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Hakim SM, Ahmad AHM, Amer AM. Effect of Preoperative Recombinant Human Erythropoietin on the Need for Blood Transfusion and Surgical Outcomes in Adult Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis with Trial Sequential Analysis. J Cardiothorac Vasc Anesth 2024; 38:2402-2411. [PMID: 38997896 DOI: 10.1053/j.jvca.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/27/2024] [Accepted: 06/11/2024] [Indexed: 07/14/2024]
Abstract
This study aimed to examine the value of preoperative recombinant human erythropoietin (rhEPO) administration to adults undergoing elective cardiac surgery. Databases were searched for randomized controlled trials (RCTs) comparing rhEPO plus standard treatment versus standard treatment only. Primary outcomes were the need for and volume of homologous blood transfusion (HBT). Secondary outcomes were the lengths of intensive care unit (ICU) and hospital stay and the incidence of major adverse events. There was very low certainty that rhEPO is associated with a reduction in the need for HBT, with a number needed to treat of 5.6 (95% confidence interval [CI], 3.9-12.5), and low certainty that it is associated with a moderate reduction in HBT volume (Hedges g = -0.55; 95% CI, -0.79 to -0.32). Meta-regression revealed that studies with a higher proportion of females or older patients demonstrated less benefit of rhEPO in terms of reduced consumption of HBT. Trial sequential analysis showed that rhEPO was superior to standard treatment only for reducing the need for and volume of HBT. Regarding secondary outcomes, there was moderate certainty that rhEPO is associated with a limited reduction in the length of ICU (Hedges g = -0.10; 95% CI, -0.19 to -0.01) and hospital stay (Hedges g = -0.13; 95% CI = -0.25 to -0.02), and low certainty for increased risk of myocardial infarction, with a number needed to harm of 36.1 (95% CI, 17.9-127.4). More well-designed, adequately powered RCTs are needed to draw conclusions regarding the value of rhEPO.
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Affiliation(s)
- Sameh M Hakim
- Department of Anesthesiology, Intensive Care and Pain Management, Ain Shams University Faculty of Medicine, Cairo, Egypt.
| | - Aya Hisham Moussa Ahmad
- Department of Anesthesiology, Intensive Care and Pain Management, Ain Shams University Faculty of Medicine, Cairo, Egypt
| | - Akram M Amer
- Department of Anesthesiology, Intensive Care and Pain Management, Ain Shams University Faculty of Medicine, Cairo, Egypt
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Boskabadi SJ, Heydari F, Mohammadnejad F, Gholipour Baradari A, Moosazadeh M, Dashti A. Effect of erythropoietin on SOFA score, Glasgow Coma Scale and mortality in traumatic brain injury patients: a randomized-double-blind controlled trial. Ann Med Surg (Lond) 2024; 86:3990-3997. [PMID: 38989196 PMCID: PMC11230820 DOI: 10.1097/ms9.0000000000002143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 04/14/2024] [Indexed: 07/12/2024] Open
Abstract
Background Recent studies suggest that erythropoietin has an anti-inflammatory effect on the central nervous system. The authors aimed to investigate the effect of erythropoietin on Glasgow Coma Scale (GCS), Sequential Organ Failure Assessment (SOFA) scores, and the mortality rate of traumatic brain injury (TBI) patients. Methods Sixty-eight patients with available inclusion criteria were randomly allocated to the control or intervention groups. In the intervention group, erythropoietin (4000 units) was administrated on days 1, 3, and 5. In the control group, normal saline on the same days was used. The primary outcomes were the GCS and SOFA score changes during the intervention. The secondary outcomes were the ventilation period during the first 2 weeks and the 3-month mortality rate. Results Erythropoietin administration significantly affected SOFA score over time (P=0.008), but no significant effect on the GCS, and duration of ventilation between the two groups was observed. Finally, erythropoietin had no significant effect on the three-month mortality (23.5% vs. 38.2% in the erythropoietin and control group, respectively). However, the mortality rate in the intervention group was lower than in the control group. Conclusion Our finding showed that erythropoietin administration in TBI may improve SOFA score. Therefore, erythropoietin may have beneficial effects on early morbidity and clinical improvement in TBI patients.
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Affiliation(s)
| | - Fatemeh Heydari
- Department of Anesthesiology, School of Medicine, Sari Imam Khomeini Hospital
| | | | | | - Mahmood Moosazadeh
- Gastrointestinal Cancer Research Center, Non-communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ayat Dashti
- Pharmacology and Toxicology, Faculty of Pharmacy
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Levett JJ, Georgiopoulos M, Martel S, Mugheiry WA, Stavropoulos NA, Vega-Arroyo M, Santaguida C, Weber MH, Golan JD, Jarzem P, Ouellet JA, Klironomos G, Demetriades AK. Pharmacological Treatment of Degenerative Cervical Myelopathy: A Critical Review of Current Evidence. Neurospine 2024; 21:375-400. [PMID: 38955515 PMCID: PMC11224758 DOI: 10.14245/ns.2448140.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/27/2024] [Accepted: 04/01/2024] [Indexed: 07/04/2024] Open
Abstract
Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.
