RU2794847C1 - Agent increasing ferritin concentration in human blood serum - Google Patents

Abstract

FIELD: pharmaceuticals; medicine.

SUBSTANCE: invention relates to the use of biologically active additives containing hydroxyethylammonium methylphenoxyacetate, vitamins: A, D ₂ , E, B ₁ , B ₂ , B ₅ , B ₉ , B ₁₂ , PP, H, C, calcium, magnesium, iron, selenium, zinc, fluorine, iodine, as a means of increasing the concentration of ferritin in blood serum, 2 tablets 2 times a day with meals for the first 4 weeks, and then a similar repeated course at the 4th month of treatment with basic medicinal products.

EFFECT: invention provides increase of ferritin concentration in human blood serum.

1 cl, 1 tbl

Description

SUBSTANCE: invention relates to medicine and pharmaceutics and concerns an agent that increases the level of ferritin concentration in human blood serum.

Ferritin (Fe) is an iron-containing α ₂ H-globulin, the molecular weight of which is about 450 kD. It is a water-soluble complex of iron hydroxyphosphate with the protein apoferritin. Its largest amount is found in the cells of the liver, spleen, bone marrow and reticulocytes, where the processes of synthesis, maturation and degradation of erythrocytes are most intensive. Fe is actively involved in the metabolism and redistribution of iron in the body. The ability to synthesize Fe appeared in cells at the early stages of evolution. Characteristic analogues of ferritin are found in fungi, bacteria, plants [see. Ragland M, Briat JF, Gagnon J. Evidence for conservation of ferritin sequences among plants and animals and for a transit peptide in soybean. The Journal of Biological Chemistry. 1990; 265, 30: 18339-18344; Theil EC Ferritin: Structure, gene regulation, and cellular function in animals, plants, and microorganisms. Ann Rev Biochem. 1987; 56: 289-315]. In vertebrates, protection against the toxic effects of iron and reactive oxygen species is provided by two iron-binding proteins: extracellular transferrins and intracellular ferritins. Both store iron in a safe, oxidized Fe(III) form that does not catalyze free radical production. Fe contains 15-20% of the total amount of iron in the body. The concentration of ferritin at birth is increased - up to 600 ng / ml, within a few months it decreases to about 30 ng / ml, after which it begins to slowly increase and by the age of 24-25 takes on values that persist until old age. The normal adult serum ferritin concentration is 20-350 ng/mL [see Trubnikov G.A. - Immunochemical markers of inflammation and tumors in clinical pulmonology // Astrakhan: Astrakhan Medical Academy. - 2000. - 209 p.]. In postmenopausal women (usually 48-50 years old), it reaches the average values characteristic of men [see. Sukharev A.E. - Tissue and serum acute phase proteins in the clinical evaluation of nonspecific diseases and lung cancer // Abstract of the thesis. dis… doc. honey. Sciences. - 1991. - 28 p.]. A drop in concentration below 10 ng / ml indicates the development of iron deficiency anemia, while with excessive accumulation of iron, the concentration of ferritin can increase to several thousand ng / ml [see. Complementary Feeding And The Control Of Iron Deficiency Anemia In The Newly Independent States Presentation By WHO At A WHO/Unicef Consultation Geneva, Switzerland 4 February (http://www.cdc.gov/mmwr/distrnds.html)]. There are tissue and serum Fe [see. Caskey Y., Iones C., Muller YE et. al. Human Ferritin gene assigned to chromosome 19 //Proc. Natl. Acad. sci. USA. - Vol.80. - R .482-486]. Tissue Fe is synthesized by cells of various organs, serum Fe is secreted by cells of the liver and reticuloendothelial system. In general, the role of serum Fe remains unclear.

