Toxicology studies with recombinant staphylokinase and with SY 161-P5, a polyethylene glycol-derivatized cysteine-substitution mutant.

SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters.

Differential inhibition of thrombin activity and thrombin generation by a synthetic direct thrombin inhibitor (napsagatran, Ro 46-6240) and unfractionated heparin in patients with deep vein thrombosis. ADVENT Investigators.

Background: Direct thrombin inhibitors belong to a new class of antithrombotic drugs whose effects on blood coagulation in vivo in patients suffering from acute thrombotic conditions have not yet been fully explored.

Methods And Results: One hundred and five patients with acute proximal deep-vein thrombosis were randomized to receive a continuous intravenous infusion of napsagatran, a novel synthetic thrombin inhibitor, at a fixed dose of 5 mg/h (n = 36) or 9 mg/h (n = 25) for five days, or APTT-adjusted unfractionated heparin (UFH, n = 44) for the same time. In these patients, thrombin activity and thrombin generation could be assessed by measuring thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2), respectively, on three occasions.

An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (napsagatran, Ro 46-6240) compared with unfractionated heparin for treatment of proximal deep-vein thrombosis -- results of the European multicenter ADVENT trial.

One hundred and ten patients with acute proximal deep-vein thrombosis were randomized in a sequential dose-finding design, to receive continuous intravenous infusion of napsagatran, a novel synthetic thrombin-inhibitor, at a fixed dose of 5 mg/h (n = 37) or 9 mg/h (n = 26), or APTT-adjusted unfractionated heparin (n = 47). Oral anticoagulants were started on the 2nd day and the study drug was discontinued from the 5th treatment day, as soon as the International Normalized Ratio was above 2. Control venogram (97 venogram pairs evaluable) after 5-8 days of treatment showed improvement in 3 napsagatran-treated patients (versus none in heparin-treated patients) and worsening in 4 napsagatran-treated patients (versus 2 in heparin-treated patients).

Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study.

Background: Ligand binding to the platelet membrane receptor glycoprotein (GP) IIb/IIIa, the final and obligatory step to platelet aggregation, can now be inhibited by pharmacological agents. This study was designed to evaluate the potential of lamifiban, a novel nonpeptide antagonist of GP IIb/IIIa, for the management of unstable angina.

Methods And Results: In a prospective, dose-ranging, double-blind study, 365 patients with unstable angina were randomized to an infusion of 1, 2, 4, or 5 micrograms/min of lamifiban or of placebo.

Randomized, Placebo-Controlled Study of Lamifiban with Thrombolytic Therapy for the Treatment of Acute Myocardial Infarction: Rationale and Design for the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) Study.

The benefits of thrombolytic therapy in the treatment of acute myocardial infarction are incontrovertible. Large-scale studies combining angiographic and clinical end-points have demonstrated a perfusion-mortality relationship, with the highest survival rate among patients with early restoration of TIMI grade 3 coronary arterial flow. Despite advances in thrombolytic strategies, a substantial number of patients fail to rapidly achieve and maintain adequate coronary perfusion with thrombolysis.

Comparative effects of enoxaparin and heparin on arterial and venous clot lysis with alteplase in dogs.

The effects of Enoxaparin with a specific anti-thrombin (anti-IIa) activity of 32 U/mg and a specific anti-factor-XA (anti-Xa) activity of 96 U/mg, and of heparin with a specific anti-IIa and anti-Xa activity of 192 U/mg, on thrombolysis with alteplase (Actilyse) were compared in a randomized blinded study using a combined arterial and venous thrombosis model in the dog. All dogs received an intravenous bolus of 5 mg/kg lysine-acetyl salicylate and 0.5 mg/kg alteplase over 60 min.

Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA).

Background And Objectives: The conjunctive use of intravenous heparin may influence the efficacy of alteplase for coronary thrombolysis in patients with acute myocardial infarction. In this study we examined the relation between the level of intravenous anticoagulation with heparin and sustained coronary artery patency in a subgroup of patients of the European Cooperative Study Group (ECSG) trial.

Methods: In the ECSG trial, patients treated with alteplase and aspirin were randomized to concomitant fixed doses of intravenous heparin (a bolus dose of 5,000 U followed by a continuous infusion of 1,000 U/h or placebo).

