Biomedical subjects

F Hirayama

Publications and source records attributed to F Hirayama.

At least 37 records · Page 2Linked to original sources

PubMed2001

A moderate interaction of maltosyl-alpha-cyclodextrin with Caco-2 cells in comparison with the parent cyclodextrin.

The cytotoxicity of maltosyl-alpha-cyclodextrin (G2-alpha-CyD) and maltosyl-beta-cyclodextrin (G2-beta-CyD) toward Caco-2 cells was compared with that of natural alpha-cyclodextrin (alpha-CyD), beta-cyclodextrin (beta-CyD) and gamma-cyclodextrin (gamma-CyD). The degree of increase in cytotoxicity was dependent on the CyD's type and the concentration: the cytotoxicity of CyDs at the same concentration increased in the order of gamma-CyD<G2-beta-CyD<G2-alpha-CyD<<alpha-CyD, although beta-CyD could not be compared to other CyDs because of low solubility in water. Alpha-CyD decreased transepithelial electrical resistance (TEER) and increased the apical-to-basolateral (AP-to-BL) transport of [3H]mannitol, a paracellular transport marker, in a concentration-dependent manner, suggesting that alpha-CyD decreased the integrity of Caco-2 cell monolayers. In addition, alpha-CyD increased the AP-to-BL transport of rhodamine 123, a transcellular transport marker, under the experimental conditions being independent of P-glycoprotein. In contrast, G2-alpha-CyD, G2-betaCyD and gamma-CyD had slight effect on both TEER and the transport of mannitol and rhodamine 123 even at relatively high concentrations up to 150 mM. The inability of G2-alpha-CyD and G2-beta-CyD to effect TEER and the transport of mannitol and rhodamine 123 could be explained by the findings that these maltosylated CyDs released only a small amount of membrane constituents from Caco-2 cell monolayers and interacted only weakly with monolayers composed of L-alpha-dipalmitoylphosphatidylcholine (DPPC) formed on water. These results indicate that G2-alpha-CyD has less cytotoxicity and less disturbing ability toward Caco-2 cell monolayers than alpha-CyD, and G2-beta-CyD has, at least, comparable cytotoxicity to beta-CyD toward them. Thus, from the safety point of view, highly water-soluble G2-alpha-CyD and G2-beta-CyD may be particularly useful in various pharmaceutical formulations.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2001

Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation.

The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD complexes.

Cyclodextrins↗

PubMed2001

Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus.

We recently reported that of all hydrophilic cyclodextrin (CyD) derivatives examined, 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) most significantly increased the aqueous solubility and the dissolution rate, resulting in the improvement of oral bioavailability of the immunosuppressive drug tacrolimus in rats. In the present study, we showed that DM-beta-CyD increased the dissolution rate and oral bioavailability of tacrolimus in rats with increases in the molar ratio of the complexes (DM-beta-CyD:tacrolimus). However, nonlinear pharmacokinetic behavior of tacrolimus after oral administration in rats was observed. Thus, an additional mechanism of the solubilizing effect of DM-beta-CyD on oral bioavailability of tacrolimus was postulated. To gain insight into this additional mechanism of action of DM-beta-CyD, its effects on the efflux of tacrolimus and rhodamine 123, a P-glycoprotein (P-gp) substrate, were examined using both Caco-2 and vinblastine-resistant Caco-2 (Caco-2R) cell monolayers. Pretreatment of the apical membranes of the monolayers with DM-beta-CyD decreased the efflux of tacrolimus and rhodamine 123 without an associated cytotoxicity. DM-beta-CyD decreased the P-gp level in the apical membranes of both Caco-2 and Caco-2R cell monolayers, probably by allowing release of P-gp from the apical membrane into the transport buffer. DM-beta-CyD, however, did not decrease the MDR1 gene expression in Caco-2 or Caco-2R cells. These results suggested that the enhancing effect of DM-beta-CyD on the oral bioavailability of tacrolimus is due not only to its solubilizing effect but also, at least in part, to its inhibitory effect on the P-gp-mediated efflux of tacrolimus from intestinal epithelial cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Comparison of sensitivity to ultraviolet B irradiation between human lymphocytes and hematopoietic stem cells.

