The anticoagulant application is an effective treatment modality for cardiovascular diseases such as coronary heart disease, unstable angina pectoris, and myocardial infarction. In this study, the antithrombotic effect of recombinant neorudin (EPR-hirudin, EH) was evaluated using a canine model of coronary artery thrombosis. A canine model with platelet thrombosis in the left circumferent branch of the coronary artery was designed using Folt’s method, and the anti-thrombus activity of EH was investigated. Femoral administration of EH intravenously had a significant dose-dependent inhibitory effect on canine coronary artery thrombosis and the effective rates were 66.7% (P < 0.05), 83.3% (P < 0.05), and 100% (P < 0.01) after injection of 0.3, 1.0, and 3.0 mg/kg EH, respectively. Furthermore, EH demonstrated lower bleeding, with shorter bleeding time and less bleeding loss than low molecular weight heparin (LMWH). Under the similar effect intensity of EH and LMWH (85 IU/kg), the bleeding time of the EH group at 30 min was shorter, and the blood loss at 30–120 min was less than that of LMWH (P<0.05 and P<0.05–0.001, respectively). EH had a significant dose-dependent inhibitory effect in the dose range of 0.3–3.0 mg/kg on the coronary artery thrombosis and lower bleeding side effects than LMWH with a similar antithrombosis effect.

AIMS: The aims of the study were to evaluate the tolerability, safety and pharmacokinetics of single and continuous administration of recombinant neorudin (EPR-hirudin, EH) by intravenous injection in healthy subjects, and to provide a safe dosage range for phase II clinical research. METHODS: A single and continuous administration dose phase I clinical study was conducted. Forty-four subjects were received EH as single-dose of 0.2-2.0 mg/kg by intravenous bolus plus drip; Eighteen healthy subjects were randomly divided into 3 dose groups (0.15-0.45 mg/kg/h) with 6 cases in each group in the continuous administration trial. RESULTS: Single or continuous doses of neorudin were generally well tolerated in healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. No subjects withdrew from the trial due to adverse events. There were no clinically relevant changes in physical examination, clinical chemistry, urinalysis or vital signs. The incidence of adverse events was not significantly related to the dose and systemic exposure. After the single-dose and continuous administration, the serum EH concentration reached a peak at 0.083h，the exposure increased with the increase of the administered dose with the mean half-life (T1/2) ranging from 1.7 to 2.5h, the clearance (Cl) ranging from 123.9 to179.7 mL/h/kg, and the apparent volume of distribution (Vd) ranging from 402.7 to 615.2 mL/kg. CONCLUSIONS: The safety, tolerability and pharmacokinetics characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies.