Injection Of Recombinant Erythropoietin Research Articles

Erythropoietin-Associated Posterior Reversible Encephalopathy Syndrome

This case demonstrates an underrecognized cause of posterior reversible encephalopathy syndrome (PRES). We report a 51-year-old male with a history of essential hypertension without preexisting renal impairment who presented with 3 days of occipital headache and convulsive status epilepticus in the setting of refractory hypertension. He had been receiving outpatient human recombinant erythropoietin injections for virally mediated bone marrow suppression, which worsened his baseline hypertension. Magnetic resosnance imaging (MRI) of the brain on admission showed diffuse bilateral, symmetric signal hyperintensities and patchy enhancement involving the cortex and white matter in both cerebral hemispheres. His blood pressure and seizures were successfully treated during hospital admission, with complete resolution of his neurological deficits. MRI brain performed 6 weeks from initial scan showed normalization of his prior findings. Recombinant human erythropoietin (RhEPO) may be an underrecognized cause of PRES and should be considered in patients receiving this treatment regardless of the absence or presence of renal impairment. RhEPO-mediated precipitation/exacerbation of hypertension, alterations in cerebral blood flow, and changes in endothelial integrity may underlie this association. MRI signal changes are reversible and typical for that of PRES, and significant improvement of symptoms can be expected.

The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research.

We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

To elucidate the safety and efficacy of exogenous erythropoietin (EPO) for the protection of photoreceptor cells in a rat model of retinal detachment (RD). Recombinant rat EPO (400 ng) was injected into the vitreous cavity of normal rats to observe the eye manifestations. Retinal function was assessed by flash electroretinograms. Histopathological examination of retinal tissue was performed at 14 days and 2 months after injection, respectively. To investigate the inhibitory effect of EPO on photoreceptor cell apoptosis in RD rats, 100, 200, or 400 ng EPO was injected into the vitreous cavity immediately after RD model establishment. Apoptosis of photoreceptor cells was determined at 3 days after injection. Caspase-3 activation was measured by western blot analysis and immunofluorescence, respectively, and the level of Bcl-X(L) expression was analyzed by western blot. Intravitreal injection of EPO 400 ng into normal rats had no significant impact on retinal function, morphology, or structure. Apoptosis of retinal photoreceptor cells apparently increased after RD and was significantly reduced following EPO treatment. The thickness of the outer nuclear layer in the RD + 400 ng group was significantly thicker than that in other experimental RD groups both at 14 days and at 2 months after RD (P < 0.05). Western blot and immunofluorescence analyses showed decreased caspase-3 activation and increased Bcl-X(L) expression following EPO treatment. Intravitreal injection of EPO 400 ng is safe, and EPO may suppress caspase-3 activation and enhance Bcl-X(L) expression, resulting in inhibition of apoptosis and protection of photoreceptor cells.

Study of serum paraoxonase activity and total antioxidant capacity changes following recombinant erythropoietin injection in rat

Study of serum paraoxonase activity and total antioxidant capacity changes following recombinant erythropoietin injection in rat

Study of serum malondialdehyde concentration and paraoxonase changes following recombinant erythropoietin injection in male rats

Study of serum malondialdehyde concentration and paraoxonase changes following recombinant erythropoietin injection in male rats

Study of relation between serum HDL and LDL concentration changes following recombinant erythropoietin injection in rat

Study of relation between serum HDL and LDL concentration changes following recombinant erythropoietin injection in rat

Study of relation between serum HDL concentration and paraoxonase activity changes following recombinant erythropoietin injection in male rats

Study of relation between serum HDL concentration and paraoxonase activity changes following recombinant erythropoietin injection in male rats

