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Background: Treatment options for severe, refractory iron deficiency anemia are limited in pregnancy. Objective: To review the available literature on the use of recombinant erythropoietin in the treatment of iron deficiency anemia in pregnancy. Search Strategy: An electronic search of seven databases from inception to March 2022 was performed using a combination of keywords. Selection Criteria: We included all randomized controlled or observational studies of pregnant patients with iron deficiency anemia who received recombinant erythropoietin or control. The primary outcome was a change in hematologic parameters (hemoglobin or hematocrit) after treatment. Studies were appraised using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data Collection and Analysis: Data were summarized using narrative synthesis and descriptive statistics as appropriate. This study was registered with PROSPERO, CRD42022313328. Main Results: Of 234 studies screened, five studies met the inclusion criteria and had sufficient data for analysis (n = 103 recombinant erythropoietin and n = 104 controls). All patients in the intervention group received iron supplementation (intravenous or oral) in addition to recombinant erythropoietin. All patients in the control group received iron supplementation (intravenous or oral) alone. As the result of variance between studies in inclusion criteria, the timing of repeat blood draws, and data reporting, a meta‐analysis could not be performed. Three studies found that serial recombinant erythropoietin combined with iron supplementation was more effective at raising hematologic laboratory parameters (hemoglobin or hematocrit) than iron alone. One study reported no difference in hemoglobin or hematocrit levels between groups at day 28. However, patients in this study only received one dose of recombinant erythropoietin, whereas those in the other studies received serial doses. Another study also found no difference in hemoglobin levels by day 28, but patients in the recombinant erythropoietin group had lower hemoglobin levels at baseline and a more rapid rise in hemoglobin than iron alone. This is demonstrated by a more significant rise in hemoglobin at day 11 in the recombinant erythropoietin group than in the control group. Conclusions: Serial recombinant erythropoietin administration and iron supplementation may be more effective at treating refractory iron deficiency anemia in pregnancy than iron supplementation alone. Synopsis: Recombinant erythropoietin plus iron supplementation is more effective at treating iron deficiency anemia in pregnancy than iron supplementation alone. [ABSTRACT FROM AUTHOR]

Summary: Microalgae are considered as attractive expression systems for the production of biologics. As photosynthetic unicellular organisms, they do not require costly and complex media for growing and are able to secrete proteins and perform protein glycosylation. Some biologics have been successfully produced in the green microalgae Chlamydomonas reinhardtii. However, post‐translational modifications like glycosylation of these Chlamydomonas‐made biologics have poorly been investigated so far. Therefore, in this study, we report on the first structural investigation of glycans linked to human erythropoietin (hEPO) expressed in a wild‐type C. reinhardtii strain and mutants impaired in key Golgi glycosyltransferases. The glycoproteomic analysis of recombinant hEPO (rhEPO) expressed in the wild‐type strain demonstrated that the three N‐glycosylation sites are 100% glycosylated with mature N‐glycans containing four to five mannose residues and carrying core xylose, core fucose and O‐methyl groups. Moreover, expression in C. reinhardtii insertional mutants defective in xylosyltransferases A and B and fucosyltransferase resulted in drastic decreases of core xylosylation and core fucosylation of glycans N‐linked to the rhEPOs, thus demonstrating that this strategy offers perspectives for humanizing the N‐glycosylation of the Chlamydomonas‐made biologics. [ABSTRACT FROM AUTHOR]

The article analyses data on the occurrence of hematological abnormalities in severe acute respiratory syndrome 2 infection. Among these hematological abnormalities, the majority of patients develop a hypercoagulable state associated with thromboembolic complications and poor prognosis. Approximately one-third of patients with severe acute respiratory syndrome 2 infection are diagnosed with mild to severe thrombocytopenia. Another hematological autoimmune disease observed in patients with coronavirus disease 2019 is autoimmune hemolytic anemia. A clinical case with the development of autoimmune hemolytic anemia in the setting of coronavirus infection was described. The diagnosis was based on the presence of anemia, reticulocytosis, a significant decrease in haptoglobin levels, and a positive antiglobulin test (Coombs test). Given the comorbidity, the risks of adverse effects of severe coronavirus disease were high, despite this, it was possible to achieve clinical and hematological remission of autoimmune hemolytic anemia by prescribing pathogenetic therapy with anti-CD-20 monoclonal antibody (rituximab), recombinant erythropoietin and glucocorticoid hormones. This clinical case demonstrates the possibility of successful treatment of patients with severe hemolytic anemia. Special attention should be paid to the discrepancy between the severity of the condition and objective data. This case demonstrates the need for a more in-depth approach to each patient with anemia associated with coronavirus disease infection, namely, in the presence of anemic syndrome, it is imperative to include a full range of laboratory tests. [ABSTRACT FROM AUTHOR]

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Context: Many clinicians, trainers, and athletes do not have a true understanding of the effects of commonly used performance-enhancing drugs (PEDs) on performance and health. Objective: To provide an evidence-based review of 7 commonly used pharmacological interventions for performance enhancement in athletes. Data Sources: PubMed and Scopus databases were searched on April 8, 2022. Study Selection: Systematic reviews (SRs) and meta-analyses (MAs) assessing the performance-enhancing effects of the following interventions were included: androgenic anabolic steroids (AAS), growth hormone (GH), selective androgen receptor modulators (SARMs), creatine, angiotensin-converting enzyme (ACE)-inhibitors, recombinant human erythropoietin (rHuEPO), and cannabis. Study Design: Umbrella review of SRs and MAs. Level of Evidence: Level 4. Data Extraction: Primary outcomes collected were (1) body mass, (2) muscle strength, (3) performance, and (4) recovery. Adverse effects were also noted. Results: A total of 27 papers evaluating 5 pharmacological interventions met inclusion criteria. No studies evaluating SARMs or ACE-inhibitors were included. AAS lead to a 5% to 52% increase in strength and a 0.62 standard mean difference in lean body mass with subsequent lipid derangements. GH alters body composition, without providing a strength or performance benefit, but potential risks include soft tissue edema, fatigue, arthralgias, and carpel tunnel syndrome. Creatine use during resistance training can safely increase total and lean body mass, strength, and performance in high-intensity, short-duration, repetitive tasks. Limited evidence supports rHuEPO benefit on performance despite increases in both VO2max and maximal power output, and severe cardiovascular risks are documented. Cannabis provides no performance benefit and may even impair athletic performance. Conclusion: In young healthy persons and athletes, creatine can safely provide a performance-enhancing benefit when taken in controlled doses. AAS, GH, and rHuEPO are associated with severe adverse events and do not support a performance benefit, despite showing the ability to change bodily composition, strength, and/or physiologic measures. Cannabis may have an ergolytic, instead of ergogenic, effect. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. Experimental Approach: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short‐term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long‐term haemoglobin responses. Key Results: The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. Conclusions and Implications: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency‐mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment. [ABSTRACT FROM AUTHOR]

