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K. Strein - One of the best experts on this subject based on the ideXlab platform.
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Rapid reversal of canine thromboembolic pulmonary hypertension by bolus injection of the novel recombinant plasminogen activator BM 06.022.
Journal of cardiovascular pharmacology, 1993Co-Authors: Ulrich Martin, G. Sponer, K. StreinAbstract:We used a canine model of embolic pulmonary hypertension induced by intravenous (i.v.) injection of autologous thrombi to evaluate whether the novel recombinant plasminogen activator (r-PA) BM 06.022 reversed pulmonary hypertension. The effects of BM 06.022 after bolus injection were compared with those of vehicle, Alteplase, urokinase, and anistreplase in 6 dogs per group. Thirty minutes after initiation of treatment, the decrease in pulmonary artery pressure (PAP) caused by a bolus of 200 kU/kg (0.35 mg/kg) BM 06.022 was greater (p < 0.05) than that caused by a 2-h infusion of 1.33 mg/kg Alteplase or of 40,000 U/kg urokinase and that caused by a bolus of 0.4 U/kg anistreplase but not that caused by a 15-min infusion of 1 mg/kg Alteplase. At 3 h, all thrombolytic agents had reduced PAP equally. The greatest measured plasma concentration of BM 06.022 was higher (p < 0.05) than that of 2-h infused Alteplase (4,498 +/- 716 vs. 519 +/- 119 IU/ml). We conclude that because of its bolus-pharmacokinetics, BM 06.022 more rapidly reversed thromboembolic pulmonary hypertension than did 2-h infusion of Alteplase or urokinase or a bolus of anistreplase.
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Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli
Naunyn-Schmiedeberg's Archives of Pharmacology, 1992Co-Authors: U. Martin, S. Fischer, U. Kohnert, U. Opitz, R. Rudolph, G. Sponer, A. Stern, K. StreinAbstract:Recombinant tissue-type plasmogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min. The thrombolytic dose-response effects were evaluated in a rabbit model with ^125I-labeled venous thrombi upon intravenous infusion over 4 h. The thrombolytic effects after intravenous bolus injection of 200 kU/kg BM 06.021 were investigated in a canine model of coronary artery thrombosis. All studies were performed comparing BM 06.021 with glycosylated rt-PA (Alteplase). BM 06.021 demonstrated a longer ( p < 0.05) half-life (5.6±2.6 vs. 2.1±0.3 min) and a lower ( p (0.05) clearance rate (7.5±0.8 vs. 22.2±3.1 ml ·min^−1·kg^−1) than Alteplase in rabbits upon intravenous infusion. The doseresponse curve of BM 06.021 for thrombolysis in a rabbit model of jugular vein thrombosis was located to the left of that for Alteplase with a 2.1-fold lower effective dose of 50% thrombolysis (ED_50) of BM 06.021 (207 vs. 436 kU/kg). Intravenous bolus injection of 200 kU/kg BM 06.021 induced the same reperfusion rate (4/6) as intravenous infusion of 800 kU/kg Alteplase over 90 min in a canine model of coronary artery thrombosis. The residual thrombus wet weight did not significantly differ between BM 06.021 and Alteplase (5.7 ± 1.8 vs. 6.3 ± 1.1 mg). The results indicate that unglycosylated rt-PA (BM 06.021) has a higher in vivo thrombolytic potency than glycosylated rt-PA (Alteplase). The increased potency seems to be due to the altered pharmacokinetic properties of BM 06.021, because the in vitro specific fibrinolytic activities of BM 06.021 and Alteplase are virtually identical (783 vs. 800 kU/mg).
Geoffrey A Donnan - One of the best experts on this subject based on the ideXlab platform.
