An improved method for the preparation of Ginsenoside Rg5 from ginseng fibrous root powder.

Ginsenoside-Rg5, which is derived from high temperature-processed ginseng, exhibits beneficial health effects. In the present study, ginsenoside-Rg5 was directly and rapidly prepared through the extraction of ginseng fibrous root powder (GFRP) at atmospheric pressure. The results showed that the highest extraction yield (3.79%) was obtained under optimal conditions (extraction temperature of 85 °C, acid concentration of 0.06 mol/L, sample to solvent ratio of 1:55 g/mL and ethanol concentration of 95% after 4 h). The current method integrates the extraction of original saponins and the modification of the saponins to rare ginsenosides Rg5, which was more simpler operation, more milder preparation condition and more efficient.

Proteomics analysis reveals a potential new target protein for the lipid-lowering effect of Berberine8998.

Berberine8998 is a newly synthesized berberine derivative with better lipid-lowering activity and improved absorption. The objective of this study was to investigate the effects of berberine8998 on serum cholesterol and lipid levels in vivo and to examine the mechanisms involved. Hamsters on high-fat diet (HFD) were administered berberine or berberine8998 (50 mg·kg-1·d-1, ig) for 3 weeks. Berberine8998 administration significantly lowered the total cholesterol, triglycerides and LDL-C levels in HFD hamsters. Bioinformatics revealed that berberine and berberine8998 shared similar metabolic pathways and fatty acid metabolism was the predominant pathway. Western blot validation results showed that peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and long-chain fatty acid-CoA ligase 1 (ACSL1), two proteins involved in fatty acid metabolism, were expressed differently in the berberine8998 group than in the untreated group and the berberine treatment group. Biochemistry results showed that berberine8998 significantly lowered the non-esterified fatty acid (NEFA) levels, which may lead to a reduction in TG levels in the berberine8998 treatment group and the differences observed in proteomics analyses. Pharmacokinetic analysis conducted in rats. After administration of berberine or berberine8998 (50 mg/kg, ig), berberine8998 exhibited a remarkably improved absorption with increasing bioavailability by 6.7 times compared with berberine. These findings suggest that berberine8998 lowers cholesterol and lipid levels via different mechanisms than berberine, and its improved absorption makes it a promising therapeutic candidate for the treatment of hypercholesterolemia and obesity.

Oral Bioavailability and Mass Balance Studies of a Novel Anti-arrhythmic Agent Sulcardine Sulfate in Sprague-Dawley Rats and Beagle Dogs.

BACKGROUND AND OBJECTIVES: Sulcardine sulfate is a newly developed candidate drug used to control arrhythmias. The aim of this research was to investigate the pharmacokinetics, bioavailability and excretion characteristics of sulcardine in animals. METHODS: Sprague-Dawley rats were orally and intravenously given sulcardine at 20 and 40 mg/kg. Beagle dogs were also orally and intravenously dosed at 10 mg/kg. Both [3H]-labeled sulcardine and unlabeled sulcardine were given to rats. Feces, urine and bile were collected at 0-72 h for mass balance study. The contents of unlabeled sulcardine and radioactivity in samples were determined by a validated LC-MS/MS method and by liquid scintillation counting, separately. RESULTS: Sulcardine was rapidly eliminated in rats after dosing. The oral bioavailability was 34-35 % in rats, while a higher exposure was observed in dogs (bioavailability = 62.7 %). More than 90 % of dosed sulcardine was recovered, and approximately 20-40 % of the dose excreted into urine as the original form, and the remaining was found in feces and bile, most of which (about 40 %) was transformed into metabolites. No difference was observed between sexes. Metabolism may occur to a large extent after oral administration in rats but to a smaller extent in dogs. CONCLUSIONS: Sulcardine was extensively absorbed in both rats and dogs after oral administration. The mass balance data indicated that sulcardine was widely metabolized in rats after oral administration.

Pharmacokinetics, safety, and tolerability of sulcardine sulfate: an open-label, single-dose, randomized study in healthy Chinese subjects.

Sulcardine sulfate (Sul) is a novel anti-arrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open-label, single-dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a seven-day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC-MS/MS method. Tolerability was determined by clinical evaluation and adverse event (AE) monitoring. Pharmacokinetic results demonstrated that Cmax and AUC(0-t) of Sul increased with an increasing dose. The mean t1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties.

Multiple Dose Pharmacokinetics and Safety of Sulcardine Sulfate in Healthy Chinese Male Subjects: An Open-Label Phase I Clinical Study.

BACKGROUND: Sulcardine sulfate is a novel antiarrhythmic agent with mechanism of action as a multi-ion channel blocker. Preclinical studies in animal models have demonstrated that sulcardine sulfate is efficacious in atrial and ventricular arrhythmias, and consequently, leads to the prevention of sudden cardiac death. OBJECTIVES: This study was conducted in healthy Chinese male subjects to investigate the pharmacokinetic profile and safety of sulcardine sulfate after repeated oral dose administration at 200, 400, and 800 mg for 5 days. METHODS: Thirty-three male subjects were enrolled in this study. In the multiple dose phase, sulcardine sulfate was administered orally twice at the interval of q12 h since day 3. Sulcardine sulfate plasma concentration was determined using a validated LC-MS/MS method. Safety was assessed using clinical evaluation and AE monitoring. RESULTS: In this repeated dose study, pharmacokinetic parameters (C max, AUC(0-t), and C ss_av) increased with the increase in dose (the dose ratio of the three cohorts was 1:2:4, while the ratio of C max and AUC(0-t) at day 1 was around 1:4:9 and 1:4:6, respectively), but in a non-linear fashion. The accumulation ratio at steady state (AR) of 200, 400, and 800 mg dose level was 1.18, 1.69, and 2.13, respectively, indicating that sulcardine sulfate has a modest accumulation upon repeated dose administration. Monitoring of pre-dose plasma concentrations on days 6, 7, and 8 for each dose level indicated that steady state was achieved at day 6 after three-day repeated dosing. CONCLUSIONS: Pharmacokinetic characteristics of sulcardine sulfate were shown to be non-linear, with the modest accumulation upon repeated dosing, and sulcardine sulfate was safe and well tolerated.

