RU2188033C2 - Combined pharmaceutical erythropoietin- and iron-containing preparations - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: combined pharmaceutical preparation includes 250-20000 U erythropoietin (EPO) in separate medicinal forms and 5-20 mg iron (III) complex, moreover, EPO-preparation and iron complex could be represented both in separate medicinal forms or in a single form. The preparation favors for considerable increase of erythrocytic number. The suggested preparations could be used to treat anemic patients or those with indication for hemodialysis. EFFECT: higher efficiency. 4 cl

Description

 The invention relates to combined pharmaceutical preparations containing erythropoietin preparations and iron preparations. These drugs are intended primarily for use in order to optimize erythropoiesis in the treatment of diseases in which it is necessary to stimulate the formation of red blood cells.

 The object of the present invention is a combined pharmaceutical preparation comprising 250-20000 units. an erythropoietin preparation and 1-40 mg of an equivalent amount of iron ions of a physiologically acceptable iron preparation, while an erythropoietin preparation and an iron preparation can be presented in separate dosage forms or in a single such form.

 A known technique for the treatment of anemia, in particular anemia associated with blood transfusion in patients with indications for hemodialysis, using recombinant human erythropoietin (rhEPO). Anemia in chronic diseases is the second of its most common forms.

 The main reason for the various forms of anemia resulting from a decrease in erythropoiesis in the bone marrow or disturbances in the reabsorption of iron is due to insufficient production of red blood cells in the body. With a daily decrease in the formation of new red blood cells by 1%, symptoms of anemia can be detected in a clinical setting only after 1-3 weeks. The daily requirement for iron to ensure normal erythropoiesis is 25 mg. And only about 1 mg of this amount enters the body from food, but the main need is usually met by re-absorption of the iron contained in hemoglobin after the decomposition of obsolete red blood cells. In chronic diseases, the intake of iron from reticular cells is significantly reduced. The reason for this is due to the fact that iron is retained in the reticuloendothelial system and, as a result, the process of erythropoiesis is disrupted. In such cases, they talk about the so-called "internal iron deficiency", in which normal compensation mechanisms are not fully utilized. In this case, reticulocytopenia and the absence of erythropoiesis necessary to compensate for anemia are typical. Decreased secretion or activity of erythropoietin may be an additional pathogenic factor. Noticeable changes in the metabolism involving iron are influenced, for example, by the absence of compensated transferrin formation. The main reason for the disturbances is, therefore, due to the absence of iron from its stores (in reticuloendothelial cells) into the plasma (and thereby into the erythron), as a result of which normal compensation mechanisms are not involved. The purpose of introducing recombinant erythropoietin into the body by therapeutic means is to contribute to a significant increase in the number of red blood cells.

 In clinical chemistry, concentrated serum ferritin is used to diagnose anemia and iron metabolism disorders. If anemia in chronic diseases is supplemented by a persistent iron deficiency, the amount of ferritin does not increase (for the most part, it remains at a level of less than 90-95 ng / ml). With simultaneous clinical symptoms of infection, inflammation or malignant disease, this indicator indicates the presence of iron deficiency in combination with anemia accompanying a chronic disease. Since serum ferritin can also react as a kind of acute phase protein in such diseases, it can be used with great success for diagnostic purposes.

 The total iron content in men is normal, approximately 3.5 g, and in women 2.5 g. Iron is actively involved in metabolism and is located in cumulative compartments. The active pool in men contains an average of 2100 mg in hemoglobin, 200 mg in myoglobin, 150 mg in tissue enzymes (nehem) and 3 mg in the compartment - the carrier of iron. In the tissue, iron accumulates inside the cells in the form of ferritin (700 mg) and in the form of hemosiderin (300 mg).

 The biocompatibility of iron can be disrupted by pathophysiological reasons, as a result of which there is a decrease in iron absorption in the body. Of the daily dietary intake of approximately 10 mg, only approximately 1 mg is resorbed in an adult. And although this indicator increases with a lack of iron, it nevertheless in rare cases exceeds 5-6 mg, unless additional administration of iron is envisaged. The mechanism of iron resorption has not yet been precisely studied. Appropriate regulation to a decisive extent is carried out due to the cells of mucose (mucous membrane) of the small intestine. The decisive signal for mucose is, apparently, the total amount of iron in the body. It was found that there is an inverse correlation (relationship) between the concentration of serum ferritin and the amount of iron absorbed.