Background: Erythropoietin resistance is present in some patients with chronic kidney disease, especially in those undergoing hemodialysis, and is often treated using roxadustat rather than iron supplements and erythropoiesis-stimulating agents (ESAs). However, some patients cannot afford full doses of roxadustat. This retrospective study investigated the efficacy of low-dose roxadustat combined with recombinant human erythropoietin (rhuEPO) therapy in 39 patients with erythropoietin-resistant renal anemia undergoing maintenance hemodialysis (3-4 sessions/week). Methods: The ability of the combination of low-dose roxadustat and rhuEPO to increase the hemoglobin concentration over 12 weeks was assessed. Markers of iron metabolism were evaluated. Eligible adults received 50-60% of the recommended dose of roxadustat and higher doses of rhuEPO. Results: The mean hemoglobin level increased from 77.67 ± 11.18 g/dL to 92.0 ± 8.35 g/dL after treatment, and the hemoglobin response rate increased to 72%. The mean hematocrit level significantly increased from 24.26 ± 3.99% to 30.04 ± 3.69%. The soluble transferrin receptor level increased (27.29 ± 13.60 mg/L to 38.09 ± 12.78 mg/L), while the total iron binding capacity (49.22 ± 11.29 mg/L to 43.91 ± 12.88 mg/L) and ferritin level (171.05 ± 54.75 ng/mL to 140.83 ± 42.03 ng/mL) decreased. Conclusion: Therefore, in patients with ESA-resistant anemia who are undergoing hemodialysis, the combination of low-dose roxadustat and rhuEPO effectively improves renal anemia and iron metabolism. [ABSTRACT FROM AUTHOR]

Background: Pure red cell aplasia (PRCA) in neuromyelitis optica spectrum disorder (NMOSD) has not been reported before. This study presents a patient with NMOSD who developed PRCA. Case presentation: A 54-year-old female was admitted in January 2023 for dysuria and progressive numbness and weakness of lower limbs. She had difficulty standing and walking in a straight line. Both lower limbs were positive for the Babinski and Chaddock signs. MRI showed abnormal signals in the spinal cord. Aquaporin-4-IgG (AQP-4-IgG) was positive (1:320), and NMOSD was confirmed. Intravenous immunoglobulin and methylprednisolone were given, and the symptoms improved. She received maintenance treatment with methylprednisolone tablets, and the dosage was gradually reduced. She was readmitted for fatigue, palpitations, and shortness of breath in May 2023. Bone marrow aspiration and biopsy showed elevated erythroid precursors and erythroid hypoplasia, with normal megakaryocytes and myeloid precursors. Chest CT showed no mediastinal lymph node enlargement or thymoma. PRCA secondary to NMOSD was diagnosed. Recombinant human erythropoietin was given. Her condition improved after 1.5 months, as indicated by blood cell count and imaging. Conclusions: This case suggests that PRCA can be secondary to NMOSD. A comprehensive immune function and bone marrow evaluation might be necessary if abnormal blood cells are found while managing NMOSD. [ABSTRACT FROM AUTHOR]

Objective To investigate the overall and subgroup efficacy, subgroup differences, predictors of efficacy and safety of roxadustat in the treatment of refractory non-severe aplastic anemia (NSAA) and low-risk myelodysplastic syndromes (LR-MDS). Methods Patients with refractory NSAA and LR-MDS who were admitted to the Department of Hematology, Peking Union Medical College Hospital from August 2020 to December 2022 were enrolled. All patients received first-line standard treatment, including recombinant human erythropoietin (rhEPO) for at least 3 months before roxadustat treatment. All patients received roxadustat 2.5 mg/kg every other day for at least 3 months, and were followed up for at least 8 months. The clinical characteristics of patients, roxadustat efficacy, predictors of efficacy, adverse effects,relapse and disease clonal evolution were analyzed. Results A total of 40 patients including 24 refractory NSAA and 16 LR-MDS were included. median age was 56 (18 - 81) years and 40% were males. 65% of the patients were transfusion dependent. Median follow-up was 21 (9 -34) months. 22.5%, 25.0%, 47.5%, 55.0%, 57.5%, 60.0% and 50.0% of the patients achieved haematological improvement-erythroid (HI-E) at months 1, 2, 3, 4, 5, 6, and end of the follow-up period, respectively, and no factors affecting HI-E were identified.The hemoglobin change from baseline was statistically different between the two groups at the end of the follow-up period. 50% of patients were relieved from transfusion dependence. Adverse reactions were reported in 22.5% of patients. 28.5% of patients relapsed after achieving HI-E, with a median time to relapse of 7 (4 - 12) months. No clonal evolution was observed at the end of the follow-up period. Conclusions Our preliminary findings suggested that Roxadustat may be effective for patients with NSAA or LR-MDS refractory to conventional therapies and rhEPO, with mild adverse effects and low relapse rate.The degree of hemoglobin improvement may be better in the refractory NSAA patients. [ABSTRACT FROM AUTHOR]

Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin‐like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti‐atherogenic potential of chronic rhPRG4 treatment. Female low‐density lipoprotein receptor knockout mice were fed an atherogenic Western‐type diet for 6 weeks and injected three times per week intraperitoneally with 0.5 mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma‐free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4‐treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 103 μm2 compared with 339 ± 15 × 103 μm2 in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti‐inflammatory M2‐like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro‐inflammatory/pro‐atherogenic cytokine TNF‐alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti‐inflammatory agent. Key points: Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility.In this study we investigated the anti‐atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low‐density lipoprotein receptor knockout mice.We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro‐inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF‐alpha levels and a lowered atherosclerosis susceptibility.Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Anaemia is one of the most common complications of chronic kidney disease (CKD), having a significant impact on quality of life, and is also associated with a number of adverse clinical outcomes. Its pathogenesis is multifactorial, caused largely by an inadequate production of erythropoietin from the diseased kidneys, with iron deficiency, inflammation, shortened red cell lifespan and enhanced blood loss also being contributory factors. The management of this condition was transformed in the late 1980s by the advent of recombinant human erythropoietin (epoetin), and treatment paradigms have developed over the last three decades, largely focusing on a combination of epoetin or its analogues (erythropoiesis-stimulating agents; ESAs) along with iron supplementation, often administered intravenously due to increased hepcidin levels limiting iron absorption from the gut. Indeed, in patients with early CKD and iron deficiency, iron per se may be sufficient to improve the anaemia, delaying the need for ESA therapy. Other causes of anaemia should be excluded and corrected (if possible) before resorting to treatment with ESAs and iron. More recently, the hypoxia-inducible factor–prolyl hydroxylase inhibitors have entered the therapeutic arena; these are orally active agents that upregulate endogenous erythropoietin production as well as a number of iron-regulatory genes which may also enhance erythropoiesis. The latter drugs are highly efficacious, and may have advantages in inflammatory conditions causing resistance to conventional ESA therapy, but concerns exist regarding their safety, particularly in the longer term. This article reviews the current standards of treatment, as well as recent novel developments in the management of anaemia in CKD. [ABSTRACT FROM AUTHOR]

