RU2563178C1 - Method for prevention of oxidative stress accompanying administration of releasing-hormone contraceptive system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: antioxidant composition containing retinol acetate in an amount of 1,650 International units (0.568 mg) - 3,300 International units (1.135 mg), α-tocopherol acetate 7.5-10 mg, ascorbic acid 35-50 mg, thiamine hydrochloride 0.581-1.0 mg, riboflavin 1.0-1.27 mg, pyridoxine hydrochloride 2.5-5.0 mg, folic acid 50-100 mg, lipoic acid 1-2 mg, ferric sulphate 2.5-5.0 mg, copper sulphate 75-400 mcg, methionine 50-100 mg, selenium 25-50 mcg is prescribed across contraception. The antioxidant composition is administered once a day, orally after meals over a period of 30 days. After 30-day pauses, the therapeutic course is repeated five times.

EFFECT: invention enables recovering the antioxidant status in the patients, reducing the risk of thromobosis accompanying prolonged hormonal contraception.

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Description

The invention relates to medicine, in particular to gynecology and female contraception.

Ensuring safe motherhood and maintaining women's health is the main task of modern medicine. One way to solve it is to prevent an unplanned pregnancy, reduce the number of medical and criminal abortions, and maternal mortality after abortions. In changing socio-demographic conditions, hormonal contraception is considered not only the most effective, among the reversible, methods of preventing unwanted pregnancies, regulating fertility, but also allowing to obtain therapeutic and preventive effects and maintain the reproductive health of young women [Radzinsky V.E., Khamoshina M .B., Abdullaeva R.G. Hormonal contraception in adolescents and young women. Farmateka, 2009. No. 1. S. 10-16]. The arsenal of contraceptives has expanded significantly, mainly due to low- and micro-dose combined oral contraceptives (COCs). However, the risk of side effects due to oxidative stress associated with the use of hormonal contraceptive systems, including the development of thrombotic complications, remains high [Thrombohemorrhagic complications in obstetric and gynecological practice. Ed. Makatsaria A.D. M .: MIA, 2011.1056 s .; Sidney S., Cheetham T.S., Connell F.A. etal. Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. // Eur. J. Contracept Reprod Health Care 2013. - N 1. - P. 93-100].

In the modern literature, there are few reports of the effects of oxidative stress and hemocoagulation changes in the body against the background of oral hormonal contraceptives in women.

I.V. It was successful for the correction of oxidative stress and hemocoagulation on the background of COCs proposed to use the original method [Lakhno I.V. Family planning. Medicus Amicus. 2002. No4. S. 13-14; Lakhno I.V. Hormone-Induced Phlebopathy: A Focus on Phleboprotective Therapy in Women Using Combined Oral Contraceptives. Consilium Medicum Ukraina. Female reproductive health / pediatrics. 2009. Volume 3. No. 6]. The action of the proposed method is aimed at preventing the possibility of the occurrence of venous thrombosis against the background of hormonal contraception, but does not prevent the development of arterial thrombotic complications (the occurrence of heart attacks, strokes, central artery thrombosis). With prolonged use of the proposed method, gastrointestinal and neurovegetative disorders are possible, which is undesirable for women who need to correct oxidative stress continuously, against the background of hormonal contraception.

Known work on the correction of hypocoagulating and antioxidant properties in the body [Patent RU No. 22259824 from 04.20.2005; Patent RU No. 2302248 of 03/10/2007]. In the proposed methods used the drug isolated from the liver of crabs. The proposed method has low efficiency due to the insufficient concentration of the drug used in the proposed method. An increase in the concentration of the drug used is undesirable due to the possibility of complications in patients with diseases of the liver, biliary tract and other diseases of the gastrointestinal tract. In addition, the high cost of the course of treatment should be taken into account due to the high cost and limited ability to obtain the drug from crabs.

