Erythropoietin solution for intravenous and subcutaneous administration. 2000 IU/ml amp. 1 ml No. 10

Erythropoietin is a hormone produced primarily by the kidneys. It plays a key role in the production of red blood cells, the red blood cells that carry oxygen from the lungs to tissues and organs.

Erythropoietin enters the blood in response to low oxygen levels - hypoxemia, and is transferred to the bone marrow, where it stimulates the production of red blood cells. The hormone remains active for a short period of time and is then excreted from the body in the urine.

The amount of hormone released depends on how low the oxygen levels are and the ability of the kidneys to produce erythropoietin. The increase in the production and release of erythropoietin into the blood continues until the level of oxygen in the blood rises to normal levels, then its production decreases. The body uses this dynamic feedback system to maintain sufficient oxygen levels and a relatively stable number of red blood cells in the blood.

However, if a person's kidneys are damaged and unable to produce sufficient amounts of erythropoietin, or if the bone marrow does not respond to stimulation by erythropoietin, red blood cell production is inhibited and anemia develops. This may result from certain bone marrow diseases or chronic diseases such as rheumatoid arthritis.

With various lung diseases and other conditions that affect the level of oxygen in the blood (smoking, occupational hazards, living in high mountainous regions, etc.), the production of erythropoietin increases in order to compensate for hypoxemia. The hormone is also produced in increased quantities in some benign or malignant tumors of the kidneys and other organs. This leads to the development of polycythemia or erythrocytosis - an excess of the concentration of red blood cells. The blood becomes more viscous, thicker, blood pressure rises and there is a risk of thrombosis, myocardial infarction and stroke.

Detailed description of the study

The main function of erythrocytes, or red blood cells, in the body is to deliver oxygen to tissues and organs. This ensures the normal course of all physiological processes. If the results of a laboratory test in the blood reveal a decrease in the number of red blood cells, it can be assumed that anemia is developing, which requires mandatory identification of the cause and selection of appropriate therapy.

Red blood cells are produced in the bone marrow. For their normal production, many factors must be observed, for example, a sufficient content of iron, vitamin B12, and folic acid in the diet. Also important is the sufficient supply of the body with the hormone erythropoietin, which stimulates the transformation of stem cells into red blood cells in the bone marrow.

Erythropoietin is a glycoprotein, that is, a substance of protein-carbohydrate nature that is produced by kidney and liver cells. Receptors for erythropoietin are located in the cells of the nervous tissue, on the ovaries, testicles, breast tissue and other organs.

Normally, its level in blood plasma is low, but relatively stable. The kidneys begin to intensively produce erythropoietin when the concentration of oxygen in the tissues decreases - hypoxia occurs. Once oxygen levels stabilize, erythropoietin stops being produced.

Not only the formation and maturation of red blood cells, but also the saturation of the body with oxygen as a whole depends on the level of this hormone. Erythropoietin also affects the functional state of the cardiovascular system, the nervous and reproductive systems, hemostasis, immune status and the urinary system.

Kidney diseases can cause decreased or, conversely, increased synthesis of erythropoietin. Hormone deficiency is observed in chronic renal failure and leads to the development of anemia.

In patients with neoplasms - benign or malignant - increased synthesis of the hormone may be observed in the kidneys, as a result of which too many red blood cells are formed. This condition is called polycythemia. As a result, the total volume of circulating blood increases, its viscosity increases, and blood pressure increases.

Testing serum erythropoietin levels helps determine the causes of anemia in people who do not have iron or vitamin B12 deficiency. The test is also important for diagnosing polycythemia and bone marrow diseases.

Why is erythropoietin deficiency dangerous?

If erythropoietin production is reduced or impaired, blood oxygen levels remain low or will fall further. This is dangerous because it leads to several pathologies, including anemia and hypoxia. When they occur, the body's tissues receive insufficient oxygen and cannot function normally.

Symptoms of anemia:

• fatigue
• dizziness
• dyspnea
• weakness
• headache
• pale skin
• cardiopalmus

A lack of erythropoietin also reduces the body's ability to adapt to changes in altitude and intense physical activity.

Diseases such as AIDS, inflammatory diseases and some types of cancer can lead to low levels of erythropoietin. Lack of oxygen can aggravate these and other chronic diseases.

Mild cases of anemia may not require any treatment, especially if there are no symptoms. However, in more severe cases, iron supplements or erythropoietin-stimulating drugs may be needed. Erythropoietin therapy has been shown to be an effective treatment for anemia in patients with chronic kidney disease, as well as in patients suffering from cancer, HIV, and organ transplants.

Erythropoetin

Treatment of anemia in patients with chronic renal failure,

P/c or i.v. When administered intravenously, the solution should be administered within 2 minutes; for patients on hemodialysis - through an arteriovenous shunt at the end of the dialysis session. For patients not on hemodialysis, it is preferable to administer the drug subcutaneously to avoid puncture of peripheral veins.