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Affiliation(s)
- Jordan J Levett
- Faculty of Medicine, University of Montreal, Montreal, QC, Canada
| | - Miltiadis Georgiopoulos
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Spinal Surgery Unit, Swansea Bay University Health Board, Swansea, UK
| | - Simon Martel
- Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - Wissam Al Mugheiry
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Nikolaos A. Stavropoulos
- First Department of Orthopaedic Surgery NKUA, “ATTIKON” University General Hospital, Athens, Greece
| | - Miguel Vega-Arroyo
- Winnipeg Spine Program, University of Manitoba, Winnipeg, MB, Canada
- Neurosurgery Department, Sanford Brain & Spine Center, Fargo, ND, USA
| | - Carlo Santaguida
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Michael H. Weber
- Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - Jeff D. Golan
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Peter Jarzem
- Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - Jean A. Ouellet
- Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - Georgios Klironomos
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Bay Shore, NY, USA
| | - Andreas K. Demetriades
- Edinburgh Spinal Surgery Outcomes Study Group, Department of Neurosurgery, Royal Infirmary, Edinburgh, UK
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Hassanpour M, Salybekov AA. Whispers in the Blood: Leveraging MicroRNAs for Unveiling Autologous Blood Doping in Athletes. Int J Mol Sci 2023; 25:249. [PMID: 38203416 PMCID: PMC10779309 DOI: 10.3390/ijms25010249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
The prevalence of autologous blood transfusions (ABTs) presents a formidable challenge in maintaining fair competition in sports, as it significantly enhances hemoglobin mass and oxygen capacity. In recognizing ABT as a prohibited form of doping, the World Anti-Doping Agency (WADA) mandates stringent detection methodologies. While current methods effectively identify homologous erythrocyte transfusions, a critical gap persists in detecting autologous transfusions. The gold standard practice of longitudinally monitoring hematological markers exhibits promise but is encumbered by limitations. Despite its potential, instances of blood doping often go undetected due to the absence of definitive verification processes. Moreover, some cases remain unpenalized due to conservative athlete-sanctioning approaches. This gap underscores the imperative need for a more reliable and comprehensive detection method capable of unequivocally differentiating autologous transfusions, addressing the challenges faced in accurately identifying such prohibited practices. The development of an advanced detection methodology is crucial to uphold the integrity of anti-doping measures, effectively identifying and penalizing instances of autologous blood transfusion. This, in turn, safeguards the fairness and equality essential to competitive sports. Our review tackles this critical gap by harnessing the potential of microRNAs in ABT doping detection. We aim to summarize alterations in the total microRNA profiles of erythrocyte concentrates during storage and explore the viability of observing these changes post-transfusion. This innovative approach opens avenues for anti-doping technologies and commercialization, positioning it as a cornerstone in the ongoing fight against doping in sports and beyond. The significance of developing a robust detection method cannot be overstated, as it ensures the credibility of anti-doping efforts and promotes a level playing field for all athletes.
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Rong J, Fu F, Han C, Wu Y, Xia Q, Du D. Tectorigenin: A Review of Its Sources, Pharmacology, Toxicity, and Pharmacokinetics. Molecules 2023; 28:5904. [PMID: 37570873 PMCID: PMC10421414 DOI: 10.3390/molecules28155904] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 07/26/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
Tectorigenin is a well-known natural flavonoid aglycone and an active component that exists in numerous plants. Growing evidence suggests that tectorigenin has multiple pharmacological effects, such as anticancer, antidiabetic, hepatoprotective, anti-inflammatory, antioxidative, antimicrobial, cardioprotective, and neuroprotective. These pharmacological properties provide the basis for the treatment of many kinds of illnesses, including several types of cancer, diabetes, hepatic fibrosis, osteoarthritis, Alzheimer's disease, etc. The purpose of this paper is to provide a comprehensive summary and review of the sources, extraction and synthesis, pharmacological effects, toxicity, pharmacokinetics, and delivery strategy aspects of tectorigenin. Tectorigenin may exert certain cytotoxicity, which is related to the administration time and concentration. Pharmacokinetic studies have demonstrated that the main metabolic pathways in rats for tectorigenin are glucuronidation, sulfation, demethylation and methoxylation, but that it exhibits poor bioavailability. From our perspective, further research on tectorigenin should cover: exploring the pharmacological targets and mechanisms of action; finding an appropriate concentration to balance pharmacological effects and toxicity; attempting diversified delivery strategies to improve the bioavailability; and structural modification to obtain tectorigenin derivatives with higher pharmacological activity.
