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41.
Tetsuya Ozeki Yoshihito Kano Norimitsu Takahashi Tatsuaki Tagami Hiroaki Okada 《AAPS PharmSciTech》2012,13(4):1130-1137
We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water-soluble carrier. In the present study, we focused on maltosyl-β-cyclodextrin (malt-β-CD) as a new water-soluble carrier and it was investigated whether drug/malt-β-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol (MAN) microspheres. The physicochemical properties of bare drug microparticles (ONO-2921, a model water-insoluble drug), drug/MAN microspheres, and drug/malt-β-CD microspheres were evaluated. In vitro aerosol performance, in vitro dissolution rate, and the blood concentration profiles after intratracheal administration were compared between these formulations. The mean diameter of both drug/MAN and drug/malt-β-CD microspheres was approximately 3–5 μm and both exhibited high aerosol performance (>20% in stages 2–7), but drug/malt-β-CD microspheres had superior release properties. Drug/malt-β-CD microspheres dissolved in an aqueous phase within 2 min, while drug/MAN microspheres failed to dissolve in 30 min. Inhalation of drug/malt-β-CD microspheres enhanced the area under the curve of the blood concentration curve by 15.9-fold than that of bare drug microparticles and by 6.1-fold than that of drug/MAN microspheres. Absolute bioavailability (pulmonary/intravenous route) of drug/malt-β-CD microspheres was also much higher (42%) than that of drug/MAN microspheres (6.9%). These results indicate that drug/malt-β-CD microspheres prepared by our four-fluid nozzle spray drier can improve drug solubility and pulmonary delivery.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-012-9826-z) contains supplementary material, which is available to authorized users.KEY WORDS: 4-fluid nozzle spray drier, inhalation therapy, maltosyl-β-cyclodextrin, microparticles, water-insoluble drug 相似文献42.
Christian Sergelius Sanna Niinivehmas Terhi Maula Mayuko Kurita Shou Yamaguchi Tetsuya Yamamoto Shigeo Katsumura Olli T. Pentikäinen J. Peter Slotte 《生物化学与生物物理学报:生物膜》2012,1818(3):474-480
The aim of this study was to examine how structural properties of different sphingomyelin (SM) analogs affected their substrate properties with sphingomyelinase (SMase) from Bacillus cereus. Using molecular docking and dynamics simulations (for SMase–SM complex), we then attempted to explain the relationship between SM structure and enzyme activity. With both micellar and monolayer substrates, 3O-methylated SM was found not to be degraded by the SMase. 2N-methylated SM was a substrate, but was degraded at about half the rate of its 2NH–SM control. PhytoPSM was readily hydrolyzed by the enzyme. PSM lacking one methyl in the phosphocholine head group was a good substrate, but PSM lacking two or three methyls failed to act as substrates for SMase. Based on literature data, and our docking and MD simulations, we conclude that the 3O-methylated PSM fails to interact with Mg2 + and Glu53 in the active site, thus preventing hydrolysis. Methylation of 2NH was not crucial for binding to the active site, but appeared to interfere with an induced fit activation of the SMase via interaction with Asp156. An OH on carbon 4 in the long-chain base of phytoPSM appeared not to interfere with the 3OH interacting with Mg2 + and Glu53 in the active site, and thus did not interfere with catalysis. Removing two or three methyls from the PSM head group apparently increased the positive charge on the terminal N significantly, which most likely led to ionic interactions with Glu250 and Glu155 adjacent to the active site. This likely interaction could have misaligned the SM substrate and hindered proper catalysis. 相似文献
43.
