RU2622024C2 - Application of liposomal dihydroquercetin emulsion "flamena" for treatment of chronic endometritis with autoimmune disorders in case of infertility - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: effective treatment method represents a complex therapy that includes enzyme therapy, physical therapy, hormone therapy, as well as application of liposomal dihydroquercetin emulsion "Flamena".

EFFECT: application of the method allows to achieve pregnancy for more than 90 percent of patients.

3 cl, 3 dwg, 3 tbl, 3 ex

Description

Technical field

The invention relates to medicine, namely to obstetrics, gynecology and reproductology, and can be used in the treatment of reproductive disorders associated with chronic endometritis with autoimmune disorders.

State of the art

In the structure of inflammatory diseases of the genital organs, chronic endometritis (CE) is one of the main places and is diagnosed mainly (75-95%) in women of reproductive age, suffering from infertility and miscarriage [1, 2, 3]. Moreover, the effectiveness of treatment of CE does not exceed 58-67% [4].

Pathological changes in the endometrium in chronic endometritis lead to defects in implantation and repeated early reproductive losses in spontaneous cycles, ovulation induction cycles, as well as in assisted reproductive technology (ART) programs. The tendency to a prolonged asymptomatic course of inflammatory processes in the endometrium, difficulties in diagnosis have a significant impact on the increase in the number of reproductive losses. Long-term persistence of microorganisms in endometrial tissue leads to maladaptive processes of the immune system in the endometrium, its functional overload, and activation of lymphocytes. As a result, pathological autoimmune reactions develop, cellular and humoral immunity are inhibited, morphofunctional transformation, secretory function and receptor expression in the endometrium decrease [5].

Disruption of microcirculation and sclerotic processes in the zone of damage to the endometrium lead to the development of ischemia and tissue hypoxia, which in turn activate angiogenesis and sclerosis of the walls of blood vessels. Thus, the chronic inflammatory process takes on a wave-like and progressive character [6, 7, 8]. The main role in the pathogenesis of nonspecific chronic endometritis is played by postinfectious autoimmune syndrome (PIAS), which is characterized by endometrial infiltration with natural killer (NK) cells, plasma cells, B cells and activated HLA-DR lymphocytes, impaired expression of stromal and epithelial cells in sexually transmitted steroids endometrium, and the formation of complete proliferation and secretory transformation [9, 6]. The absence of a targeted effect on the immune imbalance in the endometrium leads to such consequences as habitual miscarriages, infertility, as well as unsuccessful attempts at in vitro fertilization, therefore this stage of treatment is extremely important.

Thus, an understanding of the characteristics of the pathogenesis of CE contributes to a more adequate, effective and scientifically based therapy. In the treatment of chronic endometritis, it is necessary to take into account all the links of the pathogenesis of the disease, therefore it should be comprehensive, consistent, etiopathogenetic and controlled. Treatment of chronic endometritis traditionally involves the appointment of antibacterial, antiviral drugs, enzymes, immunomodulators, metabolites, and physiotherapeutic effects.

There is a method of treating chronic endometritis, in which, to increase the effectiveness of treatment, along with antibacterial or antiviral therapy, an immunomodulating drug galavit was additionally used [10].

A method for treating chronic endometritis is also known, in which, to increase the effectiveness of treatment, cytoflavin was additionally introduced along with standard therapy [11], but cytoflavin is not always effective in all cases, which is most likely due to the lack of an effect on the immune component of the disease pathogenesis.

A known method of improving the condition of the endometrium to restore the reproductive function of a woman (RU 2499594), in particular, to prepare for implantation according to the program of in vitro fertilization with donor oocytes using cyclic hormone therapy. It has certain disadvantages: the possibility of side effects that worsen the quality of life of patients (headaches, nausea, weight gain, fluid retention, the development of depression); negative effect on hemostasis, liver function, cardiovascular system; the development of allergic reactions.

