Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificia

Chemistry and Biochemistry of Oxygen Therapeutics

by Andrea Mozzarelli, Stefano Bettati

* First book to cover the full range of new oxygen therapeutics * Fills a void in the literature by addressing the biochemistry and physiology of oxygen transport, showing how use of this basic knowledge can help in the chemical design of blood substitutes for use in specific disease states.

FORMAT Hardcover LANGUAGE English CONDITION Brand New

Publisher Description

Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen – the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or "blood substitutes") which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development. The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery;  hemoglobin and myoglobin;  nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury. The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in β thalassemia and sickle cell disease Finally "old"and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion;  conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell storage;  proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell;  allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers;  oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia – industry collaboration in blood substitute development. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.

Back Cover

Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or blood substitutes ) which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development. The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery; hemoglobin and myoglobin; nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury. The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in thalassemia and sickle cell disease Finally old and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion; conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell stora≥ proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell; allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers; oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia industry collaboration in blood substitute development. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.

Flap

Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen - the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or "blood substitutes") which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development. The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery; hemoglobin and myoglobin; nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury. The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in thalassemia and sickle cell disease Finally "old"and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion; conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell storage; proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell; allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers; oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia - industry collaboration in blood substitute development. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.

Author Biography

Professor Andrea Mozzarelli, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Parma, Italy
Andrea Mozzarelli is Full Professor of Biochemistry in the Pharmacy Faculty at the University of Parma, teaching general and applied Biochemistry. He is Member of the International Advisory Board for Vitamin B6, PQQ, Carbonyl Catalysis and Quinoproteins Meetings, and was scientific organizer of the international courses on "From Structural Genomics to Drug Discovery" held at the University of Parma in 2000, 2002 and 2004. Between 2004 and 2006 Professor Mozzarrelli was head of a research unit of a EU funded project on "EuroBlood substitutes". He is President of the XII International Symposium on Blood Substitutes, to be held in Parma, Italy, on August 25-28, 2009 . Professor Stefano Bettati, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Parma, Italy.

