A new method of delivery of progesterone and its impact

 

(57) Abstract:

The invention relates to medicine. In the method described relatively low levels of progesterone in serum from 1 to 6 ng/ml, they can be used to prevent the development of endometrial cancer. Vaginal delivery of progesterone with a swab of polycarboxylic polymer with crosslinking provides this low level of progesterone in serum, at the same time providing a complete secretory transformation of the endometrium, which indicates the effectiveness of progesterone. Such low levels of serum progesterone will decrease the risk of breast cancer that exists in women who undergo hormone replacement therapy, and to minimize the possibility of other undesirable side effects associated with progesterone. 2 C. and 15 C.p. f-crystals, 3 ill.

The invention relates to medicine, namely to the method of delivery of progesterone, which is a natural steroid and chief among those, which are produced in the body women in the reproductive period of her life. This steroid extensively studied and proved that he is the main precursor in the biosynthesis of most other steroids, D. specific changes of the endometrium and myometrium. It is essential for the development of the decidual tissue and differentiation luminaries and glandular epithelial tissues. Progesterone also plays multiple roles during pregnancy, including breast enlargement, inhibition of uterine contractions, maintaining pregnancy, immunological protection of the embryo and the inhibition of prostaglandin synthesis. Progesterone is used as a pharmacological agent for treatment of a number of clinical disorders, such as deficiency luteal phase, dysfunctional uterine bleeding, endometriosis, endometrial cancer, benign breast cancer, pre-eclampsia, as well as an auxiliary agent with in vitro fertilization, to prevent miscarriages in the early stages of pregnancy and reducing the frequency of endometrial hyperplasia during estrogen replacement therapy (STA).

The most common in practice progesterone agents are synthetic progesterone agents, which have unwanted side effects such as depression and water retention. In addition, many progestins derived from 19-nortestosterone, reversiruyut positive effects of estrogen on lipoprotein levels (HDL). On the other article is x effects on the lipid levels.

Breast cancer, a disease that affects primarily women in menopause, is associated with progesterone and, thus, the risk associated with it, should be reduced as much as possible, using hormone replacement therapy (GST), i.e., by delivery of estrogen and progesterone. The proliferation of terminal ductal segments, in which appears the majority of breast cancers, has been relatively low during the follicular phase (estrogen) of the menstrual cycle. Then the level of this proliferation is increased from the mid to late luteal phase as a result of two factors (estrogen and progesterone). Thus, the combination of estrogen and progesterone has a greater stimulatory effect on cell division than estrogen, which can be compared with the action of progesterone on the endometrium as antimitoticescoy agent. These observations led to the creation of the hypothesis of the etiology of breast cancer estrogen enhance progesterone". This hypothesis suggests that breast cancer risk increases estrogen separately, but even more increases while the effect of estrogen and progesterone on the epithelium of the mammary gland. Expected in the future in the assumed what is the risk associated with combined HGST higher than the risk associated only with STA.

Another problem associated with progesterone, is depression of the Central nervous system (CNS). Too much progesterone can cause fatigue, and progesterone is used even in some cases as an anaesthetic.

There are many difficulties with the introduction of natural progesterone patients to achieve appropriate levels in serum and tissues. Oral progesterone is rapidly metabolized. See, for example, Adiecrug, N. and Martin, F., J. Steroid Biochem., 13:231-244 (1980) and Maxon, W. S. and Hargrove, J. T., Fertil. Steril., 44:622-626 (1985). Some studies have shown that a significant concentration of progesterone in the tissues can be achieved by a dose of 200 mg, whereby serum levels were observed for six hours, however, there was wide variation among different patients. Maxon, W. S. and Hargrove, J. T., Fertil. Steril., 44:622-626 (1985); Whitehead, M. I. and others, Br. Med. J., 180:825-827 (1980); Sitruk-Ware, R., and others, Contraception 36:373-402 (1987).

