caa a22 4500 475824490 CHVBK 20180406123827.0 cr unu---uuuuu 170329e20001201xx s 000 0 eng 10.1023/A:1026555510258 doi (NATIONALLICENCE)springer-10.1023/A:1026555510258 The Antithrombotic Effects of CI-1028, an Orally Bioavailable Direct Thrombin Inhibitor, in a Canine Model of Venous and Arterial Thrombosis [Elektronische Daten] [Thomas McClanahan, Gary Hicks, Diane Ignasiak, Richard Bousley, Thomas Mertz, Paul Juneau, Nancy Janiczek-Dolphin, In-Chull Kim, Kim Gallagher] Direct thrombin inhibitors represent a new class of drug that may offer a therapeutic alternative for the treatment and prevention of thrombembolic conditions, especially on the venous side of the systemic circulation. CI-1028 (PD 172524/LB30057) is a potent, highly selective inhibitor of thrombin that is orally bioavailable. The efficacy of this compound has been demonstrated in animal models in which intra-venous administration was used. The objective of this study was to evaluate the efficacy of CI-1028 after oral administration in a canine electrolytic injury model of venous and arterial thrombosis. CI-1028 was administered via oral gavage, and animals received either saline or 10, 15, 20, or 30 mg/kg of drug. Fifteen minutes later, the dogs were anesthetized and a femoral artery and vein were exposed and instrumented to induce electrolytic injury and thrombosis while continuously monitoring blood flow in the vessels. Maximum blood CI-1028 concentrations of 0.88±0.27, 1.8±0.3, 2.2±0.5, and 3.2±0.5 μg/mL were generally achieved 15 to 30 minutes after administering the compound in the 10-, 15-, 20-, and 30-mg/kg groups, respectively. Administration of CI-1028 increased the time to occlusion (TTO), the principal efficacy end point, in a dose-dependent manner in both arteries and veins. The TTO in the control group (n=8) averaged 66±11 minutes in the arteries and 69±6 minutes in the veins. In dogs treated with 10 mg/kg (n=8), the TTO was not significantly different from that of the control group. In the 15-mg/kg group (n=9) TTO averaged 140±27 minutes in the arteries (p=not significant) and 125±15 minutes (p<0.05) in the veins. In the 20-mg/kg group (n=8), TTO was significantly longer than controls in both types of vessels, averaging 168±30 minutes in the arteries (p=0.05) and 155±21 minutes (p<0.05) in the veins. Likewise, at 30 mg/kg (n=8) both the arterial (179±17 minutes) and venous (188±15 minutes) TTO was significantly prolonged compared with controls. Surgical blood loss and template bleeding times tended to increase in a dose-dependent manner but a statistically significant elevation was detected for template bleeding time only at the highest dose. Dramatic changes in thrombin time were detected, consistent with the CI-1028 mechanism of action. Virtually no changes were detected in prothrombin time. Maximum activated partial thromboplastin time (aPTT) and activated clotting time changes were detected approximately 30 minutes after dosing, and they were approximately twofold and fivefold baseline values, respectively, at the highest dose. In conclusion, these results demonstrate that CI-1028 provides dose-dependent antithrombotic efficacy after oral administration in a canine model of venous and arterial thrombosis. Kluwer Academic Publishers, 2000 thrombosis nationallicence electrolytic injury nationallicence thrombin inhibition nationallicence McClanahan Thomas Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Hicks Gary Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Ignasiak Diane Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Bousley Richard Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Mertz Thomas Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Juneau Paul Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Janiczek-Dolphin Nancy Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Kim In-Chull Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Gallagher Kim Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut Journal of Thrombosis and Thrombolysis Kluwer Academic Publishers 10/3(2000-12-01), 277-284 0929-5305 10:3<277 2000 10 11239 https://doi.org/10.1023/A:1026555510258 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1026555510258 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- McClanahan Thomas Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Hicks Gary Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Ignasiak Diane Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Bousley Richard Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Mertz Thomas Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Juneau Paul Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Janiczek-Dolphin Nancy Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Kim In-Chull Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Gallagher Kim Cardiovascular Therapeutics, Biometrics, and Pharmacokinetics; Dynamics; and Metabolism Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan, USA aut NATIONALLICENCE 773 0- Journal of Thrombosis and Thrombolysis Kluwer Academic Publishers 10/3(2000-12-01), 277-284 0929-5305 10:3<277 2000 10 11239 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer