Blood substitutes / edited by Robert M. Winslow.

Includes bibliographical references and index.

List of Contributors
Preface
Acknowledgements
Abbreviations
Introduction
Section 1: Background
Introduction
Chapter 1: Historical Background
INTRODUCTION
BLOOD CIRCULATION AND TRANSFUSION
WORLD WAR II
FIRST ‘BLOOD SUBSTITUTES’
BLOOD PLASMA, SERUM AND ALBUMIN
CELL-FREE HEMOGLOBIN
CURRENT STATUS
SUMMARY
Chapter 2: Transfusion Medicine
HISTORY OF BLOOD TRANSFUSION
ORGANIZATION OF BLOOD SERVICES
AVAILABILITY OF BLOOD
RED BLOOD CELL COMPONENTS
RED CELL COMPATIBILITY
UNIVERSAL RED CELLS
RED CELL MODIFICATION
ADVERSE EVENTS ASSOCIATED WITH RED CELL TRANSFUSION
IMMUNOMODULATORY EFFECTS
THE COST OF RED CELLS
THE ROLE OF RED CELL SUBSTITUTES
Chapter 3: Regulatory Perspectives on Clinical Trials for Oxygen Therapeutics in Trauma and Transfusion Practice
GENERAL REGULATORY BACKGROUND IN THE UNITED STATES
CONSIDERATIONS FOR CLINICAL TRIALS IN TRAUMA
CONSIDERATIONS IN TRANSFUSION AVOIDANCE
SUMMARY
Section 2: Physiological Basis
Introduction
Chapter 4: Clinical Physiology: Oxygen Transport and the Transfusion Trigger
INTRODUCTION
OXYGEN REQUIREMENTS
LOCAL REGULATION OF OXYGEN SUPPLY: THE MICROCIRCULATION
OXYGEN UPTAKE IN THE LUNG
THE ‘OPTIMAL’ HEMATOCRIT
OXYGEN DELIVERY, OXYGEN UPTAKE AND THE ‘CRITICAL OXYGEN’
BLOOD TRANSFUSION AND OXYGEN SUPPLY
THE ‘TRANSFUSION TRIGGER’
Chapter5: The Role of Oxygen and Hemoglobin Diffusion in Oxygen Transport by Cell-free Hemoglobins
INTRODUCTION
OXYGEN DIFFUSION AND ITS BARRIERS IN THE CIRCULATION
FACILITATED DIFFUSION OF OXYGEN BY OXYHEMOGLOBIN
RATE LIMITING STEPS OF IN VIVO GAS EXCHANGE
FACILITATED OXYGEN TRANSPORT AND VASOCONSTRICTION
FACILITATED DIFFUSION AND HYPEROXYGENATION OF ARTERIOLES
SUMMARY
Chapter 6: Oxygen Transport Properties of Hemoglobin-Based Oxygen Carriers: Studies using Artificial Capillaries and Mathematical Simulation
INTRODUCTION
IN VITRO SIMULATION OF OXYGEN TRANSPORT
CURRENT STATE OF OXYGEN CARRIER STUDIES IN ARTIFICIAL CAPILLARIES
CURRENT STATE OF MATHEMATICAL SIMULATION STUDIES
EXAMPLES OF EXPERIMENTS AND SIMULATIONS
IMPLICATIONS FOR IN VIVO OXYGEN TRANSPORT
SUMMARY
Chapter 7: Mechanisms of Oxygen Transport in the Microcirculation: Effects of Cell-Free Oxygen Carriers
INTRODUCTION
THE DISTRIBUTION OF OXYGEN ON THE CIRCULATION
OXYGEN DELIVERY AND CONSUMPTION
ANEMIA AND HYPEROXIA
THE HEMOGLOBIN – OXYGEN EQUILIBRIUM CURVE
TISSUE RESPIRATION
SUMMARY
ACKNOWLEDGMENTS
Chapter 8: Shear Stress Mechanotransduction and the Flow Properties of Blood
INTRODUCTION
SHEAR STRESS AND THE RELEASE OF VASOACTIVE MEDIATORS
MECHANOTRANSDUCTION AND MECHANOSENSORS
THE ROLE OF THE GLYCOCALYX
CHANGES OF SHEAR STRESS IN THE MICROCIRCULATION
EFFECTS IN THE PLASMA LAYER