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Affiliation(s)
- Juan Rong
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China; (J.R.); (C.H.)
| | - Fei Fu
- Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (F.F.); (Y.W.)
| | - Chenxia Han
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China; (J.R.); (C.H.)
| | - Yaling Wu
- Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (F.F.); (Y.W.)
| | - Qing Xia
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China; (J.R.); (C.H.)
| | - Dan Du
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China; (J.R.); (C.H.)
- Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (F.F.); (Y.W.)
- Proteomics-Metabolomics Platform, Research Core Facility, West China-Washington Mitochondria and Metabolism Centre, Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
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Reichel C, Erceg D, Lorenc B, Scheiblhofer V, Farmer L, Zanitzer K, Geisendorfer T, Gmeiner G, Thevis M. Data from a microdosed recombinant human erythropoietin administration study applying the new biotinylated clone AE7A5 antibody and a further optimized sarcosyl polyacrylamide gel electrophoresis protocol. Drug Test Anal 2023; 15:163-172. [PMID: 33450134 DOI: 10.1002/dta.2989] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/23/2020] [Accepted: 12/01/2020] [Indexed: 01/07/2023]
Abstract
Erythropoietin (EPO) is a hormone, which stimulates the production of red blood cells. Due to its performance-enhancing effect, it is prohibited by the World Anti-Doping Agency (WADA). In order to reduce the detection window of EPO doping, athletes have been applying low doses of recombinant EPO (e.g., <10 IU/kg body weight, daily or every second day) instead of larger doses twice or more per week (e.g., 30 IU/kg). Microdoses of Retacrit (epoetin zeta), an EPO biosimilar, were administered intravenously and subcutaneously to human males and females. Urine and serum samples were collected and analysed applying the new biotinylated clone AE7A5 EPO antibody and a further optimized sarcosyl polyacrylamide gel electrophoresis (SAR-PAGE) protocol. With the improved protocol, microdosed Retacrit (7.5 IU/kg body weight [BW]) was detectable for at least 52 h after intravenous administration. Detection windows were approximately the same for serum and urine and doubled after subcutaneous administration (~104 h). Previous studies applying different electrophoretic techniques and the not further optimized SAR-PAGE protocol revealed considerably shorter detection windows for recombinant human erythropoietin (rhEPO) microdoses. Because the new biotinylated antibody performed significantly more sensitive than the nonbiotinylated version, the new protocol will improve the sensitivity and hence detectability of recombinant EPO in doping control.
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Affiliation(s)
- Christian Reichel
- Doping Control Laboratory Seibersdorf, Seibersdorf Labor GmbH, Seibersdorf, Austria.,European Monitoring Center for Emerging Doping Agents, German Sport University Cologne, Cologne, Germany
| | - Damir Erceg
- Clinical Trial Unit, 'Srebrnjak' Children's Hospital, Zagreb, Croatia.,Faculty of Dental Medicine and Health, University of Osijek 'Josip Juraj Strossmayer', Osijek, Croatia.,School of Medicine, University of Osijek 'Josip Juraj Strossmayer', Osijek, Croatia.,Personalized Medicine, 'St. Catherine' Hospital, Zagreb, Croatia.,Nursing Department, Catholic University of Croatia, Zagreb, Croatia
| | - Barbara Lorenc
- Doping Control Laboratory Seibersdorf, Seibersdorf Labor GmbH, Seibersdorf, Austria
| | | | - Letizia Farmer
- Doping Control Laboratory Seibersdorf, Seibersdorf Labor GmbH, Seibersdorf, Austria
| | - Katharina Zanitzer
- Doping Control Laboratory Seibersdorf, Seibersdorf Labor GmbH, Seibersdorf, Austria
| | - Thomas Geisendorfer
- Doping Control Laboratory Seibersdorf, Seibersdorf Labor GmbH, Seibersdorf, Austria
| | - Günter Gmeiner
- Doping Control Laboratory Seibersdorf, Seibersdorf Labor GmbH, Seibersdorf, Austria
| | - Mario Thevis
- Institute of Biochemistry/Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany.,European Monitoring Center for Emerging Doping Agents, German Sport University Cologne, Cologne, Germany
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7
