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Erythropoiesis-stimulating agents and other methods to enhance oxygen transport.

ABSTRACT: Oxygen is essential for life, and the body has developed an exquisite method to collect oxygen in the lungs and transport it to the tissues. Hb contained within red blood cells (RBCs), is the key oxygen-carrying component in blood, and levels of RBCs are tightly controlled according to demand for oxygen. The availability of oxygen plays a critical role in athletic performance, and agents that enhance oxygen delivery to tissues increase aerobic power. Early methods to increase oxygen delivery included training at altitude, and later, transfusion of packed RBCs. A breakthrough in understanding how RBC formation is controlled included the discovery of erythropoietin (Epo) and cloning of the EPO gene. Cloning of the EPO gene was followed by commercial development of recombinant human Epo (rHuEpo). Legitimate use of this and other agents that affect oxygen delivery is important in the treatment of anaemia (low Hb levels) in patients with chronic kidney disease or in cancer patients with chemotherapy-induced anaemia. However, competitive sports was affected by illicit use of rHuEpo to enhance performance. Testing methods for these agents resulted in a cat-and-mouse game, with testing labs attempting to detect the use of a drug or blood product to improve athletic performance (doping) and certain athletes developing methods to use the agents without being detected. This article examines the current methods to enhance aerobic performance and the methods to detect illicit use.

SUBMITTER: Elliott S

PROVIDER: S-EPMC2439521 | biostudies-other | 2008 Jun

REPOSITORIES: biostudies-other

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Pharmacovigilance in practice: erythropoiesis-stimulating agents.

Project description:Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.

| S-EPMC4302692 | biostudies-other

Treatment of renal anemia: Erythropoiesis stimulating agents and beyond.

Project description:Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO) deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb) levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA) therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro-cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis.

| S-EPMC5592888 | biostudies-other

Quantitative assessment of minimal effective concentration of erythropoiesis-stimulating agents.

Project description:Minimal effective concentration (MEC) was proposed to explain why subcutaneous (SC) administration of erythropoietin (EPO) induces a higher hemoglobin (HGB) increase than intravenous (IV) administration. It has been further used to explain the paradox that erythropoiesis-stimulating agent (ESA) with lower receptor binding affinity may have higher in vivo activity. We have developed a pharmacokinetic and pharmacodynamic (PK/PD) model with incorporation of the operational model of agonism to characterize the data from two clinical trials. By using model-based simulations, we demonstrate that SC route is more efficacious than IV route and explain the paradoxical behavior of ESAs. We determined that MEC can be quantified by C50, which represents the concentration of an ESA producing its half-maximal effect of stimulating the proliferation of erythroid precursor cells. The model used may allow joint PK/PD modeling of data from different ESAs, and provide a platform for dosing regimen optimizations and future clinical study designs.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e62; doi:10.1038/psp.2013.39; published online 7 August 2013.

| S-EPMC3828003 | biostudies-literature

Neuroprotective effects of erythropoiesis-stimulating agents in term and preterm neonates.

Project description:The use of erythropoiesis-stimulating agents (ESAs) such as erythropoietin and darbepoetin in preterm and term infants has been studied for over 20 years. Recent investigations have explored the potential neuroprotective effects of ESAs. We review the recent clinical trials and experimental animal models that provide evidence in support of using ESA to improve the neurodevelopmental outcomes in term and preterm infants.Continued work using animal models have confirmed the neuroprotective properties of ESAs, including promotion of oligodendrocyte development in the face of neuronal injury. Clinical studies in term and preterm infants have reported the neuroprotective effects following ESA administration, and improved neurodevelopmental outcomes have been reported in the studies of preterm infants.ESAs show great promise in preventing and treating brain injury in term and preterm infants.

| S-EPMC4504847 | biostudies-literature

Harms of off-label erythropoiesis-stimulating agents for critically ill people.

Project description: Not available

| S-EPMC6373621 | biostudies-literature

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Project description:IntroductionImpaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients.MethodsIn this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index.ResultsOf the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (β = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 μg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables.ConclusionSerum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

| S-EPMC9263417 | biostudies-literature

Impact of Erythropoiesis-Stimulating Agents on Behavioral Measures in Children Born Preterm.

Project description:OBJECTIVE:To evaluate the impact of erythropoiesis-stimulating agents (ESAs) administered during initial hospitalization and family demographic factors on behavior at 3.5-4 years of age. STUDY DESIGN:Children were enrolled who had previously participated in a randomized study of ESAs (n?=?35) or placebo (n?=?14) in infants born preterm with birth weights of 500-1250 g. A term healthy control group (n?=?22) also was recruited. Behavior was evaluated by parent report with the Behavioral Assessment System of Children-2. Principal component analyses identified 2 demographic factors, a Socioeconomic Composite (SEC) and a Family Stress Composite. A multivariate general linear model evaluated the impact of study group and sex on the 4 composite scales of the Behavioral Assessment System of Children-2. Demographic factors were treated as covariates and interactions with study group (ESA, placebo, and term) were examined. RESULTS:The ESA group had significantly better scores than the placebo group on behavioral symptoms (P?=?.04) and externalizing scales (P?=?.04). An interaction was observed between study group and SEC (P?=?.001). A beneficial effect of ESAs was maximal in the children with lower SEC scores. CONCLUSIONS:The beneficial effects of ESAs on childhood behavior were maximal in children with lower SEC scores. ESAs seemed to ameliorate the adverse impact of lower SEC on behavioral domains seen in the placebo group. This effect was independent of the beneficial effect of ESAs on global cognition we reported previously. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01207778 and NCT00334737.

| S-EPMC6352724 | biostudies-literature

Effect of erythropoiesis-stimulating agents on blood pressure in pre-dialysis patients.

