ObjectivesWe aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.MethodsA single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples.ResultsThe intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%).ConclusionsAgomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies.Trial RegistrationChiCTR.org ChiCTR-TTRCC-13003835

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Mitochondrial damage is an important cause of heart dysfunction after severe burn injury. However, the pathophysiological process remains unclear. This study aims to examine the mitochondrial dynamics in the heart and the role of μ-calpain, a cysteine protease, in this scenario. Rats were subjected to severe burn injury treatment, and the calpain inhibitor MDL28170 was administered intravenously 1 h before or after burn injury. Rats in the burn group displayed weakened heart performance and decreased mean arterial pressure, which was accompanied by a diminishment of mitochondrial function. The animals also exhibited higher levels of calpain in mitochondria, as reflected by immunofluorescence staining and activity tests. In contrast, treatment with MDL28170 before any severe burn diminished these responses to a severe burn. Burn injury decreased the abundance of mitochondria and resulted in a lower percentage of small mitochondria and a higher percentage of large mitochondria. Furthermore, burn injury caused an increase in the fission protein DRP1 in the mitochondria and a decrease in the inner membrane fusion protein OPA1. Similarly, these alterations were also blocked by MDL28170. Of note, inhibition of calpain yielded the emergence of more elongated mitochondria along with membrane invagination in the middle of the longitude, which is an indicator of the fission process. Finally, MDL28170, administered 1 h after burn injury, preserved mitochondrial function and heart performance, and increased the survival rate. Overall, these results provided the first evidence that mitochondrial recruitment of calpain confers heart dysfunction after severe burn injury, which involves aberrant mitochondrial dynamics.

Purpose To investigate the predictive value of systemic immune-inflammation-index (SII) and Pan-Immune-Inflammation-value (PIV) for axillary lymph node (ALN) metastasis in patients with breast cancer. Patients and Methods We retrospectively collected data of 247 patients with invasive breast from the Affiliated Hospital of Jiangnan University. The state of axillary lymph node (ALN) metastasis was confirmed by pathological diagnosis. Clinicopathological data (age, ER, PR, HER2, Ki67 expression levels, diapause status, weight, histological grade, vascular invasion, and state of axillary lymph node) were compared between differences of SII and PIV groups and an association between clinical indexes and ALN metastasis was evaluated. Results The cut-off values of SII and PIV were 320.04 and 92.01, respectively. The significant difference between vascular invasion ( P =0.023) and axillary lymph node metastases ( P <0.001) in the high and low SII levels. Significant differences were observed in tumor size ( p =0.024), PR expression level ( P =0.033) and the status of axillary lymph node metastases ( p <0.001) between the high PIV group and the low PIV group. Univariate analysis showed that vascular invasion, tumor size, Ki67 expression level, SII, and PIV were significantly correlated with axillary lymph node metastases ( p <0.05). Then, multivariate analysis revealed that the vascular invasion ( p <0.001), HER2 expression levels ( p <0.047), SII ( p <0.001) and PIV ( p <0.030) were risk factors for axillary lymph node metastases. Conclusion High levels of SII, PIV, LVI, and HER2 are the risk factors for axillary lymph node metastases in breast cancer patients.