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Manto KM, Govindappa PK, Martinazzi B, Han A, Hegarty JP, Koroneos Z, Talukder MAH, Elfar JC. Erythropoietin-PLGA-PEG as a local treatment to promote functional recovery and neurovascular regeneration after peripheral nerve injury. J Nanobiotechnology 2022; 20:461. [PMID: 36307805 PMCID: PMC9617443 DOI: 10.1186/s12951-022-01666-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/07/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Traumatic peripheral nerve injury (TPNI) is a major medical problem with no universally accepted pharmacologic treatment. We hypothesized that encapsulation of pro-angiogenic erythropoietin (EPO) in amphiphilic PLGA-PEG block copolymers could serve as a local controlled-release drug delivery system to enhance neurovascular regeneration after nerve injury. METHODS In this study, we synthesized an EPO-PLGA-PEG block copolymer formulation. We characterized its physiochemical and release properties and examined its effects on functional recovery, neural regeneration, and blood vessel formation after sciatic nerve crush injury in mice. RESULTS EPO-PLGA-PEG underwent solution-to-gel transition within the physiologically relevant temperature window and released stable EPO for up to 18 days. EPO-PLGA-PEG significantly enhanced sciatic function index (SFI), grip strength, and withdrawal reflex post-sciatic nerve crush injury. Furthermore, EPO-PLGA-PEG significantly increased blood vessel density, number of junctions, and myelinated nerve fibers after injury. CONCLUSION This study provides promising preclinical evidence for using EPO-PLGA-PEG as a local controlled-release treatment to enhance functional outcomes and neurovascular regeneration in TPNI.
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Affiliation(s)
- Kristen M Manto
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Prem Kumar Govindappa
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, AZ, 85724, USA
| | - Brandon Martinazzi
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Aijie Han
- Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA, 16802, USA
| | - John P Hegarty
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Zachary Koroneos
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - M A Hassan Talukder
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - John C Elfar
- Department of Orthopaedics and Sports Medicine, University of Arizona College of Medicine, Tucson, AZ, 85724, USA.
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Cho KS, Jang WY, Park JE. Treatment Experience for a Child with Ewing Sarcoma who Refused to Receive Blood Transfusions for Religious Reasons as a Jehovah’s Witness. CLINICAL PEDIATRIC HEMATOLOGY-ONCOLOGY 2022. [DOI: 10.15264/cpho.2022.29.1.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Kyu Sik Cho
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Woo Young Jang
- Department of Orthopedic Surgery, Korea University College of Medicine, Seoul, Korea
| | - Jun Eun Park
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
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Erythropoietin Interacts with Specific S100 Proteins. Biomolecules 2022; 12:biom12010120. [PMID: 35053268 PMCID: PMC8773746 DOI: 10.3390/biom12010120] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 02/06/2023] Open
Abstract
Erythropoietin (EPO) is a clinically significant four-helical cytokine, exhibiting erythropoietic, cytoprotective, immunomodulatory, and cancer-promoting activities. Despite vast knowledge on its signaling pathways and physiological effects, extracellular factors regulating EPO activity remain underexplored. Here we show by surface plasmon resonance spectroscopy, that among eighteen members of Ca2+-binding proteins of the S100 protein family studied, only S100A2, S100A6 and S100P proteins specifically recognize EPO with equilibrium dissociation constants ranging from 81 nM to 0.5 µM. The interactions occur exclusively under calcium excess. Bioinformatics analysis showed that the EPO-S100 interactions could be relevant to progression of neoplastic diseases, including cancer, and other diseases. The detailed knowledge of distinct physiological effects of the EPO-S100 interactions could favor development of more efficient clinical implications of EPO. Summing up our data with previous findings, we conclude that S100 proteins are potentially able to directly affect functional activities of specific members of all families of four-helical cytokines, and cytokines of other structural superfamilies.
