Objective: To assess guanfacine extended-release (GXR) efficacy and safety in adults with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 3, double-blind, placebo-controlled study (conducted between October 2016 and July 2017) included Japanese patients aged ≥ 18 years with ADHD (DSM-5). Patients received GXR (n = 101) or placebo (n = 100) titrated from 2 mg/d to 4-6 mg/d (doseoptimization; 5 weeks), followed by 4-6 mg/d (dose-maintenance; 5 weeks), then tapered doses to 2 mg/d (2 weeks). Primary endpoint was change from baseline in total score on the Japanese version of the ADHD-Rating Scale IV with adult prompts (ADHD-RS-IV) at week 10. Other measures were ADHD-RS-IV subscales, Clinical Global Impression-Improvement scale (CGI-I) and Patient Global Impression-Improvement scale (PGI-I) (percentage of patients very much improved/much improved), treatment-emergent adverse event (TEAE) incidences, and TEAEs leading to discontinuation. Results: Compared with placebo, there was statistically significantly greater improvement in ADHD-RS-IV total score reduction with GXR (least squares mean ± SE: GXR vs placebo,-11.55 ± 1.10 vs-7.27 ± 1.07; P = .0005; effect size 0.52). There were significantly greater improvements in GXR for ADHD-RS-IV inattention (-7.39 ± 0.79 vs-4.89 ± 0.76; P = .0032) and hyperactivity-impulsivity (-3.84 ± 0.54 vs-2.10 ± 0.52; P = .0021) subscale scores, CGI-I scores (48.1% vs 22.6%; P = .0007), and PGI-I scores (25.3% vs 11.8%; P = .0283). More patients in the GXR versus the placebo group reported TEAEs (81.2% vs 62.0%) and discontinued due to TEAEs (19.8% vs 3.0%). The main TEAEs in the GXR group were somnolence, thirst, blood pressure decrease, nasopharyngitis, postural dizziness, and constipation; most TEAEs were mild to moderate in severity. Conclusions: In Japanese adults with ADHD, GXR improved ADHD symptoms without any major safety concerns.

Human airway trypsin-like protease (HAT), a novel serine protease in the airways, enhances cell growth and IL-8 production. The expression and role of HAT in the skin however, is unknown. Immunofluorescence staining and reverse transcription (RT)-PCR were done to know HAT production in normal and psoriatic tissues and keratinocyte cell lines. Cell growth and/or IL-8 release analyses were made by bromo-deoxyuridine (BrdU) uptake and ELISA. Psoriatic epidermis showed more extensive immunofluorescence expression of HAT, and less extensive expression of protease-activated receptor (PAR)-2. RT-PCR demonstrated a higher HAT and a lesser PAR-2 mRNA expressions in psoriatic epidermis. Normal keratinocyte and epidermoid carcinoma cell lines expressed HAT and PAR-2 mRNA, and immortalized keratinocytes (HaCaT) expressed PAR-2, but not HAT mRNA. PAR-2 was detected along the keratinocyte surface in culture and became invisible upon HAT stimulation, suggesting a process of its internalization. HAT or PAR-2 activating peptide did not enhance BrdU uptake, but induced an IL-8 release. Treatment with HAT and IL-1beta synergistically increased the effect of IL-8 release. Inhibition of PAR-2 resulted in a decreased HAT-induced IL-8 release. Thus, HAT might promote PAR-2-mediated IL-8 production to accumulate inflammatory cells in the epidermal layer of psoriasis.

Intensive investigations on angiogenesis and vasculogenesis have increased our understanding of molecular mechanisms of blood vessel formation during pathologic and developmental conditions. However, endothelial cells (ECs), the main component of vasculature, are heterogeneous, as revealed by our phenotypic and molecular biological studies in the laboratory, and it is still hard to adequately understand the molecular mechanisms of angiogenesis and vasculogenesis. Indeed, there are several major ligand/receptor signal pathways: VEGF/VEGFR, Jagged-1/Notch, Wnt ligand/frizzled receptor, and ephrin/Eph; each of which having distinct and independent roles during vascular formation. In this review, we focus on the angiogenic effect of the Slit and Robo signal pathway that was formally known as neuronal axon guidance. Among the existing vascular signals, this pathway is the most recently found ligand/receptor vascular signal, and may play important physiological roles as other major receptor/ligand signals do. Here, we briefly address: (1) the background of Slit and Robo families; (2) expression patterns of Slit and Robo; (3) functional roles of the Slit/Robo pathway in vascular formation; and (4) confronting tasks of this novel vascular pathway in the near future. Together, a summary of these data suggest the essential role of the Slit/Robo pathway in angiogenesis, and may explain why multiple vascular signals exist in heterogenic endothelial cells.

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Objective: Protease-activated receptors (PARs) mediate DNA synthesis in endothelial cells when activated by serine proteases. However, despite the existence of heterogeneity among endothelial cells from each tissue, the responses to PAR-1, PAR-2, and PAR-4 activation are poorly defined and compared between endothelial cells from different sites. The aim of this study was to investigate whether PAR-mediated DNA synthesis differed in various endothelial cell types. Methods: We examined the incorporation of BrdU by human pulmonary artery endothelial cells (HPAECs), human aortic endothelial cells (HAECs), and human umbilical vein endothelial cells (HUVECs). Results: When the endothelial cells were treated with the selective PAR-1-activating peptide, SFLLRN, HAECs showed the highest BrdU incorporation rate (182 ± 28%). In contrast, treatment with the PAR-2-activating peptide, SLIGKV, resulted in the highest BrdU incorporation rate (173 ± 37%) in HPAECs, when pretreated with TNF-α. The PAR-4-activating peptide, GYPGQV, induced DNA synthesis in HPAECs and HAECs, but not in HUVECs. Conclusion: These findings suggest that each PAR preferentially targets an endothelial cell type, and thus plays a distinct role in diverse physiological or pathological conditions.