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Biomedical subjects

Kaneto Uekama

Publications and source records attributed to Kaneto Uekama.

28 records · Page 2Linked to original sources
PubMed2004

[Pharmaceutical application of cyclodextrins as multi-functional drug carriers].

Owing to the increasingly globalized nature of the cyclodextrin (CyD)-related science and technology, development of the CyD-based pharmaceutical formulation is rapidly progressing. The pharmaceutically useful CyDs are classified into hydrophilic, hydrophobic, and ionic derivatives. Because of the multi-functional characteristics and bioadaptability, these CyDs are capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes or the form of CyD/drug conjugates. This review outlines the current application of CyDs in drug delivery and pharmaceutical formulation, focusing on the following evidences. 1) The hydrophilic CyDs enhance the rate and extent of bioavailability of poorly water-soluble drugs. 2) The amorphous CyDs such as 2-hydroxypropyl-beta-CyD are useful for inhibition of polymorphic transition and crystallization rates of drugs during storage. 3) The delayed release formulation can be obtained by the use of enteric type CyDs such as O-carboxymethyl-O-ethyl-beta-CyD. 4) The hydrophobic CyDs are useful for modification of the release site and/or time profile of water-soluble drugs with prolonged therapeutic effects. 5) The branched CyDs are particularly effective in inhibiting the adsorption to hydrophobic surface of containers and aggregation of polypeptide and protein drugs. 6) The combined use of different CyDs and/or pharmaceutical additives can serve as more functional drug carriers, improving efficacy and reducing side effects. 7) The CyD/drug conjugates may provide a versatile means for the constructions of not only colonic delivery system but also site-specific drug release system, including gene delivery. On the basis of the above-mentioned knowledge, the advantages and limitations of CyDs in the design of advanced dosage forms will be discussed.

Animals↗
PubMed2003

Involvement of cholesterol in the inhibitory effect of dimethyl-beta-cyclodextrin on P-glycoprotein and MRP2 function in Caco-2 cells.

We compared the inhibitory effect of various cyclodextrins (CyDs) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory effect of 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) on the efflux activity of the function in Caco-2 cell monolayers. Of various CyDs, DM-beta-CyD significantly impaired the efflux activity of P-gp and MRP2. DM-beta-CyD released P-gp and MRP2 from the monolayers in the apical side's transport buffer and decreased the extent of cholesterol as well as P-gp and MRP2 in caveolae of Caco-2 cell monolayers, but not caveolin and flotillin-1. On the other hand, DM-beta-CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory effect of DM-beta-CyD on P-gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary effects through cholesterol-depletion in caveolae after treatment of Caco-2 cell monolayers with DM-beta-CyD.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Inhibitory effect of sulfobutyl ether beta-cyclodextrin on DY-9760e-induced cellular damage: In vitro and in vivo studies.

The effects of water-soluble beta-cyclodextrin derivatives (beta-CyDs), such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutyl ether beta-cyclodextrin (SBE7-beta-CyD) on cytotoxicity of DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) toward human umbilical vein endothelial cells (HUVECs) in vitro and vascular damage of the auricular vein of rabbits by DY-9760e in vivo were investigated. The spectroscopic study revealed that of the four beta-CyDs SBE7-beta-CyD forms the most stable inclusion complex in phosphate-buffered saline, probably because of a synergetic effect of hydrophobic and electrostatic interactions. beta-CyDs inhibited DY-9760e-induced cell death toward HUVECs in an order of G(2)-beta-CyD < beta-CyD < HP-beta-CyD < SBE7-beta-CyD, which was consistent with the order of the magnitude of stability constants. When the DY-9760e solution was infused into the auricular vein of rabbits for 24 h, SBE7-beta-CyD suppressed a DY-9760e-induced irritation such as thrombus, desquamation of the endothelium vasculitis, and perivasculitis. The present data indicated that SBE7-beta-CyD formed an inclusion complex with DY-9760e in a buffer solution and possessed the protective effect on DY-9760e-induced cytotoxicity toward HUVECs and vascular damage in rabbits. These results suggested potential use of SBE7-beta-CyD as a parenteral carrier for DY-9760e.

Animals↗
PubMed2002

6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl-beta-cyclodextrin: solubilizing ability and some cellular effects.