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Votava JA, Reese SR, Deck KM, Nizzi CP, Anderson SA, Djamali A, Eisenstein RS. Dysregulation of the sensory and regulatory pathways controlling cellular iron metabolism in unilateral obstructive nephropathy. Am J Physiol Renal Physiol 2022; 322:F89-F103. [PMID: 34843656 PMCID: PMC8742730 DOI: 10.1152/ajprenal.00537.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/16/2021] [Accepted: 11/23/2021] [Indexed: 01/03/2023] Open
Abstract
Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in Irp1+/+ and Irp1-/- mice, we asked if iron regulatory proteins (IRPs), the central regulators of cellular iron metabolism and suppressors of EPO production, contribute to the etiology of anemia in kidney failure. We identified a significant reduction in IRP protein level and RNA binding activity that associates with a loss of the iron uptake protein transferrin receptor 1 (TfR1), increased expression of the iron storage protein subunits H- and L-ferritin, and a low but overall variable level of stainable iron in the obstructed kidney. This reduction in IRP RNA binding activity and ferritin RNA levels suggests the concomitant rise in ferritin expression and iron content in kidney failure is IRP dependent. In contrast, the reduction in the Epo mRNA level in the obstructed kidney was not rescued by genetic ablation of IRP1, suggesting disruption of normal hypoxia-inducible factor (HIF)-2α regulation. Furthermore, reduced expression of some HIF-α target genes in UUO occurred in the face of increased expression of HIF-α proteins and prolyl hydroxylases 2 and 1, the latter of which is not known to be HIF-α mediated. Our results suggest that the IRP system drives changes in cellular iron metabolism that are associated with kidney failure in UUO but that the impact of IRPs on EPO production is overridden by disrupted hypoxia signaling.NEW & NOTEWORTHY This study demonstrates that iron metabolism and hypoxia signaling are dysregulated in unilateral obstructive nephropathy. Expression of iron regulatory proteins (IRPs), central regulators of cellular iron metabolism, and the iron uptake (transferrin receptor 1) and storage (ferritins) proteins they target is strongly altered. This suggests a role of IRPs in previously observed changes in iron metabolism in progressive renal disease. Hypoxia signaling is disrupted and appeared to dominate the action of IRP1 in controlling erythropoietin expression.
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Affiliation(s)
- James A Votava
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
| | - Shannon R Reese
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Kathryn M Deck
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
| | - Christopher P Nizzi
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
| | - Sheila A Anderson
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
| | - Arjang Djamali
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin
- Division of Transplant, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin
| | - Richard S Eisenstein
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
- Morgridge Institute for Research, University of Wisconsin-Madison, Madison, Wisconsin
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Dahlgren AR, Knych HK, Arthur RM, Durbin-Johnson BP, Finno CJ. Transcriptomic Markers of Recombinant Human Erythropoietin Micro-Dosing in Thoroughbred Horses. Genes (Basel) 2021; 12:1874. [PMID: 34946824 PMCID: PMC8702184 DOI: 10.3390/genes12121874] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 11/30/2022] Open
Abstract
Recombinant human erythropoietin (rHuEPO) is a well-known performance enhancing drug in human athletes, and there is anecdotal evidence of it being used in horse racing for the same purpose. rHuEPO, like endogenous EPO, increases arterial oxygen content and thus aerobic power. Micro-doping, or injecting smaller doses over a longer period of time, has become an important concern in both human and equine athletics since it is more difficult to detect. Horses offer an additional challenge of a contractile spleen, thus large changes in the red blood cell mass occur naturally. To address the challenge of detecting rHuEPO doping in horse racing, we determined the transcriptomic effects of rHuEPO micro-dosing over seven weeks in exercised Thoroughbreds. RNA-sequencing of peripheral blood mononuclear cells isolated at several time points throughout the study identified three transcripts (C13H16orf54, PUM2 and CHTOP) that were significantly (PFDR < 0.05) different between the treatment groups across two or three time point comparisons. PUM2 and CHTOP play a role in erythropoiesis while not much is known about C13H16orf54, but it is primarily expressed in whole blood. However, gene expression differences were not large enough to detect via RT-qPCR, thereby precluding their utility as biomarkers of micro-doping.
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Affiliation(s)
- Anna R. Dahlgren
- School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.R.D.); (R.M.A.)
| | - Heather K. Knych
- K.L. Maddy Equine Analytical Pharmacology Lab and Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA;
| | - Rick M. Arthur
- School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.R.D.); (R.M.A.)
| | | | - Carrie J. Finno
- School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.R.D.); (R.M.A.)
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Szczesny D, Mołoniewicz K, Markuszewski MJ, Wiczling P. Proof-of-concept study on improved efficacy of rHuEPO administered as a long-term infusion in rats. Pharmacol Rep 2020; 72:1264-1270. [PMID: 32748255 PMCID: PMC7550370 DOI: 10.1007/s43440-020-00150-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 12/02/2022]
Abstract
Background Human recombinant erythropoietin (rHuEPO) is often used in the treatment of diseases associated with a decreased production of red blood cells (RBC), such as chronic renal failure. rHuEPO is typically administered as an intravenous or subcutaneous (SC) injection every few days. The low minimum effective concentration (MEC) of rHuEPO, compared to the concentrations observed after standard doses, suggests that a low dose of the drug administered as a long-term infusion should be efficacious. This study aimed to compare the efficacy observed after a single subcutaneous administration of rHuEPO with that observed after a long-term infusion of rHuEPO via implanted osmotic pumps at a similar or lower dose. Materials and methods In this study three rats received rHuEPO as a single SC injection at a dose of 1350 IU/kg, nine via osmotic pumps at a rate of 0.25, 0.5 and 1 IU/kg and at a total dose of 333 IU/kg, 667 IU/kg, 1333 IU/kg. Three rats served as a control group. The erythropoietin concentrations, RBC count and hemoglobin were measured. Results An increase in RBC count and hemoglobin was observed after SC infusion of rHuEPO. The baseline corrected area under the effect curve for hemoglobin and RBC count was more than 10-times higher for the SC infusion than for a single SC administration with a comparable dose. Conclusions This study demonstrates that administration of rHuEPO as a long-term infusion at a rate ensuring MEC allows to achieve a high efficacy of therapy using relatively small doses of the drug.
