Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons

Complement activation products are major components of the inflammatory res ponse induced by cardiac surgery and cardiopulmonary bypass which contribut e to postoperative organ dysfunction, fluid accumulation, and morbidity. Ac tivation of the complement system occurs during extracorporeal circulation, during reperfusion of ischemic tissue, and after the formation of heparin- protamine complexes. In this study we examine the efficacy of Compstatin, a recently discovered peptide inhibitor of complement, in preventing heparin /protamine-induced complement activation in baboons. The study was performe d in baboons because Compstatin binds to baboon C3 and is resistant to prot eolytic cleavage in baboon blood (similar to humans); Compstatin inhibits o nly the activation of primates' complement system. After testing various do ses and administration regimens, Compstatin produced complete inhibition at a total dose of 21 mg/kg when given as a combination of bolus injection an d infusion. Compstatin completely inhibited in vivo heparin/protamine-induc ed complement activation without adverse effects on heart rate or systemic arterial, central venous, and pulmonary arterial pressures. This study indi cates that Compstatin is a safe and effective complement inhibitor that has the potential to prevent complement activation during and after clinical c ardiac surgery. Furthermore, Compstatin can serve as the prototype for desi gning an orally administrated drug. (C) 2000 academic Press.