Method for enhancing effectiveness of antitumor agents

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of malignant tumors. Method involves administration in a patient the chemotherapeutically active dose of antitumor platinum compound, foe example, cisplatin or carboplatin and erythropoietin or erythropoietin-like substance wherein the latter is administrated before administration of platinum compound or simultaneously with its. This method provides attaining the synergistic antitumor effect.

EFFECT: improved and valuable medicinal effect.

8 cl, 2 tbl, 2 dwg, 2 ex

 

The scope of the invention

This invention relates to the field of treatment of malignant tumors. In particular, this invention relates to improving the effectiveness of chemotherapeutic agents for treating solid tumors by improving hematocrit during chemotherapy.

Background of the invention

Antitumor agents

While in the treatment of malignant tumors considerable progress has been made, solid tumors remain difficult to treat. Consequently, many patients develop deployed malignant tumors, the treatment of which is conventional ways, usually ineffectively. As a result, new types of anti-cancer drugs are examined for anti-cancer actions. In recent years, considerable interest is the coordination compounds of platinum (Rosenberg et al., 1969, Nature, 222:385-386). In structural terms, they represent the complexes formed by the Central atom of platinum surrounded in a different order by chlorine atoms and amino groups in CIS-or in TRANS-position is obtained. Multiple chemotherapy agents on the basis of platinum became the first post-operative treatment of patients with expanded ovarian cancer (American Cancer Society, 1995, Facts and Figures). Cisplatin (CIS-diaminedichloroplatinum) and carboplatin (1,1-cyclobutanedicarboxylic aminopurine (II)) - examples of cytotoxic coordination compounds of platinum, which are applicable for the treatment of various malignant neoplasms. Other platinum compounds, known ability to show cytotoxic effect on malignant cells represent complexes of 1,4 - and 1,2-diaminocyclohexane (IV) (U.S. patent No. 5434256).

Although platinum compounds applicable to struggle with malignant tumors, the development of resistance against tumors treatment limits their applicability. Many of the specific antitumor mechanisms of action of platinum is not fully understood. In the absence of detailed information on the mechanism of cytotoxicity of platinum was difficult to overcome the problem of tumor resistance to this drug called cisplatin and thus enhancing efficiency of platinum and other anticancer agents.

The composition of solid tumors include as well oxygendemand and hypoxic cells. Hypoxia usually occurs in cells that are furthest from the blood stream. These cells slowly proliferate, but relatively resistant to anticancer drugs. Examples are data indicating that the cytotoxic effects of cisplatin face greater resistance in hypoxic tumor cells than in Xianyang (Herman et al., 1988, Cancer Research 48:2342-2347; Melvic et al., 1988, Radiat. Res., 114:489-499; Grau et al., 1988, Radiother. Oncol., 13:301-309). Thus, one mechanism by which tumors show resistance to anti-cancer remedies may be associated with their relatively hypoxic state.

The efficacy of platinum compounds is limited to some frequently observed side effects such as OTO - and nephrotoxicity. Common side effect of therapy with platinum is also anemia. Anemia is especially common when therapy with cisplatin, and patients often require blood transfusion. Although anemia due to the use of cisplatin may be many reasons in these cases is detected decreased levels of erythropoietin, and therefore it is important deficiency of erythropoietin. There is a message indicating that recombinant human erythropoietin, administered during therapy with cisplatin and other chemotherapy can be effective in combating anemia that accompanies these types of therapy (Abels 1992, Seminars in Oncology, 19:29-35).

Regulators of erythropoiesis

The assumption of the existence of a hormone that regulates erythropoiesis, the production of red blood cells, originated in the early twentieth century. Since then, continued to increase the amount of evidence in favor of the existence of humoral regulation of erythropoiesis. This led to the floor of the structure pure erythropoietin (EPO), the determination of its amino acid sequence and, ultimately, to the cloning of human EPO (Jacobs et al., 1985, Nature, 313:806-810, Lin, 1985, Proc. Natl. Acad. Sci., 82:7580-7584; Lin, U.S. patent, No. 4403008). Purification of recombinant EPO is described in U.S. patent No. 4667016 issued by Lai et al.

