Safety of butylphthalide and edaravone in patients with ischemic stroke: a multicenter real-world study.

BACKGROUND: Butylphthalide (NBP) and edaravone (EDV) injection are common acute ischemic stroke medications in China, but there is a lack of large real-world safety studies on them. This study aimed to determine the incidence of adverse events, detect relevant safety signals, and assess the risk factors associated with these medications in real-world populations. METHODS: In this study, data of acute ischemic stroke patients were extracted from the electronic medical record database of six tertiary hospitals between January 2019 and August 2021. Baseline confounders were eliminated using propensity score matching. The drugs' safety was estimated by comparing the results of 24 laboratory tests standards on liver function, kidney function, lipid level, and coagulation function. The drugs' relative risk was estimated by logistic regression. A third group with patients who did not receive NBP or EDV was constructed as a reference. Prescription sequence symmetry analysis was used to evaluate the associations between adverse events and NBP and EDV, respectively. RESULTS: 81,292 patients were included in this study. After propensity score matching, the NBP, EDV, and third groups with 727 patients in each group. Among the 15 test items, the incidence of adverse events was lower in the NBP group than in the EDV group, and the differences were statistically significant. The multivariate logistic regression equation revealed that NBP injection was not a promoting factor for abnormal laboratory test results, whereas EDV had statistically significant effects on aspartate transaminase, low-density lipoprotein cholesterol and total cholesterol. Prescription sequence symmetry analysis showed that NBP had a weak correlation with abnormal platelet count. EDV had a positive signal associated with abnormal results in gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and platelet count. CONCLUSIONS: In a large real-world population, NBP has a lower incidence of adverse events and a better safety profile than EDV or other usual medications.

LPS-Induced Inflammation Affects Midazolam Clearance in Juvenile Mice in an Age-Dependent Manner.

PURPOSE: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis. METHODS: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2. RESULTS: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age. CONCLUSION: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.

Developmental Pharmacogenetics of CYP2D6 in Chinese Children: Loratadine as a Substrate Drug.

Objective: The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Methods: Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. Results: A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50-9.00) years and the mean weight was 19.64 (range 7.00-42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, p = 0.03). Weight was also found to be significantly associated with M/P ratio (p = 0.03). Conclusion: The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries.

CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Nifedipine in Chinese Renal Transplant Patients.

Purpose: The drug-drug interactions (DDIs) of tacrolimus greatly contributed to pharmacokinetic variability. Nifedipine, frequently prescribed for hypertension, is a competitive CYP3A5 inhibitor which can inhibit tacrolimus metabolism. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-nifedipine DDI in Chinese renal transplant patients. Method: All renal transplant patients were divided into CYP3A5*3/*3 homozygotes (group I) and CYP3A5*1 allele carriers (CYP3A5*1/*1 + CYP3A5*1/*3) (group II). Each group was subdivided into patients taking tacrolimus co-administered with nifedipine (CONF) and that administrated with tacrolimus alone (Controls). Tacrolimus trough concentrations (C0) were measured using high performance liquid chromatography. A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between CONF and Controls in group I and II, respectively. At the same time, a multivariate line regression analysis was made to evaluate the effect of variates on C0/D. Results: In this study, a significant DDI between tacrolimus and nifedipine with respect to the CYP3A5*3 polymorphism was confirmed. In group I (n = 43), the C0/D of CONF was significantly higher than in Controls [225.2 ± 66.3 vs. 155.1 ± 34.6 ng/ml/(mg/kg); p = 0.002]. However, this difference was not detected in group II (n = 27) (p = 0.216). The co-administrated nifedipine and CYP3A5*3/*3 homozygotes significantly increased tacrolimus concentrations in multivariate line regression analysis. Discussion: A CYP3A5 genotype-dependent DDI was found between tacrolimus and nifedipine. Therefore, personalized therapy accounting for CYP3A5 genotype detection as well as therapeutic drug monitoring are necessary for renal transplant patients when treating with tacrolimus and nifedipine.

Prediction of Unbound Ceftriaxone Concentration in Children: Simple Bioanalysis Method and Basic Mathematical Equation.

