Means for correction of pathologic changes of viable offspring, caused by cytostatic impact on mother's organism

FIELD: medicine.

SUBSTANCE: to correct pathologic changes in the condition of viable offspring under a cytostatic impact the medication glutoxim is introduced to female rats in a dose of 50 mcg/kg 5 days before and 5 days after the introduction of the cytostatic medication vepesid. The latter is introduced once intravenously in a maximal tolerable dose, equal to 30 mg/kg. It has been established that glutoxim can be applied as means for the correction of pathologic changes in the viable offspring of rats, obtained from coupling 3 months after the cytostatic impact.

EFFECT: application of glutoxim as the means of corrective therapy makes it possible to increase efficiency and reduce its side effects.

6 dwg

 

The invention relates to the field of experimental medicine and relates to means for the correction of pathological changes of viable offspring in rats, caused cytotoxic effects on the body of the mother.

Existing clinical data suggest that young patients who have undergone successful chemotherapy treatment for cancer, fertility is maintained and there is a desire to have a child [1]. At the same time remains the risk of defective offspring, because cytotoxic drugs, being obviously genotoxic compounds have the ability to cause cytogenetic aberrations in germ cells [2].

Currently there is evidence of a high risk of congenital abnormalities in the offspring of women undergoing cytotoxic treatment for cancer [3]. In the experimental work studied the offspring of female rats treated with cytotoxic drugs before mating with intact rats-males [4, 5]. It is found that this offspring is characterized by reduced survival index, increased embryonic death. The pathological changes of viable offspring are a number of signs such as an increased number of pathological changes of internal organs, the violation of the Orient�rowoco research behavior (the test "open field"), reduced learning ability (test "conditioned reflex of passive avoidance"), to the avoidance of the stressful situation (test of Henderson in the modification of N. And. Bondarenko) [4, 5]. Consequently, the search for means of correction of the revealed disorders in the offspring is relevant. Among these pharmaceuticals is a drug of plant origin extract of Baikal skullcap (ESB). When combined with the introduction of a cytostatic drug, a decrease of embryonic death, the increase in the index of survival of rat pups [6]. The disadvantage ESB is the lack of efficiency in terms of viable offspring.

Known drug synthetic origin used as proof of pathological changes in viable offspring female rats undergoing cytotoxic effects [6]. This synthetic drug is mesna. The drug belongs to SH-containing compounds (thiols) and has antioxidant activity. It is established that in a viable offspring of female rats receiving the combined administration of cytotoxic drug and mesna for 3 months before mating, revealed a smaller number of fetuses with pathological changes of internal organs [6]. This medicine is the closest to the claimed nature hap�statement and selected as a prototype.

The disadvantage of masny is the lack of efficiency, the existence of a number of side effects. It can cause nausea, vomiting, headache, decreased blood pressure, allergic reactions [7]. Mesna does not possess anti-tumor properties and combined administration with cytotoxic drugs does not increase their effectiveness [7].

The object of this invention is to expand the Arsenal of correction of pathological changes in the condition of the offspring derived from saravanaa 3 months after the administration of cytotoxic drug with intact rats-males.

The task is achieved technical solution representing the application as a means of correction of pathological changes in the offspring of female rats, paired 3 months after cytostatic effects, drug Glutoxim dose of 50 µg/kg for 5 days before and 5 days after the administration of cytotoxic agents.

The technical result of the invention is to expand the Arsenal of tools for the correction of pathological changes in the condition of the offspring derived from saravanaa 3 months after the administration of cytotoxic drug with intact rats-males. This leads to increase the effectiveness of corrective therapy and reduce its side effects.

Glutoxim plays an important role � regulation of metabolic processes in cells and tissues. It leads to the restoration of sensitivity of surface cell receptors to regulatory and transport peptide molecules that determines immunomoduliruushim, hemostimulating, toxicologically effects of the drug [7]. Glutoxim activates antiperoxidant enzymes that activate intracellular reactions of thiol metabolism and the synthesis of sulphur - and phosphorous macrorhyncha compounds necessary for normal functioning of intracellular regulatory systems. Currently the expediency and the possibility of using Glutoxim in Oncology practice. The drug is used for tumors of any localization as a component of anticancer therapy with the aim of increasing the sensitivity of tumor cells to chemotherapy, including in the development of partial or complete resistance [8]. Glutoxim is practically non-toxic compound [7].

As a result of our experimental studies found unknown until now the property Glutoxim - to exert a corrective influence in pathological disorders of viable offspring female rats undergoing cytotoxic effect.