There is also known a method for improving the condition of the endometrium, which allows to increase the frequency of pregnancy after in vitro fertilization, and also reduces the risk of miscarriage, eliminates or significantly reduces the clinical manifestations of chronic endometritis and consists in conducting local electric pulse therapy (RU 2223798). The disadvantage of this method is its limited: it cannot be used in women with uterine myoma and endometriosis (including after surgical treatment), with fibrocystic mastopathy and endometrial hyperplastic processes, as well as with acute and subacute inflammatory processes of the pelvic organs .

As can be seen from the above examples, known methods of treatment have several disadvantages - low efficiency, the duration of the processes of endometrial recovery, a large number of relapses, individual intolerance, etc.

Thus, at present, there remains a need to develop an effective method for treating reproductive disorders caused by chronic endometritis with autoimmune disorders.

Disclosure of invention

The objective (technical result) of the present invention is the development of an effective method for treating reproductive function disorders associated with chronic endometritis with autoimmune disorders, using local effects on the endometrium in pathological autoimmune reactions in patients with a complicated history, as well as achieving a more stable therapeutic effect.

The specified technical result is achieved by developing a method for treating reproductive disorders associated with chronic endometritis with autoimmune disorders, which consists of sequential complex therapy in 4 stages using systemic enzyme therapy, the use of angioprotectors, metabolic therapy, physiopharmacotherapy, hormone therapy and pregravid preparation for the upcoming pregnancy, as well as the introduction into the uterine cavity of a liposome emulsion with Flamen dihydroquercetin.

Liposomal emulsion with Flamen dihydroquercetin has the following composition:

- lecithin - 30 mg / ml,

- dihydroquercetin - 3.8 ± 0.2 mg / ml,

- glycine - 35 ± 5 mg / ml,

- purified water (as an auxiliary substance) - the rest.

The use of liposomal emulsion with Flamen dihydroquercetin is carried out at stages 2-4 of the complex treatment according to the following administration regimen in the following therapeutic dosages:

from the 5th-6th day of the menstrual cycle, after the vagina and cervical canal are treated with an aseptic solution, a liposome emulsion with Flamen dihydroquercetin is introduced into the uterine cavity, pre-heated to 37 ° C in an amount of not more than 2.0 ml for 10 days.

The proposed method for the treatment of reproductive disorders associated with chronic endometritis with autoimmune disorders, including complex 4-stage therapy, each of which is carried out sequentially in different consecutive menstrual cycles, as follows:

Stage 1 - enzyme therapy, the use of angioprotectors;

Stage 2 - metabolic therapy, physiotherapy, enzyme therapy, the use of angioprotectors, as well as the introduction of a liposome emulsion with dihydroquercetin into the uterine cavity;

Stage 3 - hormone therapy, physiotherapy, as well as the introduction of a liposomal emulsion with dihydroquercetin;

Stage 4 - pregravid preparation, hormone therapy, as well as the introduction into the uterine cavity of a liposome emulsion with dihydroquercetin.

In some embodiments of the invention, in the presence of a bacterial, viral or fungal infection, appropriate antibiotic, antiviral or antifungal therapy is additionally used in the first stage of treatment, taking into account the sensitivity and pathogenic microflora.

Flamen liposomal emulsion with dihydroquercetin has an antimicrobial, anti-inflammatory and anti-edematous effect, affecting the regenerative processes of the tissue, normalizing cellular metabolism and increasing immunity.

It has been established that the use of Flamen dihydroquercetin liposome emulsion at the second stage of treatment provides an anti-inflammatory effect, restoration of endometrial microcirculation and blood rheological properties, as well as normalization of the number of immunocompetent cells of local endometrial immunity.

The use of Flamen dihydroquercetin liposome emulsion at the third stage of treatment provides regenerative processes of the endometrium, restoration of the synthesis of endometrial receptors and secretory function of glandulocytes.

It is also extremely important that the use of Flamen’s dios-hydroquercetin emulsion with latent autoimmune chronic endometritis at the second, third and fourth stages of treatment ensures restoration of the sensitivity of the endometrium to its own hormones, its cyclic transformation, the viability of the mechanisms of adaptation of the endometrium to the ovum, which is fundamentally necessary for full implantation.