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low dose vs standard dose Alteplase for patients with acute ischemic stroke secondary analysis of the enchanted randomized clinical trial
JAMA Neurology, 2017Co-Authors: Joseph P. Broderick, Xia Wang, Thompson G Robinson, Tsonghai Lee, Hisatomi Arima, Philip M W Bath, Laurent Billot, Andrew M Demchuk, Geoffrey A DonnanAbstract:Importance A lower dose of intravenous Alteplase appears to be a safer treatment option than the standard dose, reducing the risk of symptomatic intracerebral hemorrhage. There is uncertainty, however, over how this effect translates into an overall clinical benefit for patients with acute ischemic stroke (AIS). Objective To assess whether older, Asian, or severely affected patients with AIS who are considered at high risk of bleeding after thrombolysis may benefit more from low-dose rather than standard-dose Alteplase treatment. Design, Setting, and Participants This study is a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded, end-point clinical trial of low-dose vs standard-dose intravenous Alteplase for patients with AIS. From March 1, 2012, to August 31, 2015, a total of 3310 patients who had a clinical diagnosis of AIS as confirmed by brain imaging and who fulfilled the local criteria for thrombolysis treatment were included in the Alteplase-dose arms. Patients were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus and 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus and 90% as infusion over 1 hour) Alteplase. Of the 3310 randomized patients, 13 patients were excluded for missing consent, mistaken randomization, and duplicate randomization numbers. This secondary analysis was conducted between May 1, 2016, and April 28, 2017. Main Outcomes and Measures The primary end point was a poor outcome defined by the combination of death and any disability as scored by the modified Rankin Scale (scores range from 2 to 6, with the highest score indicating death) at 90 days. Results Of the 3297 patients included in the analysis, 1248 (37.9%) were women, and the mean (SD) age was 67 (13) years. No significant differences in the treatment effects were observed between low- and standard-dose Alteplase for poor outcomes (death or disability) by age, ethnicity, or severity (allP > .37 for interaction). Similarly, the treatment effects of low- vs standard-dose Alteplase on function outcome (ordinal shift of the modified Rankin Scale) in Asians (odds ratio, 1.05; 95% CI, 0.90-1.22) was consistent with non-Asians (odds ratio, 0.93; 95% CI, 0.76-1.14) (P = .32 for interaction). There were generally consistent reductions in rates of symptomatic intracerebral hemorrhage with low-dose Alteplase, although this reduction was not statistically significant by age, ethnicity, or severity. Conclusions and Relevance This analysis found that the effects of low-dose Alteplase were not clearly superior to the effects of standard-dose Alteplase on death or disability in key demographic subgroups of patients with AIS. Further investigation is required to identify patients with AIS who may benefit from low-dose Alteplase. Trial Registration clinicaltrials.gov Identifier:NCT01422616
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effects of Alteplase for acute stroke on the distribution of functional outcomes a pooled analysis of 9 trials
Stroke, 2016Co-Authors: Kennedy R Lees, Erich Bluhmki, Stephen M Davis, Geoffrey A Donnan, Jonathan Emberson, Lisa Blackwell, James C Grotta, Markku KasteAbstract:Background— Thrombolytic therapy with intravenous Alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of Alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. Methods— Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing Alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). Results— Treatment with Alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from Alteplase (ie, the difference between those who would do better if given Alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13–91; P =0.004). Conclusions— Treatment with intravenous Alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.
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effects of Alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial epithet a placebo controlled randomised trial
Lancet Neurology, 2008Co-Authors: Stephen M Davis, Andre Peeters, Geoffrey A Donnan, Mark W Parsons, Christopher R Levi, Kenneth Butcher, Alan P Barber, Christopher F Bladin, Deidre A De Silva, Graham ByrnesAbstract:Summary Background Whether intravenous tissue plasminogen activator (Alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether Alteplase given 3–6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). Methods We prospectively and randomly assigned 101 patients to receive Alteplase or placebo 3–6 h after onset of ischaemic stroke. PWI and DWI were done before and 3–5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. Findings We randomly assigned 52 patients to Alteplase and 49 patients to placebo. Mean age was 71·6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with Alteplase and 1·78 with placebo (ratio 0·69, 95% CI 0·38–1·28; Student's t test p=0·239); the median relative infarct growth was 1·18 with Alteplase and 1·79 with placebo (ratio 0·66, 0·36–0·92; Wilcoxon's test p=0·054). Reperfusion was more common with Alteplase than with placebo and was associated with less infarct growth (p=0·001), better neurological outcome (p Interpretation Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted. Funding National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia.
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randomised double blind placebo controlled trial of thrombolytic therapy with intravenous Alteplase in acute ischaemic stroke ecass ii
The Lancet, 1998Co-Authors: Werner Hacke, Antoni Davalos, Vincent Larrue, Rüdiger Von Kummer, Markku Kaste, C Fieschi, Dieter Meier, Erich Bluhmki, Stephen M Davis, Geoffrey A DonnanAbstract:Summary Background Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with Alteplase (0·9 mg/kg bodyweight) within 6 h of stroke onset. Methods This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0–3 h or 3–6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0–1) and unfavourable (score 2–6) outcome. Analyses were by intention to treat. Findings 165 (40·3%) Alteplase-group patients and 143 (36·6%) placebo-group patients had favourable mRS outcomes (absolute difference 3·7%, p=0·277). In a post-hoc analysis of mRS scores dichotomised for death or dependency, 222 (54·3%) Alteplase-group and 180 (46·0%) placebo-group patients had favourable outcomes (score 0–2; absolute difference 8·3%, p=0·024). Treatment differences were similar whether patients were treated within 3 h or 3–6 h. 85 (10·6%) patients died, with no difference between treatment groups at day 90·14 days (43 Alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8·8%) Alteplase-group patients and 13 (3·4%) placebo-group patients. Interpretation The results do not confirm a statistical benefit for Alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with Alteplase at a dose of 0·9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.