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Affiliation(s)
- Damian Szczesny
- Department of Biopharmacy and Pharmacodynamics, Medical University of Gdańsk, 80-416, Gdańsk, Poland
| | - Katarzyna Mołoniewicz
- Department of Biopharmacy and Pharmacodynamics, Medical University of Gdańsk, 80-416, Gdańsk, Poland
| | - Michał J Markuszewski
- Department of Biopharmacy and Pharmacodynamics, Medical University of Gdańsk, 80-416, Gdańsk, Poland
| | - Paweł Wiczling
- Department of Biopharmacy and Pharmacodynamics, Medical University of Gdańsk, 80-416, Gdańsk, Poland.
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Liu EY, Zheng ZX, Zheng BZ, Xia Y, Guo MS, Dong TT, Tsim KWK. Tectorigenin, an isoflavone aglycone from the rhizome of
Belamcanda chinensis
, induces neuronal expression of erythropoietin via accumulation of hypoxia‐inducible factor‐1α. Phytother Res 2019; 34:1329-1337. [DOI: 10.1002/ptr.6599] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 10/22/2019] [Accepted: 12/01/2019] [Indexed: 01/16/2023]
Affiliation(s)
- Etta Y. Liu
- Key Laboratory of Food Quality and Safety of Guangdong Province, College of Food ScienceSouth China Agricultural University Guangzhou China
- Shenzhen Key Laboratory of Edible and Medicinal BioresourcesSRI, The Hong Kong University of Science and Technology Shenzhen Shenzhen China
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
| | - Zoey X. Zheng
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
| | - Brody Z. Zheng
- Shenzhen Key Laboratory of Edible and Medicinal BioresourcesSRI, The Hong Kong University of Science and Technology Shenzhen Shenzhen China
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
| | - Yingjie Xia
- Shenzhen Key Laboratory of Edible and Medicinal BioresourcesSRI, The Hong Kong University of Science and Technology Shenzhen Shenzhen China
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
| | - Maggie S. Guo
- Shenzhen Key Laboratory of Edible and Medicinal BioresourcesSRI, The Hong Kong University of Science and Technology Shenzhen Shenzhen China
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
| | - Tina T. Dong
- Shenzhen Key Laboratory of Edible and Medicinal BioresourcesSRI, The Hong Kong University of Science and Technology Shenzhen Shenzhen China
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
| | - Karl W. K. Tsim
- Shenzhen Key Laboratory of Edible and Medicinal BioresourcesSRI, The Hong Kong University of Science and Technology Shenzhen Shenzhen China
- Division of Life Science, Center for Chinese MedicineThe Hong Kong University of Science and Technology Hong Kong
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Figueiredo RS, Thakkar RG, Ainley PR, Wilson CH. Review of abdominal solid organ transplantation in Jehovah’s Witness patients. World J Transplant 2019; 9:94-102. [PMID: 31598468 PMCID: PMC6783403 DOI: 10.5500/wjt.v9.i5.94] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/14/2019] [Accepted: 09/16/2019] [Indexed: 02/05/2023] Open
Abstract
Managing blood loss in Jehovah’s Witness (JW) patients is a matter of controversy. These patients will not accept transfusions of red blood cells, white blood cells, platelets or plasma, even if that is required to save their lives. There are many discussions regarding safety of operating upon JW patients in general surgical procedures, but in solid organ transplantation there is a paucity of literature on this subject. We have reviewed individual case reports and small series documenting on experience with solid organ transplantation in JW patients and the strategies adopted to facilitate that. It is clear that such patients require the surgical team to dedicate more time to ensure their safe management. This begins with a thorough, detailed consent of exactly which products and interventions they will or will not accept. Planning must begin weeks before surgery if possible. Each case must be assessed individually, but provided they meet fitness requirements, there are no absolute contraindications to abdominal organ transplantation.