The goal of treatment is to achieve a hematocrit level of 30-35% or eliminate the need for blood transfusion. The weekly increase in hematocrit should not exceed 0.5%. Its level should not exceed 35%. In patients with arterial hypertension, cardiovascular and cerebrovascular diseases, the weekly increase in hematocrit and its target values ​​should be determined individually, depending on the clinical picture. For some patients, the optimal hematocrit is below 30%.

Treatment with Erythropoietin is carried out in 2 stages:

Initial therapy (correction stage). For subcutaneous administration, the initial dose is 20 IU/kg body weight 3 times a week. If the increase in hematocrit is insufficient (less than 0.5% per week), the dose can be increased monthly by 20 IU/kg body weight 3 times a week. The total weekly dose can also be divided into daily administrations in smaller doses or administered in one go.

When administered intravenously, the initial dose is 40 IU/kg body weight 3 times a week. If the hematocrit does not increase sufficiently after a month, the dose can be increased to 80 IU/kg 3 times a week. If there is a need to further increase the dose, it should be increased by 20 IU/kg 3 times a week at monthly intervals. Regardless of the route of administration, the highest dose is no more than 720 IU/kg body weight per week.

Maintenance therapy.

To maintain the hematocrit at 30-35%, the dose should first be reduced by half from the dose in the previous injection. Subsequently, the maintenance dose is selected individually, with an interval of 1-2 weeks. With subcutaneous administration, the weekly dose can be administered once or in 3-7 injections per week.

In children, the dose depends on age (as a rule, the younger the child, the higher doses of epoetin beta he needs). However, since it is not possible to predict individual response, it is advisable to start with the recommended regimen.

Treatment with Erythropoietin is usually lifelong. If necessary, it can be interrupted at any time.

Prevention of anemia in premature newborns.

SC at a dose of 250 IU/kg body weight 3 times a week. Treatment with epoetin beta should begin as early as possible, preferably from the 3rd day of life, and continue for 6 weeks.

Prevention and treatment of anemia in patients with solid tumors.

SC, dividing the weekly dose into 3-7 injections.

For patients with solid tumors receiving platinum chemotherapy, treatment with Erythropoietin is indicated if the hemoglobin level before chemotherapy is not higher than 130 g/l. The initial dose is 450 IU/kg body weight per week. If after 4 weeks the hemoglobin level does not increase sufficiently, the dose should be doubled. The duration of treatment is no more than 3 weeks after the end of chemotherapy.

If during the first cycle of chemotherapy, the hemoglobin level, despite treatment with epoetin beta, decreases by more than 10 g/l, further use of the drug may not be effective.

An increase in hemoglobin by more than 20 g/l per month or to a level above 140 g/l should be avoided. If hemoglobin increases by more than 20 g/l per month, the dose of epoetin beta should be reduced by 50%. If the hemoglobin level exceeds 140 g/l, the drug is discontinued until it decreases to a level of <120 g/l, and then therapy is resumed at half the previous weekly dose.

Treatment of anemia in patients with multiple myeloma, low-grade non-Hodgkin's lymphoma, or chronic lymphocytic leukemia.

Patients with multiple myeloma, low-grade non-Hodgkin's lymphoma, or chronic lymphocytic leukemia usually have a deficiency of endogenous erythropoietin. It is diagnosed by the relationship between the degree of anemia and the insufficient concentration of erythropoietin in the serum.

Relative deficiency of erythropoietin occurs:

The above parameters should be determined no earlier than 7 days after the last blood transfusion and the last cycle of cytotoxic chemotherapy.

The drug is administered subcutaneously; The weekly dose can be divided into 3 or 7 injections. The recommended starting dose is 450 IU/kg body weight per week. If after 4 weeks the hemoglobin level increases by at least 10 g/l, treatment is continued at the same dose. If after 4 weeks hemoglobin increases by less than 10 g/l, the dose can be increased to 900 IU/kg body weight per week. If after 8 weeks of treatment the hemoglobin level has not increased by at least 10 r/l, a positive effect is unlikely and the drug should be discontinued.

Clinical studies have shown that in chronic lymphocytic leukemia, the response to epoetin beta therapy occurs 2 weeks later than in patients with multiple myeloma, non-Hodgkin's lymphoma and solid tumors. Treatment should be continued until 4 weeks after the end of chemotherapy.

The highest dose should not exceed 900 IU/kg body weight per week.

If within 4 weeks of treatment the hemoglobin level increases by more than 20 g/l, the dose of Erythropoietin should be reduced by half. If the hemoglobin level exceeds 140 g/l, treatment with the drug should be interrupted until it decreases to <130 g/l, after which therapy is resumed at a dose half the previous weekly dose. Treatment should only be restarted if the most likely cause of the anemia is Erythropoietin deficiency.

Preparing patients for the collection of donor blood for subsequent autohemotransfusion.

IV or SC twice a week for 4 weeks. In cases where the patient's hematocrit (>33%) allows blood sampling, epoetin beta is administered at the end of the procedure. Throughout the course of treatment, the hematocrit should not exceed 48%.

The dose of the drug is determined by the transfusiologist and the surgeon individually, depending on the volume of blood that will be taken from the patient and his erythrocyte reserve. The volume of blood that will be taken from the patient depends on the estimated blood loss, available blood conservation techniques and the general condition of the patient; it must be sufficient to avoid a blood transfusion from another donor. The volume of blood that will be taken from the patient is expressed in units (one unit is equivalent to 180 ml of red blood cells).