 From intestinal mucose cells, iron is transferred to transferrin. This protein in the iron transport system has two sites for the binding of the latter. It is synthesized in the liver. This ensures the presence of a mechanism by which cells (for example, mucose of the small intestine, macrophages) can take iron and then give it to specific membrane receptors of erythroblasts, placenta cells or liver cells. The indicated transferrin-iron-receptor complex, as a result of endocytosis, enters the red blood cell precursor cells, where iron is transported further to the mitochondria. Here, heme is formed from iron and protoporphyrin.

 Iron (redundant) for erythropoiesis with the help of transferrin moves into two types of storage pools. The most important storage agent is ferritin. We are talking about a heterogeneous family of proteins, including the iron core. Ferritin is soluble and is the active form of the drive in the liver (hepatocytes), in the bone marrow, in the spleen (macrophages), in red blood cells and in serum (approximately 100 ng / ml). The ferritin pool in the tissues is very labile and easily accessible in cases where iron is required. The source of circulating serum ferritin is the reticuloendothelial system, and its circulating concentration is determined by the total iron content in the body (each ng / ml corresponds to 8 mg of iron reserve).

 It was found that in the case of hemodialysis in patients whose therapy used rhEPO, there is an acute need for iron. As a rule, such patients are prescribed additional therapy with iron, since erythropoietin (EPO) can show its optimal effectiveness only if the maximum accumulation of iron in the respective stores. For such a maximum full filling of iron stores, the introduction of high doses of iron preparations has been practiced to date. However, an overdose of the latter can lead to undesirable side effects. It is not safe from a physiological point of view, first of all, intravenous administration of iron preparations due to the extremely high toxicity of iron ions. As for patients with known manifestations of allergies, for example, in asthmatics, it is not recommended to use certain iron preparations for them at all. The level of filling of iron stores can be determined by the presence of protein, ferritin, and by the degree of transferrin saturation (see M. Wick, W. Pingerra, P. Lehmann "Eisenstoffwechsel, Diagnose und Therapie der Anämien, pp. 5-14, 38-55, 65-80, 94-98; 3rd revised edition, September 1996, Springer Verlag, Vienna, New York), with the degree of transferrin saturation being an indicator of the amount of iron from the depot to the bone marrow, while serum ferritin concentration is a measure of accumulated iron, and iron stores are considered “full” when the concentration of the collar ferritin is more than 150 μg / l, and the degree of saturation with transferrin reaches more than 20%. P. Grützmacher et al. consider (see Clinical Nephrology, Volume 38, 1, 1992, pp. 92-97) that under such conditions rely on the maximum effect of EPO therapy.

 Today, with EPO therapy, patients with indications for dialysis using iron speak of two phases: the “correction phase” and the “maintenance phase”. In the correction phase, in order to fill the iron stores as quickly as possible, iron preparations are administered in extremely high dosage levels. In this case, it is advisable to administer the appropriate iron preparations by rapid intravenous injection of large volumes of liquid. In the maintenance phase, the iron stores are then maintained in a “filled state" by the administration of lower doses of iron. Iron preparations in this phase are no longer administered by the above rapid injections, but in the form of conventional infusion preparations or by oral route.

 With rhEPO therapy in patients with indications for hemodialysis, an acute need for iron can be observed both in the correction phase and in the maintenance phase. For the synthesis of 1 g / dl of hemoglobin in the correction phase, 150 mg of iron is required, the need for which can be met either due to endogenous stores of iron, or due to exogenous (external) sources. In the maintenance phase, there is also an increased need for iron, due to the fact that in patients with an indication for hemodialysis with any type of treatment, slight blood loss occurs. Iron loss after a period of one year is estimated at approximately 1000 mg (3 mg / day). Such losses can be compensated for a long time only by external sources. For these purposes, in principle, there are formulations intended for oral and intravenous administration.

 Since the resorption of iron administered orally is only about 1 mg / day, and with extreme exercise (when administered orally about 300 mg Fe (III) / day) less than 3 mg / day, preference should be given to the intravenous administration of large amounts of iron. To date, there are two intravenously administered iron preparations on the pharmaceutical market in Germany, namely ferrlecite and ferrum vitis. “Ferrlecite” is an iron gluconate complex (3), and “ferrum vitis” is an iron hydroxide complex (3) in the form of a sugar.