Patent EP 2364697 [Antioxidant composition for reducing oxidative stress associated with the use of hormonal contraceptives has been selected as a prototype. Cornelli, Umberto, Cor. Con. International S.R.L.]. To correct oxidative stress, the authors used an unbalanced composition of the compositions used. Vitamin E is absent in the composition - the most potent natural antioxidant, which is the "first line of defense" of cellular membrane phospholipids. In addition, as a rule, against the background of hormonal contraception (HA), women have a deficiency of B vitamins, folic acid, methylation processes are disrupted, and hyperhomocysteinemia develops, which leads to a cytotoxic effect, even greater activation of lipid peroxidation (LPO) and hypercoagulation followed by increased risk of thrombosis. This composition does not contain components aimed at correcting the metabolism of the folate cycle, which is extremely important against the background of oxidative stress when using hormonal contraception. Due to the fact that the drug is prepared ex temporo, and hormonal contraception is carried out continuously for many months or years, the preparation of a solution of the powder is not always possible under conditions of air travel, night shift work, frequent business trips, and work requiring a forced body position (drivers).

In addition, the composition used is a homeopathic remedy not registered in the Russian Federation. The above facts limit the possibility of prescribing it to patients in the conditions of medical institutions in Russia against the background of prolonged hormonal systems.

The objective of the invention is, against the background of the use of hormonal releasing contraceptive systems, to restore the antioxidant status of blood, reduce the activity of lipid peroxidation (LP) processes and limit the intensity of hemocoagulation shifts as a result of using the proposed combination of drugs that have synergism in the implementation of the task.

Scientific background used to accomplish the task. In healthy women, the level of lipid peroxidation and antioxidant defense (AOD) activity are in equilibrium.

In the totality of antioxidants, enzymatic and non-enzymatic preparations are isolated that allow cells to keep the amount of free radicals at a physiological level. The depletion of the antioxidant fund transfers the summary radical processes into an uncontrollable state with the accumulation of endogenous lipid peroxides and a violation of the structure and function of the membranes, causing oxidative stress. Oxidative stress is one of the universal forms of the body's response to the effects of adverse exogenous and endogenous factors and plays a significant role in the pathogenesis of cardiovascular diseases [Skulachev, V.P. Mitochon dria, reactive oxygen species and longevity: some lessons from the Barja group.// Aring. Cell. - Vol. 3 - No. 1 - (February, 2004), pp. 17-19; Knasmuller et al. Use of conventional fnd-omics based methods for health claims of dietar for antioxidants: acritical overview. // Br. J. Nutr Vol. 99, E Suppl 1, (may 2008), pp. ES3-52].

The technical result of our proposed method is achieved by the fact that a combination of various drugs is proposed, which limits oxidative stress due to both non-enzymatic and enzymatic antioxidant defense units.

Vitamin E refers to non-enzymatic intracellular "antioxidant traps" that give off an electron from a low-activity free radical, electron acceptors are free radicals of fatty acids - metabolites of the chain reaction of peroxidation, which leads to the termination of the LPO chain. Vitamin E prevents the formation of end products (low acid lipoproteins) and stabilizes the plasma membranes of cells. Moreover, only reduced forms of vitamin E are involved in the inhibition of lipid peroxidation, and ascorbic acid is the reducing agent of the antioxidant properties of tocopherol. In addition, ascorbic acid reacts with a wide range of free radicals, protecting glutathione and sulfhydryl groups of proteins from oxidation.

Vitamin C is one of the active elements of the antioxidant defense system, protecting lipids from their peroxidation. Its antioxidant effect is manifested with a sufficient amount of other antioxidants, such as α-tocopherol and glutathione.

Lipoic acid, which is also part of the proposed combination, is necessary for the normal functioning of the ascorbate and vitamin E cycle in the body. The lipoic acid molecule contains a dithiolan ring in an oxidized form, which provides the formation of dihydrolipoic acid, which contributes to the transformation of vitamin E into a reduced form. This explains the property of lipoic acid to prevent the development of symptoms in case of deficiency of vitamins C and E.

The antioxidant activity of vitamin A is manifested in the regulation of lipid peroxidation processes in cell membranes, turning the most aggressive oxidant - singlet oxygen - into its less aggressive and more stable form. Vitamin A undergoes autooxidation with the formation of peroxide compounds, so it must be combined with other antioxidant compounds (vitamin C, selenium, vitamin E, etc.).

Trace elements of iron and copper as metal ions with variable valency also belong to the "antioxidant traps" of the non-enzymatic link. The essential amino acid methionine is a donor of sulfur atoms necessary for the biosynthesis of glutathione, a powerful hydrophilic cellular antioxidant and reducing agent for glutathione peroxidase. Methionine is involved in the synthesis of phosphatidylcholine, the main phospholipid of cell membranes.

