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Clinical Oncology

DECEMBER 10, 2016

[Treatment of anemia in cancer patients]

NAGYKÁLNAI Tamás

[Anemia in cancer can be resulted by the underlying malignant disease or related to the chemotherapy. Cancer-related anemia adversely effects quality of life and is associated with reduced survival. Clinical studies demonstrate that blood transfusions, ESAs, and correction of iron defi ciency are therapeutic options for anemic cancer patients.]

Hypertension and nephrology

APRIL 10, 2016

[Plasma ortho-tyrosine/para-tyrosine ratio predicts hyporesponsiveness to erythropoiesis-stimulating agents in dialyzed patients]

KUN Szilárd, MIKOLÁS Esztella, MOLNÁR Gergő Attila, SÉLLEY Eszter, LACZY Boglárka, CSIKY Botond, KOVÁCS Tibor, WITTMANN István

[Objectives: Patients suffering from end-stage renal failure (ESRF) are mostly treated with erythropoiesis-stimulating agents (ESAs). They often show hyporesponsiveness to ESA, which condition is associated with elevated production of free radicals. Phenylalnine (Phe) is converted into para- and ortho-tyrosine (p- and o- Tyr) by hydroxyl free radical. o-Tyr is produced exclusively in this way. However, physiological isomer p-Tyr is formed in significantly higher amounts by phenylalaninehydroxylase, mainly in the kidney. It has been shown that p-Tyr production is decreased in ESRF. As a result, p-Tyr can be replaced by o-Tyr in proteins, e.g. in proteins playing part in signal transduction of erythropoietin. We aimed to study the association of different Tyr isoforms with ESA-responsiveness. Methods: Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n=16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n=8), hemodialyzed patients with ESA-treatment (ESA-HD; n=40) and patients on continuous peritoneal dialysis (CAPD; n=21). Plasma p-, o-Tyr and Phe levels were detected using a high performance liquid chromatography (HPLC)-method, with fluorescence detection. ESA-demand was expressed as ESA-dose, ESAdose/ body weight and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Multivariate regression models were used to examine predictors of ESA-demand. In these models, most of the known predictors of ESA-hyporesponsiveness were included. Results: Lower p-Tyr levels were found in dialyzed patients compared with control subjects. In contrast, o-Tyr levels and o-Tyr/p-Tyr ratios were higher in dialyzed patients. Regarding dialyzed patients, o-Tyr level and o-Tyr/p-Tyr ratio were higher in ESA-HD than in non-ESA-HD and CAPD groups. Weekly ESA-dose/body weight and ERI1 correlated with o-Tyr/p-Tyr ratio (r=0.441, p=0.001; r=0.434, p=0.001, respectively). Finally, o-Tyr/p-Tyr ratio proved to be an independent predictor of ERI1 (β=0.330, p=0.016). Discussion: Our results suggest that elevation of o-Tyr/p-Tyr ratio could be responsible for ESA-hyporesponsiveness in dialyzed patients.]

Hypertension and nephrology

FEBRUARY 10, 2016

[Incorporation of ortho- and meta-tyrosine into cellular proteins leads to erythropoietin-resistance]

MIKOLÁS Esztella Zsóka, KUN Szilárd, LACZY Boglárka, MOLNÁR Gergő Attila, SÉLLEY Eszter, KŐSZEGI Tamás, WITTMANN István

[Introduction: Erythropoietin (EPO) is a glycoprotein hormone, which is responsible for the proliferation and differentiation of erythroid cell lines. Since it is widely used as the treatment of renal anaemia, EPO-resistance is a common concern. Aims: We aimed to perform in vitro experiments to investigate a possible mechanism of EPO-hyporesponsiveness. Methods: We used a factor dependent erythroblast cell line (TF-1). Two independent observers calculated cell counts simultaneously on day 1; 2 and 3 in Bürker cell counting chambers. Colorimetric method was used to measure protein concentrations. Measurement of protein-bound para-, ortho- and meta-tyrosine was performed with reverse phase high performance liquid chromatography with fluorescence detection. We determined ERK and STAT5 activation using Western blot method. Results: In case of ortho- and meta-tyrosine pretreated cells time-dependent, EPOinduced proliferative activity was decreased compared to the 1.7 fold elevation of cell counts seen in para-tyrosine cultured cells. Protein concentration of ortho- and metatyrosine treated samples was significantly lower than control cells on the third day. Addition of para-tyrosine reclaimed EPO-sensitivity. Erythroblasts treated with orthoor meta-tyrosine contained lower concentrations of protein-bound para-tyrosine with higher ortho- and meta-tyrosine content. EPO dependent activation of ERK and STAT5 could be inhibited by ortho- or meta-tyrosine treatment. Conclusions: Elevated level of protein-bound ortho- and meta-tyrosine in erythroblasts can result in the pathological modification of intracellular signaling, leading to EPOhyporesponsiveness.]

