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David E. Levy – One of the best experts on this subject based on the ideXlab platform.
Ancrod and Fibrin Formation Perspectives on Mechanisms of ActionStroke, 2011Co-Authors: Shuo Liu, Annlia Paganini-hill, David E. Levy, Victor J. Marder, Shur-jen Wang, Fan Yang, Mark FisherAbstract:
Background and Purpose—Ancrod, derived from Malayan pit vipeviper venom, has been tested as ischemic stroke treatment in clinical trials with inconsistent results. We studied the actions of Ancrod on f…
Ancrod in acute ischemic stroke: Results of 500 subjects beginning treatment within 6 hours of stroke onset in the Ancrod stroke programStroke, 2009Co-Authors: David E. Levy, Gregory J. Del Zoppo, Bart M. Demaerschalk, Andrew M. Demchuk, Hans-christoph Diener, George Howard, Markku Kaste, Arthur Pancioli, E. Bernd Ringelstein, Carmen SpatareanuAbstract:
Background and Purpose— Previous studies of multiple-day dosing with the defibrinogenating agent, Ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning Ancrod or placebo within 6 hours of the onset of acute ischemic stroke. Methods— Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either Ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score (“responder analysis”). Safety variables included mortality, major bleeding, and intracranial hemorrhage. Results— Although the desired changes in fibrinogen level were seen in >90% of Ancrod subjects, interim…
Ancrod for acute ischemic stroke a new dosing regimen derived from analysis of prior Ancrod stroke studiesJournal of Stroke & Cerebrovascular Diseases, 2009Co-Authors: David E. Levy, James Trammel, Warren W WasiewskiAbstract:
Background Ancrod, a fibrinogen-reducing agent, has been evaluated as treatment beginning within 3 or 6 hours of onset of acute ischemic stroke with inconsistent results. The data sets from these studies provide an opportunity to determine whether Ancrod-related variables are associated with efficacy and safety. Objective This post hoc analysis of data from the Stroke Treatment with Ancrod Trial (STAT) analyzed Ancrod-related variables as potential determinants of efficacy or safety. The resulting hypotheses were then tested in the European STAT (ESTAT) database. Methods The relationships between Ancrod-related variables and the outcomes of efficacy and symptomatic intracranial hemorrhage (ICH) were analyzed using a 3-stage multivariate process. Results Good clinical outcome at 3 months based on the Barthel Index occurred almost twice as often in rapid defibrinogenators (≥30 mg/dL/h) (52%) as in slow defibrinogenators (26%), with no increase in mortality or symptomatic ICH. Compared with a 20.7% incidence of symptomatic ICH in patients with mean post–9-hour fibrinogen levels less than or equal to 60 mg/dL, symptomatic ICH incidence was 0.8% in those with mean levels greater than 60 mg/dL (with no loss of efficacy). There were no symptomatic ICHs among 220 North American patients with mean levels greater than 70 mg/dL. It was hypothesized that an initial controlled rapid Ancrod infusion with mean post-9-hour fibrinogen levels greater than 70 mg/dL would yield superior efficacy and safety. Such ESTAT patients had statistically significant efficacy versus placebo and a marked reduction in the incidence of symptomatic ICH versus patients taking Ancrod with lower maintenance fibrinogen levels. Conclusion Modifications to Ancrod dosing may substantially improve efficacy while reducing the rate of symptomatic ICH.
David G. Sherman – One of the best experts on this subject based on the ideXlab platform.
Another Trial of Ancrod for Acute Ischemic StrokeNEJM Journal Watch, 2007Co-Authors: David G. ShermanAbstract:
Ancrod, a substance with antithrombotic properties, is derived from the venom of the Malayan pit viper. In the previously published, manufacturer-funded, randomized Stroke Treatment with Ancrod Trial (STAT), patients from North America with acute ischemic stroke had significantly better functional status at 3 months with Ancrod than with placebo — each initially administered within 3 hours after symptom onset (Journal Watch Neurology Aug …
Ancrod.Current medical research and opinion, 2002Co-Authors: David G. ShermanAbstract:
Ischaemic stroke occurs in over 500,000 US residents each year. Most strokes are due to embolic or thrombotic occlusion of an artery to the brain. Strategies to reduce thrombus formation and to improve blood flow in the compromised arterial bed have been have been a major focus of management with the goal of improving the outcome of ischaemic stroke. Ancrod is a biological agent extracted from the venom of the Malayan pit viper that reduces blood fibrinogen levels. This action prolongs blood clot formation and lowers blood viscosity. Ancrod has been studied in a variety of ischaemic conditions including stroke. The clinical studies of Ancrod in patients with stroke have shown a benefit with Ancrod treatment in neurological outcome with only a modest increase in bleeding risk.