In recent years, physiological functions of ferritin have been discovered that are not directly related to iron metabolism. It turned out that H-isoforms of ferritin can play the role of suppressors in the proliferation of blood cells [see. Smirnova L.A., Martsev S.P. Ferritin and its clinical significance // Medical News Journal, Minsk. - 1996. - No. 7. - S. 11-15]. The processes of myelosuppression (suppression of myeloid cell proliferation) correlate with the activation of the synthesis of H-subunits at the genome level [see. Broxmeyer H.E., Gentle P., Cooper S. // Blood Cells. - 1984. - V. 10. - P. 397-400; Broxmeyer H.E., Levi S., Arosio P. // Blood. - 1986. - V. 68. - P. 1257-1259; Broxmeyer H.E., Cooper S., Levi S., Arosio P. // Proc. Natl. Acad. sci. USA. - 1991. - V. 88. - P. 770-774]. N-ferritin is able to inhibit the proliferation of myeloid and lymphoid cells, and the activation of its synthesis may be associated with an attempt by the body to suppress their malignant growth [see. Broxmeyer H.E., Williams D.E., Geissler K. et al. // Blood. - 1989. - V. 73. - P. 74-79; Coccia E.M. // Blood. - 1995. - V. 86. - R. 1570-1578]. It has been established that the mechanism of inhibition of cell proliferation is directly related to the ferroxidase function of ferritin, which leads to the formation of cytotoxic oxygen radicals. Apparently, the cytotoxic effect of ferritin extends to many types of cells, but so far only a few of them have been registered, in particular, on myeloid cells, granulocyte precursors, and monocytes. Inhibition is carried out at the level of the S-phase of the cell cycle [see. Smirnova L.A., Martsev S.P. Ferritin and its clinical significance // Medical News Journal, Minsk. - 1996. -№7. - S. 11-15]. It is known that the cytotoxic effect is also characteristic of pulmonary tuberculosis [see. Sukharev A.E. - Tissue and serum acute phase proteins in the clinical evaluation of nonspecific diseases and lung cancer // Abstract of the thesis. dis... doc. honey. Sciences. - 1991. - 28 p.; Trubnikov G.A. -Immunochemical markers of inflammation and tumors in clinical pulmonology // Astrakhan: Astrakhan Medical Academy. - 2000. - 209 p.]. Therefore, the stronger the cytotoxic effect, the higher the concentration of Fe, since Fe has cytoprotective properties. Thus, it can be concluded that a high Fe concentration in pathological inflammatory conditions indicates a high level of immunity. And if the concentration of Fe in tuberculosis is low or slightly increased, then we can talk about low immunity of the patient's body.

The closest agent that increases the level of serum Fe (H-isoforms) in the human body with various chemical compounds that are not directly related to iron metabolism is the drug trekrena containing hydroxyethylammonium methylphenoxyacetate, beta-carotene, alpha-tocopherol, garlic and lactose, which modulates the concentration of ferritin in human blood serum (Patent RU No. 2486895, 2013). At the same time, treatment with trekrezan is carried out during the first 4 weeks, and then with a similar repeated course at the 4th month of treatment with basic drugs. However, with this method of treatment, the increase in the level of Fe in the blood is not effective enough. It is proposed as a means of increasing the amount of ferritin in human blood serum a biologically active additive (BAA) trekrevit containing hydroxyethylammonium methylphenoxyacetate, vitamins: A, D ₂ , E, B _{1 , B 2 ,} B ₅ , B ₉ , B ₁₂ , PP, H , C, calcium, magnesium, iron, selenium, zinc, fluorine, iodine.

Trekrevit is a biologically active food supplement (see http://siultra-r.narod.ru/bad_ser.files/bad.htm) containing hydroxyethylammonium methylphenoxyacetate, vitamins: A, D ₂ , E, B ₁ , B ₂ , B ₅ , B ₉ , B ₁₂ , PP, H, C, calcium, magnesium, iron, selenium, zinc, fluorine, iodine, the deficiency of which, according to the Institute of Nutrition of the Russian Academy of Medical Sciences, is experienced by almost every inhabitant of Russia.

According to the Decree of the Chief Sanitary Doctor of the Russian Federation No. 50 of April 17, 2003 on the optionalness of the exact quantitative composition of biologically active additives, information about this dietary supplement contains the ingredient composition in descending order in weight terms.

Trekrevit is especially effective during illnesses and during the recovery period, with intense physical exertion, for a growing body (children from 12 years old), for the prevention of premature aging, for people living in ecologically unfavorable areas and lacking vitamins and minerals, with an unbalanced diet .

EFFECT: increased concentration of ferritin in human blood serum by using a biologically active additive (BAA) trekrevit as Fe activator. This allows you to expand the scope of its application and improve the result of treatment.

The technical result is achieved by using a dietary supplement containing hydroxyethylammonium methylphenoxyacetate, vitamins: A, D ₂ , E, B ₁ , B ₂ , B ₅ , B ₉ , B ₁₂ , PP, H, C, calcium, magnesium, iron , selenium, zinc, fluorine, iodine, as a means of increasing the concentration of ferritin in human blood serum, 2 tablets 2 times a day with meals, during the first 4 weeks, and then a similar repeated course on the 4th month of treatment with basic drugs means. At the same time, patients receive trekrevitis in the first and fourth months of treatment.

The property of trekrevita to influence the functional system of maintaining the level of ferritin in the blood serum of patients with pulmonary tuberculosis has not been described in the literature.

The effective amount of trecrevit depends on body weight, comorbidities, and preferably ranges from 200 to 400 mg per day. The course of treatment is up to 4 weeks.

The use of trecrevit in the proposed method allows you to increase the level of Fe in the blood serum of patients with pulmonary tuberculosis.

