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Gwyn Hopkins - One of the best experts on this subject based on the ideXlab platform.

  • randomized double blind study comparing Saruplase with streptokinase therapy in acute myocardial infarction the compass equivalence trial
    Journal of the American College of Cardiology, 1998
    Co-Authors: U Tebbe, Bernard Charbonnier, Hannes Barth, R Michels, Jennifer Adgey, Jean Boland, Avi Caspi, Jurgen Windeler, Robert Groves, Gwyn Hopkins
    Abstract:

    Abstract Objectives. This study sought to demonstrate the equivalence of Saruplase and streptokinase in terms of 30-day mortality. Background. The use of thrombolytic agents in the treatment of acute myocardial infarction is well established and has been shown to substantially reduce post-myocardial infarction mortality. Methods. Three thousand eighty-nine patients with symptoms compatible with those of acute myocardial infarction for Results. Death of any cause up to 30 days after randomization occurred in 88 (5.7%) of 1,542 patients randomized to receive Saruplase and 104 (6.7%) of 1,547 patients randomized to receive streptokinase (odds ratio 0.84, p Conclusions. Saruplase is a clinically safe and effective thrombolytic medication. This profile ranks Saruplase favorably among the currently available thrombolytic agents.

  • rapid haemodynamic improvement following Saruplase in recent massive pulmonary embolism
    Thrombosis and Haemostasis, 1998
    Co-Authors: Gerard Pacouret, Gwyn Hopkins, Sarah J Barnes, Bernard Charbonnier
    Abstract:

    In a single centre pilot study, Saruplase (20 mg bolus plus 60 mg infusion over 1 h) was administered to twenty patients with an angiographically documented recent massive pulmonary embolism: Miller index of at least 20 and mean pulmonary artery pressure of at least 20 mmHg. The lytic ability of Saruplase to cause normalization of haemodynamic parameters over the first 12 h and reperfusion of pulmonary arteries at 24 h was assessed. A decrease of 25 ± 10% in total pulmonary resistance was evident at 30 min. Haemodynamic parameters continued to improve with total pulmonary resistance decreasing by 29 ± 8% and 40 ± 11% at 1 and 12 h respectively. Relative improvement in Miller index 24 ± 6 h after Saruplase treatment was 38 ± 9%. Two patients suffered recurrent pulmonary embolism, two severe bleeding events were observed. One patient died following a haemorrhagic stroke.

  • effect of changes in liver blood flow on the pharmacokinetics of Saruplase in patients with acute myocardial infarction
    Thrombosis and Haemostasis, 1997
    Co-Authors: J M T Van Griensven, Gwyn Hopkins, Horst Beier, W A Gunzler, R W Koster, Ria Kroon, Rik C Schoemaker, A F Cohen
    Abstract:

    BACKGROUND: The recombinant unglycosylated single chain urokinase-type plasminogen activator Saruplase is cleared for a large part by the liver. A large interindividual variation in Saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of Saruplase. METHODS AND RESULTS: Thirteen AMI patients were enrolled in this open label study. Patients received a bolus injection of 20 mg Saruplase followed by a one-hour infusion of 60 mg Saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, alpha2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and alpha2-antiplasmin (r = -0.84; p <0.01 and r = -0.65; p <0.05). CONCLUSIONS: Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize Saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow

  • Hemostatic changes after thrombolytic therapy with Saruplase (unglycosylated single-chain urokinase-type plasminogen activator) and urokinase (two-chain urokinase-type plasminogen activator).
    Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 1996
    Co-Authors: H. R. Michels, J Windeler, J. J. M. L. Hoffmann, Gwyn Hopkins
    Abstract:

    Urokinase, or two-chain urokinase-type plasminogen activator (tcu-PA), is an effective thrombolytic agent. Its single-chain precursor (scu-PA), unlike tcu-PA, is able to selectively activate fibrin-bound plasminogen. The induced clot lysis is amplified by plasmin-triggered conversion of scu-PA to tcu-PA. The aim of our study was to compare the hemostatic effects of recombinant unglycosylated scu-PA, INN Saruplase, and urokinase, at doses considered optimal (80 mg Saruplase and 3 million units urokinase) in patients with acute myocardial infarction, within 6 h of onset of pain. Complete sample sets from more than 230 patients in each treatment group have been analyzed. The median hemostatic changes caused by Saruplase and urokinase were virtually identical indicating that Saruplase is converted early in vivo to its active tcu-PA derivative with the dose regimen used. Fibrinogen degradation products were higher for Saruplase with a maximum at 2h. They rose markedly after Saruplase from 0.43 mg/l at 0 h to a maximum of 160 mg/l at 2 h, whereas the increase after urokinase (from 0.45 mg/l to 89.0 mg/l) was significantly smaller (P < 0.001).