It should also be noted that the use of liposomal emulsion with Flamen dihydroquercetin does not cause any side effects, and individual intolerance was not observed in patients.

The components included in the liposomal emulsion with Flamen dihydroquercetin provide its unique healing properties:

- dihydroquercetin, which is a compound of the flavonoid group, has an angioprotective, regenerating, detoxifying, decongestant, antioxidant effect (here, the term "dihydroquercetin" refers to the substance itself, its compounds and derivatives, which are structurally similar, having similar physicochemical properties);

- egg lecithin with a phosphatidylcholine content of at least 80% ensures the formation of a liposomal emulsion;

- glycine provides, in addition to the positive effects of biological effects, the stability of the rheological parameters of the emulsion, preventing its separation into fractions.

Description of drawings

Figure 1. Quantification of immunocompetent endometrial cells by the IHCI (immunohistochemical study) of infertile women with autoimmune chronic endometritis before and after treatment, where n is the number of patients.

Figure 2. Immunohistochemical study of patients A, B, C.

Figure 3. The effectiveness of the treatment of patients with chronic endometritis with autoimmune disorders in infertility and habitual miscarriage.

DETAILED DESCRIPTION OF THE INVENTION

Patients suffering from chronic endometritis with autoimmune disorders during infertility and habitual miscarriage are treated in stages, and if a viral, bacterial and / or fungal infection is detected in the endometrium, at the first stage of complex treatment, appropriate antibacterial, antiviral and / or antifungal therapy is carried out . Antibacterial therapy is carried out taking into account the data of culture on the sensitivity of microflora from the uterine cavity to antibiotics. Antibiotics of the broad-spectrum penicillin group are used, as well as beta-lactamase inhibitors (for example, amoxiclav 375 mg 3 times a day). As antifungal therapy, for example, pimafucin 1 tablet 4 times a day is used. When conducting antiviral therapy, antiviral drugs are used, for example, famvir (1 tablet 2 times a day for 10 days, after 1 tablet 1 time per day for 20 days) and vilprofen (500 mg 3 times a day). Therapy is carried out for 10 days.

At the first stage, systemic enzyme therapy (complex treatment using hydrolytic enzymes) is carried out whose therapeutic effectiveness is based on the effect on key body processes. Examples of drugs that are used at this stage are wobenzym or phloenzyme, which contain proteolytic enzymes of plant and animal origin, which have an immunomodulating effect, stimulate phagocytosis, secretory activity of macrophages, and natural killers, which contribute to the normalization of the parameters of the immune system. To restore the morphological structure of the endometrium, angioprotectors are used that improve microcirculation in peripheral organs and metabolic processes in the walls of blood vessels. For this purpose, Curantyl (dipyridamole) is prescribed at 0.25 mg 3 times a day and is used for three stages of treatment.

At the second stage of treatment, in order to restore full-fledged proliferation and secretory transformation of the endometrium, they undergo a course of metabolic therapy. The first complex of metabolic therapy is prescribed in the follicular phase of the menstrual cycle: cocarboxylase, riboflavin solution, calcium pantothenate, lipoic acid, tocopherol acetate. In the luteal phase of the menstrual cycle, a second complex of metabolic therapy is prescribed: riboxin, pyridoxine, folic acid, phytin, potassium orotate, tocopherol acetate. To reduce toxico-metabolic disorders in the body and create conditions for the full regeneration of the endometrium, hofitol is prescribed. In order to activate syntactic adaptation programs and increase fertility, the complex of treatment includes natural syntaxins - Omega-3-polyunsaturated fatty acids (Omega-3 PUFAs), which are essential (essential) fatty acids that are not synthesized in the human body. Omega-3 PUFAs as syntaxin (a substance that allows the body to coexist with endogenous stress) contribute to the formation of an adequate response of body cells to the action of external pathogenic factors. At the second stage of the complex treatment of chronic endometritis, physiopharmacotherapeutic procedures are also used, such as electrophoresis with a 2.5% solution of Zn sulfate to the lower abdomen in the amount of 12-15 procedures. To ensure the detoxifying effect and lowering blood viscosity that occur during autoimmune processes, 3 plasmapheresis sessions were used in the treatment complex every other day, followed by intravenous administration of ozonated solutions in a course of 12 procedures.

