Identification of Transcription Factor-Gene Regulatory Network in Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a common disease with serious mortality and morbidity, worldwide. The present study aimed to identify differentially expressed genes (DEGs) and construct a transcription factor-gene regulatory network to further study the early diagnosis of AMI. METHODS: The integrated analysis of publicly available Gene Expression Omnibus datasets of AMI was performed. Differentially expressed genes were identified between AMI and normal blood samples. Gene Ontology enrichment analyses, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the transcription factor-gene regulatory network were used to obtain insights into the functions of DEGs. Quantitative real-time polymerase chain reactions (qRT-PCR) were performed to validate the expression level of DEGs. RESULTS: A total of 2,502 DEGs, including 917 up-regulated genes and 1,585 down-regulated genes, were identified between AMI and normal blood samples by integrating four expression profiles of AMI. Differentially expressed genes were significantly enriched in pathways including complement and coagulation cascades, Staphylococcus aureus infection, and cell adhesion molecules. Transcription factors were screened and performed to construct the regulatory network. The transcription factor-gene regulatory network consisted of 871 interactions between 80 transcription factors and 716 DEGs. ETS homologous factor (EHF) was one of transcription factors that had high connectivity with DEGs and regulated CACNB4 in the network. Verification by qRT-PCR revealed that EHF, KRT6A and DSG3 were significantly up-regulated, while CACNG4 was significantly down-regulated in AMI. Furthermore, CACNG6, CACNB4 and CLDN18 had a tendency to be down-regulated, and CALML3 had a tendency to be up-regulated in AMI. CONCLUSIONS: The identification of important differentially expressed transcription factors and genes in the development of AMI would be the groundwork for the early diagnosis and early intervention of AMI.

An open-label, multiple-dose study to assess the pharmacokinetics and tolerability of sitagliptin/metformin fixed-dose combination (FDC) tablet in healthy Chinese adult subjects.

AIM: This study investigated the pharmacokinetics of sitagliptin and metformin after multiple oral doses of the sitagliptin/metformin fixed-dose combination (MK0431A) tablet in healthy Chinese volunteers. METHODS: This was a singlecenter, randomized study in 24 healthy adults. Subjects received twice-daily doses of MK0431A 50-mg/500-mg tablet and 50-mg/850-mg tablet for 7 days. Serial blood and urine samples were collected at predefined time points for bioassay of sitagliptin and metformin. Safety was assessed throughout the study. RESULTS: Based on consecutive trough concentrations, the steady states of sitagliptin and metformin were reached after twice-daily administration of MK0431A tablets for 5 days. After the last dose, the mean ± SD (standard deviation) peak sitagliptin concentration of 167.3 - 22.52 and 174.1 ± 22.16 ng/mL was reached in a median tmax of 2.25 - 3 hours. The mean ± SD Cmax of metformin appeared in a median tmax of 1.75 - 2.25 hours at 888.3 ± 195.19 and 1,337 ± 269.19 ng/mL with MK0431A 50 mg/500 mg and 50 mg/850 mg, respectively Mean ± SD AUC012h of sitagliptin was between 1,404 ± 147.48 and 1,374 ± 179.12 h×ng/mL, while mean ± SD AUC0-12h of metformin were 6,015 ± 854.98 and 8,587 ± 1,715.93 h×ng/mL with MK0431A 50 mg/500 mg and 50 mg/850 mg, respectively. Approximately 75% sitagliptin and 40% metformin were excreted unchanged in the urine, corresponding to a renal clearance of 17.84 - 18.27 L/h for sitagliptin and 27.11 - 27.94 L/h for metformin. CONCLUSION: No clinically-significant pharmacokinetic difference was identified between Chinese and foreign healthy volunteers regarding sitagliptin and metformin with multiple doses of MK0431A tablets. The treatments were well tolerated.

Pharmacokinetics and tolerability of olmesartan medoxomil plus hydrochlorothiazide combination in healthy Chinese subjects: drug-drug interaction, bioequivalence, and accumulation.

OBJECTIVES: The study is to investigate drug-drug interaction (DDI) between olmesartan medoxomil and hydrochlorothiazide (HCTZ), to confirm bioequivalence (BE) of a new combined formulation and coadministration of separate local tablets, and to receive pharmacokinetics and tolerability of the new combined formulation after multiple doses in healthy Chinese subjects. METHODS: The 3-in-1 study was separated into 2 stages. Stage 1 is a four-period crossover study. 28 healthy subjects were equally randomized into four groups. Each group received the four following regimens in a sequence as Latin square (4 × 4) design: A: olmesartan medoxomil; B: HCTZ; C: test drug (new combined formulation); D: reference drugs (co-administration of separate tablets). In stage 2, half of 28 subjects were daily dosed with regimen C for 7 days. Blood and urine samples were obtained to receive pharmacokinetics of olmesartan and HCTZ, which were analyzed using the BE evaluation method. Tolerability was also assessed. RESULTS: All subjects completed the study and nobody reported serious adverse event (SAE). The 90% confidence intervals (CI) of geometric mean ratio (GMR) of log transformed Cmax, AUC0-t, and AUC0-∞ after single dose showed no DDI and claimed BE. The mean ratio of accumulation (Ra) (SD) of olmesartan and HCTZ after multiple doses of new combination formulation is 1.03 (0.182) and 0.954 (0.128). CONCLUSIONS: No significant DDI between olmesartan and HCTZ was found. The new combination formulation is bioequivalent to co-administration of two separate local tablets. After multiple doses of the new combination formulation, no significant accumulation was observed. The new combination formulation is reasonably tolerated well in healthy Chinese subjects after multiple doses.

