Analyzing the correlation between quinolone-resistant Escherichia coli resistance rates and climate factors: A comprehensive analysis across 31 Chinese provinces.

BACKGROUND: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue. METHODS: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis. RESULT: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences. CONCLUSION: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance.

Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice.

At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study.

AIMS: Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction. METHODS: The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL-1: TBIL < 51 µmol/L; TBIL-2: 51 µmol/L ≤ TBIL < 171 µmol/L; TBIL-3: TBIL ≥ 171 µmol/L) were performed. RESULTS: Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL-1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL-2 and TBIL-3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively. CONCLUSIONS: Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

Population Pharmacokinetics and Dosage Optimization of Linezolid in Patients with Liver Dysfunction.

Linezolid is the first synthetic oxazolidone agent to treat infections caused by Gram-positive pathogens. Infected patients with liver dysfunction (LD) are more likely to suffer from adverse reactions, such as thrombocytopenia, when standard-dose linezolid is used than patients with LD who did not use linezolid. Currently, pharmacokinetics data of linezolid in patients with LD are limited. This study aimed to characterize pharmacokinetics parameters of linezolid in patients with LD, identify the factors influencing the pharmacokinetics, and propose an optimal dosage regimen. We conducted a prospective study and established a population pharmacokinetics model with the Phoenix NLME software. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. A total of 163 concentration samples from 45 patients with LD were adequately described by a one-compartment model with first-order elimination along with prothrombin activity (PTA) and creatinine clearance as significant covariates. Linezolid clearance (CL) was 2.68 liters/h (95% confidence interval [CI], 2.34 to 3.03 liters/h); the volume of distribution (V) was 58.34 liters (95% CI, 48.00 to 68.68 liters). Model-based simulation indicated that the conventional dose was at risk for overexposure in patients with LD or severe renal dysfunction; reduced dosage (300 mg/12 h) would be appropriate to achieve safe (minimum steady-state concentration [Cmin,ss] at 2 to 8 µg/ml) and effective targets (the ratio of area under the concentration-time curve from 0 to 24 h [AUC0-24] at steady state to MIC, 80 to 100). In addition, for patients with severe LD (PTA, ≤20%), the dosage (400 mg/24 h) was sufficient at an MIC of ≤2 µg/ml. This study recommended therapeutic drug monitoring for patients with LD. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900022118.).

Development and validation of a more accurate estimating equation for glomerular filtration rate in a Chinese population.

Previously published equations to estimate glomerular filtration rate (GFR) have limited accuracy in Asian populations. We aimed to develop and validate a more accurate equation for estimated GFR (eGFR) in the Chinese population, using data from 8571 adults who were referred for direct measurement of GFR by renal dynamic imaging (mGFR) at 3 representative hospitals in China. Patients from the Third Xiangya Hospital were included in our development (n=1730) and internal validation sets (n=1042) and patients from the other hospitals comprised the external validation set (n=5799). We excluded patients who were prescribed medications known to influence the tubular secretion of creatinine, patients on dialysis, kidney transplant recipients, and patients with missing creatinine values or with creatinine >700 µmol/l. We derived a novel eGFR equation by linear regression analysis and compared the performance to 12 creatinine-based eGFR equations, including previously published equations for use in Chinese or Asian populations. In the development and internal validation sets, the novel Xiangya equation had high accuracy (accuracy within 30% [P30], 79.21% and 84.33%, respectively), low bias (mean difference between mGFR and eGFR, -1.97 and -1.85 ml/min per 1.73 m2, respectively), and high precision (interquartile range of the differences, 21.13 and 18.88 ml/min per 1.73 m2, respectively). In external validation, the Xiangya equation had the highest P30 among all eGFR equations, with P30 ≤ 75% for the other 12 equations. This novel equation provides more accurate GFR estimates in Chinese adults and could replace existing eGFR equations for use in the Chinese population.

Combined Treatment with Triptolide and Tyrosine Kinase Inhibitors Synergistically Enhances Apoptosis in Non-small Cell Lung Cancer H1975 Cells but Not H1299 Cells through EGFR/Akt Pathway.

