RU2418588C1 - Method of treating endometriosis in women with anxiety-and-depressive disorders - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to psychiatry and gynecology, and can be used in treatment of endometriosis in women with anxiety-and-depressive disorders. For this purpose one month after performing laparoscopy at the background of drug hormonal treatment during 6 months phenotropil in dose 100 mg/day is additionally administered for 90 days.

EFFECT: administration of phenotropil in said dose and introduction regimen makes it possible to reduce anxiety-and-depressive symptoms, and has positive impact on functional state of immune and vegetative nervous system.

4 tbl, 3 ex

Description

The present invention relates to medicine, namely to psychiatry, gynecology, and can be used in the treatment of endometriosis in women with anxiety-depressive disorders.

The relevance of increasing the effectiveness of treatment of endometriosis is due, first of all, to the leading position of this pathology in the prevalence and severity of the course in women of reproductive age, which adversely affects the mental and physical condition, quality of life. Almost all women with endometriosis revealed the presence of affective register disorders, immune disorders and autonomic dysfunctions [1, 2, 3].

A two-stage method for the treatment of endometriosis is known, including surgical removal of endometrioid heterotopia followed by treatment with an antigonadotropic drug (danazol) for 6 months [4, 5]. This method is the closest to the claimed and selected as a prototype.

The traditional surgical and medical hormonal treatment of endometriosis, including drugs: gonadotropin releasing hormone agonists, antigonadotropic drugs, progesterone analogues, synthetic progestogens, combined monophasic estrogen-progestogen drugs, does not provide adequate correction of psychoneuroimmune disorders (anxiety and depressive anxiety and depressive symptoms) autonomic nervous system, decreased adaptive reserves of the body) accompanying the endometrium oz in women. In this connection, the search for new methods and the expansion of the arsenal of drugs that increase the effectiveness of the treatment of endometriosis in women with anxiety-depressive disorders, the main manifestations of which are psychoneuroimmune disorders, is relevant.

The objective of the invention is to increase the effectiveness of treatment and improve the quality of life of women suffering from endometriosis with anxiety and depressive disorders.

The problem is solved by the additional appointment of phenotropil in a dose of 100 mg / day for 90 days 1 month after laparoscopy on the background of drug hormonal treatment for 6 months.

The administration of phenotropil in a dose of 100 mg / day for 90 days 1 month after laparoscopy is new.

The clinical picture of endometriosis is accompanied by mental disorders, the features of which are determined by the complex and variable ratio of the severity of the pathological process, on the one hand, and the nature of the state of the organism, and above all, the central and autonomic nervous system, as well as the immune system, on the other. The development of endometriosis contributes, among other things, to the imbalance of the immune balance. According to the immunological concept for endometriosis, the following immunopathological processes are formed: the induction of autoimmune reactions against endometrial tissue and the development of secondary immunodeficiency. The main clinical manifestations of endometriosis are severe pelvic pain syndrome and anovulatory infertility, which exacerbate the lack of adaptive reactions resulting from neuroendocrine disorders, extragenital and gynecological diseases [6, 7].

Thus, this disease is one of the central medical and social problems requiring treatment optimization with a mandatory clinical and dynamic assessment of their consequences. In the clinical picture, women with gynecological diseases show asthenic, anxiety-depressive symptoms, pronounced autonomic disorders, as well as behavioral changes that aggravate the course of the reproductive system pathology, leading to a deterioration in the woman's quality of life and prognosis of the disease [8]. It is well known that the nervous, immune and endocrine systems are components of the general adaptation system [9].

In the claimed combination of new signs showed new properties of phenotropil, which are not explicitly derived from the prior art in this field and are not obvious to a specialist. No evidence has been found in the medical and patent literature on the use of phenotropil in the treatment of endometriosis in women of reproductive age with anxiety-depressive disorders.

The invention can be used in clinical practice in order to increase the effectiveness of the treatment of endometriosis (ICD-10 - N80) in women.

Based on the foregoing, the proposed invention should be considered relevant to the criteria of "Novelty", "Inventive step" and "Industrial applicability".

The method is as follows.

Women suffering from endometriosis with anxiety and depressive disorders, in a treatment that includes surgical (laparoscopy with maximum excision of endometrioid implants and restoration of reproductive function) and hormonal drug treatment (antigonadotropic drugs) for 6 months, 1 month after laparoscopy with a hormonal of treatment, phenotropil is additionally prescribed at a dose of 100 mg / day for 90 days.