EPO is a hormone important for the regulation of the content of red blood cells in circulation. Natural EPO is produced by the liver during fetal development and mainly kidneys in adults. Production of recombinant erythropoietin gene-technological methods includes the expression of the protein product of the cells, transformed with a gene coding for erythropoietin. How many secretory proteins and cell surface proteins, glycosylated EPO. Glycosylation is usually carried out in two types: O-linked oligosaccharides attached through the remainder of the serine or threonine, whereas N-linked oligosaccharides via asparagine residues. Erythropoietin derived from human urine contains three N-linked and one O-linked oligosaccharide chain, which constitute about 40% of the total molecular weight of the glycoprotein. Describes the different isoforms of erythropoietin corresponding to the different levels of glycosylation (Elliott et al., 1995, EP 640619 A1).

Erythropoietin exerts its action by binding with eritropoetinovmi Retz what porom. Activation of the EPO receptor leads to some biological effects, including stimulation of cell proliferation, stimulation of differentiation and inhibition of apoptosis (Liboi et al., 1993, Proc. Natl. Acad. Sci., USA, 1990, 11351). The EPO receptor can also be activated by agonists such as mutants, analogues and EPO peptides and antibodies against him. In addition to EPO, were identified other compounds with erythropoietin-like activity. For example, reported identified in renal cell carcinoma molecule, which had EPO-like effect on erythropoiesis, but immunological differed from him (Sytkowski et al., 1979). Other stimulants of erythropoiesis are water-soluble salts of transition metals (Brugnara et al., U.S. patent No. 5369014).

While therapy platinum has become more acceptable in the deployed against solid tumors, the clinical relationship between hematocrit, hemoglobin content and antitumor effect of chemotherapy drugs have not been evaluated in order to clarify the increase does increase the hematocrit means the sensitivity of tumors to anticancer drugs. With the increased use of unusual cancer of funds continues to exist the need to enhance their antitumor response.

The invention

The present invention relates to a method by which ysenia the effectiveness of anticancer agents. The method comprises the administration to a subject in need of such treatment antineoplastic agents in conditions of high hematocrit.

Thus, an object of the present invention is a method of treating solid tumors by administration of a combination of antineoplastic agents and tools that increase the hematocrit. In the preferred implementation of the tool, increasing hematocrit, injected before the introduction of anti-cancer drugs.

Another object of the present invention is a method of treating solid tumors by the introduction of antitumor platinum compounds and erythropoietin or erythropoietin-like connection.

Another object of the present study is a method of treatment of tumors of the ovary by the introduction of a combination of cisplatin and erythropoietin.

Brief description of figures

The figure 1 illustrates the impact of the introduction of cisplatin, erythropoietin and both drugs on the growth of an ovarian tumor as a function of time.

The figure 2 illustrates the impact of the introduction of cisplatin, erythropoietin and both drugs on the percentage change in hematocrit as a function of time.

Detailed description of the invention

The term "malonate(s) coordination(s) compound(I) of platinum", used here in the context of this description and claims, refers to CIS - and TRANS-of the measures of platinum (II) and platinum (IV), containing bidentate malonty ligand, which can be substituted and unsubstituted. Platinum (II) forms coordination compounds with planar location in space, whereas platinum (IV) forms coordination compounds with octahedral location in space. These compounds are described in issued by Cleary et al. U.S. patents No. 4140707 and 4657927, which are included here as reference.

The term "anticancer agent" and "anti-cancer agent", used interchangeably in the context of this description and claims, means a compound or composition effective for inhibiting, slowing or stopping the growth of cancer cells, or which have a cytotoxic effect on malignant cells. The term "chemotherapeutic effective amount" antineoplastic agents in the context of this description and claims refers to input the subject of the quantity sufficient to cause inhibition, slow or stop the growth of malignant cells, or sufficient to provide a cytotoxic effect on malignant cells.

The term "antitumor effect" or "antitumor activity" in the context of this description and claims is meant the inhibition, Zam is persevering (duration) or stop the growth of malignant cells, or the provision of a cytotoxic effect. An example of a measurable antitumor effect is the decrease of tumor size.

