Optimal use of ß-lactams in neonates: machine learning-based clinical decision support system.

BACKGROUND: Accurate prediction of the optimal dose for ß-lactam antibiotics in neonatal sepsis is challenging. We aimed to evaluate whether a reliable clinical decision support system (CDSS) based on machine learning (ML) can assist clinicians in making optimal dose selections. METHODS: Five ß-lactam antibiotics (amoxicillin, ceftazidime, cefotaxime, meropenem and latamoxef), commonly used to treat neonatal sepsis, were selected. The CDSS was constructed by incorporating the drug, patient, dosage, pharmacodynamic, and microbiological factors. The CatBoost ML algorithm was used to build the CDSS. Real-world studies were used to evaluate the CDSS performance. Virtual trials were used to compare the CDSS-optimized doses with guideline-recommended doses. FINDINGS: For a specific drug, by entering the patient characteristics and pharmacodynamic (PD) target (50%/70%/100% fraction of time that the free drug concentration is above the minimal inhibitory concentration [fT > MIC]), the CDSS can determine whether the planned dosing regimen will achieve the PD target and suggest an optimal dose. The prediction accuracy of all five drugs was >80.0% in the real-world validation. Compared with the PopPK model, the overall accuracy, precision, recall, and F1-Score improved by 10.7%, 22.1%, 64.2%, and 43.1%, respectively. Using the CDSS-optimized doses, the average probability of target concentration attainment increased by 58.2% compared to the guideline-recommended doses. INTERPRETATION: An ML-based CDSS was successfully constructed to assist clinicians in selecting optimal ß-lactam antibiotic doses. FUNDING: This work was supported by the National Natural Science Foundation of China; Distinguished Young and Middle-aged Scholar of Shandong University; National Key Research and Development Program of China.

Population pharmacokinetics and dose optimization of levofloxacin in elderly patients with pneumonia.

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.

Acetyl-11-keto-ß-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties.

Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-ß-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was ∼17 µM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 µM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.

Curcumin induces apoptosis in SGC-7901 gastric adenocarcinoma cells via regulation of mitochondrial signaling pathways.

Curcumin, a polyphenol compound derived from the rhizome of the plant Curcuma longa L. has been verified as an anticancer compound against several types of cancer. However, understanding of the molecular mechanisms by which it induces apoptosis is limited. In this study, the anticancer efficacy of curcumin was investigated in human gastric adenocarcinoma SGC-7901 cells. The results demonstrated that curcumin induced morphological changes and decreased cell viability. Apoptosis triggered by curcumin was visualized using Annexin V-FITC/7- AAD staining. Curcumin-induced apoptosis of SGC-7901 cells was associated with the dissipation of mitochondrial membrane potential (MMP) and the release of cytochrome c into the cytosol. Furthermore, the down-regulation of Bcl-2 and up-regulation of Bax that led to the cleavage of caspase-3 and increased cleaved PARP was observed in SGC-7901 cells treated with curcumin. Therefore, curcumin-induced apoptosis of SGC-7901 cells might be mediated through the mitochondria pathway, which gives the rationale for in vivo studies on the utilization of curcumin as a potential cancer therapeutic compound.

Pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil in healthy Chinese subjects.

AIMS: To assess the pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil (ADV) in healthy Chinese subjects. METHODS: Forty-two healthy subjects were randomized into 5, 10, 20, 40 and 60-mg dose groups for safety assessment. Nine and 10 healthy males were enrolled for a single-dose pharmacokinetic profile and assessment of the effect of food on the pharmacokinetics of adefovir (PMEA), respectively. Another 10 healthy subjects were enrolled for a multiple-dose safety assessment and pharmacokinetic profile. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining PMEA concentrations with a validated LC-MS/MS method. RESULTS: No serious adverse events occurred. The pharmacokinetic parameters of PMEA following ADV 10, 20 and 40 mg were: geometric mean [95% confidence interval (CI)] for AUC(0-24 h) 227 (205, 253), 423 (361, 506) and 686 (585, 828) microg l(-1) h, C(max) 23.0 (20.7, 27.3), 47.4 (42.8, 53.2) and 83.6 (72.6, 97.4) microg l(-1), arithmetic mean (95% CI) for t(1/2) 6.8 (6.3, 7.3), 7.4 (6.7, 8.1) and 7.7 (6.5, 8.9) h, median value (range) for t(max) 1.00 (1.00-2.00), 0.75 (0.75-2.50) and 1.00 (0.75-2.00) h, respectively. The steady-state pharmacokinetics parameters were similar to those following a single dose. The AUC of PMEA was unaffected by food. CONCLUSION: ADV is safe and well tolerated in healthy Chinese subjects. The mean C(max) of PMEA is proportional to dose, but the linearity of AUC needs further study. There is no accumulation following multiple doses of ADV and the extent of absorption of PMEA is unaffected by food.

[Safety and tolerance study of single oral dose of adefovir dipivoxil tablets in healthy volunteers].

BACKGROUND: To assess the safety and tolerance of adefovir dipivoxil tablet in Chinese healthy volunteers. METHODS: Totally 42 healthy volunteers were enrolled in the study, 21 were female and 21 were male and their age ranged from 19 to 26 years. The subjects were randomly divided into 5, 10, 20, 40 and 60 mg dose-groups (6-10 subjects in each group) based on sex and weight, beginning with the 5 mg dose-group. Clinical symptoms, vital signs, electrocardiogram, routine blood test, routine urine test, prothrombin time and blood biochemical tests were recorded and evaluated. RESULTS: No significant changes were found in clinical symptoms, vital signs and laboratory tests after dosing, except slight elevations of alanine aminotransferase in 2 subjects and bilirubin in 6 subjects observed and some gastrointestinal symptoms such as nausea and diarrhea found in 3 subjects, but the frequency and severity of all the adverse reactions were not found to be related to the dosages. CONCLUSION: The results showed that single oral dose of adefovir dipivoxil 60 mg or less was safe and tolerable.