alpha-cyclodextrin and Disease-Models--Animal

Chronic heart failure is often characterized by the elevated amounts of reactive oxygen species such as hydrogen peroxide (H

Topics: alpha-Cyclodextrins; Animals; Animals, Genetically Modified; Captopril; Disease Models, Animal; Drug Delivery Systems; Drug Liberation; Heart Failure; Hydrogen Peroxide; Nanoparticles; Porosity; Silicon Dioxide; Zebrafish

The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity.. Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic. These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.

Topics: alpha-Cyclodextrins; Amphotericin B; Animals; Antifungal Agents; Blood Platelets; Candida albicans; Candidiasis; Chemistry, Pharmaceutical; Chitosan; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Female; Hydrogels; Mice; Mice, Inbred BALB C; Mucous Membrane; Nanoparticles; Poloxamer; Swine

NF-κB and its associated pathways are complicatedly concerned about hepatic homeostasis. Discriminating inhibition of NF-κB signaling has been expected to treat various liver diseases including fulminant hepatitis. To clarify the potential use of thioalkylated mannose-appended dendrimer (generation 3; G3) conjugates with α-cyclodextrin with average degree of substitution of mannose (DSM4) (Man-S-α-CDE (G3, DSM4)) as a novel antigen presenting cell (APC)-specific siRNA carrier, we evaluated the RNAi effect of NF-κB p65 siRNA (sip65) complex with Man-S-α-CDE (G3, DSM4) both in vitro and in vivo. Man-S-α-CDE (G3, DSM4)/sip65 complex significantly suppressed NF-κB p65 mRNA expression and nitric oxide (NO) production from lipopolysaccharide (LPS)-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and mannose receptor-mediated cellular uptake. Intravenous injection of Man-S-α-CDE (G3, DSM4)/sip65 complex extended the survival rate of LPS-induced fulminant hepatitis model mice. In addition, intravenous administration of Man-S-α-CDE (G3, DSM4)/sip65 complex had the potential to induce the in vivo RNAi effect by significant suppression of mRNA expression of NF-κB p65 and inflammatory cytokines in the liver of fulminant hepatitis model mice induced by LPS/d-galactosamine (d-Gal) without any significant side effects. Also, the serum levels of enzymes were significantly attenuated by injection of Man-S-α-CDE (G3, DSM4)/sip65 complex in fulminant hepatitis model mice. Collectively, these results suggest that Man-S-α-CDE (G3, DSM4) has the potential as a novel APC-selective sip65 carrier for the treatment of LPS/d-Gal-induced fulminant hepatitis in mice.

Topics: alpha-Cyclodextrins; Animals; Antigen-Presenting Cells; Cell Survival; Dendrimers; Disease Models, Animal; Drug Carriers; Gene Transfer Techniques; Hepatitis; Humans; Lipopolysaccharides; Macrophages, Alveolar; Male; Mannose; Mice; Mice, Inbred C57BL; NF-kappa B; Rats; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Survival Rate

The purpose of the present study is to treat lipopolysaccharide (LPS)-induced fulminant hepatitis by NF-κB decoy complex with fucose-appended dendrimer (generation 2; G2) conjugate with α-cyclodextrin (Fuc-S-α-CDE (G2)). Fuc-S-α-CDE (G2, average degree of substitution of fucose (DSF2))/NF-κB decoy complex significantly suppressed nitric oxide and tumor necrosis factor-α (TNF-α) production from LPS-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and fucose receptor-mediated cellular uptake. Intravenous injection of Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex extended the survival of LPS-induced fulminant hepatitis model mice. In addition, Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex administered intravenously highly accumulated in the liver, compared to naked NF-κB decoy alone. Furthermore, the liver accumulation of Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex was inhibited by the pretreatment with GdCl3, a specific inhibitor of Kupffer cell uptake. Also, the serum aspartate aminotransferase, alanine aminotransferase and TNF-α levels in LPS-induced fulminant hepatitis model mice were significantly attenuated by the treatment with Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex, compared with naked NF-κB decoy alone. Taken together, these results suggest that Fuc-S-α-CDE (G2, DSF2) has the potential for a novel Kupffer cell-selective NF-κB decoy carrier for the treatment of LPS-induced fulminant hepatitis in mice.