To investigate the clinical applicability of prophylaxis of post-transplant graft-versus-host disease by UV-B irradiation of stem cell preparations, the UV-B sensitivities of human lymphocytes and primitive hematopoietic progenitors were compared. The mononuclear cell fractions (MNC) derived from human cord blood and granulocyte-colony-stimulating factor-mobilized peripheral blood were used. After UV-B irradiation, lymphocyte proliferation ability, hematopoietic colony-forming cells, and apoptotic cells were analyzed. At a dose of 33 J/m(2), significant differences were observed in the residual percentages of hematopoietic progenitors and lymphocyte functions [ANOVA, F (5,46) = 19.4; P <.0001], and the difference between CFU-C (85.2% + 24.0%; n = 8) and MLR (12.7% + 12. 6%; n = 10) was significant (P <.0001). There were no significant differences in the residual percentages of CFU-C, HPP-CFC, and LTC-IC. Percentages of annexin V-positive cells in the total MNC and the CD34(+) cell population in MNC after UV-B irradiation were 69.8% and 18.7%, respectively. In conclusion, there was a range of UV-B doses over which T lymphocytes were inactivated but hematopoietic progenitors, including HPP-CFC and LTC-IC, were preserved.

Annexin A5↗

PubMed2000

Controlled release of a water-soluble drug, captopril, by a combination of hydrophilic and hydrophobic cyclodextrin derivatives.

Parent beta-cyclodextrin (beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD) form 1:1 solid complexes with an orally active angiotensin-converting enzyme inhibitor, captopril, while hydrophobic perbutanoyl-beta-CyD (TB-beta-CyD) forms a solid dispersion or solid solution with the drug. The binary system of captopril/HP-beta-CyD or captopril/TB-beta-CyD and the ternary system of captopril/TB-beta-CyD/HP-beta-CyD in different molar ratios were prepared by the kneading method, and the release behavior of the drug was investigated. The release rate of captopril from the binary HP-beta-CyD system was rather fast, whereas that from the binary TB-beta-CyD system was comparatively slower, the retarding effect being dependent on the amounts of TB-beta-CyD. The release rate from the ternary captopril/TB-beta-CyD/HP-beta-CyD system was slowed down by the addition of small amounts of HP-beta-CyD, whereas the rate became faster as the molar ratio of HP-beta-CyD further increased (>.25 molar ratio). Both water penetration studies and microscopic observation suggested that the retarding effect is attributable to a gel formation of HP-beta-CyD in the TB-beta-CyD hydrophobic matrix. It was difficult to prolong plasma levels of captopril by administering orally either the binary HP-beta-CyD or TB-beta-CyD system in dogs. On the other hand, the ternary captopril/TB-beta-CyD/HP-beta-CyD system (molar ratio of 1:0.5:0.5) gave a plasma profile comparable to that of a commercially available sustained release preparation (Captoril R). Therefore, a combination of HP-beta-CyD and TB-beta-CyD is useful for the controlled release of water-soluble drugs such as captopril.

Absorption↗

PubMed2000

Release characteristics of a short-chain fatty acid, n-butyric acid, from its beta-cyclodextrin ester conjugate in rat biological media.

