Pyridoxalated hemoglobin polyoxyethylene: a nitric oxide scavenger with antioxidant activity for the treatment of nitric oxide-induced shock.
Hemoglobins modified for therapeutic use as either hemoglobin-based oxygen carriers or scavengers of nitric oxide are currently being evaluated in clinical trials. One such product, pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), is a human-derived and chemically modified hemoglobin that has yielded promising results in Phase II clinical trials, and is entering a pivotal Phase III clinical trial for the treatment of shock associated with systemic inflammatory response syndrome (SIRS). Shock associated with SIRS is a NO-induced shock. PHP, a new mechanism-based therapy, has been demonstrated in clinical trials to have the expected hemodynamic activity of raising blood pressure and reducing catecholamine use, consistent with its mechanism of action as a NO scavenger. PHP is conjugated with polyoxyethylene, which results in a surface-decorated molecule with enhanced circulation time and stability as well as in attachment of soluble red blood cell enzymes, including catalase and superoxide dismutase. PHP thus contains an antioxidant profile similar to the intact red blood cell and is therefore resistant to both initial oxidative modification by oxidants such as hydrogen peroxide and subsequent ferrylhemoglobin formation. These studies suggest both that the redox activity of modified hemoglobins can be attenuated and that modified hemoglobins containing endogenous antioxidants, such as PHP, may have reduced pro-oxidant potential. These antioxidant properties, in addition to the NO-scavenging properties, may allow the use of PHP in other indications in which excess NO, superoxide, or hydrogen peroxide is involved, including ischemia-reperfusion injury and hemorrhagic shock.
Privalle
C
C
Apex Bioscience, Inc., Research Triangle Park, NC 27709, USA. cprivalle@apexbioscience.com
Talarico
T
T
Keng
T
T
DeAngelo
J
J
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016166:Free Radical Scavengers / Q000737:chemistry / Q000627:therapeutic use*; D006454:Hemoglobins / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008706:Methemoglobin / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D010084:Oxidation-Reduction; D010108:Oxyhemoglobins / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use*; D012769:Shock / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications
D000975:Antioxidants; D016166:Free Radical Scavengers; D006454:Hemoglobins; D010108:Oxyhemoglobins; C050907:pyridoxalated-hemoglobin-polyethylene glycol conjugate; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D008706:Methemoglobin