The possibility of donation depends mainly on the blood volume of a given patient and the initial hematocrit. Both indicators determine the endogenous erythrocyte reserve, which can be calculated using the following formula:

endogenous erythrocyte reserve = blood volume (ml) x (hematocrit - 33): 100

women: blood volume (ml) = 41 (ml/kg) x body weight (kg) + 1200 (ml)

men: blood volume (ml) = 44 (ml/kg) x body weight (kg) + 1600 (ml) (for body weight >45 kg).

Indications for the use of Erythropoietin and its single dose are determined by nomograms, based on the required volume of donor blood and endogenous erythrocyte reserve.

The highest dose is with intravenous administration no more than 1600 IU/kg body weight per week; with subcutaneous administration - 1200 IU/kg body weight per week.

Is it worth using erythropoietin in sports?

In recent decades, professional athletes have discovered significant benefits from erythropoietin. This hormone significantly increases the absorption of oxygen into tissues, which can increase endurance and performance.

How are athletic achievements and genetics related?

Erythropoietin is part of a group of blood doping products that are prohibited by the Medical Commission of the International Olympic Committee (IOC) and the World Doping Agency. One of the reasons for the ban was the high health risk.

The use of erythropoietin as a doping agent results in abnormally high red blood cell counts. Blood thickening occurs and the risk of serious side effects increases:

• allergic reactions
• blood clots
• flu-like symptoms
• heart attack
• high blood pressure
• pulmonary embolism
• seizures
• stroke

Erythropoietin[edit | edit code]

Red blood cells.
Scanning microscope Erythropoietin

is a glycoprotein hormone, more precisely a cytokine, the main regulator of erythropoiesis, which stimulates the formation of red blood cells from late progenitor cells and increases the yield of reticulocytes from the bone marrow depending on oxygen consumption. As long as tissue oxygenation is not impaired, the concentration of erythropoietin, as well as the number of circulating red blood cells, remains constant. The production of erythropoietin is regulated at the level of transcription of its gene, and since the only physiological stimulus that increases the number of cells synthesizing erythropoietin is hypoxia, neither the production nor metabolism of erythropoietin depends on its concentration in plasma. In the body of a healthy person there are approximately 2.3 * 10^13 red blood cells, the lifespan of which is on average 120 days. Consequently, the body must constantly renew the pool of red blood cells at a rate of approximately 2.3 cells per second. The erythroid cell differentiation system must be strictly regulated to maintain a constant level of circulating erythrocytes under normal conditions. In addition, this system must be highly sensitive to changes in the amount of oxygen in the body. Currently, a lot of data have been obtained indicating that the key factor that controls the differentiation of erythroid cells is erythropoietin circulating in the blood.

Erythropoietin is an extremely active hormone that exerts its effect in the body in picomolar concentrations. Small fluctuations in its concentration in the blood lead to significant changes in the rate of erythropoiesis, and the normal range of its concentrations ranges from 4 to 26 IU/l. Therefore, until the hemoglobin concentration drops below 105 g/l, the erythropoietin concentration does not go beyond the specified range and it is impossible to detect its increase (unless you know its initial values). Erythrocytosis leads to suppression of erythropoietin production via a negative feedback mechanism. This is due not only to an increase in oxygen delivery to tissues due to an increase in the number of circulating red blood cells, but also to an increase in blood viscosity. For an athlete, this means a decrease in the production of one’s own hormone when exogenous is administered and a violation of the mechanisms regulating the production of red blood cells. Therefore, when using erythropoietin in sports as a doping, an athlete should think about the future fate of red blood cell production in his body.

Doping tests[edit | edit code]

Typically, erythropoietin is detected in urine or blood samples. It is more likely to be detected in blood than in urine. The half-life is 5-9 hours, that is, the probability of detection is significantly reduced after 2-3 days.

Heparin is used as a masking agent[1]. Injection of proteases into the bladder through a catheter is also used.[2]

Physiological role of erythropoietin[edit | edit code]

For a long time, the question of the cells that normally produce erythropoietin remained open. This was primarily due to the lack of direct methods for identifying cells that synthesize the hormone. Cell identification was carried out by indirect methods, including the ability of certain tissue cultures to synthesize the product in vitro. It was believed that the main candidates for the role of EPO-producing cells are glomerular cells, as well as cells of the proximal tubule. Cloning of the erythropoietin gene, as well as the development of in situ hybridization methods, which make it possible to directly identify those cells in which the expression of certain genes occurs, has changed ideas about the nature of the cells that synthesize erythropoietin. Using in situ hybridization, it was shown that the cells in which erythropoietin mRNA is synthesized are not glomerular or tubular. Apparently, the main site of EPO synthesis in the kidneys is interstitial cells or capillary endothelial cells. As already noted, the main factor regulating EPO production is hypoxia. Under hypoxic conditions, the amount of EPO circulating in the plasma increases approximately 1000 times and reaches 5-30 U/ml. Numerous experiments with the isolated kidney have shown that it contains sensors that respond to changes in oxygen concentration.