The term "erythropoietin" or "EPO" in the context of this description and claims is meant erythropoietin, whole or part, received or allocated by chemical extraction and treatment methods; and erythropoietin any type, including human, obtained using methods of recombinant DNA. This term also includes erythropoietin produced by cells of the subject as a result of transfection of exogenous genetic material, including the gene encoding EPO, or after implantation of the given subject of the transfected primary or secondary cells containing exogenous genetic material, including the gene encoding EPO. Methods of production and delivery of product transfected cells are disclosed in U.S. patent No. 5733761, the methodology of which is included here as a reference.

The term "erythropoietin-like molecule or substance in the context of this description and claims is meant any molecule, obtained by chemical separation and cleaning methods or by recombinant methods, which has the ability to activate the erythropoietin receptor or otherwise simulating this action is of erythropoietin, as stimulation of erythropoiesis. Thus, under this definition a fragment of a native or recombinant EPO, which length may be shorter than the whole molecule of EPO and is capable to activate the EPO receptor; molecule merger, including as its part of the amino acid sequences normally present in the intact molecule EPO; similar similar to those described in the issued Okasinski U.S. patent No. 5888722 included here as a reference amino acid sequence which is similar, but not identical with the natural EPO, and which has biological activity in relation to stimulation of erythropoiesis; derivatives of EPO in which the structure of the EPO modified by adding (or remove) one or more Deputy or chemical groups; isoforms of EPO, which represent different States of glycosylation of EPO, for example, Strickland described in U.S. patent No. 5856298 included here as links; the resulting recombinant methods isoforms of EPO containing additional glycosylation sites or rearranged sites of glycosylation, as described in issued to Elliott et al. European patent (EP 0640619 B1), included here as links; peptides such as those described in the issued Wrighton et al. U.S. patent No. 5773569 and issued to Wilson et al. U.S. patent No. 5835382 included here as the links, that communicate with the EPO receptor and activate it, or otherwise act as agonists EPO; mutant secretory proteins EPO, such as those described in the issued Sytkowski et al. U.S. patent No. 5614184 included here as links that have altered biological activity. This definition also includes antibodies, agonists, or fragments thereof, such as described in issued to Elliott et al. U.S. patent No. 5885574 included here as a reference, which can activate the erythropoietin receptor or otherwise mimic the action of EPO. A common feature of all the erythropoietin-like substances is their ability to simulate one or more effects of EPO.

The term "therapeutically effective" amount to increase hematocrit refers to the number of naturally selected or produced by recombinant methods EPO or EPO-like substance, sufficient to increase the production of red blood cells and carried out thus increasing hematocrit in comparison with the normal level. For example, a number in the range from 15 to 1500 units per kg of body weight, preferably 50 to 300 units/kg, described as therapeutically effective in U.S. patent No. 5013718, the description of which is included here as a reference.

The present invention relates to a method for enhancing the effect op edelenyi anticancer agents by increasing hematocrit. The method according to the present invention includes the introduction phase to a patient in need of such treatment, a combination of antineoplastic agents and tools that increase the hematocrit.

The methods described in the present invention, applicable to the treatment of malignant tumors in mammals, including malignant tumors, and especially solid tumors sensitive to treatment with platinum compounds. Non-limiting examples of such tumors are adenocarcinomas, melanomas, lymphomas, sarcomas, and tumors of the lung, breast, ovarian, head and/or neck, prostate, cervix, endometrium, colon and rectum, stomach, liver, fallopian tubes, esophagus, small intestine, pancreas, kidneys, adrenal glands, vagina, vulva, brain and testicles.

According to the method described in the present invention, one or more anticancer agents administered in combination with the tool, increasing hematocrit. Antitumor agent and a means for increasing hematocrit may be introduced simultaneously or sequentially. Preferably the means for increasing hematocrit prior to the introduction of anti-cancer drugs. An example of antineoplastic agents is a compound containing platinum, as for example, any coordination compound of platinum. Coordination shall include platinum compounds of the present invention include compounds of platinum (II) and platinum (IV), but not limited to.

Two examples of platinum compounds exerting a cytotoxic effect on malignant cells, are cisplatin and carboplatin. These two compounds belong to the group of compounds known as "malonate", thanks to the presence in their structure of communication (OOS)2-C. Cisplatin is a yellowish white powder and contains chloride group and the group of ammonia in the horizontal projection. Carboplatin is an off-white crystalline powder. As cisplatin, carboplatin is used to treat a variety of human malignant tumors, including small cell lung cancer, squamous cell carcinoma, and testicular cancer (see U.S.Pharmacists, September, 1989, pages 62-63). Not limited to any particular theory, it is assumed that the coordination compounds of platinum antineoplastic activity by disrupting the synthesis of DNA by the formation of crosslinks between complementary strands of DNA. The preferred option is used platinum compounds is cisplatin.