Intravenous Ancrod for Treatment of Acute Ischemic Stroke: The STAT Study: A Randomized Controlled TrialJAMA, 2000Co-Authors: David G. Sherman, Richard P. Atkinson, Thomas Chippendale, Kenneth A. Levin, Nancy Futrell, Chung Y. Hsu, David E. LevyAbstract:
ContextApproved treatment options for acute ischemic stroke in the United States and Canada are limited at present to intravenous tissue-type plasminogen activator, but bleeding complications, including intracranial hemorrhage, are a recognized complication.ObjectiveTo evaluate the efficacy and safety of the defibrinogenating agent Ancrod in patients with acute ischemic stroke.DesignThe Stroke Treatment with Ancrod Trial (STAT), a randomized, parallel-group, double-blind, placebo-controlled trial conducted between August 1993 and January 1998.SettingForty-eight centers, primarily community hospitals, in the United States and Canada.PatientsA total of 500 patients with an acute or progressing ischemic neurological deficit were enrolled and included in the intent-to-treat analysis.InterventionsPatients were randomly assigned to receive Ancrod (n=248) or placebo (n=252) as a continuous 72-hour intravenous infusion beginning within 3 hours of stroke onset, followed by infusions lasting approximately 1 hour at 96 and 120 hours. The Ancrod regimen was designed to decrease plasma fibrinogen levels to 1.18 to 2.03 µmol/L.Main Outcome MeasuresThe primary efficacy end point was functional status, with favorable functional status defined as survival to day 90 with a Barthel Index of 95 or more or at least the prestroke value, compared by treatment group. Primary safety variables included symptomatic intracranial hemorrhage and mortality.ResultsFavorable functional status was achieved by more patients in the Ancrod group (42.2%) than in the placebo group (34.4%; P=.04) by the prespecified covariate-adjusted analysis. Mortality was not different between treatment groups (at 90 days, 25.4% for the Ancrod group and 23% for the placebo group; P=.62), and the proportion of severely disabled patients was less in the Ancrod group than in the placebo group (11.8% vs 19.8%; P=.01). The favorable functional status observed with Ancrod vs placebo was consistent in all subgroups defined for age, stroke severity, sex, prestroke disability, and time to treatment (≤3 or >3 hours after stroke onset). There was a trend toward more symptomatic intracranial hemorrhages in the Ancrod group vs placebo (5.2% vs 2.0%; P=.06), as well as a significant increase in asymptomatic intracranial hemorrhages (19.0% vs 10.7%; P=.01).ConclusionIn this study, Ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke.
Jeffrey A. Hubbell – One of the best experts on this subject based on the ideXlab platform.
Adhesion prevention with Ancrod released via a tissue-adherent hydrogelThe Journal of surgical research, 1996Co-Authors: Sanghamitra M. Chowdhury, Jeffrey A. HubbellAbstract:
The objective of this investigation was to evaluate the effect of Ancrod, a fibrinogenolytic protease from Malayan pit vipeviper venom, locally delivered through a photopolymerized biodegradable hydrogel in preventing postoperative adhesions. The experimental model involved ischemic and serosal injury to the uterine horns of rats with measurement of adhesions 7 days after injury. Ancrod was delivered intravenously for 5 days preoperatively through 3 days postoperatively, intraperitoneally for 5 days preoperatively, intraperitoneally for 3 days postoperatively, and locally via the hydrogel formed upon the uterine horns by photopolymerization of an aqueous precursor solution. Systemic defibrinogenation by intravenous administration pre-through postoperatively reduced the extent of adhesions by 63% without dose sensitivity from 5 to 20 units/kg/day. Preoperative defibrinogenation by intraperitoneal administration reduced adhesion extent by up to 57%, while postoperative administration was more effective, reducing adhesions by up to 84% with a dose-dependent response from 5 to 20 units/kg/day. Administration of Ancrod by local release from a tissue-adherent hydrogel was more effective than either the hydrogel alone or the same amount of Ancrod administered by postoperative intraperitoneal injection. Adhesions were reduced by 82% at a local dose of 10 units/kg, compared to a reduction of 68% due to the barrier properties of the gel alone (P < 0.01) and of 19% due to the same amount of drug given at the time of surgery (P < 0.001). Local delivery of Ancrod from a tissue-adherent hydrogel barrier thus provided an efficacious prevention to postoperative adhesions while permitting administration of a low total dose of the protease.
Schwarz Margarete – One of the best experts on this subject based on the ideXlab platform.