The appointment of hormone therapy is carried out at the third stage of treatment. In cases of the predominance of estrogen receptors (ER) over progesterone receptors (PR) and progesterone receptor insufficiency, pure gestagens are prescribed in the secretory phase of the menstrual cycle: duphaston 10 mg, 1 tablet 2 times a day, trogestan 200 mg, 1 vaginal tablet 2 times a day. If the number of progesterone receptors meets the norm, and estrogen receptors exceed the norm, cyclic estrogen-gestagen hormone therapy is used (divigel - 500 mg once a day to the skin in the abdomen; Utrozhestan - 200 mg 1 vaginal tablet 2 times a day). Laser physiotherapy (vaginally) was used as physiotherapy to stimulate ovarian function.

Pregravid preparation (at the 4th stage of complex therapy) includes the second phase of hormone therapy (using gestogen, Utrozhestan, duphaston), as well as the appointment of folic acid, vitamins Ε and D.

At stages 2-4, against the background of medication and physiotherapy, an intrauterine injection of liposome emulsion with Flamen dihydroquercetin is carried out subject to the following conditions:

- complete patient awareness;

- treatment of the vagina and cervical canal with an aseptic solution, for example, miramistin;

- from the 5th-6th day of the menstrual cycle (follicular phase), an introduction to the uterine cavity in an amount of not more than 2.0 ml of sterile liposome emulsion with Flamen dihydroquercetin is heated to a temperature of 36.6-37 ° C for 10 days without trauma cervical canal, using a polymer conductor (a plastic sterile subclavian catheter with a diameter of 1.0 mm was used).

The Flamen liposomal emulsion with dihydroquercetin is administered in a therapeutically effective amount. The exact amount required may vary from subject to subject, depending on body weight. The volume of the injected solution in an amount of not more than 2.0 ml ensures the filling of the uterine cavity and eliminates the ingress of the solution into the fallopian tubes; the introduction of liposome emulsion with dihydroquercetin "Flamen" in an amount of less than 1.0 does not provide a therapeutic effect.

Liposomal emulsion with Flamen dihydroquercetin, introduced into the uterine cavity immediately after menstruation (5-6 days of the menstrual cycle), acts on the mucous membrane of the uterus after rejection of the functional layer of the endometrium, restores regeneration.

Indications for the use of the treatment method according to the invention are:

- chronic inflammatory process in the endometrium with autoimmune disorders;

- reproductive dysfunction: infertility (primary or secondary), habitual miscarriage associated with chronic endometritis with autoimmune disorders;

- AMHF protein indicators in menstrual blood is 2000-12000 ng / ml (luteal phase insufficiency);

- mismatch of the thickness of the endometrium to the day of the menstrual cycle according to ultrasound data;

- hyperechoic inclusions along the periphery in the uterine cavity;

- violation of the expression of receptors of stromal and epithelial cells to sex steroids in the endometrium;

- complicated gynecological history (abortions, sexually transmitted infections, curettage of the uterus, missed pregnancy, undeveloped pregnancy, unsuccessful attempts at in vitro fertilization (IVF) and embryo transfer, etc.).

The curability control was evaluated by the number of immunocompetent cells by the IHCI method and by the amount of AMHF protein (alpha-2-microglobulin fertility) secreted by the endometrial glands. Moreover, among the indicators, along with generally accepted ones (see, for example, RU 2236013), are the number of lymphocytes expressing markers of natural killer cells (CD56, CD16), HLA-DR (II) activation markers involved in antigen recognition, and plasma cell markers ( CD138) (see Table 1) - the number of T-helpers (CD4 +) and cytotoxic lymphocytes (CD8 +) is also taken into account, their ratio is immunoregulatory index (IRI), which is an indicator of the activity of the immune system (see Table 2).