Lung cancer is one of the most common malignant cancers in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a second- or third-line therapy for mutated non-small cell lung cancer (NSCLC). It usually becomes drug resistance after a period of treatment. Triptolide (TPL) is an epoxy diterpenoid lactone compound extracted from Tripterygium wilfordii HOOK. F. and many studies demonstrated that TPL has a synergistic effect when combined with chemotherapy drugs. In this research, we plan to evaluate the combined effect of TPL and EGFR-TKIs (Gefitinib, Erlotinib, and Icotinib) and investigate the possible mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to detect the cell viabilities, combined effect was evaluated by Combination Index. Molecular docking study was used to predict the binding ability of TPL. The expression of proteins was detected by Western blot. MTT results showed TPL had synergistic effect with three EGFR-TKIs at different concentrations on H1975 cells but not on H1299 cells. Molecular docking study demonstrated that TPL with T790M/L858R EGFR can form a more stable compound than that with wild type EGFR. Western blot results showed TPL inhibited the EGFR/Akt pathway and increased the expression of Bax and the ratio of Bax and Bcl-2 in H1975 cells. In conclusion, TPL had synergistic effect with three EGFR-TKIs on H1975 cells but not on H1299 cells, which may be due to the binding ability of TPL and different-type EGFR. The synergistic effect of TPL on H1975 cells may be partly related to the inhibition of the EGFR/Akt pathway.

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Simple and rapid UPLC-MS/MS method for quantification of entecavir in human plasma: Application to a bioequivalence study
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A simple and fast ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated to determine entecavir in human plasma with the stable isotopically labeled internal standard entecavir-13C215N. Samples (100 µL each) were pretreated by protein precipitation with methanol, and then separated on an ACQUITY UPLC BEH C18 analytical column (2.1 × 50 mm, 1.7 µm) with a simple isocratic elution. The detection was operated by a positive ionization electrospray mass spectrometry in multiple reaction monitoring mode. The method had a short chromatographic run time of 2 minutes, and obtained sharp peaks of entecavir and the internal standard. Good linearity was found within 0.1 - 20 ng/mL. The intra- and inter-day precision and accuracy met the acceptance criteria, and no matrix effect was observed. This method was successfully applied in a bioequivalence study of two kinds of entecavir tablets in healthy Chinese volunteers. And the results showed that no significant differences were found between the test and reference preparations in pharmacokinetic parameters (p > 0.05) by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ fell within the bioequivalence acceptance criteria (80 - 125%). No significant difference was found in tmax between the two preparations. The two one-sided t-tests showed that these two products were bioequivalent.
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Aberrant histone modifications of global histone and MCP-1 promoter in CD14+ monocytes from patients with coronary artery disease.

OBJECTIVES: To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease (CAD) and demonstrate the potential mechanisms. METHODS: CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme-linked immunosorbent assay. Quantitative real time-PCR was performed to detect the mRNA expression levels of MCP-1 and enzymes involved in histone modification processes. Histone modification levels in MCP-1 promoter were assessed by ChIP-qPCR assay. RESULTS: Our results showed a markedly lower global histone H3 acetylation level in monocytes from CAD patients. Global H3K27 tri-methylation level was significantly increased in monocytes from CAD patients. Furthermore, the mRNA expression levels of epigenetic modification enzymes HDAC3, SIRT1, P300, JMJD3 and SUV39H1 were decreased significantly in monocytes from CAD patients, while HDAC7 mRNA expression level was markedly increased. MCP-1 mRNA expression level was increased histone H3/H4 acetylation levels in MCP-1 promoter were markedly increased in monocytes of CAD patients. CONCLUSION: Aberrant histone modifications, including acetylation and tri-methylation, were found both in global histone and specific MCP-1 gene locos in monocytes from patients with CAD. Aberrant epigenetic modification enzymes expressions may be the regulatory mechanism responsible for aberrant histone modifications.

Impact of CYP2C19 Genotype and Liver Function on Voriconazole Pharmacokinetics in Renal Transplant Recipients.

BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine. METHODS: A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype. RESULTS: A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(-0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers. CONCLUSIONS: Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.