 Many problems of long-term oral high-dose iron therapy in the treatment of patients with hemodialysis can be relatively easily avoided by the intravenous, subcutaneous administration of physiologically acceptable salts of iron (III), since in such cases reliable access is provided by the intravenous, subcutaneous route and injections can be carried out without additional load on the patient. In recent years, the described method has found wide application, since it was believed that these drugs "ferrlecite" and "ferrum vitis" are forms with a relatively small set of side effects. However, at the same time, side effects were indicated, which are manifested, in particular, during therapy with ferrlecitis, with autologous blood transfusion, which significantly limits the indications for the use of this drug for parenteral therapy. In addition, attention is drawn to possible reactions in the circulatory system until the onset of collapse, as well as to the possibility of anaphylactic reactions. And last: the maximum allowable daily dose is determined in the amount of two ampoules of 5 ml each, which corresponds to 125 mg of iron. Thus, the intravenous administration of both of these iron preparations is associated with certain problems, since the use of both drugs has to take into account some side effects, especially in cases where relatively quick injections of large volumes of fluid are necessary. In addition, with the intravenous administration of these iron preparations, other difficulties may arise up to reactions in the acute phase, due to the fact that the dose of iron is too high or the optimal ratio between this dose and EPO dose has not been selected.

 It is quite obvious that high doses of iron, introduced during EPO therapy to patients with indications for dialysis, are unacceptable, since the risk of myocardial infarction increases, and the risk of developing "cirrhosis" of iron also noticeably increases. In the treatment of patients with indications for dialysis, the introduction of adequate amounts of iron, as well as the method for determining the concentration of iron in the body fluids to identify a possible iron deficiency, are of therapeutic importance, since the lack of sufficient iron is one of the main reasons for the unsatisfactory effectiveness of EPO , respectively, the resistance of EPO.

 An overdose of iron-containing drugs can lead to iron poisoning. The fact is that elemental iron has a toxic effect on the gastrointestinal tract, on the cardiovascular and central nervous systems. The oral lethal dose of elemental iron ranges from 200 to 250 mg / kg. The most commonly used iron-containing tablets are iron sulfate (contains about 20% elemental iron), iron fumarate (contains about 30% elemental iron) or iron gluconate (contains about 10% elemental iron).

 There are four typical stages of iron poisoning. Stage 1 (during the first 6 hours after poisoning): vomiting, diarrhea, increased irritability, abdominal pain, seizures, apathy, and coma may occur. Irritations of the gastrointestinal mucosa can lead to hemorrhagic gastritis. High serum iron levels can cause shortness of breath, tachycardia, hypotension, shock, coma, and metabolic acidosis. Stage 2 (during the first 10-14 hours after poisoning): during the latent (latent) period, which can last up to 24 hours, an apparent improvement occurs. Stage 3 (12-48 hours after poisoning): shock, hypoperfusion and hypoglycemia occur. Serum iron levels may remain normal. There may be liver damage with elevated HPT (glutamate pyruvate transaminase), temperature, leukocytosis, coagulation (blood) disorders, T-inversion in ECG, disorientation, anxiety, apathy, a tendency to seizures, coma, shock, acidosis and death. Stage 4 (after 2-5 weeks): in the first place, possible complications may occur due to obstruction (blockage) of the pylorus, antrum or any other intestinal organ, cirrhosis of the liver or damage to the central nervous system.

 In view of the foregoing, the present invention was based on the task of developing a combined preparation of an erythropoietin preparation and an iron preparation that would contain the corresponding amounts of EPO and iron ions in an optimum effective ratio necessary for the treatment of metabolic disorders involving iron. The purpose of using such combined preparations should be, in particular, so that with their help it would be possible to prevent the above-described danger of complications, side effects, etc. and especially reactions in the acute phase. In addition, in patients who were prescribed rhEPO therapy, it was necessary to ensure the optimal effectiveness of EPO and prevent the resistance of the latter.

 The composition of the combined preparation according to the invention comprises from 250 to 20,000 units. an erythropoietin preparation and 1-40 mg of an equivalent amount of iron ions of a physiologically acceptable iron preparation, primarily an iron (II) complex or iron (III) complex, wherein the EPO preparation and the iron preparation are presented in the form of combined preparations. According to the present invention, said EPO preparations can be used, for example, with an EPO content of less than 2000 units. or in an amount of more than 7000 units.

 In the context of the present description, the term "combined preparations" means not only such drugs in packaging in which the EPO preparation and the iron preparation are presented together in a single packaging ready for sale (in the so-called combined packaging), but also drugs in such packages that contain either an appropriate amount of an EPO preparation or an appropriate amount of an iron preparation, each individually, and with regard to the components contained therein, these preparations nfektsionirovany so that each of them, as indicated in the invention may be administered respectively with another drug. In these cases, as a rule, the pharmaceutical manufacturer or importer of drugs encloses a package leaflet as provided for by the legislative provisions of many countries, which contains information on the preparations and instructions for their joint administration. Combined preparations can be presented preferably in a single ready-to-use form, with the corresponding quantity of both drugs being indicated in the supplied container.