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Affiliation(s)
- Rodrigo S Figueiredo
- Department of Hepato-pancreatico-biliary and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom
| | - Rohan G Thakkar
- Department of Hepato-pancreatico-biliary and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom
| | - Paul R Ainley
- Department of Hepato-pancreatico-biliary and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom
| | - Colin H Wilson
- Department of Hepato-pancreatico-biliary and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom
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15
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Gaffney K, Weinberg M, Soto M, Louie S, Rodgers K. Development of angiotensin II (1-7) analog as an oral therapeutic for the treatment of chemotherapy-induced myelosuppression. Haematologica 2018; 103:e567-e570. [PMID: 29976741 DOI: 10.3324/haematol.2018.193771] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Kevin Gaffney
- Department of Pharmacology, University of Arizona, Tucson, AZ .,Center for Innovation in Brain Science, University of Arizona, Tucson, AZ
| | - Michael Weinberg
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Maira Soto
- Department of Pharmacology, University of Arizona, Tucson, AZ.,Center for Innovation in Brain Science, University of Arizona, Tucson, AZ
| | - Stan Louie
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Kathleen Rodgers
- Department of Pharmacology, University of Arizona, Tucson, AZ.,Center for Innovation in Brain Science, University of Arizona, Tucson, AZ
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16
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Vogel M, Dib J, Tretzel L, Piper T, Thomas A, Schänzer W, Thevis M. Analytics of nonpeptidic erythropoietin mimetic agents in sports drug testing employing high-resolution/high-accuracy liquid chromatography-mass spectrometry. Anal Bioanal Chem 2016; 408:6431-42. [DOI: 10.1007/s00216-016-9761-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/15/2016] [Accepted: 07/01/2016] [Indexed: 12/16/2022]
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Martins JP, Kennedy PJ, Santos HA, Barrias C, Sarmento B. A comprehensive review of the neonatal Fc receptor and its application in drug delivery. Pharmacol Ther 2016; 161:22-39. [PMID: 27016466 DOI: 10.1016/j.pharmthera.2016.03.007] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Advances in the understanding of neonatal Fc receptor (FcRn) biology and function have demonstrated that this receptor, primarily identified for the transfer of passive immunity from mother infant, is involved in several biological and immunological processes. In fact, FcRn is responsible for the long half-life of IgG and albumin in the serum, by creating an intracellular protein reservoir, which is protected from lysosomal degradation and, importantly, trafficked across the cell. Such discovery has led researchers to hypothesize the role for this unique receptor in the controlled delivery of therapeutic agents. A great amount of FcRn-based strategies are already under extensive investigation, in which FcRn reveals to have profound impact on the biodistribution and half-life extension of therapeutic agents. This review summarizes the main findings on FcRn biology, function and distribution throughout different tissues, together with the main advances on the FcRn-based therapeutic opportunities and model systems, which indicate that this receptor is a potential target for therapeutic regimen modification.
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Affiliation(s)
- João Pedro Martins
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo 228, 4150-180 Porto, Portugal
| | - Patrick J Kennedy
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS - Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo 228, 4150-180 Porto, Portugal; Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Hélder A Santos
- Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, FI -00014 Helsinki, Finland
| | - Cristina Barrias
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; CESPU - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal.
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18
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Jiang J, Tian F, Cai Y, Qian X, Costello CE, Ying W. Site-specific qualitative and quantitative analysis of the N- and O-glycoforms in recombinant human erythropoietin. Anal Bioanal Chem 2014; 406:6265-6274. [PMID: 25080026 PMCID: PMC4422759 DOI: 10.1007/s00216-014-8037-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/14/2014] [Accepted: 07/15/2014] [Indexed: 12/25/2022]
Abstract
Recombinant human erythropoietin (rhEPO) has been extensively used as a pharmaceutical product for treating anemia. Glycosylation of rhEPO affects the biological activity, immunogenicity, pharmacokinetics, and in-vivo clearance rate of rhEPO. Characterization of the glycosylation status of rhEPO is of great importance for quality control. In this study, we established a fast and comprehensive approach for reliable characterization and relative quantitation of rhEPO glycosylation, which combines multiple-enzyme digestion, hydrophilic-interaction chromatography (HILIC) enrichment of glycopeptides, and tandem mass spectrometry (MS) analysis. The N-linked and O-linked intact glycopeptides were analyzed with high-resolution and high-accuracy (HR-AM) mass spectrometry using an Orbitrap. In total, 74 intact glycopeptides from four glycosylation sites at N24, N38, N83, and O126 were identified, with the simultaneous determination of peptide sequences and glycoform compositions. The extracted ion chromatograms based on the HR-AM data enabled relative quantification of glycoforms. Our results could be extended to quality control of rhEPO or could help establish detection approaches for glycosylation of other proteins.
