High Doses Of Erythropoietin Research Articles

Low and sustained doses of erythropoietin prevent preterm infants from intraventricular hemorrhage

In addition to its hematopoietic function, erythropoietin (EPO) has demonstrated neuroprotective properties in preclinical studies, particularly in cases of reduced oxygenation or ischemia in the neonatal brain. While these findings have sparked optimism for its potential clinical application, the efficacy of EPO remains contentious in translational assays. Notably, while repeated administration of low doses of EPO has correlated with a decrease in adverse outcomes, the use of high EPO doses has shown either negligible or potentially detrimental effects on the incidence of brain injury. In this pilot study, we explored the effects of low and sustained doses of EPO (400 IU/kg) on the incidence of intraventricular hemorrhage (IVH) in premature infants. EPO was administered intravenously three times a week until the infants reached 32 weeks corrected gestational age. Our results indicate a significant decrease in the incidence of IVH with EPO treatment. Although, this study does not provide conclusive evidence on EPO's ability to reverse established IVH, these results strongly support the need for larger-scale clinical trials to further assess EPO's therapeutic potential.

Bone Healing of Critical-Sized Femoral Defects in Rats Treated with Erythropoietin Alone or in Combination with Xenograft.

Critical-size bone defect models are the standard in studies of the osteogenic potential of biomaterials. The present investigation aimed to evaluate the ability of recombinant human erythropoietin (EPO) to induce trabecular bone healing either alone or combined with a xenograft in a rat femoral critical-size defect model. Five-mm bone defects were created in the femoral diaphysis of fifty-six skeletally mature male Wistar albino rats. The animals were divided into six groups: one control group and five experimental groups. The defects in the control group were left empty, whereas an absorbable collagen cone soaked either with saline or erythropoietin (alone or in combination with xenograft) was placed in locally treated groups. The systemic treatment group received EPO subcutaneously. Bone formation was objectively evaluated through radiography, osteodensitometry and histological examination on post-operative days 30 and 90. The results demonstrate that EPO, locally applied on a collagen scaffold, was capable of inducing bone healing, whereas the single systemically administered high EPO dose had only an insignificant effect on bone formation. The combination of EPO with a bone substitute under the form of cancellous granules resulted in more rapid integration between the xenograft and host bone.

Erythropoietin inhibits ferroptosis and ameliorates neurological function after spinal cord injury.

Ferroptosis is one of the critical pathological events in spinal cord injury. Erythropoietin has been reported to improve the recovery of spinal cord injury. However, whether ferroptosis is involved in the neuroprotective effects of erythropoietin on spinal cord injury has not been examined. In this study, we established rat models of spinal cord injury by modified Allen's method and intraperitoneally administered 1000 and 5000 IU/kg erythropoietin once a week for 2 successive weeks. Both low and high doses of erythropoietin promoted recovery of hindlimb function, and the high dose of erythropoietin led to better outcome. High dose of erythropoietin exhibited a stronger suppressive effect on ferroptosis relative to the low dose of erythropoietin. The effects of erythropoietin on inhibiting ferroptosis-related protein expression and restoring mitochondrial morphology were similar to those of Fer-1 (a ferroptosis suppressor), and the effects of erythropoietin were largely diminished by RSL3 (ferroptosis activator). In vitro experiments showed that erythropoietin inhibited RSL3-induced ferroptosis in PC12 cells and increased the expression of xCT and Gpx4. This suggests that xCT and Gpx4 are involved in the neuroprotective effects of erythropoietin on spinal cord injury. Our findings reveal the underlying anti-ferroptosis role of erythropoietin and provide a potential therapeutic strategy for treating spinal cord injury.

Investigation into the effect of systemic single high-dose erythropoietin on the healing of Achilles tendons in rats.

This study aimed to examine systemic erythropoietin's effect on the Achilles tendon's healing in a rat model. Twenty-five adult Wistar rats were randomly assigned to one of two groups. The Achilles tendon of each rat was transected 5 mm proximal to its insertion to the calcaneus. All Achilles tendons were then repaired using modified Kessler methods. A single dose (5000 U/kg) of intraperitoneal erythropoietin (EPO) was administered to group I. Group II was a control group and did not receive an EPO injection. Four rats from each group were sacrificed at 1, 3 and 6 weeks after injection. Histopathological assessments were performed by observers blinded to the treatment. Groups I and II showed a similar increase in fibroblast cytoplasmic content and fibrillar collagen in the extracellular matrix. Collagen deposition, cellular proliferation, number of lipid vacuoles and capillary increases were similar between the groups. Evidence from this study has shown no direct effect of a single systemic high dose of EPO on the histological properties of the Achilles tendon in rats.