Antitumor agent is administered to the patient in a pharmaceutically acceptable carrier common routes of administration suitable for a particular type of chemotherapy. For example, anti-cancer agent may be administered intravenously, intraperitoneally, subcutaneously, intramuscularly or infusion is, to ensure its delivery to the bloodstream in an effective form. In addition, anti-cancer agents may be administered in the form of liposomal preparations, as described in U.S. patent No. 5620703 included here as a reference. Effective doses of the anticancer agents of the present invention represent a dose that provides anti-tumor effect. These doses are well-known qualified or can be set empirically. For example, guidelines for the dosage to many types of chemotherapy in the General form set forth in Physician''s desk Reference. Usual dosage of platinum compounds ranges from about 1 to about 200 mg/kg/dose. These compounds can be administered by a single infusion or in multiple infusions over several days, for example, 3-5 days. If necessary, the cycle can be repeated. Preferably they are administered single intravenous injection on day 1 of treatment, the Dosage of cisplatin is typically in the range 25-300 mg/m2. A more preferred range is 50 to 100 mg/m2. To achieve adequate hydration before and after infusion of cisplatin administered isotonic saline solution.

Means for increasing the hematocrit of the present invention are any tools that can increase the number of red blood glue is OK for a subject, receiving this tool. For example, applicable in the framework of the method according to the present invention the means for increasing hematocrit include, but are not limited to, erythropoietin and erythropoietin-like compounds. Means for increasing hematocrit can be introduced in a conventional routes, including intravenous, intraperitoneal or subcutaneous path and other paths, at doses known to specialists in this area, as applicable for increasing hematocrit. EPO may be administered in multiple doses, given that its half-life in plasma is about 5 hours. Alternatively, to deliver EPO to the cells of the subject can also be used transfection methods. To indicate the effectiveness of EPO, you can monitor the level of hematocrit. Similar routes of administration can be used for EPO-like substances. In a preferred embodiment, appoint 50-100 units/kg of body weight three times a week, intravenously or subcutaneously.

The effectiveness of treatment can be determined by assessing the status of the tumors. Palpable tumors can be measured by standard methods. For measurement and evaluation of tumor size can target imaging techniques such as computed tomography, magnetic resonance imaging, ultrasound and the like. As an alternative to ware the evaluation of the tumor is possible to quantify specific tumor markers, such as PSA for prostate cancer, CA-125 for ovarian cancer, CA-15-3 for breast cancer, without limitation. To assess the response to treatment you can use standard criteria. For example, you can follow the criteria outlined in the WHO handbook of Reporting Results of Cancer Treatment, WHO Offset Publication, 1979. Thus, tumors can be classified as susceptible to therapy of tumors, partially susceptible tumor and immune. Cycles of treatment with cisplatin and EPO can continue until you reach an acceptable response to treatment or unless there is unacceptable toxic effects.

EXAMPLE 1

This implementation of the invention demonstrates the effect of increasing the sensitivity to this drug called cisplatin in human cells embedded in the body of SCID mice, which arose as a result of using EPO before treatment, raising and maintaining the level of hematocrit due to the use of EPO. To illustrate this implementation, experiments were carried out with immunodeficient SCID mice bearing ovarian cancer man. These mice are recognized specialists in the field of appropriate animal models to demonstrate the antitumor activity of potential chemotherapeutic agents.

