Pharmaceutical combination preparations containing erythropoietin and iron supplements

 

(57) Abstract:

The subject of the invention is the use of (2000-7000) units of recombinant human erythropoietin and (1-20) mg equivalent amount of iron ions physiologically acceptable preparation of iron to obtain a combined pharmaceutical preparation. Pharmaceutical drug used to treat patients with hemodialysis or for the treatment of anemia in a corrective phase and the support phase during treatment with iron. Erythropoietin and iron drug can be in the same capacity as a single form of introduction or in separate containers in the form of separate forms of administration. Combined product allows optimal adaptation and treatment of patients with hemodialysis or anemia and treatment with intravenous iron does not result in acute phase reactions, provides safe treatment and easy handling of drugs for treating personnel or ongoing patient self-medication. 4 C. and 10 C.p. f-crystals.

The present invention relates to a pharmaceutical combination preparations containing erythropoietin and iron supplements. These drugs are used in sh is rmaceutical combined preparation including 2000-7000 units of recombinant human erythropoietin, then (rhEPO), and 1-20 mg of an equivalent amount of iron ions physiologically acceptable preparation of iron, with rhEPO and iron drug can be in separate forms, the introduction or in a form of introduction.

Know the treatment of anemia, in particular, due to transfusion anemia patients with hemodialysis, using recombinant erythropoietin. Anaemia in chronic diseases is a worldwide second most common form of anemia.

The main sign of anemia, which arise due to reduced erythropoiesis in the bone marrow or violations in the recycling of iron is reduced reproducibility of red blood cells. The daily decrease in the reproducibility of erythrocytes in 1% anemia clinically install only after 1-3 weeks. Daily requirement of iron for normal erythropoiesis is 25 mg. Of them only around 1 mg is out of power, the main requirement is met, usually at the expense of recycling is contained in the hemoglobin iron after the destruction of the "old" erythrocytes. In the case of chronic intake of iron from reticular cells So much talk about "internal deficiency", when the manifestation of the normal compensatory mechanisms is incomplete. Typical are reticulocytopenia, as well as the lack of the necessary to compensate for the anemia / erythropoiesis. Reduced secretion of erythropoietin or reduced activity of erythropoietin may be additional pathogenetic factor. Characteristic changes in iron metabolism, for example, is the lack of kompenserade increasing education transferrin. The main violation, therefore, is the absence of receipt of iron from storage of iron in the reticuloendothelial cells) in the plasma (thus, also in Eritrean), which does not include normal compensatory mechanisms. Receiving recombinant erythropoietin therapy is needed to cause a significant increase in the number of erythrocytes.

In clinical chemistry for diagnosis of anemia and disorders of iron metabolism determine the concentration of serum ferritin. If, in addition to anemia of chronic disease appears stable iron deficiency, ferritin concentration is not increased (most often it remains below 90-95 ng/ml). Simultaneous clinical symptoms infamie, accompanied by chronic disease. Because serum ferritin in these diseases may respond also in the sense of a protein of the acute phase, for diagnosis can be better to use ferritin erythrocytes.

The total content of iron in the body is in men of about 3.5 g, women of 2.5, the Iron is in an active exchange and accumulation of the body. In the active Fund in humans is in the middle of 2100 mg hemoglobin, 200 mg myoglobin, 150 mg tissue enzymes (heme and non-heme) and 3 mg of iron is transported in the body. Iron accumulates in the intracellular tissue in the form of ferritin (700 mg) in the form of hemosiderin (300 mg).

The ability to have iron can be pathophysiologically broken, so that the body is the least absorption of iron. About 10 mg on a daily basis that come with meals, adult Razorbill only about 1 mg of iron deficiency, the iron resorption increases, however, rarely above 5 or 6 mg, if not received additional iron. The exact mechanism of iron resorption is unclear. Regulation decisive way through the mucosal cells of the small intestine. The decisive signal for the mucous membrane, apparently, availibe with the amount of iron.

From the intestinal mucosal cells iron goes into transferrin. This transport protein iron has two iron-binding sites. It is synthesized in the liver. This is the mechanism by which iron can get the cells (e.g., the mucosa of the small intestine, macrophages) and give specific membrane receptors erythroblasts, placental cells or liver cells. The complex of transferrin-iron-receptor by endocytosis into the precursor cells of erythrocytes, where iron is transferred into the mitochondria. There of iron and protoporphyrin heme is formed.