The Swedish Blood Pass project

Manipulation of the blood's oxygen carrying capacity (CaO(2)) through reinfusion of red blood cells, injections of recombinant erythropoietin or by other means results in an increased maximal oxygen uptake and concomitantly enhanced endurance performance. Therefore, there is a need to establish a system--"A Blood Pass"--through which such illegal and unethical methods can be detected. Venous blood samples were taken under standardized conditions from 47 male and female Swedish national and international elite endurance athletes four times during the athletic year of the individual sport (beginning and end of the preparation period and at the beginning and during peak performance in the competition period). In these samples, different hematological values were determined. ON(hes) and OFF(hre) values were calculated according to the formula of Gore et al. A questionnaire regarding training at altitude, alcohol use and other important factors for hematological status was answered by the athletes. There were some individual variations comparing hematological values obtained at different times of the athletic year or at the same time in the athletic year but in different years. However, the median values of all individual hematological, ON(hes) and OFF(hre), values taken at the beginning and the end of the preparation or at the beginning and the end of the competition period, respectively, as well as median values for the preparation and competition periods in the respective sport, were all within the 95% confidence limit (CI) of each comparison. It must be mentioned that there was no gender difference in this respect. This study shows that even if there are some individual variations in different hematological values between different sampling times in the athletic year, median values of important hematological factors are stable over time. It must be emphasized that for each blood sample, the 95% CI in each athlete will be increasingly narrower. The conclusion is that there is a physiological basis for establishing an individual-based "Blood Pass" system, mainly for athletes competing at the international level. On indications of manipulations of hemoglobin concentration and red cell mass by deviations from established "Blood Pass" data, more specific methods can be applied.

Cytokine gene expression in cerebral hemispheres and behavioral reactions of (CBAxC57Bl)F1 mice.

Interleukin-1beta mRNA, interleukin-1beta receptor mRNA, and erythropoietin receptor mRNA are expressed in the brain of (CBAxC57Bl)F1 mice. Immunization with sheep erythrocytes stimulated the expression of these cytokines in the cerebral hemispheres. Injection of recombinant erythropoietin reduced expression of interleukin-1beta, interleukin-1beta receptor, and erythropoietin receptor genes in the brain of experimental animals and considerably increased their motor activity in the open field test.

Effect of Increased Hemodialysis Dose on Endogenous Erythropoietin Production in End-Stage Renal Disease

We investigated 20 patients (12 men and 8 women) with end-stage renal disease sustained on hemodialysis to determine the effect of 6 weeks of increased dialysis dose on endogenous erythropoietin production. Increased dialysis dose was achieved by increasing thrice-weekly dialysis treatment time from 4 to 4.5 h and switching from an MCA 160 dialyzer to an F80 dialyzer. The mean age of the study subjects was 51 ± 13.8 years, and the mean duration of end-stage renal disease prior to the study was 31.4 ± 55.5 months. All subjects were receiving recombinant erythropoietin for at least 4 months prior to the study. The dialysis dose was increased from a mean reduction of urea of 60.7 to 72%. At baseline, the group’s mean hematocrit was 28.4 ± 3.4%, the mean predialysis endogenous erythropoietin level was 9.1 ± 4.5 (range 2.5–18.4) mU/ml, the mean reduction of urea was 60.7 ± 4%, and the mean transferrin saturation was 22.6 ± 15.5%. Mean thrice-weekly recombinant erythropoietin injections were administered intravenously after dialysis to each patient at a dose of 51 ± 19 U/kg body weight. After 6 weeks of an increased dialysis dose, the mean hematocrit increased from 28.4 ± 3.4 to 32.3 ± 3.3% (p = 0.0001), while the mean serum endogenous erythropoietin level decreased from 9.1 ± 4.5 (range 2.5–18.4) mU/ml to 6.1 ± 3.2 (range 2.5–13.4) mU/ml (p = 0.0001). We conclude that the serum endogenous erythropoietin levels decrease with increased dialysis dose and that the increase in hematocrit following increased dialysis dose is probably not mediated by changes in endogenous erythropoietin.

Gene therapy for long-term expression of erythropoietin in rats.

The injection of recombinant erythropoietin (Epo) is now widely used for long-term treatment of anemia associated with chronic renal failure, cancer, and human immunodeficiency virus infections. The ability to deliver this hormone by gene therapy rather than by repeated injections could provide substantial clinical and economic benefits. As a preliminary approach, we investigated in rats the expression and biological effects of transplanting autologous vascular smooth muscle cells transduced with a retroviral vector encoding rat Epo cDNA. Vector-derived Epo secretion caused increases in reticulocytes, with peak levels of 7.8-9.6% around day 10 after implantation. The initial elevation in reticulocytes was followed by clinically significant increases in hematocrit and hemoglobin for up to 11 weeks. Ten control and treated animals showed mean hematocrits of 44.9 +/- 0.4% and 58.7 +/- 3.1%, respectively (P < 0.001), and hemoglobin values of 15.6 +/- 0.1 g/dl and 19.8 +/- 0.9 g/dl, respectively (P < 0.001). There were no significant differences between control and treated animals in the number of white blood cells and platelets. Kidney and to a lesser extent liver are specific organs that synthesize Epo in response to tissue oxygenation. In the treated animals, endogenous Epo mRNA was largely down regulated in kidney and absent from liver. These results indicate that vascular smooth muscle cells can be genetically modified to provide treatment of anemias due to Epo deficiency and suggest that this cell type may be targeted in the treatment of other diseases requiring systemic therapeutic protein delivery.

