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A population pharmacokinetic (pop PK) model of polymyxin B was developed using nonlinear mixed‐effects (NONMEM) modeling based on free plasma concentrations to determine whether dose adjustment is required in critically ill patients. One thousand pharmacokinetic profiles for virtual patients with a body weight of 70 kg were simulated using Monte Carlo simulation at different dose scenarios, and area under the concentration–time curve of free drug (fAUC) was computed. The probability of target attainment (PTA) at each minimum inhibitory concentration (MIC) was calculated using fAUC/MIC as a pharmacokinetic/pharmacodynamic (PK/PD) index. The final population PK model was a 2‐compartment model. PTA showed that 3.5 mg/kg/day regimens of polymyxin B effectively achieved the fAUC/MIC target of 10 (one log10 kill) against Pseudomonas aeruginosa strains with MIC of 1 mg/L or less (PTA, 90.7% or greater), while the dose regimen were ineffective against strains with an MIC of 2 mg/L or greater (PTA, 56.9% or less). For Klebsiella pneumoniae, the fAUC/MIC target of 17.4 (one log10 kill) was achieved in more than 90.4% of cases for MIC of 0.5 mg/L or less with 3 mg/kg/day regimens. However, the PTA decreased dramatically as MICs increased above 1 mg/L (PTA, 56.1% or less). The polymyxin B dosage regimen of 3.5 mg/kg/day and 3 mg/kg/day are sufficient to treat P. aeruginosa infections with an MIC of 1 mg/L or less and K. pneumoniae infections with an MIC of 0.5 mg/L or less, respectively. The current recommended dose (1.5–3 mg/kg/day) of polymyxin B appears inadequate to attain the PK/PD target for therapeutic efficacy against infections caused by P. aeruginosa and K. pneumoniae isolates when MIC is above the values. [ABSTRACT FROM AUTHOR]

Busulfan is a bifunctional alkylating agent that is widely used before hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (popPK) model for busulfan in Chinese pediatric patients. A systemic external evaluation of 11 published popPK models was conducted in Chinese pediatric patients undergoing HSCT. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE%, median absolute PE%, and percentage of PE% within ±20% and ±30% were calculated in prediction‐based diagnostics. Simulation‐based diagnostics were conducted through a prediction‐ and variability‐corrected visual predictive check and the normalized prediction distribution error. The relative individual prediction error was calculated using Bayesian forecasting with 1 to 3 concentration points. The 1‐compartment open linear popPK model, which was built by Su‐jin Rhee et al (model H), incorporating the patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other popPK models. In prediction‐based diagnostics, the median PE%, percentage of PE% within ±20%, and percentage of PE% within ±30% of model H were 8.48%, 45.35%, and 59.56%, respectively. The normalized prediction distribution error of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients. [ABSTRACT FROM AUTHOR]

The activation of hepatic stellate cells (HSCs) is associated with liver fibrosis, the pathological feature of most forms of chronic hepatic damage, and is accompanied by abnormal deposition of the extracellular matrix (ECM). During the pathological process, acid‐sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is involved in the activation of HSCs. It has previously been identified that ASIC1a is related to pyroptosis in articular chondrocytes. However, it remains unclear whether ASIC1a restrains pyroptosis during liver fibrosis. Here, we determined that the levels of pyroptosis‐associated speck‐like protein, gasdermin D, caspase‐1, nucleotide‐binding oligomerization domain (NOD)‐like receptor 3, and apoptosis‐associated speck‐like protein (ASC) decreased, while the level of α‐smooth muscle actin and collagen‐I increased upon introduction of ASIC1a into an acid‐induced model. Inhibition or silencing of ASIC1a and the use of Ca2+‐free medium were able to promote the pyroptosis of activated HSCs, which reduced their deposition. In summary, our study indicates that ASIC1a inhibits pyroptosis of HSCs and that inhibition of ASIC1a may be able to promote pyroptosis to relieve liver fibrosis. [ABSTRACT FROM AUTHOR]

Objective We aimed to examine the risk factors related to the development of osteoporosis in rheumatoid arthritis ( RA) patients and whether there is an association among the changes in bone mineral density ( BMD), disease activities (modified DAS28), serum 25-hydroxyvitamin D (25 OHD) levels, and disease duration. Methods There were 110 patients with RA and 110 age- and sex-matched healthy controls who were concurrently studied. All of the patients underwent the following measurements: erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and serum 25 OHD. Dual-energy X-ray absorptiometry ( DEXA) was also used to measure the BMD of the left femur at the time of recruitment. Patients taking vitamin D supplement or corticosteroids were excluded. Results The incidences of osteopenia (45.6% vs. 36.4%, P = 0.170) and osteoporosis (33.6% vs. 5.45%, P = 0.000) were higher in the RA patients than in the healthy controls. There was a significant negative correlation between vitamin D levels and DAS28 ( r = -0.325, P = 0.001) and a significant positive correlation between vitamin D levels and BMD ( r = 0.422, P = 0.000). The multiple regression analysis revealed that 25 OHD levels were significantly correlated with disease activity and BMD ( F = 11.087, P = 0.000). Stepwise multiple regression analysis showed that serum 25 OHD levels were the significant predictors for low BMD and high disease activity ( DAS28) in RA patients. Conclusion The incidences of osteoporosis and osteopenia were higher in RA patients compared to the age- and gender-matched healthy controls. Low serum 25 OHD levels correlate with low BMD and high disease activity in RA patients. [ABSTRACT FROM AUTHOR]