Unnecessary for erythropoiesis iron by transferrin moves in two pools-drive. The most important drive is ferritin. When it comes to heterogeneous family of proteins that include iron nuclei. Ferritin soluble and represents the cumulative active form in the liver (hepatocytes), bone marrow, spleen (macrophages), erythrocytes and serum (approximately 100 ng/ml). A pool of tissue ferritin is very labile and quickly available when you need iron. Circulating serum ferritin is formed from the reticuloendothelial system and its Curculionoidea iron).

In patients with hemodialysis discovered that the need for iron treated with rhEPO patients are considerable. Typically, these patients additionally conduct therapy with iron, as EPO may exert its optimal action only when in the body as possible filled in the appropriate drive of iron. In order to fill the drives of iron, still used to give high doses of iron supplements. However, too high doses of iron can lead to undesirable side effects in patients. In particular physiologically unsafe is intravenous iron preparations because of the extreme toxicity of iron ions. From the use of certain preparations of iron in patients with known allergic reaction, such as asthmatics, as a rule, even refuse. Assessment of the status of the drive is full of iron is possible by determining the protein ferritin and by defining transferring saturation (M. Wick, W. Pingerra, P. Lehmann "Eisenstoffwechsel. Diagnose und Therapie der Anamien", S. 5-14, 38-55, 65-80, 94-98; additional third edition, September 1996, ed. Springer, Vienna, new York), and transferrine saturation characterizes the flux is wow iron.

Drives iron are considered "completed" when the serum ferritin is the value of over 150 µg/l and transferrine saturation is the value more than 20%. P. Grutzmacher and others in Clinical Nephrology, vol. 38, N 1, 92-97 (1992) reported that under these conditions you can count on maximum exposure to EPO therapy.

Currently, in the case of treatment of iron-EPO treated patients with dialysis speak of "corrective phase" and the "maintenance phase". In the corrective phase of the injected high doses of iron supplements in order as quickly as possible to fill the drive iron. Suitable iron supplements then it is advisable to enter in the form of intravenous injections of substances. In the support phase drives iron then is maintained filled using lower doses of iron. Introduction of suitable iron preparations in this phase is no longer carried out as a rapid bolus injection, and enter them in the form of a conventional intravenous fluids or oral.

The need for iron treated with rhEPO patients with hemodialysis can be quite significant in a corrective phase and also during the maintenance phase. For the synthesis of 1 g/DL of hemoglobin in corregermany be imposed exogenously. During the maintenance phase also increases the need for iron, as in patients with hemodialysis in each treatment come to less wastage of blood. Through the period of time a year assess the loss of iron is approximately 1000 mg (3 mg / day). This loss can be recovered only by the exogenous for a long time. For this purpose, in principle, oral and intravenous forms of application.

Because oral resorce iron is only about 1 mg/day, under extreme load (in oral introduction about 300 mg of Fe (III)/day) less than 3 mg/day, prefer increasingly intravenous much larger amounts of iron. On the German pharmaceutical market at present, there are two used intravenous iron drug. When it comes to drugs "Ferrlecit" and "Ferrum Vitis". Ferrlecit is a complex of iron(III)-gluconate, while "Ferrum Vitis" is a complex of iron(III)-hydroxide-saharat.

A variety of problems carried out with the use of high doses of long-term oral treatment with iron, however, can be avoided simply by intravenous injection of iron-(III) during the hemodialysis treatment, as is agrusti on the patient. In recent years, this method finds the increasing spread as proceed from the fact that in the case of drugs "Ferrlecit" and "Ferrum Vitis" are available with relatively minor side effect of the form of application. Meanwhile, however, in connection with the treatment ferrlecit indicate side effects of autologous blood transfusion and therefore clearly narrows the use of parenteral therapy ferrlecit. Pay attention to the possible reactions of the blood circulation up to the collapse, and the possibility of anaphylactic reactions. Next, set in the highest degree acceptable daily dose of two ampoules of 5 ml, respectively, 125 mg of iron.