Ancrod reduces intracerebral hemorrhage quantified in vivo by magnetic resonance imaging in rats.Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 1998Co-Authors: Bernd Elger, Wilfried Hornberger, Schwarz Margarete, Jürgen Seega, Zahn WolfgangAbstract:
Background and Purpose: Promising results of experimental and clinical stroke studies suggest that Ancrod may provide an efficient therapy of brain ischemia. Because Ancrod has been shown to produce rapid defibrinogenation, we investigated the effects of this agent in a rat model of intracranial bleeding using noninvasive magnetic resonance imaging (MRI). Methods: Intracranial bleeding was induced in anesthetised rats by microinfusion of collagenase into the right striatum. Ancrod was intravenously infused for a period of 30 minutes starting 30 minutes after intrastriatal collagenase infusion. The dosages of Ancrod were 0.33 IU · kg −1 · min −1 in one group and 1 IU · kg −1 · min −1 in another (total dosages were 10 and 30 IU · kg −1 , respectively). Control animals received equal amounts of vehicle solution (0.9% NaCl) only. The volume of intracerebral hemorrhage (ICH) was quantified in vivo by T1-weighted spin-echo MRI in eight consecutive coronal brain planes 24 hours after collagenase infusion. Results: Plasma fibrinogen was dose-dependently diminished immediately after infusio of Ancrod at dosages of 0.33 or 1 IU · kg −1 · min −1 . Total volume of ICH was significantly ( P 3 in vehicle-treated controls (n=17) to 24 (20/37) mm 3 in rats (n=15) infused with the lower Ancrod dosage (median, 25th/75th centiles). Rats (n=15) treated with the higher dosage of Ancrod had 34 (27/39) mm 3 volume of ICH, which is 29% lower compared with vehicle-treated controls ( P =.05). Conclusions: Adverse side effects such as aggravation of intracerebral bleeding did not occur in Ancrod-infused rats despite pronounced lowering of the plasma fibrinogen level during ongoing bleeding. In contrast, significant reductions in the volumes of ICH were observed suggesting favorable influence of Ancrod in the event of intracranial bleeding in rats
mri study on delayed Ancrod therapy of focal cerebral ischaemia in ratsEuropean Journal of Pharmacology, 1997Co-Authors: Bernd Elger, Wilfried Hornberger, Schwarz MargareteAbstract:
The therapeutic window for efficient post-treatment of focal cerebral ischaemia with the fibrinogen lowering agent Ancrod was studied by magnetic resonance imaging (MRI) in spontaneously hypertensive rats (SHR). Ancrod or vehicle solution (0.9% NaCl) were i.v. infused (0.12 IU kg−1 min−1) via implanted mini pumps starting 0.5, 1.5, 3 or 6 h after permanent proximal middle cerebral arteartery occlusion and lasting until brain mapping by multislice T2-weighted magnetic resonance imaging in vivo 24 h after middle cerebral arteartery occlusion. Plasma fibrinogen concentrations were measured before middle cerebral arteartery occlusion, before pump implantation and after magnetic resonance imaging. Total brain lesilesion volumes as determined by magnetic resonance imaging 24 h after middle cerebral arteartery occlusion (means±S.D., 8–11 animals/group) were 131±36 (188±28)*, 151±39 (194±39)*, 147±44 (207±33)* and 209±60 (214±42) mm3 in rats with 0.5, 1.5, 3 and 6 h, respectively, delay of Ancrod treatment (corresponding control groups in parentheses, *P<0.05). Continuous i.v. Ancrod infusions reduced plasma fibrinogen levels significantly (P<0.05) in all Ancrod-treated groups as compared to vehicle-treated controls until the end of the experiments 24 h after middle cerebral arteartery occlusion. In conclusion, significant cerebroprotection was achieved even when the onset of Ancrod therapy for lowering of the plasma fibrinogen level was delayed for up to 3 h. To the best of our knowledge no drug efficacy has been reported so far with a therapeutic window of 3 h after permanent middle cerebral arteartery occlusion in spontaneously hypertensive rats suggesting that Ancrod may provide an efficient therapy of acute human stroke.
MRI study on delayed Ancrod therapy of focal cerebral ischaemia in ratsEuropean journal of pharmacology, 1997Co-Authors: Bernd Elger, Wilfried Hornberger, Schwarz MargareteAbstract:
The therapeutic window for efficient post-treatment of focal cerebral ischaemia with the fibrinogen lowering agent Ancrod was studied by magnetic resonance imaging (MRI) in spontaneously hypertensive rats (SHR). Ancrod or vehicle solution (0.9% NaCl) were i.v. infused (0.12 IU kg−1 min−1) via implanted mini pumps starting 0.5, 1.5, 3 or 6 h after permanent proximal middle cerebral arteartery occlusion and lasting until brain mapping by multislice T2-weighted magnetic resonance imaging in vivo 24 h after middle cerebral arteartery occlusion. Plasma fibrinogen concentrations were measured before middle cerebral arteartery occlusion, before pump implantation and after magnetic resonance imaging. Total brain lesilesion volumes as determined by magnetic resonance imaging 24 h after middle cerebral arteartery occlusion (means±S.D., 8–11 animals/group) were 131±36 (188±28)*, 151±39 (194±39)*, 147±44 (207±33)* and 209±60 (214±42) mm3 in rats with 0.5, 1.5, 3 and 6 h, respectively, delay of Ancrod treatment (corresponding control groups in parentheses, *P
Carl-erik Dempfle – One of the best experts on this subject based on the ideXlab platform.