The pharmacological activity of ceftriaxone depends on the unbound concentration. However, direct measurement of unbound concentrations is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone concentrations in pediatric patients. Ninety-five pairs of concentrations (total and unbound) from 92 patients were measured by the bioanalysis method that we developed. The predictive performance of the three equations (empirical in vivo equation, disease-adapted equation, and multiple linear regression equation) was assessed by the mean absolute prediction error (MAPE), the mean prediction error (MPE), the proportions of the prediction error within ±30% (P30) and ±50% (P50), and linear regression of predicted versus actual unbound levels (R2). The average total and unbound ceftriaxone concentrations were 126.18 ± 81.46 µg/ml and 18.82 ± 21.75 µg/ml, and the unbound fraction varied greatly from 4.75% to 39.97%. The MPE, MAPE, P30, P50, and R2 of the empirical in vivo equation, disease equation, and multiple linear equation were 0.17 versus 0.00 versus 0.06, 0.24 versus 0.15 versus 0.27, 63.2% versus 89.5% versus 74.7%, 96.8% versus 97.9% versus 86.3%, and 0.8730 versus 0.9342 versus 0.9315, respectively. The disease-adapted equation showed the best predictive performance. We have developed and validated a bioanalysis method with one-step extraction pretreatment for the determination of total ceftriaxone concentrations, and a prediction equation of the unbound concentration is recommended. The proposed method can facilitate clinical practice and research on unbound ceftriaxone in children. (This study has been registered at ClinicalTrials.gov under identifier NCT03113344.).

First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

An adapted LC-MS/MS method for the determination of free plasma concentration of cefoperazone in children: Age-dependent protein binding.

Antimicrobial activity of cefoperazone, a high protein bound cephalosporin, depends on its unbound concentration. However, the protein binding data of cefoperazone in children is limited, making it challenging to optimize antimicrobial therapy in pediatric clinical practice. Furthermore, a validated method to measure the free part in children is unavailable with the small volume of samples that can be obtained. Therefore, in the present study, we developed and validated an LC-MS/MS method for the determination of free cefoperazone in children. In this study, 70 µL of plasma was used to prepare the ultrafiltrate (only containing the free drug). Chromatographic separation of the analyte was achieved on a C18 column using gradient elution with a mobile phase of acetonitrile and water (0.1% formic acid). Negative electrospray ionisation in the multiple reaction monitoring mode was applied for the detection of cefoperazone and ceftiofur (internal standard). The calibration curve was prepared in the range of 5-5000 ng/mL with excellent linearity. For each level of quality control samples, the intra- and inter-day precision (CV) was below 9.0%, and the accuracy ranged from 91.5% to 105.0%. The matrix effect was less than 11.7%, and the recovery was between 92.9% and 95.9% of cefoperazone. The validated method has been successfully applied to the determination of free plasma concentration of cefoperazone in pediatric patients. The results of the unbound fraction showed considerable individual variability (range: 8.1-48.0%). The correlation analysis showed that age and albumin had significant effects on the protein binding of cefoperazone.

Cefotiam Treatment in Children: Evidence of Subtherapeutic Levels.

BACKGROUND: Cefotiam, a second-generation cephalosporin, is a broad-spectrum antibiotic with good antibacterial action against both gram-negative and gram-positive bacteria. It is used widely in clinical practice, although bacterial drug resistance makes its clinical use problematic. The authors hypothesized that subtherapeutic concentrations of cefotiam leads to bacterial resistance. The present study was conducted to evaluate whether the standard cefotiam dosing regimen resulted in a subtherapeutic concentrations in children. METHOD: Data were prospectively collected from pediatric patients with suspected or confirmed community-acquired pneumonia who were receiving cefotiam at the standard dosing regimen (40-80 mg/kg, 2 or 3 times daily). A blood sample was collected after 70%-100% of the dosing interval, and plasma concentrations were determined by high-performance liquid chromatography using an ultraviolet detector. RESULTS: The data from 88 patients (age, 3.0 ± 2.8 years; weight, 15.4 ± 8.3 kg) were used for analysis. The average of cefotiam concentrations was 0.06 mcg/mL (range: <0.05-0.79 mcg/mL). Most patients (n = 72, 81.8%) had concentrations below 0.1 mcg/mL; only 2 patients had concentrations higher than 0.4 mcg/mL. CONCLUSIONS: The standard dosing regimen for cefotiam resulted in extremely low plasma concentrations in children; such low concentrations may lead to antimicrobial drug resistance. Thus, an increase in cefotiam dosage in children to 80 mg/kg 4 times daily is recommended (maximum dose on the label).

Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children.

OBJECTIVES: To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment. METHODS: A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). RESULTS: A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. CONCLUSIONS: For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

Off-label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics.

Glomerular diseases are leading causes of end-stage renal disease in children. Tacrolimus is frequently used off-label in the treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children are reviewed in this paper to provide evidence to support its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6-97.6%. In four clinical trials on children with lupus nephritis, the overall remission rate was 81.8-89.5%. In a pilot study with paediatric Henoch-Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin-C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow-up are needed to demonstrate definitely the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.

Efficacy and short-term side effects of sitagliptin, vildagliptin and saxagliptin in Chinese diabetes: a randomized clinical trial.

AIMS: To investigate the difference in the efficacy among dipeptidyl peptidase-4 (DPP-4) inhibitors in Chinese adults with newly diagnosed diabetes. MATERIALS AND METHODS: In a multicenter, randomized study, we enrolled adults who were either treatment naive or off prior anti-hyperglycemic therapy for at least 3 months. Eligible patients had hemoglobin A1c (HbA1c) concentrations of 6.5-9.5%. Three hundred patients had been randomly allocated to sitagliptin 100 mg, once daily; vildagliptin 50 mg, twice daily and saxagliptin 5 mg, once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 12. This study was completed and registered with ClinicalTrials.gov, number NCT01703637. RESULTS: Totally 277 patients were enrolled in the final analysis, and 93 patients received sitagliptin, 94 received vildagliptin and 90 received saxagliptin. Compared with baseline, adjusted mean differences in change from baseline HbA1c at week 12 were -0.50% (95% CI: -0.20 to -0.90), -0.65% (95% CI: -0.40 to -1.40), -0.70 (95% CI: -0.50 to -1.00) for sitagliptin, vildagliptin and saxagliptin group, respectively. The overall HbA1c-lowering effect was similar for all three selected DPP-4 inhibitors after adjustment for age and baseline HbA1c. Notably, in secondary outcome analysis, patients in vildagliptin group showed a significant decrease in total cholesterol levels, compared with participants in sitagliptin and saxagliptin groups. No significant between-group difference was shown in adverse events (AE). CONCLUSIONS: The overall HbA1c-lowering effect and incidence of AE were similar for sitagliptin, vildagliptin and saxagliptin in Chinese adults with newly diagnosed diabetes.

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

BACKGROUND: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. METHODS: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. RESULTS: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). CONCLUSION: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.

The efficacy and safety of pharmacologic thromboprophylaxis following caesarean section: A systematic review and meta-analysis.

OBJECTIVE: Our purpose is to evaluate the efficacy and safety of pharmacologic thromboprophylaxis following caesarean section (CS). METHODS: We searched PubMed, Embase, and the Cochrane Library. Then the systematic review was performed by analysing studies that met the eligibility criteria. RESULTS: Seven studies with 1243 participants were included, including 6 RCTs and 1 prospective cohort. Results from the meta-analysis showed that low molecular weight heparin (LMWH) was associated with no obvious decrease in the risk of thrombus compared with UHF and negative control. However, LMWH was observed to be associated with a definite increase in the risk of bleeding or haematomas in comparison to negative control (RR: 8.47, CI: 1.52-47.11). CONCLUSION: According to current evidences, the efficacy of pharmacologic thromboprophylaxis which increases the risk of bleeding or hematomas remains controversial.

Association between DPP4 gene polymorphism and serum lipid levels in Chinese type 2 diabetes individuals.