Intravenous administration of two preparations of iron, therefore, is not trivial, since the introduction of both drugs should be considered with side effects, especially when you need to enter relatively quickly by injection of much larger quantities. In addition, intravenous iron preparations can cause problems until the reactions of the acute phase, if a single dose is too high, therefore not optimally matched relative to the dose of EPO.

Obviously, in DNAME. Increases the risk of myocardial infarction and also significantly increases the risk of development of cirrhosis due to iron. In the framework of the treatment of patients with dialysis significant therapeutic benefits of an adequate intake of iron in the body, as well as suitable method for determining iron deficiency in the body, because of insufficient availability of iron is one of the main reasons for insufficient exposure to EPO, respectively, for resistance to EPO.

On the basis of too high dosage of iron-containing preparations may also be of iron poisoning. Elemental iron exerts toxic effects on the gastrointestinal, cardiovascular and Central nervous system. Oral lethal dose of elemental iron ranges from 200 to 250 mg/kg is Often used tablets containing iron are ferrosulfate (containing about 20% elemental iron), perfumers (contains about 30% elemental iron) or feropont (contains about 10% elemental iron).

There are four typical stages of iron poisoning: stage I (within the first 6 hours after poisoning): can receive vomiting, diarrhea, increased the Ki can lead to hemorrhagic gastritis. At high levels of iron in the serum may appear dyspnea, tachycardia, hypotension, shock, coma and metabolic acidosis. Stage II (within the first 10-14 h after poisoning): during the latent period, which can last up to 24 hours, come to the supposed improvement. Stage III (after 12-48 h after poisoning): come the shock, hypoperfusion, and hypoglycemia. The level of iron in serum may be normal. Can cause liver damage with high content of glutamate-pyruvate-transaminase (GPT), fever, leukocytosis, blood clotting abnormalities, T-inversion in the electrocardiogram, violations orientation, anxiety, apathy, prone to seizures, coma, shock, acidosis, and death. Stage IV (after 2-5 weeks): in the foreground can be complications from the obstruction of the pylorus of the stomach, antrum or other intestinal obstruction, cirrhosis of the liver or Central nervous system.

The objective of the invention was to obtain a combined preparation of recombinant human erythropoietin and iron drug that contains optimally selected for therapy of disorders of iron metabolism and the amount of EPO and iron ions. Especially with these combined with promodo rhEPO, in addition, there should be an optimal action of EPO, and should avoid EPO resistance.

Proposed according to the invention combined product covers 2000-7000 unit rhEPO and 1-20 mg of an equivalent amount of iron ions physiologically acceptable preparation of iron, in particular Fe(II)- or Fe(III)-complex, with rhEPO and the preparation of iron are in the form of combination products.

In the sense of the present invention, the phrase "combination products" need to understand not only the packaging of medicines, in which the EPO and the preparation of iron are put up near each other in a ready-for-sale packaging unit (so-called combined packaging), but also such packaging of medicines that contain or suitable number of EPO, or a suitable quantity of the preparation of iron in the form of a separate drug, and these certain drugs in regard to the number of ingredients packaged in such a way that according to the invention can be used for combined injection, respectively, with another drug. In these cases, the pharmaceutical manufacturers or importers of drugs, as a rule, in many of the instructions or information about the combined intake of the drugs. A combination of drugs preferably may be in a single form application in which the number of EPO and iron drug are near each other in the same container.

According to the invention, as iron preparations used for oral or parenteral dosage forms. While it could be in principle about individual drugs that are as active substances contain physiologically acceptable salt of iron or complex compound of iron, or of the combined drugs, which, together with a physiologically acceptable preparation of iron contain other active ingredients, such as vitamins, folic acid, teamengland, Riboflavin, pyridoxine, ascorbic acid, nicotinamide, calcium Pantothenate, etc.

Physiologically acceptable salts of iron or complex iron compounds are, for example, sulfate iron(II) fumarate, iron(III) citrate, iron(III) gluconate, iron(II) succinate of iron(II) chloride iron(II), iron(II)-pininsula-complex, iron aspartate, sodium iron(III) gluconate complex iron(III)-hydroxide-poly maltose complex or periorbit-citrate complex. Preferred drugs is Oh from 30000 to 100000 Daltons (Da). Especially preferred saharat iron-(III). Here you can use a commercially available product "Ferrum Vitis" (firm Neoforma, Germany). Thanks proposed according to the invention, low-dose iron in the combined preparation can also be used labile complexes of iron, as iron gluconate (molecular weight of about 1000 Da; ferrlecit), although these labile complexes of iron release relatively large amounts of ionized iron, which when injecting large quantities can lead to toxicity.