Project description:INTRODUCTION: Erythropoiesis-Stimulating Agents (ESA) are hypothesized to increase cardiovascular mortality in patients with chronic kidney disease. One of the proposed mechanisms is the elevation of blood pressure (BP) by ESA. Therefore, we aimed to determine whether the use of ESA was associated with antihypertensive treatment and higher BP. MATERIALS AND METHODS: In this cohort 502 incident pre-dialysis patients were included who started specialized pre-dialysis care in 25 clinics in the Netherlands. Data on medication including ESA use and dose, co-morbidities and BP were routinely collected every 6 months. Antihypertensive treatment and BP were compared for patients with and without ESA at baseline. Differences in antihypertensive medication and BP during pre-dialysis care were estimated with linear mixed models adjusted for age, sex, body mass index, cardiovascular disease, diabetes mellitus and estimated glomerular filtration rate. RESULTS: At baseline, 95.6% of patients with ESA were treated with antihypertensive medication and 73.1% of patients without ESA. No relevant difference in BP was found. During pre-dialysis care patients with ESA used 0.77 (95% CI 0.63;0.91) more classes of antihypertensive drugs. The adjusted difference in systolic blood pressure (SBP) was -0.3 (95% CI -2.7;2.0) mmHg and in diastolic blood pressure (DBP) was -1.0 (95% CI -2.1;0.3) mmHg for patients with ESA compared to patients without ESA. Adjusted SBP was 3.7 (95% CI -1.6;9.0) mmHg higher in patients with a high ESA dose compared to patients with a low ESA dose. CONCLUSIONS: Our study confirms the hypertensive effect of ESA, since ESA treated patients received more antihypertensive agents. However, no relevant difference in BP was found between patients with and without ESA, thus the increase in BP seems to be controlled for by antihypertensive medication.

| S-EPMC3877353 | biostudies-literature

Effect of Medicare dialysis payment reform on use of erythropoiesis stimulating agents.

Project description:ObjectiveIn 2011, the Centers for Medicare and Medicaid Services (CMS) replaced fee-for-service reimbursement for erythropoiesis stimulating agents (ESAs) with a fixed-sum bundled payment for all dialysis-related care and pay-for-performance incentives to discourage maintaining patients' hematocrits above 36 percent. We examined the impact of the new payment policy on the use of ESAs.Data sourcesCMS's Renal Information Management System.Study designRegression discontinuity design assessing the use of ESAs by hematocrit level before and after the implementation of the payment policy change.Data extractionSecondary data from 424,163 patients receiving hemodialysis treatment between January 2009 and June 2011.Principal findingsThe introduction of bundled payments with pay-for-performance initiatives was associated with an immediate and substantial decline in the use of ESAs among patients with hematocrit >36 percent and little change in the use of ESAs among patients with hematocrit ≤36 percent. In the first two quarters of 2011, the use of ESAs during dialysis fell by about 7-9 percentage points among patients with hematocrit levels >36 percent. No statistically significant differences in ESA use were observed at the thresholds of 30 or 33 percent.ConclusionsCMS's payment reform for dialysis care reduced the use of ESAs in patients who may not benefit from these agents.

| S-EPMC4450930 | biostudies-literature

Erythropoiesis-stimulating agents in elderly patients with anemia: response and cardiovascular outcomes.

Project description:A specific cause of anemia cannot be identified in many elderly patients. Erythropoiesis-stimulating agents (ESAs) may play a role in treating these patients with anemia of unknown etiology (AUE). This study examines hemoglobin and cardiovascular outcomes among elderly anemic patients treated with ESAs. We conducted a retrospective cohort study that included all anemic patients older than age 60 years who had erythropoietin (EPO) measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient's anemia to 1 of 4 groups: chronic kidney disease (CKD), myelodysplastic syndrome, AUE, or other etiology. Logistic regression was used to compare treatment response (defined per the International Working Group response criteria in myelodysplasia). Adjusted Cox regression analysis was used to calculate the cardiovascular event hazard ratios associated with ESA treatment. A total of 570 patients met the inclusion criteria, of whom 101 received ESAs. There was a nonstatistically significant but quantitatively better response in AUE (47%) and CKD (54%) compared with other etiologies (22%). The adjusted odds ratio for response in AUE compared with other etiologies was 3.3 (95% confidence interval, 0.838-13.0). A baseline EPO level <200 IU/L independently predicted treatment response. There was no statistically significant difference in cardiovascular events or cardiovascular event-free survival between the treated and untreated groups after adjusting for confounders. Our results suggest that ESAs may effectively treat AUE, and responses may be similar to those in CKD. We could not detect a statistically significant increase in cardiovascular events in the studied cohort.

| S-EPMC5728467 | biostudies-literature

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