BLOOD SUBSTITUTES AND MECHANOTRANSDUCTION
ACKNOWLEDGMENTS
Chapter 9: Local Regulation of Blood Flow
INTRODUCTION
TISSUE OXYGEN SUPPLY AND DEMAND
CELLULAR METABOLIC FEEDBACK
OXYGEN-SENSITIVE MECHANISMS
MECHANISMS OF FUNCTIONAL HYPEREMIA
MECHANICAL STIMULI FOR FLOW REGULATION
INTEGRATIVE ASPECTS OF FLOW REGULATION
ACKNOWLEDGMENTS
Section 3: Clinical Applications
Introduction
Chapter 10: Clinical Indications for Blood Substitutes and Optimal Properties
INTRODUCTION
TRAUMA/RESUSCITATION
ELECTIVE SURGERY
RED CELL INCOMPATIBILITY
ISCHEMIC DISEASE AND ANGIOPLASTY
EXTRACORPOREAL ORGAN PERFUSION
CELL CULTURE MEDIA
HEMATOPOIETIC STIMULATION
CARDIOPLEGIA
SICKLE-CELL ANEMIA
TUMOR THERAPY
CHRONIC ANEMIA
RESEARCH
REQUIREMENTS FOR A BLOOD SUBSTITUTE
Chapter 11: Crystalloid Solutions
INTRODUCTION
PHYSIOLOGICAL PRINCIPLES
DISTRIBUTION VOLUMES OF WATER, SODIUM AND PROTEIN
KINETIC DISTRIBUTION VOLUMES OF FLUIDS
CRYSTALLOID SOLUTIONS
USE OF CRYSTALLOID FLUIDS IN SURGICAL PROCEDURES
USE OF CRYSTALLOID FLUIDS FOR REPLACEMENT OF BLOOD LOSS
OTHER EFFECTS OF CRYSTALLOID INFUSION
SUMMARY
Chapter 12: Hemoglobin-Based Oxygen Carriers as Resuscitative Solutions for Trauma and Combat Casualty Care
INTRODUCTION
REQUIREMENTS FOR COMBAT CASUALTY CARE
RELEVANT PROPERTIES OF HBOCs FOR TRAUMA AND COMBAT CASUALTY CARE
INTRAOPERATIVE TRIALS
PRE-HOSPITAL RESUSCITATION
PLASMA VOLUME EXPANSION
CARDIAC OUTPUT
OXYGEN UPTAKE VERSUS OXYGEN DELIVERY
HYPOTENSIVE RESUSCITATION
NEW FORMULATIONS
SUMMARY
Chapter 13: Surgical Hemorrhage
INTRODUCTION
POTENTIAL CLINICAL BENEFITS OF HBOCs IN SURGICAL CARE
POTENTIAL ROLE OF HBOCs IN SURGICAL CARE
EXCEPTION FROM INFORMED CONSENT FOR TRAUMA TRIALS
CLINICAL EVALUATION OF TETRAMERIC HEMOGLOBIN IN TRAUMA
CLINICAL SAFETY OF POLYHEME™ IN TRAUMA
CLINICAL EFFICACY OF POLYHEME TRAUMA CARE
THE NEXT GENERATION OF HBOCs FOR SURGICAL CARE
ACKNOWLEDGMENTS
Chapter 14: Clinical Trials in Cardiac Surgery
INTRODUCTION
HEMOGLOBIN SOLUTIONS
PERFLUOROCARBON EMULSIONS
SUMMARY
Chapter 15: Hemodilution
INTRODUCTION
MECHANISMS OF ADAPTATION TO REDUCED HEMOGLOBIN
MICROCIRCULATORY CHANGES AND TISSUE OXYGENATION
TISSUE OXYGENATION
BRAIN FUNCTION IN DILUTIONAL ANEMIA
PLASMA VISCOSITY
EXTREME HEMODILUTION
HYPEROXIC HEMODILUTION
SUMMARY
Chapter 16: Clinical Hemodilution
INTRODUCTION
INDICATIONS FOR ACUTE NORMOVOLEMIC HEMODILUTION
PHYSIOLOGICAL COMPENSATORY MECHANISMS
HEMODILUTION PROCEDURES
EFFICACY OF HEMODILUTION
ADJUNCTS TO ANH
SUMMARY
Chapter 17: Potential for Blood Substitutes in Tissue Ischemia
INTRODUCTION
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
TREATMENT AVAILABLE FOR CHRONIC CRITICAL LEG ISCHEMIA
POTENTIAL FOR BLOOD SUBSTITUTES IN THE TREATMENT OF CCLI
SUMMARY
Section 4: Toxicity and Side Effects