Quantitative analysis of valsartan by two-dimensional liquid chromatography (2D-HPLC) and its application in a bioequivalence study in Chinese volunteers
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PURPOSE: To develop a sensitive, two-dimensional liquid chromatography (2D-LC) method for determination of valsartan, applied to investigate bioequivalence of two valsartan tablets in Chinese volunteers under fasting condition. METHODS: A full automatic 2D-HPLC system was used to quantify valsartan in human plasma. The analytes were extracted by protein precipitation, using telmisartan as internal standard. The analytical method was applied in a randomized, crossover bioequivalence study of valsartan tablets; the study enrolled 18 Chinese volunteers (12 were men and 6 were women). The subjects received a single 160-mg dose of test or reference preparation with 7-days of washout under fasting state. Plasma samples were collected, pharmacokinetic parameters were obtained and the bioequivalence was evaluated. RESULTS: The calibration range was 9.2 - 4213.8 ng×mL-1. Inter- and intraprecision was less than 7.0%, and accuracies ranged from 99.5 to 103.8%. The extraction recovery for valsartan varied between 89.3 and 97.8%, and the stability in all conditions was excellent. The 90% CI of AUC0→36h and Cmax were 96.5 - 109.4% and 94.2 - 108.6%, respectively. The relative bioavailability was 103.9 ± 15.7%. No gender difference was observed in pharmacokinetic parameters. CONCLUSIONS: A sensitive 2D-HPLC method was established for the estimation of valsartan in human plasma and successfully applied in a bioequivalence study of valsartan, which suggests that these two formulations can be assumed to be bioequivalent.
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Pharmacokinetics and relative bioavailability of a generic amisulpride tablet in healthy Chinese volunteers
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OBJECTIVE: To assess and compare the pharmacokinetic properties and bioavailability of a newly developed formulation of amisulpride with those of a conventional formulation in healthy Chinese volunteers under fasting state. MATERIALS AND METHODS: A single-dose, two-sequence crossover study was designed. 20 healthy subjects (14 males and 6 females) were randomized into two groups. A single oral dose of amisulpride (200 mg) was given after an overnight fast of 12 hours. Blood samples were taken at scheduled time spots and separated by a washout period of 14 days. Plasma concentration of amisulpride was measured by high-performance liquid chromatography-fluorescence detector (HPLC-FLD) method. RESULTS: The pharmacokinetic parameters of AUC0-tlast, AUC0-∞, and Cmax for the 20 subjects after a single oral dose of the trial preparation or the reference preparation were 4,767.2 and 4,856.3 ng×h×mL-1; 4,891.7 and 5,043.2 ng×h×mL-1; 584.7 and 586.3 ng×mL-1, respectively. The relative bioavailability was 98.9 ± 14.5%. No significant difference was found among the main pharmacokinetic parameters in the two preparations by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax and AUC0-tlast were 90.7 - 109.1% and 92.5 - 103.6%, respectively, meeting the predetermined criteria (80 - 125%) for bioequivalence. No serious adverse events were reported. CONCLUSION: The study demonstrated that the two preparations met the regulatory criteria for bioequivalence and both formulations were well tolerated.
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Pharmacokinetics and relative bioavailability of two allopurinol tablets in healthy Chinese volunteers
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OBJECTIVE: To evaluate the pharmacokinetics and relative bioavailability of two allopurinol tablets in healthy Chinese volunteers. METHODS: A single-center, randomized, cross-over, two-period study design was conducted in healthy male subjects who were identified as not carrying the HLA-B*58:01 allele. Under fasting conditions, a single oral dose of 300 mg test or reference tablets was given with a 1-week washout period. The blood samples were collected for up to 12 hours after the administration and the plasma concentrations of allopurinol were determined by high performance liquid chromatography. Subject interviews and physical examinations were done over regular intervals to monitor the adverse events. RESULTS: 18 subjects were enrolled in the study, and none dropped out. The main pharmacokinetic parameters of allopurinol test and reference preparations were as follows: AUC0-tlast was 6,725.1 ± 1,390.0 ng×h×mL-1 and 6,425.6 ± 1,257.6 ng×h×mL-1; AUC0-∞ was 7,069.1 ± 1,503.2 ng×h×mL-1 and 6,750.6 ± 1,347.7 ng×h×mL-1; tmax was 1.3 ± 0.8 hours and 1.3 ± 0.8 hours; Cmax was 2,203.7 ± 557.4 ng×mL-1 and 2,310.8 ± 662.8 ng×mL-1; and T1/2 was 2.0 ± 1.6 hours and 1.7 ± 0.7 hours. The relative bioavailability was 105.1 ± 12.6%. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ of both preparations fell within the bioequivalence acceptance criteria (80 - 125%). No adverse events were found or reported during the study. CONCLUSION: The test allopurinol preparations and the reference preparations are bioequivalent and both are well tolerated.
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Bioequivalence and food effect study of enteric-coated mesalazine tablets in healthy Chinese volunteers by HPLC-ESI-MS/MS.

