Dose-dependent thrombus resolution due to oral plaminogen activator inhibitor (PAI)-I inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis

Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0654, USA.
Thrombosis and Haemostasis (Impact Factor: 4.98). 04/2008; 99(4):749-58. DOI: 10.1160/TH07-11-0669
Source: PubMed


This study aimed to evaluate a small-molecule PAI-1 inhibitor (PAI-039; tiplaxtinin) in a rodent stenosis model of venous thrombosis in a two-phase experiment. Phase 1 determined the efficacy of tiplaxtinin against Lovenox (LOV), while phase 2 determined the dose-dependent efficacy. For both phases, drug treatment began 24 hours after surgically induced venous thrombosis and continued for four days. Phase 1 animals (n = 24) receiving low-dose (LD; 1 mg/kg oral gavage) PAI-1 inhibitor demonstrated a 52% decrease in thrombus weight (TW) versus controls (p < 0.05) with significant reductions in active plasma PAI-1, while the high-dose (HD; 10 mg/kg oral gavage) group demonstrated a 23% reduction in TW versus controls. Animals treated subcutaneously with LOV (3 mg/kg) showed a 39% decrease in TW versus controls (p < 0.05). Coagulation tests (aPTT and TCT) were significantly different in LOV compared to PAI-1 inhibitor groups. PAI-039 treatment was also associated with significantly increased return of inferior vena cava blood flow four days post-thrombosis versus controls (p < 0.05). In phase 2 (n = 30), TW was reduced from the 0.5 mg/kg to 5 mg/kg experimental groups, with the 10 mg/kg group demonstrating a paradoxical increase. The 5 mg/kg group showed statistically significant decreases in TW versus controls after four treatment days (p < 0.05). This is the first study to demonstrate dose related effects of PAI-039 on increasing thrombus resolution and inferior vena cava blood flow without adverse effects on anti-coagulation in a rat stenosis model of venous thrombosis.

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Available from: Sanjiv M Baxi, Dec 14, 2014
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    • "In cardiovascular disease, for example, PAI-1 expression is significantly increased in severely atherosclerotic vessels (Schneiderman et al., 1992), and PAI-1 protein levels rise consistently during disease progression from normal vessels to fatty streaks to atherosclerotic plaques (Robbie et al., 1996). Studies in animal models have shown that blocking PAI-1 with antibodies (Berry et al., 1998; Biemond et al., 1995; Rupin et al., 2001; van Giezen et al., 1997) or dominant-negative PAI-1 mutants (Huang et al., 2008, 2003; McMahon et al., 2001; Wu et al., 2009), or with small molecule inactivators of PAI-1 (Abderrahmani et al., 2009; Baxi et al., 2008; Crandall et al., 2006; Hennan et al., 2005, 2008; Leik et al., 2006; Lijnen et al., 2006; Smith et al., 2006; Weisberg et al., 2005) can ameliorate the severity of various disease models. Because these studies have suggested that the inactivation of PAI-1 may be of therapeutic benefit, PAI-1 has been a molecule of significant clinical interest as a drug target. "
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