Selenium has a corrective effect on the enzymatic link of antioxidant protection, is part of the selenium-containing enzyme glutathione peroxidase, which catalyzes the reduction of hydrogen peroxide to water. The function of glutathione peroxidase is the reduction of hydroperoxides to hydroxy fatty acids. This interrupts the further course of the chain reaction. Copper is part of the copper-containing glycoprotein - ceruloplasmin, which catalyzes the oxidation of ferrous iron to ferric. In blood, unlike superoxide dismutase, which is an intracellular antioxidant, copper performs the function of intercepting superoxide radicals. Thiamine hydrochloride, riboflavin, pyridoxine hydrochloride, folic acid, methionine, cyancobalamin, a deficiency of which is observed against the background of HA, which are part of the proposed combination, prevent their deficiency, normalize methylation processes, limit the accumulation of homocysteine, prevent its cytotoxic effect on cells, which reduces the intensity of the cells, which reduces the intensity FLOOR and oxidative stress on the background of HA.

Hypercoagulation and a tendency to thrombinemia on the background of HA is accompanied by activation of platelets with the release into the bloodstream of factors that accelerate thrombinogenesis and increase the activity of platelets by the positive feedback mechanism. An important role in platelet activation is played by free radical processes, since reactive oxygen species are normal products of the conversion of arachidonic acid during the formation of prostaglandins. Acceleration of these processes can enhance coagulation hemostasis through platelet activation. Antioxidants, blocking the development of free radical processes, stabilize cell membranes, including platelets, reducing their pro-coagulant activity (aggregation, adhesion, release of pro-coagulant factors - platelet factors 1, 2, 3, 4, adrenaline, norepinephrine, serotonin other). Thus, the vicious circle of thrombinemia - LPO activation - thrombinemia is broken.

The technical result is a simple method that does not require large material costs, based on the use of a composition of antioxidants, consisting of 8 vitamins and 4 minerals, against the background of hormonal releasing systems. The proposed composition restores all links of the antioxidant protection of blood (enzyme and non-enzyme, intracellular and extracellular), relieves oxidative stress, reduces the intensity of lipid peroxidation of membranes, and prevents the activation of platelet and coagulation hemostasis.

The technical result is achieved by the fact that according to the invention, during the contraception period against the background of hormonal estrogen-progestogen releasing system, an antioxidant composition is prescribed containing retinol acetate in an amount of 1650 IU (0.568 mg) - 3300 IU (1.135 mg), α-tocopherol acetate 7.5- 10 mg, ascorbic acid 35-50 mg, thiamine gidrodchloridorid 0.581-1.0 mg, riboflavin 1.0-1.27 mg, pyridoxine hydrochloride 2.5-5.0 mg, folic acid 50-100 mg, lipoic acid 1 -2 mg, iron in the form of sulfate 2.5-5.0 mg, copper in the form of sulfate 75-400 μg, methionine 50-100 mg, selenium 25-50 μg, composition anti oxidant is administered once a day orally, after food 30 days, then after a break for 30 days, repeat the treatment five times during the year.

The proposed method is as follows: women from 1 day of contraception on the background of hormonal estrogen-gestagen releasing system are prescribed an antioxidant composition containing retinol acetate in the amount of 1650ME (0.568 mg) - 3300ME (1.135 mg), α-tocopherol acetate 7.5-10 mg , ascorbic acid 35-50 mg, thiamine hydroxychloride 0.581-1.0 mg, riboflavin 1.0-1.27 mg, pyridoxine hydrochloride 2.5-5.0 mg, folic acid 50-100 mg, lipoic acid 1-2 mg, iron in the form of sulfate 2.5-5.0 mg, copper in the form of sulfate 75-400 μg, methionine 50-100 mg, selenium 25-50 μg, composition antioxidant tov is administered once a day orally after meals for 30 days, then after a break for 30 days, the course of treatment is repeated five times during the year.