New property Glutoxim is for the specialist fact non-obvious and does not follow from the prior art and does not comprise�dinner in the patent and scientific and medical literature. Glutoxim can be used in medical practice as a means of correction of pathological changes of viable offspring of women undergoing cytotoxic effects. The advantage of Glutoxim compared to local is a wider range of positive effects on viable offspring. The drug leads not only to decrease the number of fetuses with pathological changes of external and internal organs, but also has a beneficial effect on the Central nervous system, namely normalizes the rate of formation of sensory-motor reflexes (reflex "turning on the plane"), improves orienting-exploratory behavior (the test "open field"); the ability to learn (test "conditioned reflex of passive avoidance"); the ability to adaptive behavior (the test of "avoiding the stress of the situation by Henderson in the modification of N. And. Bondarenko). Another advantage of Glutoxim compared with the impurity is no side effects and that it can be a component of anticancer therapy [7].

Thus, the proposed invention meets the patentability criteria of "novelty", "inventive step", "industrial applicability".

The present invention will be clear from the following description and the attached drawings (1-6).

In Fig. 1-6

- background (intact animals),control - the offspring of female rats treated with Vepesid,- the offspring of female rats treated with Vepesid + Glutoxim

the difference is significant ∗compared with baseline at P≤0,05. - the difference is significant ∗∗compared with the group Vepesid, when P≤0,05).

In Fig. 1 shows the data counting the number of viable fetuses with external pathological changes in the offspring of female rats that were administered anticancer drug Vepesid in combination with Glutoxim for 3 months before mating with intact males.

In Fig. 2 shows data on the number of viable fetuses with pathological changes of internal organs of offspring of female rats that were administered anticancer drug Vepesid in combination with Glutoxim for 3 months before mating with intact males.

In Fig. 3 shows the number of pups ( % ) with an established reflex "avoid the edges" on the 5th day of life in the offspring of female rats that were administered anticancer drug Vepesid in combination with Glutoxim for 3 months before mating with intact males.

In Fig.4 shows the number of crossed squares (a), rises on its hind legs (b) in male rat offspring of female rats that were administered anticancer drug Vepesid in combination with Glutoxim 3 �EU before mating with intact males (test "open field").

In Fig. 5 shows the residence time of male rats in the bright chamber on the second day of experience in the offspring of female rats that were administered anticancer drug Vepesid in combination with Glutoxim for 3 months before mating with intact males (test "conditioned reflex of passive avoidance").

In Fig. 6 depicts the lift on the grid in male rat offspring of female rats that were administered anticancer drug Vepesid in combination with Glutoxim for 3 months before mating with intact males (test of "avoiding the stress of the situation").

Example. Experiments were carried out on 45 and female rats of Wistar line. For crossing was used 24 rats-males. The animals were obtained from the laboratory of biological modeling, Institute of pharmacology, SB RAMS. The contents of rats was carried out in accordance with the rules adopted by the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes (Strasbourg, 1986). As a model of cytotoxic effects was selected widely used in Oncology practice, a drug belonging to the group of podophyllotoxin, - Vepesid (etoposide, Teva, Israel). The drug is toxic to viable offspring when administered in MTD rats-females [9]. So, its administration to rats-females for 3 months before mating leads � increase in offspring number pilafs with pathological changes of external and internal organs, the inhibition rate of the formation of sensory-motor reflexes, reduces the ability of the offspring to learn and to adaptive behavior, i.e., it has a toxic effect on the Central nervous system [9]. Experimental animals were divided into 3 groups. The first group of rats was a rat intact animals (background), who received an equivolume amount of solvent Vepesid. Rats of the second group (control) was injected Vepesid once a maximum tolerated intravenous dose (MTD equal to 30 mg/kg), calculated by the method of graphical probit analysis. Rats of the third group received Glutoxim dose of 50 µg/kg for 5 days before and 5 days after administration of the cytostatic drug. 3 months after the introduction of Vepeside female rats was fine with intact males. Mating was recorded by means of vaginal smears. Some of the females were killed by the method of displacement of the cervical vertebrae on the 20th day of pregnancy. Conducted a microscopic examination of live fetuses. Then the fruits were placed in a solution of Bowen for fixation and subsequent research on the state of internal organs by the method of Wilson [10]. The remaining females left before the birth. The status of the offspring was assessed within 2 months after birth. On the 5th and 30th day were evaluated by the rate of formation of sensory-motor reflexes. So, on the 5th day studied the ability of rats to avoid the cliff, �and 20-th day of life studied the rate of maturation of sensory-motor reflexes in the test "open field". At the 60th day of life was evaluated by the ability to learn and the ability to adaptive behavior in the tests of "conditioned reflex of passive avoidance (passive avoidance reaction) and the ability to avoid the stress situation in a test Henderson in the modification of N. And. Bondarenko [10, 11]. At statistical analysis used the Mann-Whitney test and the angular conversion Fischer.

