Overview of Hemoglobin-based Oxygen Carriers (HBOCs)

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Overview of Hemoglobin-based Oxygen Carriers
(HBOCs)

• Abdu I. Alayash, Ph.D.
• Laboratory of Biochemistry and Vascular Biology,
  DH, OBRR, CBER, FDA

BPAC Meeting, December 14, 2006
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Oxygen Therapeutics, Blood Substitutes
RBC
PFC Emulsion
Tetramer
Conjugated Tetramer
Polymer
Encapsulated Hb
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HBOC Associated Pre-Clinical and Clinical Side
Effects

• Vasoactivity/hypertension
• Gastrointestinal side effects
• Pancreatic and liver enzyme elevation
• Oxidative stress
• Cardiac involvement
• Proinflammatory responses
• Neurotoxicity

(Mackenzie C.F. and Bucci E. Hosp. Med. 65582,
2004)
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HBOCs Challenges Outside RBCs

• (A) Nature of chemical modification
• non-site specificity ? conformational heme
  instability
• (B) Vascular/oxidative effects of free Hb
• a) consumes NO ? vasoconstriction/hypertension
• b) generates/reacts with ROS ? vascular injury

ROS Reactive Oxygen Species
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Oxyglobin (HBOC-301) Biochemical and
Physiological Properties of an FDA Approved HBOC
for Veterinary Medicine
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Molecular Size Distribution of HBOC-301 and its
Fractions
(min)
Buehler et al., Anal Chem 773466, 2005
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Oxygen Equilibrium Curves (OECs) for HBOC-301 and
its Fractions
Buehler et al., Anal Chem 773466, 2005
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HBOCs Challenges Outside RBCs

• (A) Nature of chemical modification
• non-site specificity ? conformational heme
  instability
• (B) Vascular/oxidative effects of free Hb
• a) consumes NO ? vasoconstriction/hypertension
• b) generates/reacts with ROS ? vascular injury

ROS Reactive Oxygen Species
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Cell-free Hb and The Vasculature
(Alayash, A., Nature Rev. Drug Disc. 3152-159,
2004)
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HBOC-301 Associated Hypertension after 50
Exchange Transfusion
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HBOC Associated Oxidative Vascular Injury
CNmetHb
Baldwin et al. , AJP 283H1292, 2002 Baldwin et
al, AJP 284H81, 2003 and Baldwin et al., JAP
96893, 2004
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HBOCs General Summary

• Most HBOCs are vasoactive, in part due to the
  scavenging of vascular NO. The proximity of HBOCs
  or its fractions to NO vascular sources may
  determine the degree of response.
• HBOCs that can withstand initial NO/oxidative
  insult due to heme stability and/or in the
  presence of endogenous reductants may deliver
  O2.