Novel Histone Deacetylase 6 Inhibitor Confers Anti-inflammatory Effects and Enhances Gut Barrier Function

Background/Aims@#The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 inhibitor, on human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function. @*Methods@#Lipopolysaccharide-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor (TNF)-α expression was measured using an enzyme-linked immunosorbent assay. The proliferation of CD4+ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, based on examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription polymerase chain reaction, immunofluorescence, and a fluorescein isothiocyanatedextran permeability assay. @*Results@#Secretion of TNF-α, a pivotal pro-inflammatory mediator in IBD, by lipopolysaccharidetriggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction in barrier permeability in a dose-dependent manner. @*Conclusions@#The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4 T cells and improves gut barrier function, suggesting its potential as a smallmolecule therapeutic option for IBD.

Succinate-treated macrophages attenuate dextran sodium sulfate colitis in mice

The safety and effectiveness of adalimumab was demonstrated in a phase 3 trial in Japanese patients with intestinal Behçet’s disease. The aim of this study was to evaluate the long-term safety and effectiveness of adalimumab in Japanese patients with intestinal Behçet’s disease.

Succinate-treated macrophages attenuate dextran sodium sulfate colitis in mice

The safety and effectiveness of adalimumab was demonstrated in a phase 3 trial in Japanese patients with intestinal Behçet’s disease. The aim of this study was to evaluate the long-term safety and effectiveness of adalimumab in Japanese patients with intestinal Behçet’s disease.

Blood pressure lowering effect of statin drugs with an application to rosuvastatin

Hyperlipidemia and hypertension are among the major risk factors for cardiovascular disease (CVD) and they often co-exist within a single patient. Recently, many studies published results regarding the potential role of statins in decreasing blood pressure (BP) however there is still a controversy over the efficacy of statin therapy on BP. This study aimed to investigate the potential role of rosuvastatin in BP lowering properties in Korean population. Data were taken from three randomized, multiple-dose cross over studies for rosuvastatin, angiotensin II receptor blocker (ARB) and metformin monotherapies and the combined therapy of rosuvastatin and ARB, in total of 91 healthy male normotensive subjects. Measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) at the baseline before treatment begins and for 24 hours after the last dose were used in the analysis. The analysis variables used were (i) the mean change in steady-state BP from the baseline, symbolized as ΔBP, and (ii) the difference in ΔBP between the ARB monotherapy and the combined therapy, symbolized as ΔBP,d. The ΔBP and ΔBP,d for SBP from each study varied in -0.1 ~ -1.3 mmHg and 1.2 ~ 1.6 mmHg, respectively, and were not significantly different from zero. The ΔBP and ΔBP,d for DBP from each study varied in -2.8 ~ -1.4 mmHg and -2.9 ~ -1.8, respectively, which were statistically significant for ΔBP (p 0.05). These results indicated that the rosuvastatin monotherapy may produce small blood pressure lowing effect in DBP.

A quantitative approach for cardiovascular safety evaluation of a generic drug

In generic drug development, comparative pharmacokinetic (PK) studies are conducted to assess equivalence in pharmacokinetics and safety profiles between test and reference formulations. However, there is no established quantitative approach available for safety assessment. This study aimed to propose a method for drug safety evaluation in generic drug development, as assessed by drug influence on blood pressure and heart rate change. Data were taken from a randomized, open label, 2-way cross-over comparative PK study for megestrol conducted in 39 healthy male volunteers. Vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured at 0 (pre-dose), 4, 8, 12, 24, 48, 72, 96 and 120 hours after the dose. Safety parameters used in the analysis were area under vital sign change versus time curve to the last measured time (AUVlast) and maximum vital sign change (Vmax). Considering highly variable nature of vital signs, the scaled bioequivalence approach developed by US FDA was adopted as a decision rule for safety evaluation between formulations. With the FDA scaled approach, 90% confidence intervals of geometric mean ratio for DBP, 0.7969~1.0377 for Vmax and 0.7304~1.0660 for AUVlast, were both included in the equivalence ranges of 0.7694~1.2997 and 0.6815~1.4674, respectively, and similarly, those for HR were included in their respective scaled equivalence limits, while SBP satisfied the conventional equivalence criterion of 0.8-1.25. These results illustrate the feasibility of applying the suggested approach in cardiovascular safety evaluation in a generic drug.

Assessment of statistical power for covariate effects in data from phase I clinical trials

One of the important purposes in population pharmacokinetic studies is to investigate the relationships between parameters and covariates to describe parameter variability. The purpose of this study is to evaluate the model's ability to correctly detect the parameter-covariate relationship that can be observed in phase I clinical trials. Data were simulated from a two-compartment model with zero-order absorption and first-order elimination, which was built from valsartan's concentration data collected from a previously conducted study. With creatinine clearance (CLCR) being used as a covariate to be tested, 3 different significance levels of 0.001