Table of Contents

List of Contributors xvii Preface xxiii 1. Introduction 1
Richard B. Weiskopf References 5 Part I. Oxygen: Chemistry, Biochemistry, Physiology and Toxicity 9 2. Hemoglobin Reactivity and Regulation 11
Stefano Bettati and Andrea Mozzarelli 2.1 Introduction 11 2.2 Oxygen Loading and Transport 11 2.3 NO Reactivity with Hb 15 2.4 Hb Oxidation 16 2.5 Nitrite Reactivity with Hb 16 2.6 Amino-acid Determinants of Hb Reactivity: Natural and Engineered Hbs 17 2.6.1 Modulation of Oxygen Affinity and Cooperativity 17 2.6.2 NO Reactivity and Oxidation 18 2.7 Conclusion 18 Acknowledgments 19 References 19 3. The Major Physiological Control Mechanisms of Blood Flow and Oxygen Delivery 23
Raymond C. Koehler 3.1 Introduction 23 3.2 Autoregulation of Blood Flow to Changes in Perfusion Pressure 23 3.3 Metabolic Regulation of Blood Flow 26 3.4 O2 Transport 27 3.5 O2 Delivery 27 3.6 Endothelial Control of Vasomotor Tone 29 3.7 Effect of Cell-free Hb on Endothelial Function 31 3.8 Hypoxic Hypoxia 33 3.9 Carbon Monoxide Hypoxia 36 3.10 Anemia 36 3.11 Conclusion 39 References 39 4. The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen 47
Tim J. McMahon and Joseph Bonaventura 4.1 Introduction 47 4.2 Role of Mammalian Mb in O2 Homeostasis 47 4.3 What's Missing in the Mb Knockout Mouse 48 4.4 Evolutionary Origins of Mb and the Nitrogen Cycle 49 4.5 Human Hb: Evolved Sensor of pO2 and Redox 49 4.6 Broad Reactivity and Influence of NO: Lessons from the Microcosm Hb 49 4.7 Some Fish Demonstrate a Fundamental "Need" for Hb-dependent NO Cycling, as in Humans 50 4.8 Reactions of NO with Hb that Preserve NO Bioactivity 52 4.9 Mammalian RBC/Hb–NO Interactions 52 4.10 A Mutant Mouse Challenges the SNO-Hb Hypothesis, but does not Overthrow it 54 4.11 Signaling by Hb-derived SNO: A Metabolically Responsive, Regulated Pathway 54 4.12 Signaling by Hb-derived SNO: Pathway Complexity Revealed by Multiple Defects in Disease States 55 4.13 Therapeutic Implications of the Hb–NO Signaling System 56 4.14 HBOCs, NO, and SNO 56 4.15 Other Gaseous Hb Ligands of Potential Therapeutic Significance 57 4.16 NO-related Enzymatic Activities of Hb: Reconciling Nitrite Reductase and SNO Synthase Functions 57 4.17 Measuring Biologically Relevant Hb–NO Adducts 58 4.18 Conclusion 58 Acknowledgments 58 References 59 5. The Role of Reactive Oxygen and Nitrogen Species in Ischemia/Reperfusion Injury 63
Ester Spagnolli and Warren M. Zapol 5.1 Introduction 63 5.2 Redox System and Free Radicals in Biological Systems 64 5.3 Pathophysiology of Ischemia/Reperfusion Injury 65 5.3.1 Cell Death 65 5.3.2 The Inflammatory Response 67 5.4 Protection Against I/R Injury 67 5.4.1 Ischemic Pre- and Post-conditioning 67 5.4.2 Pharmacological Conditioning 68 5.4.2.1 The Protective Role of ROS and Antioxidants 68 5.4.2.2 The Protective Role of NO 69 5.4.2.3 NO-based Therapies for I/R Injury 70 5.5 Conclusion 72 Acknowledgments 72 References 72 Part II. Medical Needs for Oxygen Supply 79 6. Acute Traumatic Hemorrhage and Anemia 81
Lena M. Napolitano 6.1 Introduction 81 6.2 Blood Transfusion in Trauma 83 6.2.1 Massive Transfusion 83 6.2.2 Massive Transfusion and Coagulopathy 83 6.2.3 Hypotensive or Delayed Resuscitation 84 6.2.4 Hemostatic Resuscitation 84 6.2.5 Massive Transfusion Protocols 86 6.2.6 Transfusion after Hemorrhage Control 86 6.2.7 Efficacy of RBC Transfusion in Trauma and Associated Risks 86 6.3 Oxygen Therapeutics in Trauma 88 6.3.1 Diaspirin Crosslinked Hb 90 6.3.2 Hemopure 90 6.3.3 PolyHeme 91 6.3.4 MP4OX 93 6.3.5 Recombinant Human Hb 95 6.3.6 Adverse Effects of HBOCs 95 6.3.7 HBOCs in Trauma: A Way Forward? 96 6.4 Conclusion 97 References 97 7. Diagnosis and Treatment of Haemorrhages in 'Nonsurgical' Patients 107