Used eighty mice ST. 17-SCID/SCID (Taconic Labs). Animals were kept under sterile conditions at the control of lighting. Part of the tumors of the patients with recurrent papillary serous adenocarcinoma of the ovary stage IIIC, 3 degrees were implanted and diffused in SCID mice using well known to specialists in this field procedures. In summary, the xenografts were grown and perceivable at least five times before implantation of tumors in laboratory animals. Part of the tumor xenograft human size of 2-3 mm were implanted in the fat body and gonads (GFP) method suture by Sakakibara et al. (1996, Can. J. Sci. Amer., 2:291-300), which is included here as a reference. Tumor xenografts in GFP were grown in large abdominal mass detected during palpation of the abdomen. Later, each mouse was subjected to laparotomy through a midline incision from the sternum to the crests of the Ilium. Surrounding the tumor buildup was destroyed and raised the tumor from the peritoneal cavity without damaging the leg GFP. Tumor size was assessed in three dimensions using calipers-Vernier. Then the tumor returned in its original intraperitoneal position, and then closed the abdominal cavity single layer. Three days after the operation began to apply the treatment protocols. Randomly selected mouse was four groups of treatment. The first day intraperitoneal injection of cisplatin or phosphate-saline buffer (PBS) was designated as the zero day. Animals of group I (entry checkpoints for important locations is e) received 100 μl of PBS three times per week subcutaneously from day -15 to day +6 and 300 μl of PBS intraperitoneally on day 0. Mice of group II (group EPO) received EPO subcutaneously at a dose of 20 units in 100 μl of PBS three times per week from day -15 to day +6 and 300 μl of PBS intraperitoneally on day 0. Mouse group III (cisplatin group) received cisplatin intraperitoneally at a dose of 5 mg/kg in 300 μl PBS on day 0 and 100 μl of PBS three times per week subcutaneously from day -15 to day +6. Mouse group IV (EPO + cisplatin) received subcutaneous injection of EPO, as mice of group II, from day -15 to day +6 and intraperitoneal injection of cisplatin, as mice group III on day 0. The mice were observed until day 8.

Automatically determine the hematocrit to blood samples taken on days -15, -7, 0, +7 from the tail randomly selected three mice from each group. Day 7 mice were fixed, and conducted the autopsy. The tumor was separated and their sizes were estimated in three dimensions using calipers-Vernier. Tumor volume was calculated as follows.

(width) × (length) × (depth) = tumor volume

The growth of the tumor in percent was calculated by the following formula:

[(tumor volume at the opening/initial tumor volume)-1] × 100 = tumor growth in percent

The size of the tumors at initial laparotomy was approximately 2 cm × 1.5 cm × 1 cm in three dimensions and was similar in each treatment group. Significant differences in tumor growth were observed between the group of animals treated with cisplatin, and the group, not pelucas the th. Difference (P=0.07), indicating an increasing effect of cisplatin when receiving EPO was observed between the size of the tumors of mice that received only cisplatin, and mice treated with cisplatin plus EPO. Between the control group and the group receiving only EPO, differences were not observed.

In another illustration of this implementation cisplatin was administered twice during treatment. Part xenograft ovarian cancer man 2 mm in size were implanted forty experimental mice, six weeks of age. Animals are randomly divided into groups of treatment three days after implantation. Animals of group I (control) received 100 μl of PBS three times per week subcutaneously from day -15 to day +13 and 300 μl of PBS intraperitoneally on days 0 and 7. Mice of group II (group EPO) received EPO subcutaneously at a dose of 20 units in 100 μl of PBS three times per week from day -15 to day +13 and 300 μl of PBS intraperitoneally on days 0 and 7. Mouse group III (cisplatin group) received cisplatin intraperitoneally at a dose of 5 mg/kg in 300 μl of PBS on days 0 and 1, and 100 μl of PBS three times per week subcutaneously from day -15 to day +13. Mice of group IV (group EPO + cisplatin) received subcutaneous injection of EPO, as mice of group II, from day -15 to day +13 and intraperitoneal injection of cisplatin, as mice of group III, on days 0 and 7. Mice were observed up to day +15.

The hematocrit was determined automatically as described above, in the days -15, -7, 0, +7 and +14. Was is shown by the graph of the changes in hematocrit relative to its original value with time. Serial assessment of tumor nodules was performed in two dimensions using calipers-Vernier, starting with a zero day. Zero-day tumors in each group of animals has increased in size to approximately 4 mm × 5 mm tumours, corresponding to the days 0, +1, +3, +5, +7, +9, +11, +13 and +15, was calculated according to the formula.

