MATERIALS AND METHODS: In this trial, a total of 56 eligible subjects were randomly assigned to the fasting group and the postprandial group. The two groups were given 250 mg of the test and reference preparation, respectively. Liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was applied to determine the plasma concentration of cefalexin. PhoenixWinNonlin software (V7.0) was used to calculate the pharmacokinetic parameters of cefalexin using the non-compartmental model (NCA), and the bioequivalence and safety results were calculated by SAS (V9.4) software.
RESULTS: The main pharmacokinetic parameters of the test and reference preparations were as follows, the fasting group: Cmax 12.59 ± 2.65 μg/mL, 12.72 ± 2.28 μg/mL; AUC0-8h 20.43 ± 3.47 h×μg/mL, 20.66 ± 3.38 h×μg/mL; AUC0-∞ 20.77 ± 3.53 h×μg/mL, 21.02 ± 3.45 h×μg/mL; the postprandial group: Cmax 5.25 ± 0.94 μg/mL, 5.23 ± 0.80 μg/mL; AUC0-10h 16.92 ± 2.03 h×μg/mL, 17.09 ± 2.31 h×μg/mL; AUC0-∞ 17.33 ± 2.09 h×μg/mL, 17.67 ± 2.45 h×μg/mL.
CONCLUSION: The 90% confidence intervals of geometric mean ratios of test preparation and reference preparation were calculated, and the 90% confidence intervals of geometric mean ratios of Cmax, AUC0-10h, and AUC0-∞ were within the 80.00% ~ 125.00% range in both groups. Both Cmax and AUC met the pre-determined criteria for assuming bioequivalence. The test and reference products were bioequivalent after administration under fasting as well as under fed conditions in healthy Chinese subjects. This study may suggest that successful generic versions of cefalexin not only guarantee the market supply of such drugs but can also improve the safety and effectiveness and quality controllability of cefalexin through a new process and a new drug composition ratio.
METHODS: This study employed genomic methodologies to investigate the correlation between drug sensitivity and types of AICD in BC. Initially, data from TCGA were utilized to construct a prognostic model and classification system for AICD. Subsequently, a series of bioinformatics analyses assessed the prognostic and clinical significance of this model within the context of BC.
RESULTS: Analysis revealed a cohort of 18 genes associated with AICD, exhibiting prognostic relevance. Survival analyses indicated that overall survival rates were significantly lower in high-risk populations compared to their low-risk counterparts. Furthermore, prognostic indicators linked to AICD demonstrated high accuracy in predicting survival outcomes in BC. Immunological assessments indicated heightened expression of anti-tumor infiltrating immune cells and immune checkpoint molecules in low-risk populations, correlating with various anti-tumor immune functions. Ultimately, a comprehensive prognostic model related to AICD was developed through univariate analysis, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. As Adenosine triphosphate (ATP) concentration increased, the viability of BC cells exhibited a general decline at each time point. Notably, ATP diminished the mitochondrial membrane potential in BC cells while enhancing it in normal breast epithelial cells. Additionally, ATP inhibited the migration of BC cells and promoted their apoptosis. ATP also stimulated reactive oxygen species (ROS) production in MCF-10A cells, with implications for the immune response in BC cells. Compared to the control group, expression levels of CLIC6, SLC1A1, and CEMIP were significantly reduced in the ATP intervention group, whereas ANO6 expression was elevated. ANO6, CEMIP, and CLIC6 share genetic variants with BC, while SLC1A1 does not exhibit genetic causal variation with the disease.
CONCLUSION: A valuable prognostic model associated with AICD has been established, capable of accurately predicting BC prognosis. The induction of cell death by ATP appears to play a protective role in BC progression. These findings carry significant implications for the implementation of personalized and tailored treatment strategies for BC patients.
METHODS AND RESULTS: The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67%∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression, and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine.
CONCLUSIONS: Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.