  • comparison of the pharmacokinetics and effects on the hemostatic system of Saruplase and urokinase in patients with acute myocardial infarction
    Journal of Thrombosis and Thrombolysis, 1996
    Co-Authors: Joerg Poeppelmeier, Gwyn Hopkins, Horst Beier, J Carlsson, Wolfgang A Guenzler, Rainer Meierhenrich, U Tebbe
    Abstract:

    The aim of the study was to compare in a single trial, using identical methodology, the pharmacokinetic properties and the effect on the hemostatic system of Saruplase (unglycosylated scu-PA) and urokinase (glycosylated tcu-PA). Twenty-four patients with an acute myocardial infarction were either treated with Saruplase (n = 12; 20 mg IV bolus followed by a 60 mg infusion for 60 minutes) or urokinase (n = 12; 1.5 million IU IV bolus followed by 1.5 million IU infusion for 60 minutes). Blood samples from Saruplase-treated patients were analyzed for u-PA antigen and total u-PA and tcu-PA activities; those from urokinase-treated patients for u-PA antigen and tcu-PA activity. The effect of treatment on, including recovery of, plasma α2-antiplasmin, fibrinogen, and plasminogen was examined in both groups. The total clearance of urokinase (179 ± 55 ml/ min) is about half that of Saruplase (406 ± 154 ml/min), and the mean residence time of urokinase (59.1 ± 22.5 minutes) is nearly twice that of Saruplase (28.3 ± 7.8 minutes), which results in a slower elimination of urokinase from plasma. Whether differences in the pharmacokinetic behavior of the unglycosylated Saruplase and the glycosylated urokinase observed in this study are due to the difference in glycosylation or to other factors is not resolved. The systemic effect of Saruplase on α2,-antiplasmin, fibrinogen, and plasminogen is similar to that of urokinase, although retarded.

A F Cohen - One of the best experts on this subject based on the ideXlab platform.

  • effect of changes in liver blood flow on the pharmacokinetics of Saruplase in patients with acute myocardial infarction
    Thrombosis and Haemostasis, 1997
    Co-Authors: J M T Van Griensven, Gwyn Hopkins, Horst Beier, W A Gunzler, R W Koster, Ria Kroon, Rik C Schoemaker, A F Cohen
    Abstract:

    BACKGROUND: The recombinant unglycosylated single chain urokinase-type plasminogen activator Saruplase is cleared for a large part by the liver. A large interindividual variation in Saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of Saruplase. METHODS AND RESULTS: Thirteen AMI patients were enrolled in this open label study. Patients received a bolus injection of 20 mg Saruplase followed by a one-hour infusion of 60 mg Saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, alpha2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and alpha2-antiplasmin (r = -0.84; p <0.01 and r = -0.65; p <0.05). CONCLUSIONS: Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize Saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow

  • effects of changing liver blood flow by exercise and food on kinetics and dynamics of Saruplase
    Clinical Pharmacology & Therapeutics, 1995
    Co-Authors: Jean M T Van Griensven, Horst Beier, Joachim Gerloff, W A Gunzler, Ria Kroon, Rik C Schoemaker, K Burggraaf, Linda G M Huisman, Kees Kluft, A F Cohen
    Abstract:

    Objective To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator. Methods This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg Saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, α2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography. Results The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: −35%, −19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics. Conclusions u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow. Clinical Pharmacology & Therapeutics (1995) 57, 381–389; doi:

  • pharmacokinetics of Saruplase a recombinant unglycosylated human single chain urokinase type plasminogen activator and its effects on fibrinolytic and haemostatic parameters in healthy male subjects
    Thrombosis and Haemostasis, 1993
    Co-Authors: A C De Boer, Horst Beier, Cornelis Kluft, Joachim Gerloff, G Dooijewaard, W A Gunzler, F J M Van Der Meer, A F Cohen
    Abstract:

    Pharmacokinetics of two doses of the recombinant single-chain urokinase-type plasminogen activator (r-scu-PA) Saruplase (40 and 20 mg) and its effect on fibrinolytic and haemostatic parameters were studied in six healthy male subjects using a randomized, double-blind, placebo-controlled, cross-over study. Special precautions were taken to prevent artefactual in vitro effects on fibrinolytic activity. The clearance of Saruplase ranged from 310 to 862 ml/min and the apparent volume of distribution of the central compartment was about 8 1. Both doses of Saruplase caused alpha 2-antiplasmin consumption, indicating some systemic fibrinolytic activation. However, the 20 mg dose caused no detectable fibrinogen breakdown and only a small increase in total fibrin/fibrinogen degradation products (TDP) (from 0.16 microgram/ml [range 0.14 to 0.19] to 0.78 microgram/ml [range 0.56 to 1.26]), while the 40 mg dose produce a fibrinogen breakdown to an average value of 44% (range 19 to 60%) and TDP increased from 0.12 microgram/ml (range 0.11-0.12) to 2.29 micrograms/ml (range 0.45 to 5.55). The breakdown of fibrinogen was related to the quantity of Saruplase converted to active two-chain u-PA (tcu-PA) in vivo (6 to 22% conversion). There were no important effects of Saruplase on overall blood coagulation (activated partial thromboplastin time) and platelet function (collagen induced platelet aggregation, urinary [2,3-dinor]-thromboxane B2 excretion and plasminogen activator inhibitor 1 [PAI-1] release from platelets). Saruplase is cleared rapidly from the plasma and a variable amount is converted to tcu-PA. This two-chain form of u-PA probably causes the dose-dependent systemic fibrinolytic activation.

Frits W Bar - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics and hemostatic effects of Saruplase in patients with acute myocardial infarction comparison of infusion single bolus and split bolus administration
    Journal of Thrombosis and Thrombolysis, 1999
    Co-Authors: H. R. Michels, J J M L Hoffman, Frits W Bar
    Abstract:

    Saruplase, or unglycosylated, single-chain urokinase-type plasminogen activator (scu-PA) selectively activates fibrin-bound plasminogen, and is subsequently converted to its two-chain derivative tcu-PA (urokinase) by plasmin. The efficacy of a 20 mg IV bolus followed by an infusion of 60 mg over 1 hour (standard regimen) has been demonstrated in acute myocardial infarction (AMI). The Bolus Administration of Saruplase in Europe (BASE) study compared the efficacy of standard therapy, single bolus (80 mg), and split bolus (2 × 40 mg at 30-minute intervals) in AMI. In a substudy of BASE, the pharmacokinetics of total u-PA activity (amidolytic activity after plasmin treatment), high molecular weight (HMW) u-PA antigen, and tcu-PA activity were compared in patients receiving standard therapy (n = 4), single bolus (n = 4), or split bolus (n = 5). Total u-PA activity and HMW u-PA antigen were similar. The maximum concentration (Cmax,, mean ± SD) of total u-PA activity was 2.2 ± 0.3 µg/mL after standard therapy, 16.3 ± 3.9 µg/mL after single bolus, and 8.2 ± 1.6 ug/mL after split bolus. The area under the concentration versus time curve (AUC) values of total u-PA activity were 1.7 ± 0.1 µg/mL*h (standard therapy), 4.0 ± 0.9 µg/mL*h (bolus), and 3.0 ± 0.7 µg/mL*h (split bolus). The dominant initial half-lives (t1/2 α) were 7.1 ± 1.1 minutes (standard), 8.8 ± 0.8 minutes (bolus), and 5.1 ± 2.1 minutes (split bolus). Maximum plasma concentrations of of tcu-PA activity were observed at 5.2 ± 7 minutes (standard), 21 ± 10 minutes (bolus), and 42 ± 2 minutes (split bolus). Cmax was lowest after standard therapy (0.6 ± 0.3 µg/mL), highest after bolus (4.2 ± 2.2 µg/mL), and approximately twice as high as standard therapy after split bolus (1.3 ± 0.8 µg/mL). After standard therapy the mean fibrinogen concentration decreased gradually from approximately 300 mg/dL to 70 mg/dL at 90 and 120 minutes. After a single bolus the fibrinogen concentration decreased below the limit of quantification within 30 minutes and remained there for at least 120 minutes. Directly after the second 40 mg dose of the split bolus, the fibrinogen levels had an accelerated and more pronounced decrease to approximately 65 mg/dL at 90 and 120 minutes. A single bolus results in very high early total u-PA activity, which accelerates the appearance of tcu-PA activity and fibrinogen consumption. The pharmacokinetics and hemostatic effects of the split-bolus regimen are more comparable with those of standard therapy.

