KINDAI UNIVERSITY


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NAGAI Noriaki

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FacultyDepartment of Pharmacy / Graduate School of Medicine
PositionAssociate Professor
Degree
Commentator Guidehttps://www.kindai.ac.jp/meikan/427-nagai-noriaki.html
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Last Updated :2020/09/30

Education and Career

Academic & Professional Experience

  •   2017 ,  - 現在, Faculty of Pharmacy, Kindai University
  •   2013 04 ,  - 2017 , Faculty of Pharmacy, Kindai University

Research Activities

Research Areas

  • Life sciences, Hygiene and public health (non-laboratory)
  • Life sciences, Hygiene and public health (laboratory)
  • Life sciences, Hygiene and public health (non-laboratory)
  • Life sciences, Hygiene and public health (laboratory)
  • Life sciences, Healthcare management, medical sociology
  • Life sciences, Clinical pharmacy

Published Papers

  • Retinal proteomic evaluation of rats following streptozotocin‑injection using shotgun proteomics., Hiroko Otake, Tetushi Yamamoto, Saori Deguchi, Atushi Taga, Noriaki Nagai, Molecular medicine reports, Molecular medicine reports, 21(1), 379 - 386, Jan. 2020 , Refereed
    Summary:It is important to elucidate how retinal stimulation leads to retinal protection and dysfunction. The current study aimed to identify factors that are up‑ and downregulated in the retinas of streptozotocin (STZ)‑induced diabetic rats with acute retinal dysfunction. Retinal function was measured and changes in protein expressions were determined using electroretinograms (ERGs) and liquid chromatography/mass spectroscopy‑based shotgun proteomics, respectively. The results revealed that the plasma glucose levels of STZ rats were markedly higher when compared with normal rats. Furthermore, levels of a‑waves, b‑waves and oscillatory potential amplitudes on ERGs in STZ rats were decreased compared with healthy animals. With use of shotgun proteomics, 391 proteins were identified in the retinas of normal rats and 541 proteins were found in the retinas of STZ rats. Of the 560 proteins identified in rat retinas, 372 (66.4%) were present in both normal and STZ rats. Of these, 19 (3.39%) were unique to normal rats and 169 (30.1%) were unique to STZ rats. Gene Ontology analysis was performed on the candidate proteins that were differentially regulated in the retinas of STZ rats and focused on those classified as 'protein binding', which serve important roles in retinal neurodegeneration. The results revealed an excessive expression of retinol‑binding protein 1 (RBP1) and a negative expression of rod outer segment membrane protein 1 (Rom-1) in the retinas of STZ rats. Therefore, retinal function may be decreased with STZ‑induced injury, and expressions of Rom‑1 and RBP1 may be altered in the retinas of STZ rats.
  • Interaction between phosphate ions and Fe-Mg type hydrotalcite for purification of wastewater, Ogata Fumihiko, Nagai Noriaki, Kishida Mao, Nakamura Takehiro, Kawasaki Naohito, JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING, JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING, 7(1), Feb. 2019 , Refereed
  • Effect of hesperetin derivatives on the development of selenite‑induced cataracts in rats., Yosuke Nakazawa, Martin Pauze, Kazuya Fukuyama, Noriaki Nagai, Megumi Funakoshi-Tago, Takeshi Sugai, Hiroomi Tamura, Molecular medicine reports, Molecular medicine reports, 18(1), 1043 - 1050, Jul. 2018 , Refereed
    Summary:Cataracts are a major cause of blindness worldwide. As anti‑cataract pharmaceutical therapies require long‑term treatment, identifying anti‑cataract compounds that are ubiquitous in the human diet, have no adverse effects and are affordable, is of paramount importance. The present study focused on hesperetin and its derived compounds, hesperetin stearic acid ester (Hes‑S) and hesperetin oleic acid ester (Hes‑O), in order to investigate their therapeutic potential to treat cataracts in a selenite animal model. Thirteen‑day‑old Sprague Dawley rats were divided into 12 groups. Animals in groups 1 and 7 were subcutaneously injected with vehicle, those in groups 2 and 8 were administered hesperetin, those in groups 3 and 9 received stearic acid, those in groups 4 and 10 were injected with oleic acid, those in groups 5 and 11 were administered Hes‑S, and those in groups 6 and 12 received Hes‑O (10 nmol/kg body weight on days 0, 1 and 2). Animals in groups 7 to 12 were treated with sodium selenite (20 µmol/kg body weight given 4 h following the test compound treatment on day 0) to induce cataract. On day 6, rats had less severe central opacities and lower stage cataracts than rats in the selenite treatment‑only control groups. The levels of glutathione (GSH) and ascorbic acid (AsA) in lenses with selenite‑induced cataracts declined to one‑third of that of controls, and the reduction in GSH and AsA levels was rescued following hesperetin, Hes‑S or Hes‑O treatment, with concentrations remaining to 70‑80% of that of controls. However, there were no changes in the plasma levels of GSH and AsA following treatments. Administration of either hesperetin or hesperetin‑derived compounds prevented the reduction of chaperone activity in the lens, and rats treated with Hes‑S or Hes‑O treatment had significantly greater chaperone activity than hesperetin‑treated rats. Collectively, these results suggested that hesperetin and hesperetin‑derived compounds may be novel drug compounds that have the potential to prevent or delay the onset of cataracts.
  • Therapeutic Effect of Ophthalmic Formulation containing Nilvadipine Nanoparticles on Retinal Dysfunction in Rats Injected with Streptozotocin, Nagai Noriaki, Deguchi Saori, Ishii Miyu, Fukuoka Yuya, Otake Hiroko, Nakazawa Yosuke, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 59(9), Jul. 2018 , Refereed
  • NSAIDs起因性消化管障害の制御を目指した製剤工夫, 長井 紀章, BIO Clinica, BIO Clinica, 33(4), 371 - 373, Apr. 2018
    Summary:臨床において、非ステロイド性抗炎症薬(NSAIDs)による消化管障害は重篤な問題である。著者らは、湿式ビーズミル法を用い、平均粒子径76nmのインドメタシン(IMC)ナノ結晶経口製剤の作製法を確立した。また、本製剤は、従来の製剤と比較し、約5倍もバイオアベイラビリティが高まり、薬物投与量の減量を可能とした。さらに、これら製剤化に伴うNSAIDs投与量の減少が、薬剤の消化管粘膜直接刺激の低下を介し、障害誘発を軽減することを示した。本成果が安全なNSAIDs療法の確立に繋がることを期待する。(著者抄録)
  • 水溶性薬物の角膜透過性向上を目指して:チモロールマレイン酸・マグネシウムヒドロキシドナノ粒子配合剤の開発, NAKAZAWA Yosuke, 日本眼科学会雑誌, 日本眼科学会雑誌, 122(1), 61 - 62, Jan. 20 2018
  • NSAIDs起因性消化管障害の制御を目指した製剤工夫, 長井 紀章, BIO Clinica, BIO Clinica, 32(11), 1099 - 1101, Oct. 2017
    Summary:臨床において、非ステロイド性抗炎症薬(NSAIDs)による消化管障害は重篤な問題である。著者らは、湿式ビーズミル法を用い、平均粒子径76nmのインドメタシン(IMC)ナノ結晶経口製剤の作製法を確立した。また、本製剤は、従来の製剤と比較し、約5倍もバイオアベイラビリティが高まり、薬物投与量の減量を可能とした。さらに、これら製剤化に伴うNSAIDs投与量の減少が、薬剤の消化管粘膜直接刺激の低下を介し、障害誘発を軽減することを示した。本成果が安全なNSAIDs療法の確立に繋がることを期待する。(著者抄録)
  • Amyloid beta(1-43) Accumulates in the Lens Epithelium of Cortical Opacification in Japanese Patients, Noriaki Nagai, Yu Mano, Hiroko Otake, Teppei Shibata, Eri Kubo, Hiroshi Sasaki, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 58(7), 3294 - 3302, Jun. 2017 , Refereed
    Summary:PURPOSE. We investigated the accumulation of amyloid beta (A beta(1- 40), A beta(1-42), A beta(1- 43)) in the lens epithelium of patients with opacification of five different types (cortical cataract [COR]; nuclear cataract [NUC]; posterior subcapsular cataract [PSC]; retrodots [RD]; and water clefts [WC]). METHODS. Samples were collected from Japanese patients taken during cataract surgery; A beta levels and mRNA expression were determined by ELISA and a real- time RT-PCR method, respectively. RESULTS. Levels of A beta(1- 40) and A beta(1- 42) in the lens epithelium of patients with COR, NUC, PSC, RD, and WC showed no significant differences in comparison with transparent lens epithelium. Levels of A beta(1- 43) in the lens epithelium of patients with PSC and WC were not detected, and NUC and RD were slightly elevated. In contrast to the results in these cataract types, high A beta(1- 43) levels were observed in the lens epithelium of patients with COR, and a close relationship was observed between A beta(1- 43) levels and the degree of lens opacification (R= 0.8229, n = 6). The levels of A beta(1- 43) were also higher in the lens epithelium of patients with mixed-cataract showing cortical opacification, and the A beta(1- 43) levels in the lens epithelium of mixed-cataract patients with cortical opacification was significantly higher than in that of mixed-cataract patients without cortical opacification. In addition, the level of an amyloid precursor protein mRNA in the lens epithelium of mixed-cataract patients with cortical opacification was significantly higher than in transparent lens and mixed-cataract patients without cortical opacification. CONCLUSIONS. We found high levels of A beta(1-43) accumulation in the lens epithelium of Japanese patients with cortical opacification.
  • A positive feedback loop between nitric oxide and amyloid beta (1-42) accelerates mitochondrial damage in human lens epithelial cells, Noriaki Nagai, Yoshimasa Ito, Teppei Shibata, Eri Kubo, Hiroshi Sasaki, TOXICOLOGY, TOXICOLOGY, 381, 19 - 30, Apr. 2017 , Refereed
    Summary:We have reported that excessive nitric oxide (NO), like other reactive oxygen species (ROS), causes a decrease in cytochrome c oxidase (CCO) activity and ATP levels (mitochondrial damage) resulting in lens opacity. In addition, previous reports have shown that oxidative stress caused by ROS enhances amyloid 13 (A beta) production in mammalian lenses, and that A beta(1-42) stimulates inducible nitric oxide synthase (iNOS) promoter activity. Based on these reports, we investigated the relationship between NO and A beta(1-42) production in human lens epithelial (HLE) cells. iNOS was induced by the co-incubation of HLE cells with 1000 IU interferon-gamma (IFN-gamma) and 100 ngiml lipopolysaccharide (LPS) for 48 h. This led to enhanced NO release, an increase in the gene expression levels of proteins related to A beta production, and the cellular accumulation of A beta(1-42) . Moreover, both aminoguanidine (AG, a selective inhibitor of iNOS) and diethyldithiocarbamate (DDC, a nuclear factor-kappa B (NF kappa B) inhibitor) attenuated these changes in IFN-gamma and LPS stimulated HLE cells. Based on our finding that A beta(1-42) accumulation is induced by co incubation of HLE cells with both IFN-gamma and LPS, we prepared a HLE cell model with A beta(1-42) accumulation (A beta-accumulated-HLE cell model) by pre-stimulating cells with IFN-gamma and LPS for 48 h. A beta(1-42) accumulation caused NO production via iNOS, resulting in an enhancement in the mRNA levels for enzymes necessary for the proteolysis of amyloid precursor protein (APP) to AS in HLE cells. In addition, excessive NO produced in response to A beta(1-42) accumulation led to a decrease in CCO activity and ATP levels. Taken together, we hypothesize that excessive NO production in the lens epithelium enhances A beta(1-42) production, and that this enhancement accelerates NO release. The enhancement in NO production in the lens epithelium based on positive feedback (NO-A beta positive feedback loop, a vicious cycle) may promote the onset of cataracts (lens opacification) via the decrease in CCO activity and ATP levels. These findings provide significant information that can be used to design further studies aimed at developing anti-cataract drugs. (C) 2017 Elsevier B.V. All rights reserved.
  • Ferulic Acid Suppresses Amyloid beta Production in the Human Lens Epithelial Cell Stimulated with Hydrogen Peroxide, Noriaki Nagai, Sachiyo Kotani, Yu Mano, Akina Ueno, Yoshimasa Ito, Toshio Kitaba, Takumi Takata, Noriko Fujii, BIOMED RESEARCH INTERNATIONAL, BIOMED RESEARCH INTERNATIONAL, 2017, 5343010, 2017 , Refereed
    Summary:It is well known that oxidative stresses induce the production of amyloid beta(A beta) in the brain, lens, and retina, leading to age-related diseases. In the present study, we investigated the effects of ferulic acid on the A beta levels in H2O2 - stimulated human lens epithelial (HLE) SRA01/04 cells. Three types of A beta peptides (A beta(1- 40), A beta(1- 42), andA beta(1- 43)) were measured by ELISA, and the levels of mRNA for the expressed proteins related to A beta production (APP, BACE1, and PS proteins) and degradation (ADAM10, NEP, and ECE1 proteins) were determined by quantitative real-time RT-PCR. H2O2 stimulation augmented gene expression of the proteins related to A beta production, resulting in the production of three types of A beta peptides. Treatment with 0.1 mu M ferulic acid attenuated the augmentations of gene expression and production of the proteins related to the secretion of three types of A beta peptides in the H2O2 - stimulated HLE cells. These results provided evidence of antioxidative functions of ferulic acid for lens epithelial cells.
  • Adsorption Capability of Cationic Dyes (Methylene Blue and Crystal Violet) onto Poly-γ-glutamic Acid., Ogata F, Nagai N, Kawasaki N, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 65(3), 268 - 275, 2017 , Refereed
  • Hyperglycemia Enhances the Production of Amyloid beta(1-42) in the Lenses of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Type 2 Diabetes, Noriaki Nagai, Yoshimasa Ito, Hiroshi Sasaki, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 57(3), 1408 - 1417, Mar. 2016 , Refereed
    Summary:PURPOSE. It has been reported that the accumulation of amyloid beta(1-42) (A beta(1-42)) in human lenses can cause some forms of lens opacification. However, the factors leading to changes in the accumulation of A beta in the lens remain obscure. In this study, we investigate the effect of hyperglycemia on A beta(1-42) accumulation in lenses. METHODS. Otsuka Long-Evans Tokushima Fatty (OLETF) rats and the human lens epithelial cell line SRA 01/04 (HLE cells) were used. The expression of mRNA was determined using a quantitative real-time RT-PCR method; A beta(1-42) levels were analyzed by an ELISA method. RESULTS. Otsuka Long-Evans Tokushima Fatty rats at more than 20 weeks of age develop diabetes mellitus with hyperglycemia. Additionally, the levels of the mRNAs for A beta(1-42), amyloid precursor proteins (APP), beta-(BACE1), and gamma-secretase (PS) rise in the lenses of OLETF rats with age; high A beta(1-42) levels are observed in the lens capsule-epithelium and cortex. The enhanced expression of the genes for APP, BACE1, and PS in the lenses of OLETF rats is prevented by food restriction (25 g/d/rat). When the effect of glucose levels on the production of A beta(1-42) was investigated in the human lens epithelial cell line SRA 01/04 (HLE cells), the mRNA levels for APP, BACE1, and PS, as well as A beta(1-42) protein levels, were significantly higher under high glucose conditions (20 mM) than under normal glucose conditions (5.6 mM). CONCLUSIONS. High glucose leads to the increased expression of genes related to A beta production, resulting in the accumulation of A beta in the lens.
  • Enhanced Production of Nitric Oxide Leads to ATP Collapse in the Retinas of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Diabetes, Nagai N, Yoshioka C, Tanino T, Ito Y, Okamoto N, Shimomura Y, Curr Eye Res, Curr Eye Res, (5), 1 - 11, May 2015 , Refereed
  • Nanosizing of the Particle in Brinzolamide Ophthalmic Suspension Enhances Its Intraocular Penetration, 長井 紀章, 真野 裕, 松平 有加, あたらしい眼科, あたらしい眼科, 32(4), 545 - 549, Apr. 2015
  • 一酸化窒素を標的とした白内障予防, NAGAI NORIAKI, 日本眼科学会雑誌, 日本眼科学会雑誌, 119, 26, Mar. 18 2015
  • Effects of Ophthalmic Formulations containing Cilostazol Nanoparticles on Retinal Vasoconstriction in Rats Injected with Endothelin-1, Nagai N, Yoshioka C, Tanabe W, Tanino T, Ito Y, Okamoto N, Shimomura Y, Pharm Anal Acta, Pharm Anal Acta, 6(4), online, Mar. 2015 , Refereed
  • In Vivo Evaluation of Corneal Damages after Instillation of Commercially Available Anti-glaucoma Combination Eyedrops, Using Rat Debrided Corneal Epithelium, 長井 紀章, 吉岡 千晶, 森 愛里, あたらしい眼科, あたらしい眼科, 32(3), 419 - 424, Mar. 2015
  • Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular, Nagai N, Yoshioka C, Mano Y, Ito Y, Okamoto N, Shimomura Y, Current Eye Research Online, Current Eye Research Online, (20), 1 - 11, Oct. 2014 , Refereed
  • Preventive Effect of Sericin on Benzalkonium Chloride Stimulation of Rabbit Red Blood Cells, NAGAI NORIAKI, FUJITA HIROMI, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 眼薬理, 眼薬理, 28(1), 41 - 44, Aug. 01 2014
  • Preventive Effect of Sericin on Benzalkonium Chloride Stimulation of Rabbit Red Blood Cells, 長井 紀章, 藤田 裕美, 伊藤 吉將, あたらしい眼科, あたらしい眼科, 31(5), 729 - 732, May 2014
  • 徹底理解!点眼剤 知っておきたい!点眼剤の基礎知識―3)添加物による眼組織への影響, NAGAI NORIAKI, ITO YOSHIMASA, 薬局, 薬局, 65(5), 1731-1737,1712, Apr. 05 2014
  • Effect of Cilostazol Nanoparticles on Endothelial, Lu S, Nakagomi T, Nakano-doi A, Takata M, Okamoto N, Mimura O, Ito Y, Nagai N, Acta Med. Hyogo, Acta Med. Hyogo, 38(2), 75 - 80, Mar. 2014 , Refereed
  • Excessive hydrogen peroxide enhances the attachment of amyloid beta(1-42) in the lens epithelium of UPL rats, a hereditary model for cataracts, Noriaki Nagai, Yoshimasa Ito, TOXICOLOGY, TOXICOLOGY, 315(1), 55 - 64, Jan. 2014 , Refereed
    Summary:Several studies have reported that hydrogen peroxide (H2O2) is related to the toxicity of amyloid beta (A beta), and that the accumulation of A beta in the lenses of humans causes lens opacification. In this study, we investigate the accumulation of A beta(1-42) in the lenses of UPL rats, which then leads to lens opacification. In addition, we demonstrate the effect of disulfiram eye drops (DSF), a potent radical scavenger, on A beta(1-42) accumulation in the lenses of UPL rats. The H2O2 levels in 46- to 60-day-old UPL rat lenses are significantly higher than in normal rats, and the A beta(1-42) levels in 53- and 60-day-old UPL rats are also increased only in lens epithelium containing capsules (capsule-epithelium), not in the lens cortex and nucleus. However, no increases in amyloid precursor protein (APP), beta- or gamma-secretase mRNA were observed in lenses of the corresponding ages. It has been thought that A beta(1-42) that accumulates in the lenses of UPL rats is actually produced in another tissue containing neuronal cells, such as brain or retina. A beta(1-42) levels in the brain and retina rise with aging, and the levels of APP, beta- and gamma-secretase mRNA in the retinas of 53-day-old UPL rats with opaque lenses are significantly higher than in 25-day-old UPL rats with transparent lenses. In contrast to the results in retinas, the levels of APP, beta- and gamma-secretase mRNA in the brains of 25- and 53-day-old UPL rats are similar. On the other hand, in an in vitro study, A beta(1-42) attachment in the lens capsule-epithelium of UPL rats was found to increase in H2O2. In addition, in an in vivo study, the inhibition of H2O2 by DSF was found to attenuate the increase in A beta(1-42) in the lens capsule-epithelium of 60-day-old UPL rats. Taken together, we hypothesize that excessive H2O2 in the lens enhances the attachment of A beta(1-42) in the lens capsule-epithelium of UPL rats, and that the instillation of DSF has the ability to attenuate the attachment of A beta(1-42) by inhibiting H2O2 production in lens. These findings provide significant information that can be used to design further studies aimed at developing anti-cataract drugs. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
  • Effect of Dextrin on Residue in Syringe and Tube Obstruction for KREMEZIN Fine Granules in the Simple Suspension Method by Feeding Tube, 長井 紀章, 緒方 文彦, 塚本 あゆみ, 薬局薬学, 薬局薬学, 6(1), 22 - 27, 2014
  • An Evaluation of Usage and Utilization of Generic Drugs by Clinical Medicine Departments Using a Questionnaire of Chain Community Pharmacies in Japan, Nagai Noriaki, Kim Yusei, Matzno Sumio, Matsuyama Kenji, Otori Toru, Jpn.J.Drug Inform., Jpn.J.Drug Inform., 16(3), 137 - 142, 2014
    Summary:The creation of the National Health Insurance program has greatly contributed to giving Japan the world's highest level of life expectancy.  However, the cost of medical care in Japan has increased as a result of an aging society.  In response to this reality, the Japanese government initiated a campaign to promote the use of generic drugs (GEs).  In order to clarify some of the trends that contribute to different clinical medicine department usages of GEs, we carried out a survey of 400 pharmacies.  The survey data was analyzed using linear regression analysis.  Analysis of linear equations derived "utilization" that indicated ease of use of GEs, and a "saturation acceptable value (maximum allowed)" that indicated usage of GEs.  The breakdown for different clinical medicine department usages of GEs was determined as the following: psychosomatic medicine or psychiatry was 11±0.13%, internal medicine was 29±0.18%, orthopedics was 18±0.14%, ophthalmology or otolaryngology was 15±0.14%, other departments was 17±0.15%.  Furthermore, the highest utilization derived by linear regression analysis was orthopedics.  The highest acceptable saturation value was for psychosomatic medicine or psychiatry, while the lowest acceptable saturation value was orthopedics.  The results of the study confirm the importance of establishing evaluation methods for GE usage, and that linear regression analysis is a powerful tool for revealing trends in GE usage among different departments.  Additionally, the study suggests that determining GE spread measures is valuable, since they can serve as an aid to future pharmaceutical administration consideration.
  • Study on Prevention of Cataract Development Contributing to Mitochondrial or Cell Membrane Damage, Nagai Noriaki, The Journal of The Japanese Society for Cataract Research, The Journal of The Japanese Society for Cataract Research, 26(1), 13 - 19, 2014
    Summary:It is important to elucidate mechanisms of lens opacification in order to development of anti-cataract drugs based on evidence. In this study, we show that the mechanisms for the lens opacification is different in three hereditary cataract model rats (UPLR, SCR and ICR). In addition, we investigated that the preventive effect of eye drops containing disulfiram on lens opacification. In UPLR, excessive NO cause damage to the mitochondrial genome, resulting in a decrease in ATP production and increase in Ca2+-ATPase activity. The decrease in ATP content cause the decrease in Ca2+-ATPase function resulting in the elevation in lens Ca2+ and opacification. In SCR and ICR, excessive NO cause an enhancement of lipid peroxidation resulting in the oxidative inhibition of Ca2+-ATPase. The decrease in Ca2+-ATPase activity cause the elevation in the level of lens Ca2+, thus leading to lens opacification. Furthermore, the instillation of eye drops containing a disulfiram and hydroxypropyl-β-cyclodextrin inclusion complex delays lens opacification in hereditary cataract model rats.
  • Therapeutic effects of sericin on diabetic keratopathy in Otsuka Long-Evans Tokushima Fatty rats., Nagai N, Ito Y, World journal of diabetes, World journal of diabetes, 4(6), 282 - 289, Dec. 2013 , Refereed
  • 後発医薬品の使用状況に関するアンケートの多変量解析による問題点の抽出, 大鳥徹, 長井紀章, 橋本佳幸, 金裕生, 松野純男, 松山賢治, 医薬品情報学, 医薬品情報学, 15(3), 124 - 132, Nov. 30 2013
    Summary:Objective: Recently, the cost of medical care in Japan has increased as a result of an aging society.  In response to this reality, the Japanese government initiated a campaign to promote the use of generic drugs.  In spite of this campaign, Japanese consumers have doubts about the safety and reliability of generic drugs, resulting in lower usage of these drugs compared to usage in Europe and the US.Methods: In order to clarify some of the factors that contribute to low rates of generic drug use, we carried out a survey of 400 pharmacies.  The survey data was analyzed using factor analysis and cluster analysis, which is a technique known as multivariate analysis.Results: The results from factor analysis derived four factors: 1) generic drug usage related to generic drug prescription class, 2) the amount of generic drug prescriptions related to patient preferences, 3) patient willingness to use generic drug prescriptions, and 4) pharmacy willingness.  Cluster analysis was used to classify pharmacies participating in the survey.  The results of cluster analysis revealed three main pharmacy groups: a) low usage of generic drugs, b) moderate usage of generic drugs, and c) high usage of generic drugs.Conclusion: The results of multivariate analysis showed that pharmacists are more willing to issue generic drugs unless doctors instruct them to use a brand-name drug.
  • A case of transient myopia due to aripiprazole administration, 岡本 紀夫, 日下 俊次, 長井 紀章, 眼科臨床紀要, 眼科臨床紀要, 6(11), 903 - 905, Nov. 15 2013
  • Corneal Wound Healing Rate Delay in Ovariectomized Rats Receiving Low-calcium Diet, NAGAI NORIAKI, OGATA FUMIHIKO, FUNAKAMI YOSHINORI, ITO YOSHIMASA, KAWASAKI NAOHITO, あたらしい眼科, あたらしい眼科, 30(11), 1623 - 1627, Nov. 2013
  • Expression of Interferon-.GAMMA. and Nitric Oxide in Retina of Otsuka Long-Evans Tokushima Fatty Rat, NAGAI NORIAKI, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 眼薬理, 眼薬理, 27(1), 27 - 29, Sep. 05 2013
  • Kinetic Analysis of Corneal Epithelial Cell Damage by Commercially Available Anti-Glaucoma (Combination ) Eyedrops, Using First-Order Rate Equation, NAGAI Noriaki, OE Kyouhei, MORI Airi, ITO Yoshimasa, OKAMOTO Norio, SHIMOMURA Yoshikazu, あたらしい眼科 = Journal of the eye, あたらしい眼科 = Journal of the eye, 30(7), 1023 - 1028, Jul. 30 2013
  • Kinetic Analysis of Corneal Epithelial Cell Damage by Commercially Available Anti-Glaucoma (Combination) Eyedrops, Using First-Order Rate Equation, NAGAI NORIAKI, OE KYOHEI, MORI AIRI, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, あたらしい眼科, あたらしい眼科, 30(7), 1023 - 1028, Jul. 30 2013
  • Accumulation of Amyloid β in Lens of Otsuka Long-Evans Tokushima Fatty Rat, NAGAI Noriaki, TAKEDA Atsushi, ITO Yoshimasa, 日本白内障学会誌, 日本白内障学会誌, 25, 51 - 55, Jun. 01 2013
  • Accumulation of Amyloid .BETA. in Lens of Otsuka Long-Evans Tokushima Fatty Rat, NAGAI NORIAKI, TAKEDA ATSUSHI, ITO YOSHIMASA, あたらしい眼科, あたらしい眼科, 30(1), 97 - 101, Jan. 30 2013
  • Study on the Social Problems for the Use of Generic Drugs in Japan from a Survey Community Pharmacies, 大鳥 徹, 長井 紀章, 橋本 佳幸, 薬局薬学, 薬局薬学, 5(2), 107 - 115, 2013
  • Accumulation of Amyloid β in Lens of Otsuka Long-Evans Tokushima Fatty Rat, 30(1), 97 - 101, Jan. 2013
  • Preventive Effect of Dextrin on Residue in Syringe and Tube Obstruction for Kalimate® in the Simple Suspension Method by Feeding Tube, Nagai Noriaki, Ogata Fumihiko, Hayashi Tomonori, Nishiura Saori, Matsuoka Hiroshi, Kawasaki Naohito, Ito Yoshimasa, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 39(1), 33 - 38, 2013
    Summary:Kalimate® is often administered to patients via a simple suspension method by feeding tube. However, this method has a low recovery ratio and tube obstruction can occur. In this study, we investigated whether adding dextrin to decrease the adhesiveness and dispersibility improves the low recovery ratio and reduce tube obstruction. The addition of 0.6% dextrin significantly increased the dispersibility and fluidity of kalimate® compared to the dispersibility and fluidity of kalimate in purified water, but the addition of 0.1% and 0.2% dextrin did not. On the other hand, the 0.1 - 0.6% dextrin improved the low recovery ratio of kalimate® in the simple suspension method by feeding tube. These results show that the addition of dextrin improves the low recovery ratio and prevents tube obstruction in the simple suspension method of kalimate®. In addition, it was suggested that the decrease in recovery ratio of kalimate® is related to the adhesiveness, and the increase of dispersibility suppressed the tube obstruction in the simple suspension method by feeding tube. These findings provide significant information that can be used in improving the low recovery ratio and tube obstruction in the simple suspension method by feeding tube.
  • Dysfunction in Cytochrome c Oxidase Caused by Excessive Nitric Oxide in Human Lens Epithelial Cells Stimulated with Interferon-gamma and Lipopolysaccharide, Noriaki Nagai, Yoshimasa Ito, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 37(10), 889 - 897, Oct. 2012 , Refereed
    Summary:Purpose: We previously found two mechanisms for the dysfunction in Ca2+ regulation caused by excessive nitric oxide (NO) using the lenses of hereditary cataract model rats: the first is that NO causes a decrease in Adenosine-5'-triphosphate (ATP) level via cytochrome c oxidase (CCO), resulting in a decrease in ATPase function; the second is that NO causes enhanced lipid peroxidation, resulting in the oxidative inhibition of Ca2+-ATPase. In this study, we demonstrate the effect of excessive NO on lipid peroxidation and ATP production in human lens using a human lens epithelial cell line, SRA 01/04 (human lens epithelial (HLE) cells). Methods: Excessive NO via inducible NO synthase (iNOS) was induced by stimulating cells with a combination of interferon-gamma (1000 IU IFN-gamma) and lipopolysaccharide (100 ng/mL LPS). CCO activity was measured using a Mitochondrial Isolation kit and Cytochrome c Oxidase Assay kit, and ATP levels were determined using a Sigma ATP Bioluminescent Assay Kit and a luminometer AB-2200. Results: Cytochrome c oxidase activity and ATP levels were decreased in HLE cells stimulated with IFN-gamma and LPS, and aminoguanidine (AG) and diethyldithiocarbamate (DDC) added 6 h before cell collection significantly attenuated these decreases in cells stimulated with the IFN-gamma and LPS for 24-30 h. However, the lower CCO activity and ATP levels in HLE cells stimulated with the IFN-gamma and LPS for 30 h were not changed by treatment with AG or DDC for 6-12 h, while the CCO activity and ATP levels in HLE cells treated with AG or DDC for 18 were recovered. Conclusion: Excessive NO causes a decrease in CCO activity and ATP levels, and the recovery time for CCO activity is related to exposure time to NO in HLE cells.
  • Accumulation of Amyloid .BETA. in Retina of Otsuka Long-Evans Tokushima Fatty Rat, NAGAI NORIAKI, TAKEDA ATSUSHI, MURAO MAYUMI, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 眼薬理, 眼薬理, 26(1), 35 - 37, Aug. 31 2012
  • An Investigation on Attitudes toward the Promotion of Generic Products for Pharmacists in Chain Community Pharmacies in Japan, NAGAI NORIAKI, ONO HIKARU, YAMATO MIKIE, HORINO TOMOMI, KITAKOJI MANABU, ITO YOSHIMASA, TAKADA MITSUTAKA, 医療薬学, 医療薬学, 38(2), 111 - 117, Feb. 10 2012
    Summary:The penetration of low-priced generic drugs of good quality leads to not only a lower financial burden on patients, but also financial improvement of Japans medical insurance system. In this study, we investigated the relationship between the usage conditions of generic products (GE) and attitudes toward the reduction of national medical expense for pharmacists in chain community pharmacies in Japan using a questionnaire survey. The 20 - 25% usage conditions of GE were the highest in this study. The majority (89.2%) of pharmacists in the community pharmacy (positive group) have a positive attitude toward the reduction of national medical expense using GE, and the usage conditions of GE in the positive group are higher than that in the pharmacists that have a negative attitude toward the reduction of national medical expense using GE (negative group). In addition, the results of the questionnaire survey show that the pharmacists in the negative group still have doubts about the quality, effect and supply of GE in comparison with the positive group, and the pharmacists in the positive group were more interested in the generic drug dispensing fee in comparison with the negative group. In conclusion, the present study demonstrates that most pharmacists in this study have a positive attitude toward the reduction of national medical expense using GE, and the attitude toward GE in pharmacies relates to the usage conditions of GE. These findings provide significant information on the need for a reduction of national medical expense using GE.
  • Effects of Instillation of Eyedrops Containing Disulfiram and Hydroxypropyl-beta-Cyclodextrin Inclusion Complex on Endotoxin-Induced Uveitis in Rats, Kazutaka Kanai, Yoshimasa Ito, Noriaki Nagai, Naoyuki Itoh, Yasutomo Hori, Seishirou Chikazawa, Fumio Hoshi, Seiichi Higuchi, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 37(2), 124 - 131, Feb. 2012 , Refereed
    Summary:Objective: To investigate the anti-inflammatory effects of the instillation of disulfirum (DSF) eyedrops that enhance solubility using 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and hydroxypropylmethylcellulose (HPMC) on endotoxin-induced uveitis (EIU) in rats and mechanisms related to ocular inflammation. Methods: EIU was induced in male Lewis rats by subcutaneous injection of 200 mu g lipopolysaccharide (LPS). DSF (0.125%, 0.25% and 0.5%) or commercially available 0.05% dexamethasone (Dexa) was topically applied to both eyes of rats 1 hour before, immediately after, and 1 and 2 hours after injection of LPS. The aqueous humor (AqH) was collected 24 hours after LPS injection, and the number of infiltrating cells, protein concentration, and levels of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and prostaglandin E2 (PGE2) were determined. Immunohistochemical analysis of the iris ciliary body (ICB) cells was performed to determine the expression of activated nuclear factor kappa B (NF-kappa B), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Results: The topical administration with DSF suppressed, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of NO, TNF-alpha and PGE2 in the AqH and improved the histologic status of the ocular tissue. The anti-inflammatory potency of 0.5% DSF treatment was as strong as that of 0.05% Dexa. Topical DSF treatment also suppressed the activated NF-kappa B 3 hours after LPS injection, and iNOS and COX-2 expression in the ICB 24 hours after LPS injection. Conclusions: The present results demonstrate that the topical instillation of DSF eyedrops suppresses the inflammation in EIU, suggesting a possible novel approach for the treatment of ocular inflammation.