Introduction
Chapter 18: Redox and Radical Reactions of Hemoglobin Solutions: Toxicities and Protective Strategies
INTRODUCTION
OXIDATIVE MECHANISMS
HEMOGLOBIN AND CELL-SIGNALING PATHWAYS
ANTIOXIDATIVE PROTECTIVE STRATEGIES
SUMMARY
Chapter 19: Pro-Oxidant Activity of Hemoglobin and Endothelial Cytotoxicity
INTRODUCTION
PRO-OXIDANT ACTIVITY OF HEMOGLOBIN
HEMOGLOBIN-MEDIATED ENDOTHELIAL CYTOTOXICITY IN VITRO
PRO-OXIDANT ACTIVITY OF HEMOGLOBIN AND VASCULAR TOXICITY IN VIVO
SUMMARY
Chapter 20: Renal Toxicity
INTRODUCTION
HISTORY AND BACKGROUND
CURRENT STATE OF KNOWLEDGE
HEMOGLOBIN TOXICITY TO RENAL VASCULATURE
FUNCTIONAL CONSEQUENCES OF HEMOGLOBIN TOXICITY
ACUTE RENAL FAILURE
SUMMARY
FUTURE DIRECTIONS
Chapter 21: Hemoglobin and Neurotoxicity
INTRODUCTION
IN VITRO EXPERIMENTS
IN VIVO EXPERIMENTS
TISSUE RESPONSE TO HEMOGLOBIN METABOLITES AND POSSIBLE NEUROPROTECTION
CLINICAL EXPERIENCE WITH HBOCs
Chapter 22: The Role of Inflammation in the Toxicity of Hemoglobin-Based Oxygen Carriers
INTRODUCTION
THE INFLAMMATORY RESPONSE
BLOOD VESSELS
BLOOD SUBSTITUTES AND INFLAMMATION
MICROVESSELS AND INTESTINAL MUCOSA
CLINICAL IMPLICATIONS OF INFLAMMATION DURING USE OF BLOOD SUBSTITUTES
ANTICIPATED FUTURE DIRECTIONS
SUMMARY
Chapter 23: Hemoglobin-Induced Myocardial Lesions
INTRODUCTION
BACKGROUND
ANIMAL MODELS
LESION CHARACTERISTICS
MECHANISM OF HEMOGLOBIN-INDUCED MYOCARDIAL LESIONS
CO-MEDICAMENTS
SUMMARY
ACKNOWLEDGEMENTS
Section 5: Perfluorocarbon-Based Oxygen Carriers
Introduction
Chapter 24: Fluorocarbon Emulsions as in vivo Oxygen Delivery Systems: Background and Chemistry
FLUOROCARBON CHEMISTRY
OXYGEN DISSOLVING AND DELIVERING CAPACITY: GAS-LIKE LIQUIDS
PERFLUOROCARBON EMULSIONS FOR IN VIVO OXYGEN TRANSPORT
DEVELOPMENT OF INJECTABLE FLUOROCARBON EMULSIONS
THE SEARCH FOR IMPROVED EMULSIONS
Chapter 25: Fluosol®: The First Commercial Injectable Perfluorocarbon Oxygen Carrier
INTRODUCTION
ORIGINS OF FLUOSOL
CHEMISTRY, COMPOSITION AND PRODUCTION
PRECLINICAL STUDIES
CLINICAL TRIALS
Studies in North America
FAILURE OF REGULATORY APPROVAL OF FLUOSOL FOR THE TREATMENT OF ANEMIA
PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY
OTHER APPLICATIONS FOR FLUOSOL
LESSONS LEARNED FROM FLUOSOL
OTHER ‘FIRST-GENERATION’ EMULSIONS
Chapter 26: Perftoran®
INTRODUCTION
HISTORY AND COMPOSITION OF PERFTORAN
PRECLINICAL STUDIES
CLINICAL TRIALS WITH PERFTORAN
CURRENT USAGE OF PERFTORAN
CLINICAL IMPLICATIONS
THE FUTURE OF PERFTORAN
SUMMARY
ACKNOWLEDGMENTS
Chapter 27: Rational Development of Oxyfluor™
INTRODUCTION
EVOLUTION OF PERFLUOROCARBONS FOR OXYGEN TRANSPORT
DEVELOPMENT OF OXYFLUOR™
OXYFLUOR REGULATORY STATUS
THE FUTURE OF OXYFLUOR AND HEMAGEN
Chapter 28: Oxygent™, a Perfluorochemical-Based Oxygen Therapeutic for Surgical Patients