Umberto Rossi and Rosa Chianese 7.1 Introduction 107 7.1.1 Aetiopathogenetic Classification 107 7.1.2 Multifactorial Pathogenesis 108 7.1.3 Haemorrhagic Syndromes from Antithrombotic Treatment or Prophylaxis 108 7.2 Clinical Assessment 111 7.2.1 Medical History 111 7.2.2 Physical Examination 112 7.3 Laboratory Tests 113 7.3.1 Screening Tests 113 7.3.2 Second-level Laboratory Tests 113 7.3.3 Other Tests 114 7.4 Haemorrhagic Syndromes Clinically Indicative of Systemic Defects with Normal Screening Tests 117 7.5 Blood and Blood Components in the Treatment of Haemorrhagic Syndromes 118 Further Reading 118 8. Management of Perioperative Bleeding 121
Sibylle A. Kozek-Langenecker 8.1 Introduction 121 8.2 Pathomechanisms of Coagulopathy in Massive Bleeding 121 8.3 Perioperative Coagulation Monitoring 122 8.4 Limitations of Routine Coagulation Tests in the Perioperative Setting 123 8.5 Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) 124 8.6 Procoagulant Interventions 124 8.7 Algorithm for Coagulation Management 126 References 127 9. Oxygenation in the Preterm Neonate 131
Vidheya Venkatesh, Priya Muthukumar, Anna Curley and Simon Stanworth 9.1 Introduction 131 9.2 Physiology of Oxygen Transport in Fetal and Postnatal Life 132 9.2.1 Oxygenation of the Fetus 132 9.2.2 Measuring Oxygenation in the Neonate 133 9.3 Oxygen Therapy in the Postnatal Period 133 9.3.1 Oxidative Stresses in the Newborn Period 134 9.3.2 Clinical Sequelae of Hyperoxia 134 9.3.2.1 Retinopathy of Prematurity 134 9.3.2.2 Oxygen and Chronic Lung Disease 135 9.3.2.3 Oxygen and Periventricular Leukomalacia 136 9.4 Oxygen and Resuscitation of the Newborn Infant 136 9.5 Transfusion in the Newborn 137 9.6 ROP and Transfusions 137 9.7 Conclusion 137 References 138 10. Ischemia 145
Hooman Mirzakhani and Ala Nozari 10.1 Introduction 145 10.2 Pathophysiology 145 10.2.1 Energy Failure 145 10.2.2 Cell Membrane Damage 146 10.2.3 Increased Cytosolic Calcium 146 10.2.4 Inflammation 148 10.2.5 The No-reflow Phenomenon 149 10.2.6 Free Radicals and Reactive Oxygen Species 149 10.2.7 Excitotoxicity 150 10.3 Therapeutic Potentials 150 10.3.1 Preconditioning 150 10.3.2 Antioxidants 151 10.3.3 Anti-inflammation Therapy 151 10.3.4 Therapeutic Hypothermia 151 10.3.5 Hydrogen Sulfide 152 10.3.6 Hyperoxia and Hyperbaric Oxygen 152 10.3.7 Hemoglobin-based Oxygen Carriers 152 10.4 Conclusion 153 References 153 11. Normobaric and Hyperbaric Oxygen Therapy for Ischemic Stroke and Other Neurological Conditions 159
Ari Moskowitz, Yu-Feng Yvonne Chan and Aneesh B. Singhal 11.1 Introduction 159 11.2 Rationale of Oxygen Therapy in AIS 160 11.3 Hyperbaric Oxygen Therapy 162 11.4 Normobaric Oxygen Therapy 164 11.5 The Status of Supplemental Oxygen Delivery 165 11.6 Comparison of HBO and NBO in AIS 165 11.7 Safety Concerns 168 11.8 HBO and NBO in Other Conditions 169 11.9 Conclusion 169 References 170 12. Transfusion Therapy in β Thalassemia and Sickle Cell Disease 179
Carlo Brugnara and Lucia De Franceschi 12.1 Introduction 179 12.2 β Thalassemia and Transfusion 179 12.3 Sickle Cell Disease and Transfusion 182 12.4 Iron Chelation Tools 185 12.5 Conclusion 186 References 186 Part III. "Old" and New Strategies for Oxygen Supply 193 13. Transfusion: Political, Administrative and Logistic Issues 195
John R. Hess and Giuliano Grazzini Disclaimer 195 13.1 Introduction 195 13.2 Blood Safety 196 13.3 Blood Availability 198 13.4 Cost and Fairness 200 13.5 Transfusion Medicine 201 References 202 14. Conscientious Objection in Patient Blood Management 205