Examples of the use of the proposed dietary supplement trekrevit to increase the level of ferritin in human blood serum.

Before the start of the experiment, the Fe concentration in the blood serum is determined in 35 practically healthy people (donor volunteers), aged from 30 to 55 years (men - 25-40 years, women of the menopausal period - 50-55 years). The average Fe concentration in donors is 243.43±25.5 ng/ml. All donors on the day of the examination have a written opinion of the doctor about their state of health - “practically healthy”, in women, the period of menopause is officially established by gynecological examination.

The object of the study are primary patients aged 35 to 55 years (mean age 42.1±2.1 years) with a diagnosis of infiltrative tuberculosis of the upper lobe of the right (left) lung. Since this form of pulmonary tuberculosis is the most common, patients with this diagnosis are selected for observation. On the radiographs of all patients, inhomogeneous blackouts with fuzzy contours with a diameter of more than 1 cm are noted. At admission, the concentration of serum Fe is determined in all patients (for the experiment, patients with a serum Fe concentration below the generally accepted norm - up to 30 ng / ml) are selected [see. Smirnova L.A., Martsev S.P. Ferritin and its clinical significance // Journal of Medical News, Minsk. - 1996. - No. 7. - S. 11-15], i.e. with a weakened immune system.

A total of 32 people were examined, in which the average Fe concentration (M ± m) before treatment was 24.4 ± 1.2 ng/ml. Patients are divided into the following groups:

- control group (16 people, average Fe concentration in the group -25.5±1.8 ng/ml) who received only basic agents (Isoniazid 0.6 g + rifampicin 0.6 g + ethambutol 2.0 g + pyrazinamide 2, 0 g for 6 months of treatment in a hospital);

- the main one - volunteers (16 people, the average Fe concentration is 24.7 ± 1.9 ng / ml), who expressed a desire to take trecrevit at a dose of 400 mg / day for 4 weeks, and then a similar repeated course on the 4th month treatment during meals in addition to treatment with basic remedies.

The level of Fe in the blood serum is determined by enzyme immunoassay (ELISA), using commercial kits manufactured by CJSC "Vector-Best-South", Rostov-on-Don.

The results obtained are processed statistically using the Microsoft Excel and Biostat programs using a parametric test (Student's t-test) and a non-parametric test (Mann-Whitney U-test), taking into account small samples. Data are presented as mean and standard error values, M and m, respectively. For relative values, 95% percent confidence intervals are calculated. Differences are considered reliable at p≤0.05 (see the book - Petri A., Sabin K. Visual medical statistics / Translated from English under the editorship of V.P. Leonov; 2nd ed., revised and supplemented Moscow: GEOTAR-Media, 2009. 168 p.).

Results.

It was found that in patients of the main group, the use of dietary supplement trekrevit in addition to basic chemotherapy with isoniazid, rifampicin, ethambutol and pyrazinamide is accompanied by a significant increase in the level of serum Fe compared with the control (table 1).

Matejny, В. Hepatotoxicita u chorych s pl'ucnou tuberkulozou liecenych kombinaciou antitubekulotiks pyrazinamidom a bez pyrazinamidu / B. Matejny. Stud. Pneumol. Phfiseol. Cech. - 1986. - Vol. 46, №112. - P. 23-31). По концентрации сывороточного Фе можно судить о состоянии иммунной системы у данной категории больных - чем выше концентрация Фе в начале заболевания, тем выше иммунные силы организма. Одновременно с повышением концентрации Фе в основной группе больных отмечается в дальнейшем ускорение рассасывания инфильтратов, рентгенологически - более раннее рубцевание легочной ткани, повышается аппетит, возрастает масса тела, улучшается функция печени и раньше нормализуется температура тела. Следовательно, комплексное соединение - трекревит, обладающее впервые установленным, новым свойством - модулировать образования ферритина в организме является более эффективным, чем аналог трекрезан. При этом полученные данные можно рассматривать с разных позиций. К примеру - с точки зрения способа лечения больных туберкулезом; или с точки зрения применения трекревита для лечения больных туберкулезом легких; или с точки зрения лабораторного тестирования состояния больных туберкулезом; или с точки зрения состава для комбинированного лечения больных туберкулезом; а также с точки зрения выявленных новых свойств известного соединения.In the control group, the average Fe concentration is significantly lower than in the main group. With a combined treatment regimen, with a long-term additional intake - trekrevita, no increase in the side effects of the basic therapy of anti-TB drugs is noted. At the same time, the well-known fact that almost all anti-TB drugs are toxic to one degree or another is of particular importance.

