Frontiers in Drug Discovery: Erythropoietic Stimulating Agents


by

Elísio Costa

DOI: 10.2174/97816080574741130101
eISBN: 978-1-60805-747-4, 2013
ISBN: 978-1-60805-748-1
ISSN: 2214-6210

  
  




The development of new erythropoietic stimulating agents (ESAs) has significantly increased in recent years. Researchers are ...[view complete introduction]
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Table of Contents

Foreword , Pp. i-ii (2)

Rui Alves
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Preface , Pp. iii-iv (2)

Elísio Costa, Flávio Reis and Alice Santos-Silva
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List of Contributors , Pp. v-viii (4)

Elísio Costa, Flávio Reis and Alice Santos-Silva
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Erythropoiesis: Cellular and Molecular Implications , Pp. 3-26 (24)

Susana Coimbra and Alice Santos-Silva
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Modulation of Erythropoietin Gene Expression , Pp. 27-42 (16)

João C. Fernandes, Flávio Reis, Elísio Costa and Alice Santos-Silva
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miRNAs and Erythropoietic Stimulating Agents: a New Therapeutic Approach , Pp. 43-60 (18)

Elsa Bronze-da-Rocha
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Animal Models of Kidney Disease-Associated Anemia , Pp. 61-80 (20)

Patrícia Garrido, Elísio Costa, Alice Santos-Silva and Flávio Reis
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Risks and Benefits Associated with High Therapeutic Doses of Erythropoiesis Stimulating Agents , Pp. 81-97 (17)

Sandra Ribeiro, Elísio Costa, Flávio Reis and Alice Santos-Silva
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Resistance to Erythropoietic Stimulating Agents in Pre-Dialysis Elderly Patients , Pp. 98-114 (17)

Ana Cabrita, Ana P. Silva and Pedro L. Neves
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Heparin-Binding Erythropoietin , Pp. 115-124 (10)

Ken Toba and Masato Moriyama
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Therapeutic Effects of Pyroglutamate Helix B Surface Peptide (pHBSP) in Disease , Pp. 125-143 (19)

Kiran K. Nandra, Nimesh S.A. Patel and Christoph Thiemermann
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Erythropoietin in Familial Amyloidosis ATTR V30M , Pp. 144-159 (16)

Idalina Beirão and Paulo P. Costa
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Effects of Erythropoietin in Skin Regeneration and Repair , Pp. 160-179 (20)

Heiko Sorg, Reto Wettstein, Peter M. Vogt and Yves Harder
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Effects of Erythropoietin on Blood Vessels and the Heart , Pp. 180-204 (25)

Wolfgang Jelkmann and Steve Elliott
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Erythropoietin and Endothelial Progenitor Cell Therapy after Myocardial Infarction , Pp. 205-231 (27)

Kamellia R. Dimitrova, Gabriela R. Dincheva and I. Michael Leitman
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Erythropoietin – A Possible Adjunctive Therapy for Cerebral Malaria , Pp. 232-254 (23)

Casper Hempel and Jørgen A.L. Kurtzhals
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No Effect of Erythropoiesis-Stimulating Agents on Solid Tumour or Lymphoma Progression? , Pp. 255-270 (16)

Matti Aapro
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Subject Index , Pp. 271-294 (24)

Elísio Costa, Flávio Reis and Alice Santos-Silva
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Foreword

This remarkable edition of “Frontiers in Drug Discovery" aims to revisit the “Erythropoietic-Stimulating Agents (ESAs)” under different and interesting perspectives. It seems imperative to introduce this excellent compilation of papers by highlighting briefly the discovery of the central theme - erythropoietin. Indeed, its discovery was one of the most extraordinary advances in Medicine, perfectly demonstrating the importance of the relationship between basic research and clinical practice what we at present call Translational Medicine. Since the observations in the early nineteenth century by Carnot and Deflandre, and later confirmed by Ersley in 1953, surrounding the erythropoietic properties of serum in anemic animals, a long road has been traveled. It was then, in the second half of the twentieth century, with Goldwasser et al., that the kidney was identified as the main site of endogenous synthesis. It took roughly 20 years to isolate erythropoietin from urine in patients with aplastic anemia, and then in 1985, gene cloning opened the way for large scale erythropoietin production. Erythropoietin was finally approved in 1989 by the U.S. Food and Drug Administration (FDA) for the treatment of anemia in patients with chronic renal failure on dialysis. Its use was subsequently extended in 1990 to chronic kidney disease patients not on dialysis, and other groups of patients, such as carriers of the human immunodeficiency virus and patients undergoing major orthopedic surgery or chemotherapy. Consequently, today we can safely say that those approximately 80 years of hard work and dedication have been entirely successful. This is confirmed by about 25 years of experience in different patient populations, especially those suffering from chronic kidney disease. In this regard, it is important to remember that for over twenty years, until the systematic use of erythropoietin in clinical practice, many patients on dialysis often needed blood transfusions to maintain a relatively normal life, with all the adverse consequences resulting therefrom. However, the story of stimulating agents does not end here, since the clinical use of a recombinant molecule has opened up new challenges in the research. The biotechnological engineering of the original molecule sought to optimize its power and increase its half-life, enabling the creation of new analogues. While the primary goal focused on the correction of hemoglobin levels, numerous investigations have sought to evaluate the positive and negative effects of the use of ESAs in different organ systems. Particular controversy has been raised by the high target hemoglobin levels to achieve, especially since an association with mortality was found in patients with chronic renal failure. Moreover, many investigations have produced surprising discoveries concerning the ESAs pleotrophic effects, allowing for new and effective alternatives to the use of those molecules. Those studies are essentially based on the effects at a cellular and molecular level through anti-apoptotic and immuno-modulatory mechanisms.