MiR-135a Suppresses Calcification in Senescent VSMCs by Regulating KLF4/STAT3 Pathway.

Cellular function phenotype is regulated by various microRNAs (miRs), including miR-135a. However, how miR-135a is involved in the calcification in senescent vascular smooth muscle cells (VSMCs) is not clear yet. In the present study, we first identified the significantly altered miRNAs in VSMCs, then performed consecutive passage culture of VSMCs and analyzed the expression of miR- 135a and calcification genes in the senescent phase. Next, the effects of the miR-135a inhibition on calcification and calcification genes were analyzed. The luciferase assay was used to validate the target protein of miR-135a. The western blotting was used to determine the effects of miR-135a on Krüppel-like factor 4 (KLF4) and signal transducer and activator of transcription 3 protein (STAT3) expression, as well as the relationship between KLF4 and STAT3. Finally, the quantified cellular calcification was measured to examine the involvement of miR-135a, KLF4 and STAT3 in VSMCs calcification. Our results showed that miR-135a was significantly altered in VSMCs. Cell calcification and calcification genes were greatly altered by miR-135a inhibition. KLF4 was validated as the target RNA of miR-135a. Expression of KLF4 and STAT3 were both significantly decreased by over expressed miR-135a, while the inhibition of miR-135a and KLF4 siRNA both decreased the STAT3 protein levels. Moreover, the inhibition of miR-135a dramatically increased the calcium concentration, but co-treatment with KLF4 or STAT3 siRNA both decreased the calcium concentration. The present study identified miR-135a as a potential osteogenic differentiation suppressor in senescent VSMCs and revealed that KLF4/STAT3 pathway, at least partially, was involved in the mechanism.

Effect of berberine on acetylcholine-induced atrial fibrillation in rabbit.

The purpose of this study was to test the efficacy of Berberine (Ber) on atrial fibrillation (AF) induced by acetylcholine (ACh) and explore its underlying mechanisms of action. In vivo electrophysiology experiments were performed in adult anesthetized rabbits. Single atrial myocytes were isolated from rabbit hearts and action potentials recorded using patch clamp techniques. AF was induced by rapid atrial burst pacing during intravenous (IV) ACh infusion alone or with IV Ber. Compared to the Baseline, IV Ber (2 mg/kg) prolonged the RR interval and effective refractory period (195 ± 10 vs. 215 ± 11 msec; 80 ± 4 vs. 85 ± 5 msec, respectively; both P<0.05). The induced rate of sustained 1 min AF was lower during ACh infusion with Ber than during ACh infusion alone (4/10 vs. 30/35, P<0.01). The termination rate of ACh-induced AF was higher with IV Ber (1 mg/kg) than with IV saline (sustained 1 min AF: 6/8 vs. 6/20, sustained 10 min AF: 8/10 vs. 1/6, both P<0.05). ACh perfusion significantly shortened the action potential duration (APD) of isolated atrial myocytes (APD50: 152 ± 13 vs. 81 ± 10 msec; APD90: 256 ± 19 vs. 132 ± 13 msec, both P<0.01). Application of Ber reversed the APD shortening induced by ACh (APD50: 81 ± 10 vs. 134 ± 15 msec; APD90: 132 ± 13 vs: 213 ± 17 msec, both P<0.01). We conclude that Ber suppresses ACh-induced AF in the rabbit by increasing atrial effective refractory period and prolonging the APD of atrial myocytes.

[Assessment of overall function after percutaneous coronary intervention by cardiopulmonary exercise testing in patients with stable coronary heart disease].

UNLABELLED: Objective: In order to assess the integrative cardiopulmonary function after percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD), we used symptom limited maximum cardiopulmonary exercise testing (CPET). METHODS: All 59 patients diagnosed stable CAD by coronary angiography and echocardiography from August to December of 2014 in our hospital, were divided two groups. PCI group, 31 patients received PCI and drugs. Control group, 28 patients received drugs therapy only. All patients performed CPET before and after the treatment. RESULTS: All patients safely completed CPET without any complications. The control group, all functional parameters were unchanged (P > 0.05). PCI group, the anaerobic threshold, peak oxygen uptake and peak oxygen pulse increased significantly (P < 0.05) from baseline,but not for others (P > 0.05). For individual analysis, PCI group had higher rates of increase (≥ 10% of baseline) in both peak oxygen uptake and peak oxygen pulse than those of control group (P < 0.05). CONCLUSION: CPET is an objective, quantitative, safe and effective method to evaluate the clinical therapeutic efficiency. PCI can improve the integrative cardiopulmonary function in CAD patients.