Purpose: In competitive sport, classic methods of measuring drug prevalence, such as doping controls or questionnaires, are challenging. Here we describe a novel urine sampling method to measure drug use in athletes. We hypothesize that the prevalence of drug use in ultramarathon runners is measured more accurately with our sampling method than randomized-response questionnaires. Methods: Urine samples and associated demographic data were collected from male participants using blind, automated urinals at the start ot ultramarathon races. Various nonprohibited and prohibited substances were subsequently screened. Concomitantly, 2931 male and female runners participating in the same ultramarathons completed an anonymized, randomized-response questionnaire regarding drug use. Results: Among 412 individual urine samples, 205 (49.8%) contained at least one substance, and 16.3% of the samples contained one or more prohibited substances. Substances detected in urine included nonsteroid anti-inflammatory drugs (NSAID) (22.1%), acetaminophen (15.5%), opioids (6.6%), diuretics (4.9%), hypnotics (4.4%), glucocorticoids (2.7%), beta-2 agonists (2.2%), cannabinoids (1.9%), and stimulants (1.2%). None of the samples contained erythropoietin-receptor agonists or suspicious testosterone. Drug use was not associated with the participants' characteristics or ranking. Respondents to the questionnaire reported using acetaminophen (13.6%) and NSAID (12.9%); however, no prohibited substances were declared. Conclusions: There was a high prevalence of drug use among male ultramarathon runners, in particular, NSAID and painkillers; however, performance-enhancing drugs were marginally used. Blind urine sampling highlighted prohibited drug use not declared in questionnaires, and it is useful to assess the prevalence of drug use and/or doping in competitive athletes. [ABSTRACT FROM AUTHOR]

Background: Left ventricular hypertrophy (LVH) is highly prevalent in haemodialysis (HD) patients and is associated with an increased risk of death. Roxadustat and recombinant human erythropoietin (rHuEPO, abbreviated as EPO) are the main treatment strategies for renal anaemia in HD patients, but it has not been clear whether there is a difference in their effect on LVH. Methods: In this multi‐centre, prospective, randomized trial of 12‐month duration, study participants were randomized in a 1:1 ratio to the roxadustat group or the EPO group. The doses of both treatment regimens were adjusted so that the patients had a haemoglobin level of 10.0–12.0 g per dL. The primary study endpoint was the change from baseline to 12 months in the left ventricular mass index (LVMI, g/m2) measured by echocardiography. Results: In total, 114 patients were enrolled. The mean age was 50 years, and the median dialysis duration was 33 months. Sixty‐one patients were men, and 24 were diabetic. LVMI decreased from 116.18 ± 27.84 to 110.70 ± 25.74 g/m2 in the roxadustat group. However, it increased from 109.35 ± 23.41 to 114.99 ± 28.46 g/m2 in the EPO group, with a significant difference in the change in LVMI between the two groups [−5.48 (−11.60 to 0.65) vs. 5.65 (0.74 to 10.55), p < 0.05]. Changes in left ventricular mass, end‐diastolic volume and 6‐min walk test seemed superior in the roxadustat group. There were no significant differences in other cardiac geometry, biochemical parameters and major adverse cardiovascular events between the two groups. Conclusions: Compared to EPO, roxadustat is more helpful in the regression of LVH in HD patients. [ABSTRACT FROM AUTHOR]

Aim: Patients undergoing dialysis are at high risk for coronavirus disease 2019 (COVID‐19). Haemoglobin (Hb) levels may be changed in patients infected with the Omicron variant of COVID‐19 who are undergoing peritoneal dialysis (PD). Therefore, we aimed to explore the effect of anti‐anaemia treatment on such patients. Methods: This study enrolled patients undergoing PD who were infected with the Omicron variant of COVID‐19 at our centre between November 2022 and February 2023. We retrospectively analysed changes in Hb levels and explored the effectiveness of roxadustat and recombinant human erythropoietin (rhEPO) for patients infected with the Omicron variant of COVID‐19. Results: Among 125 enrolled patients, 83 (66.4%) were infected with the Omicron variant and 75 (90.4%) patients mainly experienced mild or moderate disease. During infection, C‐reactive protein (CRP) levels were higher than those before infection (p <.001). Additionally, their CRP levels were negatively correlated with Hb levels (p =.002). However, Hb levels were decreased 1 month after infection (109.61 ± 10.64 g/L vs. 115.69 ± 12.04 g/L; p <.001). The roxadustat treatment group did not exhibit significantly decreased Hb levels 1 month after infection (114.57 ± 14.11 vs. 117.51 ± 10.74 g/L; p =.225). Conversely, the rhEPO treatment group experienced a mild decrease in Hb levels (108.69 ± 11.20 vs. 115.03 ± 12.23 g/L; p =.001). Ferritin levels increased in both groups during infection (p =.495). Two months after infection, ferritin levels (median, 205.0 ng/mL) were significantly decreased compared with during infection (median, 377.4 ng/mL) (p <.001) in the roxadustat treatment group. Conclusion: Roxadustat was effective than rhEPO for treating anaemia in patients undergoing PD who were infected with the Omicron variant of COVID‐19. [ABSTRACT FROM AUTHOR]

This study is to evaluate the efficacy of erythropoietin in treating sepsis-associated acute respiratory distress syndrome (ARDS). One hundred patients with sepsis-related ARDS were randomized into the placebo group and Erythropoietin (EPO) group. Patients in the placebo group received saline as placebo on the standard therapy, while the EPO group received recombinant human erythropoietin injections on the standard therapy. It was found that the heart rate and mean arterial pressure did not differ significantly between days 7 and 14 after treatment initiation (p > 0.05). The partial pressure of oxygen (PaO2) and oxygenation index levels measured on days 7 and 14 were significantly higher than the placebo group and partial pressure of carbon dioxide (PaCO2) was significantly lower than the placebo group (p < 0.05). Lung capacity and functional residual capacity (and FRC) increased significantly in tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and C-reactive protein (CRP) concentrations (p < 0.05). In the EPO group, the duration of mechanical ventilation was significantly shorter and the mortality rate was significantly reduced (Log-Rank test, χ² = 4.651, p = 0.031). The results confirm that EPO significantly improves lung function and blood gas parameters, reduces serum levels of inflammatory markers, and reduces the risk of death in sepsis-induced ARDS patients, highlighting the potential therapeutic role of EPO in the management of this disease. [ABSTRACT FROM AUTHOR]