Over the following pages, I have the privilege to present the knowledge and experience of notable researchers who have dedicated themselves to thoroughly studying the effects of ESAs. From clinical to basic research, the focus is on topics as diverse as cardiovascular disease, oncology, degenerative diseases, regenerative medicine and infection. Erythropoietin, “the mother molecule”, remains at the center of them all.

Rui Alves
Faculty of Medicine
University of Coimbra
Coimbra
Portugal



Preface

The involvement of a humoral factor (named as haemopoietin) in the regulation of hematopoiesis, was firstly described in literature in 1906. However, only 40 years later a linkage between erythropoietin (EPO) and erythropoiesis was described, and only in the 1950s was established that the kidney is the main site of production of EPO. The nucleotide sequence of human EPO gene was determined in 1985 and the cloning and expression of the gene led to the production of recombinant human EPO (rhEPO). The first clinical trial using rhEPO in the treatment of the anemia of end-stage renal disease was published in 1987, and, nowadays, rhEPO is currently used for the treatment of anemia of these patients, as well as for a variety of other clinical situations associated with anemia, namely prematurity, HIV infection and non-myeloid malignancy; as supportive therapy in post chemotherapy, post transplantation and as an alternative to blood transfusion in some clinical situations.

In the last years, the research in this area increased significantly focusing different interesting issues, namely, how to increase half-life of EPO, to found different routes of administration and new erythropoietic-stimulating agents (ESA) or modified EPO molecules. Moreover, in literature there is increased evidence that EPO present other effects beyond erythropoietic-stimulation. These pleiotropic effects of EPO appear to result from the existence of two different EPO receptors (EPOR) with different affinities for EPO. In erythroid cells, EPO bind to the EPOR homodimers, whereas on the other cells and tissues, higher local EPO concentrations are needed to trigger the activation of a heterodimer EPOR, which is expressed in different tissues, namely brain, heart and kidney.

The discovery of new EPO actions beyond the hematopoietic system opened a new field of investigation with these agents. Several molecules have been developed to present the protective action, without the activation of the hematopoietic system. These agents can be potentially used in several diseases of the brain/central and peripheral nervous system, eye, heart and kidney.

This volume of “Frontiers in Drug Discovery” starts with the revision of erythropoiesis (chapter 1), EPO gene regulation (chapter 2), microRNAs and potential contribution to the development of new therapeutic strategies (chapter 3), animal models for studding kidney disease-associated anemia (chapter 4) and risk and benefits of ESA therapy (chapter 5 and 6). In chapter 7 and 8, the biological effects of the new erythropoietic stimulating agents, heparin-binding erythropoietin and of pHBSP, were presented. The remaining chapters of this book show some of the potential applications of erythropoietic stimulating agents.

Elísio Costa
Faculty of Pharmacy
Institute for Molecular and Cellular Biology
University of Porto
Portuga

Flávio Reis
Laboratory of Pharmacology and Experimental Therapeutics
IBILI
Faculty of Medicine of University of Coimbra
Portugal

Alice Santos-Silva
Faculty of Pharmacy
Institute for Molecular and Cellular Biology
University of Porto
Portugal

List of Contributors

Editor(s):
Elísio Costa
Faculty of Pharmacy of University of Porto
Institute for Molecular and Cellular Biology of University of Porto
Biology of University of Porto
Portugal




Co-Editor(s):
Flávio Reis
Laboratory of Pharmacology and Experimental Therapeutics
IBILI, Faculty of Medicine of University of Coimbra
Portugal