According to the analysis of the number of markers of immunocompetent endometrial cells detected by the IHC method before and after complex treatment using liposome emulsion with Flamen dihydroquercetin, there was a tendency to a decrease in the number of natural killers (markers CD56, CD16) with a reliability of p> 0.005, a marker of chronic endometritis plasma cells (CD138) with a reliability of p> 0.005, which confirmed the beneficial effect of therapy on chronic endometritis with autoimmune disorders (Table 2, Fig. 2).

According to the dynamics of AMHF protein indicators with a reliability of p> 0.005, it can be concluded that the receptor and secretory functions of the endometrioid glands are completely restored, which was determined by the amount of fertility protein (AMGF) (Table 2), synchronization of the uterine and ovarian cycles (receptor expression). It is important to note the normalization of synchronization processes, which creates favorable conditions for implantation of the ovum.

As a result of the treatment of patients using the complex therapy according to the invention, almost complete curability of autoimmune chronic endometritis was revealed. The treatment efficiency was 93.10%, p <0.05 (see Fig. 1, 3). At the same time, a control group of patients was treated, who underwent the whole range of therapeutic measures, with the exception of the use of liposome emulsion with Flamen dihydroquercetin. The treatment efficiency of this group of patients was only 41.67%, p <0.05.

As a result of the therapy using the treatment method according to the invention, pregnancy occurred in 46 (76.7%) of 60 patients with chronic endometritis with autoimmune disorders. At the same time, in 27 patients, pregnancy occurred on their own and in 19 patients after the IVF procedure (see Fig. 3).

In the control group (complex therapy without the use of Flamena dihydroquercetin liposome emulsion, 50 patients), pregnancy occurred only in 21 patients (42.0%), of which 13 patients had their own and 8 after the IVF procedure (see Fig. . 3).

Thus, the use of Flamen dihydroquercetin liposomal emulsion in the treatment of chronic endometritis with autoimmune disorders restores endometrial receptors (estrogen and progesterone) and its secretory function, provides restoration of local immunity. This leads to an increase in the effectiveness of the treatment of chronic endometritis with autoimmune disorders, which, in turn, helps to restore reproductive function and pregnancy both independently and using ART methods (assisted reproductive technologies).

The possibility of implementing the present invention is illustrated by the following examples, but is not limited to:

Example 1. Patient A., 39 years old, turned to a gynecologist-reproductologist for primary infertility. From the anamnesis: the beginning of sexual activity from 25 years old, the marriage is registered second, since the beginning of sexual life 4 sexual partners. For 14 years, it was repeatedly treated for sexually transmitted infections, bacterial vaginosis, 1 in vitro fertilization procedure was performed without effect, hysteroscopy with separate diagnostic curettage for endometrial hyperplasia, hysterosalpingography to control the patency of the fallopian tubes.

According to the results of ultrasound examination, the endometrium did not correspond to the day of the menstrual cycle (thin endometrium up to 7 mm in the secretory phase of the menstrual cycle, norm 9-12 mm), hyperechoic linear inclusions in the endometrium were observed. On the 8th day of the menstrual cycle, an aspiration biopsy was performed with the IHC of the endometrium, according to which a picture of autoimmune chronic endometritis was revealed. A complex phased treatment according to the invention was carried out using a liposomal emulsion with dihydroquercetin (Flamen). The cure was controlled by IHCI: autoimmune endometritis was not detected. An in vitro fertilization and embryo transfer procedure was performed, a live boy was born at 34 weeks weighing 2600 g.