 According to the invention, dosage forms intended for oral or parenteral administration can be considered as iron preparations. In this case, in principle, we can talk about such individual preparations, the composition of which as the active substance includes any physiologically acceptable salt of iron or some complex compound of iron, or such combination preparations, which, along with a physiologically acceptable preparation of iron, contain other active substances in its composition, such as vitamins, folic acid, thiamine chloride, riboflavin, pyridoxine, ascorbic acid, nicotinamide, calcium pantothenate, etc.

 Examples of physiologically acceptable salts of iron or iron complex compounds include iron (II) sulfate, iron (II) fumarate, iron (III) citrate, iron (II) gluconate, iron (II) succinate, iron (II) chloride, complex iron (II) -glycine sulfate, iron (II) aspartate, sodium-gluconate iron (III) complex, iron (III) -polymaltose hydroxide complex, or ferrisorbitocyte complex. Preferred iron preparations are primarily iron (III) complexes, and especially those with a molecular weight of from 30,000 to 100,000 Da. Most preferred is iron (III) sugar. In this regard, one can refer to the commercially available preparation "ferrum vitis" (Neopharma, Germany). Due to the low iron dosage of the invention, it is also possible to use labile iron complexes in the combination preparation, such as, for example, iron gluconate (molar mass of about 1000 Da; ferrlecite), although these labile complexes release relatively large amounts of ionized iron, which when administered intravenously fluid volumes could lead to toxicosis.

By the amounts of iron preparation indicated below, in principle, an equivalent amount of iron ions, iron (II) or iron (III) ions is respectively administered. Thanks to this rationing, the amount of any iron preparation can be calculated based on the known molecular weight of the latter. So, for example, in the case of iron (III) gluconate • 2Н ₂ О with the introduction of the iron preparation in the amount of 695 mg, this indicator in terms of iron is 80.5 mg. When, for example, 280 mg of anhydrous iron (II) succinate is introduced, the amount of iron is 95.2 mg, respectively.

 According to the invention, such active substances can be used as erythropoietin preparations which, in their physiological effect, are comparable to human EPO. Such EPO preparations include, in particular, recombinant human erythropoietin (rhEPO; cf. European applications EP 0205564 or EP 0411678) or corresponding modifications of such proteins. As modifications, for example, proteins of the above type with a molecular weight greater than or less than 34,000 Da (molecular weight of urinary EPO), as well as enzyme isoforms or proteins with different degrees of glycosylation, are acceptable. In particular, chemically modified proteins using polyethylene glycol (PEG) can also be used. In addition to the above, it is possible to use, in principle, also such proteins that are derivatives obtained by deletions, substitutions or extensions of individual or several amino acids from the amino acid sequence of natural EPO with an amino acid length of 166. Proteins of this type have basically the same physiological properties, like rhEPO. First of all, they exhibit biological properties that stimulate bone marrow cells to increase the production of reticulocytes and red blood cells and / or to intensify hemoglobin synthesis or iron absorption. Instead of such proteins, low molecular weight substances can also be used, referred to as pseudo-symmetric EPO and binding to the same biological receptor. Said pseudo-symmetric EPO can also be administered orally. The amount of such proteins or pseudosymmetric EPO required for administration is determined by comparing the biological activity of EPO and these active substances.

 For the treatment of patients with indications for hemodialysis, it is provided that the combined preparation according to the invention should contain, for example, from 250 to 15,000 units. (instead of the abbreviated designation "units" you can use the abbreviation "ME", adopted for the designation of International units) EPO-drug, especially from 500 to 10,000 units. Dosages of 250 units, 500 units, 1000 units, 2000 units, 5000 units, 7500 units are preferred. and 10000 units. on a single dose. The amount of iron ions is preferably up to 30 mg, especially 3-20 mg, preferably 5-20 mg, and particularly preferably about 10 mg. In the treatment of patients with anemia, the optimal dose is 500-10000 units, preferably about 1000-3000 units. The amount of iron ions in this case is preferably up to 30 mg, for example 3-15 mg, and especially about 5 mg.

 The concentrations of the EPO preparation and the iron complex according to the invention in their combination provide an optimal choice of treatment regimen and treatment parameters for patients with indications for hemodialysis and patients with anemia and intravenous iron administration to avoid acute phase reactions.

