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To establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations. PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole. The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively. Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60–90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30–60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI. When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively. [ABSTRACT FROM AUTHOR]

Background: Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. Objective: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. Methods: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. Results: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. Conclusion: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data. [ABSTRACT FROM AUTHOR]

Purpose: To assess ceftriaxone population pharmacokinetics in a large pediatric population and describe the proper dose for establishing an optimized antibiotic regimen. Methods: From pediatric patients using ceftriaxone, blood samples were obtained and the concentration was measured using high-performance liquid chromatography ultraviolet detection. The NONMEM software program was used for population pharmacokinetic analysis, for which data from 99 pediatric patients (2 to 12 years old) was collected and 175 blood concentrations were obtained. Results: The best fit with the data was shown by the one-compartment model with first-order elimination. According to covariate analysis, weight had a significant impact on the clearance of ceftriaxone. Using Monte Carlo simulation, in a pediatric population with community-acquired pneumonia, a dose regimen of 100 mg/kg every 24 h produced satisfactory target attainment rates while remaining within the required minimum inhibitory concentration (2 mg/L). Conclusion: Population pharmacokinetics of ceftriaxone was evaluated in children and an optimum dosing regimen was constructed on the basis of the pharmacokinetics-pharmacodynamics model-based approach. [ABSTRACT FROM AUTHOR]

Background: Children as a population have high antimicrobial prescribing rates which may lead to high resistance of bacteria according to data from some single-center surveys of antibiotic prescribing rates in China. The acquirement of baseline data of antibiotic prescribing is the basis of developing intervention strategies on inappropriate antimicrobial prescriptions. Few studies show clearly the pattern and detailed information on classes of antibiotics and distribution of indications of antibiotic prescriptions in children in China. This study aims to assess the antibiotic prescribing patterns among children and neonates hospitalized in 18 hospitals in China.Methods: A 24-hour point prevalence survey on antimicrobial prescribing was conducted in hospitalized neonates and children in China from December 1st, 2016 to February 28th, 2017. Information on the antibiotic use of patients under 18 years of age who were administered one or more on-going antibiotics in the selected wards over a 24-hour period was collected. These data were submitted to the GARPEC (Global Antimicrobial Resistance, Prescribing and Efficacy in Children and Neonates) web-based application (https://pidrg-database.sgul.ac.uk/redcap/). For statistical analysis, Microsoft Excel 2007 and SPSS 22.0 were used.Results: The antibiotic data were collected in 35 wards in 18 hospitals from 9 provinces. In total, 67.76% (975/1439) of the patients (n = 1439) were given at least one antibiotic, including 58.1% (173/298) of neonates (n = 298) and 70.3% (802/1141) of children (n = 1141). In neonates, the three most frequently prescribed antibiotics were third-generation cephalosporins (41.7%), penicillins plus enzyme inhibitor (23.8%), and carbapenems (11.2%). In children, the three most frequently prescribed antibiotics were third-generation cephalosporins (35.5%), macrolides (23.2%), and penicillins plus enzyme inhibitors (15.9%). The most common indication for antibiotics was proven or probable bacterial lower respiratory tract infection (30.9% in neonates and 66.6% in children).Conclusions: Antibiotics are commonly prescribed in the Chinese children population. It is likely that the third-generation cephalosporins and macrolides are currently overused in Chinese children. Efforts must be made to ensure safe and appropriate antibiotic prescribing to reduce and prevent the future development of antibiotic resistance. [ABSTRACT FROM AUTHOR]

The authors report on a new gold nanoparticle-based colorimetric assay for microRNA (miRNA). It is based on duplex-specific nuclease (DSN)-assisted signal amplification. Following hybridization between target miRNA and its complementary single-stranded DNA (ssDNA), the ssDNA in the DNA:RNA hybrid is selectively cleaved by DSN to produce small DNA fragments. Target microRNA is thus released and will initiate another round of hybridization and DSN digestion. In this manner, each miRNA target can specifically trigger several cycles of hybridization and DSN cleavages to yield numerous small fragments of DNA oligonucleotides. The short DNA fragments (unlike the uncleaved ssDNA probe) exhibit superior capability for stabilizing unmodified AuNP against salt-induced aggregation to the uncleaved ssDNA probe, with an accompanying color change from blue to red. These findings are exploited in a colorimetric assay for miRNA that has a 10 fmol detection limit. [ABSTRACT FROM AUTHOR]