Topics: alpha-Cyclodextrins; Animals; Cell Line; Cell Survival; Dendrimers; Disease Models, Animal; Drug Carriers; Fucose; Lipopolysaccharides; Liver Failure, Acute; Liver Function Tests; Macrophages, Alveolar; Male; Mice, Inbred C57BL; Molecular Structure; Nitric Oxide; Oligodeoxyribonucleotides; Rats; Surface Properties; Tumor Necrosis Factor-alpha

The efficacy of alpha-cyclodextrin against infection by Cryptosporidium parvum was evaluated using in vitro and in vivo models. Cyclodextrins are water-soluble cyclic hexamers of glucose units with hydrophobic cavities capable of solubilizing lipophiles and are widely used as drug excipients in the pharmaceutical industry. The viability of purified C. parvum oocysts, exposed for 30, 60, 90, 120 min and 24h to different concentrations of alpha-cyclodextrin (2.5, 5, 7.5, 10, 12.5 and 15%), was evaluated by inclusion or exclusion of two fluorogenic vital dyes and by an excystation technique. Preventive and curative efficacies against cryptosporidial infections, at different doses (2.5 and 5%) and regimes of administration of alpha-cyclodextrin, were determined in an experimental neonatal mice model. Results of the viability assay showed a decrease in oocyst viability that was associated with an increase in exposure time, for each of the concentrations used. Moreover, a high proportion of nonviable oocysts (81%) was observed when C. parvum oocysts were exposed to alpha-cyclodextrin (2.5%) for 24h. The intensity of infection, determined 7 days post-inoculation by examination of intestinal homogenates, was significantly lower (P<0.05) than in the control litters, for all the assays carried out with alpha-cyclodextrin. Only 38.8% of the animals became infected when the alpha-cyclodextrin solution (5%) was administered 2h before inoculated oocysts, and every 24h at 1 and 2 days post-inoculation.

Topics: alpha-Cyclodextrins; Animals; Animals, Newborn; Cryptosporidiosis; Cryptosporidium parvum; Cyclodextrins; Disease Models, Animal; Dose-Response Relationship, Drug; Fluorescent Dyes; Humans; Mice; Specific Pathogen-Free Organisms

An orally active prostaglandin E1 analogue, OP-1206 alpha-CD improves walking dysfunction in the rat spinal stenosis model. Loxoprofen-Na, a non-steroidal anti-inflammatory drug, is used to relieve chronic pain in patients with lumbar spinal canal stenosis. To determine whether the OP-1206 alpha-CD in combination with loxoprofen-Na could induce a greater therapeutical effect on walking dysfunction and spinal cord blood flow (SCBF) than OP-1206 alpha-CD treatment alone after chronic spinal stenosis in the rat. Spinal stenosis was induced by placing two pieces of silicon rubber strips in the lumbar (L4 and L6) epidural space of rats. After surgery, walking function was measured using a treadmill apparatus and SCBF was measured using a laser-Doppler flow meter. Drugs were administered orally twice a day for 11 days from the day 3 post-surgery. OP-1206 alpha-CD elicited a significant improvement of walking dysfunction on days 7 and 14 post-surgery and significantly increased spinal cord blood flow on day 15, whereas walking dysfunction and SCBF of rats treated with loxoprofen-Na alone remained unchanged. Combined treatment of OP-1206 alpha-CD with loxoprofen-Na did not provide additive therapeutical effect. These results suggest that a significant improvement seen after OP-1206 alpha-CD treatment is primarily mediated by improvement of the local spinal cord blood flow. This effect is not ameliorated or potentiated by a combined treatment with loxoprofen-Na.

Topics: Administration, Oral; alpha-Cyclodextrins; Alprostadil; Animals; Cyclodextrins; Disease Models, Animal; Drug Therapy, Combination; Intermittent Claudication; Male; Phenylpropionates; Prostaglandins E, Synthetic; Rats; Rats, Wistar; Regional Blood Flow; Spinal Cord; Spinal Stenosis; Walking

Ciclosporin (CS) has been shown to be a potent immunosuppressive drug. However, systemic administration of CS has been limited because of its unfavourable side effects. Thus, our attention has been focused on a topical application of CS for ophthalmic diseases. In this study, we examined the influence of a topical application of CS on experimentally induced ocular inflammation. CS was prepared by a new drug delivery system, with alpha-cyclodextrin (CD) as a solvent. Topical 0.075% CD-CS reduced ocular inflammation of rabbits induced by intravitreal injection of bovine serum albumin. The magnitude of efficacy of topical 0.075% CD-CS fell within the same level as that of topical 0.02% fluorometholone. However, the topical CD-CS showed no effect on experimental autoimmune uveitis in rats which had been induced by S-antigen or interphotoreceptor retinoid-binding protein. These findings indicate that the topical CD-CS is effective on anterior uveitis.

Topics: Administration, Topical; alpha-Cyclodextrins; Animals; Antigens; Arrestin; Cyclodextrins; Cyclosporine; Disease Models, Animal; Drug Carriers; Eye Proteins; Male; Ophthalmic Solutions; Phosphodiesterase Inhibitors; Rabbits; Rats; Rats, Inbred Lew; Retinol-Binding Proteins; Uveitis; Vitreous Body