Matejny, V. Hepatotoxicita u chorych s pl'ucnou tuberkulozou liecenych kombinaciou antitubekulotiks pyrazinamidom a bez pyrazinamidu / B. Matejny. Stud. Pneumol. Phiseol. Chech. - 1986. - Vol. 46, No. 112. - P. 23-31). By the concentration of serum Fe, one can judge the state of the immune system in this category of patients - the higher the concentration of Fe at the onset of the disease, the higher the body's immune forces. Simultaneously with the increase in Fe concentration in the main group of patients, further acceleration of resorption of infiltrates is noted, radiographically - earlier scarring of the lung tissue, appetite increases, body weight increases, liver function improves and body temperature normalizes earlier. Therefore, the complex compound - trecrevit, which has a newly established, new property - to modulate the formation of ferritin in the body, is more effective than the analogue trekrevit. At the same time, the obtained data can be considered from different perspectives. For example, from the point of view of the method of treating patients with tuberculosis; or from the point of view of the use of trecrevit for the treatment of patients with pulmonary tuberculosis; or in terms of laboratory testing of the condition of tuberculosis patients; or in terms of the composition for the combined treatment of patients with tuberculosis; and also from the point of view of the revealed new properties of the known compound.

Thus, combined treatment with the intake of the biologically active additive "Trekrevit" in addition to the basic chemotherapy of patients with pulmonary tuberculosis with anti-tuberculosis drugs can increase the effectiveness of the treatment and improve the quality of life of patients. Given the good compatibility of trekrevita with basic anti-tuberculosis drugs, it can also be included in comprehensive rehabilitation programs for restorative medicine for a certain group of patients.

SOURCES OF INFORMATION CONSIDERED

1. Ragland M, Briat JF, Gagnon J. Evidence for conservation of ferritin sequences among plants and animals and for a transit peptide in soybean. The Journal of Biological Chemistry. 1990; 265, 30: 18339-18344.

2. Theil E.C. Ferritin: Structure, gene regulation, and cellular function in animals, plants, and microorganisms. Ann Rev Biochem. 1987; 56:289-315.

3. Trubnikov G.L. - Immunochemical markers of inflammation and tumors in clinical pulmonology // Astrakhan: Astrakhan Medical Academy. - 2000. - 209 p.

4. Sukharev A.E. - Tissue and serum acute phase proteins in the clinical evaluation of nonspecific diseases and lung cancer // Abstract of the thesis. dis... doc. honey. Sciences. - 1991. -28 p.

5. Complementary Feeding And The Control Of Iron Deficiency Anemia In The Newly Independent States Presentation By WHO At A WHO/Unicef Consultation Geneva, Switzerland 4 February (http://www.cdc.gov/mmwr/distrnds.html)

6. Caskey Y., Iones C, Muller Y.E. et. al. Human Ferritin gene assigned to chromosome 19 // Proc. Natl. Acad. sci. USA. - Vol.80. - P. 482-486

7. Smirnova L.A., Martsev S.P. Ferritin and its clinical significance // Medical News Journal, Minsk. - 1996. - No. 7. - S. 11-15.

8. Broxmeyer N.E., Gentle P., Cooper S. // Blood Cells. - 1984. - V. 10. - P. 397-400.

9. Broxmeyer H.E., Levi S., Arosio P. // Blood. - 1986. - V. 68. - P. 1257-1259.

10. Broxmeyer H.E., Cooper S., Levi S., Arosio P., Proc. Natl. Acad. sci. USA. - 1991. - V .88. - P. 770-774.

11. Broxmeyer H.E., Williams D.E., Geissler K. et al. // Blood. - 1989. - V. 73. - P. 74-79; Coccia E.M.//Blood. - 1995. - V. 86. - P. 1570-1578.

12. Petri A., Sabin K. Visual medical statistics / Per. from English. ed. V.P. Leonov; 2nd ed., revised. and additional M: GEOTAR - Media, 2009. 168 p.

13.

14. Matejny, B. Hepatotoxicita u chorych s pl'ucnou tuberkulozou liecenych kombinaciou antitubekulotiks pyrazinamidom a bez pyrazinamidu / B. Matejny. Stud. Pneumol. Phiseol. Cech.-1986.-Vol. 46, No. 112. - P. 23-31.

15. Rasulov M.M., Kuznetsov I.A., Storozhenko P.A., Voronkov M.G., et al. - A drug that modulates the concentration of ferritin in blood serum - Patent RU No. 2486895 C1, 2013

Claims (1)

The use of a dietary supplement containing hydroxyethylammonium methylphenoxyacetate, vitamins: A, D ₂ , E, B ₁ , B ₂ , B ₅ , B ₉ , B ₁₂ , PP, H, C, calcium, magnesium, iron, selenium, zinc, fluorine , iodine, as a means of increasing the concentration of ferritin in the blood serum, 2 tablets 2 times a day with meals for the first 4 weeks, and then a similar repeated course at the 4th month of treatment with basic drugs.