Efforts were also attempts to introduce progesterone rectal doses of 25 mg and 100 mg, reaching peak levels of progesterone in plasma after 4 and 8 hours after administration, which gradually decreased; however, the (1987); Nillius, S. J. and Johansson, E. D. B. , Am.J.Obstet. Gynecol., 110:470- 479 (1971). Sublingual introduction has led to the rapid emergence of progesterone in serum, the content of which reached peak values 10 times higher than the initial level, but returned to baseline levels within 24 hours. Villanueva, B., and others 35:433 - 437 (1981). Nasal introduction in doses of 20 mg and 30 mg provided the average maximum concentration of 2.1 and 4.1 ng/ml, respectively, approximately 30 and 240 minutes, respectively.

Attempts were made intramuscular progesterone in doses of 100 mg, which provided serum concentrations of 40 to 50 ng/ml for 2-8 hours. Nillius, S. J. and Johansson, E. D. B., Am.J.Obstet. Gynecol., 110: 470-479 (1971). This method of introduction has shown that such injections should be done every day or every other day to get the result. Whitehead, M. and Godfree, V. , Hormone Replacement Therapy, Churchill Zivingston Edinburgh 1992, page 91. They also analysed the subcutaneous route of administration in which the puerperium implanted six pellets containing 100 mg progesterone. Croxatto, N. C., and others, Acta Endocrinol., 100:630 (1982). Progesterone levels reached a peak of 4.4 ng/ml in the first week after injection and reached a secondary peak of 1.9 mg/ml six months after implantation. Progesterone implantation.

It is shown that radioactive progesterone applied topically, can be absorbed through the skin. Mauvais-Jawis, Progesterone and others, J. Clin. Endocrinol. Metab. , 29:1580-1587 (1969). Labeled metabolites were discovered in the urine within 48 hours after topical application. However, the absorption was only 10% of the applied dose. The high solubility of progesterone in fats leads to a prolonged delay of this steroid, and extensive local metabolism reduces systemic effect of this steroid. It was shown that treatment by local application of progesterone on the mammary gland does not cause changes in the histology of the endometrium or bleeding after the cancellation. Sitruk-Ware, R., and others, J. Clin. Endocrinol. Metab., 44:771-774 (1977).

Progesterone was also administered vaginally to women in postmenopausal women treated with STA. Villanueva, B., and others, Fertil. Steril., 35:433-437 (1981). 50 mg/ml of progesterone in suspensions containing carboxymethylcellulose and methylcellulose, which was introduced in the vagina, quickly absorbed through the vaginal mucosa. Watched immediate appearance of the hormone in the peripheral blood in excess of the original serum levels (0.34 ng/ml) in 10 times in 15 minutes. Peak levels were obtained after 1 or 2 hours after injection, which exceeded ishh seven hours, they then declined over the next ten hours to 3.68 ng/ml Villanueva, B., and others, Fertil. Steril., 35:433-437 (1981). These studies suggest that absorption of progesterone was enhanced in women who also received STA.

Vaginal administration of progesterone is complicated by the variability both in one patient, and in different patients. Side effects include irritation of the vagina and selection, candidal vaginitis, itching and periodic delay menstruation. Maxon, W. S., Clinical Obstet. Gynecol., 30:465-477 (1987). However, the long-term side effects are not reported.

The present invention includes the use of the drug for delivery of medicines, based on the polymer polycarboxylic acid crosslinking, for local delivery of progesterone in the vagina. This delivery method provides serum levels of progesterone from 1 ng/ml to 6 ng/ml, causing at the same time full of secretory transformation of the endometrium. In this way low circulatory levels of progesterone reduces the risk of side effects, at the same time providing protection against endometrial cancer.

Brief description of figures

Fig. 1 illustrates the effect of a 45 mg dose of progesterone, which was administered vaginal ovarian function.

Fig. 2 illustrates the effect of a 90 mg dose of progesterone, which was administered vaginally every other day according to the present invention, on serum levels of progesterone in women with failure of ovarian function.

Fig. 3 illustrates the effect of a 180 mg dose of progesterone, which was administered vaginally every other day according to the present invention, on serum levels of progesterone in women with failure of ovarian function.