Erythropoietin metabolism and pharmacokinetics in experimental nephrosis.

We studied erythropoietin (EPO) metabolism, regulation, and pharmacokinetics in rats with nephrotic syndrome. Sprague-Dawley rats were randomized into nephrotic (puromycin-induced) and pair-fed control groups. Animals were studied at baseline and after induction of anemia or exposure to hypobaric conditions (32 cmHg). The nephrotic group showed a reduced hematocrit (P < 0.05), a significant urinary EPO excretion, and an inappropriately low plasma EPO. Induction of anemia and exposure to hypoxia resulted in a less pronounced elevation of plasma EPO in the nephrotic group than in the control group (P < 0.05). The blunted plasma EPO response to hypoxia in nephrotic animals was associated with a marked rise in urinary EPO excretion. Pharmacokinetic studies following intravenous injection of recombinant EPO, 100 U/kg, revealed a shorter plasma half-life (t1/2) (P < 0.05), larger apparent volume of distribution (P < 0.05), and greater clearance (P < 0.02) in the nephrotic group than in the controls. Estimated endogenous EPO production rate in nephrotic rats with severe anemia was significantly lower (P < 0.05) than that of equally anemic controls. Thus puromycin-induced nephrotic syndrome is associated with marked urinary loss of EPO, relatively depressed plasma EPO response to anemia and hypoxia, as well as reduced plasma t1/2, increased volume of distribution, and clearance of exogenous EPO.

Calcium Deposition in the Skin of a Hemodialysis Patient with Widespread Skin Necrosis

Rapidly progressive skin necrosis involving large areas of the skin associated with extensive vascular calcification was observed in a 39-year-old male patient on chronic hemodialysis. Histological examination of the periphery of a skin ulcer showed that subepidermal arterioles were occluded with fibrin deposits and that calcification was demonstrated in subcutaneous small arteries and arterioles. Electron microscopically, electron-dense materials, granular, crystal-like, vacuolar, or laminated, were found not only in arterial walls of the periphery of an ulcer but also, to a lesser extent, in those of normal-appearing skin. The skin necrosis gradually healed with antiseptic topical treatments and the injection of recombinant erythropoietin. The relationship between the vascular lesions in hemodialysis patients and progressive skin necrosis is not well known, although a combination of local and systemic factors may play an important role in the development of vascular calcification and skin necrosis in uremic and hemodialysis patients.

Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis

purpse: To administer recombinant erythropoietin to patients with rheumatoid arthritis who had significant anemia, while monitoring hematologic and rheumatologic clinical responses as well as potential toxicity. patients and methods: Seventeen patients with rheumatoid arthritis from five rheumatology care settings were studied. The patients had initial hematocrits of 34% or less and stable clinical status, and were not being treated with second-line drugs or corticosteroids. An 8-week randomized double-blind study involving various dosages of recombinant erythropoietin, as well as placebo, was followed by a 24-week open-label study in which dosage could be titrated to achieve a normal hematocrit. results: In the 8-week randomized study, four of 13 patients who received injections of recombinant erythropoietin showed a hematologic response, arbitrarily defined as at least a 6-unit increase in hematocrit. None of four placebo-treated patients showed a meaningful hematologic response. All 11 patients who completed the subsequent 24-week open-label study reached a normal hematocrit level at some time during the study, and 10 of 11 showed an increase of hematocrit 6 units or greater. At least one adjustment, i.e., an increase, decrease, or omission of the erythropoietin dosage, was required in all patients to maintain the hematocrit at a target range of 35% for women or 40% for men. Meaningful changes were not seen in patients' capacity to perform activities of daily living or pain levels during either the 8-week randomized study or the 24-week open-label study. No adverse effects were associated with recombinant erythropoietin therapy. conclusion: Patients with rheumatoid arthritis showed excellent hematologic responses to recombinant erythropoietin, without toxicity, during careful monitoring for appropriate dosage adjustment, although a meaningful change in rheumatologic clinical status was not seen.