2004 - Various Ancrod Links .....
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Ancrod, sold by Knoll under the
name ARVIN, has been used
widely in Europe for the treatment of
vascular disease and
deep venous thrombosis
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YEAR = 2001
ESTAT
European Stroke Treatment with Ancrod Trial
European trial terminated in March of 2000
after futility analysis at a pre-planned interim analysis.
At that time 1222 patients had been enrolled.
A 90-day mortality analysis of patient data from this interim
data set showed that mortality was higher in ancrod than placebo patients.
Purpose
To compare ancrod vs. placebo in the treatment of ischemic stroke patients.
Intervention(s)
Ancrod (Fibrinogenolytic agent. Purified fraction of pit viper venom, cleaves fibrinogen.)
Trial Location(s) Europe, Australia, Israel.
Year Presented: 2001
strokecenter.org
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YEAR = 1994
64 ANCROD AND 68 PLACEBO
Ancrod for the treatment of acute ischemic brain infarction. The Ancrod Stroke Study Investigators
METHODS: We studied the safety and efficacy of ancrod in patients with acute ischemic stroke administered within 6 hours of stroke onset. In a double-blind, randomized, placebo-controlled trial 64 patients received intravenous ancrod and 68 received placebo for 7 days. Neurological outcome, disability, and brain infarct volume were measured
RESULTS: There was no significant difference in overall mean scores on the Scandinavian Stroke Scale. No increase in bleeding occurred in the ancrod-treated patients. The target reduction of plasma fibrinogen levels of less than 100 mg/dL was achieved in only 15 (23%) of 64 ancrod-treated patients. Those patients with ancrod-induced 6-hour fibrinogen levels 130 mg/dL or less had a marginally significantly better neurological outcome on the Scandinavian Stroke Scale, mortality, and Barthel Index than ancrod-treated patients with higher fibrinogen levels.
CONCLUSIONS: Ancrod appears safe and potentially effective when administered to patients within 6 hours of onset of ischemic stroke.
stroke.ahajournals.org
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YEAR = 2000
248 ANCROD AND 252 PLACEBO
Intravenous Ancrod for Treatment of Acute Ischemic Stroke
The STAT Study: A Randomized Controlled Trial
David G. Sherman, MD; Richard P. Atkinson, MD; Thomas Chippendale, MD; Kenneth A. Levin, MD; Ken Ng, MD; Nancy Futrell, MD; Chung Y. Hsu, MD; David E. Levy, MD; for the STAT Participants
JAMA. 2000;283:2395-2403.
Interventions Patients 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.
Results Favorable 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).
Conclusion In this study, ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke.
jama.ama-assn.org
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Article dated November, 2004
drugtopics.com
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Hemorrhagic Transformation after Reperfusion
Therapy for Acute Ischemic Stroke
informedpharmacotherapy.com
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YEAR = 2004
Published online before print November 29, 2004, doi:10.1161/01.STR.0000149924.84949.9c
This Article
Fibrinogen-Depleting Agents for Acute Ischemic Stroke
Ming Liu, MD; Carl Counsell, MD, MRCP; Xiao Ling Zhao, MD; Joanna Wardlaw, MD
From the Department of Neurology (M.L., X.L.Z.), West China Hospital, Sichuan University, China; the Department of Medicine & Therapeutics (C.C), University of Aberdeen; and the Department of Clinical Neurosciences (J.W.), Western General Hospital, University of Edinburgh, UK.
Main Results
Five trials involving 2926 patients were included. A further trial (European Stroke Treatment with Ancrod Trial [ESTAT]) has not yet been published in full. Four trials tested ancrod and 1 trial tested defibrase. Allocation concealment was adequate in 4 trials. Fibrinogen-depleting agents moderately reduced the proportion of patients who were dead or disabled at the end of follow-up (RR 0.90; 95% CI, 0.82 to 0.98; 2P=0.02). There was no statistically significant difference in deaths from all causes during the scheduled treatment period (RR 0.71; 95% CI, 0.78 to 1.24). There was a nonsignificant excess of symptomatic intracranial hemorrhages with treatment (RR 2.64; 95% CI, 0.96 to 7.30; 2P=0.06; Figure).
stroke.ahajournals.org
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UCSD researchers determine fibrin depletion
decreases multiple sclerosis symptoms
Tissue damage due to Multiple Sclerosis (MS) is reduced and lifespan lengthened in mouse models of the disease when a naturally occurring fibrous protein called fibrin is depleted from the body, according to researchers at the University of California, San Diego (UCSD) School of Medicine.