Hypertension and nephrology

JULY 20, 2013

[Goals, doubts and confidences in treatment of renal anemia]

KISS István, SZEGEDI János, KULCSÁR Imre, DEÁK György, KISS Zoltán, REMPORT Ádám, AMBRUS Csaba

[The authors sum up the physiology of erythropoiesis, the history of the erythropoietin’s discovery and the steps through which it became applicable to clinical adaptation. The biologically similar erythropoietin medicines and their application are reviewed. The setting of the target hemoglobin value and the weekly amount of erythropoietin needed for successful therapy are briefly surveyed. The authors draw attention to the fact that by increasing the dose the risk of mortality rises. Considering the other side effects they conclude based on international data and studies that “less is more” in this case namely the lower target value and erythropoietin dose can mean bigger therapeutic success. The erythropoietin treatment’s practice in Hungary is expressly efficient in the authors’ view.]

Hypertension and nephrology

JULY 20, 2013

[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.]

Hypertension and nephrology

SEPTEMBER 20, 2011

[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

APRIL 01, 2009

[Anaemia of chronic disease: causes and therapeutic options]

EGYED Miklós

[Anemia observed in patients with infectious, inflammatory, or neoplastic diseases and persisting for more than one month is called anemia of chronic disease. The term anemia of chronic disease is far from perfect, the terms of anemia of inflammation, cytokine-mediated anemia, and anemia of defective iron reuse are also used. Anemia of chronic disease is more common than any other anemia syndrome - apart from anemia caused by iron deficiency secondary to blood loss. Erythrocytes usually are normocytic, but hypochromia and microcytosis may also be observed. In almost every case, this type of anemia is hypo-regenerative. Characteristic laboratory findings include hypoferremia, hyperferritinemia, and hypotransferrinemia. Cause of this anemia is complex; pathogenesis of this anemia includes moderate shortening of erythrocyte survival, blunted response to erythropoietin, reduced medullar erythropoiesis, and limited medullar iron availability. In addition to treating the underlying pathology, treatment opportunities are recombinant human erythropoietin, transfusions, and intravenous iron.]

Hypertension and nephrology

OCTOBER 20, 2010

[Biosimilar erythropoietins in nephrology - benedictio seu maledictio?]

KISS István

[Biological medicines of protein or polypeptide origin produced with biotechnology are far more complex in structure than the low molecular weight chemical ones. In conjunction with chemical drugs generic copies are completely the same, while in the field of biological medicines only similarity can be stated, as identical molecules cannot be produced. Spatial structure, isomers and side chains cause difference and for this reason these are called biosimilar drugs. Immunogenity of biosimilar drugs is very different and the risk of antibody production against them is diverse. Pure red cell aplasia, a rare side effect of erythropoietins is a life-threatening condition so every effort must be done for its prevention. Biosimilar drugs are not to be replaced with each other, and even the reference drugs should not be substituted in order to identify easily the side effects of each drug. Importantly financing should support these clinical principles namely a cheaper drug could be started as a new treatment but a former treatment should not be replaced because of cost sensitivity. It is important to provide the availability of the very expensive biologically active drugs to each patient but it is acceptable that the treatment should be as cost-effective as possible. Similarly to the generic copy program of chemical drugs biosimilar drugs are also important for the clinical practice, however their use needs appropriate regulation and farmacovigilance.]

Lege Artis Medicinae

DECEMBER 20, 2007

[PLEIOTROPIC FUNCTIONS OF ERYTHROPOIETIN]

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.]

Lege Artis Medicinae

NOVEMBER 20, 2007

[HAEMOGLOBIN CYCLICITY IN RENAL ANAEMIA]

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.]