Papers - OHTAKE Kazuo
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肥満を伴うインスリン抵抗性マウスに及ぼす亜硝酸塩摂取の影響に関する研究 Invited
大竹一男
日本食品化学研究振興財団研究成果報告書 ( 17 ) 2011
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Intranasal administration of milnacipran in rats: evaluation of the transport of drugs to the systemic circulation and central nervous system and the pharmacological effect. Reviewed
Masaki Uchida, Takuya Katoh, Mutsuhiro Mori, Takuya Maeno, Kazuo Ohtake, Jun Kobayashi, Yasunori Morimoto, Hideshi Natsume
Biological & pharmaceutical bulletin 34 ( 5 ) 740 - 7 2011
Language：English Publishing type：Research paper (scientific journal)
Recently, transnasal drug delivery has attracted a great deal of attention as an administration route to deliver drugs directly to the central nervous systems (CNS) and drug targeting of the CNS is expected to increase. In the present study, we investigated the possibility of using a transnasal delivery system for milnacipran, a serotonin-noradrenaline reuptake inhibitor (SNRI), by evaluating the transport to the systemic circulation and cerebrospinal fluid (CSF) and the pharmacological effect after intranasal (i.n.) administration. Moreover, the effect of chitosan as a bioadhesive material on the transport to the systemic circulation and CSF and the pharmacological effect after i.n. administration were evaluated. As a result, i.n. administration of milnacipran was found to produce a higher direct delivery to the CNS as well as to the systemic circulation, suggesting that this is a promising route of administration and an alternative to peroral (p.o.) administration. Furthermore, the i.n. co-administration with chitosan led to increased plasma and CSF concentrations and an enhanced pharmacological effect, evaluated by means of the forced swimming test. The results suggested that chitosan produced a long residence time of milnacipran in the nasal cavity due to its bioadhesive effect, leading to the enhanced transport of milnacipran from the systemic circulation to the CNS via the blood-brain barrier by an increase in systemic absorption as well as direct transport to the CNS, resulting in a higher antidepressant effect compared to that with p.o. administration.
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Fasting-induced intestinal apoptosis is mediated by inducible nitric oxide synthase and interferon-{gamma} in rat. Reviewed International journal
Junta Ito, Hiroyuki Uchida, Takayuki Yokote, Kazuo Ohtake, Jun Kobayashi
American journal of physiology. Gastrointestinal and liver physiology 298 ( 6 ) G916-26 2010.06
Language：English Publishing type：Research paper (scientific journal)
Nitric oxide (NO) is associated with intestinal apoptosis in health and disease. This study aimed to investigate the role of intestinal NO in the regulation of apoptosis during fasting in rats. Male Wistar rats were divided into two groups and subcutaneously injected with saline (SA) or aminoguanidine (AG), followed by fasting for 24, 48, 60, and 72 h. At each time point, the jejunum was subjected to histological evaluation for enterocyte apoptosis by histomorphometric assessment and TUNEL analysis. We performed immunohistochemistry for inducible NO synthase (iNOS) expression in the jejunum and measured tissue nitrite levels using HPLC and 8-hydroxydeoxyguanosine adduct using ELISA, indicative of endogenous NO production and reactive oxygen species (ROS) production, respectively. Jejunal transcriptional levels of iNOS, neuronal NO synthase (nNOS), and interferon-gamma (IFN-gamma) were also determined by RT-PCR. Fasting caused significant jejunal mucosal atrophy due to attenuated cell proliferation and enhanced apoptosis with increase in iNOS transcription, its protein expression in intestinal epithelial cells (IEC), and jejunal nitrite levels. However, AG treatment histologically reduced apoptosis with inhibition of fasting-induced iNOS transcription, protein expression, and nitrite production. We also observed fasting-induced ROS production and subsequent IFN-gamma transcription, which were all inhibited by AG treatment. Furthermore, we observed reduced transcriptional levels of nNOS, known to suppress iNOS activation physiologically. These results suggest that fasting-induced iNOS activation in IEC may induce apoptosis mediators such as IFN-gamma via a ROS-mediated mechanism and also a possible role of nNOS in the regulation of iNOS activity in fasting-induced apoptosis.
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The role of neuronal and inducible NOS in the regulation of intestinal apoptosis in fasting and refeeding rat. Reviewed
Ito J, Uchida H, Ohtake K, Kobayashi J.