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Affiliation(s)
- Jing Jiang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
- Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA 02118, USA
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Fang Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
| | - Yun Cai
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
| | - Xiaohong Qian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
| | - Catherine E. Costello
- Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA 02118, USA
| | - Wantao Ying
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
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19
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Oliveira CDRD, Bairros AVD, Yonamine M. Blood doping: risks to athletes' health and strategies for detection. Subst Use Misuse 2014; 49:1168-81. [PMID: 24766400 DOI: 10.3109/10826084.2014.903754] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Blood doping has been defined as the misuse of substances or certain techniques to optimize oxygen delivery to muscles with the aim to increase performance in sports activities. It includes blood transfusion, administration of erythropoiesis-stimulating agents or blood substitutes, and gene manipulations. The main reasons for the widespread use of blood doping include: its availability for athletes (erythropoiesis-stimulating agents and blood transfusions), its efficiency in improving performance, and its difficult detection. This article reviews and discusses the blood doping substances and methods used for in sports, the adverse effects related to this practice, and current strategies for its detection.
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20
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Yokoyama K, Akiba T, Fukagawa M, Nakayama M, Sawada K, Kumagai Y, Chertow GM, Hirakata H. Long-term safety and efficacy of a novel iron-containing phosphate binder, JTT-751, in patients receiving hemodialysis. J Ren Nutr 2014; 24:261-7. [PMID: 24836401 DOI: 10.1053/j.jrn.2014.03.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 03/06/2014] [Accepted: 03/15/2014] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. This study investigated long-term safety and efficacy of JTT-751 for hyperphosphatemia in patients receiving hemodialysis. DESIGN AND METHODS This was 52-week, phase 3, multicenter, open-label, dose titration, long-term study. All patients were receiving thrice-weekly hemodialysis for ≥3 months before the initiation of the study. JTT-751 was given at titrated doses between 1.5 and 6.0 g/day. MAIN OUTCOME MEASURES Safety endpoints were adverse events and adverse drug reactions. Efficacy outcomes were the change in serum phosphate, corrected serum calcium, and intact parathyroid hormone. Changes in ferritin, transferrin saturation, and doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron formulations were additional outcomes. RESULTS One hundred and eighty patients were included in the trial. Dose-titrated JTT-751 decreased mean serum phosphate after administration and satisfactorily maintained serum phosphate concentrations throughout the entire duration of the 52-week trial. Mean serum phosphate concentrations were kept lower than 5.5 mg/dL from weeks 5 to 52. The most common adverse events were gastrointestinal disorders, which were mild to moderate in intensity. Serum ferritin concentrations rose to a peak around week 28 and stabilized thereafter. The mean intravenous iron dose decreased from 57.3 mg/4 weeks (weeks 0-12) to 3.6 mg/4 weeks (weeks 28-52); weekly ESA dose declined by 25% over the same time frame, while mean hemoglobin concentrations remained stable. CONCLUSION JTT-751 1.5-6.0 g/day controls serum phosphorus concentrations and reduces the need for ESAs and intravenous iron in patients receiving hemodialysis.
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Affiliation(s)
- Keitaro Yokoyama
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
| | - Takashi Akiba
- Department of Blood Purification, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Masaaki Nakayama
- Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kenichi Sawada
- Department of Hematology, Nephrology, and Rheumatology, Akita University, Akita, Japan
| | - Yuji Kumagai
- Kitasato University East Hospital Clinical Trial Center, Sagamihara, Japan
| | - Glenn M Chertow
- Division of Nephrology, Stanford University School of Medicine, Palo Alto, California
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Abstract
Iron is an important mineral element used by the body in a variety of metabolic and physiologic processes. These processes are highly active when the body is undergoing physical exercises. Prevalence of exercise-induced iron deficiency anemia (also known as sports anemia) is notably high in athletic populations, particularly those with heavy training loads. The pathogenesis of sports anemia is closely related to disorders of iron metabolism, and a more comprehensive understanding of the mechanism of iron metabolism in the course of physical exercises could expand ways of treatment and prevention of sports anemia. In recent years, there have been remarkable research advances regarding the molecular mechanisms underlying changes of iron metabolism in response to physical exercises. This review has covered these advances, including effects of exercise on duodenum iron absorption, serum iron status, iron distribution in organs, erythropoiesis, and hepcidin’s function and its regulation. New methods for the treatment of exercise-induced iron deficiency are also discussed.
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Affiliation(s)
- Wei-Na Kong
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, P. R. China ; Bioreactor and Protein Drug Research and Development Center of Hebei Universities, Hebei Chemical & Pharmaceutical College, Shijiazhuang 050026, Hebei Province, P. R. China
| | - Guofen Gao
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, P. R. China
| | - Yan-Zhong Chang
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, P. R. China
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