INTRODUCTION
EMULSION CHARACTERISTICS
NON-CLINICAL SAFETY
CLINICAL SAFETY
PRECLINICAL EFFICACY
POTENTIAL CLINICAL APPLICATIONS
PHASE II CLINICAL STUDIES
PHASE III CLINICAL STUDIES
FUTURE CLINICAL DEVELOPMENT
ACKNOWLEDGMENTS
Section 6: Hemoglobin-Based Oxygen Carriers
Introduction
Chapter 29: The Structural and Functional Properties of Hemoglobin and their Relevance for a Hemoglobin-Based Blood Substitute
INTRODUCTION
THE STRUCTURE OF HEMOGLOBIN
DERIVATIVES WITH HEME LIGANDS
SUBUNIT INTERFACES AND TETRAMER–DIMER DISSOCIATION
COOPERATIVE OXYGEN BINDING
STEREOCHEMICAL CONSEQUENCES OF LIGAND BINDING
CONTROL OF OXYGEN AFFINITY
NON-HEME LIGANDS: H+, Cl−, CO2 AND 2,3-DPG
NITRIC OXIDE
AUTOXIDATION
ACKNOWLEDGMENTS
Chapter 30: Hemoglobin Modification
INTRODUCTION
REACTIVITY OF HEMOGLOBIN
AMINO-TERMINAL MODIFICATION
MODIFICATION AT THE 2,3-DPG BINDING SITE
αα-CROSSLINK (LYSINE G6(99) α1–LYSINE G6(99)α2)
SURFACE, MULTISITE POLYMERIZING REAGENTS
CONJUGATED HEMOGLOBIN
RECOMBINANT HEMOGLOBIN
HEMOGLOBIN SOURCES
Chapter 31: Designing Recombinant Hemoglobin for Use as a Blood Substitute
INTRODUCTION
GENETICALLY CROSSLINKED HEMOGLOBIN
OXYGEN DELIVERY
THE HYPERTENSIVE SIDE EFFECT
NO DIOXYGENATION BY OXYHEMOGLOBIN
EXPRESSION OF rHB IN E. COLI
SUMMARY
ACKNOWLEDGMENTS
Chapter 32: Design, Conformational, Functional and Physiological Characterization of Recombinant Polymeric Heme-Proteins
INTRODUCTION
DESIGN OF RECOMBINANT HEME PROTEIN POLYMERS
BIOCHEMICAL PROPERTIES
PHYSIOLOGICAL PROPERTIES
ENDOTHELIAL PERMEABILITY (EXTRAVASATION)
SUMMARY
ACKNOWLEDGMENTS
Chapter 33: αα-Crosslinked Hemoglobin
THE NEED FOR A BLOOD SUBSTITUTE
PRODUCTION
CHARACTERIZATION
PHARMACOKINETICS
VASOCONSTRICTION
HEMODYNAMICS
MICROCIRCULATION
ENDOTHELIUM
OXYGEN TRANSPORT
OXIDATION
CENTRAL NERVOUS SYSTEM
Chapter 34: DCLHb and rHb1.1
‘TETRAMERIC’ MODIFIED HEMOGLOBINS
DCLHb
RECOMBINANT HEMOGLOBINS
RETROSPECTIVE
Chapter 35: Clinical Studies with DCLHb
INTRODUCTION
PRECLINICAL CARDIAC LESIONS
PHASE I STUDY
PHASE II STUDIES
PHASE III STUDIES
EUROPEAN PRODUCT APPLICATION FOR CARDIAC SURGERY
TRAUMA STUDIES: THE BEGINNING OF THE END
THE END OF DCLHb
LESSONS LEARNED
Chapter 36: Hemopure® (HBOC-201, Hemoglobin Glutamer-250 (Bovine)): Preclinical Studies
INTRODUCTION
PRODUCT CHARACTERISTICS
PHARMACOLOGICAL ACTION
PRECLINICAL STUDIES OF TISSUE OXYGENATION AND TRAUMA
CARDIOVASCULAR STUDIES
HEMODILUTION AND COMPLETE BLOOD REPLACEMENT
CARDIAC FUNCTION, OUTPUT AND METABOLISM
POTENTIAL INDICATIONS FOR HBOC-201
SUMMARY
Chapter 37: HBOC-201 (Hemoglobin Glutamer-250 (Bovine), Hemopure®): Clinical Studies
INTRODUCTION
PHASE I STUDIES IN HUMAN VOLUNTEERS
PHASE I/II STUDIES
PHASE II STUDIES
PHASE III STUDY
OTHER POPULATIONS AND CASE STUDIES
SUMMARY