OBJECTIVE: The goal of the genetic investigation was to identify the associations of serum lipid levels and DPP-4 variants in Chinese type 2 diabetes patients. METHODS: We detected four variants of the DPP4 gene in 190 Chinese individuals with type 2 diabetes and tested for an association with dyslipidemia in 82 selected samples. Data including basic information, HbA1c, FPG, serum lipid parameters were collected. Statistical analysis was performed by SPSS 13.0 through ANOVA and χ2 test. RESULTS: The genetic polymorphism of rs4664443, rs3788979, rs7608798 and rs1558957 in Chinese type 2 diabetes were consistent with Hardy-Weinberg equilibrium. The CT genotype of rs4664443 suffered from higher serum TG (P=0.013), LDL (P=0.044) and ApoB (P=0.006) levels, whereas the TT genotype of rs7608798 exhibited a lower serum TG level (P=0.037). For rs3788979, the serum TG level (P=0.034) and BMI (P=0.04) were significantly different among genotypes. Moreover, serum TG and TC levels and BMI showed a positive correlation with the number unfavorable alleles, and individuals with more than two unfavorable alleles had higher TG (P=0.004), TC (P=0.011), and BMI (P=0.044) values. CONCLUSIONS: This is the first study to investigate DPP4 allelic distributions and their association with dyslipidemia in Chinese type 2 diabetes patients, which may have clinical significance.

Self-microemulsifying drug delivery system for improved oral bioavailability of oleanolic acid: design and evaluation.

Oleanolic acid is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) has been developed to enhance the solubility and oral bioavailability of oleanolic acid. The formulation design was optimized by solubility assay, compatibility tests, and pseudoternary phase diagrams. The morphology, droplet size distribution, zeta potential, viscosity, electrical conductivity, and refractive index of a SMEDDS loaded with oleanolic acid were studied in detail. Compared with oleanolic acid solution, the in vitro release of oleanolic acid from SMEDDS showed that the drug could be released in a sustained manner. A highly selective and sensitive high-performance liquid chromatographymass spectrometry method was developed for determination of oleanolic acid in rat plasma. This method was used for a pharmacokinetic study of an oleanolic acid-loaded SMEDDS compared with the conventional tablet in rats. Promisingly, a 5.07-fold increase in oral bioavailability of oleanolic acid was achieved for the SMEDDS compared with the marketed product in tablet form. Our studies illustrate the potential use of a SMEDDS for delivery of oleanolic acid via the oral route.

Statin therapy for the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials.

STUDY OBJECTIVES: To assess the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) for primary and secondary prevention of atrial fibrillation, and to evaluate the efficacy of individual statins and their dosages. DESIGN: Meta-analysis of 20 randomized controlled trials. PATIENTS: A total of 32,311 patients who received either a statin (16,203 patients) or a placebo or active control regimen (16,108 patients) for either primary or secondary prevention of atrial fibrillation as part of a research study. MEASUREMENTS AND MAIN RESULTS: A systemic literature search of MEDLINE, EMBASE, and the Cochrane Controlled Trials Register was performed to identify randomized controlled trials involving the prevention of atrial fibrillation with statin therapy. Effect size was expressed as odds ratio (OR) with 95% confidence interval (CI). Subgroup analysis was performed to explore the reasons for heterogeneity. Of the 20 trials, atorvastatin was studied in 11, pravastatin in five, rosuvastatin in three, and simvastatin in one. Overall, among the 32,311 patients in these trials, the risk of atrial fibrillation was significantly reduced by statins (OR 0.59, 95% CI 0.45-0.76), and the drugs were effective for both primary prevention (OR 0.67, 95% CI 0.51-0.88) and secondary prevention (OR 0.40, 95% CI 0.20-0.83). Secondary prevention was not superior to primary prevention, however. A significant benefit was observed in the atorvastatin-treated subgroup (OR 0.43, 95% CI 0.27-0.66), especially in the dose range of 10-40 mg/day (OR 0.29, 95% CI 0.19-0.45). No protective effect was observed in the pravastatin subgroup (OR 1.03, 95% CI 0.77-1.37). CONCLUSION: This meta-analysis suggests that statin therapy is useful for the prevention of atrial fibrillation. The benefit of statins in secondary prevention was significant but not superior to primary prevention. Atorvastatin was more effective than pravastatin, and its effects were dose related, with lower doses being more effective. The number of trials focusing on individual drugs is still insufficient, and more randomized controlled trials are necessary to further support these conclusions.