A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects.

AIM: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. METHODS: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 µg·kg(-1)·min(-1), each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. RESULTS: Peak concentrations (C(max)) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107-0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL(-1) (range, 3.2-6.8 ng·h·mL(-1)). The volume of distribution (V) was 48 L (range, 30.8-80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%-12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E(0), E(max), and EC(50) were 68 bpm, 73 bpm and 8.1 µg/L, respectively. CONCLUSION: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.

The pharmacokinetics, pharmacodynamics, and tolerability of liraglutide, a once-daily human GLP-1 analogue, after multiple subcutaneous administration in healthy Chinese male subjects.

In this single-center, randomized, double-blind, within dose group, placebo-controlled, dose escalation trial, the pharmacokinetics, pharmacodynamics, tolerability, and safety of liraglutide were evaluated in 37 healthy Chinese subjects. Subjects were randomized to 1 of 3 dose groups (0.6, 1.2, or 1.8 mg), and within each group, randomized to liraglutide or placebo (3:1). All subjects started at 0.6 mg liraglutide (or placebo) once daily for 1 week, and the dose was increased for dose groups 1.2 mg and 1.8 mg in weekly steps of 0.6 mg to the predefined dose targets. Liraglutide or placebo was administered once daily by subcutaneous injection for 21 consecutive days. The dose relationships of AUC(0-24h), C(max), and C(trough) at steady state do not deviate in a relevant way from dose proportionality. t(max) and t(1/2) were 8 hours (median) and 11.2 to 12.2 hours (geometric mean), respectively. The plasma glucose levels in all liraglutide groups were decreased, while reduced serum insulin level was observed in the 1.2- and 1.8-mg groups after liraglutide treatment. The most common adverse events were of gastrointestinal origin. Other adverse events were comparable between the liraglutide and placebo groups. Liraglutide was well tolerated in healthy Chinese subjects. No major safety concerns were identified.

Pharmacokinetics, safety and tolerability of single and multiple oral doses of aliskiren in healthy Chinese subjects: a randomized, single-blind, parallel-group, placebo-controlled study.

BACKGROUND: Aliskiren is the first oral direct renin inhibitor to be approved for the treatment of hypertension. The pharmacokinetic and pharmacodynamic profile of aliskiren has been extensively characterized in Caucasian individuals; however, drug disposition, treatment response and tolerability can vary among ethnic groups, and these variations are difficult to predict. OBJECTIVE: To evaluate the single- and multiple-dose pharmacokinetics of aliskiren in healthy Chinese subjects. METHODS: This was a randomized, single-blind, parallel-group, placebo-controlled study. On day -1, subjects were randomized to one of four cohorts (aliskiren 75, 150, 300 or 600 mg). On day 1, eight individuals in each cohort received a single dose of active treatment and two received placebo. Subjects randomized to aliskiren 300 mg received additional once-daily doses on days 5-11 to establish steady-state pharmacokinetics. Subjects receiving aliskiren 75, 150 or 600 mg (cohorts 1, 2 and 4) completed the study at the end of the 96-hour pharmacokinetic assessment period. Subjects receiving aliskiren 300 mg (cohort 3) had additional pharmacokinetic assessments on days 5-15. The study was carried out at the Peking Union Medical College Hospital, Beijing, China, and included 40 healthy Chinese subjects. The main outcome measures were the pharmacokinetic parameters for aliskiren, including area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). RESULTS: Aliskiren AUC(infinity) and C(max) increased greater than proportionally across the 8-fold dose range (75-600 mg; mean AUC(infinity) 291-4726 ng x h/mL, mean C(max) 62-699 ng/mL), but a dose-proportional 2-fold increase was observed within the clinically approved dose range (150-300 mg; mean AUC(infinity) 876-1507 ng x h/mL, mean C(max) 137-271 ng/mL). CONCLUSION: At steady state, the mean AUC during the dosage interval (AUC(tau)) for aliskiren 300 mg (1532 +/- 592 ng x h/mL) was similar to the AUC(infinity) observed following a single dose. Aliskiren exhibits similar single-dose and steady-state pharmacokinetics in Chinese subjects compared with those observed in Caucasian individuals in previous studies.

Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban - an oral, direct factor Xa inhibitor - in elderly Chinese subjects.

Rivaroxaban is a novel, oral, direct factor Xa (FXa) inhibitor for the prevention and treatment of thromboembolic disorders. The aim of this study was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy, elderly Chinese subjects. In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 79 subjects, aged 59-74years (mean 62.8), were randomised to receive once-daily oral doses of rivaroxaban 5, 10, 20, 30 or 40mg. Rivaroxaban was well tolerated: there was a low incidence of treatment-emergent adverse events and all events were of mild intensity. Rivaroxaban was absorbed rapidly, reaching maximum plasma concentrations within 2-4hours. The PK of rivaroxaban were dose dependent over the dose range tested. Maximal inhibition of FXa occurred 2-3hours after dosing and returned to baseline after 24-48hours, reflecting rivaroxaban plasma concentrations. Inhibition of FXa was associated with dose-dependent effects on global clotting tests. There were no clinically relevant differences in rivaroxaban plasma concentrations between male and female subjects. In conclusion, rivaroxaban was well tolerated and was found to have predictable PK and PD in healthy, elderly Chinese subjects.