Nitric Oxide. 22 S72 - S72 2010.04
Language：English Publishing type：Research paper (international conference proceedings)
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Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice. Reviewed
Ohtake K, Koga M, Uchida H, Sonoda K, Ito J, Uchida M, Natsume H, Kobayashi J.
Nitric Oxide 23 ( 1 ) 65 - 73 2010.04
Authorship：Lead author Language：English Publishing type：Research paper (international conference proceedings)
Other Link： http://libir.josai.ac.jp/il/meta_pub/G0000284repository_JOS-j.niox.2010.04.004
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カルセイン含有デンプン溶液の経鼻投与後の鼻腔滞留性とカルセイン血中動態との関係 Reviewed
入江 博美, 大竹 一男, 前野 拓也, 内田 昌希, 内田 博之, 小林 順, 夏目 秀視
薬剤学: 生命とくすり 69 ( 3 ) 219 - 227 2009.05
Language：Japanese Publisher：(公社)日本薬剤学会
ラットを用いた閉鎖実験系から得られる経鼻投与後の動態パラメータと、ラットを斜めに固定し、鼻腔に投与した薬液が傾斜により物理的に鼻腔から流出できるようにした開放実験系から得られる動態パラメータとを比較することで滞留性と吸収性を解析した。モデル薬物は、分子量約600のカルセインを選択した。また、粘膜付着性物質は、potatoおよびtapiocaの2種類のデンプンを用いた。デンプンの粘度が増加すると鼻粘膜に対する付着効果が高まり、除去クリアランスに対する抵抗が増して、粘性溶液製剤の滞留性が高まった。デンプンの添加濃度の低いタピオカデンプンの方が添加濃度が低くても滞留効果が高くなる傾向を認めた。閉鎖系と開放系から得た薬動学的パラメータを比較することで、カルセイン含有デンプン粘性溶液の付着・滞留効果とカルセインの吸収に対する効果を評価できた。
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Dietary nitrite ameliorates dextran sodium-induced acute experimental colitis in mice. Reviewed
Kobayashi J, Ohtake K, Koga M, Uchida H.
Nitric Oxide. 20 S38 - S38 2009.04
Language：English Publishing type：Research paper (international conference proceedings)
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Effect of mitochondrial Aldehyde dehydrogenase on pharmacokinetic profile of nitrite in plasma and organs. Reviewed
Nakanishi K, Kubo Y, Ohtake K, Uchida H, Kotake F, Natsume H, Kobayashi J.
Nitric Oxide. 20 S40 - S40 2009.04
Language：English Publishing type：Research paper (international conference proceedings)
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Proteomic approach for identification of protein S-nitrosylation in mouse gastric mucosa. Reviewed
Ohtake K, Shimada N, Uchida H, Kobayashi J.
Nitric Oxide. 20 S40 - S41 2009.04
Language：English Publishing type：Research paper (international conference proceedings)
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[Age, period and birth-cohort effects on marriage rates in Japanese women between 1985 and 2005, and comparison of trends of effects between marriage and birth rates]. Reviewed
Hiroyuki Uchida, Youichi Odagiri, Kazuo Ohtake, Jun Kobayashi
[Nihon koshu eisei zasshi] Japanese journal of public health 55 ( 7 ) 440 - 8 2008.07
Language：Japanese Publishing type：Research paper (scientific journal)
OBJECTIVE: An age-period-cohort (APC) analysis was performed to provide information about age-, period-, and cohort-specific effects on marriage trends in Japanese women. In addition, the relationships of the trends of age-, period-, and cohort-specific effects between marriage and birth were analyzed. METHODS: We obtained data regarding marriages of Japanese women aged between 19 and 38 years for the period of 1985 to 2005 from the National Vital Statistics. Population data used were for an estimated population, obtained from the Population Estimates Annual Reports. Standard cohort tables comprising marriage and population data were analyzed using a Bayesian APC model to identify age-, period-, and cohort-specific effects on marriage rate trends. Previously obtained data for a similar APC-analysis of birth trends were used to compare the trends in the effects of age, period, and cohort on marriage and birth patterns. For this purpose, the estimated values for each effect were normalized. RESULTS: With regard to the marriage trends in Japanese women, the effect of age was the greatest, peaking at the age of 25 years. The period effect increased after 1997; however, its effect was relatively limited as compared to the other effects. The cohort effect, which was greater than the period effect and less than the age effect, on marriage trends showed a decreasing slope for birth cohorts born after 1966 and subsequent increase after 1982. Comparison of age, period and cohort effects between the trends in marriage and birth rates showed that the age effect distinctly peaked at 25 and 28 years for marriage and births, respectively. The period effect on marriage and birth showed a decreasing trend until 1991 and subsequent increased in 1992 and 1997 for births and marriage, respectively. With regard to the cohort effect on birth rates, a decreasing trend was observed for the birth cohorts after 1961, with increase after 1977. However, with regard to the cohort effect on marriage rates, the decreasing trend observed for birth cohorts after 1966 showed an increase after 1982. CONCLUSION: Among age, period, and birth cohort, age is the most influential factor affecting marriage rates. Period effects appear relatively small, but they increased after 1997. Cohort effects reduced for birth cohorts born after 1966 and subsequently increased after 1982. Results of the comparison study showed that changing patterns of age, period and cohort effects had very similar influences on the trends for marriage and birth rates. However, a 3-year difference was observed between the peaks of the age effect on the two rates. A time lag of 5 years was observed between the turning point in the trend of period effects for marriage and birth rates. The changing patterns of cohort effects on marriage and birth rates were similar, but the turning point for the marriage pattern occurred in a 5-year younger cohort compared with the birth pattern.
