Factors associated with lack of tracheal sealing by a cuff inflated to more than 30 cmH2O during mechanical ventilation: A cross-sectional study.

Objectives: The cuff pressures > 30 cmH2O may create a seal in the trachea. The objective of this study was to identify risk factors associated with lack of tracheal sealing by an endotracheal cuff inflated to > 30 cmH2O in patients undergoing mechanical ventilation. Methods: This prospective cross-sectional study was conducted from 2019 to 2020 in the cardiothoracic intensive care unit and respiratory medical care unit of a Hospital in Nantong, China. Patients aged >16 years undergoing cardiothoracic surgery with mechanical ventilation using endotracheal intubation were included. Patient characteristics and ventilator parameters were analyzed. Cuff pressure was maintained with the minimum leak technique (MLT) and measured with a cuff pressure gauge. Cuff pressure was measured for 30 seconds when ventilation was accompanied by no leak, simultaneously detected by the ventilator or auscultation with a stethoscope. Result: Of 352 patients undergoing mechanical ventilation, 51 patients (14.5%) had a cuff pressure of >30 cmH2O. Multivariable analysis showed that cuff manufacturer (Guangzhou Weili) and nasal endotracheal intubation significantly increased the risk of an unsealed trachea. Peak inspiratory pressure, cuff diameter and male sex had a strong inverse association with an unsealed trachea. Conclusions: These findings suggest that an endotracheal cuff pressure of 20 to 30 cmH2O is adequate for most patients, but lack of a tracheal seal still occurs in a small number of people. An unsealed trachea is most likely because cuff and tracheal diameters do not match. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx Unique identifier: ChiCTR-COC-15006459.

Optimal dose of meropenem for the treatment of neonatal sepsis: Dosing guideline variations and clinical practice deviations.

AIMS: Meropenem is increasingly used to treat neonatal sepsis. There are several guidelines recommending different dosing regimens of meropenem in neonates. Furthermore, deviations from these guidelines regularly occur in daily clinical practice. Therefore, the current study aimed to evaluate the variations of meropenem dosing guidelines and compare the difference between guideline and clinical practice in terms of the probability of target attainment. METHODS: This study is based on a population pharmacokinetic model. After defining the predictive performance of the model, Monte Carlo simulations were used to calculate the probability of target attainment of the currently existing dosing guidelines of meropenem and their use in daily clinical practice. RESULTS: Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT>MIC (fraction of time when the free meropenem concentration exceeded the minimum inhibitory concentration during the dosing interval), the probability of target attainment of four recommended doses ranged from 59% to 88% (MIC = 2 mg·L-1 ) and from 17% to 47% (MIC = 8 mg·L-1 ). At the clinical practice evaluation, only 20% of patients attained target exposure for the MIC of 8 mg·L-1 with 70% fT>MIC , which was much less than those found in the Food and Drug Administration labels (40%). CONCLUSION: This model-based population pharmacokinetics simulation showed that improper guidelines and/or clinical practice deviations will result in low probability of target attainment for patients infected with resistant bacteria and critically ill patients. It is important to develop and adhere to evidence-based and clinically pragmatic guidelines.

Clinical utiliy of a model-based piperacillin dose in neonates with early-onset sepsis.

AIMS: Early-onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model-based dosing regimen of piperacillin/tazobactam in EOS patients. METHODS: A prospective, single-centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg-1 , q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected. RESULTS: A total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14-41.29) weeks. Forty-seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2-305.8) hours and 31 (30, 5-123) days. There were no obvious adverse events and no infection-related deaths occurred in the first month of life. CONCLUSIONS: A model-based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment.

Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study.

OBJECTIVES: Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS). METHODS: This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates. RESULTS: A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin. CONCLUSIONS: Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

AIMS: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia. METHODS: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). RESULTS: A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible". CONCLUSIONS: The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.

Association between social support and suicidal ideation in patients with cancer: A systematic review and meta-analysis.