G. Sponer - One of the best experts on this subject based on the ideXlab platform.
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Rapid reversal of canine thromboembolic pulmonary hypertension by bolus injection of the novel recombinant plasminogen activator BM 06.022.
Journal of cardiovascular pharmacology, 1993Co-Authors: Ulrich Martin, G. Sponer, K. StreinAbstract:We used a canine model of embolic pulmonary hypertension induced by intravenous (i.v.) injection of autologous thrombi to evaluate whether the novel recombinant plasminogen activator (r-PA) BM 06.022 reversed pulmonary hypertension. The effects of BM 06.022 after bolus injection were compared with those of vehicle, Alteplase, urokinase, and anistreplase in 6 dogs per group. Thirty minutes after initiation of treatment, the decrease in pulmonary artery pressure (PAP) caused by a bolus of 200 kU/kg (0.35 mg/kg) BM 06.022 was greater (p < 0.05) than that caused by a 2-h infusion of 1.33 mg/kg Alteplase or of 40,000 U/kg urokinase and that caused by a bolus of 0.4 U/kg anistreplase but not that caused by a 15-min infusion of 1 mg/kg Alteplase. At 3 h, all thrombolytic agents had reduced PAP equally. The greatest measured plasma concentration of BM 06.022 was higher (p < 0.05) than that of 2-h infused Alteplase (4,498 +/- 716 vs. 519 +/- 119 IU/ml). We conclude that because of its bolus-pharmacokinetics, BM 06.022 more rapidly reversed thromboembolic pulmonary hypertension than did 2-h infusion of Alteplase or urokinase or a bolus of anistreplase.
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Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli
Naunyn-Schmiedeberg's Archives of Pharmacology, 1992Co-Authors: U. Martin, S. Fischer, U. Kohnert, U. Opitz, R. Rudolph, G. Sponer, A. Stern, K. StreinAbstract:Recombinant tissue-type plasmogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min. The thrombolytic dose-response effects were evaluated in a rabbit model with ^125I-labeled venous thrombi upon intravenous infusion over 4 h. The thrombolytic effects after intravenous bolus injection of 200 kU/kg BM 06.021 were investigated in a canine model of coronary artery thrombosis. All studies were performed comparing BM 06.021 with glycosylated rt-PA (Alteplase). BM 06.021 demonstrated a longer ( p < 0.05) half-life (5.6±2.6 vs. 2.1±0.3 min) and a lower ( p (0.05) clearance rate (7.5±0.8 vs. 22.2±3.1 ml ·min^−1·kg^−1) than Alteplase in rabbits upon intravenous infusion. The doseresponse curve of BM 06.021 for thrombolysis in a rabbit model of jugular vein thrombosis was located to the left of that for Alteplase with a 2.1-fold lower effective dose of 50% thrombolysis (ED_50) of BM 06.021 (207 vs. 436 kU/kg). Intravenous bolus injection of 200 kU/kg BM 06.021 induced the same reperfusion rate (4/6) as intravenous infusion of 800 kU/kg Alteplase over 90 min in a canine model of coronary artery thrombosis. The residual thrombus wet weight did not significantly differ between BM 06.021 and Alteplase (5.7 ± 1.8 vs. 6.3 ± 1.1 mg). The results indicate that unglycosylated rt-PA (BM 06.021) has a higher in vivo thrombolytic potency than glycosylated rt-PA (Alteplase). The increased potency seems to be due to the altered pharmacokinetic properties of BM 06.021, because the in vitro specific fibrinolytic activities of BM 06.021 and Alteplase are virtually identical (783 vs. 800 kU/mg).
Xia Wang - One of the best experts on this subject based on the ideXlab platform.