Kenneth E. Nollet and Hitoshi Ohto 14.1 Introduction 205 14.2 Conscientious Objection 205 14.3 Patient Blood Management 206 14.4 Jehovah's Witnesses 207 14.5 Will the Real Objection Please Stand Up? 208 14.6 Conscientious Objection in Relation to Oxygen Therapeutics and Other Innovations 208 Acknowledgements 209 References 210 15. Red-cell Transfusion in Clinical Practice 213
Harvey G. Klein 15.1 Introduction 213 15.2 Red-cell Use 214 15.3 The Red-cell-transfusion Trigger 215 15.4 Risks of Red-cell Transfusion 216 15.5 Conclusion 218 Disclaimer 218 References 218 16. Causes and Consequences of Red Cell Incompatibility 221
Chisa Yamada and Robertson Davenport 16.1 Introduction 221 16.2 Red Cell Antigens 221 16.2.1 ABO and the H System 221 16.2.2 The Lewis System and Structurally Related Antigens 222 16.2.3 The Rh System 222 16.2.4 Other Blood Group Systems 222 16.3 Red Cell Antibodies 223 16.3.1 Naturally Occurring Antibodies and Immune Antibodies 223 16.3.2 Autoantibodies 224 16.3.3 Drug Induced Antibodies 224 16.4 Compatibility Testing 224 16.4.1 ABO and Rh D Typing 224 16.4.2 Antibody Screening and Identification 224 16.4.3 Selection of Appropriate Blood 225 16.4.4 Crossmatch Testing 225 16.5 Hemolytic Transfusion Reactions 225 16.5.1 Pathophysiology 226 16.5.2 Prevention 228 References 228 17. Biochemistry of Storage of Red Blood Cells 231
Ryan Stapley, Dario A. Vitturi and Rakesh P. Patel 17.1 Introduction 231 17.2 Pathologic Consequences of Transfusion with Aged RBCs 232 17.3 Changes in Oxygen Affinity During RBC Storage 232 17.4 Role of Oxidative Damage During RBC Storage 233 17.5 Changes in the Physical Properties of RBCs During Storage 234 17.6 RBCs as Modulators of Vascular Flow 234 17.6.1 ATP Release Hypothesis 234 17.6.2 SNO-hemoglobin Hypothesis 235 17.6.3 Nitrite Reductase/Anhydrase Hypothesis 236 17.7 RBC-dependent Modulation of Inflammation 237 17.8 Conclusion 237 Acknowledgements 238 References 238 18. Proteomic Investigations of Stored Red Blood Cells 243
Lello Zolla and Angelo D'Alessandro 18.1 Introduction 243 18.2 RBC Ageing and Metabolism in vivo 244 18.3 RBC Storage Lesions Through Proteomics 248 18.4 Conclusion 252 References 252 19. Red Blood Cells from Stem Cells 257
Anna Rita Migliaccio, Carolyn Whitsett and Giovanni Migliaccio 19.1 Introduction 257 19.2 Stem-cell Sources for ex vivo Generation of Erythroid Cells as a Transfusion Product 258 19.3 Conditions that Favor ex vivo Erythroid Cell Expansion 260 19.4 A Clinical-grade Production Process for ex vivo Generation of Red-cell Transfusion Products 261 19.4.1 The Nature of the Production Process 261 19.4.2 Cellular Composition of the Product 263 19.4.3 Functional Status of Product 264 19.4.4 Safety Considerations 265 19.5 Time Line of the Clinical Application of ex vivo-generated Erythroid Cells 266 19.5.1 Drug Discovery 266 19.5.2 Drug Delivery 267 19.5.3 Ex vivo-expanded EBs for Alloimmunized Patients 268 References 268 20. The Universal Red Blood Cell 273
Luca Ronda and Serena Faggiano 20.1 Introduction 273 20.1.1 ABO Antigens 274 20.1.2 The Rh System 274 20.2 Enzymatic Removal of A and B Antigens 275 20.2.1 Conversion of B RBCs to Group O 275 20.2.2 Conversion of A RBCs to Group O 277 20.3 RBC Camouflage Through PEGylation 277 20.3.1 Functionalized Methoxy PEG 278 20.3.2 Cyanuric Chloride PEG 279 20.3.3 Extension Arm-facilitated RBC PEGylation 279 20.3.4 Increasing the Degree of RBC PEGylation 280 20.4 Conclusion 280 References 280 21. Allosteric Effectors of Hemoglobin: Past, Present and Future 285