 Treatment with the combined preparation according to the invention is carried out from one to five times, preferably up to four times a week, and the total number of iron ions per patient should not exceed 100 mg per week. In the treatment of patients with indications for hemodialysis, it is preferable that the total amount of iron ions administered per week does not exceed 80 mg, especially 60 mg. In the treatment of anemia, it is preferable that the total amount of iron ions administered per week does not exceed 40 mg, especially 20 mg. A particular advantage of the combined preparation proposed in the invention, confirmed by clinical practice, is that in iron therapy prescribed for patients with indications for hemodialysis, it can be used both in the correction phase and in the maintenance phase, without causing toxicosis. To date, the introduction of various amounts of iron has been practiced, with lower doses of iron ions initially prescribed in the correction phase compared to the maintenance phase. Unexpectedly, it was found that when using the combined preparation according to the invention, it is no longer necessary to provide such a different dosage in both phases. The ratio of the amounts of the erythropoietin preparation and the iron preparation in the combination preparation according to the invention is so optimally selected that it is no longer necessary to observe differences in the doses administered in the maintenance phase and in the correction phase. Due to this, it is possible to increase the reliability and safety of treating patients, since the possibility of erroneous administration of optimal doses of the iron preparation in one of these phases is eliminated.

 When using the combined preparation, the EPO preparation and the iron preparation can be presented in a combination completely ready for use, i.e. as a single pharmaceutical composition containing both compounds. Such a composition may be presented, in particular, in the form of solutions for injection, infusion solutions or lyophilisates, packaged, for example, in ampoules. The advantage of such a dosage form is that during its preparation and storage, due to the presence of an iron complex, stabilization of the EPO preparation is also ensured. A ready-to-use combination of both active substances in the form of a lyophilisate also has the advantage that it is simple and reliable to use. The lyophilisate is dissolved in an ampoule using conventional pharmaceuticals for the preparation of injection solutions and is administered intravenously.

 Another possibility is for the EPO preparation and the iron complex to be released as separate pharmaceutical compositions. As a rule, they can be delivered in a common package, but each in a separate container, the first of which contains an erythropoietin preparation in a ready-to-use form (lyophilisate, injection or infusion solution), and the other contains an iron preparation also in a ready-to-use form . In general packages, an erythropoietin preparation or iron preparation can also be packaged in several single doses, and thus, for example, in one such general package there may be a certain number of single doses intended for administration over a certain period of time (for example, within one week) . The advantage of such a free choice of options for the formation of common packages is that each patient can be provided with a specific, individually assigned amount of an EPO drug and iron preparation. These combined preparations give, in addition, the advantage that the reliability of successful therapy is increased, since the optimum ratio of the quantities of the individual components of these drugs is provided and since thereby the possibility of violation of this ratio is practically eliminated if we use commercially available individual drugs offered in various dosages. Another important factor should be taken into account: in different countries, due to national needs, drugs in various dosages are often offered on the market, which with such varying ratios of the quantities of individual active substances (EPO drug and iron complex) also increases the risk of not observing the required ratios. Further, thanks to the combination preparations according to the invention, the risk of accidental overdose of iron is minimized, which may occur with the joint administration of traditional iron preparations produced in separate packages and an erythropoietin preparation. The combined preparations according to the invention provide reliable therapy and do not create difficulties in their use by medical personnel, as well as the patient conducting a course of self-medication. In this case, it is possible, for example, to deliver one active substance in the form of a solution for injection, and another active substance (iron complex) in a form ready for oral administration.

 In the event that the EPO preparation is released in the form of a lyophilizate, it should be provided that the corresponding amount of this EPO preparation, packaged in glass ampoules or replaceable cartridges, must be in the combined package. The iron preparation can be presented in solid form (tablet, powder, granules, lyophilisate) or in liquid form in a separate container. Further, in a combination package, preferably a reconstitution solution is provided for dissolving either the lyophilisate of the active substance alone or in conjunction with a solid iron preparation. If the iron preparation is presented as a ready-to-use solution, then in the case of the combined administration of EPO and the iron preparation, this solution can be mixed with the EPO solution. In principle, an iron preparation can also be produced in the form of a concentrate for its subsequent addition to traditional infusion solutions, which allows for a slower administration over several hours. In this case, the solution containing the iron complex is added in a small volume (about 0.5-10 ml) to about 500-1000 ml of the ready-to-use injection solution.

 According to the invention, combined preparations can also be produced in such general packages, which contain an optimally selected amount of EPO preparation and iron preparation for weekly administration. It is preferable to introduce an EPO preparation in an amount of 5000-50000 units. in Week. This total dose can be divided into several single daily doses (i.e. for administration 7 times a week) or 1-6 single doses, providing them for administration within one week. The amount of iron preparation intended for weekly administration, if necessary, can be used completely as a total weekly dose or divided into several single doses for the purpose of their administration for administration several times a week together with the erythropoietin preparation.