Background: The bone regeneration potential of erythropoietin (EPO) is not yet fully investigated, but some previous experimental studies demonstrated that its application activated the differentiation of osteoblasts and promoted bone formation. Aim: The aim of the present study was to evaluate the effects of recombinant human erythropoietin (rhEpo) on bone healing in cats with fragmented long bone fractures. Methods: Twelve cats were divided into two groups--control (n = 6) in which physiological saline was applied at the fracture gap site and EPO (n = 6) with the application of 1,000 IU rhEpo. The effects of EPO on blood erythrocyte counts, hemoglobin content, and hematocrit were monitored by serial complete blood cell tests, whereas bone formation was evaluated by clinical and radiographic examinations on post-operative weeks 1, 2, 3, 4, 6, and 8. Results: All tested blood parameters were within the reference range. A faster fracture healing and full limb weight-bearing were observed in the EPO group, with statistically significant differences with respect to the control group. Conclusion: The obtained results confirmed that the local application of rhEpo promoted bone healing in cats with fragmented femoral fractures and increased bone callus strength without having significant systemic effects. [ABSTRACT FROM AUTHOR]

In orthopaedics, erythropoietin (EPO) is applied in the preoperative management of anaemic patients, but also as a stimulating factor to assist bone regeneration due to its angiogenic and osteoinductive potential. Since orthopaedists mainly rely on their clinical experience to assess bone healing, additional and more objective methods such as studying the dynamics of bone markers are needed. Therefore, the aim of this study was to investigate the plasma activity of bone-specific alkaline phosphatase (BALP), the N-terminal propeptide of type I collagen (PINP), the C-terminal telopeptide of type I collagen (CTX), and deoxypyridinoline (DPD) during the first 2 months of healing of comminuted fractures in cats, either non-stimulated or locally stimulated with recombinant human erythropoietin (rhEPO). The study included twelve cats of mixed breeds, aged 7.2 ± 4 months, weighing 2.11 ± 1.1 kg, with comminuted diaphyseal fractures of the femur. Surgical treatment with plate osteosynthesis was performed in all animals. The cats were randomly divided into two groups—a control (n = 6) and an EPO group (n = 6). The locally applied EPO leads to the increased activity of bone formation markers (BALP and PINP) during the second week after the osteosynthesis, preceding the peaks in the control group by two weeks. The studied bone resorption markers (DPD, CTX) varied insignificantly during the studied period. In conclusion, erythropoietin could serve as a promoter of bone healing in comminuted fractures in cats. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is commonly complicated by anemia. Treating dialysisdependent patients with anemia, including daprodustat and other inhibitors of prolyl hydroxylase of hypoxia-inducible factor, recombinant human erythropoietin (rhEPO), and iron supplements. We conducted this study to test our postulation; daprodustat is superior to rhEPO and other conventional treatments respecting efficacy and safety parameters. We made systematic search through PubMed, Web of Science, Scopus, and Cochrane. Seven unique trials were eventually included for systematic review; six of them with a sample size of 759 patients entered our network meta-analysis (NMA). Daprodustat 25-30 mg was associated with the greatest change in serum hemoglobin (MD=1.86, 95%CI= [1.20; 2.52]), ferritin (MD= -180.84, 95%CI= [-264.47; -97.20]), and total iron binding capacity (TIBC) (MD=11.03, 95%CI= [3.15; 18.92]) from baseline values. Dialysis-dependent patients with anemia had a significant increment in serum Hemoglobin and TIBC and a reduction in serum ferritin, in a dosedependent manner, when administered daprodustat. [ABSTRACT FROM AUTHOR]

With the aging of the population, an increasing number of elderly patients are opting for artificial joint replacement, leading to the exploration of various rapid rehabilitation programs in the perioperative period. In this study, we aimed to investigate the effectiveness of combining recombinant human erythropoietin and iron sucrose in altering the range and trend of postoperative hemoglobin in patients undergoing arthroplasty. Specifically, we will examine whether this combination can effectively alter the rise and fall of postoperative haemoglobin, identify the inflection point of haemoglobin change or recovery after arthroplasty, and assess the effect of treatment on serum iron in postoperative blood. We conducted a retrospective study of 138 patients who underwent unilateral total joint arthroplasty by the same surgeon in the same hospital before July 2022. The results of this study may provide valuable insights for the development of effective rehabilitation programs for patients undergoing arthroplasty. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex glycome. EPO N-glycosylation influences important pharmacological parameters, prominently serum half-life. Therefore, EPO N-glycosylation analysis is of the utmost importance in terms of controlling critical quality attributes. In this work, we performed an interlaboratory study of glycoanalytical techniques for profiling and in-depth characterization, namely (1) hydrophilic interaction liquid chromatography with fluorescence detection after 2-aminobenzamide labeling (HILIC-FLD(2AB)) and optional weak anion exchange chromatography (WAX) fractionation and exoglycosidase digestion, (2) HILIC-FLD after procainamide labeling (PROC) optionally coupled to electrospray ionization-MS and (3) matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-MS). All techniques showed good precision and were able to differentiate the unique N-glycosylation profiles of the various EPO preparations. HILIC-FLD showed higher precision, while MALDI-TOF-MS covered the most analytes. However, HILIC-FLD differentiated isomeric N-glycans, i.e., N-acetyllactosamine repeats and O-acetylation regioisomers. For routine profiling, HILIC-FLD methods are more accessible and cover isomerism in major structures, while MALDI-MS covers more minor analytes with an attractively high throughput. For in-depth characterization, MALDI-MS and HILIC-FLD(2AB)/WAX give a similar amount of orthogonal information. HILIC-FLD(PROC)-MS is attractive for covering isomerism of major structures with a significantly less extensive workflow compared to HILIC-FLD(2AB)/WAX. [ABSTRACT FROM AUTHOR]

Polytrauma involving traumatic brain injury poses serious threats like hemorrhagic shock and consumption coagulopathy. Blood and blood components are a necessity for maintenance of homeostasis in these patients. Elizabeth Topley and R. Clarke, in their study, demonstrated a considerable drop in red cell volume following a major trauma, nearly 11% in the next 14 days. Use of extensive perioperative blood salvage techniques, recombinant erythropoietin, iron complex injections, and antifibrinolytic agents cannot replace the benefits of blood and blood component transfusion. The real challenge of blood transfusion arises in Jehovah's Witness (JW) patients where a licensed medical practitioner (LMP) is caught in the loop of protecting the sanctity of faith over saving a patient's life. This case report highlights the successful management of a 19-year-old JW patient without transfusion of blood or blood products despite an absolute indication for transfusion. We also discuss the legal and ethical perspectives necessary for a legal medical practitioner, when treating patients of JW faith. [ABSTRACT FROM AUTHOR]

Anemia in chronic kidney disease (CKD) occurs due to insufficient production of erythropoietin to compensate for the decrease in hemoglobin. Anemia in CKD has traditionally been treated with periodic injections of erythropoiesis-stimulating agents (ESAs), which are recombinant human erythropoietin preparations. Although ESA improved anemia in CKD and dramatically improved the quality of life of patients, there are some patients who are hyporesponsive to ESA, and the use of large doses of ESA in these patients may have a negative impact on patient prognosis. Currently, HIF prolyl hydroxylase (HIF-PH) inhibitors have been approved in Japan as a new treatment for anemia in CKD. HIF-PH inhibitors activate HIF and promote the production of endogenous erythropoietin. The 2019 Nobel Prize in Physiology or Medicine was awarded for groundbreaking research that uncovered the HIF pathway. Because HIF-PH inhibitors improve both erythropoietin production and iron metabolism, they are expected to be effective in treating ESA hyporesponsiveness and solve the inconvenience of injectable preparations. On the other hand, its effects are systemic and multifaceted, and long-term effects must be closely monitored. [ABSTRACT FROM AUTHOR]