Chapter 38: Polyhemoglobin–Enzymes as New-Generation Blood Substitutes and Oxygen Therapeutics
INTRODUCTION
POLYHEMOGLOBIN–CATALASE–SUPEROXIDE DISMUTASE
POLYHEMOGLOBIN–TYROSINASE
SUMMARY
Chapter 39: Surface Decoration of Hemoglobin with Polyethylene Glycol
PROTEIN MODIFICATION WITH PEG
HEMOGLOBIN MODIFICATION WITH PEG
VASOACTIVITY OF PEG-MODIFIED HEMOGLOBIN
NEW PARADIGMS FOR THE DESIGN OF HEMOGLOBIN-BASED BLOOD SUBSTITUTES
NEW PEG CHEMISTRY STRATEGIES
Structural and functional properties of Hb-PEG5K6
MODIFICATION NEEDED TO NEUTRALIZE VASOACTIVITY
MOLECULAR SHIELDING BY PEG MODIFICATION
SUMMARY
ACKNOWLEDGMENTS
Chapter 40: Hemospan® (MP4), A Human Hemoglobin Modified with Maleimide-Polyethylene Glycol
INTRODUCTION
THE AUTOREGULATORY HYPOTHESIS
CHEMISTRY AND PHYSICAL PROPERTIES
NON-CLINICAL STUDIES
TOXICOLOGY/SAFETY
CLINICAL LABORATORY INTERFERENCE
CLINICAL INDICATIONS
CLINICAL TRIALS
SUMMARY
Chapter 41: Dextran–Hemoglobin
INTRODUCTION
HIGH YIELD OF DxHB
PROTECTION OF KIDNEYS
NON-ENTRY INTO LYMPH
OXYGEN AFFINITY
PHYSICAL STABILITY
IN VIVO STUDIES
POTENTIAL FOR DxHb
Chapter 42: Development of Non-Extravasating Hemoglobin-Based Oxygen Carriers
INTRODUCTION
FUMARYL-CROSSLINKED BOVINE HEMOGLOBIN
SEBACYL-CROSSLINKED TETRAMERIC HEMOGLOBIN (DECA)
ADIPYL-CROSSLINKED BOVINE HEMOGLOBIN
ZERO-LINK POLYMERIC HEMOGLOBIN
OXYGEN DELIVERY BY HIGH AND LOW AFFINITY CARRIERS
SUMMARY
ACKNOWLEDGMENTS
Section 7: Liposomes and Related Products
Introduction
Chapter 43: Liposome-Encapsulated Hemoglobin: History, Preparation and Evaluation
HISTORICAL PERSPECTIVE
PREPARATION OF LIPOSOME-ENCAPSULATED HEMOGLOBIN
PROPERTIES
ENDOTOXIN INTERACTION
CIRCULATION TIME
TOXICITY
OXYGEN DELIVERY
STORAGE STABILITY
SUMMARY
ACKNOWLEDGMENTS
Chapter 44: Hemoglobin Vesicles as a Molecular Assembly: Characteristics of Preparation Process and Performances as Artificial Oxygen Carriers
IMPORTANCE OF CELLULAR STRUCTURE
PREPARATION OF HEMOGLOBIN VESICLES
REGULATION OF OXYGEN AFFINITY
STORAGE STABILITY
ENDOTOXIN
HEMOGLOBIN VESICLES AS OXYGEN CARRIERS IN VIVO
SUMMARY
ACKNOWLEDGMENTS
Chapter 45: Nanodimension Biodegradable Polymeric Membrane Artificial Red Blood Cells
INTRODUCTION
PROPERTIES OF HEMOGLOBIN POLYLACTIDE NANOCAPSULES
PEG-PLA COPOLYMER Hb NANOCAPSULES
Effect of crosslinking the newly formed Hb nanocapsules
ENZYMES AND MULTIENZYMES
PREVENTION OF METHEMOGLOBIN FORMATION
IMPLICATIONS FOR BLOOD SUBSTITUTE DEVELOPMENT
ACKNOWLEDGMENTS
Chapter 46: Albumin-Heme: A Synthetic Heme-Based Oxygen Carrier
INTRODUCTION
RATIONALE FOR ALBUMIN-HEME
OXYGEN BINDING AND PHYSICOCHEMICAL CHARACTERISTICS
BLOOD COMPATIBILITY IN VITRO
IN VIVO EFFECTS
PRECLINICAL SAFETY
FUTURE RESEARCH
ACKNOWLEDGMENTS
Index
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