Alice Santos-Silva
Faculty of Pharmacy of University of Porto
Institute for Molecular and Cellular Biology of University of Porto
Portugal




Contributor(s):
Alice Santos-Silva
Faculty of Pharmacy of University of Porto and
Institute for Molecular and Cellular Biology of University of Porto
Portugal


Ana Cabrita
Nephrology Department
Hospital de Faro
Portugal


Ana P. Silva
Nephrology Department
Hospital de Faro
Portugal


Casper Hempel
Centre for Medical Parasitology at Department of Clinical Microbiology and Department of Infectious Diseases
Copenhagen University Hospital (Rigshospitalet) and Department of International Health
Immunology and Microbiology, University of Copenhagen
Denmark


Christoph Thiemermann
Barts and the London School of Medicine and Dentistry
The William Harvey Research Institute, Queen Mary University of London
UK


Elísio Costa
Faculty of Pharmacy of University of Porto and Institute for Molecular
Cellular Biology of University of Porto
Portugal


Elsa Bronze-da-Rocha
Faculty of Pharmacy of University of Porto and Institute for Molecular
Cellular Biology of University of Porto
Portugal


Flávio Reis
Laboratory of Pharmacology and Experimental Therapeutics
IBILI, Faculty of Medicine of University of Coimbra
Portugal


Gabriela R. Dincheva
Department of Surgery, Division of Cardiac Surgery
Albert Einstein College of Medicine-Beth Israel Medical Center
New York
USA


Heiko Sorg
Department of Plastic, Hand and Reconstructive Surgery
Hannover Medical School
Germany


I. Michael Leitman
Department of Surgery, Division of Cardiac Surgery
Albert Einstein College of Medicine-Beth Israel Medical Center
New York
USA


Idalina Beirão
Nephrology Department, Santo António General Hospital
UMIB, Abel Salazar Biomedical Sciences Institute, University of Porto
Porto
Portugal


João C. Fernandes
IBILI, Faculty of Medicine of University of Coimbra
Institute for Molecular and Cellular Biology of University of Porto
and Laboratory of Pharmacology and Experimental Therapeutics
Portugal


Jørgen A.L. Kurtzhals
Centre for Medical Parasitology at Department of International Health
Immunology and Microbiology, University of Copenhagen and Department of Clinical Microbiology
Copenhagen University Hospital
Denmark


Kamellia R. Dimitrova
Department of Surgery, Division of Cardiac Surgery
Albert Einstein College of Medicine-Beth Israel Medical Center
New York
USA


Ken Toba
Department of Hematology
Niigata University Medical and Dental Hospital
Niigata
Japan


Kiran K. Nandra
The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry
Queen Mary University of London
UK


Masato Moriyama
Department of Hematology
Niigata University Medical and Dental Hospital
Niigata
Japan


Matti Aapro
Multidisciplinary Oncology Institute
Clinique de Genolier
Genolier
Switzerland


Nimesh S.A. Patel
The William Harvey Research Institute
Barts and The London School of Medicine and Dentistry
Queen Mary University of London
UK


Patrícia Garrido
Laboratory of Pharmacology and Experimental Therapeutics
IBILI, Faculty of Medicine of University of Coimbra
Portugal


Paulo P. Costa
Portugal and Genetics Department
UMIB, Abel Salazar Biomedical Sciences Institute, University of Porto
INSA Dr. Ricardo Jorge
Porto
Portugal


Pedro L. Neves
Nephrology Department
Hospital de Faro
Portugal


Peter M. Vogt
Department for Plastic
Hand and Reconstructive Surgery, Hannover Medical School
Hannover
Germany


Reto Wettstein
Department of Plastic, Reconstructive and Aesthetic Surgery
University Hospital of Basel and Department of Plastic, University Hospital of Lausanne
Lausanne
Switzerland


Sandra Ribeiro
Faculty of Pharmacy of University of Porto
Institute for Molecular and Cellular Biology of University of Porto
Portugal


Steve Elliott
Department of Hematology/Oncology, Amgen Inc
Institute of Physiology, University of Lübeck
Lübeck, Germany
Thousand Oaks
CA
USA


Susana Coimbra
Institute for Molecular and Cellular Biology of University of Porto
Polytechnic Health Institute of the North – Cooperative Higher Education
Polytechnic and University
Gandra-Paredes
Portugal


Wolfgang Jelkmann
Department of Hematology/Oncology, Amgen Inc.
Institute of Physiology, University of Lübeck, Lübeck, Germany
Thousand Oaks
CA
USA


Yves Harder
Department of Plastic Surgery Inselspital University Hospital
Berne
Switzerland




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