  • In Vitro Evaluation of Corneal Damage Caused by Anti-Glaucoma Eyedrops Using Human Corneal Epithelial Cell (HCE-T), NAGAI NORIAKI, OE KYOHEI, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, あたらしい眼科, あたらしい眼科, 28(9), 1331 - 1336, Sep. 30 2011
  • Kinetic Analysis of Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rat Instilled with Benzalkonium Chloride and Polysorbate 80, NAGAI NORIAKI, MURAO TAKATOSHI, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, あたらしい眼科, あたらしい眼科, 28(6), 855 - 859, Jun. 30 2011
  • 遺伝性白内障ICR/fラット水晶体への過酸化水素処理による脂質過酸化とCa2+‐ATPase活性の関連性, 長井紀章, 村尾卓俊, 小仲陽子, 伊藤吉將, 竹内典子, 日本白内障学会誌, 日本白内障学会誌, 23(1), 51 - 54, Jun. 03 2011
  • Relationship between Lipid Peroxidation and Ca^<2+>-ATPase Activity in ICR/f Rat Lenses Stimulated by Hydrogen Peroxide, NAGAI Noriaki, MURAO Takatoshi, KONAKA Yoko, ITO Yoshimasa, TAKEUCHI Noriko, Journal of the eye, Journal of the eye, 28(4), 527 - 530, Apr. 30 2011
  • Effect of Polysorbate 80 and Ethylenediaminetetraacetic Acid (EDTA) Instillation on Corneal Wound Healing in Rat Debrided Corneal Epithelium, NAGAI NORIAKI, MURAO TAKATOSHI, ITO YOSHIMASA, OKAMOTO NORIO, あたらしい眼科, あたらしい眼科, 27(9), 1299 - 1302, Sep. 30 2010
  • Sericin Addition to Anti-glaucoma Eye Drops: Effect on Proliferation of Corneal Epithelial Cell Line SV40 (HCE-T), NAGAI NORIAKI, MURAO TAKATOSHI, ITO YOSHIMASA, OKAMOTO NORIO, あたらしい眼科, あたらしい眼科, 27(9), 1295 - 1298, Sep. 30 2010
  • Kinetic Analysis of Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rats, NAGAI NORIAKI, MURAO TAKATOSHI, ITO YOSHIMASA, OKAMOTO NORIO, MIMURA OSAMU, 眼薬理, 眼薬理, 24(1), 52 - 54, Sep. 10 2010
  • Effect of sesamin solution in rat dry eye model, OKAMOTO Norio, ITO Yoshimasa, NAGAI Noriaki, HOSOTANI Yuka, MIMURA Osamu, Folia japonica de ophthalmologica clinica, Folia japonica de ophthalmologica clinica, 3(7), 649 - 652, Jul. 15 2010
  • 生体産生性ガス状物質一酸化窒素を標的とした白内障療法について, 長井紀章, 日本眼科学会雑誌, 日本眼科学会雑誌, 114, 79, Mar. 15 2010
  • Involvement of Interleukin 18 and DNase II-like Acid DNase in Cataract Formation in ICR/f Rat, NAGAI Noriaki, ITO Yoshimasa, TAKEUCHI Noriko, USUI Shigeyuki, HIRANO Kazuyuki, 眼薬理 = Japanese journal of ocular pharmacology, 眼薬理 = Japanese journal of ocular pharmacology, 23(1), 45 - 50, Aug. 31 2009
  • Effect of Enhanced Nitric Oxide Production on Plasma Membrane Ca^<2+>-ATPase Expression in Human Lens Epithelial Cell Line SRA 01/04 Treated with Combination of Interferon-γ and Lipopolysaccharide, NAGAI Noriaki, ITO Yoshimasa, USUI Shigeyuki, HIRANO Kazuyuki, Journal of the eye, Journal of the eye, 26(5), 709 - 713, May 30 2009
  • Effect of Enhanced Nitric Oxide Production on Plasma Membrane Ca2+-ATPase Expression in Human Lens Epithelial Cell Line SRA 01/04 Treated with Combination of Interferon-.GAMMA. and Lipopolysaccharide, NAGAI NORIAKI, ITO YOSHIMASA, USUI SHIGEYUKI, HIRANO KAZUYUKI, あたらしい眼科, あたらしい眼科, 26(5), 709 - 713, May 30 2009
  • Involvement of Interleukin 18 and DNase II-like Acid DNase in Cataract Formation in ICR/f Rat, NAGAI NORIAKI, ITO YOSHIMASA, TAKEUCHI NORIKO, USUI SHIGEYUKI, HIRANO KAZUYUKI, あたらしい眼科, あたらしい眼科, 26(5), 675 - 680, May 30 2009
  • Variation of particle size in triamcinolone acetonide aqueous suspension by differences of its preparation method, OKAMOTO Norio, OONO Shinichirou, ITO Yoshimasa, NAGAI Noriaki, TAKAGI Kazuyuki, MIMURA Osamu, Folia japonica de ophthalmologica clinica, Folia japonica de ophthalmologica clinica, 2(4), 326 - 330, Apr. 15 2009
  • Vitreous Body Visualization Using Fine Particle Chemical Agent of Tranilast, OKAMOTO NORIO, ITO YOSHIMASA, ONO SHIN'ICHIRO, HARINO SEIYO, NAGAI NORIAKI, MIMURA OSAMU, あたらしい眼科, あたらしい眼科, 26(2), 263 - 267, Feb. 28 2009
  • Cytochrome c Oxidase Involvement in Cataract Formation in the UPL Rat Lens, NAGAI NORIAKI, ITO YOSHIMASA, TAKEUCHI NORIKO, KAMEI AKIRA, 眼薬理, 眼薬理, 22(1), 54 - 56, Sep. 05 2008
  • Comparison of Suppression of Corneal Epithelial Cell Line SV40 (HCE-T) Proliferation by Combined Treatment Using Two Types of Anti-Glaucoma Eyedrops, NAGAI NORIAKI, ITO YOSHIMASA, OKAMOTO NORIO, KAWAKAMI YOSHIMI, あたらしい眼科, あたらしい眼科, 25(8), 1135 - 1138, Aug. 30 2008
  • An In Vitro Screening Test for Corneal Damages by Various Anti-Glaucoma Eye Drops: Comparison of Suppression to Cell Growth of Corneal Epithelial Cell Line SV40 (HCE-T) by Them, NAGAI NORIAKI, ITO YOSHIMASA, OKAMOTO NORIO, KAWAKAMI YOSHIMI, あたらしい眼科, あたらしい眼科, 25(4), 553 - 556, Apr. 30 2008
  • Examination of fine particles chemical combination agent of tranilast and hyaluronic acid sodium salt, 岡本 紀夫, 伊藤 吉將, 長井 紀章, 眼科, 眼科, 50(4), 455 - 459, Apr. 05 2008
  • Involvement of Interleukin-18 in Cataract Formation in UPL Rat, NAGAI Noriaki, SONG Yongbo, FUKUHATA Takashi, ITO Yoshimasa, OKAMURA Haruki, 日本白内障学会誌, 日本白内障学会誌, 19(1), 815 - 818, Jan. 30 2008
  • Preventive Effect of Eyedrops Containing Magnesium Ions on Conjunctivitis Anaphylaxis Reaction in Rats, FUKUHATA Takashi, NAGAI Noriaki, ITO Yoshimasa, TAI Hideyuki, HATAGUCHI Yoshihiro, UOZUMI Yoshinobu, NAKAGAWA Koji, 眼薬理 = Japanese journal of ocular pharmacology, 眼薬理 = Japanese journal of ocular pharmacology, 21(1), 37 - 40, Aug. 31 2007
  • Installing the Latest Digital Camera on the Old Type Fundus Camera, ITO YOSHIMASA, OKAMOTO NORIO, BESSHO MASASHI, KAWAKAMI YOSHIMI, MIMURA OSAMU, NAGAI NORIAKI, あたらしい眼科, あたらしい眼科, 24(8), 1125 - 1127, Aug. 30 2007
  • Involvement of Interleukin-18 in Cataract Formation in UPL Rat, NAGAI NORIAKI, SONG YONGBO, FUKUHATA TAKASHI, ITO YOSHIMASA, OKAMURA HARUKI, あたらしい眼科, あたらしい眼科, 24(6), 815 - 818, Jun. 30 2007
  • Preventive Effect of Eyedrops Containing Magnesium Ions on Conjunctivitis Anaphylaxis Reaction in Rats, FUKUHATA TAKASHI, NAGAI NORIAKI, ITO YOSHIMASA, TAI HIDEYUKI, HATAGUCHI YOSHIHIRO, UOZUMI YOSHINOBU, NAKAGAWA KOJI, あたらしい眼科, あたらしい眼科, 24(6), 831 - 834, Jun. 30 2007
  • Involvement of interleukin-18 in cataract formation in UPL rat, 長井 紀章, 宋 永波, 福畠 孝史, Journal of the eye, Journal of the eye, 24(6), 815 - 818, Jun. 2007
  • Relation between Cell Damage and Expression of iNOS mRNA in Human Lens Epithelial Cell Line SRA 01/04 with Treatment by Interferon-γ and Lipopolysaccharide, NAGAI Noriaki, FUKUHATA Takashi, LIU Ying, ITO Yoshimasa, KAWAKAMI Yoshimi, IKEDA Tomohiro, MIMURA Osamu, OKAMURA Haruki, 日本白内障学会誌, 日本白内障学会誌, 18(1), 383 - 386, Oct. 20 2006
  • Relation between Cell Damage and Expression of iNOS mRNA in Human Lens Epithelial Cell Line SRA 01/04 with Treatment by Interferon-γ and Lipopolysaccharide, NAGAI Noriaki, FUKUHATA Takashi, LIU Ying, ITO Yoshimasa, KAWAKAMI Yoshimi, IKEDA Tomohiro, MIMURA Osamu, OKAMURA Haruki, Journal of the eye, Journal of the eye, 23(3), 383 - 386, Mar. 30 2006
  • Correction: Sato, K., et al. Identification of a Novel Oligosaccharide in Maple Syrup as a Potential Alternative Saccharide for Diabetes Mellitus Patients. Int. J. Mol. Sci. 2019, 20, 5041., Kanta Sato, Noriaki Nagai, Tetsushi Yamamoto, Kuniko Mitamura, Atsushi Taga, International journal of molecular sciences, International journal of molecular sciences, 21(14), Jul. 21 2020 , Refereed
    Summary:The authors wish to make the following corrections to this paper [...].
  • Ophthalmic In Situ Gelling System Containing Lanosterol Nanoparticles Delays Collapse of Lens Structure in Shumiya Cataract Rats., Noriaki Nagai, Kazuki Umachi, Hiroko Otake, Mikako Oka, Noriko Hiramatsu, Hiroshi Sasaki, Naoki Yamamoto, Pharmaceutics, Pharmaceutics, 12(7), Jul. 04 2020 , Refereed
    Summary:We attempted to prepare ophthalmic in situ gel formulations containing lanosterol (Lan) nanoparticles (LA-NPs/ISG) and investigated the characteristics, delivery pathway into the lens, and anti-cataract effects of LA-NPs/ISG using SCR-N (rats with slight lens structure collapse) and SCR-C (rats with a combination of remarkable lens structure collapse and opacification). LA-NPs/ISG was prepared by bead milling of the dispersions containing 0.5% Lan powder, 5% 2-hydroxypropyl-β-cyclodextrin, 0.5% methylcellulose, 0.005% benzalkonium chloride, and 0.5% mannitol. The particle size distribution of Lan was 60-250 nm. The LA-NPs/ISG was gelled at 37 °C, and the LA-NPs/ISG was taken into the cornea by energy-dependent endocytosis and then released to the intraocular side. In addition, the Lan contents in the lenses of both SCR-N and SCR-C were increased by the repetitive instillation of LA-NPs/ISG (twice per day). The space and structure collapse in the lens of SCR-N with aging was attenuated by the instillation of LA-NPs/ISG. Moreover, the repetitive instillation of LA-NPs/ISG attenuated the changes in cataract-related factors (the enhancement of nitric oxide levels, calpain activity, lipid peroxidation levels, Ca2+ contents, and the decrease of Ca2+-ATPase activity) in the lenses of SCR-C, and the repetitive instillation of LA-NPs/ISG delayed the onset of opacification in the SCR-C. It is possible that the LA-NPs/ISG is useful in maintaining lens homeostasis.
  • Hydrogel Formulations Incorporating Drug Nanocrystals Enhance the Therapeutic Effect of Rebamipide in a Hamster Model for Oral Mucositis., Noriaki Nagai, Ryotaro Seiriki, Saori Deguchi, Hiroko Otake, Noriko Hiramatsu, Hiroshi Sasaki, Naoki Yamamoto, Pharmaceutics, Pharmaceutics, 12(6), Jun. 09 2020 , Refereed
    Summary:A mouthwash formulation of rebamipide (REB) is commonly used to treat oral mucositis; however, this formulation does not provide sufficient treatment or prevention in cases of serious oral mucositis. To improve treatment, we attempted to design a hydrogel incorporating REB nanocrystals (R-NPs gel). The R-NPs gel was prepared by a bead mill method using carbopol hydrogel, methylcellulose and 2-hydroxypropyl-β-cyclodextrin, and another hydrogel incorporating REB microcrystals (R-MPs gel) was prepared following the same protocol but without the bead mill treatment. The REB particle size in the R-MPs gel was 0.15-25 μm, and while the REB particle size was 50-180 nm in the R-NPs gel. Next, we investigated the therapeutic effect of REB nanocrystals on oral mucositis using a hamster model. Almost all of the REB was released as drug nanocrystals from the R-NPs gel, and the REB content in the cheek pouch of hamsters treated with R-NPs gel was significantly higher than that of hamsters treated with R-MPs gel. Further, treatment with REB hydrogels enhanced the healing of oral wounds in the hamsters. REB accumulation in the cheek pouch of hamsters treated with the R-NPs gel was prevented by an inhibitor of clathrin-dependent endocytosis (CME) (40 μM dynasore). In conclusion, we designed an R-NPs gel and found that REB nanocrystals are taken up by tissues through CME, where they provide a persistent effect resulting in an enhancement of oral wound healing.
  • Removal of arsenic(III) ion from aqueous media using complex nickel-aluminum and nickel-aluminum-zirconium hydroxides, Fumihiko Ogata, Noriaki Nagai, Megumu Toda, Masashi Otani, Chalermpong Saenjum, Takehiro Nakamura, Naohito Kawasaki, Water (Switzerland), Water (Switzerland), 12(6), Jun. 01 2020 , Refereed
    Summary:© 2020 by the authors. The technology of wastewater treatment involving removal of heavy metals using complex metal hydroxides is reported. In this study, complex nickel-aluminum (NA11 and NA12) and nickel-aluminum-zirconium (NAZ1 and NAZ2) hydroxides were prepared for the removal of arsenite ions, As(III), from aqueous solution. The characteristics of each adsorbent were evaluated, and the adsorption capacity and adsorption mechanism were determined. The adsorption capacity of As(III) on NAZ1 (15.3 mg g-1) was greater than that on NA11 (9.3 mg g-1). Coverage is directly related to the specific surface area with a correlation coefficient of 0.921. Ion exchange involving sulfate ions in the interlayer of the adsorbent also plays a role in the mechanism of As(III) adsorption as demonstrated by correlation coefficients of 0.797 and 0.944 for the NA11 and NAZ1, respectively. The results demonstrate the usefulness of NAZ1 in removing As(III) from aqueous media.
  • Enhancement of Amyloid β1-43 Production in the Lens Epithelium of Japanese Type 2 Diabetic Patients., Yu Mano, Hiroko Otake, Teppei Shibata, Eri Kubo, Hiroshi Sasaki, Noriaki Nagai, Biomedicines, Biomedicines, 8(4), Apr. 13 2020 , Refereed
    Summary:We investigated whether the accumulation of amyloid β-protein (Aβ) is enhanced in the lenses of diabetic patients. Lens epithelium samples were collected from Japanese patients during cataract surgery, and the Aβ levels and gene expression of Aβ-producing and -degrading enzymes in the samples were measured by ELISA and real-time RT-PCR, respectively. The Aβ 1-43 levels in lenses of non-diabetic patients were low (0.11 pmol/g protein), while the levels in lenses of diabetic patients were significantly (6-fold) higher. Moreover, the Aβ1-43/total-Aβ ratio in the lenses of diabetic patients was also significantly higher than non-diabetic patients (p < 0.05). In addition, the mRNA levels for Aβ-producing enzymes were also enhanced in the lenses of diabetic patients. In contrast to the results for Aβ-producing enzymes, the mRNAs for the Aβ-degrading enzymes in the lenses of diabetic patients were significantly lower than in non-diabetic patients (p < 0.05). Furthermore, Aβ 1-43/total-Aβ ratio in lenses was found to increase with plasma glucose level. In conclusion, these results suggest that high glucose levels cause both an increase in Aβ production and a decrease in Aβ degradation, and these changes lead to the enhancement in Aβ1-43 accumulation in the lenses of diabetic patients. These findings are useful for developing therapies for diabetic cataracts and for developing anti-cataract drugs.
  • Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles., Misa Minami, Ryotaro Seiriki, Hiroko Otake, Yosuke Nakazawa, Kazutaka Kanai, Tadatoshi Tanino, Noriaki Nagai, Materials (Basel, Switzerland), Materials (Basel, Switzerland), 13(7), Apr. 03 2020 , Refereed
    Summary:Eye drops containing Tranilast (TL), N-(3,4-dimethoxycinnamoyl) anthramilic acid, are used as an anti-allergic conjunctivitis drug in the ophthalmic field. Traditional eye drops are very patient compliant, although the bioavailability (BA) of most eye drops is low since eye drops cannot be instilled beyond the capacity of the conjunctival sac due to its limited volume. Thus, traditional eye drops have low BA and a short duration of the drug on the ocular surface, so solutions to these problems are highly anticipated. In this study, we designed a sustained-release drug-delivery system (DDS) for TL nanoparticles. TL nanoparticles were prepared by bead mill treatment, and the gel formulations containing TL nanoparticles (TL-NPs-Gel, particle size 50 nm-100 nm) were provided by carboxypolymethylene. The crystal structure of TL with and without bead mill treatment is the same, but the TL solubility in formulations containing nanoparticles was 5.3-fold higher compared with gel formulations containing TL microparticles (TL-MPs-Gel). The photo and thermal stabilities of TL-NPs-Gel are also higher than those of dissolved TL. Moreover, when TL-NPs-Gel is applied to the upper eyelid skin (outside), the TL is released as nanoparticles, and delivered to the lacrimal fluid through the meibomian glands. In addition, the TL release profile for TL-NPs-Gel was sustained over 180 min after the treatment. These findings can be used to develop a sustained-release DDS in the ophthalmic field.
  • Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects., Noriaki Nagai, Fumihiko Ogata, Hiroko Otake, Naohito Kawasaki, Pharmaceutics, Pharmaceutics, 12(4), Apr. 01 2020 , Refereed
    Summary:Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.
  • Potential of virgin and calcined wheat bran biomass for the removal of chromium(VI) ion from a synthetic aqueous solution, Fumihiko Ogata, Noriaki Nagai, Ryo Itami, Takehiro Nakamura, Naohito Kawasaki, JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING, JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING, 8(2), Apr. 2020 , Refereed
    Summary:Virgin wheat bran (WB) and calcined wheat bran were prepared at 500 or 1000 degrees C (WB500 or WB1000, respectively), and their physicochemical properties (such as morphological, thermal, specific surface area, point of zero charge pH, and surface functional groups) were investigated to assess their chromium(VI) ion adsorption capability. The amount of chromium(VI) ion adsorbed was in the order WB < WB500 < WB1000. These results showed that the chromium(VI) ion adsorption was related to the WB surface characteristics. Additionally, the amount of chromium (Cr) and oxygen (O) on the WB1000 surface increased after adsorption, which indicated chromium(VI) ions were adsorbed onto the WB1000 surface. Adsorption isotherm and adsorption kinetic data fit the Freundlich (0.879-0.991) and pseudo-second-order models (0.979-0.997), respectively. The optimal pH condition for the removal of chromium(VI) ion from aqueous solution was approximately 2. Finally, WB1000 could be useful for repetition of chromium(VI) ion adsorption/desorption using sodium hydroxide at 1000 mmol/L (at least five times). It was shown that WB1000 has the potential for adsorption and recovery of chromium(VI) ion from aqueous solution using sodium hydroxide.
  • Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects., Noriaki Nagai, Fumihiko Ogata, Hiroko Otake, Naohito Kawasaki, Pharmaceutics, Pharmaceutics, 12(4), Apr. 01 2020 , Refereed
    Summary:Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.
  • Oral intake of α‑glucosyl‑hesperidin ameliorates selenite‑induced cataract formation., Yosuke Nakazawa, Miki Aoki, Sho Ishiwa, Naoki Morishita, Shin Endo, Noriaki Nagai, Naoki Yamamoto, Megumi Funakoshi-Tago, Hiroomi Tamura, Molecular medicine reports, Molecular medicine reports, 21(3), 1258 - 1266, Mar. 2020 , Refereed
    Summary:Hesperetin is a natural flavonoid with robust antioxidant properties. Our previous study reported that hesperetin can prevent cataract formation. However, an important consideration regarding hesperetin consumption is the limited bioavailability due to its poor solubility. The present study investigated the anti‑cataract effects of α‑glucosyl hesperidin in vivo and in vitro using a selenite‑induced cataract model. SD rats (age, 13 days) were orally administered PBS (0.2 ml) or α‑glucosyl hesperidin (200 mg/kg) on days 0, 1 and 2. Sodium selenite was subcutaneously administered to the rats 4 h after the first oral administration on day 0. Antioxidant levels in the lens and blood were measured on day 6. In vitro, human lens epithelial cells were treated with sodium selenite (10 µM) and/or hesperetin (50 or 100 mM) for 24 h and analyzed for apoptosis markers using sub‑G1 population and Annexin V‑FITC/propidium iodide staining and DNA ladder formation. α‑glucosyl hesperidin treatment significantly reduced the severity of selenite‑induced cataract. The level of antioxidants was significantly reduced in the selenite‑treated rats compared with in the controls; however, they were normalized with α‑glucosyl hesperidin treatment. In vitro, hesperetin could significantly reduce the number of cells undergoing apoptosis induced by sodium selenite in human lens epithelial cell lines. Overall, oral consumption of α‑glucosyl hesperidin could delay the onset of selenite‑induced cataract, at least in part by modulating the selenite‑induced cell death in lens epithelial cells.
  • Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles., Noriaki Nagai, Miyu Ishii, Ryotaro Seiriki, Fumihiko Ogata, Hiroko Otake, Yosuke Nakazawa, Norio Okamoto, Kazutaka Kanai, Naohito Kawasaki, Pharmaceutics, Pharmaceutics, 12(2), Feb. 14 2020 , Refereed
    Summary:The commercially available rebamipide ophthalmic suspension (CA-REB) was approved for clinical use in patients with dry eye; however, the residence time on the ocular surface for the traditional formulations is short, since the drug is removed from the ocular surface through the nasolacrimal duct. In this study, we designed a novel sustained-release drug delivery system (DDS) for dry eye therapy by rebamipide nanoparticles. The rebamipide solid nanoparticle-based ophthalmic formulation (REB-NPs) was prepared by a bead mill using additives (2-hydroxypropyl-β-cyclodextrin and methylcellulose) and a gel base (carbopol). The rebamipide particles formed are ellipsoid, with a particle size in the range of 40-200 nm. The rebamipide in the REB-NPs applied to eyelids was delivered into the lacrimal fluid through the meibomian glands, and sustained drug release was observed in comparison with CA-REB. Moreover, the REB-NPs increased the mucin levels in the lacrimal fluid and healed tear film breakup levels in an N-acetylcysteine-treated rabbit model. The information about this novel DDS route and creation of a nano-formulation can be used to design further studies aimed at therapy for dry eye.
  • The Intravitreal Injection of Lanosterol Nanoparticles Rescues Lens Structure Collapse at an Early Stage in Shumiya Cataract Rats., Noriaki Nagai, Yuya Fukuoka, Kanta Sato, Hiroko Otake, Atsushi Taga, Mikako Oka, Noriko Hiramatsu, Naoki Yamamoto, International journal of molecular sciences, International journal of molecular sciences, 21(3), Feb. 05 2020 , Refereed
    Summary:We designed an intravitreal injection formulation containing lanosterol nanoparticles (LAN-NPs) via the bead mill method and evaluated the therapeutic effect of LAN-NPs on lens structure collapse and opacification using two rat cataract models (SCR-N, rats with slight lens structure collapse; SCR-C, rats with the combination of a remarkable lens structure collapse and opacification). The particle size of lanosterol in the LAN-NPs was around 50-400 nm. A single injection of LAN-NPs (0.5%) supplied lanosterol into the lens for 48 h, and no irritation or muddiness was observed following repeated injections of LAN-NPs for 6 weeks (once every 2 days). Moreover, LAN-NPs repaired the slight collapse of the lens structure in SCR-N. Although the remarkable changes in the lens structure of SCR-C were not repaired by LAN-NP, the onset of opacification was delayed. In addition, the increase of cataract-related factors (Ca2+ contents, nitric oxide levels, lipid peroxidation and calpain activity levels) in the lenses of SCR-C was attenuated by the repeated injection of LAN-NPs. It is possible that a deficiency of lanosterol promotes the production of oxidative stress. In conclusion, it is difficult to improve serious structural collapse with posterior movement of the lens nucleus with a supplement of lanosterol via LAN-NPs. However, the intravitreal injection of LAN-NPs was found to repair the space and structural collapse in the early stages in the lenses.
  • Removal of Sr(II) ions from aqueous solution by human hair treated with EDTA, Fumihiko Ogata, Noriaki Nagai, Akane Soeda, Kaito Yamashiro, Takehiro Nakamura, Chalermpong Saenjum, Naohito Kawasaki, Bioresource Technology Reports, Bioresource Technology Reports, 9, Feb. 2020 , Refereed
    Summary:© 2020 Elsevier Ltd Disposed human hair was treated with different concentrations of ethylenediamine-N,N,N′,N′-tetraacetic acid (EDTA) (10%, 25%, and 50% denoted as ED10, ED25, and ED50, respectively), and its Sr(II) adsorption capacity from the aqueous phase was evaluated. The amount of Sr(II) adsorbed onto ED25 was 17 mg/g. The amount of Sr(II) adsorbed using ED25 depended on the solution pH, and the optimal pH condition was approximately 4 in our experiment. Because the point of zero charge of human hair is approximately 3.67 to 3.70, electrostatic interaction between Sr(II) and human hair easily occurred. Finally, the Sr(II) adsorbed onto ED25 was easily desorbed using a sodium hydroxide solution at a pH of 3 (desorption percentage of 95.4%). EDTA treatment of human hair was useful for producing a novelty adsorbent to adsorb Sr(II) from aqueous solution. These results can be applied to the solution of problems regarding the water environment and waste materials.
  • A Combination of Cryopreservation and Kneading Maintains the Usability of Mohs Paste., Hiroyo Okamoto, Tomohiro Yoshikawa, Kenta Takeuchi, Saori Deguchi, Yuto Hatakenaka, Hiroshi Matsuoka, Atsufumi Kawabata, Noriaki Nagai, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 68(6), 516 - 519, 2020 , Refereed
    Summary:Mohs paste is useful for controlling exudates from wounds and infections and is used to treat patients with inoperable skin tumors. Unfortunately, Mohs paste is difficult to preserve because its viscosity and stickiness increase dramatically immediately after preparation, resulting in decreased usability. In this study, the combined use of cryopreservation and kneading was shown to improve long-term storage of Mohs paste. At 25°C, Mohs pastes solidified rapidly, and viscosity reached approximately 700 Pa·s 5 h after preparation. In contrast, cryopreservation at -20°C attenuated hardening of Mohs pastes, and kneading also decreased viscosity. The viscosity of Mohs pastes cotreated with cryopreservation and kneading after 7 months of storage was <70 Pa·s. In addition, tissue invasion with these stored pastes was similar to freshly prepared Mohs paste. Results suggest that the combination of cryopreservation and kneading permits Mohs paste to be stored over extended periods, which may increase the utility of the paste for clinical use.
  • An in situ Gelling System Based on Methylcellulose and Tranilast Solid Nanoparticles Enhances Ocular Residence Time and Drug Absorption Into the Cornea and Conjunctiva., Noriaki Nagai, Misa Minami, Saori Deguchi, Hiroko Otake, Hiroshi Sasaki, Naoki Yamamoto, Frontiers in bioengineering and biotechnology, Frontiers in bioengineering and biotechnology, 8, 764 - 764, 2020 , Refereed
    Summary:We previously developed ophthalmic formulations containing tranilast nanopartaicles (ophthalmic TL-NPs formulations), and found them to show high uptake into ocular tissues. In this study, we aimed to design an in situ gel incorporating TL-NPs with 0.5-3% methylcellulose (MC, type SM-4) to ensure long residence time of the drug at the ocular surface. The ophthalmic TL-NPs formulations were prepared by the bead mill method, which yielded a mean particle size of ~93 nm with or without MC (0.5-3%). Although the dispersibility of TL particles in ophthalmic formulations increased with the MC content, the diffusion behavior of TL particles in the dispersion medium decreased with MC content. In an in vivo study using rats, the TL content in the lacrimal fluid was enhanced with MC content in the ophthalmic TL-NPs formulations, and the optimum amount of MC (0.5-1.5%) enhanced the TL content in the cornea and conjunctiva, and an anti-inflammatory effect of TL in rats instilled with ophthalmic TL-NPs formulations was observed. On the other hand, excessive MC (3%) prevented the corneal uptake of TL-NPs after instillation, and the anti-inflammation effect of TL was lower than that of ophthalmic TL-NPs formulations with optimum MC (0.5-1.5%). In conclusion, we found that gel formulations of TL-NPs with 0.5 and 1.5% MC provided a prolonged pre-corneal and pre-conjunctival contact time of TL, and resulted in higher TL contents in the cornea and conjunctiva following instillation in comparison with TL-NPs with or without 3% MC. This is probably due to the balance between the higher residence time and faster diffusion of TL-NPs on the ocular surface. These findings provide significant information that can be used to design further studies aimed at developing ophthalmic nanomedicines.
  • Identification of a Novel Oligosaccharide in Maple Syrup as a Potential Alternative Saccharide for Diabetes Mellitus Patients., Kanta Sato, Noriaki Nagai, Tetsushi Yamamoto, Kuniko Mitamura, Atsushi Taga, International journal of molecular sciences, International journal of molecular sciences, 20(20), Oct. 11 2019 , Refereed
    Summary:The incidence of diabetes mellitus (DM) is increasing rapidly and is associated with changes in dietary habits. Although restrictions in the use of sweeteners may prevent the development of DM, this might reduce the quality of life of patients with DM. Therefore, there has been a great deal of research into alternative sweeteners. In the search for such sweeteners, we analyzed the carbohydrate content of maple syrup and identified a novel oligosaccharide composed of fructose and glucose, linked at the C-4 of glucose and the C-6 of fructose. This oligosaccharide inhibited the release of fructose from sucrose by invertase (IC50: 1.17 mmol/L) and the decomposition of maltose by α-(1-4) glucosidase (IC50: 1.72 mmol/L). In addition, when orally administered together with sucrose to rats with DM, the subsequent plasma glucose concentrations were significantly lower than if the rats had been administered sucrose alone, without having any effect on the insulin concentration. These findings suggest that this novel oligosaccharide might represent a useful alternative sweetener for inclusion in the diet of patients with DM and may also have therapeutic benefits.
  • Solid Nanocrystals of Rebamipide Promote Recovery from Indomethacin-Induced Gastrointestinal Bleeding., Noriaki Nagai, Ryusuke Sakamoto, Seiji Yamamoto, Saori Deguchi, Hiroko Otake, Tadatoshi Tanino, International journal of molecular sciences, International journal of molecular sciences, 20(20), Oct. 09 2019 , Refereed
    Summary:Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30-190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.
  • Value of DW-MRI in the preoperative evaluation of congenital cholesteatoma., Shinsuke Ide, Akira Ganaha, Tetsuya Tono, Takashi Goto, Noriaki Nagai, Keiji Matsuda, Minako Azuma, Toshinori Hirai, International journal of pediatric otorhinolaryngology, International journal of pediatric otorhinolaryngology, 124, 34 - 38, Sep. 2019 , Refereed
    Summary:OBJECTIVE: This study evaluated the clinical value of diffusion-weighted magnetic resonance imaging (DW-MRI) in the diagnosis and staging of congenital cholesteatoma (CC). PATIENTS AND METHODS: We retrospectively reviewed 24 patients with CC. All the patients underwent computed tomography (CT) and DW-MRI preoperatively; thereafter, surgery was performed. DW-MRI examination was performed with a 3 T MRI system using three-dimensional reversed fast imaging with steady-state precession and diffusion-weighted magnetic resonance sequence. The preoperative and operative CT and DW-MRI findings were compared. RESULTS: Using DW-MRI, cholesteatoma was successfully detected in 17 (71%) of the 24 patients with CC. Among the seven patients with false-negative results, the cholesteatoma mass diameter was <5 mm in six patients and ≥5 mm in one patient. One of these patients had open type congenital cholesteatoma (OTCC). The detection rates for closed type cholesteatoma and OTCC were 85% (17/20) and 0% (0/4), respectively, using DW-MRI. Using CT and DW-MRI, the correct stage was identified in 88% (15/17) and 59% (10/17) of the patients with aeration around the CC and in 0% (0/7) and 100% (7/7) of those without aeration around the CC, respectively. CONCLUSION: CT is the primary imaging tool for evaluating suspected CC in patients with aeration around the CC. However, CT is unreliable for the detection of the extension and staging of CC when the middle ear is filled with nonspecific imaging. DW-MRI is useful for the preoperative diagnosis and staging of CC > 5 mm in diameter with or without surrounding granulation tissue. Thus, we recommend using DW- MRI at least when CT fails to localize CC as a soft tissue mass because of non-specific tissue filling the middle ear and the mastoid.
  • Comparison of early posttreatment effects of two steroidal anti-inflammatory ophthalmic drugs on the ocular inflammatory response induced by paracentesis in healthy canine eyes., Kazuaki Sato, Kiwako Iwasaki, Noriaki Nagai, Yohei Yamashita, Seishiro Chikazawa, Fumio Hoshi, Kazutaka Kanai, Veterinary ophthalmology, Veterinary ophthalmology, 22(5), 607 - 613, Sep. 2019 , Refereed
    Summary:OBJECTIVE: We investigated the early posttreatment effects of two steroidal anti-inflammatory ophthalmic drugs on blood-aqueous barrier (BAB) breakdown by paracentesis in dogs. ANIMAL STUDIES: We studied 21 healthy beagles with normal eyes. PROCEDURES: Controlled anterior chamber paracentesis (0.5 mL) was performed in one eye of each dog. Control group dogs (n = 7) received no medication, whereas those in the treatment groups received a topical anti-inflammatory medication (difluprednate [DFBA] ophthalmic emulsion 0.05% [n = 7] or betamethasone [BMZ] sodium phosphate ophthalmic solution 0.1% [n = 7]) at 0, 15, 30, and 45 minutes after initial paracentesis in the paracentesed eyes. Secondary aqueous humor (AH) was collected 60 minutes after initial paracentesis. Protein and prostaglandin E2 (PGE2 ) concentrations in AH were determined using the bicinchoninic acid assay and commercially available immunoassay kit, respectively. All mean values in the three groups were compared using analysis of variance followed by Tukey's post hoc test. RESULTS: Aqueous protein and PGE2 concentrations were markedly increased at 60 minutes following paracentesis. Both concentrations in the secondary AH of the DFBA group were significantly lower than those of the control group; however, treatment with BMZ had no significant effects. CONCLUSIONS: Early postparacentesis treatment with DFBA was more effective than that with BMZ for reducing aqueous protein and PGE2 contents in dogs with paracentesis-induced BAB breakdown. DFBA may be an appropriate treatment during the early stage of anterior uveitis caused by intraocular surgery in dogs.
  • Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles., Noriaki Nagai, Fumihiko Ogata, Mizuki Yamaguchi, Yuya Fukuoka, Hiroko Otake, Yosuke Nakazawa, Naohito Kawasaki, International journal of molecular sciences, International journal of molecular sciences, 20(15), Jul. 25 2019 , Refereed
    Summary:This study designed the transdermal formulations containing indomethacin (IMC)-1% IMC was crushed with 0.5% methylcellulose and 5% 2-hydroxypropyl-β-cyclodextrin by the bead mill method, and the milled IMC was gelled with or without 2% l-menthol (a permeation enhancer) by Carbopol® 934 (without menthol, N-IMC gel; with menthol, N-IMC/MT gel). In addition, the drug release, skin penetration and percutaneous absorption of the N-IMC/MT gel were investigated. The particle sizes of N-IMC gel were approximately 50-200 nm, and the combination with l-menthol did not affect the particle characterization of the transdermal formulations. In an in vitro experiment using a Franz diffusion cell, the skin penetration in N-IMC/MT gel was enhanced than the N-IMC gel, and the percutaneous absorption (AUC) from the N-IMC/MT gel was 2-fold higher than the N-IMC gel. On the other hand, the skin penetration from the N-IMC/MT gel was remarkably attenuated at a 4 °C condition, a temperature that inhibits all energy-dependent endocytosis. In conclusion, this study designed transdermal formulations containing IMC solid nanoparticles and l-menthol, and found that the combination with l-menthol enhanced the skin penetration of the IMC solid nanoparticles. In addition, the energy-dependency of the skin penetration of IMC solid nanoparticles was demonstrated. These findings suggest the utility of a transdermal drug delivery system to provide the easy application of solid nanoparticles (SNPs).
  • Changes in mitochondrial cytochrome c oxidase mRNA levels with cataract severity in lens epithelia of Japanese patients., Noriaki Nagai, Yu Mano, Hiroko Otake, Teppei Shibata, Eri Kubo, Hiroshi Sasaki, Molecular medicine reports, Molecular medicine reports, 19(6), 5464 - 5472, Jun. 2019 , Refereed
    Summary:We previously reported that the collapse of ATP production via mitochondrial damage causes ATPase dysfunction, resulting in the onset or progression of lens opacification in cataracts in model rats. In the present study, it was investigated whether the mRNA expression levels of the three subtypes of mitochondrial cytochrome c oxidase (MTCO)1, 2 and 3 and ATP content change with the type and severity of cataracts in human lens. Samples of lens epithelium were collected from Japanese patients during cataract surgery, and the type and severity of the cataracts (grade) were determined according to the WHO classification [cortical (COR), nuclear (NUC), posterior subcapsular (PSC) opacification]. The MTCO1‑3 mRNA expression levels in patients with grade‑1 COR, NUC and PSC opacification were significantly enhanced compared with those of normal patients. The enhanced MTCO1‑3 mRNA levels subsequently decreased in patients with COR, and the MTCO1‑3 mRNA levels and ATP levels in patients with grade‑3 COR were similar to those in normal patients. However, the mRNA expression levels of MTCO3 in patients with grade 3‑NUC opacification and MTCO1‑3 in patients with grade‑3 PSC opacification, along with the ATP content, were significantly lower than in patients without cataracts. In conclusion, it was revealed that ATP production in lens epithelium is enhanced in early‑stage cataracts (grade‑1) in Japanese patients with COR, NUC and PSC opacification. In addition, in severe cataracts (grade‑3), ATP production and content are strongly decreased in Japanese patients with PSC opacification. ATP depletion in human lens epithelium with PSC opacification may promote lens opacification by ATPase dysfunction.
  • Therapeutic Potential of a Combination of Magnesium Hydroxide Nanoparticles and Sericin for Epithelial Corneal Wound Healing., Noriaki Nagai, Yoshie Iwai, Saori Deguchi, Hiroko Otake, Kazutaka Kanai, Norio Okamoto, Yoshikazu Shimomura, Nanomaterials (Basel, Switzerland), Nanomaterials (Basel, Switzerland), 9(5), May 19 2019 , Refereed
    Summary:We previously found the instillation of sericin to be useful as therapy for keratopathy with or without diabetes mellitus. In this study, we investigated whether a combination of solid magnesium hydroxide nanoparticles (MHN) enhances epithelial corneal wound healing by sericin using rabbits, normal rats and type 2 diabetes mellitus rats with debrided corneal epithelium (ex vivo and in vivo studies). Ophthalmic formulations containing sericin and MHN (N-Ser) were prepared using a bead mill method. The mean particle size of the N-Ser was 110.3 nm at the time of preparation, and 148.1 nm one month later. The instillation of N-Ser had no effect on the amount of lacrimal fluid in normal rabbits (in vivo), but the MHN in N-Ser was found to expand the intercellular space in ex vivo rat corneas. In addition, the instillation of N-Ser increased the phosphorylation of Extracellular Signal-regulated Kinase (ERK)1/2, a factor involved in cell adhesion and cell proliferation in the corneal epithelium, in comparison with the instillation of sericin alone. The combination with MHN enhanced epithelial corneal wound healing by sericin in rat debrided corneal epithelium (in vivo). This study provides significant information to prepare potent drugs to cure severe keratopathy, such as diabetic keratopathy.
  • Preventive effects of tyrosol, a natural phenolic compound, on anterior uveitis induced by anterior chamber paracentesis in healthy beagle dogs., Kazuaki Sato, Kazutaka Kanai, Maiko Ozaki, Takaaki Kagawa, Mizuki Kita, Yohei Yamashita, Noriaki Nagai, Kazuki Tajima, The Journal of veterinary medical science, The Journal of veterinary medical science, 81(4), 573 - 576, Apr. 16 2019 , Refereed
    Summary:We investigated the effects of tyrosol (Tyr) on anterior chamber paracentesis (ACP)-induced anterior uveitis in beagle dogs, as determined by protein and prostaglandin E2 (PGE2) concentrations in the aqueous humor (AH). Tyr at a dose of 100 or 200 mg/kg or 2.2 mg/kg of carprofen as a positive control was administered orally twice daily from 2.5 days before paracentesis. The initial ACP was performed in one eye of individual dogs and 0.5 ml AH was aspirated. The secondary AH was collected 60 min later. Pretreatment with 200 mg/kg of Tyr and carprofen significantly decreased aqueous protein and PGE2 concentrations compared to the control group. Overall, these findings suggested that Tyr was useful for the management of canine anterior uveitis.
  • Interaction between phosphate ions and Fe-Mg type hydrotalcite for purification of wastewater, Fumihiko Ogata, Noriaki Nagai, Mao Kishida, Takehiro Nakamura, Naohito Kawasaki, JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING, JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING, 7(1), Feb. 2019 , Refereed
    Summary:In this study, Fe-Mg type hydrotalcite at different molar ratios (Mg/Fe=3.0 and 5.0, Fe-HT3.0 and Fe-HT5.0) was prepared, and its physicochemical properties were investigated. The adsorption isotherms were measured, and the effects of contact time, temperature, and pH on the adsorption of phosphate ions, and the ad-desorption capability were evaluated. Elemental analysis and binding energy values of the Fe-HT adsorbent surface before and after adsorption of phosphate ions indicated that the adsorption mechanism of phosphate ions was related to the physicochemical properties of adsorbent surface. Adsorption mechanism of phosphate ion relates to ion exchange, electrostatic attraction, and surface inner sphere complex formation in this study. Moreover, the phosphate ions adsorbed onto Fe-HT were easily desorbed using sodium hydroxide solution; thus, five cycles of ad-desorption were carried out. Collectively, these results suggest that Fe-HT is promising for the adsorption and recovery of phosphate ions using sodium hydroxide solution.
  • Coffee brew intake can prevent the reduction of lens glutathione and ascorbic acid levels in HFD-fed animals., Yosuke Nakazawa, Nana Ishimori, Jun Oguchi, Noriaki Nagai, Masaki Kimura, Megumi Funakoshi-Tago, Hiroomi Tamura, Experimental and therapeutic medicine, Experimental and therapeutic medicine, 17(2), 1420 - 1425, Feb. 2019 , Refereed
    Summary:The lens has high concentrations of glutathione (GSH) and ascorbic acid (AsA) to maintain redox activity and prevent cataract formation, which is the leading cause of visual impairment worldwide. Metabolic syndrome is reported to be linked with a higher risk of age-associated cataract. As it was demonstrated previously that coffee consumption improved high-fat diet (HFD) -induced metabolic symptoms, it was hypothesized that coffee intake could delay the onset of obesity related-cataract; however, the effect of coffee consumption on this type of cataract remains unknown. Four-week-old male C57BL/6JJms SLC mice were divided into two groups and were provided ad libitum access to either a control diet (control groups) or a HFD (HFD groups). The control groups and HFD groups were further divided into three or four subgroups for each experiment. Coffee intake markedly reduced the increase in body weight in a roasting-time and concentration-dependent manner. Coffee consumption also prevented the HFD-induced decrease in the concentration of GSH and AsA, and treatment with pyrocatechol or caffeine also restored the reduction of antioxidant compounds. Plasma cholesterol and triglycerides were significantly higher in HFD groups; however, coffee brew or coffee constituent treatment in the HFD-fed mice group prevented elevation of these levels. Caffeine is a major coffee component and pyrocatechol is generated thought the roasting process. These results revealed that caffeine and pyrocatechol in coffee brew may be the key constituents responsible for preventing the reduction of lens GSH and AsA in HFD-fed animals.
  • Energy-Dependent Endocytosis is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine., Miyu Ishii, Yuya Fukuoka, Saori Deguchi, Hiroko Otake, Tadatoshi Tanino, Noriaki Nagai, International journal of molecular sciences, International journal of molecular sciences, 20(3), Jan. 22 2019 , Refereed
    Summary:We previously reported that oral formulations containing indomethacin nanoparticles (IND-NPs) showed high bioavailability, and, consequently, improved therapeutic effects and reduced injury to the small intestine. However, the pathway for the transintestinal penetration of nanoparticles remained unclear. Thus, in this study, we investigated whether endocytosis was related to the penetration of IND-NPs (72.1 nm) using a transcell set with Caco-2 cells or rat intestine. Four inhibitors of various endocytosis pathways were used [nystatin, caveolae-dependent endocytosis (CavME); dynasore, clathrin-dependent endocytosis (CME); rottlerin, macropinocytosis; and cytochalasin D, phagocytosis inhibitor], and all energy-dependent endocytosis was inhibited at temperatures under 4 °C in this study. Although IND-NPs showed high transintestinal penetration, no particles were detected in the basolateral side. IND-NPs penetration was strongly prevented at temperatures under 4 °C. In experiments using pharmacological inhibitors, only CME inhibited penetration in the jejunum, while in the ileum, both CavME and CME significantly attenuated penetration. In conclusion, we found a novel pathway for the transintestinal penetration of drug nanoparticles. Our hypothesis was that nanoparticles would be taken up into the intestinal epithelium by endocytosis (CME in jejunum, CavME and CME in ileum), and dissolved and diffused in the intestine. Our findings are likely to be of significant use for the development of nanomedicines.
  • [Effect of Methylcellulose (Cellulose Derivatives) on Ibuprofen-crushing Efficiency in Nano Pulverizer NP-100]., Noriaki Nagai, Yuka Yamasaki, Tsubasa Nakamura, Hiroko Otake, Naoya Okamoto, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 139(1), 123 - 130, 2019 , Refereed
    Summary:It is expected that drug systems using nanoparticles will improve the problem of poor water solubility and bioavailability of lipophilic drugs. However, it is difficult to prepare the formulations containing nanoparticles, and it is important to determine the concentration and kind of additives to prepare the formulations. We previously reported that a nano pulverizer NP-100 is possible to prepare drug nanoparticles for the 2-3 min, and the cellulose derivatives (metolose®, methylcellulose) is usefulness to prepare the nanoparticles by the mill method. In this study, we investigated the relationships of methylcellulose type and crushing efficiency in NP-100. First, we demonstrated the effect of viscosity in the various methylcellulose on the ibuprofen (IBU, lipophilic drug) particle size, and showed that the viscosity did not relate the crushing efficiency by the NP-100. Next, we measured the changes of cumulative size frequency curve in IBU particles by the combination of the NP-100 and 0.1-2.0% methylcellulose (SM-4, 400 and 4000). The appropriate addition reached IBU nanoparticles, although, the appropriate addition amount of methylcellulose was different in the SM-4 (0.5%), 400 (1.0%) and 4000 (1.2%). In addition, the IBU became meringue-like when subjected to the bead mill method in the less of methylcellulose, and excessive addition of methylcellulose increased the ratio of coarse particle. In conclusion, this results show that the appropriate addition amount of methylcellulose is different in the type of methylcellulose, and these changes of cumulative size frequency curve is useful as index to determine the concentration and type of additives in the nanoparticle production.
  • Evaluation of Dissolution Profile between Original and Generic Products of Zolpidem Tartrate by Microdialysis-HPLC., Kazunori Inaba, Toshiharu Oie, Hiroko Otake, Takeshi Kotake, Noriaki Nagai, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 67(2), 120 - 124, 2019 , Refereed
    Summary:The evaluation of the dissolution profile of hypnotic drugs is important to promote switching from original products to generic products by removing distrust in generic hypnotics. In this study, we investigated differences in the dissolution profiles between original and generic products (GE-D, GE-S, and GE-T) in commercially available zolpidem tartrate (ZOL) products using the HPLC method using a connected microdialysis probe (microdialysis-HPLC method). Although the degree of hardness and the disintegration time were not different among the original, GE-S, and GE-T, GE-D was 1.4 times harder than the other products. The disintegration time of GE-D was approximately twice as long as that of the original product. Generic products dissolved rapidly as compared with the original product, however, the dissolution rate in the ZOL powder (milled ZOL product) was not different between the original and generic products. Macrogol 6000 (polyethylene glycol (PEG)-6000) was used in the generic products, and this additive was the only PEG difference from the original product. We investigated whether the PEG in the product affected the solubility of ZOL and found that the addition of PEG-4000 or PEG-6000 significantly increased the dissolution rate. These results suggest that the solubility of ZOL may be increased by PEG when the product is disintegrated, resulting in the increased dissolution rate in the generic products. In conclusion, we found that the difference of PEG affected the dissolution profile in the disintegration process using the microdialysis-HPLC method. This finding can help ensure the safety of milled products and the selection of additives.
  • Energy-dependent endocytosis is responsible for drug transcorneal penetration following the instillation of ophthalmic formulations containing indomethacin nanoparticles., Noriaki Nagai, Fumihiko Ogata, Hiroko Otake, Yosuke Nakazawa, Naohito Kawasaki, International journal of nanomedicine, International journal of nanomedicine, 14, 1213 - 1227, 2019 , Refereed
    Summary:Purpose: We previously found that ophthalmic formulations containing nanoparticles prepared by a bead mill method lead to an increase in bioavailability in comparison with traditional formulations (solution type). However, the transcorneal penetration pathway for ophthalmic formulations has not been explained yet. In this study, we investigated the mechanism of transcorneal penetration in the application of ophthalmic formulations containing indomethacin nanoparticles (IMC-NPs). Materials and methods: IMC-NPs was prepared by the bead mill method. For the analysis of energy-dependent endocytosis, corneal epithelial (HCE-T) cell monolayers and removed rabbit cornea were thermoregulated at 4°C, where energy-dependent endocytosis is inhibited. In addition, for the analysis of different endocytosis pathways using pharmacological inhibitors, inhibitors of caveolae-mediated endocytosis (54 µM nystatin), clathrin-mediated endocytosis (40 µM dynasore), macropinocytosis (2 µM rottlerin) or phagocytosis (10 µM cytochalasin D) were used. Results: The ophthalmic formulations containing 35-200 nm sized indomethacin nanoparticles were prepared by treatment with a bead mill, and no aggregation or degradation of indomethacin was observed in IMC-NPs. The transcorneal penetration of indomethacin was significantly decreased by the combination of nystatin, dynasore and rottlerin, and the decreased penetration levels were similar to those at 4°C in HCE-T cell monolayers and rabbit cornea. In the in vivo experiments using rabbits, dynasore and rottlerin tended to decrease the transcorneal penetration of indomethacin (area under the drug concentration - time curve in the aqueous humor [AUCAH]), and the AUCAH in the nystatin-treated rabbit was significantly lower than that in non-treatment group. In addition, the AUCAH in rabbit corneas undergoing multi-treatment was obviously lower than that in rabbit corneas treated with each individual endocytosis inhibitor. Conclusion: We found that three energy-dependent endocytosis pathways (clathrin-dependent endocytosis, caveolae-dependent endocytosis and macropinocytosis) are related to the trans-corneal penetration of indomethacin nanoparticles. In particular, the caveolae-dependent endocytosis is strongly involved.
  • Evaluation of the Interaction between Borate Ions and Nickel-Aluminum Complex Hydroxide for Purification of Wastewater., Fumihiko Ogata, Noriaki Nagai, Megumu Toda, Masashi Otani, Takehiro Nakamura, Naohito Kawasaki, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 67(5), 487 - 492, 2019 , Refereed
    Summary:A new mixed metal hydroxide adsorbent (NA11, molar ratioNi-Al = 1 : 1) was prepared and its physicochemical properties (specific surface area, amount of hydroxyl group, scanning electron microscopy images, X-ray diffraction analysis, elemental distribution, and binding energy) were studied. In addition, the amount of borate ion adsorbed using several adsorbents, including NA11, was evaluated in this study. The specific surface area of and amount of hydroxyl group in NA11 was greater than those of the other studied adsorbents. The amount of borate ion adsorbed showed similar trends to those of the specific surface area and number of hyrdroxyl groups, which indicated that the adsorption mechanism of borate ion was related to the specific surface area and the amount of hydroxyl group. After adsorption, the binding energy of boron B(1s) peaked, and the sulfur peak intensity S(2s) and S(2p) reduced. These results suggest that ion exchange between borate and sulfate ions was one of the adsorption mechanisms. Equilibrium adsorption was reached within 6 h in the case of NA11. These data were fitted into a pseudo-second-order model (r = 0.813-0.998). The solution pH affected the capacity of NA11 for adsorbing borate ion from aqueous solution. It was found that adsorbance was greatest at pH 10. Adsorption isotherm data were fitted to both the Freundlich (r = 0.986-0.994) and Langmuir (r = 0.997-0.999) isotherm equations. Collectively, it is suggested that NA11 is prospectively useful for the adsorption of borate ion from aqueous solutions.
  • Adsorption Capability of Fe-HT3.0 for Nitrite and Nitrate Ions in a Binary Solution System., Fumihiko Ogata, Noriaki Nagai, Takehiro Nakamura, Naohito Kawasaki, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 67(10), 1168 - 1170, 2019 , Refereed
    Summary:In this study, the adsorption capability of Fe-HT3.0 for nitrite and nitrate ions in a binary solution system was evaluated. It was found that the amount of nitrite and nitrate ions adsorbed in a single solution (1.19 and 1.27 mmol/g, respectively) was higher than that in a binary solution (0.36 and 0.90 mmol/g, respectively). Equilibrium adsorption was attained within 6-24 h. The adsorption data were fitted to a pseudo-second-order model (correlation coefficient: 0.999), and indicated that the adsorption of both nitrite and nitrate ions is controlled by chemical sorption. Additionally, the binding energies before and after the adsorption of nitrite and nitrate ions in the binary solution system were measured. After adsorption, new nitrogen peaks (approx. 399 and 403 eV) were detected. The results of this study show the potential of Fe-HT3.0 for the removal of nitrite and nitrate ions from aqueous solution systems.
  • Drug Delivery System Based On Minoxidil Nanoparticles Promotes Hair Growth In C57BL/6 Mice., Noriaki Nagai, Yoshie Iwai, Akane Sakamoto, Hiroko Otake, Yoshihiro Oaku, Akinari Abe, Tohru Nagahama, International journal of nanomedicine, International journal of nanomedicine, 14, 7921 - 7931, 2019 , Refereed
    Summary:Purpose: We designed formulations based on minoxidil (MXD) nanoparticles (N-MXD) and examined whether N-MXD can increase drug delivery into the follicles. In addition, we investigated the effect of N-MXD on hair growth in C57BL/6 mice. Methods: N-MXD (1%) was prepared as follows: methylcellulose, p-hydroxyalkylbenzoates, mannitol, and MXD were dispersed in purified water and milled using zirconia beads under refrigeration (5500 rpm, 30 s×15 times, intermittent milling). C57BL/6 mice were used to evaluate hair-growth effects. The expression levels of mRNA and protein for vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) were determined by real-time PCR and ELISA methods, respectively. Results: The ratio of solid-MXD was approximately 60% in N-MXD, and the MXD nanoparticles (90-300 nm) were oblong in shape. For the design of nanomedicines, usability is important. Therefore, we measured the stability and toxicity after N-MXD treatment. No agglutination of MXD nanoparticles was detected for 2 weeks, and no redness or MXD powder residue was observed in the skin after repetitive applications of N-MXD. Next, we evaluated hair-growth effects by N-MXD treatment. MXD contents in the skin tissue from N-MXD were lower than for commercially available MXD formulations (CA-MXD). Conversely, MXD contents in the hair bulbs were higher for N-MXD than for CA-MXD, and the drug efficacy of N-MXD was also higher than that of CA-MXD. In addition, the mRNA and protein levels of IGF-1 and VEGF were enhanced by the repetitive application of N-MXD and CA-MXD, and the enhanced IGF-1 and VEGF levels were significantly higher for N-MXD than for CA-MXD. Conclusion: We designed a novel nanomedicine based on MXD nanoparticles and showed that N-MXD can deliver MXD into hair bulbs via hair follicles and that the therapeutic efficiency for hair growth is higher than for CA-MXD (solution type).
  • Hepatic cytochrome P450 metabolism suppressed by mast cells in type 1 allergic mice., Tadatoshi Tanino, Toru Bando, Yukie Nojiri, Yuna Okada, Noriaki Nagai, Yukari Ueda, Eiichi Sakurai, Biochemical pharmacology, Biochemical pharmacology, 158, 318 - 326, Dec. 2018 , Refereed
    Summary:Mast cells and Kupffer cells secrete interleukin (IL)-1β, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, which stimulate excess nitric oxide (NO) producing-inducible NO synthase (iNOS). Unlike Kupffer cells, immunoglobulin E-sensitized mast cells elicit sustained NO production. We investigated the participation of mast cell-released NO and cytokine-derived iNOS activation in type 1 allergy-suppressed hepatic cytochrome P450 (CYP) metabolism. Aminoguanidine, a selective iNOS inhibitor, completely suppressed serum nitrate plus nitrite (NOx) concentrations after primary and secondary sensitization of ICR mice and markedly attenuated allergy-suppressed hepatic CYP1A2, CYP2C, CYP2E1, and CYP3A activities. In the liver, primary and secondary sensitization enhanced iNOS-stimulating IFN-γ (5-15-fold) and TNF-α (3-5-fold) mRNA levels more than IL-1β (2-fold) and F4/80-positive Kupffer cell (2-fold) mRNA levels. When mast cell-deficient (-/-) mice were sensitized, hepatic CYP activities were not suppressed. Serum NOx levels in the sensitized -/- mice were similar with those in saline-treated ICR and -/- mice. In the liver of -/- mice, secondary sensitization markedly enhanced mRNA expression of iNOS (20-fold), IFN-γ (15-fold), and TNF-α (3-fold). However, hepatic total NOS activities in -/- mice were not significantly different between saline treatment and sensitization. Similarly, primary and secondary ICR mice did not significantly enhance total NOS activities in the liver and hepatocytes. The total NOS activities observed did not relate to the high levels of iNOS, IFN-γ, and TNF-α mRNA in the liver. Hepatic c-kit-positive mast cells in sensitized ICR mice were maintained at control levels. Therefore, our data suggest that mast cell-released NO participates in type 1 allergy-suppressed CYP1A2, CYP2C, CYP2E1, and CYP3A metabolism.
  • A Proteomic Approach for Understanding the Mechanisms of Delayed Corneal Wound Healing in Diabetic Keratopathy Using Diabetic Model Rat., Tetsushi Yamamoto, Hiroko Otake, Noriko Hiramatsu, Naoki Yamamoto, Atsushi Taga, Noriaki Nagai, International journal of molecular sciences, International journal of molecular sciences, 19(11), Nov. 18 2018 , Refereed
    Summary:Diabetes mellitus is a widespread metabolic disorder, and long-term hyperglycemia in diabetics leads to diabetic keratopathy. In the present study, we used a shotgun liquid chromatography/mass spectrometry-based global proteomic approach using the cornea of streptozotocin-induced diabetic (STZ) rats to examine the mechanisms of delayed corneal wound healing in diabetic keratopathy. Applying a label-free quantitation method based on spectral counting, we identified 188 proteins that showed expression changes of >2.0-fold in the cornea of STZ rats. In particular, the level of lumican expression in the cornea of STZ rats was higher than that of the normal rats. In the cornea of the normal rat, the expression level of lumican was elevated during the wound healing process, and it returned to the same expression level as before cornea injury after the wound was healed completely. On the other hand, a high expression level of lumican in the cornea of STZ rats was still maintained even after the wound was healed completely. In addition, adhesion deficiency in corneal basal cells and Bowman's membrane was observed in the STZ rat. Thus, abnormally overexpressed lumican may lead to adhesion deficiency in the cornea of STZ rats.
  • Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles., Noriaki Nagai, Fumihiko Ogata, Miyu Ishii, Yuya Fukuoka, Hiroko Otake, Yosuke Nakazawa, Naohito Kawasaki, International journal of molecular sciences, International journal of molecular sciences, 19(7), 2138, Jul. 23 2018 , Refereed
    Summary:We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.
  • Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles., Noriaki Nagai, Fumihiko Ogata, Miyu Ishii, Yuya Fukuoka, Hiroko Otake, Yosuke Nakazawa, Naohito Kawasaki, International journal of molecular sciences, International journal of molecular sciences, 19(7), Jul. 23 2018 , Refereed
    Summary:We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.
  • Instillation of Sericin Enhances Corneal Wound Healing through the ERK Pathway in Rat Debrided Corneal Epithelium., Noriaki Nagai, Yuya Fukuoka, Miyu Ishii, Hiroko Otake, Tetsushi Yamamoto, Atsushi Taga, Norio Okamoto, Yoshikazu Shimomura, International journal of molecular sciences, International journal of molecular sciences, 19(4), Apr. 09 2018 , Refereed
    Summary:Sericin is a major constituent of silk produced by silkworms. We previously found that the instillation of sericin enhanced the proliferation of corneal epithelial cells, and acted to promote corneal wound healing in both normal and diabetic model rats. However, the mechanisms by which sericin promotes the proliferation of corneal cells have not been established. In this study, we investigated the effects of sericin on Akt and ERK activation in a human corneal epithelial cell line (HCE-T cells) and rat debrided corneal epithelium. Although Akt phosphorylation was not detected following the treatment of HCE-T cells with sericin, ERK1/2 phosphorylation was enhanced. The growth of HCE-T cells treated with sericin was significantly increased, with the cell growth of sericin-treated HCE-T cells being 1.7-fold higher in comparison with vehicle-treated HCE-T cells. On the other hand, both of an ERK inhibitor U0126 (non-specific specific inhibitor) and SCH772984 (specific inhibitor) attenuated the enhanced cell growth by sericin, and the growth level in the case of co-treatment with sericin and ERK1/2 inhibitor was similar to that of cells treated with ERK1/2 inhibitor alone. In an in vivo study using rat debrided corneal epithelium, the corneal wound healing rate was enhanced by the instillation of sericin, and this enhancement was also attenuated by the instillation of U0126. In addition, the corneal wound healing rate in rats co-instilled with sericin and U0126 was similar to that following the instillation of U0126 alone. In conclusion, we found that the instillation of sericin enhanced cell proliferation via the activation of the MAPK/ERK pathway, resulting in the promotion of corneal wound healing in rat eyes. These findings provide significant information for designing further studies to develop potent corneal wound-healing drugs.
  • Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism., Chiaki Yoshioka, Yoshimasa Ito, Noriaki Nagai, Experimental and therapeutic medicine, Experimental and therapeutic medicine, 15(4), 3501 - 3508, Apr. 2018 , Refereed
    Summary:Cilostazol (CLZ), an anti-platelet agent, is primarily used following the onset of cerebral infarction. However, as CLZ is only marginally soluble in water, a strategy for patients with serious secondary conditions, such as impaired consciousness or aphagia, is required. In the present study, topical formulations containing CLZ nanocrystals (CLZnano) were designed to enhance percutaneous absorption. In addition, the mechanism of penetration of CLZnano through rat skin was investigated. A topical formulation containing CLZ nanoparticles (CLZnano gel patch) was prepared using a combination of recrystallization and ball milling of an aqueous gel. The particle size of CLZnano was 74.5±6.2 nm (mean ± standard deviation). The concentration of permeated CLZnano and penetration mechanism of the nanocrystals were measured in a percutaneous absorption experiment. The amount of penetrated CLZ, the penetration rate (Jc), the penetration coefficient through the skin (Kp) and the skin/preparation partition coefficient (Km) for the CLZnano gel patch were all significantly higher than those of the CLZ powder (CLZmicro) gel patch, the CLZnano ointment and the CLZmicro ointment. In in vitro percutaneous penetration experiments on the CLZnano gel patches, there was a positive correlation between the number of CLZnano. Following the application of the CLZnano gel patch on rat skin, 98% of penetrated CLZ was observed in nanoparticle form; for the CLZmicro gel patch, this figure was 9%. In addition, the CLZ concentrations in the plasma of rats administered the CLZnano gel patches were significantly higher than those of rats administered the CLZnano CP gel and PEG ointments. It was suggested that CLZnano (diameter <100 nm) were transferred through the intracellular spaces in the skin and then into peripheral blood vessels. To the best of our knowledge, this is the first report to elucidate the mechanism of the percutaneous penetration of nanocrystal medicines.
  • Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles., Noriaki Nagai, Sakie Yamaoka, Yuya Fukuoka, Miyu Ishii, Hiroko Otake, Kazutaka Kanai, Norio Okamoto, Yoshikazu Shimomura, International journal of molecular sciences, International journal of molecular sciences, 19(1), Jan. 17 2018 , Refereed
    Summary:We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 μm, and the particle size was reduced to 73.5-113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.
  • [Design of Microdialysis-CLC Method for Measurement of Drug Behavior in Lacrimal Fluid after Instillation]., Noriaki Nagai, Akina Ueno, Miyu Ishii, Yuya Fukuoka, Hiroko Otake, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 138(8), 1111 - 1117, 2018 , Refereed
    Summary:The ophthalmic application is the main route for the therapy of glaucoma, and is well-accepted by glaucoma patients. Therefore, it is important to measure the drug behavior in lacrimal fluid after instillation of eye drops. In this study, we used ophthalmic formulation (eye drops) containing timolol maleate (TM), in anti-glaucoma eye drops, and attempted to measure the drug behavior after instillation of TM eye drops. First, we collected the lacrimal fluid (5 μL) every 10 time after instillation using micropipette, and measured by the HPLC method. The TM concentration in lacrimal fluid was 21.2 μg/mL at 5 min after the instillation, and the TM was remained for 30 min after the instillation. Next, we collected the lacrimal fluid via the dialysis prove, and measured by the HPLC method. The retention of TM in lacrimal fluid was observed for 45 min after the instillation, and the measurement accuracy was enhanced by system with an automatic injection of TM solution via dialysis prove (microdialysis-HPLC method). In addition, the measurement accuracy increased more by using a capillary liquid chromatography (CLC) instead of an HPLC (microdialysis-CLC method), and the retention time of TM in lacrimal fluid was extended to 75 min after the instillation. In conclusion, we showed that the microdialysis-CLC method was suitable to measure the drug behavior in lacrimal fluid after instillation. These findings provide significant information that can be used in the design and evaluation of ophthalmic formulation.
  • An oral formulation of cilostazol nanoparticles enhances intestinal drug absorption in rats., Chiaki Yoshioka, Yoshimasa Ito, Noriaki Nagai, Experimental and therapeutic medicine, Experimental and therapeutic medicine, 15(1), 454 - 460, Jan. 2018 , Refereed
    Summary:Cilostazol (CLZ) is an anti-platelet agent that is generally used after the onset of cerebral infarction. However, CLZ is a poorly water-soluble drug and a strategy for increasing its bioavailability is required. In the present study, novel oral formulations were designed containing CLZ solid nanoparticles to improve bioavailability. The present study investigated the therapeutic effect of the oral formulations containing CLZ nanoparticles on ischemic stroke using a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The oral formulation containing CLZ nanoparticles (CLZ/Rnano tablet) was prepared using a combination of recrystallization and ball milling with the following ingredients: CLZ, docusate sodium, methylcellulose, 2-hydoxypropyl-β-cyclodextrin, gum arabic, polyvinylpyrrolidone, and mannitol. The particle size after re-dispersion of the CLZ/Rnano tablet was 64±47 nm (mean ± standard deviation). The CLZ areas under the concentration-time curve (AUC) and mean residence time (MRT) in rats that were administered CLZ/Rnano tablets were significantly greater compared with those in rats that were administered CLZ/Rmicro tablets. Results indicated, the AUC after administration of CLZ/Rnano tablets was 3.1-fold higher compared with that after administration of the commercially available CLZ OD tablet. In addition, oral administration with CLZ/Rnano tablets ameliorated neurological deficits caused by ischemic stroke in MCAO/reperfusion mice. It is possible that the oral formulation containing CLZ nanoparticles will be useful for the treatment of patients with ischemic stroke and that these findings will provide significant information that can be used to improve the drug with low bioavailability.
  • Biomass Potential of Virgin and Calcined Tapioca (Cassava Starch) for the Removal of Sr(II) and Cs(I) from Aqueous Solutions., Fumihiko Ogata, Noriaki Nagai, Erimi Ueta, Takehiro Nakamura, Naohito Kawasaki, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 66(3), 295 - 302, 2018 , Refereed
    Summary:In this study, we prepared novel adsorbents containing virgin and calcined tapioca products for removing strontium (Sr(II)) and cesium (Cs(I)) from aqueous solutions. The characteristics of tapioca, along with its capacity to adsorb Sr(II) and Cs(I), were evaluated. Multiple tapioca products were prepared and tested. The adsorbent prepared by boiling the tapioca followed by calcination at 300°C (BTP300) was the most effective. In addition, adsorption was affected by the adsorbent's surface properties. The Sr(II) and Cs(I) adsorbed onto BTP300 could be recovered through desorption by hydrochloric acid at different concentrations, which indicates that BTP300 can be used several times for adsorption/desorption. The results of this study suggest that BTP300, which was produced from tapioca biomass, can remove Sr(II) and Cs(I) from aqueous solutions.
  • Adsorption of Nitrite and Nitrate Ions from an Aqueous Solution by Fe-Mg-Type Hydrotalcites at Different Molar Ratios., Fumihiko Ogata, Noriaki Nagai, Yukine Kariya, Eri Nagahashi, Yuhei Kobayashi, Takehiro Nakamura, Naohito Kawasaki, Chemical & pharmaceutical bulletin, Chemical & pharmaceutical bulletin, 66(4), 458 - 465, 2018 , Refereed
    Summary:In this study, we prepared Fe-Mg-type hydrotalcites (Fe-HT3.0 and Fe-HT5.0) with different molar ratios and evaluated their adsorption capability for nitrite and nitrate ions from aqueous solution. Fe-HT is a typical hydrotalcite-like layered double hydroxide. Adsorption isotherms, as well as the effects of contact time and pH were investigated, and it was found that Fe-HT can adsorb larger amounts of nitrite and nitrate ions than Al-HT (normal-type hydrotalcite). Adsorption isotherm data were fitted to both Freundlich (correlation coefficient: 0.970-1.000) and Langmuir (correlation coefficient: 0.974-0.999) equations. Elemental analysis and binding energy of Fe-HT surface before and after adsorption indicated that the adsorption mechanism was related to the interaction between the adsorbent surface and anions. In addition, the ion exchange process is related to the adsorption mechanism. The adsorption amount increased with increasing temperature (7-25°C). The experimental data fit the pseudo-second-order model better than the pseudo-first-order model. The effect of pH on adsorption was not significant, which suggested that Fe-HT could be used over a wide pH range (4-12). These results indicate that Fe-HT is a good adsorbent for the removal of nitrite and nitrate ions from aqueous solution.
  • Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment., Noriaki Nagai, Fumihiko Ogata, Hiroko Otake, Yosuke Nakazawa, Naohito Kawasaki, International journal of nanomedicine, International journal of nanomedicine, 13, 5215 - 5229, 2018 , Refereed
    Summary:Purpose: In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Methods: Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Results: The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. Conclusion: We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat.
  • Ophthalmic formulation containing nilvadipine nanoparticles prevents retinal dysfunction in rats injected with streptozotocin, Saori Deguchi, Hiroko Otake, Yosuke Nakazawa, Noriko Hiramatsu, Naoki Yamamoto, Noriaki Nagai, International Journal of Molecular Sciences, International Journal of Molecular Sciences, 18(12), Dec. 15 2017 , Refereed
    Summary:Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. However, the current instillation systems do not allow a sufficient amount of drug required to treat retinopathy to reach the posterior segment (retina) therefore, a new formulation targeting the posterior segment is expected as therapy for retinopathy. We prepared ophthalmic formulations containing nilvadipine nanoparticles (NILnano), and demonstrated whether the instillation of NILnano can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats) in this study. NILnano(mean particle size, 77 nm) was prepared by wet bead mill treatment, with the inclusion of various additives (2-hydroxypropyl-β-cyclodextrin, benzalkonium chloride, D-mannitol, and methylcellulose). Retinal dysfunction was observable two weeks after rats received intraperitoneal injections of streptozotocin (100 mg/kg × 2, consecutive days, STZ rat). Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The retinal thickness, measured as the distance between the ganglion cell layer and the distal border of the outer nuclear layer, increased two weeks after the injection of streptozotocin, resulting in decreases in the levels of a-waves, b-waves, and oscillatory potential amplitudes in ERG of rats. The instillation of NILnano allowed the topical supplement of nilvadipine into the retina, and repeated instillation of NILnano (2 times/day) attenuated the retinal disorders led by the excessive streptozotocin. In conclusion, we found that retinal dysfunction in rats injected with streptozotocin can be prevented by the NILnano instillation. These results are useful in further studies aimed at the therapeutic treatment of retinopathy.
  • Co-instillation of nano-solid magnesium hydroxide enhances corneal permeability of dissolved timolol, Noriaki Nagai, Fumihiko Ogata, Hiroko Otake, Naohito Kawasaki, Yosuke Nakazawa, Kazutaka Kanai, Norio Okamoto, Yoshikazu Shimomura, EXPERIMENTAL EYE RESEARCH, EXPERIMENTAL EYE RESEARCH, 165, 118 - 124, Dec. 2017 , Refereed
    Summary:We prepared magnesium hydroxide (MH) nanoparticles by a bead mill method, and investigated whether the co-instillation of MH nanoparticles improves the low transcorneal penetration of watersoluble drugs, such as the anti-glaucoma eye drug timolol maleate (TM). MH particle size was decreased by the bead mill treatment to a mean particle size of 71 nm. In addition, the MH nanoparticles were highly stable. Next, we demonstrated the effect of MH nanoparticles on the corneal surface. MH shows only slight solubility in lacrimal fluid, and the instillation of MH nanoparticles for 14 days did not affect the behavior (balance of secretion and excretion) of the lacrimal fluid in rabbit corneas. Moreover, there was no observable corneal toxicity of MH nanoparticles, and treatment with MH nanoparticles enhanced the intercellular space ratio in the eyes of rats. MH alone did not permeate into the cornea; however, the co-instillation of MH nanoparticles and dissolved TM (nMTFC) enhanced the corneal penetration of TM. In addition, the intraocular pressure (IOP)-reducing effect of nMTFC was significantly higher than those of the TM solution or the co-instillation of MH microparticles and TM. In conclusion, we found that MH nanoparticles enhance the corneal penetration of dissolved TM with no observable corneal stimulation or obstruction of the nasolacrimal duct by the MH nanoparticles. It is possible that the co-instillation of MH nanoparticles may provide a useful way to improve the bioavailability of watersoluble drugs in the ophthalmic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs. (C) 2017 Elsevier Ltd. All rights reserved.
  • Proteomic profile of the lens in a streptozotocin-induced diabetic rat model using shotgun proteomics, Noriaki Nagai, Tetsushi Yamamoto, Kuniko Mitamura, Atsushi Taga, Biomedical Reports, Biomedical Reports, 7(5), 445 - 450, Nov. 01 2017 , Refereed
    Summary:Streptozotocin (STZ)-induced diabetic rats (STZ rats) were used to investigate diabetic cataracts. In the current study, a shotgun liquid chromatography (LC)/mass spectrom-etry (MS)-based global proteomic analysis method was used to examine the mechanism of lens opacification as a result of hyperglycemia in STZ rats. The 6-week old Wistar rats were injected with STZ for 2 days (100 mg/kg/day, i.p.) and housed for 3 weeks. The plasma glucose levels were identified to be significantly higher when compared with the normal rats and insulin was not detected in the STZ rats. Furthermore, opacification of the cortical epithelium was observed in the lenses of STZ rats. A total of 235 proteins were identified in the lenses of the STZ rats and 229 in the lenses of the normal rats. A label-free semi-quantitative method, based on spectral counting, identified 52 proteins that were differentially expressed in the lenses of STZ rats compared with normal rats. In particular, superoxide dismutase, which is a critical antioxidant enzyme that detoxifies superoxide through redox cycling, was downregulated when analyzed by the semi-quantitative method. In addition, phosphorylated-p38, which is important in the signaling pathway involved in the oxidative stress response, was significantly increased in the lenses of STZ rats when compared with normal rats (P< 0.05). Thus, the changes in protein expression were evaluated in the lenses of STZ rats using a shotgun LC/MS-based global proteomic analysis approach, and a decrease in antioxidant enzymes and an increase in oxidative stress were identified in the lenses of STZ rats. Further studies are required to examine the role of these proteins in the onset or progression of diabetic cataracts.
  • Administration of antioxidant compounds affects the lens chaperone activity and prevents the onset of cataracts, Yosuke Nakazawa, Noriaki Nagai, Nana Ishimori, Jun Oguchi, Hiroomi Tamura, BIOMEDICINE & PHARMACOTHERAPY, BIOMEDICINE & PHARMACOTHERAPY, 95, 137 - 143, Nov. 2017 , Refereed
    Summary:To prevent lens opacification and cataract formation, the lens contains alpha-crystallin, which has been shown to function as a molecular chaperone that maintains the correct folding of other proteins. Oxidative stress is known to be an important factor in the initiation and progression of a cataract. So far, several antioxidant compounds have been reported to prevent cataracts in vivo and in vitro. This stress also triggers alpha-crystallin modifications and alters its chaperone activity. However, few studies have examined the relationship between the consumption of antioxidant compounds and lens chaperone activity. To elucidate the effect of antioxidants on lens chaperone activity, antioxidants were administered to a selenite-induced cataract model of rats. The chaperone activity in lens water-soluble fraction was measured using aldehyde dehydrogenase. All antioxidant treatment groups, except decaffeinated coffee treatment, had less severe central opacities and lower stage cataracts than control groups. The chaperone activity was weaker in lens of selenite cataract rats, but antioxidant compounds and coffee treatment can prevent the chaperone activity decreasing, but not decaffeinated coffee. These results suggested that the treatment with antioxidant compounds could prevent cataract formation by the maintenance of the chaperone activity in water-soluble lens proteins. Thus, this study describes the development of an anticataract drug target for lens chaperone activity.
  • Therapeutic effect of cilostazol ophthalmic nanodispersions on retinal dysfunction in streptozotocin-induced diabetic rats, Noriaki Nagai, Saori Deguchi, Hiroko Otake, Noriko Hiramatsu, Naoki Yamamoto, International Journal of Molecular Sciences, International Journal of Molecular Sciences, 18(9), Sep. 14 2017 , Refereed
    Summary:We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZnano), and found that instillation of CLZnano into rat eyes supplies CLZ into the retina. In this study, we investigated changes in the electroretinograms (ERG) of streptozotocin-induced diabetic rats (STZ rats), a model of diabetes mellitus. In addition, we demonstrated that dispersions containing CLZ nanoparticles attenuate changes in the ERG of STZ rats. The instillation of CLZnano had no effect on body weight or plasma glucose and insulin levels. Furthermore, no corneal toxicity was observed in the in vivo study using STZ rats. The a-wave and b-wave levels in addition to oscillatory potentials (OP) amplitude decreased in STZ rats two weeks after the injection of streptozotocin, with the instillation of CLZnano attenuating these decreases. In addition, the level of vascular endothelial growth factor (VEGF) in the retinas of STZ rats was 9.26-fold higher than in in normal rats, with this increase also prevented by the instillation of CLZnano Thus, we have found that a-wave and b-wave levels in addition to OP amplitude are decreased in rats following the injection of excessive streptozotocin. Furthermore, the retinal disorders associated with diabetes mellitus are attenuated by the instillation of CLZnano. These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs.
  • Therapeutic Effect of Cilostazol Ophthalmic Nanodispersions on Retinal Dysfunction in Streptozotocin-Induced Diabetic Rats, Noriaki Nagai, Saori Deguchi, Hiroko Otake, Noriko Hiramatsu, Naoki Yamamoto, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 18(9), Sep. 2017 , Refereed
    Summary:We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZ(nano)), and found that instillation of CLZ(nano) into rat eyes supplies CLZ into the retina. In this study, we investigated changes in the electroretinograms (ERG) of streptozotocin-induced diabetic rats (STZ rats), a model of diabetes mellitus. In addition, we demonstrated that dispersions containing CLZ nanoparticles attenuate changes in the ERG of STZ rats. The instillation of CLZ(nano) had no effect on body weight or plasma glucose and insulin levels. Furthermore, no corneal toxicity was observed in the in vivo study using STZ rats. The a-wave and b-wave levels in addition to oscillatory potentials (OP) amplitude decreased in STZ rats two weeks after the injection of streptozotocin, with the instillation of CLZ(nano) attenuating these decreases. In addition, the level of vascular endothelial growth factor (VEGF) in the retinas of STZ rats was 9.26-fold higher than in in normal rats, with this increase also prevented by the instillation of CLZ(nano) Thus, we have found that a-wave and b-wave levels in addition to OP amplitude are decreased in rats following the injection of excessive streptozotocin. Furthermore, the retinal disorders associated with diabetes mellitus are attenuated by the instillation of CLZ(nano). These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs.
  • Evaluation of Retinal Function in Streptozotocin-induced Diabetic Rats by Using the Electroretinography and Immunohistochemistry Methods, Noriko Hiramatsu, Saori Deguchi, Chiaki Yoshioka, Hiroko Otake, Naoki Yamamoto, Noriaki Nagai, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 137(9), 1169 - 1175, Sep. 2017 , Refereed
    Summary:Streptozotocin-induced diabetic rat (STZ rat) was used in many studies for the diabetic mellitus. In this study, we demonstrated whether the electroretinograms (ERG) was changed in the retina of STZ rats. In addition, we investigated the histopathological alteration in the retina of STZ rats by using the immunological method. The 100 mg/kg of STZ was injected continuously for 2 d (100 mg/kgX2). The insulin level was decreased, and the glucose level was enhanced 14 d after the injection of STZ. Moreover, the levels of a-wave, b-wave and OP amplitude were decreased in the rat at 14 d after the injection of STZ. Although, the damage and apoptosis was not observed in the retinal ganglion cell of STZ rats by the immunological experiment using the phospho-H2A.X and cleaved caspase-3, the distance between cell and cell was increased in both of outer- and inner-nuclear (granule) layer in retina of STZ rats. In conclusion, we showed that the enhanced thickening in retina was caused by the injection of excessive STZ. The thickening in retina of STZ rats may lead to the dysfunction of retina, resulting in the decrease in ERG. These findings provide significant information that can be used in the design of a model of diabetic retinopathy.
  • A Nanoparticle-Based Ophthalmic Formulation of Dexamethasone Enhances Corneal Permeability of the Drug and Prolongs Its Corneal Residence Time, Noriaki Nagai, Yosuke Nakazawa, Yoshimasa Ito, Kazutaka Kanai, Norio Okamoto, Yoshikazu Shimomura, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 40(7), 1055 - 1062, Jul. 2017 , Refereed
    Summary:We designed ophthalmic formulations containing dexamethasone-loaded solid nanoparticles (DEXnano dispersion), and investigated corneal permeability and toxicity. 0.1% dexamethasone (DEX) powder (DEX microparticles), 0.026% methyl p-hydroxybenzoate (MP), 0.014% propyl p-hydroxybenzoate (PP), and 0.5% methylcellulose were used, and the DEXnano dispersion was prepared by the bead mill method. The mean particle size of DEXnano dispersion was 78 nm. Antimicrobial activity of the DEXnano dispersion were measured by using Escherichia coli, and the corneal epithelium-debrided rat model and HCE-T cells (immortalized human corneal epithelial cell line) were used to estimate the corneal toxicity. The transcorneal penetration of the DEXnano dispersion were evaluated in the corneas of rabbit. The DEXnano dispersion was found to be highly stable until 14d after its preparation. Although DEX itself did not exhibit antimicrobial activity, the DEXnano dispersion containing parabens (MP and PP) showed high antimicrobial activity, approximately equal to that of the solution containing parabens without DEX. The corneal penetration rate (J(c)) and mean residence time (MRT) of DEX from the DEXnano dispersion were approximately 5.1- and 1.3-fold higher, respectively, than those of a dispersion containing DEX microparticles (mean particle size, 11.3 mu m). In addition, no significant difference was found in corneal stimulation between the vehicle and DEXnano dispersion. In conclusion, we successfully prepared high quality dispersion containing DEX solid nanoparticles, and the nanoparticle-based ophthalmic formulation of DEX enhanced the corneal permeability and residence time of the drug. It is possible that DEXnano dispersion will show increased effectiveness in treating ocular inflammation.
  • Co-administration of Magnesium Ion Prevents Indomethacin-Induced Intestinal Ulcerogenic Lesions in Adjuvant-Induced Arthritis Rats, Noriaki Nagai, Akina Ueno, Tadatoshi Tanino, Mikako Oka, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 40(6), 910 - 915, Jun. 2017 , Refereed
    Summary:In a study to find ways to prevent the side effects of indomethacin (IMC), we previously reported that magnesium ion (Mg2+) can prevent the onset of IMC-induced gastric mucosa in adjuvant-induced arthritis (AA) rats, a model for rheumatoid arthritis (RA). In this study we investigated whether the co-administration of IMC and Mg2+ prevents the formation and aggravation of intestinal ulcerogenic lesions in AA rats. The single oral administration of an excessive dose of IMC (40 mg/kg) induces hemorrhagic lesions and nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) in the jejunal and ileal mucosa of AA rats, and the extent of the lesions, as well as iNOS and NO levels in AA rats are higher than in normal rats. On the other hand, the co-administration of 200 mg/kg Mg2+ attenuates intestinal ulceration and the elevation in the iNOS and NO levels in AA rats. Further, hemorrhagic lesioning and enhanced iNOS and NO levels in AA rats also result from the repetitive oral administration of 3 mg/kg IMC (therapeutic dose) for 42 d (once a day), and these changes are also prevented by the co-administration of 200 mg/kg Mg2+. In conclusion, the co-administration of Mg2+ suppresses the ulcerogenic response to IMC in the jejunal and ileal mucosa of AA rats, probably by preventing the elevation of iNOS and NO levels in the region.
  • Improvement of Dissolution Rate and Stability in a Pirenoxine Ophthalmic Suspension by the Bead Mill Methods, Akina Ueno, Sakie Yamaoka, Yoshimasa Ito, Takeshi Kotake, Yosuke Nakazawa, Noriaki Nagai, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 137(5), 635 - 641, May 2017 , Refereed
    Summary:Foreign matter sensation and blurred vision following instillation of ophthalmic suspension are often observed, and remaining of solid particle on cornea is related these side effects. In addition, low dispersion stability in the ophthalmic suspension affects the therapeutic effect. In this study, we have attempted to enhance the dissolution rate and stability of commercially available pirenoxine ophthalmic suspension (CA-pirenoxine eye drops), anti-cataract eye drops, by changes in particle size. Methylcellulose, zirconia beads (0.1 mm) and Micro Smash were used to mill the pirenoxine (bead mill method), and the distribution of particle size was changed to approximately 60-900 nm (nanodispersions) from 70 nm-3 mu m (CA-pirenoxine eye drops). The dissolution rate of pirenoxine increased by the bead mill, and the dissolution rate constant in pirenoxine nanodispersions was 2.1-fold than that in CA-pirenoxine eye drops. Moreover, the dispersion stability in nanodispersions also significant higher in comparison with the CA-pirenoxine eye drops. The dispersion ratio in CA-pirenoxine eye drops and pirenoxine nanodispersions at 2 d after suspension was 48%, 99%, respectively. In conclusion, we showed that the dissolution rate and dispersion stability of CA-pirenoxine eye drops were enhanced by the bead mill method. These findings provide significant information that can be used in the design of ophthalmic suspension.
  • Combination Ointment Containing Solid Tranilast Nanoparticles and Dissolved Sericin Is Efficacious for Treating Skin Wound-Healing Deficits and Redness in Diabetic Rats, Noriaki Nagai, Fumihiko Ogata, Saori Deguchi, Akina Ueno, Naohito Kawasaki, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 40(4), 444 - 450, Apr. 2017 , Refereed
    Summary:We attempted to design a combination ointment containing solid tranilast nanoparticles and dissolved sericin as a wound-healing drug (TS-combination ointment), and evaluated its usefulness as therapy for wound-healing deficits in streptozotocin-induced diabetic rat (STZ rat) using kinetic analyses as an index. Solid tranilast nanoparticles were prepared by bead mill methods with low-substituted methylcellulose; the mean particle size of the tranilast nanoparticles was 70 nm. The ointment was designed to contain the tranilast nanoparticles plus sericin powder and/or Carbopol 934. Skin wound healing in STZ rats begins significantly later than in normal rats. Although the skin wound healing rate in STZ rats treated with an ointment containing tranilast nanoparticles was lower than in STZ rats treated with vehicle, the ointment was effective' in reducing redness. An ointment containing sericin enhanced the skin-healing rate, but the preventive effect on redness was weak. On the other hand, the combination of tranilast and sericin increased both the skin healing rate and reduction in redness. In conclusion, we have adapted kinetic analyses to skin wound healing in rats, and found these analyses to be useful as an index of wound healing ability by a wound-healing drug. In addition, we show that treatment with the TS-combination ointment enhances the skin wound healing rate and reduces redness. These findings provide information significant to the search for new wound-healing therapies and for the design of wound-healing drugs.
  • Adsorption Capability of Cationic Dyes (Methylene Blue and Crystal Violet) onto Poly-gamma-glutamic Acid, Fumihiko Ogata, Noriaki Nagai, Naohito Kawasaki, CHEMICAL & PHARMACEUTICAL BULLETIN, CHEMICAL & PHARMACEUTICAL BULLETIN, 65(3), 268 - 275, Mar. 2017 , Refereed
    Summary:In this study, the adsorption capability of cationic dyes, which were methylene blue and crystal violet, by poly-gamma-glutamic acid (PGA) in a single or binary solution system was investigated. The effect of the molecular weight of PGA, initial dye concentration, solution pH, and temperature on the adsorption of dyes was evaluated. The adsorption mechanism of dyes onto PGA was the interaction between -COOH group on the PGA surface and the polarity groups of dyes. These results indicated that PGA is useful for removal of dyes and cationic organic compounds from a single or binary solution system.
  • Pharmacokinetic Studies of Gel System Containing Ibuprofen Solid Nanoparticles, Noriaki Nagai, Tadatoshi Tanino, Yoshimasa Ito, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 65(12), 1045 - 1053, Dec. 2016 , Refereed
    Summary:In the therapy of rheumatoid arthritis, ibuprofen (IBU) is widely used; however, it has been limited the clinical use by its systemic side effect, such as gastrointestinal lesions. Therefore, we prepared topical gel ointment used IBU solid nanoparticles (IBUnano-gel formulation). In addition, we demonstrated their anti-inflammatory effect by using arthritis model rat (adjuvant-induced arthritis rat, AA rat). The gel formulations were prepared using additives (Carbopol 934, 2-hydroxypropyl-beta-cyclodextrin and methylcellulose) and bead mill-method. The IBU particle size in the IBUnano-gel formulation was 208 nm. The increase in inflammation of the hind feet of AA rats was attenuated by the treatment with the IBUnano- gel formulation, and preventive effect was higher than that of a gel formulation containing IBU-microparticles (IBUmicro-gel formulation, mean particle size 85.4 mu m); the accumulation and permeability through the skin of IBU from the IBUnano-gel formulation were significantly larger in comparison with the IBUmicro-gel formulation. Further, no gastrointestinal lesions were observed in AA rats following the repetitive administration of the 5% IBUnano-gel formulation (0.30 g) for 42 days (once a day). These results suggest that the dermal application of IBU-nanoparticles provide effective and efficient therapy that spares patients from unwanted side effects.
  • An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens, Noriaki Nagai, Yu Mano, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 39(11), 1881 - 1887, Nov. 2016 , Refereed
    Summary:Disulfiram (DSF) is a dimer of diethyldithiocarbamate (DDC) that we previously added to a solution of 2-hydroxypropyl-beta-cyclodextrin (DSF solution). We found that the instillation of this DSF solution delayed lens opacification in a hereditary cataractous ICR/f rat. In this study, we attempted to design an ophthalmic formulation containing DSF nanoparticles for use as a lens targeted drug delivery system (nano-DSF suspension), and investigated the changes in drug content in the lens after the instillation of DSF solution or nanoDSF suspension. The nano-DSF suspension was prepared by a bead mill method to yield a mean particle size of nano-DSF of 181 nm. Following the instillation of 1.4% DSF solution or the nano-DSF suspension, DDC was detected only in the aqueous humor and lens; in both, the area under the curve (AUC) and mean residence time (MRT) for the nano-DSF suspension were higher than for the DSF solution. In addition, we found that the DDC residence time in the cortex and nucleus of the lens was higher than in the capsule-epithelium. Although DDC was not detected in the cortex and nucleus of lenses following the instillation of the 1.4% DSF solution, the instillation of a 1.4% nano-DSF suspension led to the accumulation of DDC in both areas. In conclusion, it is possible that the instillation of a nano-DSF suspension can supply more DDC into the aqueous humor and lens than a conventional formulation, and these findings provide information significant for the prevention of cataracts and the design of a lens targeted drug delivery system.
  • Size effect of rebamipide ophthalmic nanodispersions on its therapeutic efficacy for corneal wound healing, Noriaki Nagai, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, EXPERIMENTAL EYE RESEARCH, EXPERIMENTAL EYE RESEARCH, 151, 47 - 53, Oct. 2016 , Refereed
    Summary:In a variety of tissues including gastrointestinal mucosa, rebamipide (REB) provides cytoprotection, prevents inflammation, and promotes wound healing. Clinically, REB ophthalmic dispersions are used to treat diabetic keratopathy. In this study, we investigated the optimal particle size of REB to promote corneal wound healing using a model of diabetic keratopathy, the debrided corneal epithelium from Otsuka Long-Evans Tokushima Fatty (OLETF) rats. First, we prepared three dispersions with different REB particle sizes (REB735, REB150, REB45) by treatment with zirconia beads and Bead Smash 12 (a bead mill). The mean particle sizes of the REB735, REB150, REB45 dispersions were approximately 735 nm, 150 nm and 45 nm, respectively. Next, we measured the amounts of REB in the corneal and conjunctival tissues of rats following the instillation of the REB dispersions. The amounts of REB in the corneal and conjunctival tissues following the instillation of REB dispersions was increased by using the mill method, and the amount of REB in rats instilled with the REB150 dispersion was significantly higher than in rats instilled with the REB45 dispersion. Moreover, the corneal wound healing rate for rats instilled with the REB150 dispersion was significantly higher than for rats instilled with the REB735 or REB45 dispersions. In addition, these REB dispersions enhanced corneal epithelial cell growth, resulting an enhancement of corneal wound healing rate. Thus, we found that the ocular drug accumulation and therapeutic effect on corneal wound healing of REB dispersions is enhanced by preparing particles with a size of ca. 150 nm. These findings provide significant information that can be used to design further studies aimed at developing ophthalmic dispersions. (C) 2016 Elsevier Ltd. All rights reserved.
  • Design of Novel Ophthalmic Formulation Containing Drug Nanoparticles and Its Usefulness as Anti-glaucoma Drugs, Noriaki Nagai, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 136(10), 1385 - 1390, Oct. 2016 , Refereed
    Summary:The ophthalmic application of drugs is the primary route of administration for the therapy of glaucoma; however, in traditional formulations, only small amounts of the administered drug penetrate the cornea to reach the desired intraocular tissue due to corneal barriers. Recently, nanoparticulate drug delivery is expected as a technology to overcome the difficulties in delivering drugs across biological barriers (improvement of bioavailability). In this study, we attempted to establish a new method for preparing solid drug nanoparticles by using a bead mill and various additives, and succeeded in preparing a high quality dispersion containing drug nanoparticles. For a more concrete example, a mean particle size of disulfiram (DSF) treated with bead mill is 183 nm. The corneal penetration and corneal residence time of DSF from the ophthalmic dispersion containing DSF nanoparticles were significantly higher than those from a 2-hydroxypropyl-beta-cyclodextrin solution containing DSF (DSF solution). It is known that the administration of DSF has intraocular pressure (TOP)-reducing effects. The IOP-reducing effects of the ophthalmic dispersion containing DSF nanoparticles were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, the ophthalmic dispersion containing DSF nanoparticles is better tolerated by corneal epithelial cells than DSF solution. It is possible that dispersions containing DSF nanoparticles provide new possibilities for effectively treating glaucoma, and that ocular drug delivery systems using drug nanoparticles may expand their usage for therapy in the ophthalmologic field.
  • New Developments to Break the Limitations of the Integrated Program-Inclusive Reform of Teaching and Learning by the Jigsaw Method- Foreword, Noriko Kodama, Noriaki Nagai, Tomohisa Yasuhara, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 136(3), 359 - 360, Mar. 2016 , Refereed
  • New Developments to Break the Limitations of the Integrated Program-Inclusive Reform of Teaching and Learning by the Jigsaw Method- Foreword, Noriko Kodama, Noriaki Nagai, Tomohisa Yasuhara, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 136(3), 359 - 360, Mar. 2016 , Refereed
  • Increased Expression of Interleukin-18 in Lenses of Ovariectomized Rats, Noriaki Nagai, Fumihiko Ogata, Naohito Kawasaki, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 39(1), 138 - 142, Jan. 2016 , Refereed
    Summary:Previous studies showed an increased prevalence of cataracts in postmenopausal women. In this study, we investigated changes in the levels of calcium ion (Ca2+) and interleukin (IL)-18, which are factors in cataract development, in the lenses of ovariectomized (OVX) rats, a model of postmenopausal woman. Although the Ca2+ content in the blood of OVX rats increased 1 month after ovariectomy and subsequently decreased, the Ca2+ content in the lenses was unchanged in OVX rats 1-3 months after ovariectomy. The Ca2+-ATPase activity in the lenses of OVX rats peaked 1 month after ovariectomy, and the behavior of Ca2+-ATPase activity in lenses of OVX rats was similar to that of the Ca2+ concentration in the blood. It is possible that hypercalcemia increases the Ca2+ inflow into the lens; however, the enhanced Ca2+-ATPase activity prevents the Ca2+ level from rising. On the other hand, we found that the levels of both IL-18 and interferon (IFN)-y in the lenses of OVX rats were significantly increased as compared with the lenses of sham (control) rats during the period 1-3 months after surgery. These results suggest that the expression of IFN-gamma via IL-18 in the lenses of OVX rats is induced by ovariectomy, and that excessive IL-18 and IFN-gamma production in the lenses may be related to cataract development in postmenopausal women. These findings support those of previous studies that assessed lens opacification in postmenopausal women.
  • Enhanced Production of Nitric Oxide Leads to ATP Collapse in the Retinas of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Diabetes, Noriaki Nagai, Chiaki Yoshioka, Tadatoshi Tanino, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 41(4), 532 - 542, 2016 , Refereed
    Summary:Purpose: We determined nitric oxide (NO) production via inducible NO synthase (iNOS) by hyperglycemia using the retina of Otsuka Long-Evans Tokushima Fatty rats (OLETF rats), and investigated the relationship between ATP contents and NO production in the retinas of OLETF rats. Methods: Long-Evans Tokushima Otsuka rats (LETO rats, normal rats) and OLETF rats (model rat for diabetes mellitus) aged 60 weeks of age were used. Plasma glucose (Glu) levels were determined using an Accutrend GCT System, and NO levels were measured by the microdialysis method as nitrite (NO2-). Cytochrome c oxidase (CCO) activity was measured using a Mitochondrial Isolation Kit and Cytochrome c Oxidase Assay Kit, and ATP levels were determined using a Sigma ATP Bioluminescent Assay Kit and a luminometer AB-2200. Results: NO2- levels in the retinas of OLETF rats were significantly higher than in LETO rats, and the NO2- levels in the retinas of 60-week-old OLETF rats increased with increasing Glu. CCO activity in the retinas of OLETF rats showed no significant difference from that in LETO rats; however, ATP levels in the retinas of OLETF rats were significantly lower than those in LETO rats. The oral administration of aminoguanidine or disulfiram, an iNOS inhibitor, attenuated the decrease in ATP levels in the retinas of 60-week-old OELTF rats. Conclusion: The present study demonstrates that NO production via iNOS in the retinas of 60-week-old OLETF rats is caused by hyperglycemia, and that NO causes a decrease in ATP contents in the retinas of 60-week-old OELTF rats. It is possible that the low ATP contents caused by NO may affect the normal functioning of the retina in OLETF rats.
  • Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles, Noriaki Nagai, Aya Iwamae, Shion Tanimoto, Chiaki Yoshioka, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 38(12), 1918 - 1924, Dec. 2015 , Refereed
    Summary:We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles (KETnano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KETnano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83nm. In the in vitro skin penetration experiment, the penetration rate (J(c)) and penetration coefficient through the skin (K-p) values of the KETnano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KETmicro gel ointment; mean particle size 7.7 mu m). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (k(a)) and the areas under the KET concentration-time curve values in the skin of rats receiving the KETnano gel ointment were significantly higher than those of rats receiving the KETmicro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KETnano gel ointment were also significantly higher than those of rats receiving the KETmicro gel ointment. In addition, the application of the KETnano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KETmicro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET.
  • Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia/Reperfusion-Induced Injury Model, Noriaki Nagai, Chiaki Yoshioka, Yoshimasa Ito, Yoshinori Funakami, Hiroyuki Nishikawa, Atsufumi Kawabata, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 16(12), 29329 - 29344, Dec. 2015 , Refereed
    Summary:It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZ(nano) dispersion; particle size 81 +/- 59 nm, mean +/- S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZ(nano) dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl--cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZ(nano) dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZ(nano) dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZ(nano) dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZ(nano) dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage.
  • Use of a warmed ophthalmic viscoelastic device to accelerate the unfolding of 1-piece intraocular lenses in the capsular bag, Keiichiro Minami, Kazunori Miyata, Nobuyuki Nagai, Hiroshi Sasaki, JOURNAL OF CATARACT AND REFRACTIVE SURGERY, JOURNAL OF CATARACT AND REFRACTIVE SURGERY, 41(10), 2332 - 2333, Oct. 2015
  • Excessive Interleukin 18 Relate the Aggravation of Indomethacin-Induced Intestinal Ulcerogenic Lesions in Adjuvant-Induced Arthritis Rat, Noriaki Nagai, Tadatoshi Tanino, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 38(10), 1580 - 1590, Oct. 2015 , Refereed
    Summary:It is well known that rheumatoid arthritis patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) are more susceptible to NSAIDs-induced gastroenteropathy in comparison with other patients. In this study we demonstrate that expression levels of interleukin (IL)-18 are related to aggravation of intestinal ulcerogenic lesions in adjuvant-induced arthritis (AA) rats following oral administration of indomethacin. AA rats were administered oral indomethacin (40 mg/kg) and killed under deep isoflurane anesthesia after 24 h. The small intestinal mucosa was then examined. Oral administration of indomethacin caused hemorrhagic lesions in the small intestinal mucosa of AA rats, and the lesion score of AA rats 24 h after indomethacin treatment was approximately 5.6-fold higher than for normal rats administered indomethacin. IL-18 expression in the small intestinal mucosa of AA rats administered indomethacin was also higher in comparison with normal rats receiving indomethacin. In addition, interferon-gamma and nitric oxide levels in the small intestinal mucosa of AA rats were increased following oral administration of indomethacin. It is possible that IL-18 expression in AA rats renders the small intestinal mucosa more sensitive to indomethacin, and that IL-18 may play a role in aggravating intestinal ulcerogenic lesions in AA rats treated with this drug.
  • Cyclosporin A-sensitive cytotoxicity of flurbiprofen non-stereoselectively mediated by cytochrome P450 metabolism in three-dimensional cultured rat hepatocytes, Tadatoshi Tanino, Yoshinori Funakami, Noriaki Nagai, Yoshihisa Kato, JOURNAL OF PHARMACY AND PHARMACOLOGY, JOURNAL OF PHARMACY AND PHARMACOLOGY, 67(10), 1406 - 1415, Oct. 2015 , Refereed
    Summary:Objectives2-Arylpropionic acid (profen) drugs are associated with severe hepatotoxicity; however, risk factors are still poorly understood. Acyl-coenzyme A (acyl-CoA) thioesters of profen drugs play a more important role in the covalent binding to rat hepatocyte proteins than the respective acyl-glucuronides. Therefore, we examined whether acyl-glucuronides, acyl-CoA thioesters and oxidative metabolites of profen drugs stereoselectively participated in liver damage.MethodsCytotoxicity was determined by measuring lactate dehydrogenase (LDH) leakage from three-dimensional cultured rat hepatocytes.Key findingsLDH leakage was not induced by R-2-phenylpropionic acid and R-ibuprofen greatly forming acyl-CoA thioesters. S-Naproxen metabolized mainly by Uridine 5-diphosphate (UDP)-glucuronosyl-transferase did not enhance LDH leakage. However, flurbiprofen (FLP) induced LDH leakage. A selective cytochrome P450 (CYP) 2C11 inhibitor suppressed 40-50% of the R-FLP and S-FLP-induced cytotoxicity. Borneol non-stereoselectively accelerated the FLP-induced cytotoxicity. The R-FLP-induced cytotoxicity decreased intracellular adenosine triphosphate (ATP) levels to 50% of untreated hepatocytes. An inhibitor of mitochondrial permeability transition pore, cyclosporin A (Cys A), rescued ATP levels and LDH leakage back to control levels.ConclusionThe reactive acyl-CoA thioesters and acyl-glucuronides were not associated with liver damage, denying one of the leading hypotheses. CYP metabolism of FLP non-stereoselectively participated in Cys A-sensitive cytotoxicity, suggesting mitochondrial injury.
