A quantitative systems pharmacology model of hyporesponsiveness to erythropoietin in rats
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Pharmacodynamics
Epoetin alfa
Objective: To assess the response of unadjusted dose of erythropoietin with respect to weight in
patients on dialysis.
Subjects and Methods: Fifty-five patients who previously had three dialysis sittings, had
received erythropoietin for at least one month and were coming on regular follow up dialysis in
dialysis clinic of Shifa International Hospital, Islamabad were included in this study.
Erythropoietin was given subcutaneously twice a week adding to a dose of 4000 units per week.
Hemoglobin level was determined at the end of study period.
Results: The over all increase in hemoglobin after the administration of erythropoietin was
1.18±0.06 g/dl. 87.3% patients responded to erythropoietin and showed a rise in their
hemoglobin, while 12.7% did not respond.
Conclusion: Unadjusted dose of erythropoietin showed increase in hemoglobin but in most of
the cases failed to achieve the target hemoglobin. In order to achieve the target hemoglobin,
administration of adjusted doses of rHuEPO is required. (Rawal Med J 2006;31:17-19)
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Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50–75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.
Epoetin alfa
Erythropoietin receptor
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Hypoxia
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Hematopoietic growth factor
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Hypoxia
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Recombinant human erythropoietin (r-HuEPO; epoetin alfa) is well established as safe and effective for the treatment of anemia. In addition to the erythropoietic effects of endogenous erythropoietin (EPO), recent evidence suggests that it may elicit a neuroprotective effect in the central nervous system (CNS). Preclinical studies have demonstrated the presence of EPO receptors in the brain that are up-regulated under hypoxic or ischemic conditions. Intracerebral and systemic administration of epoetin alfa have been demonstrated to elicit marked neuroprotective effects in multiple preclinical models of CNS disorders. Epoetin alfa has also been shown to prevent the loss of autoregulation of cerebral blood flow in a model of subarachnoid hemorrhage. The mechanisms of EPO-induced neuroprotection include prevention of glutamate-induced toxicity, inhibition of apoptosis, anti-inflammatory effects, antioxidant effects, and stimulation of angiogenesis. Collectively, these findings suggest that epoetin alfa may have potential therapeutic utility in patients with ischemic CNS injury.
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A review of the pertinent literature on the relation of erythropoietin production to the presence of renal neoplasm suggests that erythropoietin may be produced either directly by the tumor or indirectly by its physical effect on the adjoining normal renal tissue. The most commonly found tumors which are associated with elevated levels of serum and urinary erythropoietin are the hypernephromas. However, the presence of erythropoietin and an associated erythrocytosis even here occurs only relatively infrequently. Some studies have demonstrated the presence of erythropoietin activity in tumor tissue itself but erythropoietin has not been isolated from renal tumor tissue. In some patients with Wilms' tumor, erythropoietin blood levels may also be increased; however, erythrocytosis in these patients is not a characteristic feature. Other renal tumors rarely produce erythrocytosis and presumably no erythropoietin. Possible explanations for the production of erythropoietin by renal tumors are discussed.
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Hematology
Iron Isotopes
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The sections in this article are: 1 The Functional Anatomy of the Erythropoietin Molecule 1 The Erythropoietin Receptor 2 Erythropoiesis and Erythroid Differentiation 3 Modulation of Serum Erythropoietin Levels 3.1 Assays for Erythropoietin 3.2 Serum Erythropoietin Levels and Their Dependence on Oxygenation 3.3 Kinetics and Quantity of Increases in Serum Erythropoietin Levels 3.4 Disturbances in Oxygen-Dependent Control of Serum Erythropoietin Levels 3.5 Clearance and Metabolic Fate of Erythropoietin 4 The Source of Erythropoietin 4.1 Organs Producing Erythropoietin 4.2 Relative Contribution of Liver and Kidneys to Erythropoietin Formation 4.3 Cellular Site of Erythropoietin Formation 5 Oxygen Sensing in the Control of Erythropoietin Formation 5.1 Evidence for Intrarenal Oxygen Sensing 5.2 The Role of Local Oxygenation in Hepatic Erythropoietin Formation 5.3 The Role of Local Oxygenation for Renal Erythropoietin Formation 5.4 Mechanism of Oxygen Sensing and Signal Transduction 6 Control of Erythropoietin Gene Expression 6.1 Modulation of Erythropoietin mRNA Levels 6.2 Cis-Acting Sequences that Coordinate Gene Expression 6.3 Sequence Conservation in Erythropoietin Genes 6.4 Hypersensitive Sites in Erythropoietin Genes 6.5 The Promoter of the Erythropoietin Gene 6.6 Enhancer Elements 3′ to the Erythropoietin Gene 6.7 Operation of Distant Cis-Acting Elements to Control Tissue Specificity of Gene Expression 6.8 Cis-Acting Sequences in Erythropoietin mRNA 7 Relationship to other Adaptive Responses to Hypoxia
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Hemoglobin levels measured after hemodialysis, as compared to hemoglobin levels measured before hemodialysis, are suggested to be a more accurate reflection of the hemoglobin levels between hemodialysis sessions, and to be a better reference point for adjusting erythropoietin dosing.The aim of this study was to compare the hemoglobin levels before and after hemodialysis, to calculate the required erythropoietin doses based on these levels, and to develop a model to predict effective erythropoietin dosing.In this cross-sectional study, the hemoglobin levels of 52 patients with end-stage renal disease were measured before and after hemodialysis. The required erythropoietin doses and the differences in cost were calculated based on the hemoglobin levels before and after hemodialysis. A model to predict the adjusted erythropoietin dosages based on post-hemodialysis hemoglobin levels was proposed.Hemoglobin levels measured after hemodialysis were significantly higher than the hemoglobin levels before hemodialysis (11.1 ± 1.1 vs. 11.9 ± 1.2 g/dL, P < 0.001, 7% increase). The mean required erythropoietin dose based on post-hemodialysis hemoglobin levels was significantly lower than the corresponding erythropoietin dose based on pre-hemodialysis hemoglobin levels (10947 ± 6820 vs. 12047 ± 7542 U/week, P < 0.001, 9% decrease). The cost of erythropoietin was also significantly lower when post-hemodialysis levels were used (15.96 ± 9.85 vs. 17.57 ± 11.00 dollars/patient/week, P < 0.001). This translated into 83.72 dollars/patient/year in cost reduction. The developed model for predicting the required dosage is: Erythropoietin (U/week) = 43540.8 + (-2734.8) × Post-hemodialysis Hb* (g/dL). [(R2) = 0.221; *P < 0.001].Using post-hemodialysis hemoglobin levels as a reference point for erythropoietin dosing can result in significant dose and cost reduction, and can protect hemodialysis patients from hemoconcentration. The prediction of the erythropoietin adjusted dosage based on post-hemodialysis Hb may also help in avoiding overdosage.
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