Fibrinolytic potential of DS-1040, a novel orally available inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa)
| Autor: | Akiko Watanabe, Naoki Miyoshi, Yusuke Ito, Aya Isobe, Naoko Edo, Yoshiyuki Morishima, Kyoji Yamaguchi, Kengo Noguchi |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Arginine medicine.medical_treatment Administration Oral 030204 cardiovascular system & hematology Pharmacology Fibrin 03 medical and health sciences 0302 clinical medicine Fibrinolytic Agents In vivo Bleeding time Oral administration Fibrinolysis medicine Animals Humans Thrombolytic Therapy Rats Wistar biology medicine.diagnostic_test Chemistry Hematology In vitro Rats biology.protein 030217 neurology & neurosurgery Fibrinolytic agent |
| Zdroj: | Thrombosis research. 168 |
| ISSN: | 1879-2472 |
| Popis: | An activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis by removing C-terminal lysine/arginine residues from partially degraded fibrin. We have identified a novel low-molecular-weight inhibitor of TAFIa, DS-1040, to be potentially useful for treating thrombotic diseases. In this study, we investigated its in vitro pharmacological profile and in vivo effects in animal models of microthrombosis and bleeding. DS-1040 inhibited human TAFIa and carboxypeptidase N (CPN) in vitro with IC50 values of 5.92 and 3.02 × 106 nmol/L, respectively, suggesting that DS-1040 is highly selective for TAFIa over CPN. DS-1040 did not affect platelet aggregation and coagulation time. In a tissue factor-induced rat microthrombosis model, intravenously administered DS-1040 reduced existing fibrin clots in the lung, whereas post-treatment with enoxaparin had limited effect. Both intravenously and orally administered DS-1040 elevated plasma D-dimer levels with similar plasma exposures of DS-1040. DS-1040 significantly augmented plasma D-dimer level on top of silent dose of recombinant tissue-plasminogen activator (t-PA), suggesting DS-1040 enhances fibrinolytic activity of t-PA. In addition, DS-1040 did not prolong the tail bleeding time beyond its efficacy dose. These results indicate that DS-1040 is a potent, selective, intravenously/orally available inhibitor of TAFIa with minimum risk of bleeding. DS-1040 is a potential novel fibrinolysis enhancer useful in treating thrombotic diseases. |
| Databáze: | OpenAIRE |
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