Anemia induced by chronic kidney disease (CKD) has multiple underlying mechanistic causes and generally worsens as CKD progresses. Erythropoietin (EPO) is a key endogenous protein which increases the number of erythrocyte progenitors that mature into red blood cells that carry hemoglobin (Hb). Recombinant human erythropoietin (rHuEPO) in its native and re-engineered forms is used as a therapeutic to alleviate CKD-induced anemia by stimulating erythropoiesis. However, due to safety risks associated with erythropoiesisstimulating agents (ESAs), a new class of drugs, prolyl hydroxylase inhibitors (PHIs), has been developed. Instead of administering exogenous EPO, PHIs facilitate the accumulation of HIF-a, which results in the increased production of endogenous EPO. Clinical trials for ESAs and PHIs generally involve balancing decisions related to safety and efficacy by carefully evaluating the criteria for patient selection and adaptive trial design. To enable such decisions, we developed a quantitative systems pharmacology (QSP) model of erythropoiesis which captures key aspects of physiology and its disruption in CKD. Furthermore, CKD virtual populations of varying severities were developed, calibrated, and validated against public data. Such a model can be used to simulate alternative trial protocols while designing phase 3 clinical trials, as well as an asset for reverse translation in understanding emerging clinical data. [ABSTRACT FROM AUTHOR]

Background: NeuroEPO plus is a recombinant human erythropoietin without erythropoietic activity and shorter plasma half-life due to its low sialic acid content. NeuroEPO plus prevents oxidative damage, neuroinflammation, apoptosis and cognitive deficit in an Alzheimer's disease (AD) models. The aim of this study was to assess efficacy and safety of neuroEPO plus. Methods: This was a double-blind, randomized, placebo-controlled, phase 2–3 trial involving participants ≥ 50 years of age with mild-to-moderate AD clinical syndrome. Participants were randomized in a 1:1:1 ratio to receive 0.5 or 1.0 mg of neuroEPO plus or placebo intranasally 3 times/week for 48 weeks. The primary outcome was change in the 11-item cognitive subscale of the AD Assessment Scale (ADAS-Cog11) score from baseline to 48 weeks (range, 0 to 70; higher scores indicate greater impairment). Secondary outcomes included CIBIC+, GDS, MoCA, NPI, Activities of Daily Living Scales, cerebral perfusion, and hippocampal volume. Results: A total of 174 participants were enrolled and 170 were treated (57 in neuroEPO plus 0.5 mg, 56 in neuroEPO plus 1.0 mg and 57 in placebo group). Mean age, 74.0 years; 121 (71.2%) women and 85% completed the trial. The median change in ADAS-Cog11 score at 48 weeks was −3.0 (95% CI, −4.3 to −1.7) in the 0.5 mg neuroEPO plus group, −4.0 (95% CI, −5.9 to −2.1) in the 1.0 mg neuroEPO plus group and 4.0 (95% CI, 1.9 to 6.1) in the placebo group. The difference of neuroEPO plus 0.5 mg vs. placebo was 7.0 points (95% CI, 4.5–9.5) P = 0.000 and between the neuroEPO plus 1.0 mg vs. placebo was 8.0 points (95% CI, 5.2–10.8) P = 0.000. NeuroEPO plus treatment induced a statistically significant improvement in some of clinical secondary outcomes vs. placebo including CIBIC+, GDS, MoCA, NPI, and the brain perfusion. Conclusions: Among participants with mild-moderate Alzheimer's disease clinical syndrome, neuroEPO plus improved the cognitive evaluation at 48 weeks, with a very good safety profile. Larger trials are warranted to determine the efficacy and safety of neuroEPO plus in Alzheimer's disease. Trial registration: https://rpcec.sld.cu Identifier: RPCEC00000232. [ABSTRACT FROM AUTHOR]

Introduction: The use of Doxorubicin (DOX) as an antineoplastic drug is limited by its cardiotoxicity. Erythropoietin (EPO) has been suggested to be a powerful cardioprotective agent. Aim of the Work: This study aimed to evaluate the protective role of EPO in DOX-induced cardiotoxicity and its role in mobilization of bone marrow-derived stem cells to the injured tissue. Materials and methods: Thirty-two adult male albino rats (180-200 gm) were divided into equal four groups: control group (Gp I) received physiological saline (1 ml/kg/day), EPO group (Gp II) received recombinant human erythropoietin (rhEPO) (2500 IU/kg, 3 times a week), DOX-treated group (Gp III) received DOX (2.5 mg /kg, 3 times a week), DOX+EPO group (Gp IV) received DOX and rhEPO concomitantly. All medications were given by intraperitoneal injection for two weeks. Specimens from the left ventricles of all rats were prepared and stained for light microscopic study (hematoxylin & eosin, Masson’s trichrome and phospho-tungstic acid hematoxylin in addition to immunohistochemical staining for caspase-3 and CD34) and transmission electron microscopic study. Results: DOX caused marked alteration in the histological features of the cardiac muscle fibers as well as a highly significant increase in area percentage of the collagenous fibers and caspase-3 immunoexpression. Co-administration of EPO with DOX caused improvement in the histological features of the cardiac muscle fibers, a highly significant decrease in area percentage of the collagenous fibers and caspase-3 immunoexpression, and a highly significant increase in CD34 immunoexpression. Conclusion: EPO exerts cardioprotective effects on DOX-induced cardiomyopathy via anti-apoptotic and anti-fibrotic pathways as well as via mobilization of stem cells to the injured tissues. [ABSTRACT FROM AUTHOR]

The polymorphism of the angiotensin-converting enzyme (ACE) gene and interleukin-1 beta (IL-1b) gene could be associated with resistance in the treatment of anemia in dialysis patients with recombinant human erythropoietin (rHuEPO). The aim of the study was to evaluate the association between the polymorphism of the ACE and IL-1b genes and the response to rHuEPO therapy in dialysis patients with anemia. The study investigated 69 patients on dialysis with anemia treated with recombinant human erythropoietin for 12 months. Genotyping of ACE and IL-1b polymorphism was done in all study patients at the initiation of the study. The patient's demographic characteristics, dialysis vintage, and laboratory parameters were also evaluated as factors associated with rHuEPO resistance. The erythropoietin resistance index (ERI) was calculated as the weekly rHuEPO dose per kg of body weight, divided by the hemoglobin (Hb) concentration in g/dl. The Hb ≥ 110 g/l was registered in 37 (53.6%) patients. Patients with Hb ≥ 110 g/l were characterized by significantly higher serum levels of albumin, cholesterol, and iron than those with Hb < 110 g/l. The serum level of the CRP, the weekly dose of rHuEPO, and ERI were significantly higher in patients with Hb < 110 g/l compared to patients with Hb ≥ 110 g/l. The ERI value of ≥ 10 IUkg/weekly/g/dl was present in 27 (39.1%) patients. The serum levels of ferritin and CRP, and weekly dose of rHuEPO were significantly higher in patients with ERI value ≥ 10 IU kg/weekly/g/dl compared with the patients with ERI value < 10 IUkg/weekly/g/dl. There was no significant association between the ERI and polymorphism of the ACE and IL-1b genes in study patients. The polymorphism of the ACE and IL-1b genes was not significantly associated with the response to erythropoietin therapy in dialysis patients with anemia. Iron deficiency, malnutrition, and inflammation were factors associated with anemia and resistance to erythropoietin therapy in dialysis patients. [ABSTRACT FROM AUTHOR]

With the aging of the population, an increasing number of elderly patients are opting for artificial joint replacement, leading to the exploration of various rapid rehabilitation programs in the perioperative period. In this study, we aimed to investigate the effectiveness of combining recombinant human erythropoietin and iron sucrose in altering the range and trend of postoperative hemoglobin in patients undergoing arthroplasty. Specifically, we will examine whether this combination can effectively alter the rise and fall of postoperative haemoglobin, identify the inflection point of haemoglobin change or recovery after arthroplasty, and assess the effect of treatment on serum iron in postoperative blood. We conducted a retrospective study of 138 patients who underwent unilateral total joint arthroplasty by the same surgeon in the same hospital before July 2022. The results of this study may provide valuable insights for the development of effective rehabilitation programs for patients undergoing arthroplasty. [ABSTRACT FROM AUTHOR]

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67 years: range 29 to 80 years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9 weeks (9.0–32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement–erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8 weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84 g/L, and patients had significantly higher hemoglobin concentrations after 12 weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500 IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to evaluate the effectiveness and cost-effectiveness of recombinant human erythropoietin (rHuEPO) and Roxadustat in treating renal anemia, particularly in athletic patients undergoing regular hemodialysis. Methods: Between January 2020 and December 2021, 150 athletic patients on continuous ambulatory regular hemodialysis were enrolled. They were divided equally into rHuEPO and Roxadustat groups. We assessed hemoglobin (Hb), hematocrit (Hct), serum ferritin (SF), and transferrin (TRF) levels, along with adverse reactions, allergic responses, coagulation function, and liver and kidney function parameters (ALT, CCr) before and after treatment. The study also compared the cost-effectiveness of these treatments. Results: Basic demographic information (gender, duration of illness, weight, dialysis method, age) showed no significant difference between groups (P > 0.05). The Roxadustat group demonstrated a significantly higher total effective rate (92.00%) compared to the rHuEPO group (74.67%), with P < 0.05. Posttreatment, improvements in Hb, Hct, SF, TRF, and coagulation and liver and kidney function indices were observed in both groups, with Roxadustat showing superior outcomes (P < 0.05). Adverse reactions were lower in the Roxadustat group (9.33%) compared to the rHuEPO group (24.00%), P < 0.05. Roxadustat's Incremental Cost-Effectiveness Ratio (ICER) was 41,134.10 yuan, deemed tolerable against the backdrop of thrice the per capita GDP. Conclusion: Both Roxadustat and rHuEPO are effective in treating renal anemia in athletes. However, Roxadustat shows superior efficacy, safety, ease of oral administration, patient acceptance, and cost-effectiveness. It becomes the preferred choice for athletic patients with a willingness to pay exceeding 41,134.10 yuan, marking it as the most economically viable option. [ABSTRACT FROM AUTHOR]

Background: Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW). Objectives: The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs). Methods: The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were "ROP stage ≥3" (primary outcome) and "any ROP." Results: Fourteen RCTs, comprising 2,040 infants of <29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of <29 weeks of GA was 1.13 (0.84, 1.53), p = 0.41 (quality of evidence: moderate). Conclusions: The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power. [ABSTRACT FROM AUTHOR]

The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Bleeding and transfusion remain important concerns during surgical correction of scoliosis even when multiple conservative strategies, such as preoperative recombinant erythropoietin and/or antifibrinolytic agents, are used. The current work aimed to determine the impact of other potential risk factors, especially the volume of intraoperative fluid intake, on the perioperative risk of allogenic transfusion during surgical correction of adolescent idiopathic scoliosis. Methods: This prospective study included all cases of adolescent idiopathic scoliosis operated in a single center during 2 years (2018–2020). Predictors analyzed were as follows: body mass index, preoperative hemoglobin concentration, thoracoplasty, preoperative halo‐gravity, volume of intraoperative crystalloid administration, use of esophageal Doppler (for goal‐directed fluid therapy), and duration of surgery. Statistical analyses were performed using a multivariable logistic regression model. Results: Two hundred patients were included in the analysis. Multivariable analysis found: an increased volume of intraoperative crystalloid administration as a significant predictor of allogenic blood transfusion. Receiving operator characteristics analysis found the model exhibiting an area under the curve of 0.85 (95% confidence interval: 0.75–0.95). Optimizing stroke volume using esophageal Doppler was associated with a decrease in intraoperative crystalloid intake. Conclusion: These results indicate a statistical association between the increase in crystalloid intake and the risk of allogenic blood transfusion during surgical correction of adolescent idiopathic scoliosis. Controlled studies are needed to address the causative relation between intraoperative fluid intake and the risk of allogenic transfusion. [ABSTRACT FROM AUTHOR]

The athlete's desire to achieve victory is why some of them decide to use doping. Blood doping, the common type of doping in endurance sports, increases hemoglobin, oxygen tissue delivery, and improves maximal aerobic capacity. The usual illegal ways for hemoglobin elevation are abuse of substances (recombinant human erythropoietin, hypoxia inducible factors) and/or methods (autologous blood transfusions) in concordance with exact protocols to avoid adverse finding either with approved direct methods or with indirect methods. Since direct methods are not sensitive enough to autologous blood transfusion, novel molecular substances, or to detect variants of recombinant human erythropoietin in different application protocols, indirect anti-doping methods marking the changes in the human body related to doping abuse, are being developed. The successful example of indirect method is the Athlete biological passport, with its hematological module consisting of twelve parameters and two scores that enable longitudinal monitoring of each athlete. Personal reference values at each sampling time are calculated in concordance with the Bayes network. Changes in blood parameters related to doping are marked as adverse analytical finding with 99% certainty, but new application regimens and various athletes' explanations for adverse analytical finding represent a novel challenge. Possibility of doping detection with Athlete biological passport has triggered athletes and their teams to use various explanations for the adverse analytical findings, which is why numerous studies are being conducted to explain influence of various conditions on the hematological biomarkers. Simultaneously, authorities are developing novel direct (e.g., additional substances, metabolites) and indirect (e.g., immature reticulocyte fraction, transcriptomics, etc.) methods to detect anti-doping rules violation. The substances/methods used by athletes to improve maximal aerobic capacity are being developed more rapidly than anti-doping authorities can implement adequate direct detection methods, which is why constant novel studies are needed. [ABSTRACT FROM AUTHOR]

