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Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R 2 = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.

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.

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child–Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child–Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor &lt, 5), implying that CYP2C19 testing makes sense for precision medicine of Child–Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child–Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

Background: Meropenem is a carbapenem antibiotic that has demonstrated excellent in vitro activity against gram-negative clinical isolates and is commonly used in critically ill patients. This study aimed to find the pharmacokinetic/ pharmacodynamic of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. Method: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix.Results: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), volume of peripheral compartment (V2) were 6.15 L/h, 2.83 L/h, 17.40L, and 17.48L, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance of 60 ml/min or less and uric acid greater than 400 μmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/L, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC＜4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4MIC, no significant statistical difference was observed in critically ill patients.Conclusions: Critically ill patients with lower creatinine clearance and higher uric acid levels were likely to need a lower dosage of meropenem. Prolonged infusion time were not always beneficial for those who need a higher therapeutic target (100% fT > MIC,100% fT > 4 MIC) or with MIC 4mg/L. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients.Trial registration: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Background: Voriconazole is a triazole antifungal agent and a commonly used first-line treatment for invasive aspergillosis (IA). The study was performed to explore the factors affecting voriconazole trough concentration and maintenance dose to optimize voriconazole dosage in pediatric patients. Method: The demographic information, concentration data, CYP2C19 genotypes, and clinical outcomes of eligible pediatric patients from January 1th, 2016 to December 31th, 2018 were collected retrospective . Result: The study finally included 145 voriconazole trough concentrations from 94 pediatric patients. Steady trough concentration ranged from 0.04 to 16.11 μg/mL. Morerover, the distinction between the maximum and the minimum corrected concentration of per kilogram maintenance dosage is as high as 907 folds and children ≤2 years old showed the minimum variation compared to other individuals (P-1kg/12h, respectively had been required in order to achieve therapeutic level (PConclusion: Pediatric patients especially those ≤12 years old might need a higher dosage regime to achieve therapeutic trough concentration. Importantly, early and repeat monitoring of voriconazole is essential to ensure the effectiveness and safety of voriconazole in children.

Meropenem is a carbapenem antibiotic, which has demonstrated excellent antimicrobial activity against gram-negative clinical isolates. It is also commonly used in critically ill patients. This study aimed to determine the pharmacokinetics/pharmacodynamics of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix. A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), and volume of peripheral compartment (V2) were 6.15 l/h, 2.83 l/h, 17.40 l, and 17.48 l, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance ≤ 60 ml/min and uric acid > 400 μmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/l, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC MIC and 100% fT > 4 MIC, no significant statistical difference was observed in critically ill patients. Critically ill patients with lower creatinine clearance and higher uric acid levels tended to need a lower dosage of meropenem. Prolonged infusion time was not always beneficial for those who needed a higher therapeutic target (100% fT > MIC, 100% fT > 4 MIC) or with MIC > 4 mg/l. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients. The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019. Meropenem is commonly used empirically or targeted in critically ill patients for bacterial infection. Many studies have reported that prolonged infusion time can improve the efficacy of meropenem therapy. However, we are skeptical about that. Meanwhile, prolonged injections can sometimes cause mobility problems for patients. A quantitative method is used to evaluate meropenem use. It is called the population pharmacokinetic model or pharmacodynamic study. Using this method, we found two significant influencing factors of meropenem metabolism: creatinine clearance and uric acid level. It is likely that patients with a lower level of creatinine clearance and a high uric acid level tend to require lower dosages of meropenem. As for the effect of infusion time, Monte Carlo simulation was used, which can do 3000 simulations on an individual. The result was complex. We found infusion time was beneficial only when bacteria were sensitive to meropenem. The evidence suggests that prolonged injection duration sometimes does not significantly improve the outcome of antimicrobial therapy.

