Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model

Kawai, Hiroshi; Umemura, Kazuo; Nakashima, Mitsuyoshi

doi:10.1254/jjp.69.143

Cited by 41 publications

(22 citation statements)

References 26 publications

(18 reference statements)

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“…In control rats, this was likely because of spontaneous reperfusion and/or collateral circulation 3-8 hours after MCA occlusion, as observed elsewhere with the same stroke model (29)(30)(31)(32). However, such late reperfusion due to endogenous thrombolysis may not be efficient enough to rescue the reversibly ischemic tissue from infarction (27).…”

Section: Comparison Of Intracerebral Hemorrhage In Four Groups Of Ratsmentioning

confidence: 86%

Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging

Chen¹,

Suzuki²,

Nagai³

et al. 2007

Radiology

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Purpose:To prospectively compare therapeutic and hemorrhagic effects of microplasmin and tissue plasminogen activator (tPA) in stroke therapy by using multiparametric magnetic resonance (MR) imaging in a photothrombotic rat stroke model. Materials and Methods:The animal experiment complied with institutional regulations for laboratory animals. Stroke was induced in rats with photothrombotic occlusion of middle cerebral artery (MCA). T2-weighted, perfusion-weighted (PW), and diffusion-weighted (DW) MR imaging was performed 1 hour and 24 hours after occlusion. On the basis of PW and DW images at 1 hour, 49 rats with cortex and subcortex involvement and with perfusion-diffusion mismatch were randomly assigned into one of four groups: control group, group treated with 7.5 mg microplasmin, group treated with 10 mg/kg microplasmin, or group treated with 10 mg/kg tPA. Agents were intravenously injected 1.5 hours after occlusion. Infarct size and hemorrhagic transformation were assessed with MR imaging and histomorphologic findings. Neurologic deficit was scored. Measurements were statistically analyzed. Results:There were 13 rats in the control group, 13 in the 7.5 mg/kg microplasmin group, nine in the 10 mg/kg microplasmin group, and 14 in the 10 mg/kg tPA group. Despite similar baseline perfusion-diffusion mismatch, histochemically defined total infarct volume was reduced from 25% Ϯ 5 (standard deviation) in control group to 21% Ϯ 2, 20% Ϯ 4, and 20% Ϯ 5 in 7.5 mg/kg microplasmin, 10 mg/kg microplasmin, and tPA groups, respectively, as similarly shown on T2-weighted, DW, and PW images at 24 hours (P Ͻ .05). Cerebral hemorrhage rate at 24 hours was higher in tPA group than in the other three groups. Bederson score of neurologic deficits was significantly reduced in treated groups compared with that in control group. Conclusion:Perfusion-diffusion mismatch appeared useful in selecting candidates for thrombolytic therapy. Multiparametric MR imaging allowed noninvasive assessment of effects of microplasmin and tPA in rats; microplasmin had a significantly lower hemorrhagic rate. Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, use the Radiology Reprints form at the end of this article. Tissue plasminogen activator (tPA) has shown therapeutic effects for the treatment of acute ischemic stroke in both animals (1,2) and patients (3,4). Results of some studies (5-7) indicate that tPA may increase the risk of hemorrhagic transformation, especially in cases of blood-brain barrier perturbation before tPA administration (5,6) and in cases of delayed (4 -6 hours) tPA treatment (5,8). In patients who received tPA, the incidence of symptomatic hemorrhage showed a 10-fold increase compared with that in a placebo group (3,9); however, there is still controversy about the adverse effects of tPA (10,11). Therefore, efforts have been made to develop new thrombolytic agents that may improve the benefit-to-risk ratio in the management of strok...

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Section: Comparison Of Intracerebral Hemorrhage In Four Groups Of Ratsmentioning

confidence: 86%

Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging

Chen¹,

Suzuki²,

Nagai³

et al. 2007

Radiology

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“…In murine models of ischemia and reperfusion, inhibition of platelet function via ␣ IIb /␤ III antagonism or the inhibition of the factor IX-dependent coagulation pathway resulted in a significant reduction in infarct development. 20,21 In similar rat models of ischemia and reperfusion 22 or thrombotic stroke, 23 inhibition of the coagulation factors Xa and thrombin with the low-molecularweight heparin enoxaparin or the direct thrombin inhibitor argatroban 24 also resulted in significantly reduced brain injury.…”

mentioning

confidence: 99%

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Toomey

Valocik

Koster

et al. 2002

Stroke

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Background and Purpose-Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti-factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA. Methods-Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed. Results-Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (PϭNS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (PϭNS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (PϭNS), respectively. Neither mortality nor hemorrhage was affected by either treatment. Conclusions-The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke. (Stroke. 2002;33:578-585.)

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“…In animal stroke models, argatroban safely augmented the benefit of recombinant tPA (rt-PA) by improving flow in the microcirculation, increasing the speed and completeness of recanalization, and preventing reocclusion. [2][3][4][5][6] In 1 large human trial of acute myocardial infarction treatment wherein argatroban and rt-PA were combined, argatroban appeared to enhance reperfusion with rt-PA in patients with acute myocardial infarction better than heparin in a dose-dependent fashion. In addition, the incidences of major bleeding and adverse clinical outcomes were lower in patients who received argatroban.…”

Section: Anticoagulantsmentioning

confidence: 99%

Combination Pharmacotherapy for Achievement and Maintenance of Vascular Patency

Pancioli

2009

Stroke

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Abstract-Acute ischemic stroke results from an abrupt interruption of focal cerebral blood flow. In the majority of cases, this interruption is caused by an acute thromboembolism. Arising from the clinical trials in acute myocardial infarction, combination pharmacotherapy is gaining significant interest as a potential method to improve current thrombolytic treatment in acute ischemic stroke. This article reviews the scientific rationale and available evidence for the potential options to improve current pharmacologic therapy for achieving and maintaining vascular patency in acute ischemic stroke.

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Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model

Cited by 41 publications

References 26 publications

Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging

Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

Combination Pharmacotherapy for Achievement and Maintenance of Vascular Patency

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