Back in 1987, J. Schuster and coworkers studied the kinetics of erythropoietin production in response to hypoxia. It was shown that approximately 1 hour after the establishment of hypoxia, the amount of erythropoietin mRNA in the kidney increases, and the mRNA continues to accumulate for 4 hours. When hypoxia is removed, the level of EPO mRNA rapidly decreases. Changes in the amount of plasma and renal erythropoietin, detected using erythropoietin-specific antibodies, occur strictly in parallel with changes in the amount of mRNA with a corresponding lag period. The results obtained in this work indicate that hypoxia stimulates de novo EPO production.

In the laboratory of S. Konry in 1989, the process of induction of EPO synthesis was studied using the method of in situ hybridization on tissue sections of the renal cortex. It was found that under conditions of anemia, EPO production increases significantly, although the intensity of hybridization with EPO mRNA in individual cells remains unchanged. It has been shown that increased EPO production is associated with an increase in the number of cells synthesizing the hormone. As normal hematocrit is restored, the number of erythropoietin-synthesizing cells rapidly decreases, and the kinetics of the change correlates with the kinetics of the decrease in the amount of EPO mRNA and circulating hormone. Histological analysis data indicate that EPO is synthesized by interstitial cells of the renal cortex.

It has been shown that 5 to 15% of plasma erythropoietin in adults is of extrarenal origin. And if in embryos the main place of erythropoietin synthesis is the liver, then in the adult body the liver is also the main organ producing EPO, but extrarenal. This conclusion was confirmed in recent experiments detecting EPO mRNA in various organs. Apparently, a change in the main site of EPO synthesis during ontogenesis is a genetically determined event.

The synthesis of erythropoietin in the body is mediated by a significant number of biochemical cofactors and stimulants. It is assumed that hypoxia leads to a decrease in oxygen levels in specific sensory cells of the kidney, which causes increased production of prostaglandins in glomerular cells. Prostaglandins have been shown to play an important role in stimulating erythropoietin production. Inhibitors of prostaglandin synthesis have a suppressive effect on EPO production during hypoxia. The main contribution to the biosynthesis of prostaglandins during hypoxia appears to be made by the cyclooxygenase system. Hypoxia (as well as the administration of cobalt ions) causes the release of neutral proteases and lysosomal hydrolases in the kidneys, which have also been shown to stimulate EPO production. The release of lysosomal enzymes appears to be associated with an increase in cGMP production. It has been shown that lysosomal enzymes are activated with the participation of protein kinases, which, in turn, are activated by cAMP.

During hypoxia, induction of phospholipase A2 activity is observed, which leads to an increase in the level of arachidonates, which, with the participation of cyclooxygenase, are converted into endoperoxides. It has been noted that hypoxia is the optimal condition for cyclooxygenase activity. The calcium system probably plays an important role in these biochemical events: calcium ions stimulate the activity of phospholipase A and the formation of prostaglandin. Prostanoids, in turn, can induce adenylate cyclase activity and trigger a cascade of biochemical events leading to phosphorylation and activation of hydrolases. What is the role of hydrolases and what is the chain that ultimately leads to increased EPO synthesis remains unclear. Some hormones of the hypothalamic-pituitary system, thyroid hormones and some steroid hormones also have activity that stimulates EPO biosynthesis. A specific inducer of EPO production is cobalt ions, the mechanism of action of which on the EPO biosynthesis system is not yet clear. This system is an attractive experimental model for studying the induction of EPO biosynthesis.

A human erythropoietin molecule, in which the carbohydrate component accounts for 40-50% of the molecular weight (the molecular weight of the glycoprotein is 32-36*10^3 a.m.u., and the calculated molecular weight of the protein part is 18,399*10^3 a.u. e.m.), consists of 193 amino acid residues. The isoelectric point of EPO is low (pH 3.5-4.0), which is due to the presence of sialic acids in the terminal positions of the carbohydrate chains of erythropoietin. Isoelectric focusing of plasma EPO in a polyacryamide gel allows us to identify several fractions that are identical in molecular weight, but differ in the size of their isoelectric points, which indicates heterogeneity in the structure of the carbohydrate part of the hormone. Cleavage of sialic acids by treatment with neuraminidase or by acid hydrolysis leads to loss of hormone stability in vivo, but does not affect its activity in vitro. In four sections, glycosidic residues are attached to the protein chain, which can represent different sugars, so there are several varieties of EPO with the same biological activity, but slightly different in their physicochemical properties.

As a result of analysis of the amino acid sequence of human erythropoietin, three potential N-glycosylation sites were identified, which include the consensus sequence Asn-X-Ser/Thr. In experiments on the treatment of the hormone with N-glycosidase, which specifically cleaves off oligosaccharide chains linked to the aspartic residue by an N-glycosidic bond, the assumption of the presence of three N-glycosylation sites in the EPO molecule was confirmed. As a result of experiments on the treatment of the hormone with O-glycosidase, it was established that it also contains oligosaccharide chains connected to the protein part through O-glycosidic bonds.

