A genetically engineered human Kunitz protease inhibitor with increased kallikrein inhibition in an ovine model of cardiopulmonary bypass.
A recombinant human serine protease inhibitor known as Kunitz protease inhibitor (KPI) wild type has functional similarities to the bovine Kunitz inhibitor, aprotinin, and had shown a potential to reduce bleeding in an ovine model of cardiopulmonary bypass (CPB). The aim of this study was to assess KPI-185, a modification of KPI-wild type that differs from KPI-wild type in two amino acid residues and which enhances anti-kallikrein activity in a further double-blind, randomized study in an ovine model of CPB, and to compare with our previous study of KPI-wild type and aprotinin in the same ovine model. Post-operative drain losses and subjective assessment of wound 'dryness' showed no significant differences between KPI-185 and KPI-wild type, despite the significant enhancement of kallikrein inhibition using KPI-185 seen in serial kallikrein inhibition assays. These preliminary findings support the hypothesis that kallikrein inhibition is not the major mechanism by which Kunitz inhibitors such as aprotinin reduce perioperative bleeding.
Ohri
S K
SK
Department of Cardiothoracic Surgery, National Heart and Lung Institute, The Imperial College School of Medicine, London.
Parratt
R
R
White
T
T
Becket
J
J
Brannan
J J
JJ
Hunt
B J
BJ
Taylor
K M
KM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000990:Antithrombin III / Q000187:drug effects; D007611:Aprotinin / Q000008:administration & dosage / Q000494:pharmacology; D016063:Blood Loss, Surgical / Q000517:prevention & control; D002315:Cardiopulmonary Bypass / Q000009:adverse effects / Q000379:methods*; D002417:Cattle; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D006488:Hemostasis, Surgical / Q000379:methods; D006490:Hemostatics / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D023421:Models, Animal; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000097:blood / Q000187:drug effects; D011446:Prospective Studies; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D012756:Sheep; D000979:alpha-2-Antiplasmin / Q000187:drug effects / Q000378:metabolism
D006490:Hemostatics; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D000979:alpha-2-Antiplasmin; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D007611:Aprotinin; D010447:Peptide Hydrolases; D007610:Kallikreins