 Another possibility according to the invention is that in each case, the individual finished dosage forms of the erythropoietin preparation or iron preparation can be presented as independent from each other drugs, while the individual preparations are configured in such a way that they contain that amount of substances , which is required for the implementation of the proposed invention a combination of EPO-drug and iron complex.

 As a rule, each package with medicines is accompanied by a package leaflet, which is provided in such cases, which contains the corresponding instruction on the combined use of the EPO preparation and the iron preparation in the required amount. Such an indication can also be applied in the form of an overprint on either the main (secondary) packaging or the primary packaging (ampoule, blister pack, etc.). So, for example, in the case of an EPO-containing drug with 250-20000 units. EPO indicates that this drug should be administered primarily in conjunction with an iron preparation containing 1-40 mg, preferably 5-30 mg of iron, and in the case of iron preparations, on the contrary, the need for combined administration with erythropoietin in the amount of 250-20000 units is indicated . last one.

 An EPO preparation can be produced in the form of corresponding multidose preparations in which this EPO preparation is contained in amounts several times higher than individual doses. Preparations in this form are primarily intended for hospitals, where a large number of patients are exposed to therapy daily. Such multidose preparations contain EPO preparations in doses up to 500,000 units, primarily up to 100,000 units. or 50,000 units. The advantage of these multidose preparations is that the medical personnel have the opportunity to select the EPO preparation from them in any desired doses, for example, by selecting from a solution ready for injection a part of its volume corresponding to a certain dose. This is especially important in the treatment of patients for whom the active substance is required in various dosages, or in the treatment of children for whom a lower dosage of EPO is required. Freshly prepared, preferably at the beginning of the day, an injection solution containing, for example, 100,000 units. EPO-medication can be "serviced" accordingly for all patients who are prescribed EPO-therapy on this day, which eliminates the need to specially prepare an injection solution for each patient each time. This approach can contribute to a significant saving of time and, accordingly, to remove part of the burden on medical staff. It is preferable to select EPO preparation from multidose preparations in separate doses of 250 units, 500 units, 1000 units. and 10000 units.

 Multidose preparations can be produced in the form of solutions packaged in replaceable cartridges. These cans can be used in the so-called syringe pens, which allows the patient to select the dose he needs and administer it to himself. So, for example, these cartridges can contain an EPO preparation in the amount of 10,000 or 20,000 units, while by adjusting the volume appropriately selected from the can, an exact dosage of 250 units, 500 units, 1000 units can be ensured. or 2000 units

 Ready-to-use pharmaceutical forms are made according to methods known in the galvanic field using conventional excipients used in pharmaceuticals.

When conducting combination therapy with the combination preparation proposed in the invention, the maximum weekly dosage can be calculated very simply by determining the diagnostic parameters of the status of iron and, first of all, indicators for iron, transferrin, transferrin saturation and ferritin. It was found that the following indicators are optimal for the patient in the correction and maintenance phases: ferritin concentration: 100-300 μg / l (corresponds to the accumulation of iron (III) in the amount of 800-1200 mg); transferrin saturation: 20-40%. Preferably, the concentration of ferritin is at least 125 μg / L, especially at least 150 μg / L and a maximum of 270 μg / L, especially a maximum of 250 μg / L. The concentration of iron in this case should preferably be from 10 to 20 μm / l (corresponding to approximately 56-112 μg / dl), and the concentration of transferrin from 30 to 60 μm / l (corresponding to approximately 240-480 mg / dl). The degree of saturation with transferrin is determined by the ratio of the concentration of iron in serum / plasma to the concentration of transferrin in serum / plasma (multiplied by a correction factor of 1.41). This refers to a dimensionless quantity independent of the hydration status of the patient. Transferrin saturation is calculated using the following formula:
transferrin saturation (%) = (iron [μg / dl] • 100) / (transferrin [mg / dl] • 1.41).

The optimum for the patient is considered to be achieved if the ratio between the degree of saturation with transferrin (in%) and the concentration of ferritin (in μg / l) is 5-40%. This parameter is called transferrin / ferritin saturation (TFP saturation). It is calculated by the following formula:
TFP saturation = (transferrin saturation in%) • 100 / ferritin 1 μg / l]).

 The preferred value for this parameter is 10-40, especially 15-20 [% • l / μg].

 Using these parameters, for example, after the administration of 1-6 ampoules per week, preferably 3, 4 or 5 ampoules (one ampoule contains from 500 to 7500 units of rhEPO and 1-20 mg of the iron complex), a diagnostic condition of the patient is monitored, determining by optimum achieved results.