Further, when referring to the quantity of the preparation of iron, in principle, understand the input equivalent amount of iron ions Fe(II)- or Fe(III) ions. Thanks to this standardization is possible to calculate the quantity of any drug of iron based on its known molecular weight. If gluconate iron-(III), x 2H2O, for example, the amount of iron is 80.5 mg, if injected is equal to 695 mg quantity of the preparation of iron. With the introduction of, for example, 280 mg of anhydrous succinate of iron-(II) the amount of iron is 95,2 mg.

Instead of rhEPO protein (see European patent 0205564; European patent 0411678) can also be used for the modification of protein with enta or proteins with different degrees of glycosylation. Next, in principle it is also possible to use such proteins, which are obtained by deletions, substitutions or extensions of individual or several amino acids of the amino acid sequence of natural EPO with a length of 166 amino acids. Such proteins have essentially comparable physiological properties as rhEPO. In particular, such proteins have biological properties, namely, that induce bone marrow cells to increase production of reticulocytes and red blood cells and/or to increase hemoglobin synthesis or iron absorption. Instead of such proteins can also be used low molecular weight substances, which are referred to as EPO-mimetics and which are associated with the same biological receptor. These mimetics can be entered preferably oral. Enter the amount of such protein or mimetics determined by comparison of the biological activities between EPO and these active substances.

For the treatment of patients with hemodialysis proposed according to the invention combined preparation contains, in particular from 3000 to 7000 units of rhEPO, especially from 4000 to 6000 units of rhEPO and preferably about 5000 rhEPO. The number of ions surveillance of patients with anemia optimal dose of from 2000 to 4000 units rhEPO, preferably about 3000 units of the Number of iron ions in this case is 3-15 mg, in particular about 5 mg.

Proposed according to the invention the concentration of rhEPO and iron complex in their combinations allow optimal adaptation and treatment of patients with hemodialysis or anemia and treatment with intravenous iron do not lead to acute phase reactions.

Treatment with combined drug exercise from once to five times, preferably up to four times a week, and the total number of patient should not exceed 60 mg of iron ions per week in the case of treatment of patients with hemodialysis. In the treatment of anemia total number should not exceed 20 mg of iron ions per week. Of particular advantage according to the invention combined drug in clinical practice is that it can be used in a corrective phase and in the maintenance treatment phase iron in patients with hemodialysis, without causing toxicity. Still had different amounts of iron, and in a corrective phase was injected first with lower concentrations of iron ions in comparison with the supporting phase. Unexpectedly when skin is camping. The number of EPO and iron drug select the optimal one with respect to each other so that you do not need to distinguish between the supporting dose and corrective dose. This ensures increased safety in the treatment of patients with hemodialysis or anemia, as there is no longer a possibility of confusion regarding the optimal dose of iron.

With combined drugs rhEPO and iron complex can be entered in the so-called fixed combination, i.e. a single pharmaceutical preparative form, which contains both compounds. This can be, for example, solution for injection, respectively, the solution for infusion or lyophilisate, which, for example, packaged in capsules. This form of application has the advantage that the EPO during preparation and storage of this form of application is stabilized by a complex of iron. In the case of freeze-dried after its dissolution EPO is activated by iron complex. A fixed combination of both active substances in the form of a lyophilisate has the further advantage that in a simple and safe treatment of this form. The lyophilized vials are dissolved by adding the complex of iron in the form of separate pharmaceutical preparative forms. Typically, this is carried out in the form of a single unit which includes two tanks, the first is a suitable form of application for EPO (lyophilisate, solution for injection or infusion), and the second is a suitable form of application for the preparation of iron. This free combination, which can reside in a single packaging unit (pack of medicines), has the advantage that each of the exposed patients can individually be assigned directly to the required number of EPO and iron drug. Such a combination of drugs, in addition, have the advantage of greater security for the success of the treatment, as in each case set optimally chosen number of preparations of iron, and that in large part, to avoid confusion with the usual commercially available individual drugs that are offered in different strengths. Also keep in mind that in different countries often are commercially available medicines with different dosages on the basis of national requirements and thus there is an increased danger of confusion with changing kolichestve.podrobnee drugs further minimize the danger of the fallacy of too high dose of iron, which can be entered when using a normal iron preparations from separate packs of medicines along with a dose of EPO. Thanks proposed according to the invention combination products provides safe treatment and easy handling of drugs for treating personnel or ongoing patient self-medication. In this case, for example, you can also use the same active substance in the form of solution for injection, and the other active substance (iron complex) in the form of a dosage form for oral administration.