(length) × (width)2/2 = tumor volume

The growth of the tumor in percent was calculated for each of the days, when measured, compared with day 0, build a graph of the dependence of the growth time. Statistical analysis included T-student test, which was applied to the total growth of the tumor in the experiment with large tumors GFP. Curves of growth, corresponding to a smaller group with subcutaneous tumors, and curves representing changes of hematocrit depending on time, were subjected to variance analysis. Statistically significant recognized by P-values below 0.05.

When cisplatin was administered twice a week, was observed a significant difference (p<0,05) between the group treated with EPO + cisplatin, and the group treated with cisplatin (figure 1). Curves of growth of the tumor, built for mice bearing subcutaneous tumor nodules showed significantly greater regression of tumors in the group treated with EPO + cisplatin, compared with the group treated with cisplatin. Again not nab who was udalos differences between the control animals and the group, administration of EPO.

Weekly hematocrit levels and percentage change depending on time of mice bearing small subcutaneous tumors are presented in table 1 and figure 2, respectively. Similar was the hematocrit in mice bearing large tumors GFP (data not shown). The introduction of EPO resulted in 25-35% increased hematocrit compared to its initial level (2thweek), and this was significantly different from control (p<0,01). Cisplatin without EPO resulted in a 20% decrease in hematocrit. Bearing tumor mice from the control group was characterized by a 2% decrease in hematocrit over time (figure 2).

Table 1
TimeThe values of haematocrit
CONTROLEPOCISPLATINEPO + CISPLATIN
Week -239,5±0,139,5±0,239,8±0,239,6±0,2
Week -139,7±0,344,9±0,239,8±0,245,1±0,3
Week 039,8±0,348,9±0,339,8±0,348,9±0,2
Week +140,8±0,249,± 0,340,7±0,152,7±0,3
Week +238,6±0,353,6±0,433,1±0,350,9±0,3

These data indicate that tumor regression when using EPO and cisplatin is significantly greater as compared to that in mice treated only with cisplatin. Mice in the group treated with EPO and cisplatin, was characterized by the rise of hematocrit by 25-35% compared with mice groups of cisplatin.

EXAMPLE 2

This implementation of the invention shows that the increase of the hematocrit decreases mortality associated with toxicity of anticancer agents. To illustrate this implementation was assessed by vital status of mice from example 1, treated with different treatment options. Assessment of vital status was given on days 0, +7 and +14 using five objective criteria morbidity and mortality of experimental mice. These criteria were as follows: (1) ruffled fur; (2) weakness/lethargy; (3) 20% weight loss, compared with an average weight of mice in the control group; (4) hunched posture, like kyphosis; (5) death. The score of 0 corresponded to normal health, and the number of points equal to 5+, meant death.

The vital status calculated for all mice on day 0 showed that mice in all groups the Ah treatment had normal health (number of points for all mice = 0). As shown in table 2, day +7 were seen signs of the disease mice from receiving cisplatin (table 2). All mice from the control group and from the group EPO has preserved the vital status at the level of 0 points. Of the 10 mice in the cisplatin group all had ruffled fur, all showed signs of weakness/lethargy, and 6 mice were characterized by a 20% weight loss compared to control mice on day +7. All mice in the group treated with EPO + cisplatin, had ruffled fur, and 7 of them showed signs of weakness/lethargy. At day +14 life condition of the mice in the cisplatin group deteriorated, including 4 fatal and bent posture in 3 mice. Only 1 death was observed in the group treated with EPO + cisplatin, and in addition, one mouse developed a hunched posture (table 2).

Table 2
No MOUSECONTROLEPOCISPLATINEPO + CISPLATIN
100+++++++
200++++++
300+++++++
400+++++ ++
500++++++++
600+++++++
700++++++
800+++++
900+++++++++
1000++++++++
Amount0043+29+

Thus, among the animals treated with cisplatin were observed to have greater morbidity compared with mice that were treated with EPO + cisplatin. Moreover, mice treated with EPO, kept the best living condition and was characterized by a lower incidence associated with receiving cisplatin. Not limited to any particular theory, the hypothesis is advanced that the increased anti-tumor effect observed in the group treated with EPO + cisplatin, was due to the increase in hematocrit, rather than acceptable working condition.

It should be understood that since the invention is described in detail here, the examples are purely for illustrative purposes. It is implied that other Modific is the implementation of the present invention, obvious for specialists in this area, are within the scope of the attached claims.