Martin K. Safo and Stefano Bruno 21.1 Introduction 285 21.2 Natural and Synthetic Allosteric Effectors 288 21.2.1 Organic Phosphates 288 21.2.2 Synthetic Aromatic Propionate Right-shifters 289 21.2.3 Aromatic Aldehyde Left-shifters 290 21.3 Molecular Mechanism of Action of Allosteric Effectors 293 21.3.1 Oxygen Binding Curve and Hb Structural Changes 293 21.3.2 How Allosteric Effectors can Bind to the Same Site and Have Opposite Allosteric Properties 294 21.3.3 Decreasing Subunit Mobility and Changes in Allosteric Properties: Molecular Ratchets 294 21.4 The First Visualization of an Important Pharmacological Theory via Hb Allosteric Effector Binding 295 21.5 The Clinical Importance of Hemoglobin Allosteric Effectors 295 References 296 22. Hemoglobin-based Oxygen Carriers: History, Limits, Brief Summary of the State of the Art, Including Clinical Trials 301
Jonathan S. Jahr, Arezou Sadighi, Linzy Doherty, Alvin Li and Hae Won Kim 22.1 Introduction 301 22.2 American Society of Anesthesiologists Guidelines and Risks of Blood Transfusion 302 22.3 Limitations of Blood Transfusion 302 22.4 History 302 22.5 Development 303 22.6 Definitive Clinical Trials 304 22.6.1 Diaspirin Crosslinked Hemoglobin (DCLHb, HemeAssist, Baxter Laboratories, Deerfield, IL) 304 22.6.2 Hemoglobin Raffimer (HR, Hemolink, Hemosol Inc., Ontario, Canada) 306 22.6.3 Human Polymerized Hemoglobin (PolyHeme, Northfield Laboratories, Evanston, IL) 307 22.6.4 Hemoglobin Glutamer-250 (Bovine) (HBOC-201, Hemopure, Biopure Corp., Cambridge, MA) 308 22.6.5 Maleimide-polyethylene Glycol-modified Hemoglobin (MP4, Hemospan, Sangart Inc., San Diego, CA) 309 22.7 Current Status and Future Directions of HBOCs 311 References 314 23. Oxygen Delivery by Natural and Artificial Oxygen Carriers 317
Enrico Bucci 23.1 Introduction 317 23.2 The Role of Oxygen Carriers 317 23.3 The Role of Natural Cell-bound Oxygen Carriers 318 23.4 Matching the Rate of Oxygen Delivery with the Rate of Oxygen Consumption 320 23.4.1 The Imbalance 320 23.4.2 The Rate of Oxygen Release from the Red Cells 320 23.4.3 Matching the Delivery/Consumption Rates 321 23.4.4 The Hematocrit is a Critical Parameter 321 23.5 The Role of Artificial Cell-free Oxygen Carriers 321 23.5.1 Facilitated Diffusion 321 23.5.2 Toxicity 322 23.6 Other Parameters 322 23.7 Clinical Use? 323 Acknowledgments 324 References 324 24. Crosslinked and Polymerized Hemoglobins as Potential Blood Substitutes 327
Kenneth W. Olsen and Eugene Tarasov 24.1 Introduction 327 24.2 Crosslinking the Hb Tetramer 328 24.3 Hb Polymers 332 24.4 Conclusion 337 References 338 25. Engineering the Molecular Shape of PEG-Hemoglobin Adducts for Supraperfusion 345
Seetharama A. Acharya, Marcos Intaglietta, Amy G. Tsai, Kulal Ananda and Fantao Meng 25.1 Introduction 345 25.2 Enzon DecaPEGylated Bovine Hb is Nonhypertensive 346 25.3 EAF HexaPEGylated Hb (EAF P5K6-Hb) is Nonhypertensive 347 25.4 Molecular and Solution Properties of EAF HexaPEGylated Human Hb (EAF-P5K6-Hb) 347 25.5 High O2 Affinity of EAF HexaPEGylated Hb and Tissue Oxygenation in Extreme Hemodilution 349 25.6 Influence of Total PEG Mass Conjugated to Hb on O2 Affinity and Tissue Oxygenation by PEG-Hbs 350 25.7 Influence of PEGylation Chemistry on Structural, Functional, and Solution Properties of HexaPEGylated Hb 351 25.8 Reductive PEGylation-induced Weakening of Interdimeric Interactions of Tetrameric Hbs 352 25.9 PEGylation-promoted Dissociation of Hb Tetramer is Attenuated by the Extension Arms of EAF PEGylated Hbs 353 25.10 Does Urethane-linkage-mediated PEGylation of Hb Promote its Dissociation? 