Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics

741 Pages·2013·12.572 MB·English

by  Thomas Ming Swi Chang (auth.), Hae Won Kim, A. Gerson Greenburg (eds.)

Hae Won Kim · A. Gerson Greenburg
Hemoglobin-
Based Oxygen
Carriers as Red
Cell Substitutes
and Oxygen
Therapeutics
Hemoglobin-Based Oxygen Carriers as Red Cell
Substitutes and Oxygen Therapeutics
Hae Won Kim A. Gerson Greenburg
•
Editors
Hemoglobin-Based Oxygen
Carriers as Red Cell
Substitutes and Oxygen
Therapeutics
123
Editors
Hae Won Kim, Ph.D. A.Gerson Greenburg,MD, Ph.D.
Brown University Brown University
Providence,Rhode Island Boulder, Colorado
USA USA
ISBN 978-3-642-40716-1 ISBN 978-3-642-40717-8 (eBook)
DOI 10.1007/978-3-642-40717-8
SpringerHeidelbergNewYorkDordrechtLondon
LibraryofCongressControlNumber:2013953266
(cid:2)Springer-VerlagBerlinHeidelberg2013
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To my parents and Hanna, Bryan, Martha
and Edward whose love and support made it
all possible
—Hae Won Kim
To my wife, Reva, whose ever-present love
and support has made it possible for me to
pursue my academic interests and passions
—A. Gerson Greenburg
Preface
It has been a while since a comprehensive review of the status of Hemoglobin-
Based Oxygen Carriers (HBOCs) has been assembled. Indeed, the field in many
wayshasbecomeorphanedasclinicalandtechnologicadvancesinbloodbanking
andthemanagementofanemiamoveforward.Spurredonintheearly1980swith
theonsetofAIDS,HBOCdevelopmentwasrichandproductive,analternativeto
risky red cell transfusions. This led to a more modern approach to red cell
transfusion and HBOCs were more or less relegated to specific applications as
‘‘oxygen therapeutics’’. All the while of course, there continued a need for an
oxygentherapeuticifonlyforusewhenbloodwasneitheranoptionnoravailable.
Clinical trials with a number of HBOCs went forward and all failed to produce
resultssufficienttopermitFDAregulatoryapproval.Intheearlypartofthecurrent
century it appeared as if there was no need for such a product and the regulatory
environment continued to be challenging.
We decided to bring the field up-to-date with the construction of this book.
Dedicated to HBOCs alone, our intention was to bring together in one place the
current status of the field, a starting point for those interested in joining in on the
adventure of discovery, a place for the veterans of the fight to read and reflect on
whatwasandthinkingaboutcreating‘‘whatcanbe’’.Weholdthattherecontinues
tobeaneedforanoxygentherapeuticandthatneedcanbemetsuccessfullywitha
HBOC.Infact, thereisanurgencytodevelop HBOCsasanalternativestodonor
bloodfortransfusion.Basedoncurrentworlddemographics,ithasbeenpredicted
that, in coming decades, there would be a serious shortage of transfusable blood
because of higher demands due to rapidly aging populations in many countries
while relative decrease in eligible younger donors.
The organization of this work is rather traditional, starting with an historical
overviewandstatement ofscientific principles asthe foundationfor the products.
Movingontoaspecificapplicationinhemorrhagicshockisanaturaldevelopment
asinadditiontoAIDS,itwasandremainsaclearlystatedpotentialapplication.A
discussion of some of the current issues and regulatory framework rounds out the
establishment of a foundation for the rest of the book.
A rather large section discussing many of the newer and older approaches to
HBOCdevelopmentfollows.Here,themanydifferentideasforresolvingsomeof
thequestionsposedbyregulatoryandexperientialreportsareaddressedcreatinga
plethoraofnewmodificationsandprocessesastheymovealong.Clearly,thenext
vii
viii Preface
step is to identify and catalog the potential applications for these products. While
theuniverseofpotentialapplicationsexceedsthosepresentedhere,thesearebuta
few specifics linked to unique HBOCs. There are many more possible, a near
endless list could be generated.
There follows a section on preclinical evaluation, a critical step in the regu-
latoryprocess.Hereagain,generalizationsfromspecificapplicationsandproducts
formthereferencemodel.Inthebackgroundremainstheissueofhowappropriate
and useful are animal models in the development of human-use products and we
are aware of many HBOC preclinical studies that may not be relevant to how
humans will respond to the product given the variation in human physiology and
disease state.
As the failure of clinical trials has been the major blockade to regulatory
approval it seems appropriate to include commentary on this issue. There are
critical questions posed in these writings that should be considered when con-
templatingHBOCclinicaltrials. Asacorollarytoadiscussionofclinicaltrials, a
section on the adverse events so critical to gaining an understanding of how they