Example 2. Patient B., 38 years old, turned to a gynecologist-reproductologist for secondary infertility, reducing ovarian reserve. From the anamnesis: the beginning of sexual activity from the age of 17, the marriage was registered first, from the beginning of sexual life 6 sexual partners. Pregnancy was completed by medical abortion for a period of 8-9 weeks, was repeatedly treated for sexually transmitted infections. There were 4 hysteroscopy with separate diagnostic curettage for endometrial hyperplasia and 3 in vitro fertilization procedures without effect, the latter with a donor egg.

Ultrasound of the endometrium revealed a discrepancy between the tissue thickness and the day of the menstrual cycle (thin endometrium up to 7 mm in the secretory phase of the menstrual cycle, normal 9-12 mm), and hyperechoic linear inclusions were also observed. On the 9th day of the menstrual cycle, an aspiration biopsy was performed with IHC of the endometrium, revealing a picture of autoimmune chronic endometritis with exacerbation. A complex phased treatment according to the invention was carried out using a Flamen liposomal emulsion with dihydroquercetin. When monitoring the cure by the IHCI, indicators of autoimmune endometritis were not found. After the course of treatment, the patient began an independent pregnancy. A live girl weighing 3,700 g was born on time.

Example 3. Patient S., 34 years old, turned to a gynecologist-reproductologist for secondary infertility. From the anamnesis: the beginning of sexual activity from the age of 17, marriage was registered first, from the beginning of sexual life 3 sexual partners. Five pregnancies: the first pregnancy ended in an urgent delivery, 3 medical abortions for 8-9 weeks, the latter was complicated by acute endometritis with an autoimmune component. It was repeatedly treated for sexually transmitted infections. The last pregnancy ended in spontaneous miscarriage in the period of 8-9 weeks, curettage of the uterine cavity was performed. For 3 years with regular sexual life without protection, pregnancy did not occur.

According to the results of ultrasound examination of the endometrium, a discrepancy between the thickness of the endometrium and the day of the menstrual cycle was revealed (thin endometrium up to 7 mm in the secretory phase of the menstrual cycle, norm 9-12 mm). On the 8-10th day of the menstrual cycle, an aspiration biopsy was performed with IHC of the endometrium, revealing a picture of autoimmune chronic endometritis.

Revealed chronic endometritis with an autoimmune component. A complex phased treatment according to the invention was carried out using a Flamen liposome emulsion with dihydroquercetin. The cure was monitored by means of the IHCI — absence of chronic endometritis with an autoimmune component. After treatment, pregnancy occurred on its own, a live boy weighing 3800 g was born on time

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Claims (10)

1. A method of treating reproductive disorders associated with chronic endometritis with autoimmune disorders, which is a complex therapy that includes 4 stages of treatment, each of which is carried out sequentially in different consecutive menstrual cycles and is: Stage 1 - enzyme therapy, the use of angioprotectors; Stage 2 - metabolic therapy, physiotherapy, enzyme therapy, the use of angioprotectors, as well as the introduction of a liposome emulsion with dihydroquercetin into the uterine cavity; Stage 3 - hormone therapy, physiotherapy, as well as the introduction of a liposome emulsion with dihydroquercin in the uterine cavity; Stage 4 - pregravid preparation, hormone therapy, as well as the introduction of a liposome emulsion with dihydroquercetin into the uterine cavity; where the liposomal emulsion with dihydroquercetin has the following composition: lecithin 30 mg / ml dihydroquercetin 3.8 ± 0.2 mg / ml glycine 35 ± 5 mg / ml purified water rest and is applied at the 2–4 stage of the complex treatment according to the following administration regimen and in the following therapeutic dosages: from the 5–6 day of the menstrual cycle after treatment of the vagina and cervical canal with an aseptic solution, a liposomal emulsion with dihydroquercetin is introduced into the uterine cavity, pre-heated to 37 ° C in amount not more than 2.0 ml for 10 days. 2. The method of claim 1, wherein the chronic endometritis with autoimmune disorders is an autoimmune chronic endometritis or chronic endometritis with an autoimmune component. 3. The method according to p. 1, characterized in that at the first stage of treatment, antibacterial, antiviral and / or antifungal therapy is additionally carried out.

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