354 25.11 Hemospan: Prototype of EAF HexaPEGylated Hb Designed at Einstein 354 25.12 EAF HexaPEGylated Hb Compared to other Blood Substitutes of Earlier Designs 355 25.13 Reversible Protection of Cys-93(β) during EAF PEGylation of Hb and Crosslinked Hbs: A Structural Requirement to Generate Medium- and Low-O2-affinity PEG-Hbs 355 25.14 Engineering Extension Arms between the Protein Core and PEG Shell Attenuates PEGylation-promoted Tetramer Dissociation 356 25.15 Attenuation of Direct HexaPEGylation-promoted Dissociation of Hb Tetramers by Increasing the Tetramer Stability Through Chemical Modification 359 25.16 Influence of the Extension Arm on the HexaPEGylation-enhanced Thermal Stability of Hb 359 25.17 PEGylation of Hb Induces a Hydrostatic Molecular Drag to the PEG-Hb Conjugate 360 25.18 EAF HexaPEGylated Hb is a Superperfusion Agent 360 25.19 EAF PEG-Hb-induced Vasodilation 361 25.20 In vivo Vasodilation by EAF PEG-Hb through its Enhanced Nitrite Reductase Activity 361 25.21 EAF PEG-Hbs as Mechanotransducers of e-NOS Activity 363 25.22 The Pattern of PEGylation of Intramolecularly Crosslinked Hbs Influences the Viscosity of the PEG-Hb Solution 364 25.23 Conclusion 364 Acknowledgments 366 References 367 26. Hb Octamers by Introduction of Surface Cysteines 371
V´eronique Baudin-Creuza, Chien Ho and Michael C. Marden 26.1 Introduction 371 26.2 Genetic Engineering of Proteins with Cysteines 373 26.2.1 Protein Expression 373 26.2.2 Oligomer Size 374 26.2.3 Disulfide Bond Formation 375 26.2.4 Functional Properties of the Octamers 376 26.2.5 Octamer Properties 378 26.2.6 Octamer Constraint 378 26.3 Conclusion 378 References 378 27. Hemoglobin Vesicles as a Cellular-type Hemoglobin-based Oxygen Carrier 381
Hiromi Sakai, Hirohisa Horinouchi, Eishun Tsuchida and Koichi Kobayashi 27.1 Introduction 381 27.2 The Concept of Hb Encapsulation in Liposomes 382 27.3 Hb Encapsulation Retards Gas Reactions 383 27.4 HBOCs as a Carrier of not only O2 but also CO 385 27.5 Conclusion 387 Acknowledgments 387 References 387 28. Animal Models and Oxidative Biomarkers to Evaluate Preclinical Safety of Extracellular Hemoglobins 391
Paul W. Buehler and Felice D'Agnillo Disclaimer 391 28.1 Introduction 391 28.2 HBOC Safety and Efficacy 392 28.2.1 Proposed Mechanisms of Toxicity 392 28.2.1.1 Hypertension 392 28.2.1.2 Oxidative Stress 392 28.2.2 Safety Pharmacology and Toxicology Studies 393 28.2.3 In vivo Models of Efficacy "Proof of Concept" 395 28.2.3.1 Tissue Blood Flow and Oxygenation 395 28.2.3.2 Traumatic Hemorrhage 396 28.2.3.3 Local Ischemia 397 28.2.3.4 Sickle Cell Disease 397 28.2.4 Experimental Approaches to Assessing Preclinical Safety of HBOCs 398 28.2.4.1 Species Antioxidant Status (Natural Evolution) 398 28.2.4.2 Chemically Induced Antioxidant Depletion 398 28.2.4.3 Endothelial Dysfunction 399 28.2.4.4 Sepsis and Endotoxemia 400 28.3 Experimental Oxidative Biomarkers and Extracellular Hb Exposure 400 28.3.1 Heme Iron Oxidation 400 28.3.2 Amino-acid Oxidation 401 28.3.3 Heme Catabolism and Iron Sequestration 401 28.4 Markers of in vivo Oxidative Stress and Tissue Damage 403 28.4.1 4-hydroxy-2-nonenal (4-HNE) Protein Adducts 403 28.4.2 8-hydroxy-2-deoxyguanosine (8-OHdG) 403 28.5 Conclusion 404 References 405 29. Academia–Industry Collaboration in Blood Substitute Development: Issues, Case Histories and a Proposal 413
Hae Won Kim, Andrea Mozzarelli, Hiromi Sakai and Jonathan S. Jahr 29.1 Introduction 413 29.2 Generic Issues in Academia–Industry Collaboration 414 29.3 Academia–Industry Collaboration in HBOC Development 415 29.4 Proposal for a New Academia–Industry Collaboration Model in HBOC Development: an HBOC Research Consortium (a Conceptual Model) 417 29.4.1 Mission 417 29.4.2 Guiding Principles 417 29.4.3 Key Objectives 417 29.4.4 Structure 418 29.4.5 Operation 419 29.5 Discussion 420 29.6 Conclusions 421 Appendix: Successful Academia–Industry Collaboration Cases in HBOC Development 422 Case A: Waseda–Keio–Industry Research Collaboration 422 Case B: EuroBloodSubstitutes Consortium 424 References 426 Index 429