G4120, an Arg-Gly-Asp containing pentapeptide, enhances arterial eversion graft recanalization with recombinant tissue-type plasminogen activator in dogs.

The effects of G4120, a cyclic Arg-Gly-Asp (RGD) containing peptide which inhibits fibrinogen binding to the platelet receptor GPIIb/IIIa, on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were investigated in a combined arterial and venous thrombosis model in heparinized dogs. The arterial thrombus model consisted of a 3 cm everted (inside-out) carotid arterial segment inserted into a transsected femoral artery which occludes within 30 min with platelet-rich material and which is resistant to recanalization with 0.5 mg/kg rt-PA.

Comparative copper coil-induced thrombogenicity of the internal mammary, left anterior descending coronary, and popliteal arteries in dogs.

The internal mammary artery (IMA) is the graft of choice for coronary artery bypass surgery because of its resistance to atherosclerosis. Studies to elucidate the mechanism of this phenomenon have focused on vasoactive properties of the vessel wall; however, low thrombogenicity might also contribute to the protection of the IMA against atherosclerosis. To test this hypothesis, copper coils 3 mm long were introduced in 14 heparinized dogs into both the IMA and the left anterior descending coronary artery (LAD) (n = 7) or into both the IMA and the popliteal artery (POP) (n = 7).

Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

Background: Fibrin generation during and after therapy with alteplase may depend on the level of concomitant anticoagulation. The hypothesis that fibrinopeptide A (FPA) levels, as markers of ongoing in vivo fibrin formation, correlate with the angiographic and clinical outcome of thrombolysis is tested.

Methods And Results: Serial plasma FPA levels were determined in 334 patients of the randomized European Cooperative Study Group trial comparing heparin versus placebo plus alteplase and aspirin in patients with acute myocardial infarction.

Plasma levels of plasminogen activator inhibitor type 1, beta-thromboglobulin, and fibrinopeptide A before, during, and after treatment of acute myocardial infarction with alteplase.

Plasma levels of plasminogen activator inhibitor type-1 (PAI-1), beta-thromboglobulin (beta TG), and fibrinopeptide A (FPA) were followed over 24 hours in 30 patients treated with alteplase for acute myocardial infarction. Samples were taken at baseline (T Oh), after 90 minutes (under alteplase, no heparin, T 1.5h), after 120 minutes (under alteplase and heparin, T 2h), 30 minutes after thrombolytic therapy (T 3.

Requirement of heparin for arterial and venous thrombolysis with recombinant tissue-type plasminogen activator.

The effect of concomitant intravenous (IV) heparin (200 U/kg bolus, followed by 100 U/kg/h) on the efficacy of arterial and venous thrombolysis with IV recombinant tissue-type plasminogen activator (rt-PA; 0.5 mg/kg over 1 hour) was investigated in a combined femoral arterial and venous thrombosis model in the dog. The arterial model consisted of a high-grade stenosis, endothelial damage, and a thrombotic occlusion, and the venous model consisted of a 125I-fibrin-labeled blood clot.

[The prehospital phase of acute myocardial infarct and its significance for thrombolytic therapy].

Early thrombolytic therapy has become the treatment of choice for acute myocardial infarction (AMI). Of 189 patients admitted with AMI to the CCU of Berne University Hospital in 1988, only 17 (9%) underwent thrombolytic treatment. 101 patients (53%) were admitted within 4 hours after onset of symptoms.

Thrombolytic and pharmacokinetic properties of a conjugate of recombinant single-chain urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin in a baboon venous thrombosis model.

Chemical conjugates between recombinant single-chain urokinase-type plasminogen activator (rscu-PA) and a murine monoclonal antibody directed against fragment D-dimer of cross-linked human fibrin (MA-15C5), rscu-PA/MA-15C5, and between rscu-PA and a control monoclonal antibody (MA-1C8), rscu-PA/MA-1C8, were produced by cross-linking with N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). In an in vitro system composed of a [125 I]fibrin-labeled baboon plasma clot immersed in autologous citrated plasma, dose- and time-dependent lysis was obtained with a ratio of the potencies of free and conjugated rscu-PA similar to that in human plasma: 50% lysis in 2 hours required 4.3 micrograms/ml rscu-PA, 1.