Clinical example

Patient K., 35 years old (medical history No. 1545/832), was admitted to the gynecological department of the MDL “Regional Clinical Hospital” in Tomsk on March 4, 2009 with complaints of heavy uterine bleeding for 10 days, pain during menstruation, dyspareunia, lack of pregnancy with regular sexual life for 2 years, decreased mood, constant anxiety, feeling of difficulty breathing, feeling of lack of air, rapid breathing with excitement or in a stuffy room, paroxysmal, diffuse, constricting headaches, fast morning Warmness, sleep disturbance were noted in the form of presomnic insomnia and superficial, shallow sleep and the absence of a sense of relaxation upon awakening.

From the anamnesis: suffers from a menstrual cycle within 2 years after a medical abortion. The disease is permanent. Menarche is 13 years old. In the last year, menstrual flow was noted irregularly, with an interval of 14 to 21 days, lasting 10 to 18 days, the number of plentiful, with clots, painful, especially on the first day of the menstrual cycle. From this time on, there was a decreased mood, a constant feeling of anxiety, a feeling of shortness of breath, a feeling of shortness of breath, rapid breathing during excitement or in a stuffy room, paroxysmal, diffuse, constricting headaches, fatigue, sleep disturbance were noted in the form of submissive insomnia and superficial, shallow sleep and lack of feeling of rest when waking up. Objectively: a state of moderate severity. Height: 162 cm, weight: 54 kg. Asthenic physique. The skin is pale pink, mucous dry. During a physical examination of the pathology of the cardiovascular, respiratory, urinary systems, gastrointestinal tract was not found.

Mental condition. Oriented completely. Looks a little older than his age. The mood background is reduced. Hypomimic. The voice is quiet, weakly modulated. Facial expression is suffering. Complaints of reduced mood, constant anxiety, shortness of breath, shortness of breath, rapid breathing during agitation or in a stuffy room, paroxysmal, diffuse, constricting headaches, fatigue, sleep disturbance were noted in the form of submissive insomnia and superficial, shallow sleep and lack of feeling of rest upon waking. Notes an increase in these symptoms in the last 2 months. Autonomic disturbances in the form of mild tremor of the hands, cooling of the extremities, sweating are detected. The memory for current events and events from the past is saved. Expresses passive suicidal thoughts. In conversation, it quickly dwindles. Fixed on the state of his health. Mental status is characterized by anxiety-depressive syndrome.

The results of a psychometric assessment of the severity of mental disorders using diagnostic scales:

Spielberg-Khanin scale: reactive anxiety - 38 points, personal anxiety - 42 points;

Hamilton's anxiety scale (HAS): mental anxiety - 15 points, somatic anxiety - 11 points, neurovegetative anxiety - 4 points;

Hamilton Depression Scale (HADS) - 14 points;

a questionnaire for identifying signs of autonomic changes - 32 points.

Conclusion of a neurologist: Autonomic dystonia syndrome.

Laboratory test results:

- general blood test: the number of red blood cells - 3.42 × 10 ¹² / l, reticulocytes - 8 ‰; hemoglobin content - 122 g / l; color indicator - 0.9; weak hypochromia of red blood cells;

- immune status - CD3 + - 53% (0.99 · 10 ⁹ / l), CD4 + - 35% (0.56 · 10 ⁹ / l), CD8 + - 18% (0.33 · 10 ⁹ / l), immunoregulatory index (CD4 + / CD8 +) - 1.7, CD72 + - 10% (0.19 · 10 ⁹ / l), CD16 + - 6% (0.11 · 10 ⁹ / l), CD25 + - 15% (0.28 · 10 ⁹ / l), CD95 + - 18% (0.33 · 10 ⁹ / l). Conclusion: a decrease in the relative and absolute content of T-lymphocytes identified as CD3 + -positive cells; CB4 + cells showing helper activity; cytotoxic T lymphocytes carrying CD8 surface molecules; NK cells and the general population of B-lymphocytes that perform the functions of antigen-presenting cells and precursors of cells that secrete antibodies of the humoral immunity.

In instrumental research:

- ECG - heart rate - 86 per minute, the deviation of the electrical axis to the left;

- Ultrasound of the pelvic organs: Conclusion: Suspicion of internal genital endometriosis (adenomyosis). Violation of the transformation of the endometrium;

- The study of heart rate variability showed a decrease in the current functional state (TP = 1283.5 ± 102.9 ms ² / Hz), excessive activation of the sympathetic-adrenal system (LF / HF ratio = 2.11 ± 0.16) and a decrease in activity (tonus) of the parasympathetic regulation system (HP component = 352.2 ± 41.9 ms ² / Hz). These changes demonstrate vegetative disturbances.