Some physicochemical and biopharmaceutical properties of a new branched cyclodextrin, 6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl-beta-cyclodextrin (GUG-beta-CyD), were investigated. The interaction of GUG-beta-CyD with drugs was studied by spectroscopic and solubility methods, and compared with those of parent beta-CyD and 6-O-alpha-maltosyl-beta-CyD (G(2)-beta-CyD). The hemolytic activity of GUG-beta-CyD on rabbit erythrocytes was lower than those of beta-CyD and G(2)-beta-CyD. GUG-beta-CyD and G(2)-beta-CyD showed negligible cytotoxicity on Caco-2 cells up to at least 0.1 M. The inclusion ability of GUG-beta-CyD to neutral and acidic drugs was comparable to or slightly smaller than those of beta-CyD and G(2)-beta-CyD, probably because of a steric hindrance of the branched sugar. On the other hand, GUG-beta-CyD showed greater affinity for the basic drugs, compared with beta-CyD and G(2)-beta-CyD, owing to an electrostatic interaction of its carboxylate anion with positive charge of basic drugs. Thus, GUG-beta-CyD may be useful as a safe solubilizing agent particularly for basic drugs.

Animals↗
PubMed2002

Cyclodextrin conjugate-based controlled release system: repeated- and prolonged-releases of ketoprofen after oral administration in rats.

6(A)-O-[2-(3-Benzoylphenyl)propinoyl]-alpha-cyclodextrin (KP-alpha-CyD conjugate), in which an anti-inflammatory drug, ketoprofen (KP), is covalently bound to one of the primary hydroxyl groups of alpha-cyclodextrin, was prepared, and its release behavior in vitro and in vivo was investigated. Further, the CyD conjugate-based repeated- and prolonged-release systems were designed by combining the conjugate (used as a delayed-release fraction) with the KP-2-hydroxypropyl-beta-CyD (HP-beta-CyD) complex (used as a fast-release fraction) or with KP-ethylcellulose (EC) solid dispersion (used as a slow-release fraction), respectively. The conjugate released KP only in rat cecum and colonic contents, whereas it was stable in other biological fluids of rats. The conjugate showed a typical delayed-release pattern after oral administration to rats, i.e., plasma levels of KP increased after a lag time of about 3 h and reached a maximum concentration at about 7 h. On the other hand, the non-covalent inclusion complex of KP with HP-beta-CyD gave a rapid increase in plasma drug levels, and the KP-EC solid dispersion retarded slightly the increase of plasma levels. The co-administration of the conjugate and the HP-beta-CyD complex gave a typical repeated release profile, i.e., double peaks were observed at about 1-2 and 8-12 h in plasma KP levels. On the other hand, the co-administration of the conjugate and the EC solid dispersion gave a typical sustained-release pattern of KP, i.e., a constant plasma KP level was maintained for at least 24 h. These repeated or long circulating release patterns in plasma KP levels after oral administration were clearly reflected in the anti-inflammatory effect using rats with carageenan-induced acute edema in paw. The results suggest that various release-controlled preparations can be designed by employing CyD conjugates in combination with other carriers with different releasing properties.

Administration, Oral↗
PubMed2002

Colon-specific delivery of prednisolone-appended alpha-cyclodextrin conjugate: alleviation of systemic side effect after oral administration.

Prednisolone (PD), a typical glucocorticoid, has been widely used for the treatment of inflammatory bowel disease (IBD). However, when PD is administered orally, a large amount of the drug is absorbed from the upper gastrointestinal (GI) tract and causes systemic side effects. In this study, the anti-inflammatory effect and systemic side effect of the PD succinate/alpha-cyclodextrin (PDsuc/alpha-CyD) ester conjugate after oral administration were studied using IBD model rats. The anti-inflammatory effect of the PDsuc/alpha-CyD conjugate was comparable to those of PD alone. On the other hand, the systemic side effect of the PDsuc/alpha-CyD conjugate was much lower than that of PD alone when administered orally. The lower side effect of the conjugate was attributable to passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specifically in the large intestine. The oral administration of PD alone gave higher plasma concentrations of PD, giving the significant systemic side effect. The results suggested that the PDsuc/alpha-CyD conjugate is useful as a delayed-release type prodrug of PD for colon-specific delivery, owing to alleviation of the systemic side effect, while maintaining the therapeutic effect.

Administration, Oral↗
PubMed2002

Inclusion complex formation of captopril with alpha- and beta-cyclodextrins in aqueous solution: NMR spectroscopic and molecular dynamic studies.

