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 cli nical trials. One such product, pyridoxalated hemoglobin polyoxyethylene co njugate (PHP), is a human-derived and chemically modified hemoglobin that h as yielded promising results in Phase II clinical trials, and is entering a pivotal Phase III clinical trial for the treatment of shock associated wit h systemic inflammatory response syndrome (SIRS). Shock associated with SIR S is a NO-induced shock. PHP, a new mechanism-based therapy, has been demon strated in clinical trials to have the expected hemodynamic activity of rai sing blood pressure and reducing catecholamine use, consistent with its mec hanism of action as a NO scavenger. PHP is conjugated with polyoxyethylene, which results in a surface-decorated molecule with enhanced circulation ti me and stability as well as in attachment of soluble red blood cell enzymes , including catalase and superoxide dismutase. PHP thus contains an antioxi dant profile similar to the intact red blood cell and is therefore resistan t to both initial oxidative modification by oxidants such as hydrogen perox ide and subsequent ferrylhemoglobin formation. These studies suggest both t hat the redox activity of modified hemoglobins can be attenuated and that m odified hemoglobins containing endogenous antioxidants, such as PHP, may ha ve reduced pro-oxidant potential. These antioxidant properties, in addition to the NO-scavenging properties, may allow the use of PHP in other indicat ions in which excess NO, superoxide, or hydrogen peroxide is involved, incl uding ischemia-reperfusion injury and hemorrhagic shock. (C) 2000 Elsevier Science Inc.