The present invention relates to an improved method of vaginal administration of progesterone to women. Progesterone, which is used to prevent endometrial cancer, must be present in the systemic circulation and in the breast in very low concentrations and the minimum number of days in each cycle, are required to achieve anti-proliferative effect on the endometrium, to minimize the risk of developing breast cancer, which produces progesterone. In addition, low serum levels of progesterone preferred due to CNS depression and other side effects. When applying bioadhesive polymer with slow release relatively small amounts of progesterone in the vagina received unexpected R is otechnyh levels of progesterone, to minimise the risk of breast cancer and other related progesterone side effects. Thus, this method provides targeted delivery of progesterone.

Secretory phase transformation of the endometrium after injection of progesterone served as an indicator of therapeutic effect of progesterone on the endometrium. Using this method, you can achieve this secretory transformation of the endometrium with the injected progesterone vaginally at the same time maintaining a low serum concentration of approximately 1 ng/ml to 6 ng/ml, preferably, from about 1 to 4 ng/ml, more preferably, from about 1 to 2 ng/ml pre-existing methods, including the use of vaginal suppositories, required to produce the same changes significantly higher levels of circulating progesterone, approximately 10 to 12 ng/ml Normal physiological serum concentration of progesterone in the luteal phase should achieve serum levels of at least 7 ng/ml to ensure secretory transformation of the endometrium, which is considered a physiological concentration necessary to ensure secretory transformation is revealed secretory phase transformation, exceeded expectations based on the levels of progesterone, suggesting the selectivity in respect of the uterus transvaginal route of administration. Thus, we can assume that part progesterone entered transvaginal passes through the uterus before to reach General circulation. The exact mechanism of this "initial passage through the uterus" is not yet quite clear. To explain the effect of the initial pass through the uterus, you can offer three hypotheses:

1) transvaginal entered progesterone can pass through the uterus local blood circulatory system;

2) may have a direct diffusion of progesterone in the uterus; or

3) progesterone can reach the uterus through the lymphatic system. In support of the latter hypothesis is established fact - vaginal cancer of the upper third of the uterus tends to dissemination through the lymphatic ducts uteri. According to the second hypothesis progesterone can diffuse passively between the cells and reach the uterus due to its proximity. Applying the method of the present invention can be directed to act on the endometrium and thus minimize loss of progesterone, circulatory levels of progesterone and accompany the tion with GST. The concentration of progesterone is introduced into the body by way of the present invention, is insufficient to increase the speed of mitoses in the terminal ductal segment; at the same time provides a positive effect on the endometrium.

Another advantage of the present invention is that when using 10 mg and 200 mg doses of progesterone to prevent endometrial cancer in women in menopause, receiving GST, coronary vasodilator effect of estrogen is not reversed.

In addition, the present invention indicates the shortcomings of the combined estrogen/progesterone patches and combined oral contraceptives for GST. These schemes expose the breast daily stimulation by a combination of high levels of estrogen and progesterone.

To achieve the desired serum levels 1-6 ng/ml of progesterone during the long period of about 48 hours, at the same time, reaching secretory transformation of the endometrium, from 10 to 200 mg of progesterone should be entered into the vagina using the delivery system of the drug of the present invention in a day for twelve days (six doses), from which all authority is of Estepona in the delivery system of the medicinal product, enter the vagina and necessary to achieve the desired level of progesterone in the serum, will vary depending on the physiological state of the patient and speed of release, provided by the polymer that is used in the delivery system of the drug. Moreover, if you want a daily or more frequent use of progesterone, the amount of progesterone delivered in each dose may be reduced.

Serum levels of progesterone are maintained in a relatively narrow boundaries, i.e., 1-6 ng/ml, using the method of the present invention and are not changed after each dose, as is the case when using previously known methods. Moreover, while the levels of progesterone in the endometrium are not easily determined, there is a permanent effect on the endometrium as secretory phase transformation extends over the entire treatment period.

45 mg of progesterone, administered vaginally every other day method of the present invention to create barely measurable serum concentrations of from 1 to 3 ng/ml, at the same time providing a secretory transformation. Clinical trials have shown that this level would the th. 90 or 180 mg dose of progesterone, administered every other day by way of the present invention provides a serum concentration of approximately 4-6 ng/ml, simultaneously producing antimitoticescoy and secretory transforming effect on the endometrium. These higher doses may be needed for women undergoing the procedure of in vitro fertilization (OIV). During this procedure, the endometrium should be able to accept the developing egg only under the action of exogenous hormones, which can be performed by applying schema substitution application of estradiol (E2) and progesterone. This low serum progesterone levels helps to avoid side effects of progesterone, such as depression of the Central nervous system and the risk of developing breast cancer during the procedure OIV.

