The antithrombotic effects of CI-1031 (ZK-807834) and enoxaparin in a canine electrolytic injury model of arterial and venous thrombosis

McClanahan, Thomas B.; Hicks, Gary W.; Morrison, Angela L; Peng, Yun-Wen; Janiczek-Dolphin, Nancy; Mertz, Thomas; Sullivan, M.; Morser, John; Juneau, Paul; Leadley, Robert J.

doi:10.1016/s0014-2999(01)01090-1

Cited by 18 publications

(20 citation statements)

References 22 publications

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Section: Discussionsupporting

confidence: 88%

“…25,26 In our experimental model, each of the above mechanisms may play a role in improved capillary perfusion after enoxaparin injection. Most probable are the antiinflammatory and anticoagulant effects of enoxaparin, which are known to be dose-dependent, as reported by others 8,27,28 and confirmed in this study. Our experimental study demonstrated that subcutaneous injection of 2 mg/kg of enoxaparin increased functional capillary perfusion at the microcirculatory level of a cremaster muscle flap up to 33% at the fifth hour postdissection without any propensity for bleeding in the pre-and postdissection period.…”

Section: à18supporting

confidence: 88%

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Dose response of enoxaparin at the cremaster muscle flap microcirculation

et al. 2005

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The effects of different dosages of enoxaparin (Lovenox), a low molecular-weight heparin, on microcirculation were investigated. The cremaster muscle model for intravital microscopy was used. Four groups were studied: in group I (n = 6), the controls no agent was given; in group II (n = 6), enoxaparin (2 mg/kg s.c.), in group III, (n = 6), enoxaparin (4 mg/kg s.c.); and in group IV, (n = 6), exoxaparin (8 mg/kg s.c.). These agents were injected before muscle dissection. All animals were observed under intravital microscopy, and measurements of capillary density and red blood cell velocity were taken at 2, 3, 5, and 7 h following subcutaneous enoxaparin injection. Statistical analysis revealed that the capillary density significantly increased in group II and group III, respectively, (by 33% (P < 0.0001) and 25% (P < 0.01) when compared to group I at the fifth hour. Group IV was not significantly different from group I in capillary density. There was no significant difference in red blood cell velocity in any of the groups. Propensity for bleeding was not observed in any of the groups during the dissections and observation periods except in group IV. In conclusion subcutaneous administration of 2 mg/kg enoxaparin improves (by 33%) capillary density without any bleeding complications at the cremaster muscle flap microcirculation at the fifth hour following injection (P < 0.0001). (c) 2005 Wiley-Liss, Inc. Microsurgery 25:147-151, 2005.

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Section: Discussionsupporting

confidence: 88%

Section: à18supporting

confidence: 88%

Dose response of enoxaparin at the cremaster muscle flap microcirculation

et al. 2005

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“…In contrast, rat and dog fXa are much less sensitive to DPC423 (K i : 2.35 nM in rat, 1.2 nM in dog; Wong et al, 2002). Other investigators have also noted that rat and dog fXa are much less sensitive than human and rabbit fXa to small-molecule fXa inhibitors (Hara et al, 1995;Taniuchi et al, 1998;Abendschein et al, 2000;McClanahan et al, 2001). We showed that DPC423 given either i.v.…”

Section: Discussionmentioning

confidence: 48%

“…Sinha et al (2000) also observed that enoxaparin at a dose similar to ours, increasing APTT by 2-fold, did not increase cuticle bleeding in rabbits. Other investigators have also noted that direct fXa inhibitors, but not direct thrombin inhibitors and heparin, at antithrombotic doses have little or no effect on the bleeding time in rats, rabbits, and dogs (Herbert et al, 1996a;Himber et al, 1997;Morishima et al, 1997;Sato et al, 1997;Abendschein et al, 2000;Sinha et al, 2000;McClanahan et al, 2001). It is not clear why fXa inhibitors prevent thrombosis without increasing the bleeding time in animals.…”

Section: Discussionmentioning

confidence: 99%

Nonpeptide Factor Xa Inhibitors III: Effects of DPC423, an Orally-Active Pyrazole Antithrombotic Agent, on Arterial Thrombosis in Rabbits

Wong

Crain

Watson

et al. 2002

J Pharmacol Exp Ther

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phenyl]-N-[3-fluoro-2Ј-(methylsulfonyl)[1,1Ј-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide] is a synthetic, competitive, and selective inhibitor of coagulation factor Xa (fXa) (K i : 0.15 nM in humans, 0.3 nM in rabbit). The objective of this study was to compare effects of DPC423, enoxaparin (low-molecular-weight heparin), and argatroban (thrombin inhibitor) on arterial thrombosis and hemostasis in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding, respectively. Compounds were infused i.v. continuously from 60 min before artery injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. Antithrombotic ED 50 values were 0.4 mg/kg/h for enoxaparin (n ϭ 6), 0.13 mg/kg/h for argatroban (n ϭ 6), and 0.6 mg/kg/h for DPC423 (n ϭ 12). DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n ϭ 6) by 1.8 Ϯ 0.07-and 1.8 Ϯ 0.13-fold, respectively, without changes in thrombin time and ex vivo thrombin activity. The antithrombotic effect of DPC423 was significantly correlated with its ex vivo anti-fXa activity (r ϭ 0.86). DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 Ϯ 4, 24 Ϯ 6, and 74 Ϯ 7, respectively (n ϭ 6/group). Cuticle bleeding times (percent change over control) determined at the maximum antithrombotic dose were 88 Ϯ 12 for argatroban, 69 Ϯ 13 for heparin, 4 Ϯ 3 for enoxaparin, 5 Ϯ 4 for DPC423, and Ϫ3 Ϯ 2 for the vehicle (n ϭ 5-6/group), suggesting dissociation of antithrombotic and bleeding time effects for DPC423 and enoxaparin. The combination of aspirin and DPC423 at ineffective antithrombotic doses produced significant antithrombotic effect. Therefore, these results suggest that DPC423 is a clinically useful oral anticoagulant for the prevention of arterial thrombosis.

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“…Orally active amidinoaryl propanoic acid reduces platelet deposition and fibrin accumulation in venous-type thrombus in baboons [308]. ZK-807834 inhibits arterial thrombosis [309] as well as venous thrombosis in vascular injury rabbits [310] and electrolytic injury canines [311]. SF 303 and 549 inhibit A-V shunt-induced thrombus formation in rabbits [312].…”

Section: Antagonisms Against Tf Signaling-evolving Thrombotic or mentioning

confidence: 99%

Tissue Factor, Blood Coagulation, and Beyond: An Overview

Chu

2011

International Journal of Inflammation

177

184

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Emerging evidence shows a broad spectrum of biological functions of tissue factor (TF). TF classical role in initiating the extrinsic blood coagulation and its direct thrombotic action in close relation to cardiovascular risks have long been established. TF overexpression/hypercoagulability often observed in many clinical conditions certainly expands its role in proinflammation, diabetes, obesity, cardiovascular diseases, angiogenesis, tumor metastasis, wound repairs, embryonic development, cell adhesion/migration, innate immunity, infection, pregnancy loss, and many others. This paper broadly covers seminal observations to discuss TF pathogenic roles in relation to diverse disease development or manifestation. Biochemically, extracellular TF signaling interfaced through protease-activated receptors (PARs) elicits cellular activation and inflammatory responses. TF diverse biological roles are associated with either coagulation-dependent or noncoagulation-mediated actions. Apparently, TF hypercoagulability refuels a coagulation-inflammation-thrombosis circuit in “autocrine” or “paracrine” fashions, which triggers a wide spectrum of pathophysiology. Accordingly, TF suppression, anticoagulation, PAR blockade, or general anti-inflammation offers an array of therapeutical benefits for easing diverse pathological conditions.

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The antithrombotic effects of CI-1031 (ZK-807834) and enoxaparin in a canine electrolytic injury model of arterial and venous thrombosis

Cited by 18 publications

References 22 publications

Dose response of enoxaparin at the cremaster muscle flap microcirculation

Dose response of enoxaparin at the cremaster muscle flap microcirculation

Nonpeptide Factor Xa Inhibitors III: Effects of DPC423, an Orally-Active Pyrazole Antithrombotic Agent, on Arterial Thrombosis in Rabbits

Tissue Factor, Blood Coagulation, and Beyond: An Overview

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