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ヨード造影剤による腎障害に対するN-アセチルシステインの経口投与の有効性 Reviewed
岡本 浩, 宮内 雅弘, 西山 雅巳, 三宅 隆之, 桜田 真己, 大竹 一男, 小林 順, 荻原 政彦, 木村 光利, 夏目 秀視
心臓 38 ( 9 ) 915 - 923 2006.09
Language：Japanese Publisher：(公財)日本心臓財団
石心会狭山病院循環器科でのカルテ調査から、造影剤を用いた心カテーテル検査および経皮的冠動脈形成術(PTCA)で発症する腎障害に対するN-アセチルシステイン(ムコフィリン)の経口投与の有効性について評価した。2004年の1年間のカルテ調査(1,128名)から、中程度に腎機能が低下した患者(血清クレアチニン値1.2～3.0mg/dL)で臨床検査データが既知の患者を抽出した結果、ムコフィリン投与群24名、ムコフィリン未投与群(コントロール群)29名であった。腎機能にかかわる検査データ、造影剤腎症の発症率、入院期間などから評価した結果、ムコフィリン投与群の患者のほうが、造影剤投与による腎障害を予防できることが示唆された。リスク疾患別に評価すると、症例数が少なかったが糖尿病および、糖尿病と高血圧を併発している患者でムコフィリンの効果が高かった。また、造影剤腎症の独立予測因子である年齢について評価すると、70歳以上の高齢患者でもムコフィリンの経口投与は有効であった。以上の結果より、造影剤を用いた心カテーテル検査およびPTCAにおいて、ムコフィリンの経口投与は中程度の腎機能の低下を有する患者に対して有効であると考えられた。(著者抄録)
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食餌由来亜硝酸塩の摂取による生活習慣病予防に関する研究～糖尿病性腎症について～
大竹一男、石山裕一、内田博之、小林順
城西大学生命科学センター報告 6 15 - 23 2006.04
Authorship：Lead author, Corresponding author Language：Japanese Publishing type：Research paper (bulletin of university, research institution)
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Improvement of transnasal absorption of macromolecular drugs using tight-junction regulation Reviewed
Hideshi Natsume, Takuya Maeno, Kazuo Ohtake, Yasunori Morimoto
Oto-Rhino-Laryngology Tokyo 48 ( 1 ) 22 - 29 2005.08
Language：Japanese Publishing type：Research paper (scientific journal)
We investigated whether a poly-L-arginine (poly-L-Arg)-induced increase in the tight-junction permeability of FITC-labeled dextran (MW 4.4 kDa, FD-4) is associated with a transient increase in transepithelial electroresistance (PD) and short-circuit current (Isc) immediately after poly-L-Arg exposure and occurs following tight-junction disassembly-related cellular signaling in the rabbit nasal epithelium. A transient PD and Isc increase was associated with increased Cl - secretion induced by poly-L-Arg but not with the enhanced paracellular FD-4 permeability. Enhanced paracellular FD-4 permeability induced by poly-L-Arg was not changed by treatment with inhibitors of possible Ca 2+ mobilization pathways followed by poly-L-Arg exposure, suggesting that the promotional effect of poly-L-Arg is independent of Ca 2+-related signaling. Protein kinase C (PKC) and tyrosine phosphatase inhibitors suppress an increase in tight-junction permeability by poly-L-Arg, indicating that serine/threonine may have been phosphorylated via Ca 2+-independent PKC and tyrosine may have dephosphorylated the junction protein. ZO-1, a tight-junction-associated protein, and occludin, an integral membrane protein localized at the tight junction, were monitored immunofluorescently after preincubation with PKC and tyrosine phosphatase inhibitors followed by poly-L-Arg treatment, showing that ZO-1 and occludin were internalized via serin/threonine phosphorylation by PKC activation and via tyrosine dephosphorylation, providing tight-junction disassembly. We concluded that poly-L-Arg enhances the paracellular permeability of macromolecular drugs via serin/threonine phosphorylation of ZO-1 involving Ca 2+- independent PKC activation and tyrosine dephosphorylation of occludin in the rabbit nasal epithelium. Such phosphorylation and dephosphorylation disperses junction proteins, particularly ZO-1 and occludin, into cytoplasm, possibly followed by tight-junction disassembly. These findings should prove useful in developing transnasal delivery systems for macromolecular drugs with polycationic materials as solute transport enhancers.