In plants, the level of ethylene is determined by the activity of the key enzyme 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS). A gene encoding an ACC synthase protein was isolated from pear ( Pyrus pyrifolia). This gene designated PpACS1a (GenBank accession no. KC632526) was 1488 bp in length with an open reading frame (ORF) encoding a protein of 495 amino acids that shared high similarity with other pear ACC synthase proteins. The PpACS1a was grouped into type-1 subfamily of plant ACS based on its conserved domain and phylogenetic status. Real-time quantitative PCR indicated that PpACS1a was differentially expressed in pear tissues and predominantly expressed in anthers. The expression signal of PpACS1a was also detected in fruit and leaves, but no signal was detected in shoots and petals. Furthermore, the PpACS1a expression was regulated during fruit ripening. In addition, the PpACS1a gene expression was regulated by salicylic acid (SA) and indole-3-acetic acid (IAA) in fruit. Moreover, the expression of the PpACS1a was up-regulated in diseased pear fruit. These results indicated that PpACS1a might be involved in fruit ripening and response to SA, IAA and disease. [ABSTRACT FROM AUTHOR]

To elucidate the roles of genes during fruit development, a fruit-predominant cDNA (designated PpPGIP1) encoding a polygalacturonase inhibitor protein (PGIP) was isolated from a pear ( Pyrus pyrifolia Nakai. cv. Whangkeumbae) fruit cDNA library. The PpPGIP1 gene shares high sequence homology at the nucleotide level in the coding region and at the amino acid level with other plant PGIP genes. Subsequently, the corresponding PpPGIP1 gene was isolated from pear genomic DNA. Real-time quantitative PCR analyses revealed that PpPGIP1 transcripts were functionally accumulated during the developing fruit of pear. The PpPGIP1 expression signals were detected at relatively low level in early stage of pear fruit development (30-140 days after full bloom). With the fruit ripening, softening and senescence, the expression of PpPGIP1 gene increased to a relative high level in 150-180 days after full bloom fruit. In addition, PpPGIP1 gene was dramatically up-regulated in 180 days after full bloom diseased fruit and by 0.2 mM salicylic acid (SA) treatment for 12 h in 150 days after full bloom fruit. These results suggested that PpPGIP1 might play an important role in response to disease resistance and SA during fruit development of pear. [ABSTRACT FROM AUTHOR]

A gene encoding an ethylene receptor protein was isolated from pear ( Pyrus pyrifolia). This gene, designated PpERS (GenBank accession No. KC517482), was 1,918 bp in length with an open reading frame encoding a protein of 638 amino acids that shared high similarity with another pear ethylene receptor protein PpERS1, and two apple ethylene receptor proteins MdERS and MdERS1. The PpERS was grouped into the ETR1 subfamily of ethylene receptor based on its conserved domain and phylogenetic status. The PpERS gene contained five exons interrupted by four introns. Quantitative RT-PCR indicated that PpERS was differentially expressed in pear tissues and predominantly expressed in petals, shoots, anthers, and 160 days after full bloom fruit. The PpERS expression was regulated during fruit development. In addition, the PpERS gene expression was regulated by salicylic acid (SA) and ethylene in fruit. The results indicated that PpERS might participate in ethylene and SA signaling transduction during pear fruit development. [ABSTRACT FROM AUTHOR]