Taiji Asami Naoki Nishizawa Yoshihiro Ishibashi Kimiko Nishibori Masaharu Nakayama Yasuko Horikoshi Shin-ichi Matsumoto Masashi Yamaguchi Hirokazu Matsumoto Naoki Tarui Tetsuya Ohtaki Chieko Kitada 《Bioorganic & medicinal chemistry letters》2012,22(20):6391-6396
Metastin/kisspeptin, a 54-amino acid peptide, is the ligand of the G-protein-coupled receptor KISS1R which plays a key role in pathways that regulate reproduction and cell migration in many endocrine and gonadal tissues. The N-terminally truncated decapeptide, metastin(45–54), has 3–10 times higher receptor affinity and intracellular calcium ion-mobilizing activity but is rapidly inactivated in serum. In this study we designed and synthesized stable KISS1R agonistic decapeptide analogs with selected substitutions at positions 47, 50, and 51. Replacement of glycine with azaglycine (azaGly) in which the α-carbon is replaced with a nitrogen atom at position 51 improved the stability of amide bonds between Phe50-Gly51 and Gly51-Leu52 as determined by in vitro mouse serum stability studies. Substitution for tryptophan at position 47 with other amino acids such as serine, threonine, β-(3-pyridyl)alanine, and d-tryptophan (d-Trp), produced analogs that were highly stable in mouse serum. d-Trp47 analog 13 showed not only high metabolic stability but also excellent KISS1R agonistic activity. Other labile peptides may have increased serum stability using amino acid substitution. 相似文献
44.
Kashiwagi T Hara K Kohara M Iwahashi J Hamada N Honda-Yoshino H Toyoda T 《The Journal of biological chemistry》2002,277(32):28700-28705
45.
Nakamoto T Suzuki T Huang J Matsumura T Seo S Honda H Sakai R Hirai H 《Biochemical and biophysical research communications》2002,294(3):635-641
p130(Cas) (Cas) is a docking protein that becomes tyrosine phosphorylated in v-Src- or v-Crk-transformed cells and in integrin-stimulated cells. Cas -/- fibroblasts show defects in stress fiber formation, cell spreading, cell migration, and transformation by activated Src. To further characterize the role of Cas in signaling, we compared the expression profile in Cas -/- fibroblasts with that in Cas-re-expressing fibroblasts using the microarray methods. In Cas -/- fibroblasts, the expression of heme oxygenase 1 and caveolin-1 was reduced, but the expression of procollagen 1 alpha 1, procollagen 3 alpha 1, procollagen 11 alpha 1, elastin, periostin, TSC-36, and MARCKS was enhanced. The domains in Cas necessary for the change varied among these genes. Activated Src reduced the expression of most of these genes both in Cas -/- and in Cas +/+ fibroblasts. These results suggest the existence of signaling pathways that emanate from Cas to gene expression. 相似文献
46.
Kondo H Mori S Takino H Kijima H Yamasaki H Ozaki M Tetsuya I Urata Y Abe T Sera Y Yamakawa K Kawasaki E Yamaguchi Y Kondo T Eguchi K 《Biochemical and biophysical research communications》2000,278(1):236-240
Low levels of intracellular antioxidant enzyme activities as well as glutathione (GSH) concentrations have been described in pancreatic beta cells. We examined the effects of intracellular GSH depletion on insulin secretion and the role of intracellular GSH in signal transduction in beta cell line, MIN6 cells. Anti-gamma-glutamylcysteine synthetase (gamma-GCS) heavy subunit ribozyme was stably transfected to MIN6 cells to reduce intracellular GSH concentration. In the presence of 10 mM glucose, ribozyme-transfected cells (RTC) increased insulin secretion from 0.58 microg/10(6) cells/h in control cells (CC) to 1.48 microg/10(6) cells/h. This was associated with increased intracellular Ca(2+) concentration in RTC, detected by fluo-3 staining. Our results demonstrated that intracellular GSH concentration might influence insulin secretion by MIN6 cells, and suggest that enhanced insulin secretion by beta cells conditioned by chronic depletion of GSH is mediated by increased intracellular Ca(2+) concentration. 相似文献
47.
Effects of Hypoxia on the Activity of the Dopaminergic Neuron System in the Rat Striatum as Studied by In Vivo Brain Microdialysis 总被引:1,自引:0,他引:1
Yoshinori Akiyama Kunio Koshimura Tetsuya Ohue Ken Lee Soichi Miwa Sen Yamagata Haruhiko Kikuchi 《Journal of neurochemistry》1991,57(3):997-1002
The purpose of the present study is to clarify the effects of hypoxia on the activity of the dopaminergic neurons in the brain and its mechanism of action. For this purpose, the effects of hypoxia on the extracellular levels of 3,4-dihy-droxyphenylethylamine (dopamine) were examined in the rat Striatum using in vivo brain microdialysis in the presence or absence of pretreatment with either tetrodotoxin (a blocker of voltage-dependent sodium channels) or nomifensine (a blocker of dopamine reuptake). Exposure to various degrees of hypoxia (15, 10, and 8% O2 in N2) increased dopamine levels in striatal dialysates to 200, 400, and 1,100%, respectively, of the control value. On reoxygenation, dopamine levels in the dialysates rapidly returned to the control level. Reexposure to hypoxia increased the dopamine levels to the same extent as during the first exposure. After addition of tetrodotoxin (40 mUM) to the perfusion fluid or pretreatment with nomifensine (100 mg/kg, i.p.), exposure to hypoxia no longer increased the dopamine levels. These results suggest that although hypoxia induces an increase in the extracellular dopamine levels (hence, an apparent increase in the activity of the dopaminergic neurons), this increase is not the result of an increase in dopamine release itself, but rather the result of inhibition of the dopamine reuptake mechanism. 相似文献
48.
Junichi Kitajima Tetsuya Komori Toshio Kawasaki Hans-rolf Schulten 《Phytochemistry》1982,21(1):187-192
From the aerial parts of Fritillaria thunbergii, three glycosidal Solanum alkaloids (basic steroid saponins) were isolated together with minor 相似文献
49.
Tetsuya Sakamaki 《Primates; journal of primatology》2009,50(4):321-332
Chimpanzees (Pan troglodytes) form multi-male and multi-female unit groups with fission–fusion grouping patterns. Short-range interaction (SRI) plays
an important role in the unity of these groups and in maintaining social bonds among members. This study evaluated three models
of chimpanzee social structure that differed according to the emphasis each placed on social bonds between the sexes, i.e.,
the male-only, the bisexual, and the male-bonded unit-group model. I investigated differences in SRI between the sexes among
group members in well-habituated wild chimpanzees in Mahale Mountains National Park, Tanzania. I followed six focal adult
males and six females, and quantified their respective SRI with other chimpanzees. Except between subordinate males and adult
females, adults in general engaged in SRI with about 60–90% of the individuals with whom they made visual contact each day,
whether in large or small parties. Although the number of social grooming (SGR) partners was limited, male–male SGR networks
were wider than were either male–female or female–female SGR networks among adults. The number of contact-seeking behavior
(CSB) partners was also limited, but dominant males had more CSB partners. Adult females mainly interacted by pant-grunt greeting
(PGG) with adult males, but tended to do so mainly with the highest-ranking male(s) within visual contact. These results indicated
that the social bonds among adult males were essential to group unity. Because of clear male dominance, adult females established
peaceful coexistence with all group members despite less frequent SRI with subordinate males by maintaining affiliative social
bonds with dominant males, thereby supporting the male-bonded unit-group model. Adult females had many female SRI partners,
but these interactions did not involve performing conspicuous behaviors, suggesting that females maintain social bonds with
other females in ways that differ from how such bonds are maintained with and between adult males. 相似文献
50.
Liping Zhu Jianting Ju Junbo Wang Manping Xie Mitsugu Nishimura Tetsuya Matsunaka Hisayoshi Terai 《Limnology》2010,11(3):281-287
Further discussion about the limnological features of Lake Puma Yum Co, South Tibet, China, is provided based on the results
of several investigations. By using depth data from all over the lake, the whole submarine topography has been compiled. Horizontal
analysis of the water's physicochemical features indicates that compared with the relatively uniform water features at other
lake areas, apparent spatial heterogeneity exists in the water of the subaquatic alluvial fan induced by the Jiaqu River,
the biggest inflow. Vertical analysis of water characteristics using two-factor analysis of variance with no re-experiment
indicates that temperature, dissolved oxygen, and pH of the water vary with water depth rhythmically, whereas other parameters
demonstrate no evident vertical variation, which shows that chemical stratification is not obvious. But this does not exclude
slightly higher concentrations of Ca2+ induced by lower pH at the bottom of deep lake water. The hydrochemistry difference between inflow water and lake water reveals
the loss of Ca2+ in lake water, which indicates calcite deposition may be an important characteristic of lake sediment. 相似文献