RU2418589C2 - Method of correcting endothelial dysfunction in pregnant women with iron-deficiency anemia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to obstetrics and gynecology and can be used for correction of endothelial dysfunction in pregnant women with iron deficiency anemia in the second trimester of gestation. Medication "Ferretab" is administered to patients in dose 1 dragee per day per os during 3 weeks.

EFFECT: method possesses high efficiency and provides possibility of timely correction of endothelial dysfunction in case of iron deficiency anemia in order to prevent possible complications of pregnancy and early neonatal period due to elimination of tissue hypoxia and normalisation of iron level in organism.

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Description

The invention relates to medicine, namely to obstetrics, and can be used to correct endothelial dysfunction in pregnant women with iron deficiency anemia in the second trimester of gestation.

The relevance of the proposed method is determined by the fact that the key problem of obstetrics is iron deficiency anemia (IDA) due to the widespread and high incidence of obstetric and perinatal complications. According to WHO, the frequency of IDA in pregnant women ranges from 21% to 80%. With anemia, the main function of red blood cells is violated - oxygen transport, the consequence of which is the development of hemic and secondary tissue hypoxia (Petrov VN Physiology and pathology of iron metabolism. - M .: Nauka, 1987. - 244 p.), Which contributes to damage to the endothelium and leads to its dysfunction. Endothelial dysfunction is a pathological condition of the endothelium, which is based on a violation of the production of endothelial factors, and therefore it is not able to ensure hemorheological and immuno-inert blood balance, which during pregnancy leads to complex disorders in the mother-placenta-fetus system. Endothelial dysfunction is the basis of many complications of the gestational process (gestosis, fetoplacental insufficiency, intrauterine infection of the fetus) (Klimov V.A. Endothelium of the fetoplacental complex in the physiological and pathological course of pregnancy // Obstetrics and gynecology. - 2008. - No. 2. - S. 7-10).

In this regard, the development of a method for the correction of endothelial dysfunction in pregnant women with iron deficiency anemia in order to prevent possible complications of pregnancy and the early neonatal period is of particular relevance.

Previously, a method for the correction of endothelial dysfunction, including the use of enalapril, has been proposed. The method consists in the fact that in an experiment, a laboratory animal was administered intragastrically enalapril at a dose of 0.5 mg / kg and intraperitoneally L-arginine at a dose of 200 mg / kg once a day (Patent No. 2271202. Method for the correction of endothelial dysfunction / M.V. Pokrovsky, T.G. Pokrovskaya, V.I. Kochkarov // Inventions. Useful models. - 2006. - No. 7).

A known method for the correction of endothelial dysfunction with a combination of amlodipine and L-arginine with L-NAME-induced nitric oxide deficiency. In the experiment, dysfunction was simulated by daily intraperitoneal administration of L-nitro-arginine methyl ester to rats at a dose of 25 mg / kg daily and amlodipine was administered intragastrically at a dose of 0.5 mg / kg and L-arginine intraperitoneally at a dose of 200 mg / kg once a day (Patent No. 2296566. Method for the correction of endothelial dysfunction with a combination of amlodipine and L-arginine with L-NAME-induced deficiency of nitric oxide / M.V. Pokrovsky, V.I. Kochkarov, T.G. Pokrovskaya, E. B.Artyushkova // Inventions. Utility models. - 2007. - No. 10).

The same authors developed a method for correcting endothelial dysfunction with a combination of losartan and resveratrol in case of L-NAME-induced nitric oxide deficiency. In the experiment, dysfunction was simulated by daily intraperitoneal administration to rats of L-nitro-arginine methyl ester in rats at a dose of 25 mg / kg daily for 7 days. Then, on the 7th day from the start of the experiment, losartan was intragastrically administered at a dose of 6 mg / kg and resveratrol was administered intraperitoneally at a dose of 2 mg / kg once a day (Patent No. 2306924. A method for correcting endothelial dysfunction with a combination of losartan and resveratrol in case of L-NAME-induced deficiency nitric oxide / M.V. Pokrovsky, V. I. Kochkarov, T. G. Pokrovskaya, E. B. Artyushkova // Inventions. Useful models. - 2007. - No. 27).