Factors contributing to the recovery from anemia in hemodialysis patients during the administration of recombitant erythropoietin

Introduction/Aim: Anemia is the commonest complication in patients on a chronic hemodialysis program and is the cause of reduced quality of life. The aim of this study was to identify the factors that contribute to the better control of anemia with the help of recombinant erythropoietin in persons undergoing hemodialysis. Methods: The cross-sectional study was conducted in 2017 and it included 52 persons on hemodialysis at the Clinical Center of Montenegro. The participants were divided into those, in whom hemoglobin values increased to satisfactory values (110 g/l or more) after three months of application of recombinant erythropoietin (group 1), and those, in whom hemoglobin values were lower than 110 g/l (group 2). Data were collected from the medical history of all participants. T-test was used for the statistical analysis of data. Results: After the three-month administration of erythropoietin, the target value of hemoglobin of 110 g/l or more (group 1) was achieved in only 21 patients (40.4%), while hemoglobin values were below 110 g/l in 59.6% of patients. Participants, in whom target values of hemoglobin were not achieved, received significantly higher average doses of erythropoietin and they had higher body mass index in comparison to participants, in whom the target values were achieved. There was no significant difference between the examined groups regarding the response to erythropoietin, duration of erythropoietin therapy, duration of hemodialysis, participants' age, skin-fold thickness, upper arm width, transferrin values, number of erythrocytes, value of albumin, hemoglobin, hematocrit and iron. Conclusion: Possible factors that contribute to worse control of anemia are higher doses of erythropoietin and greater level of nutritional status estimated according to the body mass index. Further research is necessary aimed at finding factors that would contribute to the elimination of anemia in persons on hemodialysis, because non-treated anemia may lead to numerous unfavorable outcomes (poor quality of life, cardiovascular diseases, cerebrovascular insult, decreased survival rate etc.).

From the Literature

From the Literature

Erythropoietin promotes abdominal aortic aneurysms in mice through angiogenesis and inflammatory infiltration.

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain unknown. Here, we tested the hypothesis that erythropoietin (EPO) may promote the formation of AAA. We found that EPO dose-dependently promoted the formation of AAA in both Apoe -/- (66.7%) and wild-type (WT) (60%) mice receiving a high dose of EPO. EPO monoclonal antibodies given to Apoe -/- mice receiving angiotensin II (AngII) stimulation resulted in a markedly lower incidence of AAA (from 86.7 to 20%, P < 0.001), and EPO receptor (EPOR) knockdown in Epor +/- Apoe -/- mice substantially reduced the incidence of AAA compared to Apoe -/- mice after AngII stimulation (from 86.7 to 45.5%, P < 0.05), further supporting the finding that EPO is a contributor to AAA formation. EPO-induced AAA resulted in increased microvessels, phagocyte infiltration, and matrix metalloproteinase secretion, as well as reduced collagen and smooth muscle cells (SMCs). Experiments in vitro and ex vivo demonstrated that EPO induced proliferation, migration, and tube formation of endothelial cells via the JAK2/STAT5 signaling pathway. In humans, serum EPO concentrations were higher in patients with AAA than in healthy individuals and correlated with the size of the AAA, suggesting a potential link between EPO and the severity of AAA in humans. In conclusion, we found that EPO promotes the formation of AAA in both Apoe -/- and WT mice by enhancing angiogenesis, inflammation, collagen degradation, and apoptosis of SMCs and that EPO/EPOR signaling is essential for AngII-induced AAA. The association between EPO and AAA in humans warrants further study.

Refining Hellström-Lindberg Score: Which Patients Could Benefit from Standard Dose EPO?

