Various peroxisome proliferator-activated receptor (PPAR)-γ agonists differently induce differentiation of cultured human keratinocytes.

Peroxisome proliferator-activated receptors (PPARs) are potentially useful for the treatment of skin diseases, because they stimulate keratinocyte differentiation, exert anti-inflammatory effects and improve barrier function. We examined five PPAR-γ agonists, including four thiazolidinediones (ciglitazone, troglitazone, rosiglitazone and pioglitazone) and an angiotensin-II receptor blocker (telmisartan), for their ability to upregulate filaggrin and loricrin expression at both mRNA and protein levels in cultured normal human keratinocytes (NHKs). Troglitazone, rosiglitazone, pioglitazone and telmisartan significantly increased filaggrin expression at both mRNA and protein levels in calcium-induced differentiated NHKs. Rosiglitazone and pioglitazone, but not troglitazone nor telmisartan, also significantly increased loricrin expression at both mRNA and protein levels in differentiated NHKs. These effects were not found in undifferentiated NHKs nor differentiated NHKs treated with ciglitazone. This study revealed differential effects of various PPAR-γ agonists on epidermal differentiation, and the most potent of those are rosiglitazone and pioglitazone.

Guanabenz and Clonidine, α2-Adrenergic Receptor Agonists, Inhibit Choroidal Neovascularization.

BACKGROUND: Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial growth factor (anti-VEGF)-drugs are used to treat AMD patients; however, some patients are resistant to these therapies. OBJECTIVE: The purpose of this study was to investigate the anti-angiogenic effects of α2-adrenergic agonists, including guanabenz and clonidine. METHODS: We evaluated the anti-angiogenic effects of α2-adrenergic agonists in human retinal microvascular endothelial cells (HRMECs). A proliferation assay was conducted, and the migration ratio was evaluated. In a laser-induced CNV model, guanabenz and clonidine were delivered via intraperitoneal injection or implantation of an osmotic pump device. Fourteen days following CNV induction, CNV lesion size and fundus fluorescein angiography (FFA) were evaluated. RESULTS: Guanabenz and clonidine inhibited VEGF-induced retinal endothelial cell growth and migration. In the CNV model mice, CNV lesion sizes were reduced by intraperitoneal administration of guanabenz or clonidine. Data, including body weight, systolic blood pressure, and heart rate showed that guanabenz (0.5 and 2.0 mg/kg/day) had little effect on these parameters; conversely, a high dose of clonidine (1.0 mg/kg/day) did affect these parameters. Additionally, clonidine did not affect CNV size, but continuous administration of guanabenz attenuated both CNV size and leakage from neovessels. CONCLUSION: Our study suggests a key role for α2-adrenergic receptors during CNV formation. Therefore, we suggest that α2-adrenergic receptor agonists may represent novel therapeutic drugs for patients with neovascular AMD.

[Pharmacological profile and clinical efficacy of transdermal patch containing emedastine difumarate (ALLESAGA® TAPE)].

ALLESAGA® TAPE is the first transdermal drug delivery system of emedastine difumarate, as a second-generation antihistamine, for allergic rhinitis. It has been suggested that the efficacy of emedastine difumarate in allergic rhinitis is mediated through a combination of chemical mediator release inhibitory effects and eosinophil chemotaxis inhibitory effects, in addition to a strong anti-histaminic effect. In the pharmacological evaluation on histamine-induced vascular hyperpermeability in rats, ALLESAGA® TAPE showed an anti-histaminic effect in a dose-dependent manner and exhibited a long-lasting anti-histaminic effect until 24 hours after administration. In the patients having allergic nasal symptoms, the plasma concentration of emedastine reached at steady-state within 7 days after multiple administration of ALLESAGA® TAPE. ALLESAGA® TAPE was effective for treating seasonal allergic rhinitis with sustained action throughout the day. Long-term application of ALLESAGA® TAPE raised no safety concerns in patients with perennial allergic rhinitis. Plasma drug concentrations showed little change over a long period and there was no decrease of efficacy. Based on the above results, ALLESAGA® TAPE is possible to provide a new option for the treatment of allergic rhinitis.

Pharmaceutical design of a novel colon-targeted delivery system using two-layer-coated tablets of three different pharmaceutical formulations, supported by clinical evidence in humans.

Drug delivery systems to the colon are being actively investigated in order to develop oral preparations of peptides and treat local colonic diseases. However, it is difficult to ensure that an oral preparation disintegrates specifically in the human colon. To make a colonic delivery system practical for medical use, in vitro testing methods need to be established in order to determine the specifications of the preparations. To achieve this objective, three pharmaceutical preparations, designed to have different tablet disintegration times, were used to examine three buffers in seven combinations intended to simulate pH changes in the stomach, small intestine, and colon of humans. To validate the in vitro methodology, furthermore, the fate of all the formulations was examined in the gastrointestinal (GI) tract of healthy volunteers. A three-way crossover trial by scintigraphy revealed that the three formulations--in spite of presenting different in vitro tablet disintegration profiles--have comparable transit profiles and excellent colon-targeting properties in the human gastrointestinal tract regardless of gender and age. These facts strongly suggest that this novel delivery system may be useful for the delivery of drugs to the human colon.