OBJECTIVE: To quantitatively examine the relationship between social support and suicidal ideation (SI) among patients with cancer and identify the moderators that influence the magnitude of this association. METHODS: Publications were searched in PubMed, PsycINFO, EMBASE, Cochrane Library and Chinese National Knowledge Infrastructure from database inception to May, 2020. Correlation coefficients (r) were chosen as the effect size with a random model to evaluate the overall effect size between social support and SI in patients with cancer. To assess statistical heterogeneity, we examined potential moderator variables on the social support and SI. RESULTS: A total of 881 studies were identified in initial search, and twelve studies were eligible. A negative, small but significant correlation (r = -0.22, 95% CIs: -0.30,-0.14, p < 0.001) was observed between social support and SI in patients with cancer, with a significant heterogeneity (I2  = 95.24%, Q = 231.27, p < 0.001). Moderator analyses indicated that race/ethnicity (Q(1) = 8.4, p < 0.05) and measurements of social support (Q(3) = 9.78, p < 0.05) and SI (Q(3) = 9.69, p < 0.05) significantly moderate the effect size between social support and SI. CONCLUSION: Taken together, we found a negative yet significant association between social support and SI in patients with cancer, which supported the importance of social support for the prevention of SI in patients with cancer.

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.).

Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis.

Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

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.

Precision therapy of 6-mercaptopurine in Chinese children with acute lymphoblastic leukaemia.

AIMS: Chinese children are more susceptible to the development of thiopurine-induced leukopenia compared with Caucasian populations. The aim of our study was to establish a 6-mercaptopurine (6-MP) dose-concentration-response relationship through exploration of pharmacogenetic factors involved in the thiopurine-induced toxicities in Chinese paediatric patients afflicted by acute lymphoblastic leukaemia (ALL). METHODS: Blood samples were obtained from ALL children treated with 6-MP. We determined the metabolite steady-state concentrations of 6-MP in red blood cells (RBCs) by using high-performance liquid chromatography. Pharmacogenetic analysis was carried out on patients' genomic DNA using the MassArray genotyping platform. RESULTS: Sixty children afflicted by ALL who received 6-MP treatment were enrolled in this study. The median concentration of 6-thioguanine in patients afflicted by leukopenia was 235.83 pmol/8 × 108 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 108 RBCs; P = 0.029). We determined the population special target 6-thioguanine threshold to have equalled 197.50 pmol/8 × 108 RBCs to predict leukopenia risk in Chinese paediatric patients afflicted by ALL. Among 36 candidate single nucleotide polymorphisms, our results indicated that NUDT15 (rs116855232) and IMPDH1 (rs2278293) were correlated with a 5.50-fold and 5.80-fold higher risk of leukopenia, respectively. MTHFR rs1801133 variants were found to have had a 4.46-fold significantly higher risk of hepatotoxicity vs wild-type genotype. CONCLUSION: Our findings support the idea that predetermination of genotypes and monitoring of thiopurine metabolism for Chinese paediatric patients afflicted by ALL is necessary to effectively predict the efficacy of treatments and to minimize the adverse effects of 6-MP maintenance therapy.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

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.

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).

Population pharmacokinetics and dose optimization of ceftriaxone for children with community-acquired pneumonia.

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.

Body Surface Area-Based Dosing Regimen of Caspofungin in Children: a Population Pharmacokinetics Confirmatory Study.

We evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics, compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin dosage based on body surface area is most appropriate for pediatric use.

Population Pharmacokinetics and Dosing Optimization of Imipenem in Children with Hematological Malignancies.

Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Overexpression of chloride channel-3 (ClC-3) is associated with human cervical carcinoma development and prognosis.