In that case, when the active substance EPO is in the form of a lyophilisate, packaging, pharmaceuticals (combination packaging) contain appropriate amount of EPO in glass ampoules or capsules. The preparation of iron may be in solid form (tablet, powder, granules, freeze-dried, and so on) or in liquid form in a separate container. Next combo pack contains preferably reconstitution solution, to dissolve or one freeze-dried active substance, or also together with the solid preparation of iron. If the preparation of iron available in the form of ready KJV is their EPO and iron drug. In principle, the preparation of iron may also be in the form of a concentrate for addition to the usual solutions for infusion, allowing you to exercise longer introduction for several hours. In this case, add a small volume containing the iron complex solution (approximately 0.5-10 ml) to ready-to-use solution for injection volume of approximately 500-1000 ml

Another possibility according to the present invention is that respectively separate preparations of EPO and iron supplements are in the form of independent medicines, and certain drugs are packaged in such a way that they contain the required number of individual substances for the proposed according to the invention the combination of EPO and iron complex. Typically, the packaging of medicines include packing sheets containing the indication for combination with EPO dose, respectively, with iron preparations in the required quantity. The indication may also contain, in the form printed on the packaging of the medicinal product (secondary packing means) or on the primary packaging means (ampoule, band exhaust, because this drug should be entered in features with drug-based iron complex, containing 1-20 mg of iron. In the case of iron preparations, on the contrary, is indicated on the combined reception 2000-7000 units of EPO.

Dosage forms get the regular, known in Galanova production methods using conventional pharmaceutical auxiliary substances.

In the implementation of combination therapy using the proposed according to the invention combined drug can be a very simple way to apply maximum weekly dosage that determine the diagnostic parameters for iron status, in particular the parameters: iron, transferrin, transferrine saturation and ferritin. Discovered that the patient is optimally adapted in corrective and support phase, if the content of ferritin is 100-300 µg/l (corresponds to the drive of iron(III) 800-1200 mg) and transferrine saturation is 20-40%. Preferably the concentration of ferritin is at least 125 μg/l, in particular at least 150 µg/l and a maximum of up to 270 µg/l, in particular most up to 250 ág/l iron Concentration is preferably 10-20 µmol/l (corresponding to about 56-112 µg/DL), and the concentration of transferrin is 30-60 çmol/l (scooterette/plasma concentration of transferrin in serum/plasma (multiplied by a correction factor of 1.41). It is a dimensionless number that regardless of hydration status of the patient. Transferrine saturation calculated by the formula: transferrine saturation (%) = (iron [mg/DL] 100) / (transferrin [mg/DL] 1,41).

Optimal adaptation of the patient's reach when the ratio transferring saturation (%) ferritin concentration (µg/l) is in the range of 5-40%. This parameter is defined as transferrin/Terranova saturation (TfF-saturation). It is calculated by the formula: TfF-saturation = (transferrine saturation in %) 100 / (ferritin [µg/l]. Preferably the value of this parameter lies in the region of 10-40, in particular 15-25 [% PI/ICG].

With this option, for example, with the introduction 1-6 ampoules, preferably up to 4 or 5 vials per week (one ampoule contains 2000-7000 unit rhEPO and 1-20 mg of iron complex) diagnostically control optimal adaptation of the patient.

In order reliably to avoid unwanted side effects, determine the setting of acute phase CRP (5 mg/l 100%) (CRP = C-reactive protein), and currently, CRP is considered the best protein marker of the inflammatory response. Optionally, you can define the parameters of the liver GPT (gluta who must be in the following areas (determination at a temperature of 37oC): GPT: <50 units/l; GOT: <50 units/l; -GT:<40 units /l Parameter GPT at the same time is a priority in the diagnosis of liver.