Background: Meropenem is a carbapenem antibiotic that has demonstrated excellent in vitro activity against gram-negative clinical isolates and is commonly used in critically ill patients. This study aimed to find the pharmacokinetic/ pharmacodynamic of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. Method: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix.Results: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), volume of peripheral compartment (V2) were 6.15 L/h, 2.83 L/h, 17.40L, and 17.48L, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance of 60 ml/min or less and uric acid greater than 400 μmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/L, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC＜4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4MIC, no significant statistical difference was observed in critically ill patients.Conclusions: Critically ill patients with lower creatinine clearance and higher uric acid levels were likely to need a lower dosage of meropenem. Prolonged infusion time were not always beneficial for those who need a higher therapeutic target (100% fT > MIC,100% fT > 4 MIC) or with MIC 4mg/L. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients.Trial registration: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Background Voriconazole (VRC) is a triazole anti-fungal agent and a first-line treatment for invasive fungal infection (IFI) generally. The purpose of our study was performed to explore the factors affecting voriconazole trough concentration (Ctrough) and to show VRC dose adjustment experience in children. Methods The demographic information, concentration data, CYP2C19 genotypes and clinical outcomes of eligible children from January 1th, 2016 to December 31th, 2018 were collected. Factors affecting the voriconazole trough concentration were statistically analyzed. Results A total of 145 trough concentrations in 94 patients were included in this study, 54.5% of which achieved the target concentrations; however, 35.9% and 9.6% of which were sub-therapeutic and super-therapeutic post-multiple dosing. For children ≤ 2, 2–6, 6–12, and 12–18 years, the median VRC maintenance doses of 5.7, 6.7, 5.0 and 3.3 mg/kg twice daily respectively had been required in order to achieve therapeutic level (P

Plant growth promoters produced by microorganisms can play a significant role in the induction of some important physiological responses in the growth and development of plants. In this study, we provided a first insight into revealing the diversity of cultivable yeasts associated with Nanfeng mandarin (Citrus reticulata cv. Blanco) in China. Their capability to produce indole-3-acetic acid (IAA) was analyzed. A total of 796 yeast strains were obtained by the enrichment isolation technique from citrus soil, citrus leaves, citrus peel and citrus pulp of Nanfeng mandarin samples. On the basis of the 26S rDNA partial sequence analysis, the strains were identified as 14 yeast species in 9 genera belonging to Hanseniaspora sp., Pichia sp., Candida sp., Sporidiobolus sp., Meyerozyma sp., Symmetrospora sp., Rhodotorula sp., Starmerella sp. and Aureobasidium sp. The most abundant species in citrus soil were Starmerella meliponinorum and Meyerozyma caribbica. The species prevailing in citrus peel was Hanseniaspora opuntiae. Citrus pulp was rich in Meyerozyma guilliermondii. Additionally, Aureobasidium pullulans and H. opuntiae were the dominant species in citrus leaves. All yeast species obtained were accessed for the capability to produce IAA: 26 strains in seven species showed the capability of producing IAA. Rhodotorula paludigena produced the highest IAA concentrations of 76.22 mg/L. Our study confirms the phylogenetic diversity of yeast associated with Nanfeng mandarin and highlights that these yeast strains are promising resources of microbial fertilizer.

Local officials are not functional in production, but they can affect the economic development in their jurisdiction. To examine the data of officials of economics majors and non-economics majors, we used the double independent sample Mann-Whitney test method based on non-parametric statistics .We draw conclusions that officials with a economics background can better improve the development of economy than others; and local economic level and the degree of influence of officials’ economics background on the economic development is an inverted “U” nonlinear relationship.

Voriconazole (VRC) and proton pump inhibitors (PPIs) have similar metabolic pathways. The objectives of the study are to evaluate the impact of PPIs on the pharmacokinetics of VRC. Human liver microsomes model was applied to assess the inhibitory effects of PPIs on the metabolism of VRC in vitro. A retrospective study was also carried out to explore the relationship between the plasma VRC trough concentrations and PPIs uses. Patients were divided into six groups: control (n = 166), lansoprazole (LAN, n = 38), esomeprazole (ESO, n = 19), omeprazole (OME, n = 45), pantoprazole (PAN, n = 43), and ilaprazole (ILA, n = 38) groups. All five PPIs showed concentration-dependent inhibitory effects on the VRC metabolism in human liver microsomes, among which LAN, OME and ESO were three of the most potent inhibitors. Consistently, co-administered with LAN, OME and ESO significantly increased the plasma VRC trough levels (p 0.05), whereas there was no significant association between VRC concentrations and PAN or ILA use. Interestingly, patients in the PPIs groups were more likely to reach the therapeutic VRC range of 1-5.5 μg/mL in steady state when compared with control patients (75-81% VS 69%). In conclusion, although all PPIs showed inhibitory effects on the VRC metabolism in vitro, only LAN, OME and ESO significantly increased VRC plasma concentrations. This study should be helpful for choice of the type of PPIs for patients administered with VRC.