Examples of practical use of the proposed method

Example 1

A 36-year-old patient came for the purpose of selecting contraception with complaints of pain in the mammary glands 3 days before menstruation. A history of 2 births through the natural birth canal. Previously received Diana 35 (EE 35 μg, cyproterone acetate) for 4 years, 2 years ago she stopped taking because of headaches. Against the background of Diane 35, in a blood test for hemostasiogram ABP 121.5 sec (norm 78-118 sec), fibrinogen 4.33 g / l (norm 2-4 g / l), RFMC 10 mg / dl (norm up to 4 mg / dl), platelet aggregation time 12 sec (norm 14-18 sec), antithrombin III 130% (85-115%). An increase in fibrinogen level, an increase in RFMC concentration, a shorter platelet aggregation time indicates activation of the platelet link of hemostasis, activation of continuous intravascular coagulation against the background of activation of the anticoagulation system, which, with any additional disturbing effect on hemostasis, can lead to activation of blood coagulation to any degree of thrombosis. In blood tests for hormones - a decrease in the concentration of progesterone (61.7 nmol / l from 21-24 days of the menstrual cycle). The patient showed depletion of antioxidant status.

Diagnosis. Deficiency of the II menstrual cycle. Premenstrual cider, edematous form.

For contraception and treatment, the patient is recommended an ultramicrodosed estrogen-progestogen vaginal ring Nova Ring from the second day of the menstrual cycle for 3 weeks with a 7-day break. At the same time as Nova Ring, against the background of the hormonal estrogen-progestogen releasing system, the patient was taking a composition of antioxidants containing 2000 IU retinol acetate, 9.0 mg α-tocopherol acetate, 40 mg ascorbic acid, 0.8 mg thiamine hydrochloride chloride, 1.2 riboflavin mg, pyridoxine hydrochloride 4.0 mg, folic acid 80 mg, lipoic acid 1.5 mg, iron in the form of sulfate 3.0 mg, copper in the form of sulfate 200 μg, methionine 75 mg, selenium 40 μg, the antioxidant composition was administered once per day orally after meals for 30 days, then after a break during e 30 days, a five-fold course of treatment was carried out during the year.

All complaints were stopped after the first course of using the proposed methodology. The patient noted the good tolerance of the contraceptive method. No depletion of the patient's antioxidant status was detected, oxidative stress was prevented, and antioxidant defense indices were at the level of normative indices. The parameters of the hemostasiogram did not go beyond the reference values acceptable for the population, which was the prevention of an increased risk of thrombosis against the background of hormonal releasing system.

So, the antioxidant status of blood has been restored, the activity of lipid peroxidation processes has been reduced, and the intensity of hemocoagulation shifts in the patient has been normalized.

Example 2

A 40-year-old patient has come for the purpose of contraception selection with complaints of heavy painful periods during the last 5 years. In the next five years, pregnancy is not planned. A history of menstruation of 5 days, regular, after 27 days, profuse, painless. A history of 2 births through the natural birth canal. Somatic diseases denied.

Diagnosis. Hyperpolymenorrhea. Uterine fibroids, interstitial-subserous form.

For contraception and treatment, the patient is recommended an ultramicrodosed estrogen-progestogen vaginal ring Nova Ring from the second day of the menstrual cycle for 3 weeks with a 7-day break. At the same time as Nova Ring, on the background of hormonal estrogen-progestogen releasing system, the patient was taking an antioxidant composition containing 3,000 IU retinol acetate, 8.0 mg α-tocopherol acetate, 45 mg ascorbic acid, 0.9 mg thiamine hydrochlorodoride, 1.0 mg riboflavin mg, pyridoxine hydrochloride 3.0 mg, folic acid 90 mg, lipoic acid 1.9 mg, iron sulfate 4.0 mg, copper sulfate 300 μg, methionine 90 mg, selenium 30 μg, the antioxidant composition was administered once per day orally after meals for 30 days, then after a break during e 30 days, repeated five times the course of treatment during the year.

