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.

[The primary evaluation of Sal-Ammoniac extract on the therapy action in mice bearing Lewis lung cancer].

OBJECTIVE: To evaluate the therapy action of Sal-Ammoniac extract on Lewis lung cancer and its toxicity to immunity. METHODS: The proliferation and cell cycle of Lewis lung cancer cells were determined by MTT assay and flow cytometry respectively. The antitumor effect of Sal-Ammoniac extract was observed by tumor injected subcutaneously in mice and its toxicity to immunity was examined by clearance rate of charcoal particles and delayed type hypersensitivity. RESULTS: Sal-Ammoniac extract could inhibit the proliferation of Lewis lung cancer cells with S cell cycle arrest in a dose-dependent manner in vitro. Sal-Ammoniac extract solution injected in tumor for eight days had 46.7% inhibition on Lewis lung cancer, if taken orally had only 15.7% inhibition on Lewis lung cancer in mice. Sal-Ammoniac extract solution injected subcutaneously or taken orally had no effect on the clearance rate of charcoal particles and delayed type hypersensitivity in mice. CONCLUSION: The antitumor action of Sal-Ammoniac extract has relation to its recipe and has no influence on immunity.