A genetically engineered human Kunitz protease inhibitor with increased kallikrein inhibition in an ovine model of cardiopulmonary bypass

Perfusion ◽  
2001 ◽  
Vol 16 (3) ◽  
pp. 199-206 ◽  
Author(s):  
Sunil K Ohri ◽  
Rachel Parratt ◽  
Tyler White ◽  
Jenny Becket ◽  
John J Brannan ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Protease Inhibitor ◽  
Randomized Study ◽  
Genetically Engineered ◽  
Wild Type ◽  
Ovine Model ◽  
Double Blind ◽  
Perioperative Bleeding ◽  
Kunitz Inhibitor ◽  
Kunitz Protease Inhibitor

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.

scholarly journals Safety and Efficacy of Using Tranexamic Acid at the Beginning of Robotic-Assisted Radical Prostatectomy in a Double-Blind Prospective Randomized Pilot Study

2020 ◽  
Vol 63 (4) ◽  
pp. 176-182
Author(s):  
Michal Balík ◽  
Josef Košina ◽  
Petr Hušek ◽  
Miloš Broďák ◽  
Filip Čečka
Keyword(s):  
Radical Prostatectomy ◽  
Tranexamic Acid ◽  
Randomized Study ◽  
Double Blind ◽  
Robotic Assisted ◽  
Dorsal Vein ◽  
Perioperative Bleeding ◽  
Robotic Assisted Radical Prostatectomy ◽  
And Control

Background: The prophylactic administration of tranexamic acid has been shown to be appropriate for procedures with a high risk of perioperative bleeding in cardiac surgery and orthopaedics. In urology the ambiguous results have been reported. Our goal was to evaluate the effect of tranexamic acid administration in robotic-assisted radical prostatectomy (RARP). A pilot, prospective, double-blind, randomized study was conducted to evaluate this effect. Methods: The study included 100 patients who received RARP in the period from April 2017 to January 2018. The patients were randomly assigned to study and control groups of 50 patients each. Results: The median follow-up was 6 months. Lower haemoglobin level drop weighted for gram of operated prostate was observed in the study group when treating the dorsal vein complex (DVC) at the beginning of the procedure (p = 0.004 after 3 hours and p < 0.001 after 24 hours). There was no evidence of any serious side effect of tranexamic acid. Conclusion: We demonstrated the safety of tranexamic acid at RARP. In addition, we showed that administration of tranexamic acid at the beginning of RARP significantly reduces the decrease in haemoglobin after the procedure when treating the DVC at the beginning of the procedure.

Aprotinin Reduces Blood Loss after Cardiopulmonary Bypass by Direct Inhibition of Plasmin

1997 ◽  
Vol 78 (03) ◽  
pp. 1021-1026 ◽  
Author(s):  
Michael J Ray ◽  
Neville A Marsh
Keyword(s):  
Cardiopulmonary Bypass ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Similar Degree ◽  
Plasminogen Activator Inhibitor 1 ◽  
Double Blind ◽  
Randomised Study ◽  
Postoperative Blood Transfusion ◽  
Perioperative Bleeding ◽  
Transfusion Requirements

SummaryThe effectiveness and mechanism of aprotinin reduced bleeding after cardiopulmonary bypass surgery was studied in a double blind randomised study of 106 patients undergoing valve replacement surgery. Aprotinin therapy was associated with significant reduction in perioperative bleeding and postoperative blood transfusion requirements. Although initially tissue plasminogen activator (t-PA) activity was lower in the aprotinin than placebo group, as surgery proceeded this difference was reversed due to less plasminogen activator inhibitor-1 release in the aprotinin group. This indicates that aprotinin-mediated suppression of fibrinolysis as demonstrated by reduced D-dimer concentration was not related to t-PA. Furthermore, similar perioperative reduction of plasminogen levels in aprotinin and placebo groups indicated a similar degree of conversion of plasminogen to plasmin. However, less plasmin bound with alpha 2-antiplasmin in the plasma in the aprotinin group as it was already complexed with aprotinin where it remained protected from the natural inhibitor on the intact fibrin surface. The reduced fibrinolytic activity of the aprotinin group was thus brought about by the complexing of aprotinin with the plasmin which was bound to the fibrin surface.

scholarly journals Structural and Mutational Analyses of the Molecular Interactions between the Catalytic Domain of Factor XIa and the Kunitz Protease Inhibitor Domain of Protease Nexin 2