The patient noted good tolerance to the contraceptive method. During the first menstrual cycle, she complained of intermenstrual bleeding from the genital tract, which was then not observed. By the end of the year of treatment, the proposed method of menstruation for 2-3 days became very scarce, in the form of spotting spotting. The results of the study of antioxidant status before treatment by the proposed method: G-S-T - 499 μmol / ml per min, SOD - 57.5% inhibition, vitamin A 0.72 μg / ml, vitamin E 7.9 μg / ml. The results of the study of antioxidant status after 1 year: G-S-T - 490 μmol / ml per min, SOD - 56.9% inhibition, vitamin A 0.80 μg / ml, vitamin E 8.9 μg / ml. In the blood test for hemostasiogram to Mirena: ABP 105.1 sec (norm 78-118 sec), APTT 30.1 sec (norm 24-39 sec), PO 0.98 (norm 0.9-1.3), IPT 102% (norm 80-100%), MHO 1.0 (norm 1), PTV 13.7 sec, TV 15.8 sec (14-17 sec), fibrinogen 3.22 g / l (norm 2-4 g / l), RFMC 4.5 (norm up to 4 mg / dl), platelet aggregation time 15 sec (norm 14-18 sec), D-dimer <0.1 g / l (norm <0.1 g / l) , antithrombin III 110% (85-115%), RPI 100% (norm 100 ± 10%). In a blood test for a hemostasiogram after 1 year, depletion of the patient's antioxidant status was not detected, oxidative stress was prevented, antioxidant defense indices were at the level of normative indices. The parameters of the hemostasiogram did not go beyond the reference values acceptable for the population, which was the prevention of an increased risk of thrombosis against the background of hormonal releasing system.

So, the antioxidant status of blood has been restored, the activity of lipid peroxidation processes has been reduced, and the intensity of hemocoagulation shifts in the patient has been normalized.

The given examples illustrate the possibility of using this method for the correction of oxidative stress with the use of hormonal release contraceptive systems. The method ensures the safety of long-term hormonal contraception, preventing abortion and their complications, while maintaining the reproductive health of women.

The method of correction of oxidative stress on the background of hormonal contraceptive systems was tested during 2008-2013. on the basis of the obstetric and gynecological department and the clinical diagnostic laboratory of the multidisciplinary clinic GBOU VPO TyumGMA of the Russian Ministry of Health and in the problem biochemical laboratory TSNIL GBOU VPO TyumGMA of the Russian Ministry of Health. A total of 303 women were examined, including 95 women of early reproductive age (18-35 years old) using a monophasic ultramicro-dosed combined estrogen-progestogen contraceptive, the NovaRing intravaginal ring, which continuously releases 15 μg of ethinyl estradiol and 120 mg of ethonogestrel (primary active desogestrel) per day, of which 35 women, along with vaginal HRS, received complex treatment according to the proposed method; 80 women of late reproductive and premenopausal age (36-50 years old) using progestational contraceptive with intrauterine route Mirena (constantly releasing 20 μg of levonorgestrel per day) using the proposed method for contraceptive and therapeutic purposes.

The results of laboratory tests of the examined women are presented in table 1. The economic and positive effects of the proposed method in comparison with the prototype are presented in table 2.

The money savings resulting from the treatment of one patient by the method of preventing oxidative stress on the background of a hormonal contraceptive release system amounted to 10,680 rubles.

The overall economic effect of the treatment of 100 patients with the proposed method compared to the prototype is 1068 thousand rubles.

The proposed method for the correction of oxidative stress on the background of a hormonal contraceptive release system ensures the safety of long-term hormonal contraception, prevents abortions and their complications, while maintaining the reproductive health of women.

Claims (1)

A method for the prevention of oxidative stress on the background of hormonal contraceptive releasing system, characterized in that during the period of contraception on the background of hormonal estrogen-gestagen releasing system, an antioxidant composition is prescribed containing retinol acetate in the amount of 1650ME (0.568 mg) - 3300ME (1.135 mg), α- tocopherol acetate 7.5-10 mg, ascorbic acid 35-50 mg, thiamine hydrochloride 0.581-1.0 mg, riboflavin 1.0-1.27 mg, pyridoxine hydrochloride 2.5-5.0 mg, folic acid 50- 100 mg, lipoic acid 1-2 mg, iron in the form of sulfate 2.5-5.0 mg, copper in the form of sulfate 75- 400 mcg, methionine 50-100 mg, selenium 25-50 mcg, the antioxidant composition is administered once a day orally after meals for 30 days, then after a break for 30 days, the treatment is repeated five times during the year.