Also, in literature there is a method for the correction of hypoestrogen-induced endothelial dysfunction, which consists in the fact that in the experiment female rats were injected daily intraperitoneally with furostanol glycosides from Dioscorea deltoidea cell culture at a dose of 1 mg / kg once a day for 9 days (Patent No. 32, 7 Patent No. 2, No. 7) 2 times a day2 (Patent No. 2, No. 7) Method for correction of hypoestrogen-induced endothelial dysfunction with furostanol glycosides from plant cell culture Dioscorea deltoidea / M.V. Korokin, AMNosov // Inventions. Utility models. - 2008. - No. 21).

However, all of the above methods have several disadvantages:

- these methods are developed in experiments on laboratory animals;

- pharmacological substances in various combinations that are not drugs (except enalapril) are used for correction;

- there is no data on the effectiveness of the methods;

- no information on practical application.

Closest to the technical solution to the claimed method is a method of restoring the endothelial lining of blood vessels in individuals with arterial hypertension in the metabolic syndrome. The method consists in the use of an individually selected diet, rationally dosed static and dynamic physical activities and drugs lisinopril 10 mg in the morning, rosuvastatin 20 mg in the evening and oligovit 1 tablet 3 times a day for 4 months (Patent No. 2,337,679. A method for restoring endothelial lining of blood vessels persons with arterial hypertension in the metabolic syndrome / I.N. Medvedev, BD Bespartochny // Inventions. Useful models. - 2008. - No. 31). This method is selected as a prototype.

However, this method has several disadvantages:

1. The method is used in a limited group of people suffering from hypertension with metabolic syndrome.

2. The treatment regimen includes several types of non-drug therapy along with the administration of drugs.

3. The method involves taking a combination of drugs over a long period of time (4 months).

These disadvantages are proposed to eliminate in the present method.

The technical solution of the proposed method is the correction of endothelial dysfunction in pregnant women with iron deficiency anemia in the second trimester of gestation with Ferretab, 1 tablet per day per os for 3 weeks with an efficiency of 86.7%.

The novelty of the proposed method lies in the fact that for the first time it is proposed to carry out the correction of endothelial dysfunction in pregnant women with iron deficiency anemia in the second trimester of gestation (13-26 weeks) with the Ferretab preparation, registration number - P No. 013723 / 01-2002, 02.10.02 .

Ferretab (iron fumarate 154 mg, folic acid 500 μg, elemental iron content 50 mg) is a combined antianemic drug that is used to treat iron deficiency anemia, including in pregnant women. The effect of the drug is due to the properties of the components that make up its composition. Iron fumarate is a salt of iron, a trace element necessary for the synthesis of hemoglobin. Folic acid stimulates erythropoiesis, participates in the synthesis of amino acids, nucleic acids, purines and pyrimidines (Vidal Handbook. - M .: AstraFarmService, 2004. - 1488 p.).

Previously, a double-blind, randomized study was conducted, the results of which were presented by the Journal of American College of Cardiologi, where the authors showed that the addition of folic acid to the writing led to a significant improvement in endothelial function in patients with coronary arteriosclerosis. In atherosclerosis, low-density lipoproteins (LDL) and very low density (VLDL), deposited in the intima of blood vessels, have a damaging effect on the endothelium (Atherosclerosis [Electronic resource] // www. Athero.ru - 2009); while in case of anemia, endotheliopathy develops due to tissue hypoxia (Petrov VN Physiology and pathology of iron metabolism. - M .: Nauka, 1987. - 244 p.). A randomized study in China earlier showed that supplementation with multivitamins containing folic acid reduced mortality from strokes, and the New England Medical Journal published a paper demonstrating a reduction in the number of restenoses after angioplasty (Vitamin B9 (folic acid, folacin , vitamin BC) [Electronic resource] // www.bezdoktorov.ru.-2008).