In the antenatal period in the offspring of female rats treated with Vepesid (control), revealed a statistically significant increase in the number of live fetuses with external pathological changes and changes in the internal organs (Fig. 1, 2). In the postnatal period there was a decrease in the rate of formation of the reflex "avoid the edges" (Fig. 3), reduced horizontal and vertical locomotor activity in the test "open field" (Fig. 4). In the test passive avoidance reaction revealed that the time spent by rat pups obtained from females that were administered Vepesid, in light of the camera on the second day of experience was reduced (Fig. 5), indicating that in this group of animals there was a decline in learning ability. Due to the introduction of Vepeside also revealed a decrease in the ability of offspring to getting rid of the stress of the situation. So, you lift on the grid was increased 5-fold (Fig. 6).

The introduction of Glutoxim neutralized the damaging effects of Vepeside on the status of the offspring of rats-self� experimental group. From Fig. 1 and Fig. 2 shows that combined administration of drugs the number of fetuses with pathological changes in the external and internal organs was significantly reduced and did not differ from those in intact animals (background). The percentage of rats with an established reflex avoidance cliff" in the experimental group of animals was statistically significantly higher than that in controls and did not differ from background values (Fig. 3). In Fig. 4. the results of study of vertical and horizontal motor activity of the rats of the experimental group in the "open field". So, horizontal and vertical locomotor activity of offspring after concomitant introduction of Vepeside and Glutoxim rats-females increased by 2-3 times as compared with that with the introduction of one of Vepeside and did not differ from background values (Fig. AB.) The offspring of female rats treated with Vepesid and Glutoxim, was characterized by greater ability to learn, as the time spent in the light chamber on the second day of the experience was increased compared with that in controls and did not differ from background values. (Fig. 5). The offspring of experimental group are better adapted to the stress situation (test of Henderson). So, against the combined administration of medications you lift on the grid amounted to a 5.25±1,83, while using a single ve�of ezida - 23,83±14,07.

The data presented indicate that the viable offspring of female rats treated during administration of Vepeside of Glutoxim, was characterized by a smaller number of pathological changes than the offspring of female rats treated with Vepesid one that allows to make a conclusion that Glutoxim is an effective means of correli pathological changes of the status of offspring of female rats undergoing cytotoxic effect.

Literature

1. Urmancheyeva A. F., Kutusheva G. F. fertility Problems, contraception and replacement therapy in patients after treatment for breast cancer. // Practical Oncology. 2002. Vol. 3, No. 1. P. 53.

2. Durnev, A. D., Seredenin S. B. Mutagens screening and pharmacological prevention of impacts. M.: Medicine. 1998. P. 60.

3. Gavrilenko T. V., Zaeva G. E., Nechushkina I. V., Moiseenko E. I., Kozlov V. M., SALEWA N. And., Shmakov R. G. Health of offspring of patients in childhood cured from cancer // In the book. Cancer and reproduction. ed Paracanoe A. M., 2011. P. 102.

4. Bohr T. G., Goldberg, V. G., Poluektova, M. E., Pakhomova V. A., Thymine, E. A., and Goldberg, E. D. Status of the offspring of rats treated with platinum cytotoxic drugs. // Bull. experim. Biol. and honey. 2004. T. 138, No. 9. With 302-305.

5. Bohr T. G., Goldberg, V. E., Semenova J. A., Perov, A. V., Thymine E. A., �Pahomova V. A. Assessment of the status of the offspring of rats treated with an inhibitor of topoisomerase II Vepesid // bull. experim. Biol. and honey. 2006. - T. 1. No. 5. P. 515-518.

6. Pakhomova V. A. Gonadotoxic effects of cytotoxic drugs. Author. Dis. Biol. Sciences. Tomsk. 2004. P. 20-21.

7. Vidal Expert // Guide “Oncology”. - 2011. - S. 318. S. 204.-205.

8. Manikhas G. M., Filatov I. E., Bilinska E. N., Antonov V. G., E. M. Konstantinov, Andrushkova J. A. the Use of the drug Glutoxim with concomitant radiotherapy for locally advanced cervical cancer // Russian journal of cancer. - 2008. - No. 1. - P. 23-28.

9. Perov V. A. Experimental study variationsi effects of anticancer drugs of plant origin and ways of reducing them.// Author. dis. Biol Sciences. Tomsk. 2004. Pp. 16-17.