The delivery system for the drug of the present invention are described in U.S. patent No. 4 615 697 Robinson, included in the description by reference.

Named bioadhesive polymer system has the advantage that it is delayed in the vagina for a relatively long time, i.e., from 48 to 72 hours, while most delivery systems drug is washed away from the vaginal wall is less than the drug provides direct contact with the epithelium of the vagina, that provides targeted delivery to the target organ, as discussed above. This delivery system delivers a sufficient amount of progesterone to the endometrium, at the same time maintaining its low circulatory levels, thus providing a way directed delivery of progesterone.

The polymers described in patent N 4.615.697 are polymers with crosslinking, in which at least eighty percent of the available monomers contain at least one carboxyl functional group. The preferred polymer for such use is Polycarbophil (Polycarbophil, USP), which can be purchased from company B. F. Goodrich Specialty Polymers of Cleveland, HE under the trade name of a Noveon -AA1. These polymers should not be used in the form of their salts, as this reduces their bioadhesive properties. Agent, forming cross-linkage, must be present in an amount of from about 0.1 to 6.0 percent by weight of polymer, preferably from about 1.0 to 2.0 percent by weight. Suitable agents that form cross-linkage include divinylbenzene, N,N-diallylamine, 3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene and similar agents is in it, in addition to the polymer with a crosslinking should be included optionally auxiliary substances specified in the patent 697. Such excipients include lubricants, plasticizers, binders, fillers, dyes, flavor and/or scent the corrigentov, agents, controlling viscosity, etc.

The polymers described in the patent 4.615.697, can give different rates of release of progesterone, for example, varying the amount of agent that forms a cross-linkage. In General, the rate of release is determined primarily by the amount of the drug in the polymer, and therefore the rate of release should be chosen in such a way as to deliver the right amount of progesterone given the fact that the polymer remains in place for about 48 hours. It is established that approximately 10-12% of the progesterone in the delivery system of the medicinal product actually released from the polymer over a period of 24 hours.

The delivery system of the medicinal product containing the drug may be injected into the vagina of various known ways, for example by using a plunger, douching or manually. The preferred method of introduction is the use of devices, opener with one open end and another end, containing the main amount of the drug that want to enter and which you can squeeze. Such devices allow you to place a pre-measured amount of polymer and drug in a sealed container which is relatively easy to apply. These containers contain the drug and the polymer in a sterile environment until use. When using the container opening and the open end is placed in the vagina and the other end squeeze to eject the contents of the container into the vagina.

Example

Volunteers in the trials were eighteen young women with premature lost of function of the ovaries, which were candidates for in vitro fertilization with donor eggs. Excellent rates of pregnancy using donor eggs received all over the world, led to the use of substitution cycles of estradiol and progesterone as an experimental model for the analysis of hormonal control of endometrial receptivity. Previously it was shown that significant reduction or increase levels of luteal estradiol does not affect the morphology of the endometrium changing levels of progesterone. All patients participating in the study were documented complete failure of the ovaries using the original ultrasound and determine the hormonal profile (low E2(estradiol) and high follicle-stimulating hormone (FSH)). After a thorough explanation of the upcoming study patients were included in the testing program and they received percutaneous by E2in doses of from 0.1 to 0.4 mg using one or more systems for percutaneous delivery of a drug (Estradem TM TTS 100, Ciba Pharmaceuticals, Paris, France) delivering 0.1 mg E2in each day. On the 15th day after the initial introduction of E2within 14 days, patients were placed in a clinical research center. From the morning of 15 days, patients were divided blind selection on groups that received one of three doses of progesterone. Progesterone was administered intrawaginalno using the system with a slow release drugs, manufactured in accordance with the present invention, which contained 12,9% by weight of glycerol, of 4.2 weight percent oil, 1 weight percent hydrogenated glycerides of palm oil, of 0.08 weight percent sorbic Kiselevich percent progesterone, the rest of the water. Entered 45, 90 and 180 mg dose of progesterone using a composition containing 4 wt% of the progesterone to 45 mg doses and composition containing 8% by weight of progesterone, 90 and 180 mg doses. For example, for the delivery of a 45 mg dose of progesterone used 1,125 g of the composition containing 4 wt% of the progesterone. These 3 doses of progesterone used in random blind selected three groups of 6 patients each. These doses were administered in 11 o'clock in the morning of 15 days, and then repeated every other day up to 25 days (a total of 6 injections). Within 6 days of stay in hospital of patients had blood tests every 6 hours to determine the amount of hormones (E2, estrone, LH (luteinizing hormone), FSH and progesterone). Conducted daily transvaginal ultrasound using high-resolution sensor (ATZ-HDI, 5-9 MHZ). 15-minute sequence of ultrasound scanning was printed on the system S-VHS for subsequent offline analysis of the image using the appropriate computerized system.