Ferretab was not previously used to correct endothelial dysfunction; apparently, its effect on endothelium is due to the effects of folic acid. Perhaps the positive effect of folic acid on endothelium is due to the fact that it participates in the synthesis of hemoglobin, along with iron fumarate, it restores the normal level of iron in the body, thereby eliminating the main link in the pathogenesis of endothelial dysfunction in anemia - tissue hypoxia. Markers of endothelial dysfunction are tissue plasminogen activator (t-PA) - glycoprotein, the main activator of the fibrinolytic system in the blood and plasminogen activator inhibitor PAI-1 - in the active state binds t-PA and blocks the conversion of plasminogen to plasmin, thereby providing procoagulant activity of the endothelium ( Makatsaria A.D. Thrombophilia and pregnancy // Bulletin of the Russian Association of Obstetricians and Gynecologists - 1994.- No. 1 - P.76-85). The above markers are endothelial factors, the synthesis of which under normal conditions practically does not occur, but increases with stimulation of the endothelium, which is physiological for pregnancy (Klimov V.A. Endothelium of the fetoplacental complex in the physiological and pathological course of pregnancy // Obstetrics and gynecology. - 2008. - No. 2. - S.7-10). In our studies, pregnant women with anemia showed an increase in t-PA antigen levels to 7.34 ± 1.25 ng / ml and PAI-1 to 14.7 ± 0.75 v / ml compared to pregnant women without anemia (t- PA antigen - 4.22 ± 0.39 ng / ml and PAI-1 12.44 ± 0.58 v / ml; ρ <0.05 and ρ <0.02, respectively), which is regarded as the presence of endothelial dysfunction. After correction with Ferretab, the markers of endothelial damage significantly decreased, which made it possible to judge about an improvement in the state of endothelium. The research results are presented in table 1.

The method is as follows:

1) To assess the condition of the endothelium in pregnant women with iron deficiency anemia in the second trimester of gestation, 5 ml of fasting venous blood is taken before the appointment of Ferretab, the plasma of which determines the amount of t-PA and PAI-1 antigen by the enzyme immunoassay in microplates using a commercial test systems from Technoclone.

2) For 3 weeks, patients take the drug "Ferretab" (iron fumarate 154 mg, folic acid 500 μg, elemental iron content 50 mg), 1 tablet per day per os.

3) To assess the effectiveness of the correction of endothelial dysfunction after treatment, re-sampling of venous blood in the amount of 5 ml is performed, in the plasma of which the level of t-PA and PAI-1 antigen is determined.

Distinctive features of the method are: correction of endothelial dysfunction in pregnant women with iron deficiency anemia in the second trimester of gestation with Ferretab, 1 tablet per day per os for 3 weeks.

The essence of the proposed method is illustrated by the following examples:

Example 1. Pregnant E., 24 years old, pre-pregnant, primiparous. Clinical diagnosis during the examination: Pregnancy 13 weeks. Anemia of the I degree. Duodenal ulcer, remission.

At the time of the examination, hemoglobin of blood 107 g / l. Prior to the administration of the iron-containing preparation Ferretab, the amount of t-PA antigen (2.98 ng / ml) and PAI-1 (12.74 v / ml) in the peripheral blood was determined, which indicates the presence of endothelial dysfunction.

To stop the disturbed endothelial condition and correct hemoglobin level, a course of therapy with Ferretab was carried out at 1 tablet per day per os for 3 weeks (hemoglobin after treatment 113 g / l).

After treatment, the amount of t-PA antigen (2.66 ng / ml) and PAI-1 (4.8 v / ml) was determined in peripheral blood, and the levels of endothelial damage markers decreased, which indicates an improvement in the state of the endothelial lining.