BackgroundHellström-Lindberg score (HLS-1997) is a useful tool to predict the probability of response to erythropoietin (EPO) treatment in anemic MDS patients. HLS response criteria was not assessed according to the IWG criteria published by Cheson et al. in 2006. To date, international guidelines suggest a front-line therapy with high doses of EPO (80000 U/week) in MDS anemic patients with Hb <10 g/dL and endogenous EPO levels <500 mU/mL. In our previous report, we validated the HLS in a single center cohort according to the IWG criteria of response (Molteni et al. Int J Hematol 2013). Of note, observing the response rate of the “good” responders group (score 3 or 4), a significant difference between patients with a score 3 vs 4 was detected (p= 0.004), identifying two new categories (“good” and “very good”) with different probability of response. The high likelihood of responding with patients with a “very good” score was such as to suggest that even standard therapy doses (40000 U/week) would be effective for this group.AimTo validate our previous report on a new cohort of MDS patients treated with erythropoietin.Patients and methodsHellström-Lindberg score variables considered were: erythropoietin serum levels in pre-treatment (<100, 100-500 or >500 mU/mL) and RBC transfusion requirements (≥2 or <2 RBC per month). We decided not to consider the patients with “poor” HLS (EPO >500 mU/mL and ≥2 RBC per month) on the basis of our previous report and on the evidence of the very modest efficacy of EPO in these cases. Therefore, we applied a “revised HLS” (figure 1), that distinguishes three prognostic groups: “very good” response (score 4), “good” (score 3) and “intermediate” response (score -1 to +1). With this premise, we retrospectively evaluated 57 “low” or “intermediate-1” IPSS risk MDS patients treated with a standard dose of EPO between 2005 and 2017. According to our score: 15 of them were “intermediate”, 12 “good” and 30 “very good”. Response to EPO therapy was based on the revised IWG criteria (2006). Statistical analysis was conducted using Fisher's exact test and ordinal logistic regression followed by Wald's test. Then the quality of the response with the different scores was compared using the Bonferrion - Adjusted for multiple comparison test.ResultsAmong the 57 patients 14 were transfusion dependent before treatment. Initial EPO dose was 40000 U/week. Dose was modulated in relationship to response from a maximum of 40000 U every 5 days to a minimum of 40000 U every two weeks. Response rate observed was 76% (64% in the previous series described) in “good” + “very good” group and 33% (33% in the previous series) in “intermediate” group. Scoring “very good” patients had a higher response rate (80%) than scoring good patients (67%). In the previous experience the results were 79% and 33% respectively. The difference in response rate between “very good” and “intermediate” scoring was statistically significant (p=0.009). No difference was instead noticed between “good” and “very good” scoring (p=0.187) and between “good” and “intermediate” scoring (p=0.384). Furthermore, scoring “very good” patients showed a 700% (it was 667% in the previous report) increase in odds of response compared to scoring “intermediate” patients (p=0.004), meanwhile a not significant difference in odds of response between scoring “good” and scoring “intermediate” was found, just as in the previous described series.Conclusion:These data confirm our previous report which describes a very high probability of responding to standard EPO dose (40000 U/week) in the “very good” group and suggests a “standard” starting dose in these patients. “High” initial doses (80000 U/week) have to be recommended for the “intermediate” group. Considering the “good” group, the difference between the two analysis suggests that it would be appropriate to expand the sample in order to assess whether these patients may benefit from high doses of therapy or may also be candidate, in the first instance, for the standard doses. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review.

Introduction: Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The aim of this study was to review the literature in available scientific databases on NFS—complication after gadolinium-containing contrast agents. Methods: PubMed and Cochrane Library databases were searched using adequate key words. A literature review of the described cases of NSF occurrence after exposure to gadolinium-containing contrast agents was performed. A review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A review written protocol was not drafted. Results: Originally, 647 studies were searched in scientific databases. After rejecting the duplicate results, 515 results were obtained. Finally, nine studies were included in the review. A total of 173 cases with NSF were included in the analysis. The majority of patients were undergoing dialysis. The contrast agent used for MRI was most often gadodiamide and gadopentetate dimeglumine. The time from exposure to NSF symptoms was from two days to three years. Three authors pointed out other factors in their papers that could potentially influence the occurrence of NSF. These included: metabolic acidosis, ongoing infection, higher doses of erythropoietin and higher serum concentrations of ionized calcium and phosphate. Since 2008, the number of reported cases of NSF has decreased significantly. More recent guidelines and reports indicate that not all contrast agents are associated with the same risk of developing NSF. Conclusions: Most NSF occurs after exposure to linear contrast agents. Therefore, it is recommended to limit their use, especially in dialyzed patients and patients with a GFR < 30 mL/min.

Pure red cell aplasia after major or bidirectional ABO incompatible hematopoietic stem cell transplantation: to treat or not to treat, that is the question.