OBJECTIVE: To establish a developed HPLC-ESI-MS/MS method for simultaneous determination of mesalazine (5-ASA) and its major metabolite N-Ac-5-ASA in human plasma and to investigate bioequivalence of two enteric-coated mesalazine tablets as well as the effect of high-fat food on the pharmacokinetics of 5-ASA and N-Ac-5-ASA. METHODS: In this open-label, randomized, crossover, two-states, four-period study, 20 healthy Chinese volunteers were randomized to receive a single oral dose of trial or reference preparation (2 × 250 mg) under fasting and fed state. Plasma samples were obtained at 0, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 24, and 36 hours postdose and were measured by a developed HPLC-ESI-MS/MS method. Safety and tolerability were assessed throughout the study. RESULTS: The HPLC-ESI-MS/MS method required only 7.0 minutes run time and was successfully applied in analyzing ~ 2,000 samples. High-fat-food administration prolonged tmax of 5-ASA and N-Ac-5-ASA (p < 0.05), while AUC was not significantly affected by the meal (p > 0.05). The 90% confidence intervals (CIs) of the fed/fasting and trial/reference ratios of log-transformed Cmax and AUC were within 80-125%. The two one-sided t-tests showed that the trial and reference preparation were bioequivalent (p > 0.05). CONCLUSIONS: This developed HPLC-ESI-MS/MS method is suitable for massive biomedical analysis. Trial and reference preparations are bioequivalent under fasting and fed state. High-fat-food administration delays the absorption of mesalazine while total exposure is not affected. Dietary habits should always be taken into consideration when enteric-coated mesalazine tablets were prescribed to patients.

Pharmacokinetic properties and bioequivalence of spironolactone tablets in fasting and fed healthy Chinese male subjects.

BACKGROUND AND PURPOSE: Spironolactone is a potassium-sparing diuretic and is a competitive antagonist of aldosterone, which is widely used in the treatment of primary aldosteronism, essential hypertension, congestive cardiac failure, and various edematous states. The purpose of this study was to compare the pharmacokinetic properties and bioequivalence of the two formulations of spironolactone tablets in healthy Chinese male subjects under fasting and fed condition. METHODS: A total of 40 male subjects were enrolled in this randomized, open-label, two-period crossover study, subjects in 2 groups (20 individuals in each group) received a single 100-mg dose of test or reference spironolactone tablet formulations with a 2-week washout period under both fasting and fed condition. The plasma concentrations of canrenone, a major active metabolite of spironolactone, were quantified by a validated high performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic parameters including AUC0-tlast, AUC0-∞, tmax, and Cmax were employed to test bioequivalence. RESULTS: The relative bioavailability was 99.2 ± 11.6% and 97.6 ± 7.4% under fasting and fed condition, respectively. The 90% confidence intervals of the adjusted geometric mean ratio (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ were 89.7-113.8%, 93.9-103.3%, and 90.0-103.0% in fasting study and 87.7-102.3%, 95.1-99.5%, and 94.1-98.9% in fed study, respectively. CONCLUSIONS: Based on pharmacokinetic parameters and the Chinese Food and Drug Administration's guidance and regulatory criteria for bioequivalence, the test and reference formulations of spironolactone were bioequivalent under both fasting and fed condition. Both formulations were generally well tolerated, with no adverse reaction reported.

Isoliquiritigenin protects against triptolide-induced hepatotoxicity in mice through Nrf2 activation.