Patients with renal anaemia are usually treated with recombinant human erythropoietin (EPO) because of insufficient renal EPO secretion. The establishment of a good haemoglobin (Hgb) response model is a necessary condition for dose optimization design. The purpose of this paper is to apply physics‐informed neural networks (PINN) to build the Hgb response model under EPO treatment. Neural network training is guided by a physiological model to avoid overfitting problems. During the training process, the parameters of the physiological model can be estimated simultaneously. To handle differential equations with impulse inputs and time delays, we propose approximate model equations for the pharmacokinetic (PK) model and the pharmacodynamic (PD) model, respectively. The modified PK/PD model was incorporated into PINN for training. Tests on simulated data and clinical data show that the proposed method has better performance than data‐driven modelling methods and the traditional physiological modelling based on the least squares method. [ABSTRACT FROM AUTHOR]

Background: Administration of recombinant erythropoietin (EPO), a kidneyproduced hormone with erythropoietic functions, has been shown to have multiple immunoregulatory effects in mice and humans, but whether physiological levels of EPO regulate immune function in vivo has not been previously evaluated. Methods: We generated mice in which we could downregulate EPO production using a doxycycline (DOX)-inducible, EPO-specific silencing RNA (shEPOrtTAPOS), and we crossed them with B6.MRL-Faslpr/J mice that develop spontaneous lupus. We treated these B6.MRL/lpr shEPOrtTAPOS with DOX and serially measured anti-dsDNA antibodies, analyzed immune subsets by flow cytometry, and evaluated clinical signs of disease activity over 6 months of age in B6.MRL/lpr shEPOrtTAPOS and in congenic shEPOrtTANEG controls. Results: In B6.MRL/lpr mice, Epo downregulation augmented anti-dsDNA autoantibody levels and increased disease severity and percentages of germinal center B cells compared with controls. It also increased intracellular levels of IL-6 and MCP-1 in macrophages. Discussion: Our data in a murine model of lupus document that endogenous EPO reduces T- and B-cell activation and autoantibody production, supporting the conclusion that EPO physiologically acts as a counterregulatory mechanism to control immune homeostasis. [ABSTRACT FROM AUTHOR]

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and β-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: In doping control, the presence of the exon5 c.577del variant in the human erythropoietin gene may be a confounding factor in the interpretation of the results from the analytical method currently in force for the detection of human recombinant erythropoietin, based on immunoelectrophoresis on SDSPAGE and/or SAR-PAGE. This variant, determining the transcription of a higher molecular weight protein, can erroneously suggest the presence of recombinant erythropoietin in a biological sample, causing the possibility of a false positive result. Although the variant was now identified only in East Asian populations and with a very low frequency, it can threaten the reliability of current anti-doping tests. Methods: We have implemented a genetic test to identify the presence of this variant in the biological samples that are presently collected for anti-doping analysis (whole blood, urine, and dried blood spots). The test is based on the Sanger sequencing of the human erythropoietin gene exon 5, where the c.577del variant falls. Results and Discussion: The method has a specificity of 100% and allows identification of the possible presence of the variant starting from 100 pg of genomic DNA extracted from each biological sample. The efficacy of the test has been confirmed by the analysis of real samples from subjects showing and not showing the exon c.577del variant. [ABSTRACT FROM AUTHOR]

Purpose: Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown. Methods: We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010–2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5–8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI. Results: Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47–1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI - 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2–22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome. Conclusion: EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI. [ABSTRACT FROM AUTHOR]

In this article mechanisms of anaemia development in patients with lymphatic tissue malignant diseases are presented. Therapy efficacy of erythropoiesis-stimulating agents (EPO) in patients with lymphoproliferative disorders and anaemia (n = 21) is studied. Study group included patients with a chronic lymphoid leukemia (n = 5), indolent lymphomas (n = 7) and multiple myeloma (n = 9). Patients were 49–80 years of age (63.6 ± 8.2 years). The positive response to EPO therapy was considered if hemoglobin level increased on 20 g/l or its rising to 120 g/l. With given therapy hemoglobin level was increased from 86.8 ± 18.5 g/l to 111.4 ± 26.5 g/l (p < 0.001). EPO therapy efficacy was 61.9 % for total group of patients. Importance of TNF-alpha detection as the prognosis factor of EPO therapy efficacy was studied. Patients with low level of TNF-alpha (less than 15 pg/ml) achieved the positive response in 92.9 %, with a high level of TNF-alpha (more than 15 pg/ml) – the positive response was not observed. Inversely proportional correlation between initial TNF-alpha level and therapy response has been established (r = -0.487; p < 0.03; n = 21). Thus, detection of TNF-alpha level in patients with lymphoproliferative disorders before EPO therapy allows to predict therapy response with high degree of significance.

Case report of a patient with simultaneously developed lymphoid and myeloid hemoblastosis is presented. Diagnosis of multiple myeloma and chronic idiopathic myelofibrosis are confirmed by complete blood count, myelogramm, trephinebiopsy, immunohistochemical, cytogenetic, biochemical and radiological examination. Complete remission of multiple myeloma was achieved after 7 courses «VAD» and 11-weeks treatment with recombinant erythropoietin beta with subsequent maintenance therapy courses of bortezomib and reaferon. However, chronic idiopathic myelofibrosis was progressed to acute myeloid leukemia. Disease stabilization was achieved with 3 therapy courses «5+2».

Myelodysplastic syndromes (MDS) are broadly categorized as lower- and higher-risk with lower-risk dominated by cytopenias and higher-risk plagued by the risk of transformation to acute myeloid leukemia (AML). The management of MDS utilize a risk-adapted approach aimed at ameliorating cytopenias in lower-risk MDS (LR-MDS) and preventing AML transformation in higher-risk MDS. Hematopoietic stem cell transplantation is a potentially curative intent therapy in higher-risk MDS; however, it is not routinely recommended in LR-MDS in view of unfavorable risk/benefit ratio. Therefore, the goal of treatment in LR-MDS is aimed at improving the transfusion burden and health related quality of life. Currently, erythropoiesis stimulating agents (recombinant erythropoietin), erythroid maturation agents (luspatercept), disease modifying agents (lenalidomide) and hypomethylating agents are the agents of choice in the treatment of LR-MDS. This review will discuss the current treatment standards, meaningful clinical outcomes, and emerging therapies in LR-MDS. [ABSTRACT FROM AUTHOR]