  • thrombolysis with Saruplase versus streptokinase in acute myocardial infarction five year results of the primi trial
    American Heart Journal, 1999
    Co-Authors: Martin Spiecker, Frank Vermeer, R Michels, Jurgen Windeler, Ricardo Seabragomes, Jurgen Vom Dahl, Sebastian Kerber, Freek W A Verheugt, Pieter W Westerhof, Frits W Bar
    Abstract:

    Abstract Background Short-term safety and efficacy of thrombolysis with Saruplase in acute myocardial infarction have been shown in several trials. To assess long-term outcome of patients treated with Saruplase or streptokinase for myocardial infarction, a 5-year follow-up of patients included in the Pro-Urokinase in Myocardial Infarction Trial was performed. Methods and Results Follow-up data are available from 8 centers on 255 (92.4%) of 276 included patients. The 5-year mortality rate was comparable with 20.8% of patients in the Saruplase group and 16.9% in the streptokinase group (odds ratio 1.29, 95% confidence interval 0.69 to 2.42). In both groups, a considerable number of fatal cardiovascular events occurred more than 1 year after study inclusion. Rates of percutaneous transluminal coronary angioplasty and coronary artery bypass grafting were comparable in both groups. Reinfarction within 5 years occurred in 19.0% of patients in the Saruplase group and tended to be less frequent at 10.8% after streptokinase treatment (odds ratio 1.94, 95% confidence interval 0.98 to 3.84). In both groups, the majority of reinfarctions took place more than 3 months after study inclusion. The 5-year stroke rate was 3.6% and 7.2% in the Saruplase and streptokinase groups, respectively (odds ratio 0.49, 95% confidence interval 0.16 to 1.47). Subjective symptoms of heart failure and angina pectoris were comparable in both groups. Conclusions Our data are consistent with a similar long-term outcome for patients treated with Saruplase or streptokinase. Despite the low-risk profile of the patient cohort, there were considerable adverse event rates over a 5-year period. (Am Heart J 1999;138:518-24.)

  • Saruplase is a safe and effective thrombolytic agent observations in 1698 patients results of the pass study
    Journal of Thrombosis and Thrombolysis, 1999
    Co-Authors: Frank Vermeer, I Bosl, Jurgen Meyer, Frits W Bar, Bernard Charbonnier, J Windeler, Hannes Barth
    Abstract:

    Saruplase (unglycosylated human-type high molecular weight single-chain urokinase-type plasminogen activator) was given to 1698 patients in the open-label Practical Applicability of Saruplase Study (PASS), which assessed the safety and efficacy of Saruplase in the treatment of acute myocardial infarction. Thirty-seven hospitals in Europe participated in the study. All patients received 20 mg Saruplase as a bolus followed by an infusion of 60 mg Saruplase over 1 hour. Prior to the infusion of Saruplase, 62% of the patients received a bolus of 5000 U of heparin, and after Saruplase a 24-hour intravenous infusion of heparin was given to 95% of patients. The mean age of the patients was 59 years and 80.1% were male. The median delay from the onset of chest pain to the start of Saruplase infusion was 145 minutes. Acute angiography was performed in 8 of the participating 37 centers in 350 patients (20.6%), on average 85 minutes (median) after the start of the Saruplase infusion. TIMI 3 flow was obtained in 186 patients (53.1%) and TIMI 2 flow in 61 patients (17.4%). Patency rates were similar for patients with anterior and inferior infarction. ECG signs suggestive of reperfusion were seen in 63% of the patients. In-hospital mortality was low (92 patients; 5.4%), and nonfatal recurrent myocardial infarction was seen in 60 patients (3.5%). Severe bleeding complications occurred in 92 patients (5.4%), 21 of whom (1.2%) needed a blood transfusion. An intracerebral hemorrhage was observed in eight patients (0.5%), and seven patients (0.4%) suffered from a thromboembolic stroke. At discharge 85.9% of the patients were in NYHA functional class I. One-year mortality was low (142 patients; 8.4%). Mortality was high in patients with TIMI 0 or 1 flow at the acute angiography who did not undergo rescue PTCA (9/39; 23.1%), lower in patients with TIMI 0 or 1 flow followed by successful rescue PTCA (7/64; 10.9%), and low in patients with TIMI 2 flow (1/61; 1.6%) or with TIMI 3 flow (2/186; 1.1%). Patency rates and (bleeding) complications did not differ between patients with a body weight greater than or less than 70 kilograms. No antibodies against Saruplase were detected in samples from 455 patients. In conclusion, it can be stated that Saruplase, given in combination with aspirin and intravenous heparin, can be given safely and effectively to patients with acute myocardial infarction.