Pure red cell aplasia (PRCA) is a complication related to major or bidirectional ABO mismatched hematopoietic stem cell transplantation. This disorder is characterized by anemia, reticulocytopenia, and the absence or virtual absence of erythroid progenitors, other causes such as infections, hemolysis, disease relapse, or drug toxicity having been excluded. Patients with PRCA may become RBC transfusion dependent for long periods, suffering an important long-term iron overload, alloimmunization, and transfusion reactions. The persistence of recipient isoagglutinins against donor ABO antigens produced by host residual plasmatic cells has been considered as the immunological cause of the prolonged erythroid aplasia. PRCA behaves in many cases as a self-limited condition and resolution may occur spontaneously within weeks, months, and even years. Many different therapeutic approaches have been reported for posttransplant PRCA as plasmapheresis, high doses of erythropoietin, donor lymphocyte infusions, anti-thymocyte globulin, Rituximab and steroids, among others. However, to date there is no standard of care and the question if patients with PRCA should be treated and at which point remains. The objective of this article is to review the natural evolution of PRCA, and the treatments that have been used over time focusing on their suitability and efficacy.

A Single 60.000 IU Dose of Erythropoietin Does Not Improve Short-Term Aerobic Exercise Performance in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial.

Erythropoietin (EPO) boosts exercise performance through increase in oxygen transport capacity following regular administration of EPO but preclinical study results suggest that single high dose of EPO also may improve exercise capacity. Twenty-nine healthy subjects (14 males/15 females; age: 25 ± 3 years) were included in a randomized, double-blind, placebo-controlled crossover study to assess peak work load and cardiopulmonary variables during submaximal and maximal cycling tests following a single dose of 60.000 IU of recombinant erythropoietin (EPO) or placebo (PLA). Submaximal exercise at 40%/60% of peak work load revealed no main effect of EPO on oxygen uptake (27.9 ± 8.7 ml min–1⋅kg–1/ 37.1 ± 13.2 ml min–1⋅kg–1) versus PLA (25.2 ± 3.7 ml min–1⋅kg–1/ 33.1 ± 5.3 ml min–1⋅kg–1) condition (p = 0.447/p = 0.756). During maximal exercise peak work load (PLA: 3.5 ± 0.6 W⋅kg–1 vs. EPO: 3.5 ± 0.6 W kg–1, p = 0.892) and peak oxygen uptake (PLA: 45.1 ± 10.4 ml⋅min–1 kg–1 vs. EPO: 46.1 ± 14.2 ml⋅min–1 kg–1, p = 0.344) reached comparable values in the two treatment conditions. Other cardiopulmonary variables (ventilation, cardiac output, heart rate) also reached similar levels in the two treatment conditions. An interaction effect was found between treatment condition and sex resulting in higher peak oxygen consumption (p = 0.048) and ventilation (p = 0.044) in EPO-treated males. In conclusion, in a carefully conducted study using placebo-controlled design the present data failed to support the hypothesis that a single high dose of EPO has a measurable impact on work capacity in healthy subjects.