come about and more importantly how they can be mediated or prevented is a
logical follow-on.
We think this discussion is critical to understanding how HBOCs work, how
their use to date in general, and in trials specifically as well as in compassionate
usesituations.Therearemanyreasonsforanadverseeventtoappearanditisnot
alwaysclearintherigidanalysisofdatafromarandomizedtrialthattheHBOCis
responsible for the observation.
Tothatend,weconcludewithawhitepaperthatproposesaconsortialapproach
to facilitate development of safer and more effective HBOCs. A HBOC research
consortium composed of committed independent investigators would allow
objective investigations of critical issues based on unbiased scientific principles
and methods.
This book is meant to bring an up-to-date perspective to the HBOC field, a
referenceforwherethefieldstandsatthispointintime.Itisoursincerehopethat
it accomplishes this objective and meets your specific needs.
Sincerely,
October 2013 Hae Won Kim
A. Gerson Greenburg
Acknowledgments
WearedeeplygratefultoalltheAuthorswho,despiteotherprioritiesthatdemand
ontheirtime,havewillinglyandenthusiasticallycontributedtoourbook.Mostof
them are longtime colleagues who have dedicated a significant portion of their
careerstoHBOCresearchanddevelopment.Writingabookchapterisregardedby
many as secondary and a distraction, diverting energy from discovery and crea-
tivity. We hope that this finished product serves as a small consolation for their
effortsasitprovidesfreshinsightsforthedevelopmentofsaferandmoreeffective
HBOCs. Lastly, HWK would like to express a special thanks to Professor
Chi-MingHaiandProfessorChairWayneBowen,DepartmentofMPPBprogram
at Brown University, who have kindly made arrangements that allowed him to
work on this worthy task.
ix
Contents
Part I Introduction and Scientific Principles
1 From Hemoglobin Based Oxygen Carrier to Oxygen
Therapeutics, Blood Substitutes, Nanomedicine
and Artificial Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Thomas Ming Swi Chang
2 From the Atmosphere to the Mitochondrion:
The Oxygen Cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
George P. Biro
3 Biochemistry of Hemoglobin. . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Andrea Mozzarelli, Stefano Bruno and Luca Ronda
4 The Role of Blood and Plasma Viscosity in Restoring
Oxygen Delivery Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Amy G. Tsai, Judith Martini, Beatriz Y. Salazar Vázquez,
Pedro Cabrales, Seetharama A. Acharya and Marcos Intaglietta
Part II Hemorrhagic Shock and Current Treatments
5 Pathophysiology of Hemorrhagic Shock and Resuscitation. . . . . . 97
Fredric M. Pieracci and Walter L. Biffl
6 Allogeneic Blood Transfusion for Surgical
and Traumatic Hemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Mercy Kuriyan and Jeffrey L. Carson
7 Pre-Hospital Fluid Resuscitation in Civilian
and Military Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Robert M. Van Haren, Chad M. Thorson,
Col Lorne H. Blackbourne and Kenneth G. Proctor
xi
xii Contents
Part III Current Issues of HBOCs and Regulatory Framework
8 NIH/FDA/DOD Interagency Working Group
on Oxygen Therapeutics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Phyllis Mitchell, Richard Weiskopf, Warren M. Zapol
and Oxygen Therapeutics Working Group
9 Regulatory Framework for Hemoglobin-Based
Oxygen Carrier Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Basil Golding
Part IV Approaches to HBOCs
10 HBOCs from Chemical Modification of Hb. . . . . . . . . . . . . . . . . 159
Ronald Kluger and Francine E. Lui
11 Design of Nonhypertensive Conjugated Hemoglobins
as Novel Resuscitation Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Seetharama A. Acharya, Marcos Intaglietta,
Amy G. Tsai and Fantao Meng
12 Cellular-Type Hemoglobin-Based Oxygen Carriers to Mimic
the Red Blood Cell Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Hiromi Sakai
13 Recombinant Octameric Hemoglobins as Resuscitation
Fluids in a Murine Model of Traumatic Brain Injury
Plus Hemorrhagic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Xianren Wu, Nancy T. Ho, Tong-Jian Shen, Vincent Vagni,
David K. Shellington, Keri Janesko-Feldman, Tsuey Chyi S. Tam,
Ming F. Tam, Patrick M. Kochanek, Chien Ho
and Virgil Simplaceanu
14 Liposome-Encapsulated Hemoglobin as an Artificial Oxygen
Carrier: Technological Features, Manufacturing and Issues
for Practical Application. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Shinichi Kaneda, Takanobu Ishizuka, Hiroshi Goto
and Hiroaki Kasukawa
15 Zero-Link Hemoglobin (OxyVita(cid:3)): Impact of Molecular
Design Characteristics on Pre-clinical Studies . . . . . . . . . . . . . . . 283
John P. Harrington and Hanna Wollocko