BACKGROUND: Cervical carcinoma is a major gynecological cancer and causes cancer-related deaths in worldwide, the latent pathogenesis and progress of cervical cancer is still under research. ClC-3 may be an important promoter for aggressive metastasis of malignant tumors. In this research, we explore the ClC-3 expression in cervical carcinoma and its underlying clinical significance, trying to illuminate ClC-3 probable function in the neoplasm malignant behavior, development and prognosis. METHODS: Paraffin-embedded cervical (n = 168) and lymph node (n = 100) tissue specimens were analysed by immunohistochemistry. Fresh human cervical tissue specimens (n = 165) and four human cervical cell lines were tested for ClC-3 mRNA and protein expression levels by quantitative real-time PCR and western blotting. The relationship between the expression levels of ClC-3, the pathological characteristics of the carcinoma, and the clinical prognosis were statistically analysed. RESULTS: In normal and precancerous (LSIL, HSIL) cervical tissues as well as cervical carcinoma tissues, both ClC-3 mRNA and protein expression levels increased significantly (p < 0.05). The expression level of ClC-3 was closely-related to the histological differentiation (p = 0.029), tumour staging (p = 0.016), tumour size (p = 0.039), vascular invasion (p = 0.045), interstitial infiltration depth (p = 0.012), lymphatic metastasis (p = 0.036), and HPV infection (p = 0.022). In an in vitro experiment, ClC-3 mRNA and protein were found to be overexpressed both in the HeLa and SiHa cell lines, but low expression levels were detected in the C-33A and H8 cell lines (p < 0.05). Furthermore, the high expression levels of ClC-3 was significantly correlated to poor survival in cervical carcinoma patients (Log-rank test, p = 0.046). CONCLUSIONS: These data suggest that overexpression of ClC-3 is closely associated with human cervical carcinoma progression and poor prognosis; this suggests that ClC-3 may function as a patent tumour biomarker and a latent therapeutic target for cervical carcinoma patients.

Stable Diindeno-Fused Corannulene Regioisomers with Open-Shell Singlet Ground States and Large Diradical Characters.

The synthesis of open-shell polycyclic hydrocarbons with large diradical characters is challenging because of their high reactivities. Herein, two diindeno-fused corannulene regioisomers DIC-1 and DIC-2, curved fragments of fullerene C104 , were synthesized that exhibit open-shell singlet ground states. The incorporation of the curved and non-alternant corannulene moiety within diradical systems leads to significant diradical characters as high as 0.98 for DIC-1 and 0.89 for DIC-2. Such high diradical characters can presumably be ascribed to the re-aromatization of the corannulene π system. Although the DIC compounds have large diradical characters, they display excellent stability under ambient conditions. The half-lives are 37 days for DIC-1 and 6.6 days for DIC-2 in solution. This work offers a new design strategy towards diradicaloids with large diradical characters yet maintain high stability.

Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection.

Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. A target area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 50 µg · h/ml is recommended. The standard dose has resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization for this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach. The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC0-24 to ensure its efficacy. A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC0-24 after being given the standard dose. For all the subtherapeutic patients (achieving <80% of the target AUC) (n = 5), a model-based dosage adjustment was performed using the Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased by 28.6% to 60.0% in these five patients, and all adapted AUC0-24 values achieved the target (range, 48.6 to 66.1 µg · h/ml). The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. The population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinically feasible method to adapt the ganciclovir dose in neonatal clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT03113344.).

Penetration of Cefotaxime into Cerebrospinal Fluid in Neonates and Young Infants.

Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study was to evaluate the penetration of cefotaxime into CSF in neonates and young infants. Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy, and concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The analysis was performed using NONMEM and R software. Thirty neonates and young infants (postmenstrual age range, 25.4 to 47.4 weeks) were included. A total of 67 plasma samples and 30 CSF samples were available for analysis. Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter and from 0.39 to 25.38 mg/liter, respectively. The median ratio of the CSF concentration to the plasma concentration was 0.28 (range, 0.06 to 0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg of body weight three times a day (TID) would reach the pharmacodynamic target (the percentage of the dosing interval that the free antimicrobial drug concentration remains above the MIC, 70%) using the standard EUCAST MIC susceptibility breakpoints of 2 mg/liter and 4 mg/liter, respectively. The penetration of cefotaxime into the CSF of neonates and young infants was evaluated using an opportunistic sampling approach. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MICs of <2 mg/liter. Individual dosage adaptation was required for more resistant bacterial strains, such as Staphylococcus aureus.

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia.

Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.