Long Description

Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or blood substitutes ) which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development. The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery; hemoglobin and myoglobin; nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury. The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in thalassemia and sickle cell disease Finally old and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion; conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell stora≥ proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell; allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers; oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia industry collaboration in blood substitute development. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.

Details ISBN0470686685 Year 2011 ISBN-10 0470686685 ISBN-13 9780470686683 Format Hardcover Subtitle From Transfusion to Artificial Blood Short Title CHEMISTRY & BIOCHEMISTRY OF OX Language English Media Book DEWEY 615.836 Pages 466 Illustrations Illustrations Edited by Stefano Bettati Edition 1st Country of Publication United States Publisher John Wiley & Sons Inc Imprint John Wiley & Sons Inc Place of Publication New York UK Release Date 2011-08-12 AU Release Date 2011-09-13 NZ Release Date 2011-09-13 Author Stefano Bettati Publication Date 2011-08-12 Audience Professional & Vocational US Release Date 2011-08-12

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TheNile_Item_ID:137300312;

• Condition: Brand New
• ISBN-13: 9780470686683
• Book Title: Chemistry and Biochemistry of Oxygen Therapeutics
• ISBN: 9780470686683
• Subject Area: Physical Therapy
• Publication Name: Chemistry and Biochemistry of Oxygen Therapeutics: from Transfusion to Artificial Blood
• Publisher: John Wiley & Sons Inc
• Subject: Chemistry
• Publication Year: 2011
• Type: Textbook
• Format: Hardcover
• Language: English
• Item Height: 252mm
• Author: Stefano Bettati, Andrea Mozzarelli
• Item Width: 171mm
• Item Weight: 958g
• Number of Pages: 466 Pages

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