  • bolus administration of Saruplase in europe base a pilot study in patients with acute myocardial infarction
    Journal of Thrombosis and Thrombolysis, 1998
    Co-Authors: Frits W Bar, Jurgen Meyer, Bernard Charbonnier, H. R. Michels, U Tebbe, Jean Boland, Martin Spiecker, A Betriu, B Artmeyer, F Vermeer
    Abstract:

    To study the safety and efficacy of the thrombolytic agent Saruplase as a bolus, the angiographic and clinical outcomes of three bolus regimens were investigated in a pilot study conducted in 192 patients with an acute myocardial infarction and were compared with the standard regimen. Fifty-two patients received a double bolus of 40 mg and 40 mg after 30 minutes, 51 patients a bolus of 80 mg, and 36 patients a bolus of 60 mg. Fifty-three patients received the standard regimen (a bolus of 20 mg and 60 mg IV infusion over 1 hour). At 60 minutes TIMI 2 and 3 flow were, respectively, 9.6% and 61.5% with the 40/40-mg bolus, 15.7% and 51.0% with the 80-mg bolus, 16.7% and 30.6% with the 60-mg bolus, and 7.5% and 54.7% with the standard 20/60-mg infusion. At 90 minutes TIMI 2 and 3 flow improved to 9.6% and 73.1%, 15.7% and 56.9%, 13.9% and 36.1%, and 5.7% and 71.7%, respectively. The primary endpoint, persistent patency (TIMI 2 + 3) at 24–45 hours, was seen in 69.2%, 64.7%, 44.4%, and 67.9% of patients who had no rescue PTCA, respectively. Inclusion in the 60-mg bolus group was prematurely stopped because of their low patency rates. The 40/40-mg bolus group had the highest mortality rate (13.5%), whereas the 60-mg bolus group had no deaths. Other adverse event rates were similar in the four groups. This clinical outcome is highly influenced by rescue PTCA of patients with insufficient TIMI flow. This pilot study indicates that in patients with an acute myocardial infarction, a double bolus of 40/40 mg resulted in the highest patency but also had the highest complication rate. The 80-mg single bolus is an attractive alternative for further evaluation because of its acceptable patency and event profile, and its easy form of administration.

  • comparison of Saruplase and alteplase in acute myocardial infarction
    American Journal of Cardiology, 1997
    Co-Authors: Frits W Bar, Frank Vermeer, Jurgen Meyer, Bernard Charbonnier, Martin Spiecker, R Michels, Klaus Haerten, Carlos Macaya, Michel Hanssen, Magda Heras
    Abstract:

    Four hundred seventy-three patients with acute myocardial infarction (AMI) were treated with either Saruplase (80 mg/hour, n = 236) or alteplase (100 mg every 3 hours, n = 237). Comedication included heparin and acetylsalicylic acid. Angiography was performed at 45 and 60 minutes after the start of thrombolytic therapy. When flow was insufficient, angiography was repeated at 90 minutes. Coronary angioplasty was then performed if Thrombolysis In Myocardial Infarction (TIMI) trial 0 to 1 flow was seen. Control angiography was at 24 to 40 hours. Baseline characteristics were similar. Angiography showed comparable and remarkably high early patency rates (TIMI 2 or 3 flow) in both treatment groups: at 45 minutes, 74.6% versus 68.9% (p = 0.22); and at 60 minutes 79.9% versus 75.3% (p = 0.26). Patency rates at 90 minutes before additional interventions were also comparable (79.9% and 81.4%). Angiographic reocclusion rates were not significantly different: 1.2% versus 2.4% (p = 0.68). After rescue angioplasty, angiographic reocclusion rates of 22.0% and 15.0% were observed. Safety data were similar for both groups. Thus, (1) early patency rates were high for Saruplase and alteplase treatment, (2) reocclusion rates for both drugs were remarkably low, and (3) complication rates were similar. Thus, Saruplase seems to be as safe and effective as alteplase.

Horst Beier - One of the best experts on this subject based on the ideXlab platform.

  • effect of changes in liver blood flow on the pharmacokinetics of Saruplase in patients with acute myocardial infarction
    Thrombosis and Haemostasis, 1997
    Co-Authors: J M T Van Griensven, Gwyn Hopkins, Horst Beier, W A Gunzler, R W Koster, Ria Kroon, Rik C Schoemaker, A F Cohen
    Abstract:

    BACKGROUND: The recombinant unglycosylated single chain urokinase-type plasminogen activator Saruplase is cleared for a large part by the liver. A large interindividual variation in Saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of Saruplase. METHODS AND RESULTS: Thirteen AMI patients were enrolled in this open label study. Patients received a bolus injection of 20 mg Saruplase followed by a one-hour infusion of 60 mg Saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, alpha2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and alpha2-antiplasmin (r = -0.84; p <0.01 and r = -0.65; p <0.05). CONCLUSIONS: Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize Saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow

  • comparison of the pharmacokinetics and effects on the hemostatic system of Saruplase and urokinase in patients with acute myocardial infarction
    Journal of Thrombosis and Thrombolysis, 1996
    Co-Authors: Joerg Poeppelmeier, Gwyn Hopkins, Horst Beier, J Carlsson, Wolfgang A Guenzler, Rainer Meierhenrich, U Tebbe
    Abstract:

    The aim of the study was to compare in a single trial, using identical methodology, the pharmacokinetic properties and the effect on the hemostatic system of Saruplase (unglycosylated scu-PA) and urokinase (glycosylated tcu-PA). Twenty-four patients with an acute myocardial infarction were either treated with Saruplase (n = 12; 20 mg IV bolus followed by a 60 mg infusion for 60 minutes) or urokinase (n = 12; 1.5 million IU IV bolus followed by 1.5 million IU infusion for 60 minutes). Blood samples from Saruplase-treated patients were analyzed for u-PA antigen and total u-PA and tcu-PA activities; those from urokinase-treated patients for u-PA antigen and tcu-PA activity. The effect of treatment on, including recovery of, plasma α2-antiplasmin, fibrinogen, and plasminogen was examined in both groups. The total clearance of urokinase (179 ± 55 ml/ min) is about half that of Saruplase (406 ± 154 ml/min), and the mean residence time of urokinase (59.1 ± 22.5 minutes) is nearly twice that of Saruplase (28.3 ± 7.8 minutes), which results in a slower elimination of urokinase from plasma. Whether differences in the pharmacokinetic behavior of the unglycosylated Saruplase and the glycosylated urokinase observed in this study are due to the difference in glycosylation or to other factors is not resolved. The systemic effect of Saruplase on α2,-antiplasmin, fibrinogen, and plasminogen is similar to that of urokinase, although retarded.

  • effects of changing liver blood flow by exercise and food on kinetics and dynamics of Saruplase
    Clinical Pharmacology & Therapeutics, 1995
    Co-Authors: Jean M T Van Griensven, Horst Beier, Joachim Gerloff, W A Gunzler, Ria Kroon, Rik C Schoemaker, K Burggraaf, Linda G M Huisman, Kees Kluft, A F Cohen
    Abstract:

    Objective To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator. Methods This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg Saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, α2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography. Results The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: −35%, −19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics. Conclusions u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow. Clinical Pharmacology & Therapeutics (1995) 57, 381–389; doi:

  • pharmacokinetics of Saruplase a recombinant unglycosylated human single chain urokinase type plasminogen activator and its effects on fibrinolytic and haemostatic parameters in healthy male subjects
    Thrombosis and Haemostasis, 1993
    Co-Authors: A C De Boer, Horst Beier, Cornelis Kluft, Joachim Gerloff, G Dooijewaard, W A Gunzler, F J M Van Der Meer, A F Cohen
    Abstract:

    Pharmacokinetics of two doses of the recombinant single-chain urokinase-type plasminogen activator (r-scu-PA) Saruplase (40 and 20 mg) and its effect on fibrinolytic and haemostatic parameters were studied in six healthy male subjects using a randomized, double-blind, placebo-controlled, cross-over study. Special precautions were taken to prevent artefactual in vitro effects on fibrinolytic activity. The clearance of Saruplase ranged from 310 to 862 ml/min and the apparent volume of distribution of the central compartment was about 8 1. Both doses of Saruplase caused alpha 2-antiplasmin consumption, indicating some systemic fibrinolytic activation. However, the 20 mg dose caused no detectable fibrinogen breakdown and only a small increase in total fibrin/fibrinogen degradation products (TDP) (from 0.16 microgram/ml [range 0.14 to 0.19] to 0.78 microgram/ml [range 0.56 to 1.26]), while the 40 mg dose produce a fibrinogen breakdown to an average value of 44% (range 19 to 60%) and TDP increased from 0.12 microgram/ml (range 0.11-0.12) to 2.29 micrograms/ml (range 0.45 to 5.55). The breakdown of fibrinogen was related to the quantity of Saruplase converted to active two-chain u-PA (tcu-PA) in vivo (6 to 22% conversion). There were no important effects of Saruplase on overall blood coagulation (activated partial thromboplastin time) and platelet function (collagen induced platelet aggregation, urinary [2,3-dinor]-thromboxane B2 excretion and plasminogen activator inhibitor 1 [PAI-1] release from platelets). Saruplase is cleared rapidly from the plasma and a variable amount is converted to tcu-PA. This two-chain form of u-PA probably causes the dose-dependent systemic fibrinolytic activation.