P1476IRON PARAMETERS PREDICT CARDIOVASCULAR EVENTS IN MAINTENANCE HEMODIALYSIS PATIENTS

Abstract Background and Aims Previous studies revealed the association between iron deficiency and thromboembolic events, whereas the association between high serum ferritin and poor prognosis of cerebral haemorrhage was reported in the general population. Since few reports have revealed the relationship between iron parameters and cardiovascular events in hemodialysis (HD) patients so far, our purpose was to examine whether iron parameters predict cardiovascular events in HD patients based on the nation-wide database of patients undergoing dialysis in Japan. Method We enrolled 126,560 patients aged between 20 and 100 who had been on maintenance HD more than 1 year and three times weekly at the end of 2012. We divided baseline transferrin saturation (TSAT) levels into 3 categories (T1: &amp;lt;20, T2: 20-25, T3: &amp;gt;25%) and serum ferritin levels into quartile (Q1: &amp;lt;31, Q2: 31-73, Q3: 73-158, Q4: &amp;gt;158 ng/mL). The study outcomes were new onset of myocardial infarction (MI), cerebral infarction (CIF), and cerebral haemorrhage (CHM) and death due to these three diseases between 2012 and 2013. We performed multivariate logistic regression for the incident events and also employed Cox proportional hazards analyses for death. Multiple imputation method with 5 data sets was performed for missing values. Results During a 1-year follow-up, a total of 2,087 MI (373 deaths), 2,930 CIF (283 deaths), and 1,371 (359 deaths) CHM occurred. After adjustment for demographic and clinical factors, odd ratios (ORs) for MI and CIF were significantly higher among patients with T1 of TSAT than those with T3 (OR; 1.19 (95% confidence interval (CI), 1.07-1.33), 1.16 (95% CI, 1.06-1.27, respectively), and serum ferritin levels were not associated with those outcomes. On the other hand, TSAT was not associated with CHM, however, stepwise increase of OR with the increase of ferritin quartile was observed; patients with Q4 of ferritin had the highest risk for CHM (OR; 1.32 (95% CI, 1.12-1.57) as compared to Q1). In the multivariable Cox regression models, the hazard ratios (HRs) for death due to MI and CIF of the patients with T1 of TSAT were 1.28 (95% CI, 1.00-1.65) and 1.40 (95% CI, 1.06-1.86) as compared to T3, respectively. HR for death due to CHM in patients with Q1-Q4 of ferritin was 1.00 (Reference), 1.59 (95% CI, 1.12-2.25), 1.90 (95% CI, 1.35-2.67), 1.61 (95% CI, 1.13-2.29), respectively (Figure). Furthermore, high dose of erythropoietin stimulating agents was a risk factor of all three cardiovascular events and mortality. Conclusion Low TSAT levels predicted MI and CIF and high serum ferritin levels predicted CHM in HD patients. These results suggest that functional iron deficiency could affect thromboembolic events, while increase in storage iron could affect microvascular fragility.

Development of a Neuroprotective Erythropoietin Modified with a Novel Carrier for the Blood-Brain Barrier.

Extremely high doses of erythropoietin (EPO) has been used for neuroprotection in ischemia-reperfusion brain injury to deliver sufficient amounts of EPO across the blood-brain barrier (BBB); however, harmful outcomes were observed afterward. We aimed to test the ability of HBHAc (heparin-binding haemagglutinin adhesion c), an intracellular delivery peptide for macromolecules, as an EPO carrier across the BBB. The cellular internalization and transcytosis ability of HBHAc-modified EPO (EPO-HBHAc) were evaluated in bEnd.3 cells and in the bEnd.3/CTX TNA2 co-culture BBB model, respectively. Subsequently, the NMDA-induced-toxicity model and ischemia-reperfusion rat model were used to understand the neuronal protective activity of EPO-HBHAc. The biodistribution of EPO-HBHAc was demonstrated in rats by the quantification of EPO-HBHAc in the brain, plasma, and organs by ELISA. Our results demonstrate that EPO-HBHAc exhibited significantly higher cellular internalization in dose- and time-dependent manners and better transcytosis ability than EPO. In addition, the transported EPO-HBHAc in the co-culture transwell system maintained the neuronal protective activity when primary rat cortical neurons underwent NMDA-induced toxicity. The calculated cerebral infarction area of rats treated with EPO-HBHAc was significantly reduced compared to that of rats treated with EPO (29.9 ± 7.0% vs 48.9 ± 7.9%) 24h after occlusion in 3VO rat experiments. Moreover, the EPO amount in both CSF and damaged cortex from the EPO-HBHAc group was 4.0-fold and 3.0-fold higher than the EPO group, respectively. These results suggest that HBHAc would be a favorable tool for EPO brain delivery and would further extend the clinical applications of EPO in neuroprotection.

Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

Influence of secondary hyperparathyroidism in management anemia in patients on regular hemodialysis