In 18 patients participating in the study took a biopsy of the endometrium on day 24 (6 patients in the group with each dose of progesterone). In addition to the serial of the week throughout the treatment period.

The endometrial biopsies obtained from 18 patients on day 24, showed a complete secretory changes stroma of the endometrium, with the exception of the biopsies of two patients who showed changes normally observed during menstruation (menstrual endometrium). These two patients observed a degree of secretory changes in the endometrial stroma. These two patients received 180 and 90 mg doses, respectively. Secretory changes in the stroma of the endometrium in the remaining 16 patients showed complete predecidual. Echographic data confirmed the adequacy of E2priming by determining the individual values of the thickness of the endometrium, comprising 5-12 mm. Levels of progesterone in plasma during the first 6 days of therapy with progesterone shown in Fig. 1-3, each of which reflects these women treated with 45, 90 and 180 mg doses, respectively. The obtained mean levels of serum progesterone in ng/ml were placed on the chart depending on the days of progesterone therapy, in which the shaded area represents the 95% confidence interval. As can be seen from the drawings, the levels of progesterone, which was achieved by two large doses (90 and 180 mg), appear to be similar and are within 2-8 ng/m is odilis in the range of 1-3 ng/ml From these data it is evident that a complete secretory transformation was observed in all patients receiving 45 mg dose. In fact, according to the data existing in the scientific literature and in the experience of the researchers who conducted this experiment, it was possible to expect that such lower levels of progesterone plasma will lead to a pronounced anomalous changes in biopsies 24 days.

1. The tool vaginal delivery of a drug containing polymer and progesterone, characterized in that the polymer it contains cross stitched polycarboxylic polymer and progesterone contains in the range from 10 to 200 mg per dose.

2. Means under item 1, characterized in that the polymer is polycarbophil.

3. Means under item 1 or 2, characterized in that it is in the form of dosage units.

4. A tool according to any one of paragraphs.1 to 3, characterized in that it is used to treat or prevent clinical disorders amenable to treatment with progesterone in women.

5. Means on p. 4, characterized in that the clinical infringement is deficiency luteal phase, dysfunctional uterine bleeding, endometriosis, endometrial carcinoma, benign is zamestitelei therapy.

6. Means on p. 5, characterized in that the clinical infringement is a violation of the endometrium.

7. A tool according to any one of paragraphs.1 to 3, characterized in that it is used to ensure secretory transformation of the endometrium.

8. A tool according to any one of paragraphs.1 to 3, characterized in that it is suitable to maintain a serum level of progesterone from about 0.1 to 6.0 ng/ml at delivery the vagina.

9. The method of delivery of progesterone in a woman's body, including the introduction of tools for drug delivery, including progesterone, together with pharmaceutically acceptable organic media in the vagina, characterized in that the pharmaceutically acceptable carrier is a cross stitched polycarboxylic polymer, the number of transverse cross-linked polymer and progesterone sufficient to cause secretory transformation of the endometrium and maintain the level of progesterone in serum below 6.0 ng/ml for at least 48 hours

10. The method according to p. 9, wherein the progesterone is administered in an amount of 10 to 200 mg per dose.

11. The method according to p. 9 or 10, wherein the progesterone is administered in an amount to provide the level of progesterone in syware.