In order to avoid unwanted side effects, it is recommended to measure such an acute phase parameter as CRP (5 mg / L ± 100%) [CRP = C-active protein], which today is considered the best protein marker (indicator) of inflammation. In addition to this, you can also determine indicators regarding the liver, namely: GPT (glutamate pyruvate transaminase), GOT (glutamate oxalacetate transaminase) and γ-HT (gamma glutamyl transferase), which should be within the following limits (definition at 37 ^o C): GPT: <50 units / l; GOT: <50 units / l; γ-GT: <40 units / l. The first place among them in the diagnosis of the liver currently belongs to the HPT. Along with those indicated, if necessary, you can use control hematological parameters, such as hematocrit (the proportion of red blood cells in the total volume) or an increase in the number of hypochromic red blood cells. If higher parameters are established on the basis of control parameters, then the weekly dose of iron should be reduced and rhEPO should be added in this case. If the control parameters, especially the degree of saturation with transferrin, turn out to be lower, the weekly dose of iron should be increased.

 According to the invention, it was unexpectedly further found that, when an individual, optimal therapeutic dose of EPO and iron ions for the treatment of anemia is given to a patient, one can proceed by determining the concentration of soluble TfR (transferrin receptor). This therapeutic dose of EPO and iron (III) can be considered optimal if the concentration of soluble TfR no longer increases. In order to ensure the availability of a sufficient amount of iron, it is advisable to increase the alternately administered intravenous dose of iron and the dose of EPO until the desired level is reached. This corresponds to a TfR concentration of 1500-2000 μg / L.

 When conducting combination therapy using the combination preparation according to the invention for the treatment of anemia, it is very simple to calculate the maximum weekly dosage by determining the following diagnostic parameters: transferrin receptor (TfR), ferritin and the ratio of TfR to ferritin. It was found that the following indicators are optimal for the patient in the correction phase and in the maintenance phase: ferritin: 100-300 μg / l (corresponds to the accumulation of iron (III) in an amount of 400-1200 mg); TfR:> 15. Preferably, the concentration of TfR was 1500-2500 μg / L, and the ratio between the concentration of TfR (in μg / L) and ferritin (in μg / L) would be primarily from 15 to 35, preferably more than 20.

 Using these parameters, for example, after the administration of 1-6 ampoules per week, preferably 3, 4 or 5 ampoules (one ampoule contains, for example, 3000 units of rhEPO and 5 mg of iron complex), a diagnostic condition of the patient is monitored to determine by the optimum reached. In this case, first of all, it is not patients with indications for hemodialysis that are meant, but patients with anemia caused by other causes, who are prescribed EPO therapy and / or iron preparations.

In order to avoid unwanted side effects, it is recommended to measure an acute phase parameter such as CRP (2-10 mg / L) [CRP means C-reactive protein]. In addition to this, it is also possible to determine the indicator regarding the liver, namely HPT (glutamate pyruvate transaminase), which should be less than 50 units / l at 37 ^o C (<30 units / l at 25 ^o C). Along with those indicated, if necessary, you can use control hematological parameters, such as hematocrit (the proportion of red blood cells in the total volume) or an increase in the number of hypochromic red blood cells. The content of reticulocytes in this case can increase to 15 / 1000-30 / 1000.

 The concentration of hemoglobin is normally 12-18 g / dl. If there is an increase in soluble TfR, the weekly dose of iron should be increased to 35 mg. If soluble TfR values are reduced, the weekly dose of EPO should be increased.

 The status of iron is determined by analyzing samples of fluids (blood, serum, urine, etc.) contained in the body of the corresponding patient. In order to determine the status of iron, the concentration of iron, transferrin, ferritin, transferrin receptor and saturation with transferrin / ferritin are first of all revealed. In the case of patients with indications for hemodialysis, the iron, transferrin, ferritin and transferrin saturation rates are preferably determined using conventional analytical methods for this purpose. It is important to first identify saturation with transferrin / ferritin. In patients with non-hemodialysis anemia, the concentration of ferritin and the concentration of transferrin receptor are determined primarily. It is important to first identify the relationship between the transferrin receptor and ferritin (transferrin receptor: an indicator of saturation with ferritin).

 The optimal combination preparation according to the invention, intended for the treatment of patients with anemia, contains 500-10000 units, especially 2000-4000 units. An EPO preparation and 3-10 mg, preferably 5 mg of iron ions, preferably an iron (III) complex, wherein the EPO preparation and an iron (III) complex can be presented in separate dosage forms or in a single such form.

 The dosage forms of the invention also make it possible to prescribe iron preparations 1-3 days before the administration of EPO preparations so as to ensure that iron stores are filled before the start of EPO therapy.