The study, reported online the week of April 19, 2004 in the Proceedings of the National Academy of Sciences, identifies fibrin as a potential target for therapeutic intervention in the disease, which affects an estimated one million people worldwide.
However, the research team cautions that fibrin plays an important role in blood clotting and systemic fibrin depletion could have adverse effects in a chronic disease such as MS. Therefore, additional research is needed to specifically target fibrin in the nervous system, without affecting its ability as a blood clotting protein.
"Multiple sclerosis is a nervous system disease with vascular damage, resulting from the leakage of blood proteins, including fibrin, into the brain," said the study’s first author, Katerina Akassoglous, Ph.D., a UCSD School of Medicine assistant professor of pharmacology. "Our study shows that fibrin facilitates the initiation of the inflammatory response in the nervous system and contributes to nerve tissue damage in an animal model of the disease."
MS is an autoimmune disease that affects the central nervous system (CNS), causing a variety of symptoms including loss of balance and muscle coordination, changes in cognitive function, slurred speech, bladder and bowel dysfunction, pain, and diminished vision. While the exact cause of MS is unknown, a hallmark of the disease is the loss of a material called myelin that coats nerve fibers, and the inability of the body’s natural processes to repair the damage.
Although fibrin is best known for its important role in blood clotting, recent studies have shown that fibrin accumulates in the damaged nerves of MS patients, followed by a break down of myelin. However, the cellular mechanisms of fibrin action in the central nervous system have not been known, nor have scientists determined if fibrin depletion could alleviate or lessen the symptoms of MS.
In work performed at The Rockefeller University, New York and the UCSD School of Medicine, in collaboration with colleagues at the University of Vienna, Austria and Hellenic Pasteur Institute, Greece, researchers studied normal mice and transgenic mice with an MS-like condition. The normal mice had normal spinal cords and with no fibrin deposits in the central nervous system. In contrast, the transgenic mice showed fibrin accumulation, inflammation and a degradation of the myelin in their spinal cord. When transgenic mice were bred without fibrin, they developed a later onset of the MS-like paralysis as compared to their transgenic brothers that had fibrin. In addition, the fibrin-depleted mice lived for one additional week longer than the normal, disease-impacted mice. This difference is significant in animal models such as mice that have very short lifespans.
Fibrin’s role in excessive inflammation was shown in a follow-up experiment where transgenic mice were shown to experience high expression of pro-inflammatory molecules, followed by myelin loss, as compared to the fibrin-negative transgenic mice with no signs of inflammation or myelin destruction.
In addition to the genetic deletion of fibrin, the researchers tested drug-induced fibrin depletion, which was accomplished by administering ancrod, a snake venom protein, to the transgenic mice. Consistent with the genetics-based experiments, the pharmacological depletion also delayed the onset of inflammatory myelin destruction and down-regulated the immune response. Previous studies by other investigators who used ancrod in experimental autoimmune encephalomyelitis (EAE), another animal model of MS, also showed amelioration of neurologic symptoms.
In the current study, the investigators also used cell culture studies to determine that fibrin activates macrophages, the major cell type that contributes to inflammatory myelin destruction.
Akassoglou said that "further research to identify the cellular and molecular mechanisms that fibrin utilizes in the nervous system will provide pharmacologic targets that will specifically block the actions of fibrin in nervous system disease."
The study was funded by grants from the National Institutes of Health, the Wadsworth Foundation Award, and the National Multiple Sclerosis Society.
Sidney Strickland, Ph.D., Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, in whose lab Akassoglou first began her studies, was the senior author of the paper. Additional authors were Ryan Adams, Ph.D., UCSD Department of Pharmacology; Jan Bauer, Ph.D. and Hans Lassmann, M.D., Laboratory of Experimental Neuropathology, University of Vienna, Austria; Lesley Probert, Ph.D., and Vivi Tseveleki, B.Sc., Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece; and Peter Mercado, B.Sc., The Rockefeller University
Original article can be found here
thisisms.com
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Neuroscience
Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis
Katerina Akassoglou * , Ryan A. Adams * , Jan Bauer ¶, Peter Mercado , Vivian Tseveleki ||, Hans Lassmann ¶, Lesley Probert || and Sidney Strickland
pnas.org |