Two genes encoding putative auxin-repressed proteins, designated PpARP1 and PpARP2, were isolated from pear ( Pyrus pyrifolia). The deduced PpARP1 and PpARP2 proteins contain the typical auxin_repressed Dormancy/auxin associated protein domains. Phylogenetic analyses clearly demonstrated that PpARP1 has high homology with pear ARPs except PpARP2 which belongs to another clade. Using PCR amplification technique, the genomic clones corresponding to PpARP1 and PpARP2 were isolated and shown to contain two introns with typical GT/AG boundaries defining the splice junctions. PpARP1 and PpARP2 genes were predominantly expressed in fruit. PpARP1 transcripts were also detected in shoots, petals, and anthers, but a relatively low expression signal was detected in young leaves. PpARP2 transcripts were also detected in other tissues. In particular, expression of PpARP1 and PpARP2 was developmentally regulated in fruit. Further study demonstrated that PpARP1 and PpARP2 expression in pear fruit was remarkably inhibited by salicylic acid and induced by IAA. These data suggested that PpARP1 and PpARP2 might be involved in the response to salicylic acid signaling during fruit development of pear. The study of the pear PpARP genes also demonstrated a link between salicylic acid and auxin signaling. [ABSTRACT FROM AUTHOR]

GAST (GA-stimulated transcript)-like genes have been reported as targets of GA regulation in some plant species. In this study, we isolated seven GAST-like cDNAs from cotton ( Gossypium hirsutum) cDNA libraries (designated as GhGASL1- GhGASL7). Meanwhile, the genomic DNA clones corresponding to the seven GhGASL genes were isolated by using PCR amplification technique. Analysis of gene structure revealed that four genes ( GhGASL1/3/5/6) contain two exons and one intron, while the rest have four exons and three introns. All of the deduced GhGASL proteins contain a putative signal peptide in the N-terminus and a conservative cysteine-rich C-terminal domain. Quantitative RT-PCR analysis indicated that the seven GhGASL genes are differentially expressed in cotton tissues. Among them, GhGASL1/4/7 were predominantly expressed in cotyledons, while the transcripts of GhGASL2/5 were preferentially accumulated at hypocotyls. GhGASL3 mRNA was largely accumulated in fibers, while GhGASL6 transcripts were mainly detected in ovules. Furthermore, GhGASL2/3/5 displayed a relatively high expression levels during early fiber elongation stages, and were regulated by GA. These data suggested that GhGASL genes may be involved in fiber elongation and in response to GA signaling during fiber development. [ABSTRACT FROM AUTHOR]

1-Aminocyclopropane-1-carboxylate (ACC) oxidase catalyzes the final reaction of the ethylene biosynthetic pathway, converting ACC into ethylene. Past studies have shown a possible link between ACC oxidase and salicylic acid during fruit ripening in pear, but the relationship has received no more than modest study at the gene expression level. In this study, two cDNA clones encoding putative ACC oxidase, PpACO1 and PpACO2, were isolated from a cDNA library constructed by our own laboratory and produced using mRNA from mesocarp of pear ( Pyrus pyrifolia Nakai. cv.Whangkeumbae). One cDNA clone, designated PpACO1 (GenBank accession No. JN807390), comprised an open reading frame of 945 bp encoding a protein of 314 amino acids. The other cDNA, designated PpACO2 (GenBank accession No. JN807392), encodes a protein with 322 amino acids that shares high similarity with the known plant ACOs. Using PCR amplification techniques, two genomic clones corresponding to PpACO1 and PpACO2 were isolated and shown to contain independently three introns with typical GT/AG boundaries defining the splice junctions. The PpACO1 gene product shared 99 % identity with an ACC oxidase from pear ( Pyrus × bretschneideri Rehd.cv.Yali), and phylogenetic analyses clearly placed the gene product in the ACC oxidase cluster of the pear 2-oxoglutarate-dependent dioxygenase superfamily tree. Quantitative RT-PCR analysis indicated that the two PpACO genes are differentially expressed in pear tissues. PpACO1 and PpACO2 were predominantly expressed in fruit. The transcripts of PpACO1 were accumulated at relatively low levels in early fruit, but strongly high levels in fruit ripening and senescence stages, while the transcripts of PpACO2 were accumulated at higher levels in early fruit and much lower levels with further fruit cell development than the transcripts of PpACO1. In addition, PpACO1 gene was down-regulated in fruit by salicylic acid (SA). Nevertheless, PpACO2 gene was dramatically up-regulated in fruit by SA. These results suggested that the PpACOs may participate in regulation of fruit ripening and in response to SA in pear. [ABSTRACT FROM AUTHOR]

Purpose: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. Methods: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. Conclusions: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL. [ABSTRACT FROM AUTHOR]