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The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR‐hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty‐four subjects received EH as a single dose of between 0.2 and 2.0 mg/kg by intravenous bolus and drip infusion. In addition, 18 healthy subjects were randomly divided into three dose groups (0.15, 0.30, and 0.45 mg/kg/h) with 6 subjects in each group for the continuous administration trial. Single or continuous doses of neorudin were generally well tolerated by healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. Moreover, no subjects withdrew from the trial because of AEs. There were no clinically relevant changes in physical examination results, clinical chemistry, urinalysis, or vital signs. The incidence of adverse events was not significantly related to drug dose or systemic exposure. After single‐dose and continuous administration, the serum EH concentration reached its peak at 5 min, and the exposure increased with the increase in the administered dose. The mean half‐life (T1/2), clearance (Cl), and apparent volume of distribution (Vd) of EH ranged from 1.7 to 2.5 h, 123.9 to 179.7 ml/h/kg, and 402.7 to 615.2 ml/kg, respectively. The demonstrated safety, tolerability, and pharmacokinetic characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. Clinical trial registration: Chinadrugtrials.org identifier: CTR20160444. 62 subjects were separately grouped into single dose and continuous dose trials, and 14 AEs and 68 AEs from the two trials were respectively reported to be related to neorudin. The pharmacokinetic parameters were determined in this phase I study.

In order to better understand the therapeutic mechanism of dual-function peptide 5rolGLP-HV in treatment of treat diabetes and its complication of thrombosis, the pharmacological effects and pharmacokinetic properties of 5rolGLP-HV were conducted in this study. 5rolGLP-HV was orally administered to diabetic mice, and the hypoglycemic mechanism was investigated. Thrombotic mice were applied to study the thrombus dissolving ability of 5rolGLP-HV. The concentration of rolGLP and rHV in rat plasma following single oral dose or intravenous injection of 5rolGLP-HV was measured. Treatment with 5rolGLP-HV decreased insulin resistance (2.96 ± 1.43 vs. 9.35 ± 1.51, p  < 0.05) of diabetic mice. 5rolGLP-HV shortened the length of thrombus in thrombosis mice (2.92 ± 0.74 vs. 5.92 ± 1.16 cm, p  < 0.01) and extended the thrombin time (15.35 ± 1.22 vs. 8.67 ± 0.89 s, p  < 0.01) of normal mice. Meanwhile, 5rolGLP-HV restored the damage of pancreatic, liver, kidney, and adipose tissues induced in the diabetic mice. 5rolGLP-HV exhibited a fast absorption and slow elimination phase after digested into rolGLP-1 and rHV in vivo. These results suggested that 5rolGLP-HV had an ideal therapeutic potential in the prevention of β cell dysfunction in type 2 diabetes and delay of the thrombus.

To compare the analytical methods used to study the pharmacokinetics of recombinant hirudin in the plasma of rats that had been injected with (125)I-recombinant hirudin. 2.0 mg/kg (125)I-recombinant hirudin were injected intravenously into rats. The recombinant hirudins in the plasma was analyzed by chromogenic substrate assay, enzyme-linked immunosorbent assay (ELISA), total radioisotope assay (RA) and trichloroacetic acid pre-treated total radioisotope assay (TCA-RA). The chromogenic substrate assay standard curve was linear over the concentration range from 3.12 to 40.00 ng/ml for the recombinant hirudin in plasma. The relative standard deviations (RSD) for the intra- and inter-day variation were 5.0 to 6.3% and 11.9 to 12.6%, respectively. The recoveries of recombinant hirudin was 89.8% to 100.7%. The limit of quantification (LOQ) was 3.12 ng/ml. The concentration-time curve of the recombinant hirudin in the plasma could be explained as a two-compartment model. Pharmacokinetic parameters, including the half-life of distribution phase (t1/2 α), the half-life of elimination phase (t1/2 β), volume of apparent distribution (Vd), and area under the concentration-time curve from zero to infinite time (AUC0-t) were 7.59 min, 46.99 min, 0.17 L/kg, and 204.5 mg/L/min, respectively, as determined by chromogenic substrate assay; 6.41 min, 47.28 min, 1.24 L/kg, and 575.18 mg/L/min, respectively, as determined by ELISA; 3.69 min, 701.90 min, 0.04 L/kg, and 4189 mg/L/min, respectively as determined by RA; and 4.57 min, 724.9 min, 0.09 L/kg, and 2329 mg/L/min, respectively, as determined by TCA-RA. The chromogenic substrate assay on the concentration dynamics of the recombinant hirudin in the plasma is a specific, sensitive, and accurate analytical method for pharmacokinetic studies. Moreover, the pharmacokinetic parameters determined by the chromogenic substrate assay and ELISA are congruent except for AUC.

