof, but it should be noted that various modifications are possible within the scope of the claimed invention. So, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, specialists in the art can be modifications and changes of the inventions described in this text, and that such modifications and changes are included in the scope of the present invention.

All documents cited or listed as references in this text, including any manufacturers instructions, descriptions, product specifications and process maps for any products mentioned herein or in any document given in the link included in this text as links and can be used in the application of the invention in practice. Quoting Il is the designation of any document in this application is not an admission of the fact, this document serves as prior art to the present invention.

This invention has been described broadly and generally. Each of the narrower representatives of smaller groups that fall under the General description, also forms part of the invention. This includes a General description of the invention with the proviso or negative limitation removing from the total group of any object, regardless of whether the excluded material specifically identified in the text.

Other embodiments of the are within the following further claims. In addition, when describing the elements or aspects of the invention by means of Markush groups, specialists in the art will understand that the present invention thus described also for any individual member or subgroup of members of the Markush group.

1. Application connection tri-substituted glycerol, corresponding to the formula (I)

I
or its enantiomer or diastereoisomer, or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient for the manufacture of a medicinal product for the prevention and/or treatment of radiation damage or destruction,
where X is selected from the group consisting of phosphate and sulfate;
R1selected from the group consisting the th of 16-C20Akilov;
R2selected from the group consisting of C1-C3Akilov and C1-C3hydroxyalkyl;
R3selected from the group consisting of hydrogen and C1-C3Akilov;
R4selected from the group consisting of C1-C3Akilov and C3-C6cycloalkyl; and
R5selected from the group consisting of hydrogen and methyl.

2. The use according to claim 1, where X is a phosphate, R1represents -(CH2)17-CH3, R2represents CH3, R3represents H, R4represents -(CH2)2-, and R5represents CH3.

3. The use according to claim 1, where the medicinal product is a pharmaceutical form for oral administration.

4. The use according to claim 3, where the dosage form is a solid dosage form.

5. The use according to claim 4, where the dosage form is selected from the group consisting of tablets, pills, capsules and granules.

6. The use according to claim 1, where the number of connection tri-substituted glycerol in the medicinal product is in the range from 30 to 250 mg.

7. The use according to claim 6, where the number of connection tri-substituted glycerol in the medicinal product is in the range from 50 to 150 mg.

8. The use according to claim 1, where the daily dose of a compound trisemester of glycerol is in the range from 50 to 350 mg

9. The use according to claim 1, where radiation damage or failure caused by ionizing radiation.

10. The use according to claim 9, where the ionizing radiation is selected from the group consisting of neutron radiation, alpha radiation, beta radiation, gamma rays and x-rays.

11. The use according to any one of claims 1 to 10, where radiation damage or loss associated with cancer therapy.

12. The application of claim 11, where radiation damage or loss is associated with bone marrow transplantation during cancer therapy.



 

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FIELD: chemistry.

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FIELD: medicine.

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FIELD: biotechnology.

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28 cl, 13 ex

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FIELD: medicine, pharmaceutics.

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2 cl, 17 ex, 9 tbl

FIELD: medicine, pharmaceutics.

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10 ex, 7 tbl, 3 dwg

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FIELD: medicine, pharmaceutics.

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8 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

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1 dwg, 2 tbl, 2 ex

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2 tbl, 5 ex

FIELD: medicine.

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5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

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8 cl, 17 dwg, 11 ex, 2 ex

FIELD: medicine, pharmaceutics.

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3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

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4 tbl, 8 ex

FIELD: chemistry.

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