6(A)-O-(n-Butanoyl)-beta-cyclodextrin was prepared and its hydrolysis behavior in aqueous solutions and in rat intestinal fluids was investigated. Furthermore, the enzymatic hydrolyses of the n-butyric acid-beta-cyclodextrin conjugate using alpha-amylase and esterase were studied to gain insight into the release behavior of n-butyric acid from the conjugate. The hydrolysis of the conjugate proceeded according to a first-order kinetics in aqueous solution, and gave a V-shaped pH profile, indicating a specific acid-base-catalyzed hydrolysis at acidic and neutral-alkaline regions, respectively. The half-lives (t(1/2)) of the conjugate at pH 4.4, 6.8, and 7.4 at 37 degrees C were approximately 580, 43, and 6 days, respectively, indicating that the conjugate is stable in aqueous solution. No appreciable release of n-butyric acid from the conjugate was observed in the stomach and small intestinal contents of rats, or in the small and large intestinal homogenates of rats. On the other hand, a fast disappearance of the conjugate and an appearance of n-butyric acid were observed in the cecal and colonic contents of rats. The t(1/2) values of the disappearance were approximately 4, 1, and 6 h in 10 and 15% cecal contents and 10% colonic contents, respectively, and the appearance of n-butyric acid after 6 h was approximately 10% in the 15% cecal contents. Aspergillus oryzae alpha-amylase hydrolyzed the conjugate to small saccharide conjugates, such as the triose and maltose conjugates, but there was no appreciable release of n-butyric acid. The conjugate was less susceptible to carboxylic esterase (from porcine live), thus releasing no appreciable amounts of n-butyric acid. On the other hand, a fast release of n-butyric acid was observed when the esterase was employed after amylase hydrolysis, suggesting that two types of enzymes, sugar-degrading and ester-hydrolyzing enzymes, are necessary for the release of n-butyric acid from the conjugate in large intestinal contents.

Animals↗

PubMed2000

X-ray crystallographic characterization of nilvadipine monohydrate and its phase transition behavior.

Crystals of nilvadipine monohydrate were obtained from aqueous acetonitrile solution and characterized by powder and single crystal X-ray crystallography and thermal analysis. Water molecules of crystallization exist in nilvadipine monohydrate crystals in a molar ratio of 1:1 (drug-to-water) and were fixed by three hydrogen bonds with two carbonyl groups of the methyl and isopropyl esters, respectively, and one imino group of neighboring nilvadipine molecules. The conformation of the methyl and isopropyl esters in the monohydrate crystal was the reversal of that in the anhydrate crystal due to the presence of hydrogen bonds with water in the former crystal. The monohydrate crystal was slowly converted to the dehydrate at low humidity, and the latter rapidly converted to the former at high humidity. Powder X-ray diffraction studies indicated that the dehydrate retains the original structure of the monohydrate, i.e., a layer structure stacked on the ac plane perpendicular to the b-axis The solubility of the monohydrate in water was lower than that of the dehydrate and anhydrate forms, although the initial dissolution rate of the monohydrate was faster than that of the anhydrate. The present results indicated that the conformation of 1, 4-dihydropyridine-type calcium channel antagonists such as nilvadipine is easily changed by hydrogen bonds with water molecules of crystallization, and the water molecules are mobile through the void spaces formed between the layers in crystals.

Calcium Channel Blockers↗

PubMed2000

Stromal cell-dependent ex vivo expansion of human cord blood progenitors and augmentation of transplantable stem cell activity.

In vitro maintenance and expansion of human hematopoietic stem cells is crucial for many clinical applications. Thrombopoietin (TPO) and flt3/flk2 ligand (FL) have been suggested to support the proliferation of primitive hematopoietic progenitors and the expansion of transplantable stem cells in culture. In this study, we examined the synergistic effects of the murine stromal cell line MS-5 and a combination of the two cytokines, TPO and FL, on the ex vivo expansion of human cord blood primitive progenitors and transplantable stem cells. A monolayer of MS-5 cells with TPO/FL synergistically supported a more than 600-fold expansion of human cord blood CD34+ cells and CD34+CD38- cells in 2 weeks of culture. Colony-forming unit in culture (CFU-C) and 5-week and 8-week cobblestone area-forming cells (CAFC) were also expanded approximately 300-, 4- and 13-fold, respectively. When MS-5 cells were physically separated from progenitors by a Transwell filter, the synergy was reduced to a quarter of the control, suggesting that direct cell-cell contact between MS-5 cells and progenitors is required for maximum expansion. The severe-combined immunodeficient (scid) mouse-reconstituting cell (SRC) assay demonstrated the slight augmentation of transplantable stem cell activity in culture. These results indicated that MS-5 cells provide a milieu that stimulates the proliferation of primitive progenitors including transplantable stem cells.