  • Phloridzin-sensitive transport of echinacoside and acteoside and altered intestinal absorption route after application of Cistanche tubulosa extract, Tadatoshi Tanino, Noriaki Nagai, Yoshinori Funakami, JOURNAL OF PHARMACY AND PHARMACOLOGY, JOURNAL OF PHARMACY AND PHARMACOLOGY, 67(10), 1457 - 1465, Oct. 2015 , Refereed
    Summary:ObjectivesThe objective of this study was to address the beneficial effects of Cistanche tubulosa extract on improving the low intestinal permeability of echinacoside (ECH) and acteoside (ACT).MethodsAbsorption of ECH and ACT in C.tubulosa extract was characterized using human intestinal Caco-2 cell monolayers with intact compounds. Glucose transporter-dependent absorption of ECH and ACT was confirmed by an in-situ intestinal perfusion technique.Key findingsThe apparent permeability (P-app) was not significantly different between intact ECH and intact ACT. In the presence of phloridzin, the P-app of the ECH and ACT at a high dose was reduced to 20% of the respective non-treatment, but was not altered by phloretin and verapamil. C.tubulosa extract at low and high doses enhanced the P-app of ECH and ACT (both by threefold), resulting in their large participation in sodium-dependent glucose transporter-independent absorption. At a low concentration, concomitant ECH and ACT levels in portal blood were significantly suppressed by phloridzin.ConclusionThe dietary and medicinal C.tubulosa extract enhancing the intestinal absorption of ECH and ACT may serve to better manage human health, although the involvement of phloridzin-sensitive transport should be reduced.
  • Hypercalcemia Leads to Delayed Corneal Wound Healing in Ovariectomized Rats, Noriaki Nagai, Fumihiko Ogata, Naohito Kawasaki, Yoshimasa Ito, Yoshinori Funakami, Norio Okamoto, Yoshikazu Shimomura, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 38(7), 1063 - 1069, Jul. 2015 , Refereed
    Summary:Hypercalcemia is often observed in postmenopausal women as well as in patients with primary hyperparathyroidism or malignant tumors. In this study, we investigated the relationship between calcium ion (Ca2+) levels in lacrimal fluid and the rate of corneal wound healing in hypercalcemia using ovariectomized (OVX) rat debrided corneal epithelium. We also determined the effects of Ca2+ levels on cell adhesion, proliferation and viability in a human cornea epithelial cell line (HCE-T). The calcium content in bones of OVX rats decreased after ovariectomy. Moreover, the Ca2+ content in the blood of OVX rats was increased 1 month after ovariectomy, and decreased. The Ca2+ content in the lacrimal fluid of OVX rats was also increased after ovariectomy, and then decreased similarly as in blood. Corneal wound healing in OVX rats was delayed in comparison with Sham rats (control rats), and a close relationship was observed between the Ca2+ levels in lacrimal fluid and the rate of corneal wound healing in Sham and OVX rats (y=-0.7863x+8.785, R=0.78, n=25). In addition, an enhancement in Ca2+ levels caused a decrease in the viability in HCE-T cells. It is possible that enhanced Ca2+ levels in lacrimal fluid may cause a decrease in the viability of corneal epithelial cells, resulting in a delay in corneal wound healing. These findings provide significant information that can be used to design further studies aimed at reducing corneal damage of patients with hypercalcemia.
  • Decrease in Corneal Damage due to Benzalkonium Chloride by the Addition of Mannitol into Timolol Maleate Eye Drops, Noriaki Nagai, Chiaki Yoshioka, Tadatoshi Tanino, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 64(7), 743 - 750, Jul. 2015 , Refereed
    Summary:We investigated the protective effects of mannitol on corneal damage caused by benzalkonium chloride (BAC), which is used as a preservative in commercially available timolol maleate eye drops, using rat debrided corneal epithelium and a human cornea epithelial cell line (HCE-T). Corneal wounds were monitored using a fundus camera TRC-50X equipped with a digital camera; eye drops were instilled into rat eyes five times a day after corneal epithelial abrasion. The viability of HCE-T cells was calculated by TetraColor One; and Escherichia coli (ATCC 8739) were used to measure antimicrobial activity. The reducing effects on transcorneal penetration and intraocular pressure (IOP) of the eye drops were determined using rabbits. The corneal wound healing rate and rate constant (k(H)), as well as cell viability, were higher following treatment with 0.005% BAC solution containing 0.5% mannitol than in the case BAC solution alone; the antimicrobial activity was approximately the same for BAC solutions with and without mannitol. In addition, the k(H) for rat eyes instilled with commercially available timolol maleate eye drops containing 0.5% mannitol was significantly higher than that for eyes instilled with timolol maleate eye drops without mannitol, and the addition of mannitol did not affect the corneal penetration or TOP reducing effect of the timolol maleate eye drops. A preservative system comprising BAC and mannitol may provide effective therapy for glaucoma patients requiring long-term treatment with anti-glaucoma agents.
  • Effect of High Glucose Levels on Amyloid beta Production in Retinas of Spontaneous Diabetes Mellitus Otsuka Long-Evans Tokushima Fatty Rats, Noriaki Nagai, Yoshimasa Ito, Tadatoshi Tanino, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 38(4), 601 - 610, Apr. 2015 , Refereed
    Summary:The accumulation of amyloid beta(1-42) peptide (A beta(1-42)) in retina is implicated in the development of retinal ganglion cell apoptosis and diabetic retinopathy. In this study we demonstrate that spontaneous diabetes mellitus Otsuka Long-Evans Tokushima Fatty (OLETF) rats can be used as an animal model in studies to identify the expression of A(beta) in diabetic retinas. In addition, we investigated the relation between glucose level and A beta production in the retinas of OLETF rats. In the retinas of Long-Evans Tokushima Otsuka (LETO) rats used as normal controls and OLETF rats, no expression of neprilysin (NEP), which degrades A beta, was detected, and the expression levels of genes associated with A beta production (amyloid precursor protein, beta site APP cleaving enzyme, and presenilin) and A beta(1-42) levels in the retinas of 60-week-old OLETF rats with diabetes mellitus were significantly higher than in 60-week-old LETO rat retinas. Furthermore, the increase in the expression levels of genes associated with A beta production was enhanced by administration of glucose (3.0 g/kg; OGT test), and close relations between the retinal A beta(1-42) level and plasma blood glucose and HbA1c were observed. In conclusion, we have found that A beta accumulates easily in the retinas of LETO and OLETF rats due to the absence of NEP. In addition, we determined that the accumulation of A beta(1-42) in the retinas of OLETF rats is promoted by high plasma glucose levels. Therefore OLETF rats may be a suitable model for studies to identify the expression of A beta in diabetic retinas.
  • A nanoparticle formulation of disulfiram prolongs corneal residence time of the drug and reduces intraocular pressure, Noriaki Nagai, Chiaki Yoshioka, Yu Mano, Wataru Tnabe, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, EXPERIMENTAL EYE RESEARCH, EXPERIMENTAL EYE RESEARCH, 132, 115 - 123, Mar. 2015 , Refereed
    Summary:The goal in the search for successful therapies for glaucoma is the reduction of intraocular pressure (IOP), and the search for effective eye drops that reduce IOP is a high priority. We previously reported the potential of a 2-hydroxypropy1-beta-cyclodextrin (HPPCD) solution containing 0.5% DSF (DSF solution) to provide effective anti-glaucoma treatment in eye drop form. In this study, we designed new ophthalmic formulations containing 0.5% DSF nanoparticles prepared by a bead mill method (DSFnano dispersion; particle size 183 +/- 92 nm, mean +/- S.D.), and compared the IOP-reducing effects of a DSFnano dispersion with those of a DSF solution. The high stability of the DSFnano dispersion was observed until 7 days after preparation, and the DSFnano dispersion showed high antimicrobial activity against Escherichia coil (ATCC 8739). In transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while no DSF was detected. The DDC penetration level (area under the curve, AUC) and corneal residence time (mean residence time, MRT) of the DSFnano dispersion were approximately 1.45- and 1.44-fold higher than those of the DSF, respectively. Moreover, the IOP-reducing effects of the DSF,, dispersion were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, DSFnano dispersion are tolerated better by a corneal epithelial cell than DSF solution and commercially available timolol maleate eye drops. It is possible that dispersions containing DSF nanoparticles will provide new possibilities for the effective treatment of glaucoma, and that an ocular drug delivery system using drug nanoparticles may expand their usage as therapy in the ophthalmologic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma drugs. (C) 2015 Elsevier Ltd. All rights reserved.
  • Changes in Plasma Glucose in Otsuka Long-Evans Tokushima Fatty Rats After Oral Administration of Maple Syrup, Noriaki Nagai, Tetsushi Yamamoto, Wataru Tanabe, Yoshimasa Ito, Satoshi Kurabuchi, Kuniko Mitamura, Atsushi Taga, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 64(3), 331 - 335, Mar. 2015 , Refereed
    Summary:We investigate whether maple syrup is a suitable sweetener in the management of type 2 diabetes using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The enhancement in plasma glucose (PG) and glucose absorption in the small intestine were lower after the oral administration of maple syrup than after sucrose administration in OLETF rats, and no significant differences were observed in insulin levels. These data suggested that maple syrup might inhibit the absorption of glucose from the small intestine and preventing the enhancement of PG in OLETF rats. Therefore, maple syrup might help in the prevention of type 2 diabetes.
  • Topical Therapies for Rheumatoid Arthritis by Gel Ointments containing Indomethacin Nanoparticles in Adjuvant-Induced Arthritis Rat, Noriaki Nagai, Chiaki Yoshioka, Yoshimasa Ito, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 64(3), 337 - 346, Mar. 2015 , Refereed
    Summary:Indomethacin (IMC), a nonsteroidal anti-inflammatory drug, has been used in the treatment of rheumatoid arthritis (RA), although its clinical use has been limited by its systemic side effects that include gastrointestinal lesions. Therefore, the development of IMC formulations that do not cause gastrointestinal lesions is highly anticipated. In this study, we designed new topical formulations containing IMC solid nanoparticles (IMCnano gel ointment), and investigated their pharmacokinetics. In addition, we demonstrate the preventive effects of this topical application of IMC nanoparticles on inflammation in adjuvant-induced arthritis rat (AA rat). The IMCnano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including 2-hydroxypropyl-beta-cyclodextrin, methylcellulose and Carbopol 934; the mean particle size of the IMC nanoparticles was 173 +/- 91 nm (means +/- S.D.). The application of the IMCnano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with gel ointment containing IMC microparticles (IMCmicro gel ointment, particle diameter 17.1 +/- 11.6 mu m, means S.D). In addition, the accumulation of IMC from the IMCnano gel ointment in skin tissue was significantly large than for the IMCmicro gel ointment; however, the plasma IMC concentrations were similar for the IMCmicro and IMCnano gel ointments. Our findings suggest that the dermal application of nanoparticles may enable a medication to be applied without high-systemic drug levels, which could provide efficient and effective therapy that spares patients from unwanted side effects. A formulation of a topical drug delivery system using IMC nanoparticles may provide a delivery option for the clinical treatment of RA.
  • Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular Pressure in Rabbit Models, Noriaki Nagai, Chiaki Yoshioka, Yu Mano, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 40(10), 990 - 1000, 2015 , Refereed
    Summary:Purpose: We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-beta-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models. Methods: Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. Delta IOP and Delta NO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively. Results: Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of Delta IOP or Delta NO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops. Conclusions: The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC-based drug delivery system promotes drug effectiveness and effective time.
  • Effect of Solid Nanoparticle of Indomethacin on Therapy for Rheumatoid Arthritis in Adjuvant-Induced Arthritis Rat, Noriaki Nagai, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 37(7), 1109 - 1118, Jul. 2014 , Refereed
    Summary:We designed new oral formulations containing indomethacin (IMC) solid nanoparticles, and investigate their usefulness by evaluating bioavailability and gastrointestinal lesions. The IMC solid nanoparticles were prepared using methylcellulose (MC), 2-hydroxypropyl-beta-cyclodextrin (HP beta CD),. and the bead mill method, and high quality dispersions containing 1.0% IMC nanoparticles were prepared (IMCnano, particle size: 76 +/- 58 nm, means +/- S.D.). The fate of serum IMC and the induction of paw edema in adjuvant-induced arthritis (AA) rats receiving low-doses IMCnano. (0.4mg/kg) were similar to those following the administration of a therapeutic dose of conventional IMC prepared with MC and HP beta CD (conventional IMC, 2 mg/kg), and the bioavailability in 0.4 mg/kg IMCnano. was 5.3-fold higher in comparison with that in 2 mg/kg conventional IMC. IMC-induced gastrointestinal lesions in AA rats administered IMCnano (8 mg/kg), in consideration of bioavailability, were significantly less than for conventional IMC (40 mg/kg). On the other hand, the toxicity caused by conventional IMC and IMCnano was similar in Caco-2 cells. It is possible that the oral administration of IMC solid nanoparticles will show increased effectiveness in treating RA without causing IMC-induced gastrointestinal lesions, since the bioavailability is higher than that of conventional IMC. An oral drug delivery system using drug nanoparticles may expand the usage of NSAIDs for therapy in the inflammatory field.
  • A nanoparticle formulation reduces the corneal toxicity of indomethacin eye drops and enhances its corneal permeability, Noriaki Nagai, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, TOXICOLOGY, TOXICOLOGY, 319(1), 53 - 62, May 2014 , Refereed
    Summary:Indomethacin (IMC) has been shown to reduce post-operative inflammation and to decrease intraocular irritation after cataract extraction and in cystoid macular edema; however, the clinical use of its most commonly used eye drops is limited due to topical side-effects that include burning sensation, irritation and epithelial keratitis. It is known that decreasing direct cell stimulation and reducing the amount applied via increasing bioavailability are useful for improving these issues. In this study, we designed ophthalmic formulations containing 0.5% IMC nanoparticles using zirconia beads and Bead Smash 12 (IMCnano eye drops; particle size 76 +/- 59 nm, mean +/- S.D.), and investigated the corneal toxicity of these IMCnano eye drops. IMCnano eye drops are tolerated better by a human cornea epithelial cell line (HCE-T) than commercially available NDSAIDs preparations (IMC, pranoprofen, diclofenac, bromfenac and nepafenac eye drops), and corneal wound healing in rat eyes with debrided corneal epithelium instilled with IMCnano eye drops is significantly better than that of eyes instilled with commercially available IMC eye drops. In addition, the accumulation of IMC in HCE-T cells treated with the IMCnano eye drops for 30 min was 19.9% that of the accumulation from commercially available IMC eye drops. On the other hand, the corneal penetration of IMC from IMCnano eye drops was significantly greater than in the case of the commercially available IMC eye drops in both in vivo and in vitro studies using rabbit corneas. Taken together, we hypothesize that a nanoparticle formulation reduces the corneal toxicity of IMC eye drops, probably because the accumulation of IMC from IMCnano eye drops in the eye is lower than that from commercially available IMC eye drops. In addition, the nanoparticle formulation may allow a decrease in the amount of IMC used due to the increase in bioavailability, resulting in reduced drug toxicity. These findings provide significant information that can be used to design further studies aimed at developing less toxic eye drops. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Fundamental Study on Effect of High-mineral Drinking Water for Osteogenesis in Calciprivia Ovariectomized Rats, Fumihiko Ogata, Noriaki Nagai, Yoshimasa Ito, Naohito Kawasaki, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 134(5), 679 - 685, May 2014 , Refereed
    Summary:Since osteoporosis is a major public health problem in Japan, it is important to clarify the effect of high-mineral drinking water consumption on osteogenesis. Therefore, in this study, we investigated the relationship between high-mineral drinking water consumption and osteogenesis in ovariectomized rats that received a low-calcium diet and purified water (PW group) or a low-calcium diet and high-mineral drinking water (CR group). High-mineral drinking water affected the rats' body weight. After 3 months, the bone density of the CR group was higher than that of the PW group (p<0.05). Furthermore, the CR group showed a decrease in the amount of calcium in the bones after 3 months. These results suggest that high-mineral drinking water contributes to the maintenance of bone density and not to the amount of calcium in bone. On the other hand, serum alkaline phosphatase levels in the PW group at 3 months were higher than those in the CR group, which indicates that the blood concentration of calcium in the CR group was maintained. Moreover, the amount of magnesium in the bones and the blood concentration of magnesium in the CR group after 3 months were higher than the corresponding values in the PW group. These results suggest that consumption of high-mineral drinking water could be beneficial for osteogenesis (i.e., for maintaining bone quantity)
  • Improved Corneal Toxicity and Permeability of Tranilast by the Preparation of Ophthalmic Formulations Containing Its Nanoparticles, Noriaki Nagai, Hikaru Ono, Miho Hashino, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 63(2), 177 - 186, Feb. 2014 , Refereed
    Summary:We prepared ophthalmic formulations containing 0.5% tranilast (TL) nanoparticles using 0.005% benzalkonium chloride (BAC), 0.5% D-mannitol, and 2-hydroxypropyl-beta-cyclodextrin (HP beta CD), and investigated their usefulness in the ophthalmologic field by evaluating corneal toxicity and permeability. TL nanoparticles were prepared using zirconia beads and Bead Smash 12, which allowed the preparation of high quality dispersions containing 0.5% TL nanoparticles (particle size, 34 +/- 20 nm, means +/- S.D.). Dispersions containing TL nanoparticles are tolerated better by human corneal epithelium cells than a commercially available 0.5% TL preparation (RIZABEN (R) eye drops). In addition, the addition of TL nanoparticles to the dispersions does not affect the antimicrobial activity of BAC against Escherichia con (ATCC 8739), and the corneal penetration of TL from dispersions containing TL nanoparticles was significantly higher than in the case of the commercially available 0.5% TL eye drops. It is possible that dispersions containing TL nanoparticles will show increased effectiveness against ocular inflammation, and that ocular drug delivery systems using drug nanoparticles may lead to an expansion of their usefulness for therapy in the ophthalmologic field.
  • Therapeutic Effects of Gel Ointments Containing Tranilast Nanoparticles on Paw Edema in Adjuvant-Induced Arthritis Rats, Noriaki Nagai, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 37(1), 96 - 104, Jan. 2014 , Refereed
    Summary:Tranilast (TL), an antiallergic agent, has been clinically used in the treatment of bronchial asthma, although its clinical use has been limited by its poor solubility in water, photodegradation and systemic side effects. In this study, we prepared a gel ointment containing TL nanoparticles (TLnano gel ointment), and investigated its usefulness. In addition, we demonstrated the preventive effects of the TLnano gel ointment on inflammation in adjuvant-induced arthritis (AA) rats. The TLnano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including sodium docusate, 2-hydroxypropyl-beta-cyclodextrin, methylcellulose and Carbopol 934; the mean particle diameter of the TL nanoparticles was 71.0 +/- 25.4 am. In in vitro skin penetration experiments, the amount of penetrated TL, the penetration rate (J(c)) and the penetration coefficient through the skin (K-p) of the TLnano gel ointment were significantly higher than those of a gel ointment containing TL microparticles (TLmicro gel ointment; particle diameter 50.5 +/- 26.3 mu m). The TL concentrations in the skin tissue and plasma of rats receiving the TLnano gel ointment were also higher than in rats receiving the TLmicro gel ointment. In addition, the application of the TLnano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with the TLmicro gel ointment. These results suggest that TL nanoparticles can be applied to the formulation of a transdermal system, and that a transdermal formulation using TL nanoparticles might be a delivery option for the clinical treatment of RA.
  • Comparison of the Enhancement of Plasma Glucose Levels in Type 2 Diabetes Otsuka Long-Evans Tokushima Fatty Rats by Oral Administration of Sucrose or Maple Syrup, Noriaki Nagai, Yoshimasa Ito, Atsushi Taga, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 62(9), 737 - 743, Sep. 2013 , Refereed
    Summary:Maple syrup is used as a premium natural sweeter, and is known for being good for human health. In the present study, we investigate whether maple syrup is suitable as a sweetener in the management of type 2 diabetes using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. OLETF rats develop type 2 diabetes mellitus by 30 weeks of age, and 60-week-old OLETF rats show hyperglycemia and hypoinsulinemia via pancreatic beta-cell dysfunction. The administration of sucrose or maple syrup following an OGT test increased plasma glucose (PG) levels in OLETF rats, but the enhancement in PG following the oral administration of maple syrup was lower than in the case of sucrose administration in both 30- and 60-week-old OLETF rats. Although, the insulin levels in 30-week-old OLETF rats also increased following the oral administration of sucrose or maple syrup, no increase in insulin levels was seen in 60-week-old OLETF rats following the oral administration of either sucrose or maple syrup. No significant differences were observed in insulin levels between sucrose- and maple syrup-administered OLETF rats at either 30 or 60 weeks of age. The present study strongly suggests that the maple syrup may have a lower glycemic index than sucrose, which may help in the prevention of type 2 diabetes.
  • Reduction of Enhanced Rabbit Intraocular Pressure by Instillation of Pyroglutamic Acid Eye Drops, Yoshimasa Ito, Noriaki Nagai, Norio Okamoto, Yoshikazu Shimomura, Kunio Nakanishi, Ryuichiro Tanaka, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36(6), 1017 - 1023, Jun. 2013 , Refereed
    Summary:L-Pyroglutamic acid (PGA) is an endogenous molecule derived from L-glutamate. We demonstrate the effects of PGA on intraocular pressure (lOP) in experimentally induced ocular hypertension in rabbits. In the in vitro and in vivo transcorneal penetration studies, the PGA solution (PGA in saline) did not penetrate the rabbit cornea. On the other hand, the penetration of PGA was improved by the addition of zinc chloride and 2-hydroxypropyl-beta-cyclodextrin (HPCD), and PGA penetration was enhanced with increasing HPCD concentration. Therefore, PGA solutions containing 0.5% zinc chloride and 5% or 10% HPCD (PGA/HPCD5% or 10% eye drops) were used to investigate the effects for IOP in this study. An elevation in IOP was induced by the rapid infusion of 5% glucose solution (15 mL/kg of body weight) through the marginal ear vein or maintaining under dark phase for 5h. In the both models, the induced elevation in IOP was prevented by the instillation of PGA/HPCD eye drops, and the IOP-reducing effect enhanced with increasing HPCD concentration in the drops. Nitric oxide (NO) levels elevated in the aqueous humor following the infusion of 5% glucose solution, and this increase was also suppressed by the instillation of PGA/HPCD eye drops. In conclusion, the present study demonstrates that the instillation of PGA/HPCD eye drops has an IOP-reducing effect in rabbits with experimentally induced ocular hypertension, probably as a result of the suppression of NO production.
  • Decrease in Corneal Damage due to Benzalkonium Chloride by the Addition of Sericin into Timolol Maleate Eye Drops, Noriaki Nagai, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 62(3), 159 - 166, Mar. 2013 , Refereed
    Summary:We investigated the protective effects of sericin on corneal damage due to benzalkonium chloride (BAC) used as a preservative in commercially available timolol maleate eye drops using rat debrided corneal epithelium and a human cornea epithelial cell line (HCE-T). Corneal wounds were monitored using a fundus camera TRC-50X equipped with a digital camera; eye drops were instilled into the rat eyes five times a day after corneal epithelial abrasion. The viability of HCE-T cells was calculated by TetraColor One; and Escherichia con (ATCC 8739) were used to measure antimicrobial activity. The reducing effects on transcorneal penetration and intraocular pressure (TOP) of the eye drops were determined using rabbits. The corneal wound healing rate and rate constants (k(H)) as well as cell viability were higher following treatment with 0.005% BAC solution containing 0.1% sericin than in the case of treatment with BAC solution alone; the antimicrobial activity was approximately the same for BAC solutions with and without sericin. In addition, the k(H) for rat eyes instilled with commercially available timolol maleate eye drops containing 0.1% sericin was significantly higher than that of eyes instilled with timolol maleate eye drops without sericin, and the addition of sericin did not affect the corneal penetration or IOP reducing effect of commercially available timolol maleate eye drops. A preservative system comprising BAC and sericin may provide effective therapy for glaucoma patients requiring long-term anti-glaucoma agents.
  • Effect of magnesium ion supplementation on obesity and diabetes mellitus in Otsuka Long-Evans Tokushima Fatty (OLETF) rats under excessive food intake, Noriaki Nagai, Yoshimasa Ito, Journal of Oleo Science, Journal of Oleo Science, 62(6), 403 - 408, 2013 , Refereed
    Summary:Several epidemiologic studies have found that magnesium ion (Mg2+) is related to obesity and type 2 diabetes mellitus. However, there have been almost no reports on the effects of a combination of excessive food intake and Mg2+ supplementation on metabolic syndrome and various blood tests values for diabetes mellitus. In this study, we investigated changes in body weight and blood test values for diabetes mellitus of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes mellitus via metabolic syndrome, under conditions of combined excessive food intake and Mg2+ supplementation. The rats received Mg2+ supplementation by drinking magnesium water (Mg2+ 200 mg/l). No significant differences were observed in the levels of food or water intake between OLETF rats drinking purified water (PW) or magnesium water (MW). Type 2 diabetes mellitus with metabolic syndrome developed at 30 weeks of age, and the body weights and plasma insulin levels of OLETF rats at 60 weeks of age were lower than those of normal rats. The plasma glucose (PG) levels in 38-week-old OLETF rats drinking MW were significantly lower than in those of rats drinking PW, while the body weights and the levels of triglycerides (TG) and insulin of 38-week-old MW-drinking OLETF rats were significantly higher than those of their PW-drinking counterparts. On the other hand, the decreases in body weight and insulin levels in 60-weekold OLETF rats were suppressed by MW supplementation. The present study demonstrates that Mg2+ supplementation delays the development of diabetes mellitus in OLETF rats under conditions of excessive food intake. In addition, obesity and high blood TG levels were observed in OLETF rats receiving Mg2+ supplementation in conjunction with excessive food intake. ©2013 by Japan Oil Chemists' Society.
  • Changes in interleukin 18 in the retinas of Otsuka Long-Evans Tokushima Fatty Rats, a model of human type 2 diabetes, Noriaki Nagai, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, Haruki Okamura, Journal of Oleo Science, Journal of Oleo Science, 62(7), 513 - 523, 2013 , Refereed
    Summary:Recent findings have implicated the involvement of interferon-γ (IFN-γ), a part of the Th1 cytokine response, in the retinal inflammation of diabetic patients. In the present study, we investigate whether hyperglycemia relates to the expression of interleukin 18 (IL-18), and leads to the production of IFN-γ in the retinas of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Plasma blood glucose, triglyceride and cholesterol levels in 60-week-old OLETF rats, in which the development of diabetes mellitus was observed, were significantly higher than in 60-week-old Long-Evans Tokushima Otsuka (LETO) rats used as normal controls. The expression levels of genes that cause IL-18 activation (IL-18, IL-18 receptor and caspase-1) in OLETF rats were increased at 60 weeks of age, and the levels of IL-18 and IFN-γ in 60-week-old OLETF rat retinas were also higher than in 60-week-old LETO rats. Furthermore, IFN-γ levels increased with increasing IL-18 levels in the retinas of OLETF rats, and a close relationship was observed between the levels of IL-18 and HbA1c. The rapid increase in plasma glucose levels following the oral administration of glucose solution (3.0 g/kg) did not affect the IL-18 and IFN-γ levels in the retinas of LETO rats, whereas the levels in the retinas of OLETF rats increased significantly. In conclusion, the expression of IL-18 is increased in the retinas of OLETF rats, and chronic hyperglycemia may accelerate the release of IL-18 and IFN-γ from inflammatory cells in retinal blood vessel. It is possible that IFN-γ production via IL-18 in the retinas of 60-week-old OLETF rats is caused by hyperglycemia, and plays a role in the inflammation of the OLETF rat retinas. © 2013 by Japan Oil Chemists' Society.
  • Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat, Noriaki Nagai, Atsushi Takeda, Yuri Itanami, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 35(12), 2230 - 2237, Dec. 2012 , Refereed
    Summary:Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200, mu g/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.
  • Improvement of Dissolution Test Using Micro-controlled Roller Pump, Noriaki Nagai, Nahoko Konishi, Tadahisa Nitta, Atsushi Taga, Yoshimasa Ito, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 132(11), 1307 - 1316, Nov. 2012 , Refereed
    Summary:The dissolution test is a core performance test in pharmaceutical development and quality control of solid drug products. The conventional HPLC dissolution method (batch-sampling method) involves many steps including the filtration, collection and replenishment of sample solutions. We previously reported a dissolution test that involved microdialysis methods (microdialysis-HPLC method) and allowed many steps to be omitted. However, the recovery rate of theophylline by the microdialysis-HPLC method was lower, and the decrease in the flow rate through the dialysis probe caused variation between each tablet. In this study, we have attempted to improve the dissolution test by using a precise micro-controlled roller pump and microfiltering probe (microfiltering-HPLC method). Sustained release preparations of Theodur (R) (100 mg) were used, and the test solutions used were water, buffer at pH 1.2 and pH 6.8, and pH 6.8-buffer containing 0.1-1% polysorbate 80 or sodium lauryl sulfate. In all test solutions, the microfiltering-HPLC method was able to accomplish continuous sampling of sample solutions, and the recovery rate of theophylline was over 90%. The dissolution behavior by the microfiltering-HPLC method tends to reflect the pharmaceutical design in comparison with the batch-sampling method, and the standard deviations by the microfiltering-HPLC are lower than with the batch-sampling method. In addition, the microfiltering-HPLC method allows many steps to be omitted, such as the filtration, collection and replenishment of sample solutions. These findings provide significant information that can be used in the pharmaceutical development and quality assessment of solid drug products.
  • An In Vitro Evaluation for Corneal Damages after Instillation of Eye Drops Using Rat Debrided Corneal Epithelium: Changes in Corneal Damage of Benzalkonium Chloride by Addition of Thickening Agent, Noriaki Nagai, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 132(7), 837 - 843, Jul. 2012 , Refereed
    Summary:Benzalkonium chloride (BAC) is known to cause corneal epithelial damage. In this study we investigated the effect of a BAC solution containing a thickening agent, which enhanced residence time in the eyes, on corneal wound healing using in vivo rat model debrided corneal epithelium. 0.5% or 1.0% methylcellulose (MC), carboxymethylcellulose (CMC) and hydroxypropyl-methylcellulose (HPMC) were used as the thickening agent. The levels of corneal wound healing of rat eyes injected with saline were alone approximately 45.0% at 12 h and 93.6% at 24 h after corneal epithelial abrasion, and healing was almost complete at 36 h. The healing rate in the rat eye treated just with MC, CMC and HPMC was higher than that in those injected with saline. In contrast to the treatment result using only this thickening agent, the healing rate in the eye treated with BAC was lower than that in those injected with saline: the corneal wounds in the BAC-treated eye showed approximately 20% healing at 12 h after abrasion. The injection of 0.02% BAC solution containing MC, CMC and HPMC more significantly delayed the healing than did the injection of 0.02% BAC alone. The results show that the in vivo evaluation method for corneal damage using rat debrided corneal epithelium reflects a toxic change depending upon residence time. These findings provide valuable safety and efficacy information for use in the design of eye drops.
  • Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-cataract Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose Using ICR/f Rats as a Hereditary Cataract Model, Noriaki Nagai, Yoshimasa Ito, Noriko Takeuchi, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 35(2), 239 - 245, Feb. 2012 , Refereed
    Summary:We attempted to develop anti-cataract eye drops using disulfiram (DSF) and low-substituted methylcellulose (MC), and evaluated their anti-cataract effect in terms of the lens pacification vs. age-profile curves using a one-exponential equation. The eye drops were prepared using 0.5% DSF and 2% MC (DSF eye drops), and ICR/f rats, a recessive-type hereditary cataractous strain, were used as the experimental model. Gelation of DSF eye drops containing MC was first observed at about 35 degrees C, close to body temperature. In in viva transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The DDC penetration level of DSF eye drops containing MC was approximately 1.3-fold higher than that of DSF eye drops. The pacification rate constant (k) of ICR/f rat instilled with DSF eye drops with or without MC was lower, and the initial time of opacification (tau) was longer than those of ICR/f rats instilled with saline. Furthermore, the k of ICR/f rats instilled with DSF eye drops with MC was lower than that of ICR/f rats instilled with DSF eye drops without MC. In conclusion, the analysis of kinetic parameters including k and tau using a one-exponential equation provided useful information for clarifying the anti-cataract effect of eye drops. ICR/f rats instilled with DSF eye drops using a low-substituted MC-based drug delivery system demonstrated a delay in cataract development, probably resulting from an increase in the retention of DSF eye drops on the cornea.
  • A case of propranolol therapy for infantile capillary hemangiomas of the parotis, Shinya Hirahara, Keiji Matsuda, Katsuhiro Toyama, Yuki Nagano, Noriaki Nagai, Tetsuya Tono, Journal of Otolaryngology of Japan, Journal of Otolaryngology of Japan, 115(6), 632 - 635, 2012 , Refereed
    Summary:A 4-month-old healthy female infant presented with rapid onset of subaural swelling over a three-month period. A head and neck exam demonstrated a subaural elastic hard mass with a red birthmark below the left auricle. MRI of the neck demonstrated a well-defined parotid mass consistent with a haemangioma. We treated this infant with lmg/kg of propranolol, which was gradually increased over two months to a dose of 2mg/kg daily. The tumor began to reduce in size within three days after drug administration, and became less prominent in one month, and had almost totally disappeared within four months. On ten-month follow-up, the patient was asymptomatic and repeated MRI demonstrated further regression of the tumor. Propranolol could be the first-line choice for treating haemangioma rather than simple observation, steroids, or invasive methods such as laser irradiation and sclerotherapy.
  • Correlation between Hyper-Sensitivity to Hydrogen Peroxide and Low Defense against Ca2+ Influx in Cataractogenic Lens of Ihara Cataract Rats, Noriaki Nagai, Yoshimasa Ito, Noriko Takeuchi, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 34(7), 1005 - 1010, Jul. 2011 , Refereed
    Summary:Our previous studies have demonstrated that lipid peroxidation in the lenses of hereditary cataract model rats (Ihara cataract rat (ICR)/f rats) caused a dysfunction in Ca2+ regulation. In the present study, we investigated the effect of in vitro hydrogen peroxide (H2O2) stimulation on lipid peroxide (LPO) and the activities of sarco-/endoplasmic reticulum and plasma membrane Ca2+-ATPase (SERCA and PMCA) in the ICR/f rat lenses. An increase in LPO level and decreases in the SERCA and PMCA activities were observed with increasing H2O2 concentration, and pretreatment with diethyldithiocarbamate, a potent radical scavenger, attenuated these changes in normal and ICR/f rat lenses. The glutathione levels, glutathione peroxidase and glutathione reductase activities are significantly lower in ICR/f rat lenses than in normal rat lenses. Furthermore, we presented as two kinetic parameters such as DP (defense point) and K-s (reactive constant) analyzed from above various biological responses vs. H2O2 concentration-profile curves using a one-exponential equation. The DPs for LPO, SERCA and PMCA in ICR/f rat lenses is lower than in normal rat lenses. In contrast to the results in DP, the K-s for LPO, SERCA and PMCA in ICR/f rat lenses is higher than in normal rat lenses. In addition, the closed relationship of was observed between DP and K-s for LPO, SERCA and PMCA. These results show that the resistance to H2O2 in the ICR/f rat lenses is lower than that of normal rats. The DP and K-s values can provide an useful information for resistances to various stimuli in cells and tissues.