Comparison of intravenous bolus injection or continuous infusion of recombinant single chain urokinase-type plasminogen activator (saruplase) for thrombolysis. A canine model of combined coronary arterial and femoral venous thrombosis.

The thrombolytic efficacy of recombinant unglycosylated full length single chain urokinase-type plasminogen activator (rscu-PA, saruplase), applied either as single intravenous bolus or as a continuous infusion over 60 minutes, was studied in 5 randomized blinded groups of 5 dogs with combined copper coil induced coronary artery thrombosis and 125I-fibrin labeled femoral vein clots. Infusion of 1 mg/kg recu-PA (group I) induced coronary recanalization in 4 of 5 dogs and 98 +/- 1% (mean +/- SEM) venous clot lysis. Bolus injection of 1 mg/kg recu-PA (group II) caused reflow in 3 of 5 dogs and 88 +/- 5 percent venous clot lysis.

Monitoring of fibrin generation during thrombolytic therapy of acute myocardial infarction with recombinant tissue-type plasminogen activator.

Fibrinopeptide A (FPA) is a very sensitive marker of fibrin generation in vivo. Because an imbalance between thrombogenic and thrombolytic forces may be responsible for the failure to recanalize and for reocclusion of coronary arteries, such a marker could be of eminent value during thrombolytic treatment of acute myocardial infarction. Thirty-four consecutive patients with acute myocardial infarction (peak creatine kinase level, 1,869 +/- 1,543 IU/l) were treated with 100 mg recombinant tissue-type plasminogen activator (rt-PA) 3.

Fibrin formation and platelet activation in patients with myocardial infarction and normal coronary arteries.

Coronary spasm is the mechanism most often postulated to explain the rare combination of myocardial infarction and angiographically normal coronary arteries, although the reported evidence for its role is circumstantial rather than conclusive. Whereas the importance of thrombosis in myocardial infarction is uncontested in the presence of significant coronary artery disease, there is little in vivo evidence for thrombosis in angiographically normal coronary arteries. Among 11 consecutive patients with acute myocardial infarction undergoing thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 3.

Restenosis and its determinants in first and repeat coronary angioplasty.

Restenosis is the main problem limiting long-term success of percutaneous transluminal coronary angioplasty (PTCA) and is most accurately evaluated by follow-up angiography. We compared the primary and long-term results of angioplasty in 268 consecutive patients (293 segments) with first PTCA (PTCA 1, angiographic follow-up 98%) and in 66 patients (76 segments) with repeat PTCA after restenosis (PTCA 2, angiographic follow-up 92%). Forty clinical, angiographic and procedural factors were assessed in relation to outcome.

[Thrombolysis in acute myocardial infarct: prerequisites, current experiences and remaining problems].

Left ventricular pump failure is today's main cause of in-hospital mortality from acute myocardial infarction and is directly dependent on infarct size. The first clinical attempts to preserve myocardium after acute infarction and to improve morbidity and prognosis by thrombolysis date from about twenty years ago. Through large multicenter studies and promising new agents, coronary thrombolysis has again attracted increased attention in the past two years.

Clinical and angiographic assessment 6 months after double vessel percutaneous coronary angioplasty.

Percutaneous transluminal coronary angioplasty is an accepted treatment for selected patients with single vessel disease but has not been rigorously evaluated in patients with double vessel disease. Among 769 patients undergoing transluminal coronary angioplasty between 1980 and 1984, 74 with double vessel stenosis of 50% or more underwent double vessel coronary angioplasty. Primary success was obtained for both lesions in 63 patients (85%), for one lesion in 11 patients (15%) and for 137 (93%) of 148 segments overall.

[Prolonged coma caused by diazepam sedation in ventilated patients. Diagnostic and therapeutic use of the benzodiazepine antagonist Ro 15-1788].

Repeated administration of diazepam in two ventilated patients had caused drug cumulation and coma over several days. In both cases central nervous depression could be demonstrated by the benzodiazepin antagonist Ro 15-1788 which induced reversal of coma. Estimation of plasma concentrations in a 70-year-old female patient 150 hours after the last administration showed a diazepam concentration of 437 ng/ml and a desmethyl-diazepam concentration of 483 ng/ml.