Further, if necessary, you can use the Hematology control parameters, as the hematocrit (percentage of red blood cells in the total blood volume) or increasing the number of hypochromic erythrocytes. If the control parameters show higher growth, lower weekly dose of iron, then you have to enter rhEPO. If the control parameters, first of all transferrine saturation, show lower values, it is necessary to increase weekly dose of iron.

Further, according to the present invention unexpectedly found that it is possible to carry out the purpose for the individual patient, the optimal therapeutic dose of EPO and iron ions for the treatment of anemia by determining the soluble TfR (transferring receptor). The optimal therapeutic dose of EPO and iron(III) is reached when the concentration of soluble TfR is no longer increases. To establish that there is sufficient mobilized iron, alternately raise intravenous dose of iron and EPO dose, until it reaches the plateau. This corresponds to a concentration of 1,500-2,000 µg/binyavanga drug to treat anemia can be a very simple way to apply maximum weekly dosage of topics to determine the diagnostic parameters: atransferrinemia receptor (TfR), ferritin and the ratio of TfR to ferritin. Discovered that the patient is optimally adapted in corrective and support phase, when the content of ferritin is 100-300 µg/l (corresponds to accumulation of iron(III) 400-1200 mg) and the ratio of TfR/ferritin is the value of > 15. The TfR concentration is preferably 1500-2500 μg/L. the Ratio of TfR concentrations (in µg/l) ferritin (µg/l) in particular is in the range 15-35, preferably higher than 20.

Using these parameters, for example, with the introduction 1-6 ampoules, preferably up to 4 or 5 vials per week (one ampoule contains 3 000 units rfEPO and 5 mg of iron complex) diagnostically control optimal adaptation of patients. It is especially not about patients with hemodialysis, and such patients are treated on the basis of another kind caused anemia with EPO and/or iron preparations.

In order reliably to avoid side effects, determine the setting of acute phase CRP (2-10 mg/l) (CRP = C-reactive protein). Optionally, you can define the parameter of the liver GPT (glutamine-pyruvate-transaminase levels), which should be < 50 units/l at 37the parameters as the hematocrit (percentage of red blood cells in the total blood volume) or the increase in the content of hypochromic erythrocytes. The number of reticulocytes may be increased to values up to 15/1000-30/1000. A typical concentration of hemoglobin is 12-18 g/DL. If soluble TfR shows a higher elevation, it is necessary to increase weekly dose of iron up to 35 mg. If soluble TfR shows lower values, it is necessary to increase weekly dose of EPO.

Determining the status of iron is carried out by analysis of samples from body fluids (blood, serum, urine, and so on) of the respective patients. To determine the status of iron in the body specifically determine the concentration of iron, transferrin, ferritin, transferring receptor, transferrine saturation and transferrin/ferritine saturation. In patients with hemodialysis preferably define parameters such as the content of iron, transferrin, ferritin and transferrine saturation in itself conventional methods of analysis. It is essential, in particular, determination of the transferrin/ferritine saturation. In patients with anemia, the anemia which is caused not by hemodialysis, first of all, determine the con is their ratio transferring receptor to ferritin (value atransferrinemia receptor/ferritine saturation).

Optimal according to the invention combined preparation for the treatment of patients with anemia includes 2000-4000 units of EPO and 3-10 mg, preferably 5 mg, iron ions, preferably of the complex Fe(III), and EPO and the complex Fe(III) may be separate applications or a single application form.

Proposed according to the invention forms the introduction also allow to carry out the administration of iron preparations for 1-3 days before the introduction of the EPO, before applying with EPO assistance to replenish the storage of iron.

The subject invention also is the use of 3000-700 unit rhEPO and 5-20 mg of iron ions physiologically acceptable preparation of iron to obtain the combined drugs for the treatment of patients with hemodialysis.

For the study of iron metabolism in clinical chemistry to determine the concentration of iron in the blood and iron binding capacity. You need to carry out is always both tests, as the results of their measurements to each other is important. Usually the normal level of iron in serum for men is 75-150 mg/DL, and in the case of women, it is 60-140 mg/DL. Full binding capacity of iron is 250-450 mg/DL. The level of iron in serum number of the Shen in the case of hemolysis and syndromes with iron overload (e.g., hemochromatosis or hemosiderosis). Patients undergoing oral medication iron, can have a normal level of iron in serum, although they actually have a deficiency. Full iron binding capacity (transferrin x 2) increased by iron deficiency, but, on the contrary, decreased with anemia during the course of chronic diseases.

