Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Epithelial polarization in the 3D matrix requires MST3 signaling to regulate ZO-1 position.

Apical-basal cell polarity must be tightly controlled for epithelial cyst and tubule formation, and these are important functional units in various epithelial organs. Polarization is achieved through the coordination of several molecules that divide cells into an apical domain and a basolateral domain, which are separated from tight and adherens junctions. Cdc42 regulates cytoskeletal organization and the tight junction protein ZO-1 at the apical margin of epithelial cell junctions. MST kinases control organ size through the regulation of cell proliferation and cell polarity. For example, MST1 relays the Rap1 signal to induce cell polarity and adhesion of lymphocytes. Our previous study showed that MST3 was involved in E-cadherin regulation and migration in MCF7 cells. In vivo, MST3 knockout mice exhibited higher ENaC expression at the apical site of renal tubules, resulting in hypertension. However, it was not clear whether MST3 was involved in cell polarity. Here, control MDCK cells, HA-MST3 and HA-MST3 kinase-dead (HA-MST3-KD) overexpressing MDCK cells were cultured in collagen or Matrigel. We found that the cysts of HA-MST3 cells were fewer and smaller than those of control MDCK cells; ZO-1 was delayed to the apical site of cysts and in cell-cell contact in the Ca2+ switch assay. However, HA-MST3-KD cells exhibited multilumen cysts. Intensive F-actin stress fibers were observed in HA-MST3 cells with higher Cdc42 activity; in contrast, HA-MST3-KD cells had lower Cdc42 activity and weaker F-actin staining. In this study, we identified a new MST3 function in the establishment of cell polarity through Cdc42 regulation.

[Clinical investigation on characteristics of traditional Chinese medical syndrome of hepatocirrhosis].

OBJECTIVE: To explore the characteristics of traditional Chinese medical syndrome (TCM syndrome) of hepatocirrhosis. METHODS: Clinical information from the four diagnosis methods of traditional Chinese medicine (TCM) and related laboratorial indexes were systematically collected from 223 hepatocirrhosis cases, and the multi-statistical methods including systematic cluster analysis, principal component analysis, stepwise discrimination and variance analysis were made with the software SAS 6.11. RESULTS: Multi-analysis showed that there were 3 categories of syndrome characteristics. Type 1 (134 cases): damp heat, blood stasis, deficiency of liver and spleen Qi; Type 2 (62 cases): deficiency of both Qi and Yin with severe deficiency of Qi, heat with severe dampness, blood stasis; Type 3 (27 cases): deficiency of both Qi and Yin with severe deficiency of Yin, stasis and heat or dampness. Analysis of the changes of the related laboratorial indexes among the three types of syndrome showed that Type 1 mainly manifested asthenia syndrome with sthenia syndrome, and its indexes of AST, ALT, GGT levels were markedly higher than those of Type 2 and Type 3, both of which mainly showed sthenia syndrome with asthenia syndrome, and that Type 3 was in active inflammation, deficiency of both Qi and Yin (deficiency of Yin > deficiency of Qi), and its FN, Alb, FV, FVII, PLT, PCT levels were obviously reduced. CONCLUSION: The multi-statistical methods can reveal the characteristics and regularity of TCM syndrome of hepatocirrhosis, and the 3 categories of syndrome characteristics basically conform to clinical manifestations. The result of TCM syndrome distribution and laboratorial indexes infer that damp heat is the pathological basis of hepatocirrhosis, and the degree of liver function disorder and liver damage may be the pathological basis of deficiency of Yin of both liver and kidney.