13. The method according to any of paragraphs.9 to 12, characterized in that the vagina is pre-treated with estradiol.

14. The method according to any of paragraphs.9 to 13, wherein the progesterone is administered in an amount to provide secretory transformation of the endometrium and maintenance of the level of progesterone in serum from 1 to 6 ng/ml

15. The method according to any of paragraphs.9 to 14, characterized in that the means for delivery of the drug further comprises at least one auxiliary substance.

16. The method according to any of paragraphs.9 to 15, characterized in that the polymer is cross-linked with 0.1 to 6.0 wt.% cross linking agent.

17. The method according to any of paragraphs.9 to 16, characterized in that it is used to treat deficiency luteal phase, dysfunctional uterine bleeding, endometriosis, endometrial carcinoma, deprecating disease, breast cancer, pre-eclampsia, spontaneous abortion and hyperplasia of the endometrium to estrogen replacement therapy.

 

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Hygienic layer // 2266092

FIELD: manufacture of absorbing article for women, made in the form of hygienic layer, insert for pants or protective means used in case of incontinence.

SUBSTANCE: hygienic layer has absorbing body laid between liquid permeable outer sheet and liquid impermeable outer sheet. Absorbing body has front part adapted to face forward during wearing of article, and rear part. Absorbing body is 140-260 mm long and is narrowing in backward direction from part, having maximal width and disposed in front part of article, up to end of rear part of said article. Absorbing body has maximal width of 60-80 mm in its front part and minimal width of 5-20 mm in its rear part, and comprises layer of cellulose filaments formed by dry process. Said layer has density of at least 250 g/dm3 and is extending substantially over the whole surface of absorbing body up to front and rear edges of said body.

EFFECT: increased efficiency by allowing user to effectuate free motions without deteriorating absorbing qualities of hygienic layer, wider operational capabilities and convenient use.

10 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: method involves carrying out radiation treatment combined with textile material application on the tumor. Tumor-transformed vaginal uterus neck portion volume is determined with ultrasonic examination techniques. Koletex napkin impregnated with therapeutic cytostatic preparation dose is used as the textile material. The napkin pattern is produced on the basis of ultrasonic examination data. The napkin is quilted with ligature along the perimeter and fixed at the level of vagina fornix by drawing tightly in purse-string mode. Napkin is changed every 24 h within 10-20 days long treatment course.

EFFECT: improved life quality.

FIELD: medicine.

SUBSTANCE: invention relates to disposable absorbing product, such as diapers, sanitary napkins and protective devices used in case of incontinence. Absorbing product contains liquid-permeable upper sheet, liquid-impermeable posterior sheet and absorbing core, located between them. Permeable for flowing media upper sheet and impermeable for flowing media posterior sheet extend beyond absorbing core, at least, in direction of width (X) and are connected with each other in zone outside absorbing core for formation of marginal suture. Absorbing product contains two absorbing elements, each elastic element passing along one longitudinal edge of absorbing core in such a way that along larger part of extension of elastic elements in direction of length (Y) elastic elements cover both part of absorbing core and part of marginal suture in direction of width (X).

EFFECT: construction ensures improved formation of three dimensional shape of product, which provides possibility of fast and efficient reception, distribution and holding of large amount of organism secretions.

16 cl, 10 dwg

FIELD: medicine.

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EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of chronic lympholeukosis. Method involves intravenous drop and jet administration of antitumor chemopreparations and carrying out the autochemotherapy. At the 1-st and 8-th day of treatment cyclophosphan in the dose 750 mg/m2, vincristine in the dose 1.4 mg/m2 and doxorubicin in the dose 30 mg/m2 incubated with 200 ml of autoblood are administrated to patients. From the 1-st to 14-th day of treatment prednisolone is used every day in the therapeutic dose. The treatment course is repeated in 30-35 days depending on blood indices and patient state. The total treatment of courses is 4-5. Method provides reducing cardiotoxicity of doxorubicin and cumulative toxicity of chemopreparations that allows carrying out administration of antitumor chemopreparations in the full volume to patients of elderly age groups.

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1 ex

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

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1 ex, 5 tbl

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EFFECT: higher efficiency of therapy.

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EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

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