The erythropoietin gene (Gene: [07q21/EPO] erythropoietin) consists of five exons and four introns. The gene encodes a protein consisting of 193 amino acid residues. Four types of RNA involved in the interaction with the erythropoietin gene have been identified, and two types are represented in extracts after the introduction of cobalt chloride with a significantly lower copy number than in normal extracts. These data indicate the presence of negative regulatory factors (probably ribonucleoproteins) involved in the regulation of erythropoietin gene expression. The assumption of negative regulation of EPO gene expression was confirmed by Semenza G. and co-workers in 1990, who obtained a series of transgenic mice carrying the coding part of the human EPO gene and various fragments of the S-flanking region. Analysis of gene expression in various transgenes made it possible to identify three regulatory elements of the human erythropoietin gene:

• a positive regulatory element required to induce erythropoietin gene expression in the liver;
• negative regulatory element;
• a regulatory element required for inducible gene expression in the kidney.

It has been experimentally shown that there are two transcription initiation sites of the erythropoietin gene, which carry multiple initiation sites. Under normal conditions, transcription initiation occurs from a limited number of sites located in both regions. When anemia is induced or treated with cobalt chloride, the number of functioning transcription initiation sites in both regions increases. In all cases, the production of erythropoietin is limited by difficulties associated with the isolation and cultivation of cells, the instability of hormone production and, finally, its low concentration in culture fluids.

A fundamentally different approach to obtaining large quantities of highly purified EPO was associated with the use of genetic and cellular engineering methods. An attempt was made to create a bacterial producer of erythropoietin. The protein produced in Escherichia coli is recognized by antibodies against EPO and has a molecular weight approximately corresponding to deglycosylated human EPO. It is known that bacterial cells have a glycosylation system that is fundamentally different from the eukaryotic one. Therefore, it is impossible to obtain correctly glycosylated protein in bacterial cells. In the case of EPO, obtaining a correctly glycosylated glycoprotein is of fundamental importance. Therefore, creating a hormone producer based on bacterial cells is impractical. An effective producer of erythropoietin, biologically active both in vitro and in vivo, can only be obtained from cells of higher animals.

When studying the properties of recombinant EPO, it was shown that the presence of an incomplete carbohydrate component (the molecular weight of erythropoietin synthesized in this system is 23 * 10^3 a.m.u.) does not affect the activity of the hormone in vitro, but significantly reduces its activity in vivo . At the same time, complete cleavage of the carbohydrate part with the help of glycosidases leads to an 80% loss of the biological activity of the hormone in an in vitro test. These data are in conflict with existing ideas that the carbohydrate component of EPO is not strictly necessary for its activity in vitro.

Historical background[edit | edit code]

In 1989, a detailed analysis of the structure of recombinant EPO obtained by transfecting cells from the Chinese hamster ovary into the human EPO genome was carried out. It has been established that two types of EPO (called bi- and tetra-forms) are synthesized in cells, differing in the degree of branching of N-linked carbohydrate chains. The bi-form of EPO, containing a less branched carbohydrate component, differs significantly in biological activity from native erythropoietin, used as a standard: the biological activity of the bi-form of EPO in vivo is 7 times lower, and in vitro - 3 times higher. The biological activity of the tetra form of EPO is very close to that of native EPO. These data indicate an essential role of the structure of the carbohydrate component for the biological activity of erythropoietin in vivo. Apparently, the higher in vitro activity of those forms of erythropoietin that contain an incomplete carbohydrate component is associated with facilitating the interactions of erythropoietin with receptors. At the same time, it appears that it is the carbohydrate component that ensures the stability of the hormone in the body and, accordingly, a high level of biological activity in in vivo tests.

By the mid-1980s, the first recombinant erythropoietin was produced by introducing the human EPO gene (located in humans on the seventh chromosome in the region 11q-12q) into ovarian cells of hamsters. Recombinant human r-EPO, obtained by genetic engineering (Recormon), is identical in amino acid composition to natural human EPO. Recormon provides a flexible and cost-effective method for the effective treatment of anemia combined with a high safety profile and excellent tolerability. Thanks to the use of Recormon, the need for blood transfusions, which today are the most common method of correcting anemia, is significantly reduced. Thus, according to numerous studies, the use of Recormon allows one to restore normal hemoglobin levels and eliminate the need for replacement blood transfusions in cancer patients suffering from anemia. At the same time, there is a significant improvement in the quality of life of these patients; the risk of infection that exists when correcting anemia with the help of blood transfusions during the treatment of viral infectious diseases such as HIV and hepatitis C is significantly reduced. Recormon is available in the form of a convenient device for administering and indicating the drug (syringe pen).

However, there are minor differences in the composition of glycosidic residues, which affect the physicochemical properties of the entire hormone molecule. For example, certain differences have been found in the distribution of electrical charge for certain types of erythropoietin. Erythropoietin preparations are produced by various pharmaceutical companies in five types: alpha, beta, retard (NESP), theta and omega).

Since 1988, alpha-EPO and beta-EPO have been used. When administered subcutaneously, their bioavailability is about 25%, the maximum concentration in the blood is after 12-18 hours, the half-life is up to 24 hours (with intravenous administration - 5-6 hours). Erythropoietin retard (NESP) has been used for the last few years and lasts longer than other EPO drugs. Theta-EPO is considered the most effective and least allergenic today, and has the highest degree of purity. This is due to the fact that it is obtained by genetic engineering in human cells (some unscrupulous athletes and sports doctors believe that this makes it undetectable). In fact, theta EPO is only 99% identical to human. Omega-EPO, which is obtained from hamster kidneys, is the most different from other EPO preparations from human EPO, so it is the easiest to identify. Sold only in Eastern Europe and South America.

Erythropoietin preparations[edit | edit code]

Recombinant biosimilar a-EPO from different manufacturers, even having a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, may have different properties, degrees of purity and, most importantly, have different biological activities . When erythropoietin preparations from different manufacturers were analyzed, 5 of the 12 products examined showed significant variations in potency between different batches, and three samples showed unacceptable levels of bacterial endotoxins.

Another study compared 11 EPO products (obtained from eight manufacturers) marketed outside the EU and based on the content, potency and isoform composition of the active substance (erythropoietin). In vitro bioactivity ranged from 71-226%, with 5 samples not meeting specifications. Among the deviations in the isoform composition are the presence of one or more additional acidic and/or basic isoforms, as well as an altered quantitative ratio of various isoforms. Inter-run differences were also identified; Some products did not meet their own specifications, meaning that manufacturers did not provide adequate control over their production processes. The amount of active substance also did not always correspond to the declared quantity. Such deviations from the stated parameters may have important clinical significance, since they may lead to an overdose or, conversely, the administration of a lower dose. The data presented clearly indicate the threat of using recombinant erythropoietins without medical indications.

Application in medicine[edit | edit code]

In medical practice, erythropoietin is used to treat anemia of various origins, including in cancer patients and patients with chronic renal failure. Since, as noted above, the body produces endogenous erythropoietin in the kidneys, patients with chronic renal failure always suffer from anemia. In addition, a decrease in the concentration of EPO in human plasma and, accordingly, in the number of red blood cells, is observed in the following pathological conditions and diseases:

• secondary polycythemia;
• inadequate stimulation of one's own EPO;
• benign kidney diseases (hydronephrosis);
• general tissue hypoxia;
• impaired blood supply to the kidneys
• reduction of oxygen concentration in the environment;
• chronic obstructive pulmonary disease;
• diseases of the cardiovascular system (discharge of blood from right to left);
• abnormalities in the structure of the hemoglobin molecule (sickle cell anemia);
• exposure to carbon oxides on the body due to smoking;
• arteriosclerosis of the renal artery;
• graft rejection;
• aneurysms of the renal vessels.

Before the advent of recombinant erythropoietin, such patients regularly received blood transfusions of both whole blood and red blood cells. However, since 1989, the need for such procedures has disappeared, since they have been replaced by the administration of erythropoietin drugs. In some cases, anemia of other origins is also successfully treated with recombinant EPO. The fact that administration of recombinant EPO induces additional erythropoiesis even with completely intact endogenous EPO levels has been exploited by autologous blood donors. As an alternative to red blood cell transfusion, high-dose EPO therapy appears to be an effective anti-anemic measure as an accompanying therapy in the treatment of chronic polyarthritis, AIDS, some tumors, as well as in a number of surgical interventions. The genesis of hypertension as a side effect during the therapeutic use of recombinant EPO still remains unclear. During hemodialysis patients, erythropoietin preparations are usually administered intravenously. In some cases, the same drug can be administered subcutaneously.

An increase in the number of red blood cells under the influence of erythropoietin, in turn, leads to an increase in the oxygen content per unit volume of blood and, accordingly, to an increase in the oxygen capacity of the blood and the delivery of oxygen to tissues. Ultimately, the body's endurance increases. Similar effects are achieved during training sessions in mid-altitude conditions, when the lack of oxygen in the air causes a state of hypoxia, which stimulates the production of endogenous EPO. Naturally, compared to the use of a recombinant drug, hypoxic training is a physiological mechanism for regulating erythropoiesis and improving the oxygen transport function of hemoglobin, which is actually the purpose of using EPO as a doping.

Due to the effect of erythropoietin on oxygen capacity and oxygen transport in tissues, this substance causes an increase in performance in sports with a predominant manifestation of aerobic endurance. These sports disciplines include all types of athletics running, starting from 800 m, as well as all types of skiing and cycling. In addition, recently information has begun to appear in bodybuilding publications that EPO can replace the widespread use of anabolic steroids. EPO preparations are used in combination with stanazolol, insulin and growth hormone (GH) -

Erythropoietin preparations are well-tolerated pharmacological agents that have virtually no side effects. However, an overdose of EPO and uncontrolled use can lead to an increase in blood viscosity and, consequently, to an increased risk of disorders in the circulatory system, including peripheral vascular thrombosis and pulmonary embolism, which is usually fatal. The risk of these side effects of EPO increases when training in mid-altitude areas, as well as when the body is dehydrated.