Conducted in a hospital: hysteroscopy and laparoscopy.

During hysteroscopy, endometrioid passages, a rough relief of the walls in the form of ridges and crypts were identified. The degree of prevalence of endometriosis according to the classification of V.G. Breusenko (1997) corresponded to 2 stages of the process. During laparoscopy, retrocervical endometriosis was diagnosed, electrocoagulation of the revealed foci of external genital endometriosis was performed.

After a comprehensive examination, the diagnosis was made: External (retrocervical) and internal (adenomyosis) genital endometriosis. Menometrorrhagia. Alnodysmenorrhea. Dyspareunia. Secondary infertility

Treatment measures were prescribed: the antigonadotropic drug danazol in a dose of 800 mg / day for 6 months as a second stage of treatment of endometriosis on an outpatient basis. Objective criteria for assessing the clinical efficacy of danazol as a treatment for endometriosis was the onset of pharmacological amenorrhea in a patient.

1 month after endoscopic surgery (laparoscopy), phenotropil was prescribed at a dose of 100 mg / day for 90 days during treatment with danazol. The effectiveness of phenotropil was evaluated by reducing the severity of symptoms. As a result of the treatment, the patient reduced anxiety and depressive symptoms, autonomic disorders. These changes were recorded using the diagnostic scales:

Spielberg-Khanin scale: reactive anxiety - 19 points, personal anxiety - 29 points;

Hamilton's anxiety scale (HAS): mental anxiety - 7 points, somatic anxiety - 6 points, neurovegetative anxiety - 1 point;

Hamilton Depression Scale (HADS) - 6 points;

a questionnaire for identifying signs of autonomic changes - 16 points.

Clinical improvement was accompanied by normalization of immune status indicators: CD3 + - 72% (1.80 · 10 ⁹ / L), CD4 + - 43% (1.08 · 10 ⁹ / L), CD8 + - 29% (0.72 · 10 ⁹ / k), immunoregulatory index (CD4 + / CD8 +) - 1.48; CD72 + - 8% (0.20 · 10 ⁹ / l), CD16 + - 12% (0.30 · 10 ⁹ / l), CD25 + - 17% (0.43 · 10 ⁹ / l), CD95 + - 7% ( 0.17 · 10 ⁹ / l).

The results of the study of heart rate variability after treatment recorded an increase in the total spectrum power (TP = 2837 ms ² / Hz), slow wave power (LF component = 1023 ms ² / Hz) and fast periods (HF component = 1468 ms ² / Hz), normalization of the balance of the sympathetic and parasympathetic parts of the autonomic (ratio LF / HF = 0.69) of the nervous system.

After completing this course of treatment, the patient did not need to re-prescribe the antigonadotropic drug (danazol) for 6 months.

Thus, phenotropil had a positive effect on anxiety-depressive symptoms, the state of the immune (specific and non-specific links of the immune system, pro-apoptotic readiness of lymphocytes) and the autonomic nervous system while reducing the duration of the repeated use of drug hormonal treatment for 6 months.

The method proposed by the authors was applied in 25 women of reproductive age with endometriosis.

The analysis of evaluating the effectiveness of the course of treatment and the control group included 46 patients. The distribution of patients into groups was as follows:

- 1 group - 25 patients who received 100 mg / day of phenotropil for 90 days;

- group 2 - 21 patients who did not receive phenotropil.

In addition to phenotropil, patients of all groups received basic treatment:

- Stage 1 - endoscopic surgery (laparoscopy) with maximum excision of endometrioid implants and restoration of reproductive function;

- Stage 2 - antigonadotropic drugs (danazol 800 mg / day) in the postoperative period for the prevention of relapse for 6 months.

These patients underwent a repeated clinical, psychopathological, immunological and functional examination.

An analysis of the dynamics of indicators of the severity of psychopathological symptoms using clinical and psychopathological studies and a psychometric assessment of the severity of mental disorders using diagnostic scales (Spielberg-Hanin scales, Hamilton anxiety and depression scales (HADS and HAS) showed an almost complete reduction in anxiety-depressive disorders in the group of patients who received phenotropil with a high level of significance (p <0.001) for all the studied parameters compared with the comparison group (Table 1).

When assessing the state of the autonomic nervous system in accordance with the recommendations of the Center for Pathology of the Autonomic Nervous System (Wayne AM, 1998), studying the structure and severity of vegetative disorders using a questionnaire proposed by the Center for Vegetative Pathology (Wayne AM, 1991): “Questionnaire for identifying signs of autonomic changes "And" Study design for identifying signs of autonomic disorders "revealed a statistically significant decrease in the manifestations of autonomic disorders, compared with a group of patients who did not receive arata (table 1).