 The subject of the invention is also the use of an EPO preparation in an amount of 1000-10000 units. and 5-20 mg of iron ions of a physiologically acceptable iron preparation for the manufacture of a combination preparation intended for the treatment of patients with indications for hemodialysis.

 In clinical chemistry, for the study of metabolism involving iron, the concentration of iron in the blood and the ability to bind iron are determined. In all cases, it is necessary to carry out both tests, since the ratio of the results obtained among themselves is an important factor. Typically, serum iron levels in men are normally between 75 and 150 mg / dl, and in women between 60 and 140 mg / dl. The ability to bind iron is generally characterized by an indicator of 250-450 mg / dl. Serum iron levels do not remain constant throughout the day. With a lack of iron and with anemia associated with chronic diseases, it decreases, while with hemolysis and with syndromes associated with an excess of iron (for example, with hemochromatosis or hemosiderosis), it increases. Patients who are prescribed iron-containing medications for oral administration may have normal levels of serum iron, although they essentially have iron deficiency. The overall rate of iron binding (= transferrin x 2) increases with iron deficiency, and with anemia during chronic diseases it decreases.

 In addition, serum ferritin levels are determined. Ferritin is an iron-accumulating glycoprotein that is a source of tissue-specific isoferritins and the presence of which in serum can be detected immunologically, for example, using radioimmunoassay (RIA) or using turbidimetry methods. The ferritin index is a measure of the accumulation of iron in tissue. According to data obtained in most laboratories, this indicator is usually in the range from 30 to 300 ng / ml, and the geometric mean in men is 88 and in women is 49. Serum ferritin is closely related to the total iron stores in the body. Therefore, a decrease in serum ferritin level is observed only with iron deficiency, while an increased level occurs with an excess of iron. An increase in serum ferritin is also observed with liver damage or in connection with some forms of neoplasia, in which ferritin can also bind to proteins in the acute phase. With equal success, serum transferrin receptor parameters can be detected using an enzyme immunosorbent assay (ELISA) for this purpose. In this case, monoclonal antibodies to the soluble receptor are used. The reference range may be from 0.5 to 3.0 mg / L. An increase in this level occurs with some iron deficiency in storage. To characterize iron stores, the concentration of specific ferritins in red blood cells can be determined especially in cases where serum ferritin is not suitable for use due to tissue damage or acute phase reactions.

 Further, for metabolism studies involving iron, the level of ferritin in erythrocytes is also determined. In heparinized blood, red blood cells are separated by centrifugation from white blood cells and platelets (also containing ferritin). Then red blood cells are lysed and the amount of accumulated ferritin is determined immunologically. Ferritin contained in red blood cells characterizes the status of iron stores over the past 3 months (i.e., the life span of an erythrocyte). Normal, as a rule, are considered values in the range from 5 to 48 attograms (ag) per red blood cell. Values <5 are observed with anemia associated with a lack of iron, and increased values (often> 100) with an excess of iron (in particular, with hemochromatosis). A similar pattern is observed in the determination of zinc protoporphyrin.

Clinical researches
Patients are prescribed a weekly dose of iron (III) complex in the amount of 5-30 mg and a weekly dose of EPO-drug in a total of 7000-15000 units. Both drugs are administered respectively on the same day. Determining diagnostic indicators for transferrin, transferrin saturation, CRP (C-active protein), GOT / GPT and γ-GT, the status of iron in patients is revealed. If the indicator for ferritin varies in the normal range <500 μg / l, we can assume that the optimal results are achieved.

Claims (5)

 1. A combined drug containing low doses of erythropoietin in an amount of less than 2000 units. EPO and physiologically acceptable low doses of iron preparations containing 1-30 mg of an equivalent amount of iron (III) ions, intended for the treatment of patients with indications for hemodialysis or for the treatment of anemia until a normal ferritin level of less than 500 μg / l is achieved, while the combined preparation is used both in the correction phase and in the phase of supporting iron therapy, without quantitative variations, and the weekly dose is 5-30 mg of iron and 7000-15000 units. EPO.  2. The combined preparation according to claim 1, characterized in that they use an iron preparation containing an equivalent amount of iron ions equal to 5-20 mg.  3. The combined preparation according to claim 1 or 2, characterized in that an erythropoietin preparation containing 250-2000 units is used.  4. The combined preparation according to any one of claims 1 to 3, characterized in that a complex with a molecular weight of from 30,000 to 100,000 Da, preferably iron (III) sugar, is used as the iron preparation.  5. The combined preparation according to any one of claims 1 to 3, characterized in that iron (III) gluconate is used as the iron preparation.