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  • Saruplase is a safe and effective thrombolytic agent observations in 1698 patients results of the pass study
    Journal of Thrombosis and Thrombolysis, 1999
    Co-Authors: Frank Vermeer, I Bosl, Jurgen Meyer, Frits W Bar, Bernard Charbonnier, J Windeler, Hannes Barth
    Abstract:

    Saruplase (unglycosylated human-type high molecular weight single-chain urokinase-type plasminogen activator) was given to 1698 patients in the open-label Practical Applicability of Saruplase Study (PASS), which assessed the safety and efficacy of Saruplase in the treatment of acute myocardial infarction. Thirty-seven hospitals in Europe participated in the study. All patients received 20 mg Saruplase as a bolus followed by an infusion of 60 mg Saruplase over 1 hour. Prior to the infusion of Saruplase, 62% of the patients received a bolus of 5000 U of heparin, and after Saruplase a 24-hour intravenous infusion of heparin was given to 95% of patients. The mean age of the patients was 59 years and 80.1% were male. The median delay from the onset of chest pain to the start of Saruplase infusion was 145 minutes. Acute angiography was performed in 8 of the participating 37 centers in 350 patients (20.6%), on average 85 minutes (median) after the start of the Saruplase infusion. TIMI 3 flow was obtained in 186 patients (53.1%) and TIMI 2 flow in 61 patients (17.4%). Patency rates were similar for patients with anterior and inferior infarction. ECG signs suggestive of reperfusion were seen in 63% of the patients. In-hospital mortality was low (92 patients; 5.4%), and nonfatal recurrent myocardial infarction was seen in 60 patients (3.5%). Severe bleeding complications occurred in 92 patients (5.4%), 21 of whom (1.2%) needed a blood transfusion. An intracerebral hemorrhage was observed in eight patients (0.5%), and seven patients (0.4%) suffered from a thromboembolic stroke. At discharge 85.9% of the patients were in NYHA functional class I. One-year mortality was low (142 patients; 8.4%). Mortality was high in patients with TIMI 0 or 1 flow at the acute angiography who did not undergo rescue PTCA (9/39; 23.1%), lower in patients with TIMI 0 or 1 flow followed by successful rescue PTCA (7/64; 10.9%), and low in patients with TIMI 2 flow (1/61; 1.6%) or with TIMI 3 flow (2/186; 1.1%). Patency rates and (bleeding) complications did not differ between patients with a body weight greater than or less than 70 kilograms. No antibodies against Saruplase were detected in samples from 455 patients. In conclusion, it can be stated that Saruplase, given in combination with aspirin and intravenous heparin, can be given safely and effectively to patients with acute myocardial infarction.

  • bolus administration of Saruplase in europe base a pilot study in patients with acute myocardial infarction
    Journal of Thrombosis and Thrombolysis, 1998
    Co-Authors: Frits W Bar, Jurgen Meyer, Bernard Charbonnier, H. R. Michels, U Tebbe, Jean Boland, Martin Spiecker, A Betriu, B Artmeyer, F Vermeer
    Abstract:

    To study the safety and efficacy of the thrombolytic agent Saruplase as a bolus, the angiographic and clinical outcomes of three bolus regimens were investigated in a pilot study conducted in 192 patients with an acute myocardial infarction and were compared with the standard regimen. Fifty-two patients received a double bolus of 40 mg and 40 mg after 30 minutes, 51 patients a bolus of 80 mg, and 36 patients a bolus of 60 mg. Fifty-three patients received the standard regimen (a bolus of 20 mg and 60 mg IV infusion over 1 hour). At 60 minutes TIMI 2 and 3 flow were, respectively, 9.6% and 61.5% with the 40/40-mg bolus, 15.7% and 51.0% with the 80-mg bolus, 16.7% and 30.6% with the 60-mg bolus, and 7.5% and 54.7% with the standard 20/60-mg infusion. At 90 minutes TIMI 2 and 3 flow improved to 9.6% and 73.1%, 15.7% and 56.9%, 13.9% and 36.1%, and 5.7% and 71.7%, respectively. The primary endpoint, persistent patency (TIMI 2 + 3) at 24–45 hours, was seen in 69.2%, 64.7%, 44.4%, and 67.9% of patients who had no rescue PTCA, respectively. Inclusion in the 60-mg bolus group was prematurely stopped because of their low patency rates. The 40/40-mg bolus group had the highest mortality rate (13.5%), whereas the 60-mg bolus group had no deaths. Other adverse event rates were similar in the four groups. This clinical outcome is highly influenced by rescue PTCA of patients with insufficient TIMI flow. This pilot study indicates that in patients with an acute myocardial infarction, a double bolus of 40/40 mg resulted in the highest patency but also had the highest complication rate. The 80-mg single bolus is an attractive alternative for further evaluation because of its acceptable patency and event profile, and its easy form of administration.

