Intravenous Ancrod for Treatment of Acute Ischemic Stroke

Sherman, David G.; Atkinson, Richard; Chippendale, Thomas J.; Levin, Kenneth; Ng, Kelvin; Futrell, Nancy; Hsu, Chung Y.; Levy, David E.

doi:10.1001/jama.283.18.2395

Cited by 276 publications

(93 citation statements)

References 34 publications

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“…Fibrinogen can be depleted by the toxin, ancrod, which cleaves fibrinogen at the thrombin cleavage site, resulting in soluble fibrin monomers that are removed by the reticuloendothelial system (33). Ancrod has been used to specifically deplete fibrinogen in experimental models of inflammation and for treatment of acute ischemic stroke in clinical medicine (12,38). We evaluated morbidity in an air pouch abscess model of skin infection by measuring daily weight loss after infection.…”

Section: Fibrinogen Depletion Prevents Morbidity and Mortality After mentioning

confidence: 99%

“…In addition, this same protection was observed after infection with a recent clinical S. aureus isolate and in BALB/c mice, indicating that this protection was not limited to a single strain of bacteria or mice (data not shown). To address whether fibrinogen would protect against a lethal infection, we evaluated survival in a peritonitis abscess model that results in sepsis (38). After infection with WT bacteria, transient fibrinogen depletion significantly improved survival (Fig.…”

Section: Fibrinogen Depletion Prevents Morbidity and Mortality After mentioning

confidence: 99%

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Fibrinogen Depletion Attenuates Staphyloccocus aureus Infection by Preventing Density-Dependent Virulence Gene Up-Regulation

Rothfork

Dessus-Babus

Wamel

et al. 2003

The Journal of Immunology

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Staphylococcus aureus undergoes a density-dependent conversion in phenotype from tissue-adhering to tissue-damaging and phagocyte-evading that is mediated in part by the quorum-sensing operon, agr, and its effector, RNAIII. Contributions of host factors to this mechanism for regulating virulence have not been studied. We hypothesized that fibrinogen, as a component of the inflammatory response, could create spatially constrained microenvironments around bacteria that increase density independently of bacterial numbers and thus potentiate quorum-sensing-dependent virulence gene expression. Here we show that transient fibrinogen depletion significantly reduces the bacterial burden and the consequential morbidity and mortality during experimental infection with wild-type S. aureus, but not with bacteria that lack expression of the quorum-sensing operon, agr. In addition, it inhibits in vivo activation of the promoter for the agr effector, RNAIII, and downstream targets of RNAIII, including α hemolysin and capsule production. Moreover, both in vitro and in vivo, the mechanism for promoting this phenotypic switch in virulence involves clumping of the bacteria, demonstrating that S. aureus responds to fibrinogen-mediated bacterial clumping by enhancing density-dependent virulence gene expression. These data demonstrate that down-modulation of specific inflammatory components of the host that augment bacterial quorum sensing can be a strategy for enhancing host defense against infection.

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Section: Fibrinogen Depletion Prevents Morbidity and Mortality After mentioning

confidence: 99%

Section: Fibrinogen Depletion Prevents Morbidity and Mortality After mentioning

confidence: 99%

Fibrinogen Depletion Attenuates Staphyloccocus aureus Infection by Preventing Density-Dependent Virulence Gene Up-Regulation

Rothfork

Dessus-Babus

Wamel

et al. 2003

The Journal of Immunology

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“…A previous study of intravenous ancrod for acute treatment of ischemic stroke suggested that, when started within 3 hours of stroke onset, ancrod improved outcome. 6 In an early study of 132 subjects starting treatment within 6 hours of stroke onset, there was evidence of efficacy when the data were analyzed using a patient-weighted analysis. 10 The larger ESTAT study using a 6-hour window, however, failed to confirm this finding, and there was a significant increase in mortality and sICH with ancrod in ESTAT.…”

Section: Discussionmentioning

confidence: 99%

“…Sherman et al published a study 6 showing a good functional outcome for ancrod based on the proportion of subjects at 90 days who were alive and had Barthel Index total scores of 95 to 100 or at least as high as the prestroke score (for subjects with prestroke disability), covariate-adjusted for age and pretreatment Scandinavian Stroke Scale score. When started within 3 hours of stroke onset and continued for 5 days, 42.2% of ancrod subjects achieved a good functional outcome vs 34.4% of placebo subjects (Pϭ0.04; effect size, 7.8%).…”

