Weihua Dong

Identification of factors influencing the pharmacokinetics of voriconazole and the optimization of dosage regimens based on Monte Carlo simulation in patients with invasive fungal infections

OBJECTIVES The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs). METHODS To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole. RESULTS The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily. CONCLUSIONS This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations.

Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces

Aim:To study the metabolic and pharmacokinetic profile of scutellarin, an active component from the medical plant Erigeron breviscapus (Vant) Hand-Mazz, and to investigate the mechanisms underlying the low bioavailability of scutellarin though oral or intravenous administration in rats.Methods:HPLC method was developed for simultaneous detection of scutellarin and scutellarein (the aglycone of scutellarin) in rat plasma, urine and feces. The in vitro metabolic stability study was carried out in rat liver microsomes from different genders.Results:After a single oral dose of scutellarin (400 mg/kg), the plasma concentrations of scutellarin and scutellarein in female rats were significantly higher than in male ones. Between the female and male rats, significant differences in AUC, tmax2 and Cmax2 for scutellarin were found. The pharmacokinetic parameters of scutellarin in the urine also showed significant gender differences. After a single oral dose of scutellarin (400 mg/kg), the total percentage excretion of scutellarein in male and female rats was 16.5% and 8.61%, respectively. The total percentage excretion of scutellarin and scutellarein in the feces was higher with oral administration than with intravenous administration. The in vitro t1/2 and CLint value for scutellarin in male rats was significantly higher than that in female rats.Conclusion:The results suggest that a large amount of ingested scutellarin was metabolized into scutellarein in the gastrointestinal tract and then excreted with the feces, leading to the extremely low oral bioavailability of scutellarin. The gender differences of pharmacokinetic parameters of scutellarin and scutellarein are due to the higher CLint and lower absorption in male rats.

Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway

Breast cancer is one of the most prevalent types of malignant tumor. Paclitaxel is widely used in the treatment of breast cancer; however, the major problem contributing to the failure of chemotherapy in breast cancer is the development of drug resistance. Therefore, it is necessary to identify novel therapeutic targets and reversal agents for breast cancer. In the present study, the protein expression levels of SET, protein phosphatase 2A (PP2A) and phosphatidylinositol 3-kinase (PI3K)/Akt pathway were determined in MCF-7/PTX human breast carcinoma paclitaxel-resistant cells using western blot analysis. Small interference RNAs (siRNAs) were used to knock down the gene expression of SET in MCF-7/PTX cells and the cell viability was assessed following treatment with paclitaxel, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and flow cytometry. In addition, western blot analysis was used to determined PI3K/Akt pathway activity following SET knockdown. Furthermore, the reversal effects of paeonol on paclitaxel, and its underlying mechanisms of action, were investigated using western blot analysis and reverse transcription-quantitative polymerase chain reaction. The results demonstrated that increased levels of SET and PI3K/Akt pathway proteins were present in the MCF-7/PTX cells, compared with normal MCF-7 cells. Knockdown of SET significantly sensitized MCF-7/PTX cells to paclitaxel and induced cell apoptosis. In addition, the expression levels of the adenosine triphosphate binding cassette (ABC) transporter proteins were significantly reduced in the MCF-7/PTX cells compared with the normal MCF-7 cells. SET-induced paclitaxel resistance was found to be associated with the activation of the PI3K/Akt pathway. Paeonol significantly reduced the mRNA and protein expression levels of SET in the MCF-7/PTX cells. Furthermore, paeonol significantly sensitized the MCF-7/PTX to paclitaxel via regulation of ABC transporters, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein. In addition, paeonol inhibited SET-mediated paclitaxel resistance by attenuating PI3K/Akt pathway activity in the MCF-7/PTX cells. In conclusion, the results of the present study demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells, and that paeonol reversed paclitaxel resistance in MCF-7/PTX cells by downregulating the activity of the SET/PP2A/Akt pathway.

An assessment of teicoplanin use and monitoring serum levels in a Chinese teaching hospital.

OBJECTIVE To validate a high performance liquid chromatography (HPLC) method for serum teicoplanin measurement and use the method for clinical monitoring of teicoplanin levels to analyze the clinical application of teicoplanin. METHODS 55 patient profiles were collected and analyzed for the clinical teicoplanin application. 10 critically ill patients of the 55 cases were monitored for teicoplanin trough concentration using the HPLC method. RESULTS The modified HPLC method exhibited excellent linearity, with correlation coefficient r = 0.9995. The intra-day and inter-day coefficients of variation were less than 10%. The lower limit of detection of teicoplanin was 5.63 mg/l. The recovery of teicoplanin was above 90%. Of the 55 patients in this study, there were 42 patients without load-dosing. There were only 29 patients treated with teicoplanin documented Gram-positive infections by etiological diagnoses. In the 10 patients with teicoplanin serum trough concentration monitoring, all cases received a loading dose of 400 mg every 12 h for 3 doses, and the mean trough concentration of teicoplanin was 10.82 ± 4.51 mg/l. The mean trough levels were 13.04 ± 6.23 mg/l in 4 patients with microbiological eradication and improvement of symptoms of diseases and 9.34 ± 2.61 mg/l in 6 patients with persistence of previous clinical infectious symptoms, respectively. CONCLUSION The modified HPLC method is robust, highly reproducible and suited to monitor the concentration of teicoplanin. In critically ill Chinese patients, we should consider more appropriate loading doses and evaluate the relationship between teicoplanin trough concentration and the efficacy using microbiological and clinical parameters.