  • randomized double blind study comparing Saruplase with streptokinase therapy in acute myocardial infarction the compass equivalence trial
    Journal of the American College of Cardiology, 1998
    Co-Authors: U Tebbe, Bernard Charbonnier, Hannes Barth, R Michels, Jennifer Adgey, Jean Boland, Avi Caspi, Jurgen Windeler, Robert Groves, Gwyn Hopkins
    Abstract:

    Abstract Objectives. This study sought to demonstrate the equivalence of Saruplase and streptokinase in terms of 30-day mortality. Background. The use of thrombolytic agents in the treatment of acute myocardial infarction is well established and has been shown to substantially reduce post-myocardial infarction mortality. Methods. Three thousand eighty-nine patients with symptoms compatible with those of acute myocardial infarction for Results. Death of any cause up to 30 days after randomization occurred in 88 (5.7%) of 1,542 patients randomized to receive Saruplase and 104 (6.7%) of 1,547 patients randomized to receive streptokinase (odds ratio 0.84, p Conclusions. Saruplase is a clinically safe and effective thrombolytic medication. This profile ranks Saruplase favorably among the currently available thrombolytic agents.

  • rapid haemodynamic improvement following Saruplase in recent massive pulmonary embolism
    Thrombosis and Haemostasis, 1998
    Co-Authors: Gerard Pacouret, Gwyn Hopkins, Sarah J Barnes, Bernard Charbonnier
    Abstract:

    In a single centre pilot study, Saruplase (20 mg bolus plus 60 mg infusion over 1 h) was administered to twenty patients with an angiographically documented recent massive pulmonary embolism: Miller index of at least 20 and mean pulmonary artery pressure of at least 20 mmHg. The lytic ability of Saruplase to cause normalization of haemodynamic parameters over the first 12 h and reperfusion of pulmonary arteries at 24 h was assessed. A decrease of 25 ± 10% in total pulmonary resistance was evident at 30 min. Haemodynamic parameters continued to improve with total pulmonary resistance decreasing by 29 ± 8% and 40 ± 11% at 1 and 12 h respectively. Relative improvement in Miller index 24 ± 6 h after Saruplase treatment was 38 ± 9%. Two patients suffered recurrent pulmonary embolism, two severe bleeding events were observed. One patient died following a haemorrhagic stroke.

  • comparison of Saruplase and alteplase in acute myocardial infarction
    American Journal of Cardiology, 1997
    Co-Authors: Frits W Bar, Frank Vermeer, Jurgen Meyer, Bernard Charbonnier, Martin Spiecker, R Michels, Klaus Haerten, Carlos Macaya, Michel Hanssen, Magda Heras
    Abstract:

    Four hundred seventy-three patients with acute myocardial infarction (AMI) were treated with either Saruplase (80 mg/hour, n = 236) or alteplase (100 mg every 3 hours, n = 237). Comedication included heparin and acetylsalicylic acid. Angiography was performed at 45 and 60 minutes after the start of thrombolytic therapy. When flow was insufficient, angiography was repeated at 90 minutes. Coronary angioplasty was then performed if Thrombolysis In Myocardial Infarction (TIMI) trial 0 to 1 flow was seen. Control angiography was at 24 to 40 hours. Baseline characteristics were similar. Angiography showed comparable and remarkably high early patency rates (TIMI 2 or 3 flow) in both treatment groups: at 45 minutes, 74.6% versus 68.9% (p = 0.22); and at 60 minutes 79.9% versus 75.3% (p = 0.26). Patency rates at 90 minutes before additional interventions were also comparable (79.9% and 81.4%). Angiographic reocclusion rates were not significantly different: 1.2% versus 2.4% (p = 0.68). After rescue angioplasty, angiographic reocclusion rates of 22.0% and 15.0% were observed. Safety data were similar for both groups. Thus, (1) early patency rates were high for Saruplase and alteplase treatment, (2) reocclusion rates for both drugs were remarkably low, and (3) complication rates were similar. Thus, Saruplase seems to be as safe and effective as alteplase.