Physiologically based pharmacokinetic modeling of apixaban to predict exposure in populations with hepatic and renal impairment and elderly populations.

BACKGROUND: Apixaban is a factor Xa inhibitor with a limited therapeutic index that belongs to the family of oral direct anticoagulants. The pharmacokinetic (PK) behavior of apixaban may be altered in elderly populations and populations with renal or hepatic impairment, necessitating dosage adjustments. METHODS: This study was conducted to examine how the physiologically based pharmacokinetic (PBPK) model describes the PKs of apixaban in adult and elderly populations and to determine the PKs of apixaban in elderly populations with renal and hepatic impairment. After PBPK models were constructed using the reported physicochemical properties of apixaban and clinical data, they were validated using data from clinical studies involving various dose ranges. Comparing predicted and observed blood concentration data and PK parameters was utilized to evaluate the model's fit performance. RESULTS: Doses should be reduced to approximately 70% of the healthy adult population for the healthy elderly population to achieve the same PK exposure; approximately 88%, 71%, and 89% of that for the elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 96%, 81%, and 58% of that for the Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment elderly populations, respectively to achieve the same PK exposure. CONCLUSION: The findings indicate that the renal and hepatic function might be considered for apixaban therapy in Chinese elderly patients and the PBPK model can be used to optimize dosage regimens for specific populations.

Comprehensive analysis of cell death genes in hepatocellular carcinoma based on multi-omics data.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common tumor of the digestive system. Cell death is an essential process in normal tissue that consists of 3 classical pathways: apoptosis, necrosis and autophagy. OBJECTIVES: To perform a comprehensive analysis of the impact of cell death on liver cancer. MATERIAL AND METHODS: The Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the Cancer Genome Atlas (TCGA) datasets were used to analyze the relationships between mutations in cell death-related genes and clinical variables of HCC. Then, we applied the DESeq2 package to identify aberrantly expressed genes in HCC and their related biological functions through a Pearson correlation analysis. Finally, a cell death-related signature of HCC was constructed using the single-factor Cox regression. RESULTS: We identified the genes involved in apoptosis, necrosis and autophagy, of which TP53 and SPTA1 had the highest frequency of mutations. The results revealed that cell death-related tumor mutational burden (TMB) was significant for the pathologic stage and had a strong relationship with the prognosis. Moreover, 53 cell death-related genes that are differentially expressed in HCC were screened, and 3 of them were correlated with HCC prognosis. Harvey rat sarcoma viral oncogene homolog (HRAS) affected the infiltration of immune cells and was closely correlated with ferroptosis. Peptidylprolyl isomerase A (PPIA) played a significant role in mitochondrial pathways. At last, we constructed a cell death-related signature of HCC using 10 prognosis-related genes and a nomogram based on 3 variables (expression, group and stage). CONCLUSIONS: This study provided a comprehensive analysis of cell death-related genes in HCC based on multi-omics data, identified the contribution of each variable to clinical outcome and predicted the survival probability of HCC patients more directly.

Cytotoxicity of anti-tumor herbal Marsdeniae tenacissimae extract on erythrocytes.

Marsdeniae tenacissimae extract (MTE) has been used as an adjuvant medicine for cancer therapy for a long time. Although massive studies demonstrated its considerable anti-cancer effect, there is no research on its influence on erythrocytes, which are firstly interacted with MTE in the circulation. To investigate the influence of MTE on erythrocytes, we used a flow cytometer to detect the MTE-treated alternations of morphology, calcium concentration, and reactive oxygen species (ROS) level in erythrocytes. We used hemolysis under different osmotic solutions to evaluate the fragility of erythrocytes. Data showed that MTE treatment dose-dependently increased the ratio of erythrocyte fragmentation (P<0.001) and shrinking, and elevated the forward scatter (FSC) value (P<0.001) and calcium accumulation (P<0.001). MTE induced ROS production of erythrocytes under the high glucose condition (P<0.01) and consequently caused a rise in fragility (P<0.05). These results suggest that MTE induces cytotoxicity and aging in erythrocytes in a dose-dependent manner, and presents the possibility of impairment on cancer patients' circulating erythrocytes when MTE is used as an anti-cancer adjuvant medicine.