10. Durnev A. D. N. Smolnikova.M. . Methodical recommendations for study of reproductive toxicity of pharmaceuticals. / In the book. Guidance on the preclinical testing of medicines. Edited by Mironov A. N. // M.: Publishing fsbi "NCASE 2013. P. 90-91, 87.

11. Bondarenko N. And. The manuscript DEP. VINITI. 1980. No. 2038. S. 80. The means for correcting violations of viable offspring, caused cytotoxic effects.

Drug usage Glutoxim rats-females at a dose of 50 µg/kg for 5 days before and 5 days after the introduction of cytostatics�CSOs drug Vepesid intravenously once a maximum tolerated dose, equal to 30 mg/kg, as a means for the correction of pathological changes in viable offspring derived from mating 3 months after cytotoxic effects.



 

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SUBSTANCE: invention refers to medicine and can be used for making a drug for removing subcutaneous fat. That is ensured by using a composition containing: at least one phospholipid, at least one glycyrrhizic acid or a glycyrrhizic acid salt, and wherein total content of phospholipids and glycyrrhizic acid or its salts makes 2-80 wt % and a weight ratio of phospholipids and glycyrrhizic acid or its salts makes from 30:1 to 0.5:1. The composition can additionally contain additives. As phospholipid, the composition contains animal or herbal phosphatidylcholine. The composition can also contain glycyrrhizic acid or potassium, sodium, ammonium or magnesium salt of glycyrrhizic acid. As an additive, the composition contains sugar, particularly glucose, or maltose, and/or their derivatives, mannitol, sorbitol or lactose. The composition contains phosphatidylcholine in a total amount of 15 to 98 wt %, preferentially 30 to 98 wt %, more preferentially 50 to 98 wt %, especially preferentially 75 to 98 wt %, and most preferentially 75 to 90 wt % of total content of phospholipids. The composition is used in the dry form, preferentially in the form of lyophilisate prepared by freezing and drying, or in the form of a solution. The composition can contain physiologically acceptable solvents, including water, normal saline, glucose solution, such monohydric alcohols, as ethanol, 2-propanol, n-propanol, such polyatomic alcohols, as glycerol and/or propane diol, such polyglycols, as polyethylene glycol and/or Miglyol, glycerol, formal, dimethylisosorbitol, natural and synthetic oils and/or esters. Diseases of subcutaneous fatty tissue can be particularly related to local fat maldistribution. Fatty tissue tumour decomposition and reduction can be also solved. The drug can be presented in the form of cream, ointment, gel, hydrogel, lotion, paste, powder or solution. Undesired unaesthetic and pathological local fat maldistribution involve lipoedema, adipose growth, abdominal adiposis, cellulites, pseudogynecomasty, "buffalo hump" in HIV-infected patients, panniculitis or nonspecific subcutaneous fat deposition. The preparation is administered by subcutaneous, intra-abdominal, intramuscular or intravenous injection. The administration is implemented by a method specified in a group consisting of ioophoresis, electroporetion and phonophoresis.

EFFECT: described invention is successfully used for the above purposes.

17 cl, 11 ex, 7 tbl, 11 dwg

FIELD: medicine.

SUBSTANCE: what is presented is using meso-tetra(3-pyridyl)bacteriochlorin of structural formula (I) as a near-infrared photosensitiser for a photodynamic therapy. Doses 1.0-2.5 mg/kg of the declared photosensitiser have provided 70-100% tumour growth inhibition, 80-131% increase in life expectancy and 25-100% animals' recovery by selective tumour collection and fast clearance.

EFFECT: high photoinduced activity on human tumour cells of various epithelial origin and high dose-dependent anti-tumour effectiveness in the animal with tumours of various origins.

5 dwg, 8 ex

FIELD: veterinary medicine.

SUBSTANCE: product comprises Lycopodium clavatum, Acidum arsenicosum, Phosphorus, Podophyllum peltatum, Thuja occidentalis, Echinacea purpurea, Silybum marianum, Selenocysteine, and the components are taken in the dilutions described below in the following ratio, in parts: Lycopodium clavatum ⌀=D1 0.004, Podophyllum peltatum ⌀ 0.003, Acidum arsenicosum ⌀=D2 0.0001, Phosphorus ⌀=D3 0.001, Thuja occidentalis ⌀ 30, Echinacea purpurea ⌀ 30, Silybum marianum ⌀ 60, Selenocysteine 0.2.

EFFECT: product has an effective stress-protective and growth-stimulating effect, it regulates the metabolism in young farm animals.

3 cl, 10 tbl, 1 ex

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