The inclusion complex formation of alpha-cyclodextrin (alpha-CyD), beta-cyclodextrin (beta-CyD), and 2-hydroxylpropyl-beta-cyclodextrin (HP-beta-CyD) with an angiotensin converting enzyme inhibitor, captopril, in aqueous solution was studied by (1)H- and (13)C-nuclear magnetic resonance spectroscopies, including ROESY and GROESY techniques, by kinetic methods and by molecular dynamic calculations. The oxidative degradation of captopril was markedly suppressed in alpha-CyD solutions, whereas beta-CyD and HP-beta-CyD had negligible stabilizing effects. These NMR and kinetic results suggested that alpha-CyD includes preferably the propyl thioalcohol moiety of captopril, depositing the proline moiety outside the cavity. On the other hand, beta-CyD includes a whole molecule of captopril in the cavity, locating the carboxylic acid within the cavity and the terminal thiol moiety outside the cavity. These inclusion structures were supported by molecular dynamic studies.

Captopril↗
PubMedDate not supplied

Effects of structure of polyamidoamine dendrimer on gene transfer efficiency of the dendrimer conjugate with alpha-cyclodextrin.

To improve gene transfer activity of a new nonviral vector, a polyamidoamine dendrimer (G2) conjugate with alpha-cyclodextrin (alpha-CDE conjugate (G2)), we prepared alpha-CDE conjugates with dendrimer having different generations (G3 and G4), and their gene transfer activities were compared with those of alpha-CDE conjugate (G2) and TransFast, a novel transfection reagent. alpha-CDE conjugates (G2, G3, and G4) formed the complexes with pDNA, changing the zeta-potential and particle size of pDNA complexes and the protection of pDNA from DNase I in a charge ratio-dependent manner, although their differences at higher charge ratios (vector/pDNA) were small. The gene transfer activity of alpha-CDE conjugates (G2, G3, and G4) was higher than that of the corresponding dendrimer alone in NIH3T3 and RAW264.7 cells. Of these CDE conjugates, alpha-CDE conjugate (G3) had a superior gene transfer activity which was comparable to that of TransFast in NIH3T3 cells. The intracellular distribution of pDNA after application of the pDNA complex with alpha-CDE conjugate (G3) to NIH3T3 cells was different from that with dendrimer alone (G3), although the cellular association of pDNA was almost comparable among all vectors. alpha-CDE conjugate (G3) strongly interacted with a fluorescence probe, 2-(p-toluidinyl)-naphthalene-6-sulfonate (TNS), suggesting that the conjugate possesses the inclusion ability with biomembrane constituents such as phospholipids after transfection. These results suggest that alpha-CDE conjugates, particularly the G3 conjugate, could be novel nonviral gene transfer agents.

3T3 Cells↗
PubMedDate not supplied

In vitro and in vivo gene transfer by an optimized alpha-cyclodextrin conjugate with polyamidoamine dendrimer.

The purpose of the present study is to optimize the structure of the polyamidoamine starburst dendrimer (dendrimer) conjugate with alpha-cyclodextrin (alpha-CDE conjugate) as a nonviral vector. alpha-CDE conjugates of dendrimer (generation 3, G3) with various average degrees of substitution (DS) of alpha-CyD of 1.1, 2.4, and 5.4 were prepared. alpha-CDE conjugates formed the complexes with pDNA, resulting in a change of the particle sizes of pDNA complexes, but the distinction of physicochemical properties among their vector/pDNA complexes was only very slight. The membrane-disruptive ability of alpha-CDE conjugates on liposomes encapsulating calcein and their cytotoxicity to NIH3T3 and HepG2 increased with an increase in the DS value of alpha-CyD. In vitro gene transfer activity of alpha-CDE conjugates in both NIH3T3 and HepG2 cells augmented as the charge ratio (vector/pDNA) increased, and the activity of alpha-CDE conjugate (DS 2.4) was the highest at higher charge ratios among dendrimer (G3), the three alpha-CDE conjugates, and TransFast. After intravenous administration of pDNA complexes in mice, alpha-CDE conjugate (DS 2.4) delivered pDNA more efficiently in spleen, liver, and kidney, compared with dendrimer and other alpha-CDE conjugates (DS 1.1 and 5.4). The potential use of alpha-CDE conjugate (G3, DS 2.4) could be expected as a nonviral vector in vitro and in vivo, and these data may be useful for design of alpha-CyD conjugates with other nonviral vectors.

3T3 Cells↗