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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. [ABSTRACT FROM AUTHOR]

Abstract Background Moguisteine is a non-narcotic peripheral antitussive drug that has been effective and well-tolerated in clinical studies. The aim of the present work was to investigate the pharmacokinetics of moguisteine given as single or multiple doses to healthy Chinese subjects. Methods In Stages 1–3 of this study, 12 healthy Chinese subjects (6 males and 6 females) participated in a randomized, open-label, single-dose, 3-period, 3-way crossover study, with a 24-h washout period between each treatment. Eligible subjects were randomized to receive a single dose of 100, 200 or 400 mg moguisteine. Blood was sampled before and up to 10 h after administration. In those receiving 200 mg moguisteine, urine was sampled at intervals of 0–2, 2–4, 4–6, 6–10, and 10–24 h. In Stage 4, subjects received a moguisteine tablet containing 200 mg three times daily for five consecutive days. Blood was sampled for up to 10 h after the last dose. HPLC-tandem mass spectrometry was used to determine concentrations of the moguisteine metabolite M1 in serum, while HPLC-UV was used to determine concentrations of M1 in urine. Safety of the dosing schedules was assessed based on physical examination, recording of adverse events, 12-lead electrocardiography, and laboratory tests. Results All subjects completed all four stages of the study. M1 was detectable at the shortest time points after moguisteine administration; the time to achieve peak concentration was 0.5–1.0 h in single dosing and 1.5 h in multiple dosing. Elimination half-life (t 1/2) was 0.91–1.54 h in single dosing and 1.57 h in multiple dosing. AUC increased roughly proportionally with dose, while C max increased much more gradually with dose. During 5-day dosing of three tablets per day, a steady state concentration was reached on day 3, and the mean accumulation ratio was 0.87. At 24 h after a single dose of 200 mg moguisteine, approximately 34.0% of the resulting M1 was recovered in urine. Pharmacokinetics of moguisteine did not differ significantly between men and women, except among those receiving a single dose of 100 mg (P < 0.05). Mild adverse events (nausea, loose stool, abdominal distention, or dizziness) occurred in six subjects and resolved without treatment, while no serious adverse events were observed. Conclusion Moguisteine was safe and well-tolerated by our healthy subjects, and it exhibited dose linearity but not proportionality when a single dose of 100–400 mg was given. M1 did not accumulate in subjects after multiple doses of moguisteine. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Aims The aims of the study were to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of a novel, pegylated recombinant human consensus interferon-α variant ( PEG-IFN- SA) in healthy volunteers. A pharmacokinetic and pharmacodynamic comparison of PEG-IFN- SA and peginterferon-α-2a in healthy subjects was evaluated. Methods A randomized, dose-escalating, single administration dose phase I clinical study was conducted. Thirty healthy subjects received PEG-IFN- SA as a single dose of 0.5-2.0 μg kg−1 by subcutaneous (s.c.) injection in four parallel groups. Eight subjects received peginterferon-α-2a as a single dose of 180 μg s.c. Results The incidence rates of adverse events for PEG-IFN- SA and peginterferon-α-2a were 29 of 30 and 7 of 8, respectively. The adverse events for PEG-IFN- SA were mild to moderate and similar to those of peginterferon-α-2a. Within 168 h after injection, the mean values of maximal concentration and area under the plasma concentration-time curve from time of dosing to 168 h [ AUC(0-168h)] for 2′,5′-oligoadenylate, neopterin and β2-microglobulin for PEG-IFN- SA at 1.5 μg kg−1 s.c. were similar to or higher than those for peginterferon-α-2a at a dose of 180 μg s.c. After s.c. injection of PEG-IFN- SA at 1.5 μg kg−1, the mean geometric mean values of plasma half-life, time to maximal concentration, maximal concentration and AUC(0-168h) were 55.3 h, 26.9 h, 0.53 μg l−1 and 44.0 μg l−1 h, respectively. Conclusions The tolerance, pharmacokinetic and pharmacodynamic characteristics of PEG-IFN- SA support its administration by s.c. injection as a single dose of 1.5 μg kg−1 or at 2.0 μg kg−1 per week. [ABSTRACT FROM AUTHOR]

Yogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed. A randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192 h afterwards. Urine samples were collected until 120 h after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay. A total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3 years; mean weight, 58.8 kg; mean BMI, 21.8 kg/m2). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (T max) of 3.0 h and was eliminated slowly with a t 1/2 of 25.45–43.84 h. The maximum observed concentration (C max) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400 mg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24 h after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72 h at doses from 25 to 400 mg. DPP-4 inhibition was >80% for 1 week in the group receiving 400 mg. Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25–200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients. Trial Registration: ChiCTR-IIR-17010311 (Chictr.org). Unlabelled Image [ABSTRACT FROM AUTHOR]

Background: Alstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in 'dai' ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA).Purpose: The aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses.Methods: In this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects' plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr.org.cn/showproj.aspx?proj=11736), number ChiCTR-IPR-15006976.Results: 40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation.Conclusion: Pharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen. [ABSTRACT FROM AUTHOR]