title: Evaluating antithrombotic activity of HY023016 on rat hypercoagulable model.
abstract: The generation of thrombus is not considered as an isolated progression without other pathologic processes, which may also enhance procoagulant state. The purpose of this study was to assess whether HY023016, a novel dabigatran prodrug and an oral direct thrombin inhibitor, or dabigatran etexilate, another thrombin inhibitor can improve the state of whole blood hypercoagulability in vitro/vivo. By using whole blood flow cytometry we explored the effects of HY023016 and dabigatran etexilate on thrombin and ADP-induced human platelet-leukocyte aggregation generated in vitro. With the method of continuous infusion of thrombin intravenous, we successfully established a rat hypercoagulable model and evaluated the effect of HY023016 or dabigatran etexilate in vivo. HY023016 was able to inhibit thrombin- or ADP-induced platelet P-selectin or CD40L expression, leukocyte CD11b expression and formation of platelet-leukocyte aggregates in dose-dependent manner. Dabigatran etexilate was unable to affect ADP-induced platelet P-selectin or CD40L expression, leukocyte CD11b expression and formation of platelet-leukocyte aggregates. Based on rat hypercoagulable model, dabigatran etexilate could reverse thrombin-induced circulatory system hypercoagulable state in a concentration-dependent manner. Dabigatran etexilate also inhibited electrical stimulation induced formation of arterial thrombus in rat under hypercoagulable state, and extracorporal circulation-induced formation of thrombus in dose-dependent manner. Compared with dabigatran etexilate, HY023016 showed nearly equal or even better antithrombotic activity, regardless of reversing the cycle of rat hypercoagulable state or inhibiting platelet-leukocyte aggregation. In surrmary, HY023016 could effectively improve hypercoagulable state of circulatory system.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Qiu-Fang
authors.initials: QF
authors.lastname: Chen
authors.affiliation: State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China.
authors.forename: Yun-Zhan
authors.initials: YZ
authors.lastname: Li
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Xin-Hui
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: You-Rui
authors.initials: YR
authors.lastname: Su
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Ming-Xing
authors.initials: MX
authors.lastname: Miao
authors.affiliation: National Drug Screening Center, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Zhen-Zhou
authors.initials: ZZ
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Ai-Dou
authors.initials: AD
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: xu_yungen@hotmail.com.
authors.forename: Yun-Gen
authors.initials: YG
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: gonggq@hotmail.com.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Gong
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D013917:Thrombin / Q000008:administration & dosage / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D039481:CD11b Antigen; D005343:Fibrinolytic Agents; D013917:Thrombin
keywords: HY023016; Hypercoagulable state; Intravenous; Rat model; Thrombin