However, there is evidence that long-term use of erythropoietin drugs can be dangerous to health, and sometimes even to life. In particular, the use of EPO is associated with constant headaches in athletes, which develop as a result of blood thickening and disruption of its circulation in the brain. In addition, iron metabolism may be disrupted: the body's need for it increases despite the presence of a relatively small reserve in the liver. When exogenous iron is administered, it begins to be deposited in the liver, as a result of which cirrhosis of the liver associated with excess iron appears after 20-25 years.

How is erythropoietin controlled?

Although the exact mechanisms that control erythropoietin production are poorly understood, it is well known that specialized cells in the kidneys are able to detect and respond to low oxygen levels by increasing erythropoietin production. When there is enough oxygen in the circulation, erythropoietin production decreases, but when oxygen levels decrease, erythropoietin production increases.

This is an adaptive method because it promotes the production of more red blood cells to transport more oxygen throughout the body, thereby increasing tissue oxygen levels.

For example, erythropoietin production increases when moving to higher altitudes. This is because the air pressure is lower, the oxygen pressure is lower and therefore less oxygen is absorbed into the blood, which stimulates the production of erythropoietin. In low oxygen conditions, people are at risk of developing hypoxia - oxygen starvation.

Hypoxia can also occur with poor ventilation, such as with emphysema or cardiovascular disease. Erythropoietin production is reduced in kidney failure and various chronic diseases such as AIDS, some types of cancer, and chronic inflammatory diseases such as rheumatoid arthritis.

Erythropoietin solution for intravenous and subcutaneous administration. 2000 IU/ml amp. 1 ml No. 10

Indications

Symptomatic anemia in chronic kidney disease in patients on dialysis; symptomatic anemia of renal origin in patients not yet receiving dialysis; treatment of symptomatic anemia in adult patients with solid and hematologic non-myeloid tumors receiving chemotherapy; prevention of anemia in premature newborns born with a body weight of 750-1500 g before the 34th week of pregnancy. Increasing the volume of donor blood intended for subsequent autotransfusion. The reported risk of thromboembolic events should be taken into account. Use for this indication is indicated only in patients with moderate anemia (Hb 100-130 g/l (6.21-8.07 mmol/l), without iron deficiency), if it is impossible to obtain a sufficient amount of banked blood, and planned major elective surgery may require extensive blood volume (>4 units for women or >5 units for men).

pharmachologic effect

Recombinant human erythropoietin (purified glycoprotein), consisting of 165 amino acids, which, as a mitogenic factor and differentiation hormone, promotes the formation of red blood cells from partially determined erythropoiesis precursor cells. Recombinant epoetin beta, obtained by genetic engineering, is identical in its amino acid and carbohydrate composition to human erythropoietin.

Epoetin beta after intravenous and subcutaneous administration increases the number of red blood cells, reticulocytes and hemoglobin levels, as well as the rate of incorporation of iron (59Fe) into cells, specifically stimulates erythropoiesis without affecting leukopoiesis. No cytotoxic effect of epoetin beta on human bone marrow or skin cells has been detected.

Drug interactions

With the simultaneous use of drugs that affect hematopoiesis (for example, iron supplements), the stimulating effect of epoetin beta may be enhanced.

Epoetin beta should not be mixed with solutions of other drugs.

Dosage regimen

Doses, regimen and duration of treatment are determined individually and depend on the severity of anemia, the severity of the patient’s condition, the nature of the disease, and the patient’s age. Injected subcutaneously and intravenously.

Contraindications for use

History of hypersensitivity to epoetin beta; uncontrolled arterial hypertension; myocardial infarction or stroke within the previous month, unstable angina or increased risk of deep vein thrombosis (with a history of venous thromboembolism) - when prescribed to increase the volume of donor blood for autohemotransfusion.

Carefully

Refractory anemia in the presence of blast-transformed cells, thrombocytosis, epilepsy and chronic liver failure. Body weight less than 50 kg to increase the volume of donor blood for subsequent autotransfusion.

Use in children

It can be used in children according to indications, in doses and regimens recommended according to age.

When treating anemia associated with chronic kidney disease, epoetin beta should not be used in children under 2 years of age.

Restrictions for children

Use with caution

Restrictions for elderly patients

No data

Use for liver dysfunction

Use with caution in chronic liver failure.

Restrictions for liver dysfunction

Use with caution

Use during pregnancy and breastfeeding

During pregnancy and breastfeeding, epoetin beta is used only when the expected benefit to the mother outweighs the potential risk to the fetus or child.

In experimental studies

no teratogenic effect was detected.

Restrictions when breastfeeding

Use with caution

Restrictions during pregnancy

Use with caution

Use for renal impairment

Use with caution in patients with nephrosclerosis who are not receiving hemodialysis, as a more rapid deterioration of renal function is possible.

Restrictions for impaired renal function

Use with caution

special instructions

During therapy with epoetin beta, platelet counts, hematocrit and hemoglobin should be regularly monitored.

Epoetin beta should be used with caution in refractory anemia in the presence of blast-transformed cells, epilepsy, thrombocytosis and chronic liver failure.