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low dose vs standard dose Alteplase for patients with acute ischemic stroke secondary analysis of the enchanted randomized clinical trial
JAMA Neurology, 2017Co-Authors: Joseph P. Broderick, Xia Wang, Thompson G Robinson, Tsonghai Lee, Hisatomi Arima, Philip M W Bath, Laurent Billot, Andrew M Demchuk, Geoffrey A DonnanAbstract:Importance A lower dose of intravenous Alteplase appears to be a safer treatment option than the standard dose, reducing the risk of symptomatic intracerebral hemorrhage. There is uncertainty, however, over how this effect translates into an overall clinical benefit for patients with acute ischemic stroke (AIS). Objective To assess whether older, Asian, or severely affected patients with AIS who are considered at high risk of bleeding after thrombolysis may benefit more from low-dose rather than standard-dose Alteplase treatment. Design, Setting, and Participants This study is a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded, end-point clinical trial of low-dose vs standard-dose intravenous Alteplase for patients with AIS. From March 1, 2012, to August 31, 2015, a total of 3310 patients who had a clinical diagnosis of AIS as confirmed by brain imaging and who fulfilled the local criteria for thrombolysis treatment were included in the Alteplase-dose arms. Patients were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus and 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus and 90% as infusion over 1 hour) Alteplase. Of the 3310 randomized patients, 13 patients were excluded for missing consent, mistaken randomization, and duplicate randomization numbers. This secondary analysis was conducted between May 1, 2016, and April 28, 2017. Main Outcomes and Measures The primary end point was a poor outcome defined by the combination of death and any disability as scored by the modified Rankin Scale (scores range from 2 to 6, with the highest score indicating death) at 90 days. Results Of the 3297 patients included in the analysis, 1248 (37.9%) were women, and the mean (SD) age was 67 (13) years. No significant differences in the treatment effects were observed between low- and standard-dose Alteplase for poor outcomes (death or disability) by age, ethnicity, or severity (allP > .37 for interaction). Similarly, the treatment effects of low- vs standard-dose Alteplase on function outcome (ordinal shift of the modified Rankin Scale) in Asians (odds ratio, 1.05; 95% CI, 0.90-1.22) was consistent with non-Asians (odds ratio, 0.93; 95% CI, 0.76-1.14) (P = .32 for interaction). There were generally consistent reductions in rates of symptomatic intracerebral hemorrhage with low-dose Alteplase, although this reduction was not statistically significant by age, ethnicity, or severity. Conclusions and Relevance This analysis found that the effects of low-dose Alteplase were not clearly superior to the effects of standard-dose Alteplase on death or disability in key demographic subgroups of patients with AIS. Further investigation is required to identify patients with AIS who may benefit from low-dose Alteplase. Trial Registration clinicaltrials.gov Identifier:NCT01422616
U. Martin - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli
Naunyn-Schmiedeberg's Archives of Pharmacology, 1992Co-Authors: U. Martin, S. Fischer, U. Kohnert, U. Opitz, R. Rudolph, G. Sponer, A. Stern, K. StreinAbstract:Recombinant tissue-type plasmogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min. The thrombolytic dose-response effects were evaluated in a rabbit model with ^125I-labeled venous thrombi upon intravenous infusion over 4 h. The thrombolytic effects after intravenous bolus injection of 200 kU/kg BM 06.021 were investigated in a canine model of coronary artery thrombosis. All studies were performed comparing BM 06.021 with glycosylated rt-PA (Alteplase). BM 06.021 demonstrated a longer ( p < 0.05) half-life (5.6±2.6 vs. 2.1±0.3 min) and a lower ( p (0.05) clearance rate (7.5±0.8 vs. 22.2±3.1 ml ·min^−1·kg^−1) than Alteplase in rabbits upon intravenous infusion. The doseresponse curve of BM 06.021 for thrombolysis in a rabbit model of jugular vein thrombosis was located to the left of that for Alteplase with a 2.1-fold lower effective dose of 50% thrombolysis (ED_50) of BM 06.021 (207 vs. 436 kU/kg). Intravenous bolus injection of 200 kU/kg BM 06.021 induced the same reperfusion rate (4/6) as intravenous infusion of 800 kU/kg Alteplase over 90 min in a canine model of coronary artery thrombosis. The residual thrombus wet weight did not significantly differ between BM 06.021 and Alteplase (5.7 ± 1.8 vs. 6.3 ± 1.1 mg). The results indicate that unglycosylated rt-PA (BM 06.021) has a higher in vivo thrombolytic potency than glycosylated rt-PA (Alteplase). The increased potency seems to be due to the altered pharmacokinetic properties of BM 06.021, because the in vitro specific fibrinolytic activities of BM 06.021 and Alteplase are virtually identical (783 vs. 800 kU/mg).