Purpose: The objective of this study was to determine: 1) the incidence and the risk factors of diclofenac/acetaminophen combination as a single agent induced Acute Kidney Injury (AKI) in postoperative pain relief 2) the average cost and length of hospital stay for patients in AKI group and non-AKI group. Methods: All patients with no prior history of chronic kidney disease (CKD) and normal serum creatinine [44~130 μmol /l] who received diclofenac and acetaminophen combination as a single agent intramuscularly (IM) between January and December 2015 in The Second Xiangya Hospital, Changsha, Hunan, China were included in this retrospective own-control study. Baseline serum creatinine (SCr) and SCr during NSAID use were collected. AKI is defined as an increased of Scr over 1.5 times the baseline. Multivariate analyses were performed with a logistic regression model to assess the significant risk factors of AKI. Results: A total of 821 patients were included in the study with 63 [7.7%] patients had diclofenac/acetaminophen combination single agent induced AKI. Multivariate analysis confirmed that using diclofenac/acetaminophen combination after surgeries within 24 h were significantly associated with AKI [odds ratio, OR, 2.173; 95% CI, 1.113-4.243; P=0.023]. The average cost and length of hospitalization in AKI group was 1.87 times [p=0.000] and 1.2 times [p=0.043] comparison than non-AKI group, respectively. Conclusions: The incidence of diclofenac/acetaminophen combination single agent induced AKI in postoperative pain relief was 7.7%. Patients with hypertension or liver cirrhosis was more likely to develop AKI and using diclofenac/acetaminophen combination after surgeries within 24 h was significant risk factors for AKI. AKI prolonged the cost and length of hospitalization. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Summary Objective: To investigate the pharmacokinetics and tolerability of modafinil in Chinese subjects. Methods: Twelve healthy volunteers were given an escalating single dose of modafinil (100, 200 and 400 mg) in a three-period study (study 1). Another 12 volunteers received 100 mg twice daily for 7 days in multiple-dose study (study 2). Blood samples were taken from 0 to 60 h for study 1. And samples for study 2 were collected before administration on three consecutive morning and then from 0 to 60 h after the last dose. Pharmacokinetic parameters were calculated and compared with results from published data. Results: In study 1, Cmax and area under the concentration–time curve of modafinil and modafinil acid were increased proportionally with dose levels; t1/2 was independent on the dose levels. In study 2, the steady state was reached on day 4, and mean trough plasma concentration of modafinil was 1·36 ± 0·34 μg/mL. Apparent plasma clearance and apparent volume of distribution were lower in 100 mg twice-daily group than those in 100 mg single group. The adverse events were mild and moderate in study 1 and 2. Conclusions: In this pharmacokinetic study, modafinil was safe and well tolerated by young healthy Chinese subjects. The major pharmacokinetic parameters of modafinil in Chinese subjects are similar to those reported in Caucasians although the half-life seems to be longer in the former than in the latter. This apparent difference requires investigation.

Ke-Qing Qian1, Heng Ye1, Yi-Wen Xiao1, Yong-Yi Bao2, Chun-Jian Qi11Department of Oncology; 2Department of Pathology, the Changzhou No. 2 People’s Hospital Affiliated to Nanjing Medical University, Changzhou, ChinaAbstract: Tumor lysis syndrome (TLS), a result of rapid cell lysis following tumor therapy, is a well recognized complication during the treatment of rapidly growing tumors. TLS rarely occurs in solid tumors. We present a case report of TLS in a patient with primary retroperitoneal soft tissue sarcoma. TLS occurred in the patient after four days’ combinational chemotherapy with cisplatin, adriamycin, and dacarbazine. These drugs were selected on the basis of an ex vivo ATP-based tumor sensitivity assay. TLS was properly controlled in the patient with concomitant remission of the sarcoma. Therefore, precautions should be taken to avoid this potentially fatal complication during treatment of solid tumors, especially with tumors highly sensitive to drugs.Keywords: tumor lysis syndrome, retroperitoneal soft tissue sarcoma, ATP-based tumor sensitivity assay (ATP-TCA)

Infection is a leading cause of mortality and morbidity in the newborn and preterm neonates due to immuno-incompetence in these patients. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can protect the body from infection. In theory, morbidity and mortality due to infections in newborns and preterm infants could be reduced by the administration of IVIG. Two meta-analyses were evaluated comparing IVIG to treat various infection versus conventional treatments. The results showed that IVIG is not effective as an adjunctive treatment for suspected or proven infections in neonates.