These changes were confirmed by the study of the modulating effect of the autonomic and central nervous system, a number of humoral and reflex effects on the heart rhythm at rest and when performing experimental clinical tests based on spectral and temporal analysis of heart rate variability using the Poly-Spectrum-Rhythm computer program "According to" International Standards "in accordance with the recommendations of the European Society of Cardiology and the North American Society for Electrical Stimulation and and Electrophysiology (1996), using the "SNC-Micro" (Neurosoft, Ivanovo).

The study of spectral indicators of heart rate variability after treatment with phenotropil recorded a significant increase in the total spectrum power, wave power of slow and fast periods, normalization of the balance of the sympathetic and parasympathetic sections of the autonomic nervous system compared to the results of this study of the control group (Table 2). The results of the study of the battery of Iving tests after treatment with phenotropil moved to normal values (according to Ewing D.J.), in contrast to the group not taking the drug (Table 3).

An immunological study revealed a significant increase, when compared with similar parameters in patients who did not receive the drug, in the absolute number of peripheral blood lymphocyte subpopulations carrying the following cell differentiation markers: CD3 +, CD4 +, CD8 +, CD72 +, CD16 +, CD25 +; the relative and absolute content of cells bearing the CD95 + receptor on their surface was statistically significantly reduced (Table 4). The results obtained demonstrate the effect of phenotropil on the immunomodulating (increasing specific and nonspecific immunity links, decreasing proapoptotic readiness of lymphocytes).

In patients treated with phenotropil, there was a decrease in the rate of progression of endometriosis, in this group re-administration of hormonal drugs was required in 32% of cases, which was statistically significantly less (p <0.01) than in the comparison group (72%).

Thus, the use of phenotropil led to an increase in the effectiveness of the treatment of endometriosis in women with anxiety and depressive disorders due to a reduction in anxiety and depressive symptoms, a positive effect on the functional state of the immune system (an increase in specific and non-specific links of the immune system, and a decrease in proapoptotic readiness of lymphocytes) and the autonomic nervous system reducing the duration of the use of repeated drug hormonal treatment for 6 months. In this regard, the phenotropil drug at a dose of 100 mg / day can be recommended for use in the complex drug treatment of endometriosis in women of reproductive age with anxiety-depressive disorders, which improves the effectiveness of treatment and their quality of life.

Bibliography

1. Nasyrova R.F., Sotnikova L.S., Novitsky V.V. et al. The state of autonomic regulation in endometriosis in women of reproductive age with anxiety-depressive disorders // Bulletin of Siberian medicine. - 2009. - Volume 8, No. 3. - S. 58-63.

2. Chandra P.S., Ranjan S. Psychosomatic obstetrics and gynecology - a neglected field? // Curr. Opin. Psychiatry. - 2007. - V.33 (1). - P.11-16.

3. Lorrencatto C., Petta C.A., Navaro M.J. et al. Depression in women with endometriosis with and without chronic pelvic pain // Acta Obstet. Gynecol. Scand. - 2006. V.85. - P.88-92.

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Table 1

Current status according to the scales: situational and personal anxiety Spielberg, anxiety and depression of Hamilton in patients at the 2nd visit

Indicator A group of patients taking phenotropil at a dose of 100 mg / day Comparison group Scale for identifying signs of autonomic changes, points 9.23 ± 1.87 28.02 ± 3.86 p ₁ <0.001 p ₁ <0.05 p ₂ <0.001 Hamilton Depression Scale, points 6.21 ± 1.78 12.96 ± 3.04 p ₁ <0.001 p ₁ <0.05 p ₂ <0.001 Spilberger-Khanin situational and personal anxiety scale Situational anxiety, points 18.34 ± 3.46 38.15 ± 4.91 p ₁ <0.001 p ₁ <0.01 p ₂ <0.001 Personal anxiety, points 29.71 ± 4.02 45.34 ± 5.46 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 Hamilton Alarm Scale Mental anxiety scores 6.42 ± 1.09 13.97 ± 2.89 p ₁ <0.001 p ₁ <0.05 p ₂ <0.001 Somatic anxiety, points 7.02 ± 1.31 14.62 ± 2.73 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 Neurovegetative anxiety scores 1.02 ± 0.35 3.07 ± 0.81 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 Note: hereinafter in tables 2, 3, 4, 5 p ₁ - significance of differences in indicators compared with similar parameters in patients of this group at the 1st visit; p ₂ - the reliability of differences in indicators compared with similar parameters in patients at the 2nd visit who did not take phenotropil.

