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Background Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation. Methods We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels. Results AD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD. Conclusion Baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.

Aims The present extension study evaluated the long-term safety and efficacy of gemigliptin during a 40-week follow-up period after a 12-week study. Methods The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) with moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7-11% and an estimated glomerular filtration rate (eGFR) of 15–59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, the patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas the patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study. Results The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in the HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00 ± 0.21% and 0.65 ± 0.22% lower at week 52 than at baseline (P

The aim of this study is to assess the quality of Telmi plus V® tablet (test formulation) by comparing its pharmacokinetic parameters with Micardis plus® tablet (reference formulation) in forty healthy Korean male volunteers. Seven subjects were withdrawn during the periods. This study was performed under fasted condition with a randomized, single-dose, 2-period crossover design. The dissolution studies of both formulations were conducted using USP apparatus 2 at 75 rpm with 1000 mL of phosphate buffer solution (pH 7.5) at 37 ± 0.5 °C. Forty healthy Korean male volunteers were enrolled in this study with 19–34 years (24.7 ± 3.9), height 164–184 cm (174.9 ± 5.3) and weight 52–85 kg (71.2 ± 9.0). The results of telmisartan were as follows: the mean AUC0−∞ of reference tablet and test tablet was 3290 ± 2270 and 3080 ± 2010 ng h/mL, respectively; the mean Cmax was 674 ± 366 and 612 ± 252 ng/mL, respectively; the mean Tmax was 0.92 ± 0.44 and 0.99 ± 0.46 h, respectively. The results of HCTZ were as follows: the mean AUC0−∞ of reference tablet and test tablet was 525 ± 94.3 and 536 ± 96.8 ng h/mL, respectively; the mean Cmax was 90.8 ± 25.4 and 86.2 ± 21.4 ng/mL, respectively; the mean Tmax was 1.58 ± 0.60 and 1.78 ± 0.66 h, respectively. The 90 % confidence intervals for geometric mean ratios of test to reference formulation of AUC0−t and Cmax were 0.9132–1.0441 and 0.8579–1.1048 for telmisartan, and 0.9737–1.0713 and 0.8801–1.0326 for HCTZ, respectively. The results of this study in healthy Korean male volunteers showed that the test and reference formulations of 80/12.5 mg telmisartan/hydrochlorothiazide met the MFDA regulatory criteria for bioequivalence. Both formulations were well tolerated, with no serious adverse events reported.

Objectives For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. Materials and methods This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. Results Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. Conclusion The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.