RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.

No abstract

The efficacy of various drugs used to treat ulcerative colitis, (sulfasalazine, 5-aminosalicylate, hydrocortisone) was investigated in a model of acetic acid-induced colitis in the rat. Subsequently, we tested the ability of antioxidant/5-lipoxygenase inhibitors (gossypol and nordihydroguiaretic acid [NDGA]) and a cyclooxygenase inhibitor (indomethacin) to attenuate the macroscopic colonic damage and/or neutrophil influx (myeloperoxidase activity [MPO]) associated with this model of colitis. Oral pretreatment with either sulfasalazine, gossypol, or NDGA significantly decreased colonic MPO activity induced by acetic acid. Intrarectal administration of such drugs resulted in an even larger reduction of the colonic inflammation, with gossypol being the most potent compound. Oral or intrarectal administration of corticosteroids (dexamethasone, hydrocortisone) also attenuated the parameters of acetic acid induced colitis. In contrast, pretreatment with indomethacin was ineffective, or when administered daily after colitis induction, indomethacin actually increased colonic neutrophil influx significantly. Our data suggest that both the route of drug administration and dosing regimen employed affect the antiinflammatory potency and/or efficacy of compounds on colitis induced by acetic acid in the rat. Drugs which were effective against this colitis may act by scavenging of oxygen derived free radicals.

SummaryThe in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p <0.05 vs saline-treated animals) by RPR120844 at 30 and 100 μg/kg/min. At doses of 10, 30 and 100 μg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 ± 0.3, 1.5 ± 0.9 and 2.4 ± 0.6 μM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

Introduction: BMS-986120 (BMS) is a novel orally-active antagonist of protease-activated receptor-4 (PAR4), a human platelet thrombin receptor, and is in phase I clinical trial. The antithrombotic potential of BMS was studied in models of electrically-mediated carotid artery thrombosis and bleeding time (BT) in cynomolgus monkeys, which have platelet thrombin receptors similar to human. Methods: Individual anesthetized monkeys were given orally of BMS (0.2, 0.5,1 mg/kg) or vehicle (n=8/group) 2 hour before a combination of thrombosis, BT and ex vivo biomarker experiments. Aspirin alone (ASA, 4 mg/kg/h IV) or in combination with BMS (0.5, 1 mg/kg) was also studied (n=8/group). Thrombus weight (TW) reduction, BT increase over vehicle in kidney (KBT) and mesenteric artery (MBT), and platelet aggregation (PA) inhibition were determined. Peak PA responses to activation peptides selective for PAR4 (PAR4-AP, 12.5 μM) and PAR1 (PAR1-AP, 18 μM), ADP (20 μM), and collagen (5 μg/ml) were determined by whole blood aggregometry. Results: BMS comparably inhibited PA induced by PAR4-AP in human and monkey blood in vitro (IC 50 of 9.5±2.7 and 2.1±0.4 nM, respectively). In monkeys, BMS produced parallel rightward shifts in the log PA dose response to PAR4-AP without affecting maximum response, suggesting surmountable antagonism. BMS (1 mg/kg) did not inhibit PA induced by PAR1-AP, ADP and collagen, supporting selectivity. BMS (0.2, 0.5, 1 mg/kg) reduced TW by 35±5, 49±4, and 83±4%, respectively. Maximum KBT and MBT increases were only 2.2-fold and 1.8-fold, respectively. A maximum antiplatelet dose of ASA (4 mg/kg/h, n=8) slightly reduced TW by 12±2% and increased KBT and MBT by 2.2- and 2.7-fold, respectively. Co-administration of ASA and BMS (0.5 or 1 mg/kg) reduced TW by 54±3 and 95±2%, increased KBT by 3.1- and 3.6-fold, and increased MBT by 2.6- and 3.3-fold, respectively (n=8/group). In companion monkey studies, clopidogrel (0.3 mg/kg/day, n=6) alone reduced TW by 49±6%, but increased KBT and MBT by 7.3- and 8.1-fold, respectively. Conclusion: In monkeys, BMS alone or combined with ASA prevents occlusive carotid artery thrombosis with limited impact on BT, demonstrating a wider therapeutic window than the standard of care antiplatelet drugs, aspirin and clopidogrel.