table 2

Background spectral indicators of heart rate variability in patients at visit 2

Indicator A group of patients taking phenotropil at a dose of 100 mg / day Comparison group Total spectrum power (TR), ms ² / Hz 2978.90 ± 221.38 1469.72 ± 182.46 p ₁ <0.05 p ₁ > 0.05 p ₂ <0.001 Power of waves of a very slow period (VLF component), ms ² / Hz 335.46 ± 69.43 601.32 ± 89.12 p ₁ <0.001 p ₁ <0.05 p ₂ <0.05 Power of the waves of the slow period (LF component), ms ² / Hz 1364.75 ± 129.78 597.98 ± 123.08 p ₁ <0.001 p ₁ <0.05 p ₂ <0.001 Power of waves of the fast period (HF component), ms ² / Hz 1697.21 ± 123.95 418.92 ± 67.45 p ₁ <0.001 p ₁ <0.01 p ₂ <0.001 The balance indicator of the sympathetic and parasympathetic divisions of the ANS (LF / HF) 0.64 ± 0.09 1.61 ± 0.14 p ₁ <0.001 p ₁ <0.05 p ₂ <0.01

Table 3

Indicators of autonomic (cardiovascular) tests in patients at 2 visits

Indicator A group of patients taking phenotropil at a dose of 100 mg / day Comparison group Coefficient of deep breathing test (K resp.) 1.61 ± 0.12 1.19 ± 0.09 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.05 Coefficient 30:50 in an active orthostatic sample (K 30:50) 1.42 ± 0.21 1.19 ± 0.08 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.05 Valsava Sample Ratio (To Vals.) 1.73 ± 0.23 1.25 ± 0.11 p ₁ <0.001 p ₁ <0.05 p ₂ <0.01 Change in blood pressure systole. with active orthostatic test (decrease) 10.09 ± 1.65 17.12 ± 2.32 p ₁ <0.001 p ₁ <0.05 p ₂ <0.01 Change in blood pressure diastole. at isometric load test (increase) 15.87 ± 1.91 13.02 ± 1.52 p ₁ <0.001 p ₁ <0.01 p ₂ <0.05

Table 4

The population and subpopulation composition of peripheral blood lymphocytes in patients at visit 2

Cell differentiation markers A group of patients taking phenotropil at a dose of 100 mg / day Comparison group CD3 + % 74.92 ± 6.23 61.95 ± 7.64 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 10 ⁹ / l 1.72 ± 0.15 1.24 ± 0.26 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.01 CD4 + % 46.82 ± 3.94 39.07 ± 5.28 p ₁ <0.001 p ₁ <0.001 p ₂ <0.01 10 ⁹ / l 1.23 ± 0.09 0.69 ± 0.08 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 CD8 + % 30.23 ± 2.78 23.06 ± 3.94 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 10 ⁹ / l 0.70 ± 0.11 0.45 ± 0.06 p ₁ <0.001 p ₁ <0.001 p ₂ <0.001 Immunoregulatory index (CD4 + / CD8 +) 1.62 ± 0.24 1.97 ± 0.38 p ₁ <0.001 p ₁ > 0.05 p ₂ > 0.05 CD72 + % 8.01 ± 1.03 5.99 ± 0.89 p ₁ <0.05 p ₁ > 0.05 p ₂ <0.05 10 ⁹ / l 0.17 ± 0.11 0.10 ± 0.01 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 CD16 + % 7.96 ± 1.43 4.93 ± 0.81 p ₁ <0.001 p ₁ <0.01 p ₂ <0.001 10 ⁹ / l 0.20 ± 0.02 0.08 ± 0.01 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 CD25 + % 15.87 ± 1.97 10.02 ± 1.46 p ₁ <0.05 p ₁ > 0.05 p ₂ <0.001 10 ⁹ / l 0.29 ± 0.08 0.17 ± 0.03 p ₁ <0.001 p ₁ > 0.05 p ₂ <0.001 CD95 + % 4.1 ± 0.64 9.21 ± 0.83 p ₁ <0.001 p ₁ <0.001 p ₂ <0.001 10 ⁹ / l 0.12 ± 0.09 0.19 ± 0.08 p ₁ <0.001 p ₁ <0.001 p ₂ <0.001

Claims (1)

A method of treating endometriosis in women with anxiety-depressive disorders, including surgical intervention with laparoscopic access and hormonal drug treatment for 6 months, characterized in that 1 month after laparoscopy, phenotropil is additionally prescribed at a dose of 100 mg / day for 90 days.