  • Involvement of Interleukin 18 in Lens Opacification of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Type 2 Diabetes, Noriaki Nagai, Takatoshi Murao, Yoshimasa Ito, Norio Okamoto, Haruki Okamura, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 36(6), 497 - 506, Jun. 2011 , Refereed
    Summary:Purpose: Mature interleukin 18 (IL-18) leads to the production of interferon-gamma, nuclear factor kappa B, and inducible nitric oxide synthase, and we previously reported that the enhancement of IL-18 in lens of hereditary cataract model rats was involved in lens opacification. In this study, we investigated whether the expression of IL-18 relates to lens opacification in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Methods: Male Long-Evans Tokushima Otsuka (LETO) and OLETF rats at 60 weeks of age were used in this study. Expression of IL-18 mRNA was measured by quantitative real-time RT-PCR method, and IL-18 and interferon-gamma levels were determined using the ELISA method. The transparency of the lenses was monitored using an EAS-1000, and analyzed by image analysis software connected to the EAS-1000. Results: The plasma levels of glucose, triglycerides and cholesterol in the OLETF rats were significantly higher than in LETO rats as normal controls, and the development of diabetes mellitus was observed. The gene expression levels causing IL-18 activation (IL-18, IL-18 receptor, and caspase-1) are increased at 60 weeks of age, and the levels of IL-18 and interferon-gamma in 60-week-old OLETF rat lenses were also higher than those in the 60-week-old LETO rat. Furthermore, the interferon-gamma levels increased with increasing IL-18 levels in the lenses of OLETF rat, and a close relationship was observed between the levels of IL-18 and opacity. Conclusion: The expression of IL-18 was increased in the lenses of OLETF rat. It is possible that activated IL-18 in the lenses of OLETF rat may be related to the lens epithelial cell apotosis and lens opacification.
  • An In Vitro Evaluation for Corneal Damages by Anti-glaucoma Combination Eye Drops Using Human Corneal Epithelial Cell (HCE-T), Noriaki Nagai, Takatoshi Murao, Kyouhei Oe, Yoshimasa Ito, Norio Okamoto, Yoshikazu Shimomura, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 131(6), 985 - 991, Jun. 2011 , Refereed
    Summary:The combination of anti-glaucoma eye drops is frequently used in clinical treatment, and it is known that the combination can cause corneal damage. Recently, an anti-glaucoma combination eye drops is developed, and the treatment by the combination eye drops is expected to enhance quality of life. However, effects of the combination eye drops on corneal epithelial cell damage have not been clarified. In this study, we investigated the corneal epithelial cell damage of commercially available anti-glaucoma combination eye drops, such as Xalacome (R) (latanoprost/timolol maleate combination eye drops), Duotrav (R) (travoprost/timolol maleate combination eye drops) and Cosopt (R) (dorzolamide hydrochloride/timolol maleate combination eye drops) using the human corneal epithelial cell (HCE-T). The cytotoxicity in Xalacom (R) was higher than that in Xalatan (R) (eye drops containing latanoprost) and Timoptol (R) (eye drops containing timolol maleate), and the benzalkonium chloride (BAC) and timolol maleate were related to cytotoxicity in Xalacom (R). The cytotoxicity in Duotrav (R) and Cosopt (R) was lower than that in Timoptol (R). The Duotrav (R) is preserved with a non-BAC system (POLYQUAD, polidronium chloride). Therefore, it was suggested that the POLYQUAD related to the low cytotoxicity in Duotrav (R). On the other hand, the D-mannitol reduced the cytotoxicity by BAC in this study. This result suggested that the cytotoxicity in Cosopt (R) was reduced by D-mannitol. The Duotrav (R) and Cosopt (R) may be less damaging to the ocular surface of glaucoma patients receiving long-term eye drop therapy in compared with the combination of anti-glaucoma eye drops.
  • Anti-Inflammatory Potency of Oral Disulfiram Compared with Dexamethasone on Endotoxin-Induced Uveitis in Rats, Kazutaka Kanai, Naoyuki Itoh, Yoshimasa Ito, Noriaki Nagai, Yasutomo Hori, Seishirou Chikazawa, Fumio Hoshi, Seiichi Higuchi, JOURNAL OF VETERINARY MEDICAL SCIENCE, JOURNAL OF VETERINARY MEDICAL SCIENCE, 73(4), 517 - 520, Apr. 2011 , Refereed
    Summary:To investigate potency of oral disulfiram (DSF) compared with that of dexamethasone (Dexa), on endotoxin-induced uveitis (EIU) in rats. The oral administration with 750 mg/kg DSF suppressed the number of inflammatory cells, protein concentration, and levels of tumor necrosis factor (TNF)-alpha, Nitric oxide (NO) and prostaglandin (PG) E2 in the aqueous humor and improved the histiologic status of the ocular tissue at 24 hr after lipopolysaccharide (LPS) injection. The anti-inflammatory potency of DSF oral administration was as strong as that observed with 0.5 mg/kg Dexa in the present study. The results suggest that DSF might pave the way for a novel therapeutic agent for the management of uveitis.
  • Quality Assessment for Sustained Release Pharmaceutical Preparations by Dissolution Test Using Microdialysis-HPLC Method, Noriaki Nagai, Takatoshi Murao, Rino Inubuse, Nahoko Konishi, Yoshimasa Ito, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 131(4), 621 - 628, Apr. 2011 , Refereed
    Summary:Dissolution testing is a core performance test in pharmaceutical development and quality control. The conventional HPLC dissolution method (batch-sampling method) has many steps such as the filtration, collection and replenishment of sample solutions. We previously reported the dissolution test by using microdialysis methods (microdialysis-HPLC method) that can omit many steps. In this study, we investigated whether the microdialysis-HPLC method can be applied to quality assessment for sustained release preparations by a dissolution test. Calcium-channel blockers nifedipine tablets (20 mg) were used, and the test solution used was 0.2 M hydrogen phosphate-citric acid buffer (pH 6.8) with or without 1% sodium lauryl sulfate. In both test solutions, the microdialysis-HPLC method is able to accomplish continuous sampling of sample solutions, and the dissolution behaviors of original nifedipine tablets by the microdialysis-HPLC method were similar to that of the batch-sampling method. In contrast, the dissolution behaviors by the microdialysis-HPLC method were different between original nifedipine tablets and generic products, and the dissolution behaviors in the microdialysis-HPLC method tend to reflect the pharmaceutical design in comparison with the batch-sampling method. In addition, standard deviation in the microdialysis-HPLC method was lower than that of the batch-sampling method. We found that the recovery rate of nifedipine by the microdialysis-HPLC method was increased with the decrease in flow rate through dialysis probe. These findings provide significant information that can be used in pharmaceutical development and quality assessment for original and generic pharmaceutical products, which are sustained release preparations.
  • Inhibitory Effects of Oral Disulfiram on Endotoxin-Induced Uveitis in Rats, Kazutaka Kanai, Naoyuki Itoh, Kazuki Yoshioka, Tomohiro Yonezawa, Hiromi Ikadai, Yasutomo Hori, Yoshimasa Ito, Noriaki Nagai, Seishirou Chikazawa, Fumio Hoshi, Seiichi Higuchi, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 35(10), 892 - 899, Oct. 2010 , Refereed
    Summary:Purpose: Disulfiram (DSF) exhibits a wide variety of biological activities, including an anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the effect of oral DSF on endotoxin-induced uveitis (EIU) in rats. Methods: We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in the anterior chamber. Some eyes were enucleated for histologic examination and immunohistochemical analysis. EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour before the LPS injection, either 250, 500, or 750 mg/kg DSF was administered orally. Twenty-four hours later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF-alpha, NO, and PGE2 were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis in the iris ciliary body (ICB) cells was perfomed to determine the expression of activated nuclear factor kappa B (NF-kappa B), inducible-nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Results: The oral administration with DSF suppressed, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of TNF-alpha, NO, and PGE2 in the aqueous humor and improved the histiologic status of the ocular tissue. The expression of activated NF-kappa B-positive cells in the ICB was significantly inhibited by oral administrated with DSF 3 hr after the LPS injection. The LPS-induced increased expressions of iNOS and COX-2 proteins in the ICB were also inhibited by oral DSF 24 hr after LPS injection. Conclusions: The present results indicate that oral DSF suppresses the inflammation in EIU by inhibiting the NF-kappa B-dependent pathway and the subsequent production of pro-inflammatory mediators.
  • Reduction in Intraocular Pressure by the Instillation of Eye Drops Containing Disulfiram Included with 2-Hydroxypropyl-beta-cyclodextrin in Rabbit, Yoshimasa Ito, Noriaki Nagai, Yoshikazu Shimomura, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 33(9), 1574 - 1578, Sep. 2010 , Refereed
    Summary:We have studied the effect of disulfiram (DSF) solution containing 2-hydroxypropyl-beta-cyclodextrin and hydroxypropylmethylcellulose (DSF eye drops) on intraocular pressure (IOP) in experimentally induced ocular hypertension in rabbits. In both in vitro and in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The amount of DDC penetration for 0.25% DSF eye drops was about 4-fold that for 0.1% DSF eye drops in in vivo transcorneal penetration experiments. The elevation in IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein, and LOP was measured with an electronic tonometer. The induced elevation in IOP was reduced by the instillation of 0.1-0.5% DSF eye drops, and the IOP-reducing effect increased with the increase in DSF concentration in the drops. Nitric oxide (NO) levels increased in the aqueous humor following the infusion of the 5% glucose solution, and this increase was also suppressed by the instillation of DSF eye drops. In conclusion, the present study demonstrates that the instillation of DSF eye drops has an IOP-reducing effect in rabbits with experimentally induced ocular hypertension, probably caused by the suppression of NO production.
  • Preparation of Ophthalmic Formulations Containing Cilostazol as an Anti-glaucoma Agent and Improvement in Its Permeability through the Rabbit Cornea, Norio Okamoto, Yoshimasa Ito, Noriaki Nagai, Takatoshi Murao, Yusuke Takiguchi, Takuji Kurimoto, Osamu Mimura, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 59(8), 423 - 430, Aug. 2010 , Refereed
    Summary:To evaluate the pharmacological properties of cilostazol (CLZ), we examined its intraocular pressure (IOP)-lowering effect. CLZ is an inhibitor of Type 111 phosphodiesterase that increases intracellular cyclic AMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water solubility. We attempted to enhance CLZ solubility using 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The solubility of CLZ increased with increasing HP beta CD concentrations, and 0.05% CLZ was dissolved in 10% HP beta CD. Moreover, fine particle suspension of 0.5% CLZ in 5% HP beta CD (soluble CLZ: ca. 0.027%) were prepared using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration experiment through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solutions and suspensions. When a 0.05% CLZ ophthalmic solution was instilled into a rabbit eye, the absorption rate constant for CLZ into an aqueous humor was 0.0059 +/- 0.001 min(-1), and the elimination rate constant was 0.048 +/- 0.024 min(-1). Also CLZ ophthalmic solutions and fine particle suspension were examined to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solutions and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solutions and fine particle suspensions may represent an effective anti-glaucoma formulation.
  • Kinetic Analysis of the Rate of Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rats, a Model of Type 2 Diabetes Mellitus, Noriaki Nagai, Takatoshi Murao, Norio Okamoto, Yoshimasa Ito, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 59(8), 441 - 449, Aug. 2010 , Refereed
    Summary:Diabetic keratopathy is a well-known ocular complication secondary to type 2 diabetes mellitus. In this study, we performed a kinetic analysis of corneal wound healing in Long-Evans rats (normal rat) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Corneal wound healing in 7-week-old normal rats was mostly complete 24 h after corneal epithelial abrasion, and the process of corneal wound healing took place according to an equation with a first-order rate constant. The rate of corneal wound healing in normal rats decreased with aging. The process of corneal wound healing in 38- and 60-week-old normal and OLETF rats occurred in two phases with rate constants for the first and second phases represented as alpha and beta, respectively. The alpha and beta values in 38- and 60-week-old OLETF rats were lower than those in normal rats of the corresponding age. Furthermore, a close relationship was observed between the corneal wound healing rate constant and plasma glucose levels in OLETF rats. The present studies suggest the sequence of events that occur following damage to the corneal surface in OLETF rats as a model animal for a human type 2 diabetes mellitus.
  • Ossiculoplasty with a cartilage-connecting hydroxyapatite prosthesis for tympanosclerotic stapes fixation, Hirokazu Kawano, Keiji Matsuda, Haruka Nakanishi, Katsuhiro Toyama, Noriaki Nagai, Tetsuya Tono, EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY, EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY, 267(6), 875 - 879, Jun. 2010 , Refereed
    Summary:Many cases of tympanosclerotic stapes fixation are accompanied by fixation or erosion of malleus and/or incus. This status of the ossicular chain is one of the reasons that ossiculoplasty for tympanosclerotic stapes fixation is more difficult than that for otosclerosis. We conducted a retrospective review of seven patients who were operated on for tympanosclerotic stapes fixation between 2002 and 2006. All of the patients had abnormal conditions of the malleus and/or incus and underwent stapedectomy and total ossiculoplasty with hydroxyapatite prosthesis (Apaceram T-7 type), which has a planar-like head portion that contacts a piece of cartilage. Postoperative hearing results were assessed in all seven patients after at least 1 year. The postoperative air-bone gap (ABG) was closed within 10 dB in two of seven patients, and was less than 20 dB in six of seven patients. The mean postoperative ABG was closed within 10 dB at 1 and 2 kHz and less than 20 dB at low frequencies (0.25 and 0.5 Hz). There was almost no hearing improvement at high frequencies (4 and 8 kHz). There were no patients with postoperative sensorineural hearing loss. The present study shows that stapedectomy and total ossiculoplasty with cartilage-connecting hydroxyapatite prosthesis is effective and safe for stapes fixation accompanied by fixation or erosion of the malleus and/or incus.
  • Comparison of Corneal Wound Healing Rates after Instillation of Commercially Available Latanoprost and Travoprost in Rat Debrided Corneal Epithelium, Noriaki Nagai, Takatoshi Murao, Norio Okamoto, Yoshimasa Ito, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 59(3), 135 - 141, Mar. 2010 , Refereed
    Summary:We compared the corneal toxicity of two commercially available anti-glaucoma ophthalmic solutions, travoprost eye drops with sofzia consist of boric acid (H3BO3) and zinc chloride (ZnCl2) and latanoprost eye drops with benzalkonium chloride (BAC), using rat debrided corneal epithelium. Rat corneal epithelium was removed with a BD Micro-Sharp (TM), and the wounded corneas were dyed with a 1% fluorescein solution. The corneal wounds were monitored using a fundus camera TRC-50X equipped with a digital camera. Eye drops were instilled into the rat eyes five times a day after corneal epithelial abrasion. The corneal wound of a rat eye instilled with saline showed 50.9% and 83.4% healing 12 and 24 h after corneal epithelial abrasion, respectively. The healing rate of the corneal wound of a rat eye instilled with travoprost eye drops with sofzia was similar to that of the eye instilled with saline, and this rate was higher than in an eye instilled with latanoprost eye drops with BAC. The rates of corneal wound healing were also lower in eyes instilled with BAC and H3BO3 eye drops than in eyes instilled with saline. In contrast to the results with BAC and H3BO3, the instillation of ZnCl2 enhanced corneal wound healing in comparison with the instillation of saline The present study demonstrates that the classic preservative system using BAC may be more toxic to rat corneal epithelium than the new preservative system using H3BO3/ZnCl2. Travoprost eye drops with sofzia may provide effective therapy for glaucoma patients using long-term ophthalmic agents.
  • Improvement of Dissolution Test Using Microdialysis Method, Noriaki Nagai, Takatoshi Murao, Yoshimasa Ito, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 129(12), 1515 - 1521, Dec. 2009 , Refereed
    Summary:Dissolution testing is a core performance test in pharmaceutical development and quality control. Generally, the HPLC method uses the analysis of dissolution testing. In this study, we attempted to improve the dissolution test by using microdialysis methods. We also investigated the comparison of the conventional HPLC dissolution method (batch-sampling method) and the improved dissolution test (microdialysis method). Histamine H-2-receptor antagonist cimetidine tablets (200 mg), which are used clinically and of which there are also some generic examples, were selected for this comparison, and the dissolution behavior of the tablets by the two methods were found to be similar. On the other hand, standard deviation in the microdialysis method was lower than that of the batch-sampling method. In addition, the microdialysis method can omit many steps such as the filtration, collection and replenishment of sample solutions, and is also able to accomplish continuous sampling of sample solutions. These findings provide significant information that can be used in the pharmaceutical development and quality control of original and generic products.
  • Disulfiram Reduces Elevated Blood Glucose Levels in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats, a Model of Type 2 Diabetes, Noriaki Nagai, Takatoshi Murao, Norio Okamoto, Yoshimasa Ito, JOURNAL OF OLEO SCIENCE, JOURNAL OF OLEO SCIENCE, 58(9), 485 - 490, Sep. 2009 , Refereed
    Summary:The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established model of human type 2 diabetes mellitus. We investigated the effect of the oral administration of disulfiram (DSF), a powerful antioxidant, on some blood test values of diabetes mellitus in OLETF rats. DSF (100 or 200 mg/kg body weight/day) was administered orally to rats once a day (5:00 PM) beginning when the rats were 7 weeks of age, and the plasma levels of glucose (PG), triglycerides (TG), total cholesterol (Total-cho) and insulin were measured from 10 to 38 weeks of age. The PG, TG, Total-cho and insulin levels did not change with aging in Long-Evans Tokushima Otsuka (LETO) rats, the strain used as a normal control. In contrast to the results in LETO rats, PG, TG and Total-cho levels all increased in OLETF rats with aging. The plasma insulin level in OLETF rats was also significantly higher than in LETO rats from 20 to 38 week of age. The Total-cho level in OLETF rats did not differ significantly between the saline and DSF administered groups. On the other hand, the oral administration of DSF attenuated the age-related increase in PG and TG levels in OLETF rats. In addition, the insulin level in DSF-administered OLETF rats was higher in comparison with saline-administered rats. The present study demonstrates that the oral administration of DSF to OLETF rats potently prevents the increase in PG levels and the decrease in insulin levels suggesting that DSF may provide effective therapy for type 2 diabetes mellitus.
  • Enhancing Effects of Sericin on Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rats as a Model of Human Type 2 Diabetes, Noriaki Nagai, Takatoshi Murao, Yoshimasa Ito, Norio Okamoto, Masahiro Sasaki, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 32(9), 1594 - 1599, Sep. 2009 , Refereed
    Summary:The protein sericin is the main constituent of silk. We investigated the effects of sericin on corneal wound healing in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes. Corneal wounds were prepared by removal of the corneal epithelium, and documented using a TRC-50X equipped with a digital camera. Sericin solutions were instilled into the eyes of rats five times a day following corneal abrasion. Plasma glucose and triglycerides were determined using an Accutrend GCT. Cholesterol and insulin were measured using a Cholesterol E-Test Kit and ELISA Insulin Kit, respectively. The plasma levels of glucose, triglycerides, cholesterol and insulin in 38-week-old OLETF rats were significantly higher than in Long-Evans Tokushima Otsuka (LETO) rats used as normal controls, and the rate of corneal wound healing in OLETF rats was slower than in LETO rats. The corneal wounds of rats instilled with saline showed almost complete healing by 72 h after corneal epithelial abrasion. On the other hand, the corneal healing rate of OLETF rats instilled with 10% sericin solution was significantly higher than that of LETO rats instilled with saline, and the wounds showed almost complete healing at 48 h after abrasion. The corneal healing rate increased with increasing sericin concentration. The present study demonstrates that the corneal wound healing rate in OLETF rat is slower than in LETO rats, and the instillation of sericin solution has a potent effect in promoting wound healing and wound-size reduction in LETO and OLETF rats.
  • Enhancing Effects of Sericin on Corneal Wound Healing in Rat Debrided Corneal Epithelium, Noriaki Nagai, Takatoshi Murao, Yoshimasa Ito, Norio Okamoto, Masahiro Sasaki, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 32(5), 933 - 936, May 2009 , Refereed
    Summary:The protein sericin is the main constituent of silk. We demonstrate the effects of sericin on corneal wound healing in rat debrided corneal epithelium. We also determined the effects of sericin on cell adhesion and proliferation in a human cornea epithelial cell line (HCE-T). Epithelium was removed from the corneas of rats with a BD Micro-Sharp (TM), and wounded corneas were dyed with a 1% fluorescein solution. The corneal wounds were monitored using a fundus camera TRC-50X equipped with a digital camera. The corneal wound of rats instilled with saline was approximately 10% healing at 12 h, and approximately 65% healing at 24 h after corneal epithelial abrasion. The corneal wounds of rats instilled with saline showed almost complete healing by 36 h after corneal epithelial abrasion. On the other hand, the corneal healing rate of rats instilled with sericin solution was higher than that of rats instilled with saline, and the corneal healing rate constant increased with increasing sericin concentration. In addition, the adhesion and proliferation of HCE-T cells treated with 0.01-0.5% sericin solutions were enhanced, reaching a maximum at treatments with 0.2 and 0.1% sericin solutions, respectively. The present study demonstrates that the instillation of sericin solution has a potent effect in promoting wound healing and wound-size reduction in rats, probably caused by increasing cell movement and proliferation.
  • Involvement of interleukin 18 in indomethacin-induced lesions of the gastric mucosa in adjuvant-induced arthritis rat, Noriaki Nagai, Takashi Fukuhata, Yoshimasa Ito, Shigeyuki Usui, Kazuyuki Hirano, TOXICOLOGY, TOXICOLOGY, 255(3), 124 - 130, Jan. 2009 , Refereed
    Summary:It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAIDs-induced gastric lesions in comparison with other patients. The pathogenic mechanism of these lesions is not fully understood. We demonstrate whether interleukin 18 (IL-18) expression relate the aggravation of gastric lesion in adjuvant-induced arthritis (AA) rats following the oral administration of indomethacin. Arthritis was induced by injecting 50 mu l of a suspension of 10 mg/ml heat-killed butyricum (Mycobacterium butyricum) in Bayol F oil into the plantar region of the right hind foot and tail of Dark Agouti rats resulting in an arthritis incidence of 100%. Two weeks after injection, the rats were administered indomethacin (40 mg/kg) orally, and were killed under deep ether anesthesia 6 h later. The gastric mucosa was then examined. Oral administration of indomethacin caused hemorrhagic lesions in the gastric mucosa of AA rats, and the lesion score for AA rats following indomethacin treatment was significantly higher than for normal rats administered indomethacin. The expression of the IL-18 mRNA and mature IL-18 protein in the gastric mucosa of AA rats administered indomethacin were also higher in comparison with normal rats receiving indomethacin. In addition, interferon-gamma and nitric oxide levels in the gastric mucosa of AA rats were increased by the oral administration of indomethacin. It is possible that IL-18 expression in rats is more sensitive to indomethacin, and the IL-18 may play a role in the aggravation of gastric lesions in AA rats treated with indomethacin. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
  • Preventive Effect of Co-administration of Water Containing Magnesium Ion on Indomethacin Induced Lesions of Gastric Mucosa in Adjuvant-Induced Arthritis Rat, Noriaki Nagai, Takashi Fukuhata, Yoshimasa Ito, Shigeyuki Usui, Kazuyuki Hirano, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 32(1), 116 - 120, Jan. 2009 , Refereed
    Summary:It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) have significant side effects, such as gastroenteropathy, and that rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAIDs-induced gastric lesions as compared with patients with other diseases. We demonstrate the preventive effect of the co-administration of bittern water (BW, nigari-sui in Japanese), which enables the effective intake of Mg2+, on the ulcerogenic response to indomethacin in adjuvant-induced arthritis (AA) rats. Four kinds of BW with different Mg2+ contents; ranging from 10-200 mg/l Mg2+ (BW-10, 25, 50, 200) were used in this study. Arthritis was induced by the injection of 50 ill of a suspension of 10 mg/ml heat-killed butyricum (Myobacterium butyricum) in Bavol F oil into the plantar region of the right hind foot and tail of rats. Oral administration of indomethacin (40 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats at 14 d after adjuvant injection, and the lesion score of AA rats administered indomethacin was significantly higher than that of normal rats administered indomethacin. The expression of the mRNA for inducible nitric oxide synthase (iNOS) mRNA expression and the production of nitric oxide (NO) in the gastric mucosa of AA rats were also increased by the administration of indomethacin. The co-administration of BWs decreased the ulcerogenic response to indomethacin in AA rats. In addition, the administration of BW attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving indomethacin. The oral administration of Mg2+ to AA rats had a potent preventive effect on the ulcerogenic response to indomethacin in AA rats, probably due to an inhibition in the rise in iNOS and NO levels in the gastric mucosa.
  • Comparison of the Mechanisms of Cataract Development Involving Differences in Ca2+ Regulation in Lenses among Three Hereditary Cataract Model Rats, Noriaki Nagai, Yoshimasa Ito, Noriko Takeuchi, Shigeyuki Usui, Kazuyuki Hirano, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31(11), 1990 - 1995, Nov. 2008 , Refereed
    Summary:We previously found that the increases in Ca2+ content in the lenses of three hereditary cataract model rats, UPL rat (UPLR), Shumiya cataract rat (SCR) and Ihara cataract rat (ICR), are inhibited by aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, and that the mechanisms of Ca2+ enhancement in these rat models differ. In this study, we compare the mechanisms for dysfunction in Ca2+ regulation in UPLR, SCR and ICR. Decreases in the activity of Ca2+-ATPase were found in the lenses of SCR and ICR concurrent with cataract development. In contrast, the Ca2+-ATPase activity in UPLR with opaque lenses was higher than in those with transparent lenses. On the other hand, ATP levels were markedly decreased in UPLR with opaque lenses. The expression of cytochrome c oxidase (CCO)-1 mRNA and CCO activity in UPLR lenses was found to decrease during cataract development. The nitric oxide (NO) and lipid peroxide levels were also increased in the lenses of UPLR, SCR and ICR with opaque lenses. In UPLR, excessive NO may cause damage to the mitochondrial genome, resulting in a decrease in ATP production and increase in Ca2+-ATPase activity. The decrease in ATP content may cause the decrease in Ca2+-ATPase function resulting in the elevation in lens Ca2+. In SCR and ICR, excessive NO may cause an enhancement of lipid peroxidation resulting in the oxidative inhibition of Ca2+-ATPase. The decrease in Ca2+-ATPase activity may cause the elevation in the level of lens Ca2+, thus leading to lens opacification. Our findings show that the Ca2+ contents in the cataractous lenses of all three model rats are increased, the mechanisms for this Ca2+ enhancement is different in each rat model.
  • Contribution of aldehyde dehydrogenase 3A1 to disulfiram penetration through monolayers consisting of cultured human corneal epithelial cells, Noriaki Nagai, Mitsushi Inomata, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31(7), 1444 - 1448, Jul. 2008 , Refereed
    Summary:We previously prepared 2-hydroxypropyl-p-cyclodextrin (HPPCD) solutions containing disulfiram (DSF) and hydroxypropylmethylcellulose (HPMC, DSF solutions), and found the instillation of this DSF solutions delayed lens opacification in ICR/f rats, a recessive-type hereditary cataractous strain. In this study, we determined the corneal penetration mechanism of DSF solutions using human cornea epithelial cell monolayers based on the immortalized human cornea epithelial cell line (HCE-T) developed by Tropainen et al. [Invest. Ophthalmol. Vis. Sci., 42, 2942-2948 (2001)]. The transepithelial electrical resistance (TER) values of HCE-T cells increases from approximately 275 to 388 S2. cmz by exposure to an air-liquid interface for 2 weeks. The penetration of DSF into the basolateral chamber was prevented by the increase in TER values. The DSF in solution was converted to diethyldithiocarbamate (DDC) during the penetration experiment using HCE-T cell monolayers, and a close relationship between the penetration coefficient of DDC and aldehyde dehydrogenase (ALDH) 3A1 mRNA expression (y=41.202x+18.587, R=0.9413) was observed. In addition, an anti-ALDH3A1 antibody significantly inhibited the DSF-DDC conversion. These results suggest that DSF in DSF solutions is converted to DDC via catalysis by an ALDH3A1 in the cornea, and then transited from the apical side to the basolateral side.
  • Inhibitive effects of enhanced lipid peroxidation on Ca2+-ATPase in lenses of hereditary cataract ICR/f rats, Noriaki Nagai, Yoshimasa Ito, Noriko Takeuchi, TOXICOLOGY, TOXICOLOGY, 247(2-3), 139 - 144, May 2008 , Refereed
    Summary:Our previous studies have demonstrated that the instillation of eye drops containing disulfiram, a radical scavenger and nitric oxide synthase inhibitor, delays cataract development in ICR/f rats, and we have suggested that the production of nitric oxide (NO) and lipid peroxide (LPO) in the lens may relate to the delay in cataract development brought about by disulfiram. However, the involvement of NO and LPO in lenses of ICR/f rats during cataract development has not yet been established. In the present study, we determined changes in NO and LPO levels in lenses of ICR/f rats during cataract development. Opacification of ICR/f rat lenses started at 77 days of age, and the lenses of 91-day-old ICR/f rats were almost entirely opaque. The Ca2+-ATPase activity in the lenses of ICR/f rats decreased with increasing age, and an elevation in Ca2+ content was observed in ICR/f rat lenses with the decrease in Ca2+-ATPase activity. NO levels in the lenses of ICR/f rats increased from 63 to 85 days of age, reaching a maximum at 77 days of age. In addition, LPO levels in the lenses of ICR/f rats also increased with increasing age. LPO levels in the lenses of 63- to 91-day-old ICR/f rats were found to be significantly higher compared with those in 22-day-old ICR/f rats. These changes of Ca2+, Ca2+-ATPase, NO and LPO were attenuated by instillation of DSF eye drops. These results suggest that excessive NO may cause enhanced lipid peroxidation resulting in the inhibition of Ca2+-ATPase. The decrease in Ca2+-ATPase activity may cause the elevation in lens Ca2+, leading to lens opacification in ICR/f rats. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
  • Effect of disulfiram eye drops on lipid peroxide formation via excessive nitric oxide in lenses of hereditary cataract ICR/f rats, Noriaki Nagai, Yoshimasa Ito, Noriko Takeuchi, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31(5), 981 - 985, May 2008 , Refereed
    Summary:The ICR/f rat is a recessive-type hereditary cataractous strain, and opacity in the lens usually becomes evident at around 75 d of age. We previously found that the instillation of eye drops containing a disulfiram and by droxypropyl-beta-eyelodextrin inclusion complex (DSF eye drops) delays lens opacification in ICR/f rats. In this study, we attempted to clarify the mechanisms of the delaying effect of DSF eye drops on cataract development in ICR/f rats. The calcium ion (Ca2+) content in the lenses of ICR/f rats increases at 77 d of age, and this elevation is preceded by a decrease in Ca2+-ATPase activity. On the other hand, the levels of nitric oxide (NO) and lipid peroxide (LPO) also increase in the lenses of ICR/f rats at 63 d of age, while the lenses are still transparent. The instillation of DSF eye drops reduces the changes in Ca2+ content, Ca2+-ATPase activity, NO and LPO levels in the lenses of ICR/f rats. The present study demonstrates that excessive NO production induces the increase in LPO, which causes the decrease in Ca2+-ATPase activity, and the increase in Ca2+ content in the lenses of ICR/f rat during cataract development. DSF eye drops have the ability to attenuate the increase in the NO and LPO levels, resulting in a delay in cataract development.
  • Value of Non Echo-Planar Diffusion-Weighted Magnetic Resonance Imaging in the Detection of Middle Ear Cholesteatoma, Noriaki Nagai, Tetsuya Tono, Keiji Matsuda, Katsuhiro Toyama, Hirokazu Kawano, Takao Kodama, MEDITERRANEAN JOURNAL OF OTOLOGY, MEDITERRANEAN JOURNAL OF OTOLOGY, 4(3), 197 - 202, 2008 , Refereed
    Summary:OBJECTIVE: This study was conducted to determine the clinical value of diffusion-weighted magnetic resonance imaging (MRI) (DWI) in detecting the presence of cholesteatoma. MATERIALS AND METHODS: Fifty-six patients (21 female and 35 male; mean age, 43 years old) who underwent middle ear surgery were referred to the Radiology Department for preoperative DWI study. MRI (1.5-T) was performed using fast advanced spin echo (FASE) DWI, T2-weighted spin echo imaging (T2WI), and T1-weighted spin echo imaging (T1WI). RESULTS: DWI identified 41 of 48 cholesteatomas involving the middle ear cavity (sensitivity, 85.4%). Seven patients with middle ear cholesteatoma who showed negative DWI findings (false-negative cases) had limited keratin accumulation due to simple atelectasis or meticulous evacuation of keratin debris before the MRI study. No false-positive cases were found in this study (specificity, 100%). The positive and negative predictive values were 100% and 53.3%, respectively. The minimum size of middle ear cholesteatoma detected by the current MRI system was 5mm. CONCLUSION: DWI was useful for the detection of middle ear cholesteatoma.
  • Adverse effects of excessive nitric oxide on cytochrome c oxidase in lenses of hereditary cataract UPL rats, Noriaki Nagai, Yoshimasa Ito, Toxicology, Toxicology, 242(1-3), 7 - 15, Dec. 05 2007 , Refereed
    Summary:The UPL rat is a newly developed hereditary cataract model. We previously found that the ATP content in UPL rat lenses decreases during cataract development, and the decrease in ATP content causes Ca2+-ATPase dysfunction resulting in an elevation in Ca2+ and cataract development. In addition, we reported that the oral administration of disulfiram and aminoguanidine ameliorates the decrease in ATP content and the elevation in Ca2+ content in UPL rat lenses. In this study, we demonstrate the effect of nitric oxide (NO) on the expression and activity of cytochrome c oxidase (CCO) in normal and UPL rat lenses during cataract development. We also determined the effects of the oral administration of disulfiram and aminoguanidine on the mRNA expression and activity of CCO and NO production in UPL rat lenses. The expression of CCO-1 mRNA in UPL rat lenses, determined by a quantitative real-time RT-PCR method, decreased during cataract development. CCO activity in UPL rat lenses also decreased with aging. On the other hand, the oral administration of disulfiram and aminoguanidine attenuated the decrease in CCO-1 mRNA expression and CCO activity. These results suggest that excessive NO causes the decrease in CCO-1 mRNA expression and CCO activity, and that the decrease in CCO may cause the decrease in ATP production in UPL rat lenses. Disulfiram and aminoguanidine may attenuate the decrease in ATP production, resulting in a delay in cataract development. © 2007 Elsevier Ireland Ltd. All rights reserved.
  • Involvement of interleukin 18 in cataract development in hereditary cataract UPL rats, Noriaki Nagai, Yoshimasa Ito, Haruki Okamura, JOURNAL OF BIOCHEMISTRY, JOURNAL OF BIOCHEMISTRY, 142(5), 597 - 603, Nov. 2007 , Refereed
    Summary:Our previous studies have demonstrated that lens epithelial damage by excessive nitric oxide causes an elevation in lens opacification in UPL rats, and it has been reported that interferon-gamma production in lens epithelial cells is involved in cataract development. In this study, we investigated the involvement of interleukin (IL)-18, which leads to interferon-gamma, in UPL rat lenses. The opacification of UPL rat lenses starts at 39 days of age. The gene expression levels causing IL-18 activation (IL-18, IL-18 receptor and caspase-1) are increased at 32 days of age, and the expression of mature IL-18 protein in the UPL rat lenses also increases with ageing. On the other hand, the interferon-gamma levels in UPL rat lenses are increased, and the increase in interferon-gamma levels in UPL rat lenses reaches a maximum at 39 days of age. Mature IL-18 expression and interferon-gamma production are achieved prior to the onset of lens opacification. In conclusion, the expression levels of IL-18 in the lenses of UPL rats are increased with aging. In addition, interferon-gamma levels in the lenses of UPL rats are also increased. It is possible that interferon-gamma generated by the activated IL-18 may induce cataract development in UPL rats.