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Tight junctionの調節を介した高分子医薬品の経鼻吸収性の改善 Reviewed
夏目 秀視, 前野 拓也, 大竹 一男, 森本 雍憲
耳鼻咽喉科展望 48 ( 補冊1 ) 22 - 29 2005.08
Language：Japanese Publisher：耳鼻咽喉科展望会
電気生理学的な手法を主に用い,家兎摘出鼻粘膜におけるポリ-L-アルギニン(poly-Arg)の細胞間隙開口作用について検討を行った.poly-Arg適用後のFITC標識したデキストラン(FD-4)の透過性および電気生理学的パラメータの変化,一過的な自発的膜電位(PD)および短絡電流(Isc)変化とその後の透過促進効果の関連性,poly-Arg適用後のみかけの透過係数(Pappa)と経上皮電気抵抗逆数(Gt)の増加に対する種々阻害剤の影響,poly-Arg適用後のtight junction関連タンパク質(ZO-1, occludin)に対する種々阻害剤の影響について調べた.その結果,poly-Argの促進効果はtight junctionの調節と深く関わり,水溶性高分子薬物の透過を促進することが明らかになった
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S-ニトロソアルブミンは循環血液中で最も豊富な高分子NOキャリアーとして働いている Invited
大竹 一男
ファルマシア 39 ( 12 ) 1200 - 1201 2003.12
Language：Japanese Publishing type：Research paper (other academic) Publisher：(公社)日本薬学会
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Effect of poly-L-arginine on the nasal absorption of FITC-dextran of different molecular weights and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats. Reviewed
Miyamoto M, Natsume H, Satoh I, Ohtake K, Yamaguchi M, Kobayashi D, Sugibayashi K, Morimoto Y.
Int J Pharm. 226 127 - 138 2001.04
Language：English Publishing type：Research paper (scientific journal)
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Improved nasal absorption of drugs using poly-L-arginine: effects of concentration and molecular weight of poly-L-arginine on the nasal absorption of fluorescein isothiocyanate-dextran in rats. Reviewed
Miyamoto M, Natsume H, Iwata S, Ohtake K, Yamaguchi M, Kobayashi D, Sugibayashi K, Yamashina M, Morimoto Y.
Eur J Pharm Biopharm. 52 21 - 30 2001.04
Language：English Publishing type：Research paper (scientific journal)
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Screening of cationic compounds as an absorption enhancer for nasal drug delivery. Reviewed
Natsume H, Iwata S, Ohtake K, Miyamoto M, Yamaguchi M, Hosoya K, Kobayashi D, Sugibayashi K, Morimoto Y.
Int J Pharm. 185 1 - 12 1999.04
Language：English Publishing type：Research paper (scientific journal)
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Enhancing mechanism of macromolecule permeation by poly-L-arginine in rabbit nasal mucosa Reviewed
K. Ohtake, H. Natsume, Y. Morimoto
Proceedings of the Controlled Release Society ( 26 ) 206 - 207 1999
Language：English Publishing type：Research paper (international conference proceedings)
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Enhancing mechanism of poly-L-arginine in nasal absorption of fitc-dextran Reviewed
K. Ohtake, H. Natsume, M. Miyamoto, K. Sugibayashi, Y. Morimoto
Proceedings of the Controlled Release Society ( 25 ) 687 - 688 1998
Language：English Publishing type：Research paper (international conference proceedings) Publisher：Controlled Release Society