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confidence: 99%

Ancrod in Acute Ischemic Stroke

Levy

Zoppo

Demaerschalk

et al. 2009

Stroke

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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 Ͼ90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects (Pϭ0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; Pϭ0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects (Pϭ0.19), was approximately twice as high (3.9% vs 2.0%; Pϭ0.19). Conclusion-These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

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“…[3][4][5][6][7][8][9][10][11][12][13][14] Repinotan is a potent full agonist at the serotonin (5-HT 1A ) receptor. 15 In animal models, repinotan demonstrated neuroprotectant activity over a broad range of doses for up to five hours postischemia [15][16][17] and was well-tolerated with no safety concerns in healthy volunteers.…”

mentioning

confidence: 99%

The BRAINS Study: Safety, Tolerability, and Dose-finding of Repinotan in Acute Stroke

Teal

Silver²,

Simard³

2005

Can. j. neurol. sci.

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Stroke is the third most common cause of death and the leading cause of chronic disability in North America. 1 While the prevention of ischemic stroke has improved over recent decades, only tissue plasminogen activator (t-PA) given within the first three hours after onset of symptoms has been approved for acute stroke therapy. 2 The restrictive three-hour therapeutic window, ongoing safety concerns, exclusion criteria, and the need for skilled stroke teams has limited delivery of t-PA to only a small proportion of stroke patients. Neuroprotective agents with a longer potential treatment window and broader clinical ABSTRACT: Background and Purpose: Repinotan is a potent, serotonin (5-HT 1A ) full receptor agonist that interferes with ischemiamediated neuronal cell death in animal models. This double-blind, placebo-controlled phase II study examined the safety, tolerability, and dose of repinotan in patients with acute ischemic stroke. Methods: Patients with acute hemispheric ischemia and a National Institutes of Health Stroke Scale of 4 to 25 were randomized to placebo or repinotan 0.5, 1.25, or 2.5 mg/day (d) given by continuous intravenous infusion for 72 hours. Treatment was started within six hours of symptom onset. Evaluations were performed at four weeks and three months. Results: Among 240 patients in the safety analysis, repinotan was well-tolerated, with adverse events appearing more frequently in the highest dose group (2.5 mg/d). The most common adverse event was headache (21.3% to 35% with repinotan and 24.1% with placebo). Most (75%) adverse events were of mild or moderate severity. The most common severe adverse events were neurological worsening, cerebral hemorrhage, and brain edema. The number of deaths and serious adverse events were similar among placebo and repinotan groups. Compared to the placebo group, the proportion of patients with good outcomes at three months was greatest in the group receiving repinotan 1.25 mg/d, although the difference was not statistically significant. Conclusions: This study indicates that the incidence of adverse events was comparable with all doses of repinotan and placebo, and no safety issues were observed. A trend toward better tolerability with evidence of efficacy was observed with the repinotan 1.25 mg/d dose.RÉSUMÉ: Étude BRAINS: sécurité, tolérance et détermination de la dose du repinotan dans l'accident vasculaire aigu. Introduction et objectif: Le repinotan est un agoniste puissant du récepteur de la sérotonine (5-HT1A) qui interfère dans la mort neuronale médiée par l'ischémie chez les modèles animaux. Cette étude de phase II, à double insu, contrôlée par placebo, évalue la sécurité, la tolérance et la dose de repinotan chez des patients atteints d'accident vasculaire cérébral ischémique aigu. Méthodes: Des patients atteints d'ischémie hémisphérique aiguë et ayant un score de 4 à 25 au National Institutes of Health Stroke Scale ont été répartis au hasard au groupe recevant un placebo ou au groupe recevant du repinotan à 0,5, 1,25 ou 2,5 mg/j en infusion...

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Intravenous Ancrod for Treatment of Acute Ischemic Stroke

Abstract: In this study, ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke.

Cited by 276 publications

References 34 publications

Fibrinogen Depletion Attenuates Staphyloccocus aureus Infection by Preventing Density-Dependent Virulence Gene Up-Regulation

Fibrinogen Depletion Attenuates Staphyloccocus aureus Infection by Preventing Density-Dependent Virulence Gene Up-Regulation

Ancrod in Acute Ischemic Stroke

The BRAINS Study: Safety, Tolerability, and Dose-finding of Repinotan in Acute Stroke

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