  • Value of diffusion-weighted MR imaging in the detection of middle ear cholesteatoma, Noriaki Nagai, Tetsuya Tono, Keiji Matsuda, Katsuhiro Toyama, Hirokazu Kawano, Takao Kodama, Journal of Otolaryngology of Japan, Journal of Otolaryngology of Japan, 110(11), 707 - 712, Nov. 2007 , Refereed
    Summary:[Objective] This study was conducted to determine the clinical value of diffusion-weighted MR imaging (DWI) in detecting the presence of cholesteatoma. [Subject and methods] Fifty-six patients (21 female and 35 male patients mean age, 43 years) who underwent middle ear surgery were referred to the radiology department for a preoperative DWI study. [Results] DWI depicted 41 out of 48 cholesteatomas involving the middle ear cavity (sensitivity, 85.4%). Seven patients with middle ear cholesteatoma who showed negative DWI findings (false-negative cases) had limited keratin accumulation due to simple atelectasis or meticulous evacuation of keratin debris before the MRI study. No false-positive cases were found in this study (specificity, 100%). The positive predictive value and negative predictive value were 100% and 53.3%, respectively. The minimum size of middle ear cholesteatoma detected by the current MRI system was 5mm. [Conclusion] Diffusion-weighted MR imaging was useful for the detection of middle ear cholesteatoma.
  • Preventive effect of water containing magnesium ion on paw edema in adjuvant-induced arthritis rat, Noriaki Nagai, Takashi Fukuhata, Yoshimasa Ito, Hideyuki Tai, Yoshihiro Hataguchi, Koji Nakagawa, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 30(10), 1934 - 1937, Oct. 2007 , Refereed
    Summary:We demonstrate the preventive effect of bittern water (BW), which enables the effective intake of magnesium ion (Mg2+), on paw edema in adjuvant-induced arthritis (AA) rat. BW (five kinds; BW-1, 2, 3, 4, 5) containing 10-200 mg/l Mg2+ was used in this study. Arthritis was induced by the injection of 50 mu l of a suspension of 10 mg/ml heat-killed butyricum (Mycobacterium butyricum) in Bayol F oil into the plantar region of the right hind foot and tail of rats. Paw edema of the right and left hind feet of AA rats were reduced by the administration of BW for 14d after adjuvant injection in comparison with those of AA rats administered purified water. The preventive effect increased with the increasing Mg2+ content of the BW. In addition, a combination of indomethacin (IM, 2 mg/kg) and BW-5 (200 mg/l Mg2+) prevented paw edema of the right and left hind feet of AA rats in comparison with IM alone. The fate of plasma IM after the oral administration of the combined IM (2 mg/kg/d) and BW-5 was similar to that after the administration of IM alone. In conclusion, the oral administration of Mg2+ to AA rats potently prevents the development of inflammation, and the combination of IM and Mg2+ may provide an effective therapy of arthritic edema.
  • Delay in ICR/f rat lens opacification by the instillation of eye drops containing disulfiram and hydroxypropyl-beta-cyclodextrin inclusion complex, Noriaki Nagai, Maki Takeda, Yoshimasa Ito, Noriko Takeuchi, Akira Kamei, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 30(8), 1529 - 1534, Aug. 2007 , Refereed
    Summary:In this study, we attempted to enhance disultiram (DSF) solubility using a 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and hydroxypropylmethylcellulose (HPMC). We also investigated the effect of an HP beta CD solution containing DSF and HPMC (DSF eye drops) on cataract development in ICR/f rat. The solubility of DSF increased with increasing HP beta CD concentration, and the solubility of DSF in HP beta CD solution containing 0.1% HPMC was approximately 20% greater than that of DSF in HP beta CD solution without HPMC. In in vivo transcorneal penetration experiments using rabbits, only diethyldithiocarbamate (DDC) was detected (DSF was not detected) in the aqueous humor. This DSF-DDC conversion in the cornea was inhibited by treatment with a sulfhydryl (SH) inhibitor, p-mercuribenzoate and N-ethylmateimide, in in vitro transcorneal penetration experiments using rabbit corneas. On the other hand, the instillation of 0.25% and 0.5% DSF eye drops delayed cataract development in ICR/f rats, a recessive-type hereditary cataractous strain. The present study demonstrates that DSF in HP beta CD solution with HPMC is converted to DDC by the catalysis of proteins containing SH residues in the cornea, and this DDC may cause the delay in cataract development in ICR/f rats.
  • Effect of magnesium deficiency on intracellular ATP levels in human lens epithelial cells, Noriaki Nagai, Takashi Fukuhata, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 30(1), 6 - 10, Jan. 2007 , Refereed
    Summary:Cataractous lenses have an altered distribution of the intracellular ionic environment, and the lens ionic imbalance with increased levels of calcium (Ca2+) and sodium (Na+), coupled with decreased levels of magnesium (Mg2+) and potassium (K+), is related to cataract development in human senile cataracts. We previously found that the decrease of ATP in lenses caused lens ionic imbalance, and probably decrease in ATPase function. In this study, we investigated the effect of Mg2+ deficiency on cataract progression using human lens epithelial (HLE) cells. Expression levels of inducible nitric oxide synthase (iNOS) mRNA in HLE cells were significantly greater in Mg2+-deficient medium (Mg2+ 0.021 mm) than in normal Mg2+ medium (Mg2+ 0.77 mm). The NO release from the HLE cells cultured with Mg2+-deficient medium also increased. On the other hand, the ATP levels in HLE cells 24 h after incubation with Mg2+-deficient medium were lower than that with normal Mg2+ medium. The Ca2+- and Na+/K+-ATPase activities in HLE cells until 24 h incubation with normal Mg2+ or Mg2+-deficient medium did not change. Both diethyldithiocarba mate 10 mu m and aminoguanidine 250 mu m attenuated the increase of NO release, and caused an increase in ATP levels in HLE cells 24 h after incubation with Mg2+-deficient medium. These results suggest that Mg2+ deficiency enhances NO production via iNOS in the lens. It is possible that the excessive production of NO cause the decrease of ATP levels. These results show that Mg2+ deficiency in the lens may cause an acceleration of the progression of lens opacification.
  • Delay of cataract development in the Shumiya cataract rat by water containing enhanced concentrations of magnesium and calcium, Noriaki Nagai, Yoshimasa Ito, CURRENT EYE RESEARCH, CURRENT EYE RESEARCH, 32(5), 439 - 445, 2007 , Refereed
    Summary:We demonstrate a delaying effect of deep-sea drinking water (DDW) containing enhanced magnesium ion (Mg2+) and calcium ion (Ca2+) concentrations on cataract development in Shumiya cataract rats (SCRs). The lenses of SCRs administered DDW-200 (Mg2+, 200 mg/L, Ca2+; 71 mg/L) were less opaque than those in SCRs administered purified water (PW). In SCRs administered DDW-200, a decrease in Mg2+ content and an increase in Ca2+ content in the lenses was prevented in comparison with SCRs administered PW. Nitric oxide (NO) levels in the lenses of SCRs administered DDW-200 were lower than those in SCRs administered PW. In conclusion, the administration of DDW-200 to SCRs has a potent delaying effect on cataract development, possibly due to preventing an increase in NO levels in the lens.
  • Effects of Magnesium Content in the Feed on Cataract Development in Shumiya Cataract Rat, Noriaki Nagai, Yoshimasa Ito, Hideyuki Tai, Yoshihiro Hataguchi, Koji Nakagawa, Journal of Oleo Science, Journal of Oleo Science, 56(1), 29 - 33, 2007 , Refereed
    Summary:Cataract is a phenomenon in which the eye becomes opaque resulting in severe visual impairment, and senile cataract is the most common cause of blindness in the world. We investigated the effect of magnesium (Mg) supplementation on cataract development using shumiya cataract rat (SCR). The SCR were fed on either a low Mg (Mg 50 mg/kg), standard Mg (Mg 500 mg/kg), or high Mg (Mg 5000 mg/kg) diet from aged 5 to 15 weeks. The growth curve of SCRs fed on a low Mg diet was the same as that of SCRs fed on a standard diet. The growth curve of SCRs fed on a high Mg diet was significantly suppressed in comparison with those fed on a standard diet. The opacification of lenses from SCR fed on a standard Mg diet started at 11 weeks of age. The opacification of lenses from SCR fed on a high Mg diet was similar to that from SCR fed on a standard Mg diet. On the other hand, the low Mg diet accelerated the onset of cataract development, and the opacity started at 10 weeks of age. In addition, the calcium ion (Ca2) content in SCR lenses fed on a low Mg diet significantly increased in comparison with that in lenses from SCR fed on a standard Mg diet. These results suggest that Mg deficiency causes acceleration of cataract development in SCR, probably due to a rise in the Ca2 content in the lens. © 2007, Japan Oil Chemists' Society. All rights reserved.
  • Involvement of DNase II-like acid DNase in the cataract formation of the UPL rat and the Shumiya cataract rat, Noriaki Nagai, Noriko Takeuchi, Akira Kamei, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 29(12), 2367 - 2371, Dec. 2006 , Refereed
    Summary:The loss of organelles and DNA is important to ensure transparency of the lenses, and DNase II-like acid DNase (also called DNase lip, DLAD) is related to the loss of organelles and DNA in the lenses. We investigated the relation between the degradation of DNA and DLAD mRNA expression in the lenses of two hereditary cataract rats, the UPL rat (UPLR) and the Shumiya cataract rat (SCR), during cataract development. Undigested DNA was detected in the lens cortexes of normal UPLRs and SCRs, and undigested DNA was degraded in the lens nuclei of normal UPLRs and SCRs. DLAD does not affect common cataract formation, since DLAD mRNA expression levels in the lenses of cataractous SCRs were not changed with an increase in age, and undigested DNA was degraded in the lens nuclei of cataractous SCRs. On the other hand, an accumulation of undigested DNA was found in the lens nuclei of cataractous UPLRs at 46 and 53 d of age with opaque lenses, and the decrease in DLAD mRNA expression levels occurred prior to the accumulation of undigested DNA in the lens nuclei. It is possible that UPLRs are a good model for cataract caused by a decrease of DNA degradation in the lenses.
  • Inhibitors of inducible nitric oxide synthase prevent damage to human lens epithelial cells induced by interferon-gamma and lipopolysaccharide, Noriaki Nagai, Ying Liu, Takashi Fukuhata, Yoshimasa Ito, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 29(10), 2077 - 2081, Oct. 2006 , Refereed
    Summary:We previously found that Ca2+ concentrations, inducible nitric oxide synthase (iNOS) mRNA, and protein expression in lenses of the Shumiya cataract rat (SCR) increase with the development of cataracts. In this study, we investigated the change in Ca2+-ATPase activities and ATP levels in the human lens epithelial cell line SRA 01/04 (HLE cells) with the stimulation of interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Expression levels of iNOS mRNA in HLE cells, which were determined using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time RT-PCR methods, increased during stimulation with IFN-gamma (1000 IU) and LPS (100 ng/ml). NO release from HLE cells, expressed as the sum of NO2- and NO3- levels, increased with the increase in iNOS expression levels. Ca2+-ATPase activities increased and ATP levels decreased in HLE cells stimulated with the combination of IFN-gamma and LPS. Furthermore, both diethyldithiocarbamate and aminoguanidine attenuated the increase in Ca2+-ATPase activities and the decrease in ATP levels. These results suggest that excessive production of NO may cause mitochondrial damage, resulting in an increased Ca2+ concentration in the lens. The increase in Ca2+ concentration in the lens may increase Ca2+-ATPase activities.
  • Delay of cataract development in the Shumiya cataract rat by the administration of drinking water containing high concentration of magnesium ion, Noriaki Nagai, Yoshimasa Ito, Mitsushi Inomata, Seigo Shumiya, Hideyuki Tai, Yoshihiro Hataguchi, Koji Nakagawa, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 29(6), 1234 - 1238, Jun. 2006 , Refereed
    Summary:We discovered that the cataract development in the Shumiya cataract rat (SCR) can be prevented by the administration of deep-sea drinking water (DDW). A standard diet based on the American Institute of Nutrition guidelines (AIN-76) and DDW containing a high mineral concentration such as low, medium and high Mg2+ Content (50, 200 and 1000 mg of Mg2+/l, respectively) were used in this study. SCRs were freely fed with combinations of the standard diet and purified water or DDW during 5-15 weeks of age. The opacities of SCR lenses were documented by anterior eye segment analysis system EAS-1000. The onset of opacification of cataractous SCR lenses administered a combination of standard diet and purified water started at 11 weeks of age, and mature cataracts had formed at 13 weeks of age. However, the supplementation of Mg2+ by administration with medium DDW showed the greatest effect of delay of cataract onset in SCR. In addition, even cataractous SCR lenses at 14 weeks of age showed differences in opacity level. The opacification and Ca2+ of the lenses in cataractons SCR administered medium DDW were lower than those administered purified water. In conclusion, the present study demonstrates that administration of DDW potently delays cataract development in SCR, and this may be caused by inhibiting the increase in Ca2+ levels in the lens.
  • Preventive Effect of Eye Drops of Liposomes Containing Disulfiram and Cefmetazole on Selenite-Induced Cataract in Rat Pups, Yoshimasa Ito, Noriaki Nagai, Hong Cai, Maki Takeda, Yuichi Koizumi, Journal of Oleo Science, Journal of Oleo Science, 55(1), 15 - 22, 2006 , Refereed
    Summary:Disulfiram (DSF) and cefmetazole (CMZ), which possess with anti-oxidative activities were tested for anti-cataract effect in rats and were compared with pirenoxine (PRX), which is a marketed product used for the treatment of cataract. These compounds were encapsulated in liposomes and the results were compared with the anti-cataract effect of suspension and solution formulations containing same contents of each other agents. Instillations of DSF- and CMZ-liposomes prevented the development of cataract in selenite-injected rat pups. On the other hand, no anti-cataract effects were observed in selenite-induced cataract rats instilled with DSF suspensions and CMZ solutions. The reduced form of glutathione (GSH) content of the lenses was decreased by approximately 60% of normal level 96 h after the sodium selenite-injection and the calcium (Ca2+) content was increased. The decreased GSH and increased Ca2+ levels were prevented by instillation of DSF- and CMZ-liposomes. Instillation of PRX-liposomes and 0.03% PRX solution had no effect on the development of cataract. The results of this study confirmed that anti-oxidative agents such as DSF and CMZ were useful to prevent cataract development related to oxidative stress. © 2006, Japan Oil Chemists' Society. All rights reserved.

Conference Activities & Talks

  • 新規院内製剤セレン含有口腔内崩壊錠の作製と実用化についての検討, 中尾 元紀, 松尾 世為子, 大橋 香菜子, 田邨 保之, 永井 聡子, 覺野 律, 中村 明美, 福永 聖子, 川端 成佐, 寺倉 智子, 松野 純男, 緒方 文彦, 川崎 直人, 大竹 裕子, 長井 紀章, 国立病院総合医学会講演抄録集,   2018 11
  • カプセル組成の変更に伴う吸入粉末剤の薬物放出性制御に関する研究, 大竹 裕子, 石井 美有, 福岡 侑也, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • 重合度の異なるセルロース誘導体が自転・公転ナノ粉砕機の薬物破砕効率へ与える影響, 長井 紀章, 中村 翼, 山崎 由夏, 大竹 裕子, 高塚 隆之, 日本薬剤学会年会講演要旨集,   2018 05
  • ラロキシフェンを用いたナノ経皮吸収製剤の開発と骨粗鬆症治療への有用性評価, 出口 粧央里, 梁 宇紀, 大竹 裕子, 緒方 文彦, 川崎 直人, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • レバミピドナノ口腔内崩壊錠の製造とレバミピドの薬剤性消化管障害治療への応用, 福岡 侑也, 上田 純也, 大竹 裕子, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • ドライアイ治療への応用を目指した新規経眼瞼レバミピドナノ製剤の開発, 石井 美有, 上野 祥奈, 大竹 裕子, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • カプセル組成の変更に伴う吸入粉末剤の薬物放出性制御に関する研究, 大竹 裕子, 石井 美有, 福岡 侑也, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • 重合度の異なるセルロース誘導体が自転・公転ナノ粉砕機の薬物破砕効率へ与える影響, 長井 紀章, 中村 翼, 山崎 由夏, 大竹 裕子, 高塚 隆之, 日本薬剤学会年会講演要旨集,   2018 05
  • ラロキシフェンを用いたナノ経皮吸収製剤の開発と骨粗鬆症治療への有用性評価, 出口 粧央里, 梁 宇紀, 大竹 裕子, 緒方 文彦, 川崎 直人, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • ドライアイ治療への応用を目指した新規経眼瞼レバミピドナノ製剤の開発, 石井 美有, 上野 祥奈, 大竹 裕子, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • レバミピドナノ口腔内崩壊錠の製造とレバミピドの薬剤性消化管障害治療への応用, 福岡 侑也, 上田 純也, 大竹 裕子, 長井 紀章, 日本薬剤学会年会講演要旨集,   2018 05
  • ショットガンプロテオミクス解析を用いた糖尿病白内障要因の解析, 大竹 裕子, 山本 哲志, 三田村 邦子, 多賀 淳, 長井 紀章, 日本薬学会年会要旨集,   2018 03
  • ヘスペレチンおよびその誘導体の白内障予防効果の検討, 中澤 洋介, Martin Pauze, 長井 紀章, 多胡 めぐみ, 須貝 威, 田村 悦臣, 日本薬学会年会要旨集,   2018 03
  • 毛根を標的とした新規薬物送達技術の開発 ナノ結晶技術はミノキシジルの発毛効果を高める, 長井 紀章, 岩井 淑恵, 川瀬 七愛, 坂本 茜, 大竹 裕子, 緒方 文彦, 川崎 直人, 日本薬学会年会要旨集,   2018 03
  • 網膜電図および免疫組織染色によるストレプトゾトシン誘発糖尿病ラットの網膜機能障害の評価, 長井 紀章, 平松 範子, 出口 粧央里, 大竹 裕子, 山本 直樹, 日本眼薬理学会プログラム・抄録集,   2017 09
  • 犬の前房穿刺誘発性ぶどう膜炎に対する副腎皮質ステロイド点眼液の穿刺後投与による抑制効果の検証, 佐藤 和昭, 金井 一享, 岩崎 喜和子, 尾崎 末以子, 加川 貴章, 長井 紀章, 山下 洋平, 近澤 征史朗, 星 史雄, 日本獣医学会学術集会講演要旨集,   2017 08
  • 犬の前房穿刺誘発性ぶどう膜炎モデルにおけるステロイド性抗炎症点眼液の穿刺後早期の炎症抑制効果について, 岩崎 喜和子, 金井 一享, 佐藤 和昭, 尾崎 末以子, 加川 貴章, 長井 紀章, 山下 洋平, 近澤 征史朗, 星 史雄, 比較眼科学会年次大会講演要旨集,   2017 07
  • 薬物粒子径変更に伴うレバミピド懸濁性点眼液の製剤機能の向上, 長井 紀章, 川崎 真緒, 上野 祥奈, 大竹 裕子, 岡本 紀夫, 下村 嘉一, 日本薬剤学会年会講演要旨集,   2017 05
  • ナノ結晶製造技術を核とした骨粗鬆症治療薬"ラロキシフェン経皮吸収製剤"の開発, 伊藤 吉將, 中塚 淳生, 中屋 仁美, 長井 紀章, 日本薬学会年会要旨集,   2017 03
  • ナノ化技術が可能としたドラック・リポジショニング ニルバジピンナノ結晶点眼製剤による糖尿病網膜症治療, 上野 祥奈, 出口 粧央里, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集,   2017 03
  • 次世代型経皮治療システムの開発 ケトプロフェンナノ結晶含有軟膏による関節リウマチ治療, 石井 美有, 岩前 亜弥, 長井 紀章, 伊藤 吉將, 日本薬学会年会要旨集,   2017 03
  • 傷を綺麗に治すための新技法 トラニラスト・セリシン配合製剤による難治性創傷治癒, 福岡 侑也, 出口 粧央里, 長井 紀章, 伊藤 吉將, 日本薬学会年会要旨集,   2017 03
  • 納豆による高血圧予防効果の解明 納豆菌酵素発酵代謝物は本態性高血圧の発症を抑制する, 長井 紀章, 真野 裕, 船上 仁範, 緒方 文彦, 伊藤 吉將, 後藤 和子, 川崎 直人, 日本薬学会年会要旨集,   2017 03
  • 糖尿病罹患は水晶体中アミロイドβ蓄積を高める, 長井 紀章, 真野 裕, 小谷 幸代, 上野 祥奈, 伊藤 吉將, 柴田 哲平, 久保 江理, 佐々木 洋, 日本眼薬理学会プログラム・抄録集,   2016 09
  • 水溶性薬物の角膜透過性向上を可能とする新技術"ミネラルナノキャリア"の開発, 長井 紀章, 山岡 咲絵, 真野 裕, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集,   2016 03
  • ナノ化技術を用いた新たなメロキシカム経口製剤の開発とその有用性評価, 真野 裕, 山岡 大起, 上田 利香, 長井 紀章, 伊藤 吉將, 日本薬学会年会要旨集,   2016 03
  • ナノ結晶を用いた新規経皮投与システムの確立とその薬物吸収動態の解析, 伊藤 吉將, 長井 紀章, 中屋 仁美, 谷本 紫苑, 日本薬学会年会要旨集,   2016 03
  • 点眼による網膜治療を目指した新規ナノ結晶点眼製剤の開発 シロスタゾールを用いた糖尿病網膜症治療, 田辺 航, 古瀬 のぞみ, 出口 粧央里, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集,   2016 03
  • シロスタゾール結晶多形間におけるナノ化製剤の安定性の比較, 吉岡 千晶, 長井 紀章, 伊藤 吉将, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集,   2016 03
  • カルシウム欠乏卵巣摘出ラットを用いた永久硬水および一時硬水の骨形成効果に関する基礎研究, 緒方 文彦, 長井 紀章, 伊藤 吉將, 川崎 直人, 日本薬学会年会要旨集,   2016 03
  • トラニラストナノ結晶を用いた新規経眼瞼適用剤の開発とその涙液移行性評価, 上野 祥奈, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集,   2016 03
  • ケトプロフェン・ナノ結晶を用いた新規経皮適用製剤の設計とその有用性評価, 岩前 亜弥, 長井 紀章, 伊藤 吉將, 松井 誠, 守本 英二, 日本薬学会年会要旨集,   2016 03
  • 点眼用添加物EDTAが種々保存剤の抗菌効果及び角膜傷害性へ与える影響, 田辺 航, 長井 紀章, 辻 朗子, 勝井 結美, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集,   2015 09
  • 表面麻酔剤オキシブプロカイン塩酸塩点眼液の角膜傷害性評価, 真野 裕, 長井 紀章, 辰巳 賀陽子, 川崎 真緒, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集,   2015 09
  • トラニラストナノ粒子分散液によるリポポリサッカライド刺激RAW264.7細胞に対する抗炎症効果および作用機序の解明, 佐藤 和昭, 荒井 直紀, 金井 一享, 伊藤 吉將, 長井 紀章, 山下 洋平, 木村 祐哉, 近澤 征史朗, 堀 泰智, 星 史雄, 伊藤 直之, 日本獣医学会学術集会講演要旨集,   2015 08
  • トラニラストナノ粒子分散液による抗炎症効果の検証および作用機序の解明 in vitro試験, 佐藤 和昭, 金井 一享, 伊藤 吉將, 長井 紀章, 山下 洋平, 木村 祐哉, 近澤 征史朗, 堀 泰智, 星 史雄, 伊藤 直之, 比較眼科学会年次大会講演要旨集,   2015 07
  • トラニラストナノ粒子分散点眼液のぶどう膜炎に対する抗炎症効果と機序の解明 in vivo試験, 二階堂 寛, 金井 一享, 能美 君人, 伊藤 吉將, 長井 紀章, 山下 洋平, 近澤 征史朗, 堀 泰智, 星 史雄, 伊藤 直之, 比較眼科学会年次大会講演要旨集,   2015 07
  • シロスタゾールナノ結晶含有眼瞼適用ゲルパッチの開発:貼付後の薬物移行性と涙液中薬物動態, YOSHIOKA CHIAKI, NAGAI NORIAKI, ITO YOSHIMASA, TAKAHASHI HIDEYA, SHIMIZU EIJI, MATSUI MAKOTO, MORIMOTO EIJI, 日本薬学会年会要旨集(CD-ROM),   2015 03
  • 眼検査によるアルツハイマー病早期診断を目指して:自然発症糖尿病モデルOLETFラットを用いた水晶体中アミロイドβ蓄積機構の解明, NAGAI NORIAKI, MANO YU, KOTANI SACHIYO, ITO YOSHIMASA, 日本薬学会年会要旨集(CD-ROM),   2015 03
  • カルシウム欠乏卵巣摘出ラットを用いた高ミネラル水の骨形成促進効果に関する基礎研究, OGATA FUMIHIKO, NAGAI NORIAKI, ITO YOSHIMASA, KAWASAKI NAOHITO, 日本薬学会年会要旨集(CD-ROM),   2015 03
  • 新しいNSAIDs服用方法の提案―マグネシウム併用によるインドメタシン惹起消化管傷害の軽減効果―, TANABE WATARU, HAYASHI MAHO, YAMAOKA TAIKI, NAGAI NORIAKI, ITO YOSHIMASA, 日本薬学会年会要旨集(CD-ROM),   2015 03
  • アジュバント誘発関節炎ラットにおけるインドメタシン惹起小腸粘膜傷害とインターロイキン18の関与, ITO YOSHIMASA, NAGAI NORIAKI, TADA NATSUMI, HAYASHI MAHO, 日本薬学会年会要旨集(CD-ROM),   2015 03
  • イブプロフェンナノ結晶を用いた外用皮膚剤の設計とその評価, MANO YU, TANIMOTO SHION, NAKAYA HITOMI, NAGAI NORIAKI, ITO YOSHIMASA, 日本薬学会年会要旨集(CD-ROM),   2015 03
  • デキサメタゾンを用いたナノ結晶点眼製剤の創製:角膜傷害性の軽減と眼内移行性向上, ITO YOSHIMASA, NAGAI NORIAKI, MATSUHIRA YUKA, YAMAOKA SAKIE, MANO YU, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2015
