Safety, Pharmacokinetics and Pharmacodynamics of TNHH, a Novel Targeted Neutrophil-Inhibitory Hirulog Hybrid Glycoprotein, in Healthy Volunteers.

BACKGROUND: Targeted neutrophil inhibitory-hirulog (TNHH) is a novel hybrid glycoprotein that may be a potential drug candidate for acute ischaemic stroke. OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TNHH in healthy volunteers and thereby determine the dose range for future clinical studies. METHODS: This randomized, placebo-controlled study was a single ascending dose design with dose levels of 0.05-1.8 mg/kg (n = 4-6 active, 2 placebos per cohort) in 68 participants. In the TNHH 0.2-1.8 mg/kg and control cohorts, pharmacokinetic and pharmacodynamic blood samples were collected over 168 h after intravenous (IV) administration. TNHH occupancy in peripheral blood neutrophils and blood coagulation were evaluated as the markers of target engagement. RESULTS: Two subjects withdrew from the trial before administration of the study treatment, 66 subjects are included in the data analysis. TNHH was well tolerated in all dose regimens. In total, five mild, self-limiting adverse events (AEs) were observed in 4 of the 66 study subjects. Dose-proportional increases in maximum plasma concentration (Cmax) and area under the curve (AUC0-t) of TNHH were observed. Traces of TNHH were excreted in urine. The elimination half-life (t½) ranged from 0.6 to 1.3 h in the eight groups with ascending dose levels. TNHH combined with CD11b/CD18 quickly achieved > 90% receptor occupancy in groups with doses above 0.2 mg/kg. The Cmax and AUC of binding TNHH with CD11b/CD18 increased with the dose. A significant prolongation with dose was observed on thrombin time (TT), and weak influences were observed on prothrombin time (PT) and activated partial thromboplastin time (APTT). CONCLUSION: TNHH was well-tolerated following IV infusion. The pharmacokinetic and pharmacodynamic characteristics of TNHH indicate that it merits clinical trials. It is recommended that the single dose of TNHH should be 1.0 mg/kg in future studies, and the expected effect may be achieved after 5-7 days of continuous administration. TRIAL REGISTRATION: The study is registered at http://www.chictr.org.cn as ChiCTR-TQR-14004752.

[Effect of HOE642 on ischemic myocardium reperfusion injury]

OBJECTIVE: To investigate whether the specific sodium-hydrogen antiporter HOE642 could modifies myocardial ischemia and reperfusion injury. METHODS: The isolated working rat heart model was used. The rats were divided into four subgroups: Ischemic reperfusion (Control group),HOE642 given before Ischemia (HOE-Pr), HOE642 given during Ischemia (HOE-Is), HOE642 given during reperfusion (HOE-Re). LVDP, LVEDP, arrythmia, coronary flow and myocardial enzymes were measured. RESULTS: HOE642 given 15 minutes before ischemia increased coronary flow and significantly improved cardiac function, reduced the severity of ischemia, reperfusion arrhythmia and myocardial CK-MB, LDH release, but had no effect on heart rate. HOE642 given during ischemia only reduced LVEDP, the ischemia severity, reperfusion arrhythmia and myocardial enzyme release. It had no effect on heart rate or LVDP. There were no effects when the drug was given during reperfusion. CONCLUSION: HOE642 demonstrates significant cardioprotective effects. These protective effects are most significant when the drug is given before ischemia is induced.