Animals↗

PubMed2000

Stromal cell-independent differentiation of human cord blood CD34+CD38- lymphohematopoietic progenitors toward B cell lineage.

To study the cytokine regulation of early stages of human B-lymphopoiesis, we developed a stroma-free two-step culture system. Single human cord blood CD34+CD38- cells were individually cultured by micromanipulation with interleukin (IL)-3, stem cell factor (SCF), fIt3 ligand (FL), IL-6 and granulocyte colony-stimulating factor (G-CSF). About 10% of the cells formed primary colonies, which were individually tested for myeloid and B-lymphoid potentials by reculturing aliquots of the primary colony cells into secondary myeloid and B-lymphoid cultures. One third of the primary colonies proved capable of differentiation into CD19+IgM+ cells, as well as into myeloid lineage cells. RT-PCR analyses revealed that some cells in the primary culture had already matured to express B cell-specific transcripts. Thus, the combination of IL-3, SCF, FL, IL-6 and G-CSF supported the differentiation of CD34+CD38- lymphohematopoietic progenitors toward B cell lineage in addition to myeloid lineages. Screening of cytokines to identify the minimum requirement of cytokines in the primary culture revealed that IL-3 and SCF were essential and that the addition of FL, and to a lesser extent IL-6 or G-CSF, to the combination of IL3 and SCF remarkably enhanced the primary colony formation and the generation of CD19+ cells in the secondary B-lymphoid culture.

Antigens, CD34↗

PubMed2000

Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin.

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its beta-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-gamma-CyD < G2-beta-CyD < beta-CyD < HP-beta-CyD. Spectroscopic studies also revealed that HP-beta-CyD and beta-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-beta-CyD < or = beta-CyD. HP-beta-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-beta-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its beta-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-beta-CyD complex were much higher than in either that of rutin alone or in its beta-CyD complex. The in vivo absorption study suggests that HP-beta-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-beta-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2000

Improvement of subcutaneous bioavailability of insulin by sulphobutyl ether beta-cyclodextrin in rats.

The objective of this study was to examine and compare how hydrophilic beta-cyclodextrin derivatives (beta-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-beta-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substitution of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8 h. The bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-CyD may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.

Animals↗

PubMed2000

Hydrolysis behavior of prednisolone 21-hemisuccinate/beta-cyclodextrin amide conjugate: involvement of intramolecular catalysis of amide group in drug release.

Prednisolone 21-hemisuccinate/beta-cyclodextrin (beta-CyD) amide conjugate was prepared by binding prednisolone 21-hemisuccinate covalently to the amino group of mono(6-deoxy-6-amino)-beta-CyD through amide linkage. Prednisolone 21-hemisuccinate was intramolecularly transformed to prednisolone 17-hemisuccinate, and the parent drug, prednisolone, was slowly released from the 21-hemisuccinate with a half life of 69 h in pH 7.0 at 37 degrees C; the drug release at 25 degrees C was less than 10% for 48 h. In sharp contrast, the hydrolysis of prednisolone 21-hemisuccinate/beta-CyD amide conjugate was significantly faster (half life of 6.50 min at 25 degrees C) and gave prednisolone and mono(6-deoxy-6-succimino)-beta-CyD as products. The hydrolysis of the beta-CyD amide conjugate was subject to a specific-base catalysis in the alkaline region. The rapid hydrolysis of the conjugate can be ascribed to the involvement of an intramolecular nucleophilic catalysis of the amide group in the reaction. The succinic acid, bound to a drug through ester linkage at one carboxylic group and bound to a pro-moiety through amide linkage at another carboxylic group, may be useful as a spacer for construction of the immediate release type prodrugs of CyDs.

Amides↗

PubMed2000

Inclusion complex of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098) with heptakis(2,6-di-O-methyl)-beta-cyclodextrin: interaction and dissolution properties.

Interactions of KCA-098 with heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in solution and in the solid state were studied by the solubility method, UV and fluorescence spectroscopy, powder X-ray diffractometry, and thermal analysis. The KCA-098/DM-beta-CyD system showed an A(L) type solubility diagram with stability constants of 5870 and 2220 M(-1) in aqueous and 10% methanol solutions, respectively. Following the addition of DM-beta-CyD, the maximum UV wavelength of KCA-098 was shifted to a longer wavelength and the fluorescence intensity was decreased. A similar spectral change was observed when KCA-098 was dissolved in less polar solvents, especially in proton-acceptor solvents, such as acetone and dimethylsulfoxide, suggesting that KCA-098 interacts with DM-beta-CyD through not only a hydrophobic interaction but also hydrogen bonding. The solid complex of KCA-098 with DM-beta-CyD in a molar ratio of 1:1 was prepared by the kneading method and the solvent evaporation method, using organic solvents. Powder X-ray diffractometric and differential scanning calorimetric studies indicated that KCA-098 was dispersed as microparticles on the DM-beta-CyD complex in the solid state prepared by the solvent evaporation method although it dispersed as crystals in the sample prepared by the kneading method. The dissolution of KCA-098 from the solid complex prepared by the former method was markedly faster than that prepared by the latter method, although it slowed down with the passage of time. The reduced dissolution of KCA-098 was explained by crystallization to the hydrate form in the medium. These data indicate that poorly water-soluble KCA-098 interacts with DM-beta-CyD in water and in the solid state and that a fast-dissolving form of KCA-098 can be obtained by evaporating with DM-beta-CyD using organic solvents.

Calorimetry, Differential Scanning↗

PubMed2000

Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex.

The effects of storage on the crystallization, dissolution and absorption of tolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex were investigated, in comparison with those of polyvinylpyrrolidone (PVP) solid dispersion. The amorphous solid complex of tolbutamide with HP-beta-CyD and the solid dispersion of tolbutamide with PVP were prepared by a spray-drying method. During storage, a stable form of tolbutamide (form I) was crystallized from the amorphous PVP dispersion, whereas a metastable form of tolbutamide (form II) was crystallized from the HP-beta-CyD complex. The dissolution rate of tolbutamide from both HP-beta-CyD complex and PVP dispersion was significantly faster than that of tolbutamide alone. However, the dissolution rate from the PVP dispersion markedly decreased with storage, because of the formation of slow dissolving form I crystals. On the other hand, the dissolution rate from the HP-beta-CyD complex was only slightly decreased due to the formation of fast dissolving formII crystals. These in vitro dissolution characteristics were clearly reflected in the in vivo absorption of tolbutamide and the glucose plasma level after oral administration in dogs. The results suggested that HP-beta-CyD is useful not only for converting crystalline tolbutamide to an amorphous substance, but also for maintaining the fast dissolution rate of the drug over a long period. Furthermore, the crystallization of drugs from CyD complexes, with storage, seemed to be different from that involving polymer excipients such as PVP.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2000

[New anticoagulants].

The quest to develop new antithrombotic agents has been stimulated by clinical needs and by advances in biotechnology that have made it possible to produce drugs that target specific steps in thrombogenesis. Established anticoagulants such as unfractionated heparin and the coumarins are effective, but have two major limitations: narrow therapeutic windows and highly unpredictable dose-response relationships. Consequently, these drugs often cause complications such as serious bleeding that require close monitoring of their use by laboratory tests to balance safety and effect. These limitations provided the impetus for the development of new anticoagulants that inactivate thrombin, factor Xa, factor IXa or the factor VIIa/tissue factor complex. Similarly, agents that enhance the protein C anticoagulant pathway have also been developed. Of these, direct thrombin inhibitors, soluble thrombomodulin, protein C, and activated protein C have been evaluated clinically for parenteral administration. However, there is enormous interest in the development of safer and more effective oral anticoagulants. In the future, such orally active direct inhibitors of thrombin and factor Xa, if they can be given safely without the need for laboratory monitoring, may replace the coumarins for the long-term treatment of thromboembolic disorders. To achieve these goals, these compounds need high, consistent oral bioavailability.

Animals↗

PubMed1999

Differentiation in culture of murine primitive lymphohematopoietic progenitors toward T-cell lineage.

Earlier, we described a stromal cell-free two-step clonal culture system in which murine primitive lymphohematopoietic progenitors produce myeloid and B-lymphoid lineage cells. In the same culture T-cell potential of the progenitors was maintained. We now report that, in addition to myeloid and B-lymphoid cells, putative T-cell progenitors are also produced in culture. Lineage-negative (Lin-) Ly-6A/E+ c-kit+ bone marrow cells from 5-fluorouracil-treated mice were cultured in methylcellulose in the presence of SF (Steel factor), interleukin (IL)-11, and IL-7, and the resulting primary colonies were picked and pooled. When injected into severe combined immune deficiency (scid) mice, the pooled cells reconstituted the T-cell compartment of the scid mice earlier than freshly prepared primitive marrow cells. This reconstitution activity of the pooled primary colony cells was enriched in the Ly-6A/E+ and FcgammaRII/III-/low cell fractions. Reverse transcriptase-polymerase chain reaction (RT-PCR) and DNA-PCR analyses showed that some of the primary colony cells are differentiated sufficiently to express messenger RNA (mRNA) of T-cell receptor (TCR) beta-chain and pre-TCR alpha (pTalpha) and, although not frequently, to perform Dbeta-Jbeta rearrangement of the TCR gene. Micromanipulation studies confirmed the clonal origin of myeloid lineage cells and the cells positive for the T-cell-specific transcripts and D-J rearrangement of TCR beta-chain. These results suggested that, in the presence of SF, IL-11, and IL-7, primitive lymphohematopoietic progenitors differentiate toward T-cell lineage in addition to myeloid and B-cell lineages.

Animals↗

PubMed1999

Characterization of itraconazole/2-hydroxypropyl-beta-cyclodextrin inclusion complex in aqueous propylene glycol solution.

The interaction of itraconazole, a triazole antifungal agent, with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in water and 10% v/v propylene glycol/water solution at pH 2.0 was investigated by the solubility method and ultraviolet and 1H-nuclear magnetic resonance (NMR) spectroscopies. The solubility of itraconazole in water significantly increased as the concentrations of HP-beta-CyD were augmented, showing an AP type phase solubility diagram. The upward curvature closely corresponded to the simulation curve which was calculated on the basis of the 1:2 (guest:host) complexation model. The 1:2 complex was formed even in the presence of 10% v/v propylene glycol, although the co-solvent system made the interaction with HP-beta-CyD weaker due to the competitive inclusion. The ultraviolet spectroscopic studies also supported the 1:2 complex formation of itraconazole with HP-beta-CyD in 10% v/v propylene glycol/water solution at pH 2.0. The 1H-NMR spectroscopic studies suggested that the triazole and triazolone moieties of itraconazole are involved in the 1:2 inclusion complexation.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1999

Cyclodextrin-based controlled drug release system.

Because of their bioadaptability and multi-functional characteristics, cyclodextrins (CDs) are capable of alleviating the undesirable properties of drug molecules in various routes of administration through the formation of inclusion complexes. This article outlines the current application of natural and chemically modified CDs in the design of advanced dosage forms. In an oral drug delivery system (DDS), the hydrophilic and ionizable CDs can serve as potent drug carriers in the immediate release- and delayed release-formulations, respectively, while the release rate of water-soluble drugs can be retarded by hydrophobic CDs. Since CDs are able to extend the function of pharmaceutical additives, the combination of molecular encapsulation with other carrier materials will become effective and a valuable tool in the improvement of drug formulation. Moreover, the most desirable attribute for the drug carrier is its ability to deliver a drug to a targeted site; conjugates of a drug with CDs can be a versatile means of constructing a new class of colon-targeting prodrugs. On the basis of this knowledge, the advantages and limitations of CDs in DDS are addressed.

Journal Article↗