Fibrin Formation and Proteolysis during Ancrod TreatmentAnnals of the New York Academy of Sciences, 2006Co-Authors: Carl-erik Dempfle, Sotiria Argiriou, Sonja Alesci, Klaus Kucher, H. Müller-peltzer, Klaus Rübsamen, Dieter L. HeeneAbstract:
: Ancrod is a purified fraction of venom from the Malayan pit viper Calloselasma rhodostoma, containing a serine protease that cleaves fibrinopeptides A from fibrinogen. We report on a study that involved intravenous and subcutaneous application of Ancrod in healthy subjects in which it was shown that Ancrod induces the formation of desAA-fibrin complexes that are partially crosslinked by factor XIII proenzyme, and act as cofactor in tPA induced plasminogen activation. The plasmin generated degrades fibrin, as well as fibrinogen, leading to the appearance of large amounts of fibrinogen and fibrin degradation products in the circulation, including fragment D-dimer. At low concentrations of Ancrod, formation of desAA-fibrin is preceded by production of desA-profibrin, lacking only one fibrinopeptide A.
Plasminogen activation without changes in tPA and PAI-1 in response to subcutaneous administration of Ancrod.Thrombosis Research, 2001Co-Authors: Carl-erik Dempfle, Sonja Alesci, Klaus Kucher, H. Müller-peltzer, Klaus Rübsamen, Martin BorggrefeAbstract:
Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of ischemic stroke. The therapeutic effect is ascribed to a lowering of plasma fibrinogen. Thirty-two healthy volunteers received subcutaneous Ancrod at doses of 1.0, 1.5 and 2.0 IU/kg body weight or placebo. Blood samples were drawn before the injection and at various time points until 96 h after the injection. Ancrod leads to the formation of desAA-fibrin, which serves as cofactor in tissue plasminogen activator activity (tPA)-induced plasminogen activation. Unchanged concentrations of prothrombin fragment F1.2 and thrombin–antithrombin complex (TAT) indicate that fibrin formation occurs independent of thrombin. Plasmin generation is independent of an increase in tPA activity or changes in plasminogen activator inhibitor-1 (PAI-1) concentration in plasma. Subcutaneous injection of Ancrod leads to a generalized fibrino(geno)lytic response caused solely by providing tPA with soluble fibrin as its cofactor in plasminogen activation. Maximal plasmin activity is present 12 h after subcutaneous injection.
Analysis of fibrin formation and proteolysis during intravenous administration of Ancrod.Blood, 2000Co-Authors: Carl-erik Dempfle, Sotiria Argiriou, Klaus Kucher, H. Müller-peltzer, Klaus Rübsamen, Dieter L. HeeneAbstract:
Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma , currently under investigation for treatment of acute ischemic stroke. Treatment with Ancrod leads to fibrinogen depletion. The present study investigated the mechanisms leading to the reduction of plasma fibrinogen concentration. Twelve healthy volunteers received an intravenous infusion of 0.17 U/kg body weight of Ancrod for 6 hours. Blood samples were drawn and analyzed before and at various time points until 72 hours after start of infusion. Ancrod releases fibrinopeptide A from fibrinogen, leading to the formation of desAA-fibrin monomer. In addition, a considerable proportion of desA-profibrin is formed. Production of desA-profibrin is highest at low concentrations of Ancrod, whereas desA-profibrin is rapidly converted to desAA-fibrin at higher concentrations of Ancrod. Both desA-profibrin and desAA-fibrin monomers form fibrin complexes. A certain proportion of complexes carries exposed fibrin polymerization sites EA, indicating that the terminal component of the protofibril is a desAA-fibrin monomer unit. Soluble fibrin complexes potentiate tissue-type plasminogen activator-induced plasminogen activation. Significant amounts of plasmin are formed when soluble fibrin in plasma reaches a threshold concentration, leading to the proteolytic degradation of fibrinogen and fibrin. In the present setting, high concentrations of soluble fibrin are detected after 1 hour of Ancrod infusion, whereas a rise in fibrinogen and fibrin degradation products, and plasmin-α2–plasmin inhibitor complex levels is first detected after 2 hours of Ancrod infusion. Ancrod treatment also results in the appearance of cross-inked fibrin degradation productd-dimer in plasma.