Sepsis-induced acute kidney injury (SI-AKI), a common critically ill, represents one of the leading causes of global death. Emerging evidence reveals autophagy as a pivotal modulator of SI-AKI. Autophagy affects the cellular processes of renal lesions, including cell death, inflammation, and immune responses. Herein, we conducted a systematic and comprehensive review on the topic of the proposed roles of autophagy in SI-AKI. Forty-one relevant studies were finally included and further summarized and analyzed. This review revealed that a majority of included studies (24/41, 58.5%) showed an elevation of the autophagy level during SI-AKI, while 22% and 19.5% of the included studies reported an inhibition and an elevation at the early stage but a declination of renal autophagy in SI-AKI, respectively. Multiple intracellular signaling molecules and pathways targeting autophagy (e.g. mTOR, non-coding RNA, Sirtuins family, mitophagy, AMPK, ROS, NF-Kb, and Parkin) involved in the process of SI-AKI, exerting multiple biological effects on the kidney. Multiple treatment modalities (e.g. small molecule inhibitors, temsirolimus, rapamycin, polydatin, ascorbate, recombinant human erythropoietin, stem cells, Procyanidin B2, and dexmedetomidine) have been found to improve renal function, which may be attributed to the elevation of the autophagy level in SI-AKI. Though the exact roles of autophagy in SI-AKI have not been well elucidated, it may be implicated in preventing SI-AKI through various molecular pathways. Targeting the autophagy-associated proteins and pathways may hint towards a new prospective in the treatment of critically ill patients with SI-AKI, but more preclinical studies are still warranted to validate this hypothesis. [ABSTRACT FROM AUTHOR]

Germinal matrix-intraventricular hemorrhage (GM-IVH) is among the devastating neurological complications with mortality and neurodevelopmental disability rates ranging from 14.7% to 44.7% in preterm infants. The medical techniques have improved throughout the years, as the morbidity-free survival rate of very-low-birth-weight infants has increased; however, the neonatal and long-term morbidity rates have not significantly improved. To this date, there is no strong evidence on pharmacological management on GM-IVH, due to the limitation of well-designed randomized controlled studies. However, recombinant human erythropoietin administration in preterm infants seems to be the only effective pharmacological management in limited situations. Hence, further high-quality collaborative research studies are warranted in the future to ensure better outcomes among preterm infants with GM-IVH. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the effects of early postnatal administration of erythropoietin (EPO) on neurodevelopmental outcomes and morbidities in preterm infants with severe grades of intraventricular hemorrhage (IVH). Methods: We retrospectively reviewed the medical records of preterm infants of gestational age 23+0 weeks to 31+6 weeks, who were diagnosed with severe grades of IVH and received EPO over at least 2 weeks. We compared clinical characteristics, major complications, and neurodevelopmental impairment between the two groups. The primary outcome was severe neurodevelopmental impairment at 18 to 26 months of corrected age. Severe neurodevelopmental impairment was defined as a mental developmental index or psychomotor developmental index of <70 on the Bayley Scales of Infant Development II or diagnosis of cerebral palsy. Results: The study included 33 preterm infants (mean gestational age 25.2±1.6 weeks and mean birth weight 775.1±224.5 g). EPO was administered at a dose of 400 or 1,000 IU/kg thrice weekly and was maintained over a mean period of 58.6± 25.9 days beginning from 10.7±6.9 days after birth. We observed no difference in perinatal characteristics between the EPO (n=14) and the control group (n=19). Similarly, severe neurodevelopmental impairment rates did not differ between the EPO (85.7%) and control groups (78.9%). The incidence of neonatal morbidities including bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity was also similar between the EPO and control groups. Conclusion: Early administration of EPO did not reduce the risk of severe neurodevelopmental impairment in preterm infants with severe IVH. [ABSTRACT FROM AUTHOR]

Patients with myelodysplastic syndromes and ring sideroblasts (MDS RS) are clinically characterized by severe anemia and transfusion need. Erythropoiesis‐stimulating agents (ESAs), which stimulate hemoglobin production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time. Luspatercept, an inhibitor of the TGF‐beta pathway, is beneficial in unblocking late‐stage erythropoiesis and has been approved for MDS RS patients failing or not‐candidate to ESAs. ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life‐long transfusion dependent. Here, we describe the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40–80 000 IU/week) in seven MDS RS patients. Two patients had ESAs as pre‐existing therapy, while five were re‐challenged with ESAs as add‐on treatment due to luspatercept failure. Three patients achieved hematologic improvement, and one became transfusion independent. No adverse events were noted. This is the first clinical evidence that stimulating both early and late‐stage erythropoiesis may offer a further option for this challenging patient population. [ABSTRACT FROM AUTHOR]

Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPOM was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPOM (asialo-rhuEPOE) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPOP). Both types of asialo-rhuEPO, like rhuEPOM, displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPOM, discuss potential reasons for the clinical failure of rhuEPOM with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate how obesity affects the pharmacokinetics of biologics in a rat model.Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings.Method: To investigate how obesity affects the pharmacokinetics of biologics in a rat model.Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings.Results: To investigate how obesity affects the pharmacokinetics of biologics in a rat model.Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings.Conclusions: To investigate how obesity affects the pharmacokinetics of biologics in a rat model.Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

A number of drugs based on recombinant erythropoietin contain human serum albumin as an auxiliary component. The presence of this protein hinders the proper control of the drug quality in accordance with the requirements of regulating agencies. We propose the novel method for separation of recombinant erythropoietin (epoetin beta) and human serum albumin. It is based on the subsequent use of hydrophobic sorbent and anion exchange resin placed in gravity flow columns (without the use of spin-columns). The proposed approach makes it possible to concentrate and purify the preparations containing the epoetin beta both at high and at minimal concentrations (the ratio of the amount of albumin and erythropoietin in the used preparations can reach 125:1). The average yield of epoetin beta after the use of hydrophobic sorbent and anion exchange resin was 75 % and 97 %, respectively. It was shown that the determined conditions of sample preparation had no affect on the content of the epoetin beta in the product. [Display omitted] • Epoetin beta and HSA well separated with hydrophobic and anion-exchange sorbents. • Epoetin beta preparations with high content of HSA had been concentrated and purified. • Sample preparation conditions have not an effect on the content of related impurities. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is a glycoprotein hormone that stimulates red blood cell production. It is produced naturally in the body and is used to treat patients with anemia. Recombinant EPO (rEPO) is used illicitly in sports to improve performance by increasing the blood's capacity to carry oxygen. The World Anti-Doping Agency has therefore prohibited the use of rEPO. In this study, we developed a bottom-up mass spectrometric method for profiling the site-specific N-glycosylation of rEPO. We revealed that intact glycopeptides have a site-specific tetra-sialic glycan structure. Using this structure as an exogenous marker, we developed a method for use in doping studies. The profiling of rEPO N-glycopeptides revealed the presence of tri- and tetra-sialylated N-glycopeptides. By selecting a peptide with a tetra-sialic acid structure as the target, its limit of detection (LOD) was estimated to be < 500 pg/mL. Furthermore, we confirmed the detection of the target rEPO glycopeptide using three other rEPO products. We additionally validated the linearity, carryover, selectivity, matrix effect, LOD, and intraday precision of this method. To the best of our knowledge, this is the first report of a doping analysis using liquid chromatography/mass spectrometry-based detection of the rEPO glycopeptide with a tetra-sialic acid structure in human urine samples. [ABSTRACT FROM AUTHOR]