Effect of prostaglandin E1 on TNF-induced vascular inflammation in human umbilical vein endothelial cells.

Prostaglandin E1 (PGE1) is a member of the prostaglandins and has a variety of cardiovascular protective effects. Increasing attention has been paid to the anti-inflammation activity of PGE1, but little direct evidence has been found. We investigated the effects of PGE1 on cell adhesion and inflammation and the mechanisms responsible for this activity in tumor necrosis factor (TNF)-treated human umbilical vein endothelial cells. Results demonstrated that pretreatment with PGE1 decreased the adhesion between vascular endothelial cells and monocytes, reduced the expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin in vascular endothelial cells. In addition, PGE1 suppressed TNF-induced NF-kappaB activation and production of reactive oxygen species. We concluded that PGE1 suppressed the vascular inflammatory process, which might be closely related to the inhibition of reactive oxygen species and NF-kappaB activation in human umbilical vein endothelial cells.

In vitro interaction between azoles and cyclosporin A against clinical isolates of Candida albicans determined by the chequerboard method and time-kill curves.

OBJECTIVES: To investigate the in vitro interaction between three azoles (fluconazole, itraconazole and voriconazole) and cyclosporin A against five azole-susceptible (azole-S) and five azole-resistant (azole-R) clinical Candida albicans isolates. METHODS: By using a chequerboard technique and time-kill curves, synergistic, indifferent or antagonistic effects when drugs were used in combination were assessed. In the chequerboard assay, the antifungal activity of drug combinations was determined by the microdilution method based on the CLSI M27-A2 guidelines. The effects of the interactions were assessed by two non-parametric approaches (fractional inhibitory concentration index model and deltaE model). In the time-kill assay, a colony counting method was employed against one azole-S strain and one azole-R strain at 0, 6, 12, 24 and 48 h of incubation at 35 degrees C. RESULTS: Good concordance was found between the chequerboard method and time-kill curves. Indifference or synergism was observed for azole-S isolates in interactions of azoles and cyclosporin A, while strong synergism was observed for azole-R isolates in all drug combinations. CONCLUSIONS: Cyclosporin A showed potent synergism when combined with the three azoles, especially against azole-R C. albicans strains, and there was good agreement between various methods used in this study.

[The absorption kinetics of oleanolic acid self-microemulsion in rat stomach and intestine].

OBJECTIVE: To study the absorption kinetics of oleanolic acid self-microemulsion in rat stomach and intestine. METHODS: The absorption kinetics were obtained by using the in situ perfusion method in rat. The absorption of drug was determinated by the decrease in stomach and intestine with the HPLC as the detection method. RESULTS: The absorption percent of oleanolic acid microemulsion for 2 hours was 10.15% in stomach; The absorption rate constants of oleanolic acid microemulsion and micelle were 0.0901/h and 0.0486/h in small intestine, respectively; The best absorption segment in intestine was duodenum, ileum, jejunum and colon by turns. CONCLUSION: The oleanolic acid self-microemulsifying system significantly enhances the absorption of oleanolic acid in the gastrointestinal tract and improves its bioavailability.

Study on warfarin plasma concentration and its correlation with international normalized ratio.

A sensitive high-performance liquid chromatographic (HPLC) method was developed for warfarin determination in plasma of patients who undertook cardiac valve replacement and were on anticoagulation with warfarin. The method described proved to be accurate, sensitive, easy to perform, reproducible and specific for plasma warfarin measurement with relative standard deviation (R.S.D.) of <5.27% for inter-day and <6.89% for intra-day. The assay was linear in warfarin concentration ranges of 0.12-3 microg/ml (r=0.9995) with mean recovery of 94.6%. The mean warfarin plasma concentration of 58 patients with heart valve replacement within 1 month of post operation was 567.6+/-122.3 ng/ml. The anticoagulant effect of the drug was monitored by international normalized ratio (INR). The correlation of warfarin dosage and concentration with INR was analysed, and the coefficients were 0.21, 0.1