III trimester of pregnancy in this patient proceeded without complications; hemoglobin before childbirth - 120 g / l; childbirth occurred in 39-40 weeks in a natural way; a healthy baby weighing 3100 grams was born.

Example 2. Pregnant B., 17 years old, re-pregnant, primiparous. Clinical diagnosis during the examination: Pregnancy 26 weeks. Anemia of the I degree. A burdened gynecological history. Hyperplasia of the thyroid gland of the 1st degree. Euthyroidism.

At the time of the examination, hemoglobin of blood was 108 g / l. Before the appointment of the iron-containing preparation Ferretab, the amounts of t-PA antigen (4.69 ng / ml) and PAI-1 (13.05 v / ml) were determined in peripheral blood, which indicates the presence of endothelial dysfunction.

To stop the disturbed endothelial condition and correct hemoglobin level, a course of therapy with Ferretab was carried out at 1 tablet per day per os for 3 weeks (hemoglobin after treatment 114 g / l).

After treatment, the amount of t-PA antigen (3.54 ng / ml) and PAI-1 (3.77 v / ml) was determined in peripheral blood, and the levels of endothelial damage markers decreased, which indicates an improvement in the state of the endothelial lining.

III trimester of pregnancy in this patient proceeded without complications; hemoglobin before childbirth - 106 g / l; childbirth occurred at 39 weeks through the natural ways, a healthy baby weighing 3400 grams was born.

Example 3. Pregnant S., 29 years old, pre-pregnant, primiparous. Clinical diagnosis during the examination: Pregnancy 20 weeks. Anemia of the I degree. Body mass deficiency.

At the time of the examination, hemoglobin of blood is 96 g / l. Before the appointment of the iron-containing preparation Ferretab, the amounts of t-PA antigen (4.26 ng / ml) and PAI-1 (13.14 v / ml) were determined in peripheral blood, which indicates the presence of endothelial dysfunction.

To stop the disturbed endothelial condition and correct hemoglobin level, a course of therapy with Ferretab was carried out at 1 tablet per day per os for 3 weeks (hemoglobin after treatment 103 g / l).

After treatment, the amount of t-PA antigen (3.32 ng / ml) and PAI-1 (1.63 v / ml) was determined in peripheral blood, and the levels of endothelial damage markers decreased, which indicates an improvement in the state of the endothelial lining.

III trimester of pregnancy in this patient proceeded without complications; hemoglobin before childbirth - 103 g / l; childbirth occurred at 39 weeks by Caesarean section (indications - exacerbation of genital herpes). A child weighing 2650 grams, healthy.

Example 4. Pregnant P., 37 years old, multiparous. Clinical diagnosis during the examination: Pregnancy 22 weeks. Anemia of the I degree. A burdened obstetric and gynecological history.

At the time of the examination, hemoglobin of blood 100 g / l. The amount of t-PA antigen (3.26 ng / ml) and PAI-1 (9.43 v / ml) in the peripheral blood was determined, which indicates the presence of endothelial dysfunction.

Correction of hemoglobin level was carried out with Fenyuls (iron sulfate 150 mg, including iron 45 mg, ascorbic acid 50 mg, riboflavin 2 mg, thiamine mononitrate 2 mg, nicotinamide 15 mg, pyridoxine hydrochloride 1 mg, pantothenic acid 2.5 mg) 1 capsule per day per os for 3 weeks (hemoglobin after treatment 110 g / l).

After treatment, the amount of t-PA antigen (3.42 ng / ml) and PAI-1 (11.15 v / ml) was determined in peripheral blood, and no markers of endothelial damage were reduced as a result of treatment, i.e. there was no correction of endothelial dysfunction.