In addition, determine the level of serum ferritin. Ferritin is an accumulating iron-glycoprotein, which are typical for tissue isoferritins and which can be determined in serum immunological, for example, by radioimmune assay (RIA), or also by means of turbidimetric methods. The amount of ferritin is a measure of the accumulation of iron in tissues. In most laboratories, the normal range is 30-300 ng/ml, and compound value is 88 men and 49 women. The content of ferritin in serum is closely related to the General reserve of iron in the body. Therefore, decreased levels of serum ferritin are found only when the deficiency. Elevated levels found iron overload. Similarly, elevated levels of serum ferritin between the proteins of the acute phase. Also the receptor for serum transferrin can be determined by reinforced enzyme immunoabsorption test (enzyme-linked immunosorbent assay = ELISA). Using a monoclonal antibody against the soluble receptor. Standard area is 0.5-3 mg/L. elevated with a slight deficit in the storage of iron. You can determine the concentration of a specific ferritin of red blood cells, to characterize the storage of iron, especially when serum ferritin is unsuitable in the case of damage to the tissue or due to acute phase reactions.

For the study of iron metabolism hereinafter also determine the level of ferritin in the blood. In heparinised blood erythrocytes are separated from the leukocytes and platelets (which also contain ferritin) by centrifugation. Perform lysis of erythrocytes and conduct immunological determination of accumulated ferritin. The erythrocyte ferritin reflects the drive state of iron in the past three months (i.e. during the lifetime of erythrocytes). Normal values are in General 5-48 g Atto-grams (AG) on the erythrocyte. Values < 5 are in the case of anemia associated with iron deficiency, the activity is the determination of zinc protoporphyrin.

The invention is explained in detail on the basis of the following examples, and in the case of iron preparations quantitative data refer to an equivalent amount of iron ions (and not to the amount of iron complex).

Example 1: the Patient And (hemodialysis)

a) Standard drug

At normal therapeutic method to a patient once per week administered 100 mg of the complex Fe(III) and three times a week to introduce 5000 rEPO intravenously. When this diagnostic parameters - transferrin, transferrine saturation, CRP, GOT/GPT and GT are in the region of normal values, the content of ferritin, comprising 800-1300 mg/l is too high. To reduce the content of ferritin to a value of < 500 µg/l three times a week to introduce 5000 rEPO within a time period of three weeks.

b) according to the invention, the drug

In the subsequent three introduction week proposed according to the invention combo drug consisting of 10 mg of saharat iron(III) and 5000 rEPO, you can reach the content of ferritin in the region of normal values and support for further treatment. All other parameters are in the region of normal values.

Example 2: P is Alu 50 mg drug iron(III) and three times per week 5000 the rEPO. Despite the lower dose of iron than in example 1, ferritin and transferring saturation is too high.

The content of ferritin decrease to a value of < 500 µg/l and transferrin saturation is reduced to a value of < 25% by introducing three times a week for 5000 rEPO within a time period of three weeks.

b) according to the invention, the drug

After from double to triple the introduction week proposed according to the invention a combined Supplement of 10 mg of the preparation of iron(III) and 5000 rEPO all parameter values are in the region of normal values and also in the further processing using the proposed according to the invention of the drug no longer appear no extreme values.

Example 3: Patient (hemodialysis)

a) Standard drug

The patient receives twice weekly 50 mg drug iron(III) and twice a week 2000 units rEPO. It turns out that in this case, the content of ferritin, comprising 1500-2500 μg/l is very high and increased parameter-GT. By implementing infusion iron content of ferritin decreased to 500 ág/l for three weeks.

b) according to the invention, the drug

Example 4: a Patient (the patient with anemia)

a) Standard drug

On conventional therapy method of treatment the patient is given once a week 100 mg of the complex of iron(III) and three times per week 5000 rEPO intravenously. When this diagnostic parameters - transferrin, transferrine saturation, CRP, GOT/GPT and GT are in the region of normal values, the content of ferritin, comprising 800-1300 mg/l is too high, the content transferring receptor is 100-500 µg/l and thus is too low.