The therapeutic effectiveness of epoetin beta may be reduced if there is a deficiency of iron, folic acid, or vitamin B12.

Iron deficiency should be excluded before starting treatment with epoetin beta, as well as throughout the entire period of therapy. If necessary, additional therapy with iron supplements may be prescribed in accordance with clinical recommendations.

The effectiveness of treatment decreases with iron deficiency in the body, with infectious and inflammatory diseases, and hemolysis.

The possibility of epoetin beta influencing the growth of certain types of tumors, especially bone marrow malignancies, cannot be completely excluded.

While using epoetin beta, it is necessary to monitor blood pressure levels, paying attention to the occurrence or worsening of unusual headaches. This may require adjustment of therapy or prescription of antihypertensive drugs.

Use with caution for epilepsy, thrombocytosis, liver failure, vascular insufficiency, and malignant neoplasms; in patients with nephrosclerosis not receiving hemodialysis, since a more rapid deterioration of renal function is possible.

The decision to use epoetin beta in patients with nephrosclerosis not receiving dialysis must be made individually, since the possibility of a more rapid deterioration of renal function cannot be completely excluded. In most cases, along with an increase in hemoglobin, the concentration of ferritin in the serum decreases. Ferritin levels must be determined throughout the course of treatment. If it is less than 100 ng/ml, iron replacement therapy is recommended.

Patients who donate autologous blood and are in the pre- or postoperative period should also receive additional adequate amounts of iron until ferritin levels normalize.

Side effect

From the cardiovascular system:

arterial hypertension, hypertensive crisis, shunt thrombosis.

From the nervous system:

encephalopathy (more often during hypertensive crises), headache, confusion.

From the blood coagulation system:

rarely - thrombocytosis, thrombotic complications.

From the hematopoietic system:

partial red cell aplasia (PRCA).

Allergic reactions:

rarely - skin rash, itching, urticaria, anaphylactoid reactions.

For the skin and subcutaneous tissues:

Stevens-Johnson syndrome.

From the laboratory parameters:

a decrease in plasma ferritin with a simultaneous increase in hemoglobin, an increase in the level of potassium and phosphates in plasma.

Other:

flu-like syndrome, local reactions.

What affects the production of erythropoietin?

Here's what contributes to decreased oxygen levels in the blood and increased production of erythropoietin:

• high altitude
• hypoxia
• lung diseases
• heart disease

High altitude

At higher altitudes, air pressure is lower, which means there is less oxygen in each breath. The body compensates by increasing the production of erythropoietin and red blood cells to maintain stable oxygen levels in the blood. This response helps combat symptoms of altitude sickness caused by decreased oxygen levels.

☝️When adapting to high altitudes, different people show big differences: some quickly produce more erythropoietin, others much more slowly.

The body's response to high altitude is partly determined by genetics. Populations that have traditionally lived at high altitudes for thousands of years, such as the Himalayan Sherpas, produce more erythropoietin and have, on average, more red blood cells than people living at sea level.

Interpretation:

• Anemia, including aplastic; secondary polycythemia (eg, hypoxia at high altitudes, chronic obstructive pulmonary disease, pulmonary fibrosis); erythropoietin-secreting tumors (for example, cerebellar hemangioblastomas, pheochromocytoma, renal tumors); pregnancy; polycystic kidney disease; kidney transplant rejection; moderate bleeding in a healthy person.
• Kidney failure; primary (true) polycythemia; anemia of chronic inflammatory, infectious, oncological diseases.

Sample result (PDF)

What happens if I have too little erythropoietin?

If you have too little erythropoietin, which is usually caused by chronic kidney disease, you will have fewer red blood cells and you will be anemic. Erythropoietin was produced synthetically to treat anemia resulting from chronic renal failure. It is also prescribed to patients with other rarer types of cancer.

Professional athletes have used this type of erythropoietin (known as blood doping) to improve their performance, especially to increase endurance. Artificially increasing erythropoietin levels produces more hemoglobin and red blood cells and therefore improves the amount of oxygen delivered to tissues, especially muscles. This can improve performance, although this type of doping practice is prohibited by most professional sports committees.

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What does excess erythropoietin mean?

Increasing erythropoietin levels causes the bone marrow to produce more red blood cells. Constantly elevated levels of this hormone signal a chronic lack of oxygen in the blood, for example, due to iron deficiency anemia. Also, an increase in erythropoietin levels can be caused by a tumor that secretes the hormone. For example, renal cell carcinoma.

In rare cases, too many red blood cells can cause a condition known as secondary polycythemia. It is associated with a number of serious health risks:

• increased blood viscosity
• less efficient blood supply and oxygen saturation
• high blood pressure in the lungs
• life-threatening blood clots
• stroke

What happens if I have too much erythropoietin?

What happens if I have too much erythropoietin?
Excess erythropoietin occurs due to chronic low oxygen levels or due to rare tumors that produce high levels of erythropoietin. This causes a condition known as polycythemia, which is an increased number of red blood cells. For many people, polycythemia does not cause any symptoms. However, there are general and nonspecific symptoms, including weakness, fatigue, headache, itching, joint pain and dizziness.