Utility of a Novel Micro-Spraying Device for Intranasal Administration of Drug Solutions to Mice.

Intranasal administration has attracted attention as a means of delivering drugs because it bypasses the blood-brain barrier. However, conventional intranasal administration of drug solutions to mice using the micropipette method (MP method) is complicated and time-consuming because it requires small doses to be administered under inhalation anesthesia. This study evaluated the effectiveness of a novel intranasal administration method using Micro FPS™, a novel micro-spraying device (the MSD method). The MSD method allowed more reliable administration of the solution to the nasal mucosa than the MP method did. The transfer of inulin, a model water-soluble macromolecule compound, to the olfactory bulb and brain (cerebrum, cerebellum, brainstem, and striatum) was similar with the two methods. It also allowed the drug to be administered in a shorter time. These results suggest that the MSD method is simpler and more rapid than the MP method for intranasal administration of drugs to mice and achieves comparable delivery of inulin to the olfactory bulb and brain. Therefore, the Micro FPS™ device is a potentially useful tool for intranasal drug administration to rodents and could facilitate the development of intranasal formulations, contributing to drug development for central nervous system diseases.

Application of ionic liquid to enhance the nose-to-brain delivery of etodolac.

The purpose of this study was to enhance the delivery of Etodolac (ETD) to the brain through intranasal administration using an ionic liquid (IL) consisting of ETD and proline ethyl ester. The IL of ETD was prepared by mixing ETD with proline ethyl ester as a counterion in a molar ratio of 1:2.The formation of the IL was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and proton nuclear magnetic resonance (1H-NMR).The solubility of ETD in simulated nasal fluids was improved by approximately 200-fold due to the formation of IL. The intranasal administration of ETD-containing IL, which is viscous, increased the nose-to-brain delivery by approximately 7-fold 30 min after an administration of the ETD solution alone. The enhancement of ETD delivery to the brain from the nose was attributed to the enhanced retention of ETD in the nasal mucosal surface due to the viscosity of IL. The induction of prostaglandin E2 in the brain inflammation that was induced by lipopolysaccharides was significantly suppressed by up to 40% in the IL-treated group compared with the drug-untreated group. Therefore, ETD-containing IL were suggested to be useful in designing intranasal formulations for the nasal delivery of ETDs to the brain.

Pitavastatin-induced downregulation of CCR2 and CCR5 in monocytes is associated with the arrest of cell-cycle in S phase.

The pleiotropic effects of statin, including its anti-inflammatory effects, via chemokines may be independent of statin-induced cholesterol reduction. Therefore, we examined the effect of pitavastatin on cell proliferation and the association between chemokine receptors (CCR2 and CCR5) and their ligands, RANTES (regulated upon activation, normal T cell-expressed and secreted) and monocyte chemotactic protein-1 (MCP-1), in monocytes. Pitavastatin but not pravastatin inhibited cell proliferation in a dose-dependent manner and showed S-phase arrest associated with the downregulation of CCR2 and CCR5 expression in human monocytic tumor cells (U937 cells). Although the anti-proliferative effects of pitavastatin were not inhibited by lower concentrations of RANTES and MCP-1, overexpression of CCR2/CCR5 significantly blocked the anti-proliferation with a low concentration of RANTES or MCP-1. Pitavastatin upregulated p21(waf1) but not p27(kip1), and did not change the expression levels of cyclin D1 or cdk4. In addition, RANTES and MCP-1 upregulated cyclin D1 in the presence of pitavastatin. In conclusion, the anti-proliferative effect of pitavastatin, but not pravastatin, through the downregulation of CCR2/CCR5 may be a pleiotropic effect. This effect may be anti-atherogenic in monocytes.

CXCR3 chemokine receptor-plasma IP10 interaction in patients with coronary artery disease.

In rat models of transplant vasculopathy, the strongest staining of CXCR3 is observed in the innermost layer of the neointima and because neointimal hyperplasia is seen after coronary angioplasty, the CXC chemokines may be targets for preventing stenosis. The expression of leukocyte surface chemokine receptors (CCR2/CCR5/CXCR2/CXCR3), as determined by flow cytometry, and plasma concentrations of monocyte chemoattractant protein (MCP)-1 and interferon-inducible protein (IP)10, as determined by enzyme immunoassays, were investigated in 55 patients with coronary artery disease (CAD) who underwent percutaneous transluminal coronary angioplasty (PTCA) and 20 patients without significant coronary stenosis based on the results of coronary catheterization during the same period (C group). The patients with CAD were divided into 3 groups: 20 with de novo stenosis (D group), 15 with restenosis (R group) and 20 without restenosis (N group) after PTCA. CXCR3 expression on lymphocytes, but not monocytes, in the R group was significantly lower than that in the C group. Although the plasma concentrations of IP10 in the D and N groups did not differ from that in the C group, the concentration in the R group was significantly higher. Increased plasma concentrations of IP10 were accompanied by a compensatory decrease in the CXCR3 expression on lymphocytes, but not monocytes, suggesting that a high plasma concentration of IP10 strongly induces monocytes signaling. The CXCR3 - plasma IP10 chemokine receptor - chemokine interaction on monocytes may affect the development of coronary restenosis, but not de novo stenosis, in patients with CAD.