Lege Artis Medicinae



OCTOBER 21, 2007

Lege Artis Medicinae - 2007;17(10)

[Recombinant human erythropoietin has been used for more than 20 years for the treatment of renal anaemia, with epoetin-alfa and -beta representing the common traditional preparations. By the modification of the molecule’s carbohydrate moiety or structure a longer duration of erythropoietin receptor stimulation was achieved. The administration of these new molecules (darbepoetin, C.E.R.A.) once or twice a month is also sufficient to achieve serum haemoglobin target levels, making the treatment safer and more comfortable both for the patients and the personnel. These recently developed synthetic erythropoietin receptor stimulating molecules, along with recombinant human erythropoietin, are together called “Erythropoiesis Stimulating Agents”. In haemodialysed patients the intravenous route is preferred, but the subcutaneous administration can substantially reduce dose requirements. In praedialysed, transplanted or peritoneally dialysed patients, erythropoiesis stimulating agents should preferably be given subcutaneously both for economic and practical reasons. There are ongoing clinical trials with erythropoiesis stimulating molecules that can be administered by inhalation or per os. Current evidence suggests that the serum haemoglobin level should preferably not exceed 12 g/dl with the use of erythropoiesis stimulating agents. No cardiovascular protective effect of higher serum haemoglobin levels was demonstrated in two large clinical trials. Further well-designed studies are necessary to set evidence-based haemoglobin targets for erythropoiesis stimulating treatment. Arguments for a more widespread use of agents with extended duration include medical, financial and patient satisfaction reasons. The release of new erythropoiesis stimulating agents may further simplify the treatment of renal anaemia.]



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Hypertension and nephrology

[Practical aspects of therapy by erythropoiesis stimulating agents in renal anaemia]

DEÁK György, HERSZÉNYI Eszter, AMBRUS Csaba, KISS István

[Prevalence of renal anaemia due to insufficient production of erythropoietin increases progressively in the course of renal function deterioration. Renal anaemia is treated by erythropoesis stimulating agents (ESA). Outcomes of randomized clinical trials have taught us to avoid the strategy of normalization of hemoglobin (HGB) levels by ESA therapy as it may increase the risk of cardiovascular events and mortality. The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anaemia published in 2012 recommends to start ESA therapy in the 90-100 g/l HGB range and suggests to keep HGB concentrations below 115 g/l. It is an inappropriate strategy to aim at normalizing hemoglobin (HGB) levels by ESA therapy because it may lead to progressive escalation of ESA doses even in the presence of diminished ESA responsiveness. High ESA doses and diseases causing ESA hyporesponsiveness eg. infections, chronic inflammation, malnutrition, insufficient dose of dialysis, severe hyperparathyroidism, iron deficiency are related to increased risk of mortality. KDIGO Clinical Practice Guideline for Anaemia emphasizes the importance of assessing and treating causes of ESA hyporesponsiveness, limits ESA dose escalation and recommends gradually changing ESA doses to avoid high amplitude HGB oscillation.]

Lege Artis Medicinae


NAGY Judit, KISS István

[Erythropoietin produced by the foetal liver and the adult kidney is the major stimulator of erythropoiesis. Erythropoietin production is regulated by hypoxic activation of erythropoietin gene transcription. Recently, new sites of erythropoietin production have been found mainly in the central nervous system and in the cardiovascular system. These tissues have a paracrine and/or autocrine system of erythopoietin. The pleiotropic function of erythropoietin in these systems is tissue and cell protection by several mechanisms including inhibition of apoptosis, attenuation of ischaemic or reperfusion injury, anti-inflammatory and antioxidative effects. Furthermore, it promotes vascular recovery and enhances neoangiogenesis. In vivo and in vitro studies have proved that systemically administered human erythropoietin can also provide tissue protection. However, adverse effects of erythropoietin treatment such as hypertension, hyperviscosity and thrombosis may override the beneficial effect of systemic erythropoietin treatment. There are preliminary data that erythropoietin analogues, e.g., asyaloerythropoietin or carbamylated erythropoietin can provide tissue protection without stimulating erythropoiesis.]

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[Biosimilar erythropoesis stimulating agents - from registration to clinical practice]

KISS István

[The original patent drugs appear immediately on expiry of all rights in generic and biosimilar drugs in the pharmaceutical market, favorable supply option which helps in the rational management of medicines, mainly for generic drugs cheaper to allow more patient care. Of course, this is a well-organized legal and regulatory framework, thoughtful strategy can be successful in every respect. In another non-identical molecular structure biosimilar drugs in different immunogenicity of knowledge and risk is not defined in clinical practice and therefore the risk is still underestimated and not well regulated in the world, and increasing the number reported is the antibody formation case of a biosimilar erythropioetin also. The immunogenicity of original biological and of biosimilar drugs in identifying, defining a prominent role in the post-marketing surveillance, pharmacovigilance, and the special methods of control of immunogenicity. The original and the biosimilar medicines interchangeability, marketability of the assets relating to the regulations are not uniform in Europe or the European registration scheme is an important new biosimilar medicinal products, is that the medicinal product, the documentation is not expected to be accompanied by a risk management plan, as well as action to ensure the safety (pharmacovigilance) as part of the collection and reporting of adverse reactions to the official. It is important that the professional management of renal anemia guidelines - the practice of nephrology erythropoietin therapy - clearly define the biological medicines (originator and biosimilar erythropoietin) application requirements and suggestions. Consequently, this summary wants to draw attention to the therapeutic potential of biosimilar drugs, generic drugs to distinguish between explicit and the potential risks and the need to reduce the risks of professional and health policy decisions.]

Lege Artis Medicinae


REUSZ György, SZABÓ J. Attila

[Erythropoiesis stimulating agents are glycoproteins in which the oligosaccharide chains that terminate in sialic acid bind to the peptide with glycosidic bond. The lower the sialic acid content of the erythropoietin, the higher its receptor affinity, while its half-life in the circulation decreases. The biological effect depends on the balance of these factors. In the third-generation erythropoiesis stimulating molecule CERA (continuous erythropoietin receptor activator) a large polyethylene glycol molecule is substituted for sialic acid to ensure slow elimination and better biological efficiency. During treatment with erythropoiesis stimulating agents, haemoglobin levels show cyclic fluctuation. This cyclicity is undesirable, so its frequency and amplitude should be reduced as much as possible. The most recent results suggest that CERA may reduce haemoglobin cyclicity.]


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