Background/Aim. Anemia is a common complication in hemodialysis patients. Treatment of anemia is affected by iron deficiency, insufficient dose of erythropoietin, microinflammation, vitamin D deficiency, increased intact parathyroid hormone concentration and inadequate hemodialysis. The aim of the study was to determine the prevalence of vitamin D deficiency and its impact on hemoglobin con-centration, iron status, microinflammation, malnutrition, dialysis adequacy and erythropoietin dose in patients on regular hemodialysis. Methods. The study involved 120 patients divided into three groups: severely deficient of vitamin D: 25- hydroxyvitamin D[25(OH)D] &lt; 10 ng/mL; deficient ? 25(OH)D within range of 10?20 ng/mL, and insufficient ? 25(OH)D &gt; 20 ng/mL. For statistical analysis Kolmogorov- Smirnov test, the single-factor parametric analysis of variance ? ANOVA and Kruskal-Wallis test were used. Results. The prevalence of vitamin D deficiency in patients on regular hemodialysis was 75.83%, while the prevalence of severe vitamin D deficiency was 24.7%. Patients with severe vitamin D deficiency had lower blood concentration of hemoglobin, hematocrit, serum concentration of total proteins and albumin, and dialysis indices were also lower compared to the other two groups of patients. The level of C-reactive protein was significantly higher in the group of patients with severe vitamin D deficiency than in the two rest groups. Conclusion. Hemodialysis patients with severe vitamin D deficiency have lower hemoglobin, lower dialysis adequacy, significant microinflammation, malnutrition, bone metabolism disorders and need higher dose of erythropoietin than patients whose vitamin D was higher than 10 ng/mL. Vitamin D is important risk factor for development of anemia in hemodialysis patients and important factor that can affect treatment of anemia in these patients.

Causes of Erythropoiesis-Stimulating Agent Resistant Anemia in Children with Chronic Kidney Disease at a Tertiary Hospital

PBackground and Aim: Routine clinical and laboratory assessments facilitate the diagnosis of erythropoietin (EPO) resistant anemia. Resistance to erythropoietin (EPO) rarely occurs in children with chronic kidney disease (CKD). It may be caused by several factors, such as poor compliance, hyperparathyroidism, malnutrition, inadequate dosages, and medication. This study was conducted to evaluate the frequency and causes of EPO resistant anemia in CKD children.Methods: This observational retrospective study was performed in Ali Asghar Children’s Hospital in 2008. Children who were treated by EPO and still had hemoglobin concentrations (Hb) below 10 g/dl or required very high erythropoietin doses (more than 150 IU/kg/week) were considered as EPO resistant anemic cases. Therefore, their data including demographic data, EPO dosage, medications, underlying diseases, mode of dialysis, and lab test results were collected from their medical records.Results: The Hb concentration was below 8 g/dl in eight cases (40%). The male to female ratio was 1.66 and the median age was 7.9 years old. The median hemoglobin concentration was 6.25 g/dL. Three patients (37.5%) were true cases of resistance in EPO (two patients had bone marrow fibrosis due to hyperparathyroidism and one had EPO Ab) while five cases (62.5%) received inadequate doses of EPO (anemia improved upon an acceptable EPO dosage).Conclusion: True resistance to erythropoisis stimulatin agent is not frequent and because of there are heterogeneous causes for Lack of appropriate response to EPO, so full investigation is needed especially complete history to find the underlying reason. Keywords: Anemia; Chronic Kidney Disease; Erythropoietin.

Effects of early high-dose erythropoietin on acute kidney injury following cardiac arrest: exploratory post hoc analyses from an open-label randomized trial.

BackgroundAcute kidney injury (AKI) is frequent in patients resuscitated from cardiac arrest (CA) and may worsen outcome. Experimental data suggest a renoprotective effect by treating these patients with a high dose of erythropoietin (Epo) analogues. We aimed to evaluate the efficacy of epoetin alpha treatment on renal outcome after CA.MethodsWe did a post hoc analysis of the Epo-ACR-02 trial, which randomized patients with a persistent coma after a witnessed out-of-hospital CA. Only patients admitted in one intensive care unit were analysed. In the intervention group, patients received five intravenous injections of Epo spaced 12 h apart during the first 48 h, started as soon as possible after resuscitation. In the control group, patients received standard care without Epo. The main endpoint was the proportion of patients with persistent AKI defined by Kidney Disease: Improving Global Outcomes criteria at Day 2. Secondary endpoints included the occurrence of AKI through Day 7, estimated glomerular filtration rate (eGFR) at Day 28, haematological indices and adverse events.ResultsA total of 162 patients were included in the primary analysis (74 in the Epo group, 88 in the control group). Baseline characteristics were similar in the two groups. At Day 2, 52.8% of the patients (38/72) in the intervention group had an AKI, as compared with 54.4% of the patients (46/83) in the control group (P = 0.74). There was no significant difference between the two groups regarding the proportion of patients with AKI through Day 7. Among patients with persistent AKI at Day 2, 33% (4/12) in the intervention group had an eGFR <75 mL/min/1.73 m2 compared with 25% (3/12) in the control group at Day 28 (P = 0.99). We found no significant differences in haematological indices or adverse events.ConclusionAfter CA, early administration of Epo did not confer any renal protective effect as compared with standard therapy.