Isoliquiritigenin, a flavonoid found in licorice, has been considered as an antioxidive and hepato-protective agent. Recent studies have shown that a possible mechanism for triptolide-induced hepatotoxicity is related to oxidative damage induced by reactive oxygen species. This study was done to investigate the protection effect of isoliquiritigenin against triptolide-induced hepatotoxicity and the mechanism involved. An acute liver injury model was established by intraperitoneal injection of triptolide (1.0 mg · kg-1) in mice. Different doses of isoliquiritigenin (12.5, 25 and 50 mg · kg-1) were employed as protection. The activities of AST, ALT, ALP and LDH in serum and levels of GSH, GPx, SOD, CAT and MDA in liver tissue were detected. The histopathological changes of liver tissues were observed after HE staining. The protein expression of Nrf2 was detected by western blot. Pretreatment with isoliquiritigenin significantly prevented the triptolide-induced hepatotoxicity indicated by reduced activities of AST, ALT, ALP and LDH. Moreover, isoliquiritigenin pretreatment also prevented from triptolide-induced hepatotoxicity by inhibiting MDA and restoring the levels of GSH, GPx, SOD and CAT. In addition, isoliquiritigenin could attenuate histopathological changes induced by triptolide. Furthermore, the results indicated that isoliquiritigenin pretreatment caused an increase in the protein expression of Nrf2. These results indicated that isoliquiritigenin could protect against triptolide-induced hepatotoxicity via activation of the Nrf2 pathway.

[Advances in cardiovascular effects of tanshinone II(A)].

Cardiovascular diseases, like coronary heart disease and myocardial infarction, are the most common cause of death worldwide. Chinese medicines have demonstrated rich cardioprotective activities for clinical applications. Salvia miltiorrhiza, a very important component of traditional Chinese medicine, can promote blood circulation and relieve blood stasis. Salvia miltiorrhiza is widely used in treatment of cardiovascular and cerebrovascular disease such as coronary heart disease and cerebral infarction ( CI). Tanshinone II(A), the major lipophilic components extracted from the root of S. miltiorrhiza, possesses anti-atherosclerosis, anti-cardiac hypertrophy, anti-oxidant, anti-arrhythmia and so on. This paper discusses current research status of tanshinone II(A) in cardioprotective effects.

Progress on mechanism of Tripterygium wilfordii-induced liver injury and detoxification mechanism of licorice.

Tripterygium wilfordii has exihibited multiple pharmacological activities, such as anti-inflammatory, immune modulation, anti-tumor and anti-fertility. T. wilfordii have been used for the therapy of inflammation and autoimmune diseases including rheumatoid arthritis, immune complex nephritis and systemic lupus erythematosus clinically. However, it is well known that T. wilfordii has small margin between the therapeutic and toxic doses and could cause serious injury on digestive, reproductive and urogenital systems. Among all the organs, liver is one of the most remarkable targets of T. wilfordii-induced toxicities, and the damage is more serious than others. It is generally accepted that T. wilfordii-induced liver injury is a result of the combined effects of toxic elements of T. wilfordii. It is reported in several studies that the mechanism of T. wilfordii-induced liver injury may be related to lipid peroxidation, cell apoptosis and immune damage, and so on. Licorice is one of the most commonly used Chinese herbal medicine, with effects of heat- clearing and detoxicating, anti-inflammatory and hepatoprotective, reconciling various drugs, and so on. Licorice often accompany T. wilfordii in clinical application which can significantly reduce the liver injury induced by T. wilfordii. The attenuated effect is exact, but the mechanism is still a lack of in-depth study. This paper reviews the studies on T. wilfordii-induced liver injury and the related mechanism as well as licorice and other traditional Chinese medicine accompany T. wilfordii to reduce the injury in recent years, so as to provide reference for related research in the future.

Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) may be a biomarker for vascular function and cardiovascular risk in patients with coronary artery disease (CAD). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the function of EPCs. This study aimed to examine whether hypermethylation of DDAH2 promoter contributes to impaired function of EPCs in CAD patients. METHODS: Peripheral blood mono-nuclear cells from 25 CAD patients and 15 healthy volunteers were collected and differentiated into EPCs. EPCs were tested for their adhesive capability. DDAH2 mRNA expression was analyzed by real-time PCR, and the methylation of DDAH2 promoter was detected by bisulfite genomic sequencing. RESULTS: DDAH2 promoter in EPCs from CAD patients was hypermethylated and the methylation level was negatively correlated to DDAH2 mRNA level and adhesion function of EPCs. Homocysteine impaired the adhesion function of EPCs, accompanied by lower DDAH2 expression and higher methylation level of DDAH2 promoter, compared to controls. These effects of homocysteine were reversed by pretreatment with Aza, an inhibitor of DNA methyltransferase. CONCLUSION: Hypermethylation in DDAH2 promoter is positively correlated to the dysfunction of EPCs in CAD patients. Homocysteine disrupts EPCs function via inducing the hypermethylation of DDAH2 promoter, suggesting a key role of epigenetic mechanism in the progression of atherosclerosis.