1. The way to increase the effectiveness of antineoplastic agents, including the introduction phase to a subject in need of treatment,

a) active chemotherapeutic number of antitumor platinum compounds and

b) erythropoietin or eritropoyetina substances.

2. The method according to claim 1, where the platinum compound is malonate the platinum compound.

3. The method according to claim 2, where malonate a platinum compound selected from the group consisting of cisplatin and carboplatin.

4. The method according to claim 3, in which the platinum compound is cisplatin.

5. The method according to claim 3, in which the platinum compound is carboplatin.

6. The method according to claim 4, where cisplatin is administered in doses of 25 to 300 mg/m2.

7. The method according to claim 6, where cisplatin is administered in doses of 50 to 100 mg/m2.

8. The method according to claim 1, where erythropoietin or eritropoyetina substance is injected prior to the introduction of platinum compounds.



 

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3 tbl

FIELD: medicine.

SUBSTANCE: method involves carrying out radical surgical intervention. Abdominal cavity lavage is carried out using lavage solutions during 15-20 min after having accomplished all surgical intervention stages. The lavage solution is removed from abdominal cavity. Draining silicon tubes are set into the right subdiaphragmal space, into the right subhepatic space and into the right lateral canal, into the left subdiaphragmal space, into the right lateral canal and into small pelvis. Abdominal reservoir is formed by suspending laparotomic wound edges by means of Seagal retractor. Polyethylene film having cruciform cut in its center is fixed on laparotomic wound edges. The abdominal reservoir is filled with isotonic solution on sodium chloride bases or on dialysis solution base or on Ringer-Lock solution base as perfusate. The solution contains primary and additional chemopreparations. Perfusion solution has Cysplatin or Platinol or Carboplatin at a dose of 50 mg/m2 of patient skin area or Mytomicin C at a dose of 20 mg/m2 of patient skin area as the primary preparation and 5-Fluorouracyl as the additional preparation at a dose of 1 mg/m2 of patient skin area. The perfusion solution is introduced via draining tubes at 44-46°C into upper regions of the abdominal cavity. The solution is evacuated from it at a temperature not lower than 42.5°C via draining tubes arranged in pelvic cavity and iliac regions. Perfusion solution chemopreparations temperature control is carried out by means of heat sensor transducers mounted in draining tubes. Chemotherapy is carried out with closed perfusion solution chemopreparations circulation during 60-120 min in abdominal cavity at a rate of 500-2000 ml/min concurrently manually mixing the chemopreparation solution. The abdominal cavity is tightly sutured after having applied the hyperthermic intraoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy is carried out in postoperative period daily from the first to the fifth day after the operation. To do it, chemotherapeutic solution based on physiologic sodium chloride solution or on dialysis solution or on Ringer-Lock solution containing 5-Fluorouracyl at a dose of 1 mg/m2 of patient skin area is introduced via retained draining tubes with its exposure time being equal to 8-12 h. Then the draining tubes are removed.

EFFECT: enhanced effectiveness of treatment; prevented abdominal cavity and small pelvis region from being inseminated; prolonged survival period; improved life quality.

9 cl

FIELD: medicine.

SUBSTANCE: method involves carrying out radical surgical intervention. Abdominal cavity lavage is carried out using lavage solutions during 15-20 min after having accomplished all surgical intervention stages. The lavage solution is removed from abdominal cavity. Draining silicon tubes are set into the right subdiaphragmal space, into the right subhepatic space and into the right lateral canal, into the left subdiaphragmal space, into the right lateral canal and into small pelvis. Abdominal reservoir is formed by suspending laparotomic wound edges by means of Seagal retractor. Polyethylene film having cruciform cut in its center is fixed on laparotomic wound edges. The abdominal reservoir is filled with isotonic solution on sodium chloride bases or on dialysis solution base or on Ringer-Lock solution base as perfusate. The solution contains primary and additional chemopreparations. Perfusion solution has Cysplatin or Platinol or Carboplatin at a dose of 50 mg/m2 of patient skin area or Mytomicin C at a dose of 20 mg/m2 of patient skin area as the primary preparation and 5-Fluorouracyl as the additional preparation at a dose of 1 mg/m2 of patient skin area. The perfusion solution is introduced via draining tubes at 44-46°C into upper regions of the abdominal cavity. The solution is evacuated from it at a temperature not lower than 42.5°C via draining tubes arranged in pelvic cavity and iliac regions. Perfusion solution chemopreparations temperature control is carried out by means of heat sensor transducers mounted in draining tubes. Chemotherapy is carried out with closed perfusion solution chemopreparations circulation during 60-120 min in abdominal cavity at a rate of 500-2000 ml/min concurrently manually mixing the chemopreparation solution. The abdominal cavity is tightly sutured after having applied the hyperthermic intraoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy is carried out in postoperative period daily from the first to the fifth day after the operation. To do it, chemotherapeutic solution based on physiologic sodium chloride solution or on dialysis solution or on Ringer-Lock solution, containing 5-Fluorouracyl at a dose of 1 mg/m2 of patient skin area is introduced via retained draining tubes with its exposure time being equal to 8-12 h. Then the draining tubes are removed.