Application of polymeric nanoparticles in oral delivery of recombinant human erythropoietin: A review

Recombinant Human Erythropoietin drugs are known as erythropoietin stimulating agents which stimulate the bone marrow to produce more red blood cells in the body. It is used an antianemic in the treatment of renal anemia and chemotherapy induced anemia. It also use in treatment of HIV, cerebral malaria and neurological disease like schizophrenia. The recombinant human erythropoietin dosage form currently available in the market is parenteral dosage form that is ready for injection liquid vial (syringe), which is usually administered 2-3 times weekly. To achieve a therapeutic effect of parenterally administered EPO, cumulative doses are required that significantly exceed levels of endogenous EPO. These high serum levels result in prolonged circulation times of EPO and unspecific binding to non-targeted tissue, which may lead to severe undesired side effects i.e. growth of tumor and also increased risk of death. By using the nanotechnology, side effects and toxicity related to high dose of erythropoietin should be reduces and prolong drug release. this will achieve by reducing administration frequency and lowering dosage of erythropoietin.&#x0D; Keywords: Recombinant Human Erythropoietin, Nanoparticle, Prolong drug release, Anemia

Long-term pre- and postconditioning with low doses of erythropoietin protects critically perfused musculocutaneous tissue from necrosis

It has been shown that pre- and postconditioning of ischemically challenged tissue with erythropoietin (EPO) is able to reduce necrosis in a dose-dependent manner. The aim of this study was to determine the tissue-protective effects of different EPO dosages and administration regimes. Three groups of six C57Bl/6-mice each were analyzed: (1) pre- and postconditioning with initial high doses of EPO (starting at 2500 I.U./kg bw i.p.) followed by low doses of EPO (125 I.U./kg bw i.p.) (EPO-high-dose); (2) pre- and postconditioning with low doses of EPO (125 I.U./kg bw i.p.) (EPO-low-dose); and (3) untreated control group. Randomly perfused musculocutaneous flaps were mounted on dorsal skinfold chambers undergoing acute persistent ischemia and developing ∼50% necrosis without treatment. Intravital epifluorescence microscopy was performed at days 1, 3, 5, 7, and 10 after surgery, assessing flap necrosis, microcirculation, and angiogenesis. The hematocrit was measured at days 0, 3, 7, and 10. Only the EPO-low-dose regimen was associated with a significant reduction of necrosis when compared to untreated controls. EPO-low-dose showed a higher increase in both arteriolar diameter and velocity, thereby resulting in a significantly increased arteriolar blood flow and a hence higher functional capillary density (FCD) of the critically perfused zone. EPO-induced angiogenesis was significantly increased in EPO-low-dose at days 7 and 10. Only EPO-high-dose reached a significant hematocrit increase by day 10. Tissue pre- and postconditioning with low doses of EPO protects the critically perfused musculocutaneous tissue by maintaining capillary perfusion because of increased arteriolar blood flow mediated by nitric oxide (NO) expression.

Gender Differences in Dose of Erythropoietin to Maintain Hemoglobin Target in Hemodialysis Patients.

Dialysis patients receiving erythropoietin (EPO) for anemia management are a challenge due to the significant interindividual variability in erythropoietic response. Our objective was to determine if there is a gender-dependent difference in the EPO doses required to maintain the hemoglobin (Hb) targets in adult patients undergoing hemodialysis. We conducted a historic cohort study with a 12-month follow-up. We include patients with the Hb target, normal serum albumin, and normal transferrin saturation index. Monthly data were gathered for the following: Hb level, EPO doses, and intravenous iron doses. In the 11 hemodialysis facilities included, 1844 patients were on hemodialysis. We considered 389 patients for follow-up, 190 of which were excluded mainly for failing to keep the Hb level in the established range. The final cohort for analysis included 141 men (70.9%) and 58 women (29.1%). At baseline, men weighed more than women (P < 0.001). At the end of the follow-up period, the EPO required to maintain Hb level between 10 and 13 g/dl was significantly higher in women in the monthly dose, weekly dose, and weekly EPO dose/patient weight, with no difference in the monthly iron dose. There was a significant association between female gender and the use of high EPO doses (odds ratio, 4.1; 95% confidence interval, 1.4–12.2; P = 0.01). Our study demonstrates that women require higher doses of EPO to achieve Hb targets.