Association between reduced folate carrier G80A polymorphism and methotrexate toxicity in childhood acute lymphoblastic leukemia: a meta-analysis.

Abstract Methotrexate (MTX) is a key component of chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL), and enters the cell via active transport mediated by the reduced folate carrier (RFC1). A major single-nucleotide polymorphism of the RFC1 gene, G80A, which affects the activity of RFC1, may influence MTX toxicity in pediatric ALL. We collected all studies that investigated the association of RFC1 G80A polymorphism and MTX toxicity in pediatric ALL, and found inconsistency among their results. The aim of this meta-analysis was to summarize all of these studies in order to clarify the correlation between the RFC1 G80A polymorphism and MTX toxicity in pediatric ALL. A recessive model demonstrated no influence of the RFC1 G80A genotype on MTX toxicity. In conclusion, the RFC1 G80A polymorphism does not seem to be a good marker of MTX-related toxicity in pediatric ALL.

Meta-analysis of Comparison of the Newer P2Y12 Inhibitors (Oral Preparation or Intravenous) to Clopidogrel in Patients With Acute Coronary Syndrome

Aims: New P2Y12 adenosine diphosphate receptor antagonists have been used in the treatment of acute coronary syndrome (ACS) with different results. This systematic review analyzed and compared the evidence from large, clinical trials regarding the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of cardiovascular events in patients with ACS. Methods and Results: This analysis compared newer P2Y12 inhibitors with clopidogrel of 13 clinical trials involved a total of 87,985 patients with ACS. The newer P2Y12 inhibitors include cangrelor, prasugrel, and ticagrelor. Newer P2Y12 inhibitors significantly decreased the risk of myocardial infarction and showed a trend toward reduction of cardiovascular death (odds ratio [OR] = 0.86, 95% confidence interval [CI], 0.77–0.96, and I2 = 54%, P < 0.05); (OR = 0.85, 95% CI, 0.77–0.93, and I2 = 42%, P < 0.001). The rates of stroke events and the incidence in patients with ACS did not differ statistically between the clopidogrel group and the group with newer P2Y12 inhibitors (OR = 0.95, 95% CI, 0.79–1.14, and I2 = 0%, P = 0.57). However, newer P2Y12 inhibitors showed a significant increase in thrombosis in MI major or minor bleeding (OR = 1.21, 95% CI, 1.03–1.42, and I2 = 56%, P = 0.02) compared with clopidogrel. Conclusions: Based on this meta-analysis, newer P2Y12 inhibitors were significantly more effective than clopidogrel in the events of myocardial infarction and cardiovascular death in patients with ACS, although the incidence of thrombosis in MI-defined bleeding was higher compared with clopidogrel.

Choosing Optimal Antifungal Agents To Prevent Fungal Infections in Nonneutropenic Critically Ill Patients: Trial Sequential Analysis, Network Meta-analysis, and Pharmacoeconomic Analysis

ABSTRACT The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed and the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that compared untargeted antifungal treatments applied to nonneutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2,556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease the incidence of all-cause mortality (odds ratio [OR] = 0.89, 95% confidence interval [95%CI] = 0.70 to 1.14), but it did reduce the incidence of proven IFI (OR = 0.45, 95%CI = 0.29 to 0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR = 0.35, 95%CI = 0.19 to 0.65). Based on drug and hospital costs in China, the incremental cost-effectiveness ratios per life-year saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention corresponded to US

Risk Factors for Voriconazole-Associated Hepatotoxicity in Patients in the Intensive Care Unit

889, US

A sensitive liquid chromatography-tandem mass spectrometry method for monitoring the caspofungin trough plasma concentration and its association with caspofungin efficacy in intensive-care-unit patients

9,994, and US

Fluconazole versus mould-active triazoles for primary antifungal prophylaxis in adult patients with acute lymphoblastic leukemia: clinical outcome and cost-effectiveness analysis

10,351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in nonneutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Among the well-tolerated antifungals, fluconazole remains the only one that is effective for IFI prevention and significantly cheaper than echinocandins.