EFFECT: enhanced effectiveness of treatment; prevented abdominal cavity and small pelvis region from being inseminated; prolonged survival period; improved life quality.

9 cl

The invention relates to medicine, namely to a gastroenterologist, and can be used in the treatment of a dysbacteriosis of intestines
The invention relates to medicine, namely to gastroenterologie, and can be used in the treatment of irritable bowel syndrome

FIELD: medicine, endocrinology, biochemistry, peptides.

SUBSTANCE: invention represents new peptides that act in vivo as stimulators of insulin secretion by pancreas beta-cells in glucose-dependent regimen. Such peptides as enhancers of insulin secretion stimulate insulin secretion by insula cells in rats in vitro and in vivo. Proposed peptides represent a new way for treatment of patients with reduced secretion of endogenous insulin, in particular, for treatment of diabetes mellitus type 2. In particular, invention represents polypeptide taken among the specific group VIP/PACAP-related polypeptides or their functional equivalents. Also, invention claims method for preparing both recombinant and synthetic peptides. The advantage of invention involves new peptides that can be used as stimulators of insulin secretion.

EFFECT: improved and valuable medicinal properties of peptides.

47 cl, 4 tbl, 10 dwg, 18 ex

FIELD: medicine, therapy, gastroenterology, pharmacy.

SUBSTANCE: method involves oral intake of solid medicinal formulation at vertical position of patient and change of medicinal formulation position into stomach is carried out in each 5 min, not rare. Change of medicinal formulation position is carried out by pressing on epigastrium region by hand or by cyclic change of position of patient body from its vertical position to horizontal position and back. Method provides enhancing safety in enteral using a solid medicinal formulation due to diminishing its ulcerogenic effect. Invention can be used in enteral using solid medicinal formulations.

EFFECT: improved method for diminishing ulcerogenic effect.

2 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to medicinal agents, in particular, to the hormonal pharmaceutical composition. Invention proposes new pharmaceutical compositions and a method for preparing such compositions formed by the estrogen-gestagen combination with a single gestagen compound in mixture with one or some nontoxic, inert pharmaceutically acceptable carriers designated for oral administration. Also, invention relates to the estrogen-gestagen mixture wherein estrogenic component and gestagenic component are used by the combined method. Proposed composition is designated for treatment of estrogenic insufficiency, prophylaxis of osteoporosis and cardiovascular diseases in women in the menopause period. Invention provides the development of the new estrogen-gestagen combination showing activity in the oral route of applying and administrated by the combined method.

EFFECT: improved and valuable medicinal properties of composition.

12 cl, 8 tbl, 3 ex

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: one should treat deformation in laryngeal and tracheal lumen due to excessive growth of granulation tissue in the sites of their lesions. One should introduce hormonal preparations, moreover, one should apply Diprosan as a hormonal preparation injected once intramucosally at 0.1 ml/sq. cm of granulation tissue, but not more than 0.3 ml.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction
The invention relates to veterinary

The invention relates to aqueous pharmaceutical compositions of erythropoietin that are free from the products of human serum, stable amino acid, sorbitan mono-9-octadecenoate poly(oxy-1,2-ethandiyl) derived

The invention relates to medicine, and is concerned medicines, which have immunomodulatory effects that are used for non-injection use for the prevention and treatment of diseases caused by impaired immune functions
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