To improve the content transferring receptor to values above 1500 ág/l and to reduce the amount of ferritin to the value of 500 µg/l three times a week to introduce 5000 rEPO for three weeks.

b) according to the invention, the drug

In the subsequent five-introduction week proposed according to the invention a combined Supplement of 5 mg saharat iron(III) and 3000 units rEPO can be achieved content transferring receptor and ferritin in the region of normal values and support the Example 5: a Patient (the patient with anemia)

a) Standard drug

Patient D receives, according to the example 4, once a week, 50 mg of the preparation of iron(III) and three times per week 5000 rEPO. Despite the lower dose of iron than in example 4, the parameters of ferritin and transferring saturation is too high.

Content transferring receptor is increased to values above 1500 ág/l and the amount of ferritin decreased to < 500 µg/l, and transferrine saturation is reduced to a value of < 25% by introducing three times a week for 5000 rEPO within a time period of three weeks.

b) according to the invention, the drug

After from fourfold to fivefold introduction week proposed according to the invention a combined Supplement of 5 mg of the preparation of iron(III) and 3000 units rEPO all values are in the region of normal values and also in the further processing using the proposed according to the invention of the drug no longer appear no extreme values.

Example 6: Patient E patient with anemia)

a) Standard drug

Patient E receives twice weekly 50 mg drug iron(III) and twice a week 2 000 units rEPO. It turns out that in this case related to atransferrinemia recipe upgraded option-GT. By implementing infusion of iron-related atransferrinemia receptor values increase to values above 1500 ág/l and related to ferritin values reduced to < 500 µg/l for three weeks.

b) according to the invention, the drug

Again by the subsequent five injection per week proposed according to the invention a combined Supplement of 5 mg gluconate iron(III) and 3000 units rEPO reach normal values for ferritin, transferring receptor, transferring saturation, CRP, and GOT-GT and support for further treatment.

1. Application (2000-7000) units of recombinant human erythropoietin (EPO) and (1-20) mg equivalent amount of iron ions physiologically acceptable preparation of iron to obtain a combined pharmaceutical preparation for the treatment of patients with hemodialysis or for the treatment of anemia using combined drug in the corrective phase and the support phase during treatment with iron.

2. Application under item 1 (3000-7000) units of EPO and (5-20) mg of iron ions to receive the combined drug.

3. Application under item 1 or 2 5000 EPO and 10 mg of iron ions to obtain combined the aqueous drug.

5. Application under item (4 3000 units of EPO and 5 mg of iron ions to receive the combined drug.

6. The use according to any one of paragraphs.1-5 preparation of iron, which is a complex with a molecular mass of 30000-100000 Yes, preferably of saharat iron (III).

7. The use according to any one of paragraphs.1-5 preparation of iron, which is the gluconate iron (III).

8. The use according to any one of paragraphs.1-3, 6, or 7 to obtain a combined medication used for the treatment of patients with hemodialysis.

9. The use according to any one of paragraphs.1 or 4 to 7 to obtain a combined medication used for the treatment of anemia.

10. The use of recombinant human erythropoietin (EPO) to obtain a combined preparation containing 2000-7000 units of EPO for the combined injection with 1-20 mg of an equivalent amount of iron ions physiologically acceptable preparation of iron for use in correcting the phase and the support phase during treatment with iron in patients with hemodialysis.

11. The use of EPO to obtain a combined preparation containing 2000-4000 units of EPO, for a combined introduction together with 3-10 mg of an equivalent amount of iron ions the overall phase during treatment with iron in the treatment of anemia.

12. Pharmaceutical packaging unit comprising 2000-7000 units of EPO and 1-20 mg of an equivalent amount of iron ions physiologically acceptable preparation of iron in the form of a single form of introduction in one capacity or as separate forms of introduction, in separate containers, for use in correcting the phase and the support phase during treatment with iron.

13. Packing unit under item 12, characterized in that the EPO and the preparation of iron each are separate forms of administration in the form of solutions for injection, respectively, infusion or in the form of liofilizatow.

14. Packing unit under item 12, characterized in that the EPO and the preparation of iron are in a single form of administration in the form of solution for injection, respectively, for infusion or in the form of a lyophilisate.

 

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