Appropriate timing of bivalirudin discontinuation as a bridge to warfarin is complicated, as bivalirudin may cause a falsely prolonged international normalized ratio (INR). The purpose was to evaluate patient and medication characteristics associated with differences in INR prolongation caused by bivalirudin. Adult patients receiving bivalirudin as a bridge to warfarin in 2014 were retrospectively evaluated. Patients were excluded if they had known thrombophilia or inappropriate INR monitoring after discontinuation of bivalirudin. Data recorded included indication for bivalirudin use, bivalirudin dosing, and coagulation assays. Univariate analysis was performed to determine variables associated with a larger change in INR when discontinuing bivalirudin. Variables with P < .3 were included in multivariate analysis. In total, 50 patient admissions were included in the analysis. Patients with ventricular assist devices represented the majority of the patient population (74%). The most common INR goals were 2.0 to 3.0 and 2.5 to 3.5. The mean initial weight-based bivalirudin rate was 0.076 mg/kg/h, and the mean increase in INR when starting bivalirudin was 0.6. The mean final weight-based bivalirudin rate was 0.13 mg/kg/h, and the mean change in INR after stopping bivalirudin was 0.8. On multivariate analysis, factors associated with a larger change in INR after stopping bivalirudin included higher serum creatinine (P = .033), greater change in INR after initiation of bivalirudin (P = .028), and higher final bivalirudin rate (P < .001). The change in INR when starting or stopping bivalirudin appears to be patient specific and dose related. A nomogram was developed to predict the ideal timing of bivalirudin discontinuation. Prospective evaluation of the nomogram is under way.

Platelets and the coagulation cascade play key roles in initiation, amplification, and perpetuation of acute coronary syndromes (ACS). In the past few years, there has been great progress in ACS antithrombotic treatment with the introduction of novel anticoagulants (fondaparinux and bivalirudin), more potent P2Y12 inhibitors (prasugrel and ticagrelor) and protease-activated receptor antagonists (vorapaxar). Nonetheless, patients with ACS frequently have recurrent ischemic events despite the use of currently recommended dual antiplatelet therapy, revascularization procedures as appropriate, and other evidence-based secondary preventive measures. This is the rationale beyond intensification of antiplatelet therapy. However, the major downside of intensive antithrombotic therapy is bleeding. When treating ACS patients, clinicians should find the adequate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Numerous antithrombotic cocktails including oral anticoagulants with or without aspirin have been tested in large clinical trials with the goal of further reduction of ischemia and bleeding risk. The aim of this review is to discuss clinical outcomes resulting from inhibition of multiple coagulative pathways in patients with ACS in light of evidence from large randomized controlled clinical trials.

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax®, The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.

Aim: To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects. Methods: Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time (ACT). Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and prediction-corrected visual predictive check (pcVPC) approaches. Results: The final PK model was a two-compartment model without covariates. The typical PK population values of clearance (CL), apparent distribution volume of the central-compartment ( V 1 ), inter-compartmental clearance (Q) and apparent distribution volume of the peripheral compartment ( V 2 ) were 0.323 L·h -1 ·kg -1 , 0.086 L/kg, 0.0957 L·h -1 ·kg -1 , and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid E max model without the Hill coefficient. In this model, a covariate, red blood cell count (RBC * ), had a significant effect on the EC 50 value. The typical PD population values of maximum effect ( E max ), EC 50 , baseline ACT value ( E 0 ) and the coefficient of RBC * on EC 50 were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of E max , EC 50 , and E 0 were 6.80%, 46.4%, and 4.10%, respectively. Conclusion: Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.

Bivalirudin is a synthetic 20 amino acid polypeptide that directly inhibits both fibrin-bound and soluble thrombin. In the randomized, open-label, multicentre HORIZONS-AMI trial in patients with ST-segment elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention (PCI), compared with unfractionated heparin (UFH) plus a glycoprotein (GP) IIb/IIIa inhibitor, bivalirudin was associated with a significantly lower 30-day rate of net adverse clinical events that was largely due to the significantly lower 30-day rate of non-coronary-artery bypass grafting major bleeding. There was no significant between-group difference in the 30-day rate of major adverse cardiovascular events. These 30-day clinical outcomes were maintained at the 1- and 2-year follow-up. Bivalirudin, compared with UFH plus a GP IIb/IIIa inhibitor, was associated with lower short- (30-day) and long- (1- and 2-year) term overall and cardiac mortality rates. Although there was an increased risk of acute stent thrombosis within 24 hours in recipients of bivalirudin compared with UFH plus a GP IIb/IIIa inhibitor, there was no significant between-group difference between 24 hours and 30 days, ≤30 days, ≤1 year or ≤2 years.

Monitoring of direct inhibitors of thrombin (DTI) is critical for their safe and effective use as anticoagulants. We examined samples containing several concentrations of argatroban or lepirudin in reconstituted standard human plasma and plasma from medical outpatients and intensive care patients. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were determined using automated analyzers. Ecarin clotting time (ECT) was measured using a 10 IU/mL dilution of ecarin in 0.05 mol/L CaCl2. Calibration curves were approximately linear for TT and ECT in samples containing argatroban and lepirudin, respectively. Activated partial thromboplastin curves reached a plateau at DTI concentrations ≥2 µg/mL, suggesting that the aPTT may not reliably detect overdosing. Prothrombin time increased exponentially. A broad range of clotting times was seen in patient samples with all tests suggesting that individual morbidity and therapies may strongly influence test results and may lead to underestimation of DTI doses.