2005 ◽  
Vol 280 (43) ◽  
pp. 36165-36175 ◽  
Author(s):  
Duraiswamy Navaneetham ◽  
Lei Jin ◽  
Pramod Pandey ◽  
James E. Strickler ◽  
Robert E. Babine ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Catalytic Domain ◽  
Point Mutations ◽  
Protein Data Bank Code ◽  
Mutant Form ◽  
Wild Type ◽  
Site Mutation ◽  
Kunitz Protease Inhibitor ◽  
Factor Xia ◽  
Protease Nexin

Factor XIa (FXIa) is a serine protease important for initiating the intrinsic pathway of blood coagulation. Protease nexin 2 (PN2) is a Kunitz-type protease inhibitor secreted by activated platelets and a physiologically important inhibitor of FXIa. Inhibition of FXIa by PN2 requires interactions between the two proteins that are confined to the catalytic domain of the enzyme and the Kunitz protease inhibitor (KPI) domain of PN2. Recombinant PN2KPI and a mutant form of the FXI catalytic domain (FXIac) were expressed in yeast, purified to homogeneity, co-crystallized, and the structure of the complex was solved at 2.6 Å (Protein Data Bank code 1ZJD). In this complex, PN2KPI has a characteristic, disulfide-stabilized double loop structure that fits into the FXIac active site. To determine the contributions of residues within PN2KPI to its inhibitory activity, selected point mutations in PN2KPI loop 1 11TGPCRAMISR20 and loop 2 34FYGGC38 were tested for their ability to inhibit FXIa. The P1 site mutation R15A completely abolished its ability to inhibit FXIa. IC50 values for the wild type protein and the remaining mutants were as follows: PN2KPI WT, 1.28 nm; P13A, 5.92 nm; M17A, 1.62 nm; S19A, 1.86 nm; R20A, 5.67 nm; F34A, 9.85 nm. The IC50 values for the M17A and S19A mutants were not significantly different from those obtained with wild type PN2KPI. These functional studies and activated partial thromboplastin time analysis validate predictions made from the PN2KPI-FXIac co-crystal structure and implicate PN2KPI residues, in descending order of importance, Arg15, Phe34, Pro13, and Arg20 in FXIa inhibition by PN2KPI.

Ex Vivo Inhibition of Platelet Aggregation in Patients with Severe Limb Arteriopathy Treated with BAY U3405, a Specific IX A2 Receptor Antagonist

1994 ◽  
Vol 72 (05) ◽  
pp. 659-662 ◽  
Author(s):  
S Bellucci ◽  
W Kedra ◽  
H Groussin ◽  
N Jaillet ◽  
P Molho-Sabatier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Randomized Study ◽  
In Vivo Studies ◽  
Walking Distance ◽  
Peripheral Blood Flow ◽  
Walking Ability ◽  
Double Blind ◽  
Platelet Factor

SummaryA double-blind, placebo-controlled randomized study with BAY U3405, a specific thromboxane A2 (TX A2) receptor blocker, was performed in patients suffering from severe stade II limb arteriopathy. BAY U3405 or placebo was administered in 16 patients at 20 mg four times a day (from day 1 to day 3). Hemostatic studies were done before therapy, and on day 2 and day 3 under therapy. On day 3, BAY U3405 was shown to induce a highly statistically significant decrease of the velocity and the intensity of the aggregations mediated by arachidonic acid (56 ± 37% for the velocity, 58 ± 26% for the intensity) or by U46619 endoperoxide analogue (36 ± 35% for the velocity, 37 ± 27% for the intensity). Similar results were already observed on day 2. By contrast, such a decrease was not noticed with ADP mediated platelet aggregation. Furthermore, plasma levels of betathrombo-globulin and platelet factor 4 remained unchanged. Peripheral hemodynamic parameters were also studied. The peripheral blood flow was measured using a Doppler ultrasound; the pain free walking distance and the total walking ability distance were determined under standardized conditions on a treadmill. These last two parameters show a trend to improvement which nevertheless was not statistically significant. All together these results encourage further in vivo studies using BAY U3405 or related compounds on a long-term administration.

To Compare the Insertion Conditions For I-Gel, Using Propofol, Thiopentone and Thiopentone With Topical Lignocaine Spray. - A Double Blind Randomized Study

2011 ◽  
Vol 4 (2) ◽  
pp. 14-16
Author(s):  
DR .SUHAS RAMASWAMY ◽  
◽  
DR.SAROJA SHARMA ◽  
DR.SAURAB MOHAN ◽  
DR.MADHUSUDAN UPADYA ◽  
...  
Keyword(s):  
Randomized Study ◽  
Double Blind
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