III trimester of pregnancy in this patient proceeded against a background of nephropathy of the first degree, placental insufficiency; hemoglobin before birth 110 g / l; prompt timely delivery occurred (indications for combined Cesarean section - scar on the uterus, short stature, uniformly narrowed pelvis of the 1st degree, unavailability of the birth canal). A child weighing 3450 grams, with perinatal damage to the central nervous system (cerebral ischemia of the 1st degree), hypertensive syndrome, conjugation jaundice. Discharged on day 11 under the supervision of a neurologist at the place of residence.

In this way, endothelial dysfunction was corrected in 30 pregnant women. The research data are shown in table 2. 26 of them had a positive effect from taking the drug "Ferretab". Thus, the efficiency of the method was 86.7%.

Table 1 Endothelial dysfunction correction efficacy indicators in women with anemia in the second trimester of gestation Full name Before treatment After treatment PAI-1 (v / ml) t-PA (ng / ml) PAI-1 (v / ml) t-PA (ng / ml) one 2 3 four 5 1. Elnikova N.E. 12.74 2.98 4.8 2.66 2. Sedova A.V. 13.14 4.26 1,63 3.32 3. Bodyunova M.S. 13.05 4.69 3.77 3,54 4. Nikanorova O.A. 13.02 4.26 11.45 3,54 5. Guseva N.A. 17.78 3.98 15.44 3.91 6. Smirnova T.A. 12.32 3.94 10.13 4.15 7. Morozova L.V. 19.1 4.74 9.9 3.04 8. Anikina R.E. 12.97 2.5 10.05 2.01 9. Savchenko L.V. 14.08 4.08 10.11 2.07 10. Raguzina Yu.S. 14.41 2.81 2.83 4.81 11. Litukhina O.A. 15.75 3,7 13.21 1,6 12. Skrebova S.A. 16.94 16,42 10.13 4.32 13. Korshunova V.V. 27.12 3.97 21.41 3.04 14. Migunova O.A. 13.06 3.26 10.17 2.54 15. Gorshkova L.M. 15.34 4.66 14.82 5.15 16. Polikarpova E. 11.61 3.9 10.15 3.82 17. Krikunenko O.N. 11.24 4.86 10.01 3.24 18. Surina N.E. 12.75 4.26 11.25 3.26 19. Shlykova Yu.A. 13.61 3.26 9.8 2,3 20. Ilyushkina N.S. 13.08 3.26 10.11 2.0 21. Prokhorova EB 6.29 1,69 1,63 1.65 22. Abdullaeva G. 7.04 10.77 1,57 5.26 23. Kiriya N.I. 14.74 4.23 14.36 4.01 24. Malinova N.M. 16.75 8.24 21.49 6.4 25. Legkova E.V. 22.21 8.24 7.76 3.25 26. Buts S.V. 18.93 32.31 16.23 4.99 27. Parashchak N.A. 17.33 18.85 15.49 5,6 28. Smolina O.A. 12.22 13.84 11.02 10.64 29. Kletskina S.V. 19.07 19.93 13.17 4.3 30. Chastukhina N.V. 13.41 12.36 11.17 6.8

table 2 Indicator The number of examined Total women thirty positive result 26 Total: the effectiveness of the proposed method = 26/30 · 100 = 86.7%

The advantages of the proposed method:

1. A method for the correction of endothelial dysfunction is carried out in pregnant women with iron deficiency anemia.

2. The drug for the correction of endothelial dysfunction is simultaneously used to treat iron deficiency in this category of patients.

3. The drug is a registered drug, available for purchase in pharmacy chains.

4. The method is practically applicable both in the clinic and on an outpatient basis.

5. The method has a high efficiency correction of endothelial dysfunction - 86.7%.

6. The method allows to prevent possible complications of pregnancy and the early neonatal period.

Claims (1)

A method for correcting endothelial dysfunction in pregnant women with iron deficiency anemia by administering drug therapy, characterized in that in the second trimester of gestation, pregnant women with iron deficiency anemia are prescribed Ferretab 1 tablet per day per os for 3 weeks.