  • ラット角膜上皮剥離モデルを用いた種々市販緑内障治療配合剤の角膜傷害性評価, OKAMOTO NORIO, NAGAI NORIAKI, MORI AIRI, ITO YOSHIMASA, SHIMOMURA YOSHIKAZU, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2015
  • 近赤外分光法によるロサルタンカリウム後発薬の非破壊的試験と溶出試験の比較, OTORI TOORU, SHIMOMURA TAKUYA, NAGAI NORIAKI, MATSUYAMA KENJI, 日本医薬品情報学会総会・学術大会講演要旨集,   2014 07
  • 薬物ナノ結晶化による製剤機能の向上:レバミピドナノ結晶点眼製剤による角膜創傷治療, NAGAI NORIAKI, HASHINO MIHO, KATSUI YUMI, OKAMOTO NORIO, SHIMOMURA KIICHI, ITO YOSHIMASA, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2014
  • ナノ化技術を応用した眼瞼適用ゲルパッチ「貼るめぐすり」の開発とその有効性, YOSHIOKA CHIAKI, NAGAI NORIAKI, ITO YOSHIMASA, TAKAHASHI HIDEYA, SHIMIZU EIJI, MATSUI MAKOTO, MORIMOTO EIJI, 日本薬学会年会要旨集(CD-ROM),   2014
  • ナノ化技術を用いた新規注射用製剤の開発とその有用性評価―シロスタゾール静脈内投与による脳梗塞治療―, TANABE WATARU, MATSUSHITA SHOKO, NISHIMOTO NATSUMI, NAGAI NORIAKI, ITO YOSHIMASA, NISHIKAWA HIROYUKI, KAWABATA ATSUFUMI, 生体機能と創薬シンポジウム要旨集,   2014
  • 種々点眼用保存剤による角膜上皮細胞傷害性とEDTAによる保護効果, ITO YOSHIMASA, NAGAI NORIAKI, MORI AIRI, KATSUI YUMI, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2014
  • インターロイキン18の発現亢進はNSAIDs誘発消化管傷害を高める―関節リウマチモデルラットを用いた胃粘膜傷害機構の解明―, MANO YU, NAGAI NORIAKI, ITO YOSHIMASA, 生体機能と創薬シンポジウム要旨集,   2014
  • 皮質白内障患者におけるアミロイドβ蓄積とATP量の低下, NAGAI NORIAKI, MANO YUTAKA, ITO YOSHIMASA, SHIBATA TEPPEI, KUBO ERI, SASAKI YO, 日本白内障学会総会プログラム・講演抄録集,   2014
  • 眼圧降下と網膜症治療を同時標的とした次世代緑内障治療薬“医薬品ナノ結晶点眼製剤”の開発, NAGAI NORIAKI, HIRATA MANA, TANABE WATARU, ITO YOSHIMASA, 日本薬学会年会要旨集(CD-ROM),   2014
  • メープルシュガーにおける血糖値上昇抑制効果, TAGA ATSUSHI, NAGAI NORIAKI, YAMAMOTO TETSUSHI, MITAMURA KUNIKO, ITO YOSHIMASA, 日本薬学会年会要旨集(CD-ROM),   2014
  • ポリソルベート80またはEDTA併用使用が種々点眼用保存剤の効力に及ぼす影響, TANABE WATARU, NAGAI NORIAKI, TSUJI AKIKO, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 日本眼薬理学会プログラム・講演抄録集,   2014
  • インドメタシン惹起小腸粘膜傷害に対するマグネシウムイオンの保護効果, ITO YOSHIMASA, NAGAI NORIAKI, TADA NATSUMI, HAYASHI MAHO, 日本薬学会年会要旨集(CD-ROM),   2014
  • ベシル酸アムロジピン製剤を用いた簡易懸濁法適用時における吸着剤の影響, OGATA FUMIHIKO, NAGAI NORIAKI, HAYASHI TOMONORI, NISHIURA SAORI, MATSUOKA HIROSHI, ITO YOSHIMASA, KAWASAKI NAOTO, 日本薬学会年会要旨集(CD-ROM),   2014
  • 薬物粒子径変更に伴うブリンゾラミド懸濁性点眼液の角膜透過性向上, MANO YU, NAGAI NORIAKI, MATSUDAIRA YUKA, YAMAOKA SAKIE, ITO YOSHIMASA, OKAMOTO NORIO, SHIMOMURA YOSHIKAZU, 日本眼薬理学会プログラム・講演抄録集,   2014
  • 薬局薬剤師のジェネリック医薬品に対する認識(重視点)とその使用状況の関連性, 大鳥徹, 長井紀章, 金裕生, 松山賢治, 日本医薬品情報学会総会・学術大会講演要旨集,   2013 08 01
  • 水晶体におけるアミロイドβの蓄積と水晶体混濁への関与, NAGAI NORIAKI, 日本白内障学会総会/日本白内障屈折矯正手術学会総会プログラム・講演抄録集,   2013 05 24
  • ミトコンドリア及び細胞膜傷害に伴う水晶体混濁機構の解明とその予防・治療薬の開発, NAGAI NORIAKI, 日本白内障学会総会/日本白内障屈折矯正手術学会総会プログラム・講演抄録集,   2013 05 24
  • 市販緑内障治療薬による角膜傷害性のキネティクス解析, 岡本紀夫, 長井紀章, 大江恭平, 下村嘉一, 伊藤吉將, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2013
  • アクリル酸ポリマーを基剤とするシロスタゾール含有保水性ゲルシートの開発とその皮膚透過性, 吉岡千晶, 長井紀章, 伊藤吉將, 志水英二, 守本英二, 丸野正徳, 日本薬学会年会要旨集(CD-ROM),   2013
  • ロキソプロフェン惹起胃粘膜傷害に対するマグネシウムイオンの保護効果, 長井紀章, 竹田厚志, 板並優里, 伊藤吉將, 日本薬学会年会要旨集(CD-ROM),   2013
  • 薬物ナノ粒子分散液の調製と点眼製剤としての応用性:ナノ粒子分散液の角膜傷害性評価, 伊藤吉將, 長井紀章, 大野ひかる, 岡本紀夫, 下村嘉一, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2013
  • ジェネリック医薬品の普及とそれを阻む要因の解析, 松山賢治, 長井紀章, 金裕生, 橋本佳幸, 大鳥徹, 日本薬学会年会要旨集(CD-ROM),   2013
  • 長期連続使用を可能とする点眼用保存システムの確立:BAC/マンニトール保存システム, 伊藤吉將, 長井紀章, 岩部江里, 日本薬学会年会要旨集(CD-ROM),   2013
  • ウサギ赤血球を用いたベンザルコニウム塩化物の傷害性評価とセリシンによる保護効果, 長井紀章, 藤田裕美, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本眼薬理学会プログラム・講演抄録集,   2013
  • 糖尿病モデル動物OLETFラット水晶体におけるアミロイドβの蓄積, NAGAI NORIAKI, TAKEDA ATSUSHI, MURAO MAYUMI, ITO YOSHIMASA, 日本白内障学会総会/日本白内障屈折矯正手術学会総会プログラム・講演抄録集,   2012 05 15
  • シロスタゾールナノ粒子を用いた口腔内崩壊錠の有効性比較, 吉岡千晶, 長井紀章, 伊藤吉將, 岡本紀夫, 日本薬学会年会要旨集,   2012 03 05
  • ラット角膜上皮剥離モデルを用いた点眼薬の角膜傷害性評価:粘稠化剤メチルセルロース添加に伴うBAC角膜傷害性の変化, 長井紀章, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本薬学会年会要旨集,   2012 03 05
  • ナノ化技術を応用したシロスタゾールの経皮吸収製剤の設計, 伊藤吉將, 西口宏一, 長井紀章, 岡本紀夫, 日本薬学会年会要旨集,   2012 03 05
  • ヒト角膜上皮細胞を用いた緑内障治療配合剤のin Vitro角膜細胞傷害性評価, 長井紀章, 大江恭平, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2012
  • ヒト角膜上皮細胞を用いた緑内障治療薬のin vitro角膜細胞傷害速度論的評価, 伊藤吉將, 長井紀章, 岡本紀夫, 下村嘉一, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2012
  • 糖尿病モデル動物OLETFラット網膜におけるIL‐18の発現亢進, 長井紀章, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本眼薬理学会プログラム・講演抄録集,   2012
  • ジェネリック医薬品普及と薬局薬剤師の意識に関する調査研究, 長井紀章, 大野ひかる, 大和幹枝, 堀野智美, 北小路学, 伊藤吉將, 松野純男, 高田充隆, 日本医療薬学会年会講演要旨集,   2011 09 09
  • 薬局薬剤師を対象としたジェネリック医薬品使用に関する意識調査と問題点の把握, 長井紀章, 大和幹枝, 堀野智美, 大野ひかる, 北小路学, 伊藤吉將, 松野純男, 高田充隆, 医療薬学フォーラム講演要旨集,   2011 07
  • Relationship between Lipid Peroxidation and Ca^<2+>-ATPase Activity in ICR/f Rat Lenses Stimulated by Hydrogen Peroxide, NAGAI Noriaki, MURAO Takatoshi, KONAKA Yoko, ITO Yoshimasa, TAKEUCHI Noriko, 日本白内障学会誌,   2011 06 03
  • 栄養学的視点からの白内障予防―ミネラル摂取と水晶体混濁―, 長井紀章, 日本白内障学会総会/日本白内障屈折矯正手術学会総会プログラム・講演抄録集,   2011 06 01
  • 脳虚血モデルラットにおけるシロスタゾール・ナノ粒子分散液の脳血流改善効果, 村尾卓俊, 南部義徳, 井上晃博, 長井紀章, 伊藤吉將, 船上仁範, 市田成志, 岡本紀夫, 松山知弘, 日本薬学会年会要旨集,   2011 03 05
  • マイクロダイアリシス法を用いた溶出試験による徐放性製剤の品質評価, 伊藤吉將, 長井紀章, 犬伏梨乃, 小西菜穂子, 日本薬学会年会要旨集,   2011 03 05
  • トラニラスト・ナノ経皮吸収製剤による関節リウマチの治療効果, 長井紀章, 小林竜也, 村尾卓俊, 伊藤吉將, 日本薬学会年会要旨集,   2011 03 05
  • 新規逆相HPLCカラムを用いたTranilastの生体中定量分析における基礎検討, 多賀淳, 長井紀章, 藤原宏之, 寺島弘之, 橋本淳一, 伊藤吉将, 日本薬学会年会要旨集,   2011 03 05
  • ジェネリック医薬品推進に関する薬局薬剤師の意識調査に関する研究, 大和幹枝, 堀野智美, 大野ひかる, 長井紀章, 北小路学, 伊藤吉將, 高田充隆, 日本薬学会年会要旨集,   2011 03 05
  • 糖尿病モデル動物OLETFラット網膜におけるアミロイドβの発現, 長井紀章, 竹田厚志, 村尾まゆみ, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本眼薬理学会プログラム・講演抄録集,   2011
  • 種々抗緑内障点眼薬における角膜傷害性評価に関する研究, 伊藤吉將, 長井紀章, 村尾卓俊, 大江恭平, 岡本紀夫, 下村嘉一, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2011
  • セリシンを用いた低侵襲保存剤の確立と抗緑内障薬への応用, 長井紀章, 村尾卓俊, 関菜穂子, 家門麻耶, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本角膜学会総会・日本角膜移植学会プログラム・抄録集,   2011
  • 主たる点眼剤添加物が糖尿病モデル動物OLETFラット角膜傷害治癒へ与える影響, 長井紀章, 村尾卓俊, 伊藤吉將, 岡本紀夫, 下村嘉一, 日本眼薬理学会プログラム・講演抄録集,   2010 10
  • エンドトキシン誘発ぶどう膜炎モデルにおけるジスルフィラムの点眼効果, 金井一享, 伊藤吉將, 長井紀章, 伊藤直之, 近澤征史朗, 堀奏智, 星史雄, 樋口誠一, 日本獣医学会学術集会講演要旨集,   2010 09 01
  • 薬学部4年制課程から6年制課程への移行に伴う本学学生の就職意識動向調査, 川瀬篤史, 長井紀章, 木下充弘, 関口富美子, 桑島博, 鈴木茂生, 西田升三, 松尾圭造, 掛樋一晃, 医療薬学フォーラム講演要旨集,   2010 07
  • KINETIC ANALYSIS OF THE RATE OF CORNEAL WOUND HEAALING IN OLETF RATS, A MODEL OF TYPE 2 DIABETES MELLITUS, XIX International Congress of Eye Research,   2010 07 , XIX International Congress of Eye Research
  • INSTILLATION OF PYROGLUTAMIC ACID REDUCES THE ENHANCED OF INTRAOCULAR PRESSURE IN RABBIT, XIX International Congress of Eye Research,   2010 07 , XIX International Congress of Eye Research
  • ENHANCING EFFECTS OF SERICIN ON CORENAK WOUND HEALING IN OLETF RATS, A MODEL OF TYPE 2 DIABETES MELLITUS, XIX International Congress of Eye Research,Montrea,   2010 07 , XIX International Congress of Eye Research,Montrea
  • 過酸化水素による水晶体酸化ストレスがCa2+‐ATPase活性へ与える影響, 長井紀章, 村尾卓俊, 小仲陽子, 伊藤吉將, 竹内典子, 日本白内障学会総会/日本眼内レンズ屈折手術学会総会プログラム・講演抄録集,   2010 05 20
  • セリシンを用いた低角度障害薬物療法に関する研究, 長井紀章, 村尾卓俊, 伊藤吉將, 岡本紀夫, 日本薬学会年会要旨集,   2010 03 05
  • チーム基盤型学習(TBL)を導入した薬学部・医学部連携教育, 木村健, 安原智久, 船上仁範, 長井紀章, 喜多綾子, 北小路学, 大鳥徹, 岩城正宏, 松尾理, 日本薬学会年会要旨集,   2010 03 05
  • シロスタゾールのナノ粒子化とその分散液調製法の改善, 伊藤吉將, 長井紀章, 村尾卓俊, 岡本紀夫, 日本薬学会年会要旨集,   2010 03 05
  • Cilostazolナノ粒子分散液の静脈内投与の検討, 村尾卓俊, 長井紀章, 伊藤吉將, 岡本紀夫, 船上仁範, 市田成志, 日本薬学会年会要旨集,   2010 03 05
  • エンドトキシン誘発ぶどう膜炎モデルにおけるジスルフィラム経口投与の効果, 金井一享, 堀泰智, 伊藤直之, 星史雄, 伊藤吉將, 長井紀章, 樋口誠一, 日本獣医学会学術集会講演要旨集,   2009 09
  • II型糖尿病モデル動物OLETFラットにおける角膜傷害治癒の速度論的解析, 長井紀章, 村尾卓俊, 伊藤吉將, 岡本紀夫, 三村治, 日本眼薬理学会プログラム・講演抄録集,   2009 09
  • ヒト水晶体上皮細胞における一酸化窒素過剰産生と細胞膜Ca2+‐ATPase遺伝子発現, 長井紀章, 伊藤吉將, 日本白内障学会総会/日本眼内レンズ屈折手術学会総会プログラム・講演抄録集,   2009 05 27
  • 新規製剤評価法に関する研究:マイクロダイアリシス‐HPLC法の溶出試験への応用, 長井紀章, 伊藤吉將, 日本薬学会年会要旨集,   2009 03 05
  • Cilostazolのナノ粒子化による角膜透過性の改善, 伊藤吉將, 長井紀章, 岡本紀夫, 三村治, 日本薬学会年会要旨集,   2009 03 05
  • II型糖尿病モデル動物OLETFラットにおける角膜傷害治癒の遅延, 長井紀章, 伊藤吉將, 岡本紀夫, 三村治, 角膜カンファランス・日本角膜移植学会プログラム・抄録集,   2009 02
  • セリシン溶液の点眼による角膜傷害治癒促進効果, 伊藤吉將, 長井紀章, 岡本紀夫, 三村治, 角膜カンファランス・日本角膜移植学会プログラム・抄録集,   2009
  • BAC非含有プロスタグランジン製剤トラボプロスト点眼液の角膜障害性の評価, 岡本紀夫, 長井紀章, 伊藤吉將, 三村治, 角膜カンファランス・日本角膜移植学会プログラム・抄録集,   2009
  • 遺伝性白内障ラット(UPL)の白内障発症に伴うクリスタリン変化, 竹内典子, 石神志浦, 今村知紗, 林理紀, 本多祐美, 長井紀章, 伊藤吉將, 亀井鑠, 湯川和典, 生化学,   2008 12
  • 遺伝性白内障ICR/fラットの水晶体混濁におけるインターロイキン18及びDNA分解酵素の関与, 長井紀章, 伊藤吉將, 竹内典子, 臼井茂之, 平野和行, 日本眼薬理学会プログラム・講演抄録集,   2008 09
  • PREPARATION OF CILOSTAZOL EYE DROPS AS AN ANTI-GLAUCOMA AGENT AND IMPROVEMENT FOR ITS PERMEABILITY THROUGH THE RABBIT CONEA, XVIII International Congress of Eye Research,   2008 09 , XVIII International Congress of Eye Research
  • MECHANISM FOR ANTI-CATARACT EFFECT OF DISULFIRAM TO ICR/F RAT AS A HEREDITARY CATARACT MODEL, XVIII International Congress of Eye Research,   2008 09 , XVIII International Congress of Eye Research
  • HP β CD包接ジスルフィラム点眼液のICR/fラット白内障抑制効果の解明, 長井紀章, 伊藤吉將, 竹内典子, 日本白内障学会総会/日本眼内レンズ屈折手術学会総会プログラム・講演抄録集,   2008 05 20
  • 遺伝性白内障ラット(ICR/f)における鉄の動態, 竹内典子, 城後英美, 伊藤実沙子, 黒田奈巳, 鈴木麻知子, 中村大祐, 亀井鑠, 長井紀章, 伊藤吉將, 日本薬学会年会要旨集,   2008 03 05
  • 遺伝性白内障UPL,SCR及びICR/fラットにおける白内障発症機構の比較, 長井紀章, 伊藤吉將, 竹内典子, 日本薬学会年会要旨集,   2008 03 05
  • Cilostazolの緑内障治療への応用:ウサギ暗所高眼圧モデルに対するその点眼剤の眼圧降下作用, 伊藤吉將, 長井紀章, 岡本紀夫, 川上吉美, 日本薬学会年会要旨集,   2008 03 05
  • 遺伝性白内障UPLラットにおける白内障発症とチトクロムcオキシダーゼとの関係, 長井紀章, 伊藤吉將, 竹内典子, 亀井鑠, 日本眼薬理学会プログラム・講演抄録集,   2007 09
  • Cilostazolによる新たな眼圧下降効果と神経保護効果, 栗本拓治, 岡本紀夫, 伊藤吉將, 川上吉美, 長井紀章, 三村治, 日本眼薬理学会プログラム・講演抄録集,   2007 09
  • 遺伝性白内障UPLラットにおける白内障発症とインターロイキン‐18との関係, 長井紀章, 齋藤真理, 福畠孝史, 伊藤吉將, 日本薬学会年会要旨集,   2007 03 05
  • アジュバント関節炎ラットにおける海洋深層水より調製した“にがり水”によるインドメタシン消化管傷害修復作用, 伊藤吉將, 長井紀章, 福畠孝史, 太井秀行, 端口佳宏, 魚住嘉伸, 中川光司, 日本薬学会年会要旨集,   2007 03 05
  • PREPARATION OF DISULFIRAM EYE DROP AS AN ANTI-GLAUCOMA AGENT USING 2-HYDROXYPROPYL-β-CYCLODEXTRIN, XVII International Congress of Eye Research,   2006 10 , XVII International Congress of Eye Research
  • IS DNASE II-LIKE ACID DNASE IN LENS A KEY ENZEME FOR CATARACT DEVELOPMENT ?, XVII International Congress of Eye Research,   2006 10 , XVII International Congress of Eye Research
  • マグネシウム欠乏によるヒト水晶体上皮由来細胞SRA01/04でのNO産生とCa2+‐及びNa+/K+‐ATPase活性低下, 長井紀章, 角谷瑠里子, 福畠孝史, 宋永波, 伊藤吉将, 日本薬学会年会要旨集,   2006 03 06
  • マグネシウム含有液によるラット結膜anaphylaxis反応抑制, 福畠孝史, 野間裕美子, 長井紀章, 伊藤吉将, 太井秀行, 端口佳宏, 魚住嘉伸, 中川光司, 池田誠宏, 松葉沙織, 三村治, 日本薬学会年会要旨集,   2006 03 06
  • ピログルタミン酸亜鉛キレート点眼液の眼圧降下作用について, 伊藤吉将, 福畠孝史, 長井紀章, 中西邦夫, 川上吉美, 岡本紀夫, 三村治, 日本薬学会年会要旨集,   2006 03 06
  • マグネシウム含有点眼液によるラット結膜anaphylaxis反応抑制効果, 福畠孝史, 長井紀章, 伊藤吉將, 日本眼薬理学会プログラム・講演抄録集,   2006 03
  • ヒト水晶体上皮由来細胞SRA01/04に対するIFN‐γ及びLPS刺激によるiNOS誘導と細胞内ATPの変動, 福畠孝史, 劉穎, 長井紀章, 伊藤吉将, 日本薬学会年会要旨集,   2005 03 05
  • ヒト培養角膜上皮細胞(HCE‐T)の細胞単層膜形成及びトランスポーターALDH3A1の発現とジスルフィラム膜透過性との関係について, 福沢貴裕, 伊藤吉将, 長井紀章, 劉穎, 日本薬学会年会要旨集,   2005 03 05
  • アジュバント誘発関節炎ラットにおけるインドメタシン消化管障害とマグネシウムイオンによる保護効果, 長井紀章, 池堂知章, 伊藤吉将, 太井秀行, 端口佳宏, 魚住嘉伸, 中川光司, 日本薬学会年会要旨集,   2005 03 05
  • Delay of cataract development in Shumiya cataract rat by administration of high mineral water, XVI International Congress of Eye Research,   2004 09 , XVI International Congress of Eye Research
  • グルタミン酸2分子から成る環状ペプチドの角膜透過性及び眼圧降下作用, 伊藤吉将, 長井紀章, 高橋知子, 中西邦夫, 日本薬学会年会要旨集,   2004 03 05
  • ジスルフィラムのヒト培養細胞単層膜の透過メカニズム, 長井紀章, 福沢貴裕, 佐々木宏子, 谷野公俊, 岩城正宏, 伊藤吉将, 日本薬学会年会要旨集,   2004 03 05
  • Suppressive effect of nitric oxide production in aqueous humor of rabbit by various eye drops containing disulfiram as an anti.glaucoma agent, 長井紀章, 李徳馨, 鍋倉智裕, 伊藤吉将, 川上吉美, 池田誠宏, 岡村春樹, 日本薬学会年会要旨集,   2003 03 05

Misc

  • フランツ型拡散セルを用いた市販フェンタニルテープの経皮吸収性の評価 温熱条件下における薬物放出と皮膚透過性の測定, 林 友典, 高科 結衣, 川口 陽奈子, 永福 紡, 松岡 寛, 川畑 篤史, 長井 紀章, 医療薬学, 45, 7, 416, 422,   2019 07 , Refereed
    Summary:フランツ型拡散セルを用いて、温熱条件下におけるフェンタニル経皮吸収製剤の薬物皮膚透過機構について基礎的検討を行った。37℃および42℃条件におけるin vitro薬物放出性試験では、ともにテープ中薬物残存量は検出限度以下であり、すべてのフェンタニルが基剤から放出された。一方、ex vivo薬物皮膚透過試験において、42℃条件下ではすべてのフェンタニルが基剤から放出されたが、37℃条件下では基剤中に薬物の残存が認められ、その値は実験開始前の製剤中薬物量の7.8%であった。試験終了後の支持体を回してメンブランへの薬物吸着量(in vitro薬物放出性試験)と皮膚滞留性(ex vivo薬物皮膚透過試験)を測定したところ、in vitroではメンブランへの薬物吸着は認められなかったが、ex vivoでは皮膚中での薬物滞留が認められた。一方、37℃条件下におけるラット皮膚中フェンタニル濃度は0.34±0.03μmol、42℃条件下では0.36±0.01μmolと両条件間で有意な差はみられなかった。
  • ナノ結晶を基盤とした経口製剤化に伴うNSAIDs消化管障害発現頻度の軽減, 福岡 侑也, 大竹 裕子, 長井 紀章, BIO Clinica, 34, 7, 746, 748,   2019 07 , Refereed
    Summary:臨床において、非ステロイド性抗炎症薬(NSAIDs)による消化管障害は重篤な問題である。著者らは、湿式ビーズミル法を用い、平均粒子径76nmのインドメタシン(IMC)ナノ結晶経口製剤の作製法を確立した。また、本製剤は、従来の製剤と比較し、約5倍もバイオアベイラビリティが高まり、薬物投与量の減量を可能とした。さらに、これら製剤化に伴うNSAIDs投与量の減少が、薬剤の消化管粘膜直接刺激の低下を介し、障害誘発を軽減することを示した。本成果が安全なNSAIDs療法の確立に繋がることを期待する。(著者抄録)
  • 【今話題の白内障研究、治療を検証する】ラノステロールで水晶体は透明化できるのか?, 長井 紀章, 日本白内障学会誌, 31, 1, 17, 19,   2019 06 , Refereed
  • 【私の研究を聞いて欲しい】薬物眼内移行性の向上を目的としたナノ点眼製剤の開発, 大竹 裕子, 真野 裕, 長井 紀章, 日本白内障学会誌, 31, 1, 33, 35,   2019 06 , Refereed
  • 認知症患者組織を用いた水晶体中アミロイドβ関連mRNA量の測定, 長井 紀章, 福岡 侑也, 真野 裕, 大竹 裕子, 柴田 哲平, 久保 江理, 佐々木 洋, 日本白内障学会誌, 31, 1, 53, 57,   2019 06 , Refereed
    Summary:近年、アルツハイマー病の要因であるアミロイドβ(Aβ)が水晶体にも存在することが報告され、水晶体混濁(白内障)への関与が注目されている。しかし、日本人における水晶体中Aβ産生・蓄積機構については未だ十分に解明されていない。そこで今回、日本人の非認知症患者および認知症患者水晶体を対象として、組織中のAβ産生・分解関連mRNA発現量の変化について比較検討を行った。Aβ産生(APP、BACE1、PS)および分解(ADAM10、NEP、ECE-1)関連mRNA発現量の測定にはリアルタイムPCR法を用い、ヒト試料(水晶体上皮細胞)は硝子体および白内障手術患者から得た。認知症患者の混濁水晶体では、Aβ分解を促す酵素であるNEPおよびECE-1 mRNA発現量が非認知症患者と比べて有意に低値であった。これらAβ分解能の低下は、日本人の認知症患者における水晶体混濁機構の一つであると考えられる。(著者抄録)
  • 【今話題の白内障研究、治療を検証する】ラノステロールで水晶体は透明化できるのか?, 長井 紀章, 日本白内障学会誌, 31, 1, 17, 19,   2019 06
  • 【私の研究を聞いて欲しい】薬物眼内移行性の向上を目的としたナノ点眼製剤の開発, 大竹 裕子, 真野 裕, 長井 紀章, 日本白内障学会誌, 31, 1, 33, 35,   2019 06
  • 認知症患者組織を用いた水晶体中アミロイドβ関連mRNA量の測定, 長井 紀章, 福岡 侑也, 真野 裕, 大竹 裕子, 柴田 哲平, 久保 江理, 佐々木 洋, 日本白内障学会誌, 31, 1, 53, 57,   2019 06
    Summary:近年、アルツハイマー病の要因であるアミロイドβ(Aβ)が水晶体にも存在することが報告され、水晶体混濁(白内障)への関与が注目されている。しかし、日本人における水晶体中Aβ産生・蓄積機構については未だ十分に解明されていない。そこで今回、日本人の非認知症患者および認知症患者水晶体を対象として、組織中のAβ産生・分解関連mRNA発現量の変化について比較検討を行った。Aβ産生(APP、BACE1、PS)および分解(ADAM10、NEP、ECE-1)関連mRNA発現量の測定にはリアルタイムPCR法を用い、ヒト試料(水晶体上皮細胞)は硝子体および白内障手術患者から得た。認知症患者の混濁水晶体では、Aβ分解を促す酵素であるNEPおよびECE-1 mRNA発現量が非認知症患者と比べて有意に低値であった。これらAβ分解能の低下は、日本人の認知症患者における水晶体混濁機構の一つであると考えられる。(著者抄録)
  • 白内障術後試料を用いたアルツハイマー病早期発見・予防法の実用化, 長井 紀章, 佐々木 洋, 久保 江理, 大和証券ヘルス財団研究業績集, 42, 91, 96,   2019 03
    Summary:白内障手術時における水晶体中アミロイドβ(Aβ)量の測定がアルツハイマー病(AD)への早期診断につながるか検討した。まず、加齢、性差、混濁、病歴(糖尿病)がヒト水晶体中Aβ蓄積に影響を与えるかどうかについて検討した。さらに、上記検討から得られた水晶体でのAβ蓄積関連因子を排除した試料を用い、AD発症と水晶体中Aβ蓄積量の関係を模索した。その結果、年齢、男女間において、Aβ蓄積量間に有意な差は認められなかった。混濁タイプについては、Aβ1-40およびAβ1-42蓄積量ではいずれの白内障タイプにおいても有意な差は見られなかった一方で、Aβ1-43では皮質混濁タイプの水晶体が他の白内障タイプ群と比較し有意に高値であった。この結果をうけて、糖尿病と水晶体中Aβ値の確認には皮質混濁を伴わない検体を中心に評価を行った。皮質混濁を示さない糖尿病患者水晶体中におけるAβ1-40、Aβ1-42、Aβ1-43蓄積量は、Aβ1-40およびAβ1-42においてClear(透明水晶体)、Opaque(皮質混濁を除いた白内障患者)、DM(皮質混濁を除いた糖尿病罹患白内障患者)群では、有意な差は見られなかった。一方、Aβ1-43では、DM群がClear群やOpaque群と比較し有意に高値を示した。皮質混濁を有さずかつ非糖尿病患者から得た検体を用い、AD罹患の有無と水晶体中Aβ蓄積量の関係を調査した。その結果、AD罹患のAβ蓄積量は、皮質混濁を除いた糖尿病非罹患白内障患者に比べて高値であった。
  • 白内障抑制・治療に対する多角的アプローチ 白内障抑制に関する薬学的アプローチ 薬による混濁抑制, 長井 紀章, 日本眼科学会雑誌, 123, 臨増, 48, 48,   2019 03
  • 【ぶどう膜炎2019】眼科DDS(ドラッグデリバリー・システム)の必要性 点眼薬による眼内疾患治療, 長井 紀章, 獣医眼科プラクティス, 3, 2, 47, 54,   2019 02
  • Effect of Methylcellulose (Cellulose Derivatives) on Ibuprofen-crushing Efficiency in Nano Pulverizer NP-100, 長井紀章, 山崎由夏, 中村翼, 大竹裕子, 岡本直也, 薬学雑誌(Web), 139, 1, 123‐130(J‐STAGE),   2019 , https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201902215119825526
  • 添加物メチルセルロースが遊星ボールミルによるイブプロフェン微粒子化へ与える影響, 長井 紀章, 山崎 由夏, 中村 翼, 大竹 裕子, 岡本 直也, 薬学雑誌, 139, 1, 123, 130,   2019 01 , Refereed
    Summary:遊星ボールミル法適用時における添加物選択及び添加量設定の指標を確立すべく、重合度の異なるメチルセルロースが破砕効率へ与える影響について検討した。破砕薬物としてイブプロフェン(IBU)粉末を用い、添加物をメチルセルロースに固定し、1.0%SM-4、15、25、100、400、1500、4000使用時における遊星ボールミル法の破砕効率を薬物粒子径から評価した。その結果、添加物の粘度の増加に伴い、破砕後のIBU粒子径は増大したが、両因子間において直線性は認められなかった。次に、粘度と破砕効率の関係をより詳細に評価すべく、SM-4、SM-400及びSM-4000を用い、各添加物の濃度を0.1〜1%に変更した際の破砕効率を比較評価した。その結果、SM-4使用群では粘度は低いものの、高い破砕効率が得られた。一方、SM-400使用群では低濃度(0.1%)よりも高濃度(1.0%)で破砕効率が高まり、SM-4000使用群では、低濃度(0.1%)ではIBUはナノサイズまで破砕されなかった。次にSM-4、SM-400及びSM-4000の濃度変化が、破砕後の薬物粒度分布挙動に及ぼす影響について検討を行った。その結果、粘度は破砕効率に直接影響しないものの、破砕効率に対してメチルセルロース添加濃度には最適値が存在し、これら濃度(最適値)は、重合度が高いタイプほど上昇することを示した。さらに、添加物濃度が最適値よりも低い場合には、粒度分布がテーリングのような形状を示し、過剰に添加物を使用した際にはマイクロサイズの再凝集を示すピークが確認された。
  • 添加物メチルセルロースが遊星ボールミルによるイブプロフェン微粒子化へ与える影響, 長井 紀章, 山崎 由夏, 中村 翼, 大竹 裕子, 岡本 直也, 薬学雑誌, 139, 1, 123, 130,   2019 01
    Summary:遊星ボールミル法適用時における添加物選択及び添加量設定の指標を確立すべく、重合度の異なるメチルセルロースが破砕効率へ与える影響について検討した。破砕薬物としてイブプロフェン(IBU)粉末を用い、添加物をメチルセルロースに固定し、1.0%SM-4、15、25、100、400、1500、4000使用時における遊星ボールミル法の破砕効率を薬物粒子径から評価した。その結果、添加物の粘度の増加に伴い、破砕後のIBU粒子径は増大したが、両因子間において直線性は認められなかった。次に、粘度と破砕効率の関係をより詳細に評価すべく、SM-4、SM-400及びSM-4000を用い、各添加物の濃度を0.1〜1%に変更した際の破砕効率を比較評価した。その結果、SM-4使用群では粘度は低いものの、高い破砕効率が得られた。一方、SM-400使用群では低濃度(0.1%)よりも高濃度(1.0%)で破砕効率が高まり、SM-4000使用群では、低濃度(0.1%)ではIBUはナノサイズまで破砕されなかった。次にSM-4、SM-400及びSM-4000の濃度変化が、破砕後の薬物粒度分布挙動に及ぼす影響について検討を行った。その結果、粘度は破砕効率に直接影響しないものの、破砕効率に対してメチルセルロース添加濃度には最適値が存在し、これら濃度(最適値)は、重合度が高いタイプほど上昇することを示した。さらに、添加物濃度が最適値よりも低い場合には、粒度分布がテーリングのような形状を示し、過剰に添加物を使用した際にはマイクロサイズの再凝集を示すピークが確認された。
  • Pharmaceutical applications of nanoparticulate drug delivery systems enhance the membrane permeability, 石井美有, 國松紬, 蛭子小春, 大竹裕子, 長井紀章, 電気学会研究会資料, OQD-18-071-079, 11‐15,   2018 12 21 , https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201902288815854288
  • 新規院内製剤セレン含有口腔内崩壊錠の作製と実用化についての検討, 中尾元紀, 松尾世為子, 大橋香菜子, 田邨保之, 永井聡子, 覺野律, 中村明美, 福永聖子, 川端成佐, 寺倉智子, 松野純男, 緒方文彦, 川崎直人, 大竹裕子, 長井紀章, 国立病院総合医学会(Web), 72回, 656, 656,   2018 11 , http://jglobal.jst.go.jp/public/201902227131229724
  • 製剤学特性に基づく点眼薬評価とナノ医薬品の応用性, 長井 紀章, 医療薬学, 44, 10, 481, 490,   2018 10 , Refereed
    Summary:ベンザルコニウム塩化物を含む点眼薬の長期使用は、膜破壊、細胞質の変性を起こし、薬剤性角膜上皮傷害に繋がる。著者らは、臨床で多用される種々点眼薬を対象に、1)点眼薬の角膜傷害性評価、2)新規点眼保存システムの開発、3)懸濁点眼製剤中の粒子サイズと薬物組織移行性の関係を調査するとともに、ヒト患者組織検体を用いて、1)白内障発症要因の解明、2)新規ナノ点眼製剤の開発について検討を行ってきたので、その研究成果について概説した。
  • 涙液中薬物動態研究に向けたマイクロダイアリシス-キャピラリー液体クロマトグラフィー法の開発, 長井 紀章, 上野 祥奈, 石井 美有, 福岡 侑也, 大竹 裕子, 薬学雑誌, 138, 8, 1111, 1117,   2018 08
    Summary:キャピラリー液体クロマトグラフィー(CLC)とマイクロダイアリシス法を連結した手法を用い、市販チモロールマレイン酸塩(TM)点眼薬点眼後の涙液中薬物挙動の把握について検討した。マイクロダイアリシス-HPLC法における検量線は直線性を示し、r値は0.9971であった。ウサギ涙液中薬物濃度を測定したところ、点眼50分後まで薬物の検出が認められ、透析膜回収法と類似した薬物消失を示した。一方、点眼15分後の涙液中薬物量の標準誤差は2.4μg/mLと透析膜回収法と比較し、涙液中薬物量のバラツキが軽減された。TM点眼薬点眼後の涙液中薬物挙動に関して、マイクロダイアリシス-CLC法の検量線において、r値は0.9982であり、点眼後のウサギ涙液中薬物濃度変化を測定したところ、点眼75分後まで経時的な薬物の消失が確認できた。また、バッチサンプリング法や透析膜回収法に比べバラツキも少なく、高い再現性が確認された。
  • 涙液中薬物動態研究に向けたマイクロダイアリシス-キャピラリー液体クロマトグラフィー法の開発, 長井 紀章, 上野 祥奈, 石井 美有, 福岡 侑也, 大竹 裕子, 薬学雑誌, 138, 8, 1111, 1117,   2018 08 , Refereed
    Summary:キャピラリー液体クロマトグラフィー(CLC)とマイクロダイアリシス法を連結した手法を用い、市販チモロールマレイン酸塩(TM)点眼薬点眼後の涙液中薬物挙動の把握について検討した。マイクロダイアリシス-HPLC法における検量線は直線性を示し、r値は0.9971であった。ウサギ涙液中薬物濃度を測定したところ、点眼50分後まで薬物の検出が認められ、透析膜回収法と類似した薬物消失を示した。一方、点眼15分後の涙液中薬物量の標準誤差は2.4μg/mLと透析膜回収法と比較し、涙液中薬物量のバラツキが軽減された。TM点眼薬点眼後の涙液中薬物挙動に関して、マイクロダイアリシス-CLC法の検量線において、r値は0.9982であり、点眼後のウサギ涙液中薬物濃度変化を測定したところ、点眼75分後まで経時的な薬物の消失が確認できた。また、バッチサンプリング法や透析膜回収法に比べバラツキも少なく、高い再現性が確認された。
  • 分子生物学的解析入門, 長井 紀章, 日本白内障学会誌, 30, 1, 65, 67,   2018 06
  • 分子生物学的解析入門, 長井 紀章, 日本白内障学会誌, 30, 1, 65, 67,   2018 06
  • 重合度の異なるセルロース誘導体が自転・公転ナノ粉砕機の薬物破砕効率へ与える影響, 長井 紀章, 中村 翼, 山崎 由夏, 大竹 裕子, 高塚 隆之, 日本薬剤学会年会講演要旨集, 33年会, 202, 202,   2018 05
  • カプセル組成の変更に伴う吸入粉末剤の薬物放出性制御に関する研究, 大竹 裕子, 石井 美有, 福岡 侑也, 長井 紀章, 日本薬剤学会年会講演要旨集, 33年会, 243, 243,   2018 05
  • レバミピドナノ口腔内崩壊錠の製造とレバミピドの薬剤性消化管障害治療への応用, 福岡 侑也, 上田 純也, 大竹 裕子, 長井 紀章, 日本薬剤学会年会講演要旨集, 33年会, 116, 116,   2018 05
  • ドライアイ治療への応用を目指した新規経眼瞼レバミピドナノ製剤の開発, 石井 美有, 上野 祥奈, 大竹 裕子, 長井 紀章, 日本薬剤学会年会講演要旨集, 33年会, 129, 129,   2018 05
  • 重合度の異なるセルロース誘導体が自転・公転ナノ粉砕機の薬物破砕効率へ与える影響, 長井 紀章, 中村 翼, 山崎 由夏, 大竹 裕子, 高塚 隆之, 日本薬剤学会年会講演要旨集, 33年会, 202, 202,   2018 05
  • カプセル組成の変更に伴う吸入粉末剤の薬物放出性制御に関する研究, 大竹 裕子, 石井 美有, 福岡 侑也, 長井 紀章, 日本薬剤学会年会講演要旨集, 33年会, 243, 243,   2018 05
  • ラロキシフェンを用いたナノ経皮吸収製剤の開発と骨粗鬆症治療への有用性評価, 出口 粧央里, 梁 宇紀, 大竹 裕子, 緒方 文彦, 川崎 直人, 長井 紀章, 日本薬剤学会年会講演要旨集, 33年会, 145, 145,   2018 05
  • ラロキシフェンを用いたナノ経皮吸収製剤の開発と骨粗鬆症治療への有用性評価, 出口 粧央里, 梁 宇紀, 大竹 裕子, 緒方 文彦, 川崎 直人, 長井 紀章, 日本薬剤学会年会講演要旨集, 33年会, 145, 145,   2018 05
  • NSAIDs起因性消化管障害の制御を目指した製剤工夫, 長井 紀章, BIO Clinica, 33, 4, 371, 373,   2018 04
    Summary:臨床において、非ステロイド性抗炎症薬(NSAIDs)による消化管障害は重篤な問題である。著者らは、湿式ビーズミル法を用い、平均粒子径76nmのインドメタシン(IMC)ナノ結晶経口製剤の作製法を確立した。また、本製剤は、従来の製剤と比較し、約5倍もバイオアベイラビリティが高まり、薬物投与量の減量を可能とした。さらに、これら製剤化に伴うNSAIDs投与量の減少が、薬剤の消化管粘膜直接刺激の低下を介し、障害誘発を軽減することを示した。本成果が安全なNSAIDs療法の確立に繋がることを期待する。(著者抄録)
  • ショットガンプロテオミクス解析を用いた糖尿病白内障要因の解析, 大竹 裕子, 山本 哲志, 三田村 邦子, 多賀 淳, 長井 紀章, 日本薬学会年会要旨集, 138年会, 3, 243, 243,   2018 03
  • ショットガンプロテオミクス解析を用いた糖尿病白内障要因の解析, 大竹 裕子, 山本 哲志, 三田村 邦子, 多賀 淳, 長井 紀章, 日本薬学会年会要旨集, 138年会, 3, 243, 243,   2018 03
  • 毛根を標的とした新規薬物送達技術の開発 ナノ結晶技術はミノキシジルの発毛効果を高める, 長井 紀章, 岩井 淑恵, 川瀬 七愛, 坂本 茜, 大竹 裕子, 緒方 文彦, 川崎 直人, 日本薬学会年会要旨集, 138年会, 4, 158, 158,   2018 03
  • 毛根を標的とした新規薬物送達技術の開発:ナノ結晶技術はミノキシジルの発毛効果を高める, 長井紀章, 岩井淑恵, 川瀬七愛, 坂本茜, 大竹裕子, 緒方文彦, 川崎直人, 日本薬学会年会要旨集(CD-ROM), 138th, 4, ROMBUNNO.28PA‐pm142, 158,   2018 03 , http://jglobal.jst.go.jp/public/201802287421642773
  • 網膜電図および免疫組織染色によるストレプトゾトシン誘発糖尿病ラットの網膜機能障害の評価, 長井紀章, 平松範子, 出口粧央里, 大竹裕子, 山本直樹, 日本眼薬理学会プログラム・講演抄録集, 37th, 43, 43,   2017 09 , http://jglobal.jst.go.jp/public/201702262810219389
  • 【白内障・水晶体への多角的アプローチ】 白内障への薬学的アプローチ, 岡 美佳子, 長井 紀章, 日本白内障学会誌, 29, 1, 48, 49,   2017 06 , 10.14938/cataract.09-011
  • 薬物粒子径変更に伴うレバミピド懸濁性点眼液の製剤機能の向上, 長井 紀章, 川崎 真緒, 上野 祥奈, 大竹 裕子, 岡本 紀夫, 下村 嘉一, 日本薬剤学会年会講演要旨集, 32年会, 172, 172,   2017 05
  • 薬物粒子径変更に伴うレバミピド懸濁性点眼液の製剤機能の向上, 長井 紀章, 川崎 真緒, 上野 祥奈, 大竹 裕子, 岡本 紀夫, 下村 嘉一, 日本薬剤学会年会講演要旨集, 32年会, 172, 172,   2017 05
  • ビーズミル破砕に伴うピレノキシン点眼製剤の薬物溶解速度及び分散安定性の改善, 上野 祥奈, 山岡 咲絵, 伊藤 吉將, 小竹 武, 中澤 洋介, 長井 紀章, 薬学雑誌, 137, 5, 635, 641,   2017 05 , 10.1248/yakushi.16-00267
    Summary:湿式破砕処理によるピレノキシンナノ懸濁液の調製は、1%メチルセルロース(MC)添加・非添加条件下、市販ピレノキシン点眼液をビーズ式破砕装置で湿式破砕処理を行った。市販ピレノキシン点眼液中の懸濁薬物は70nm〜3μmとナノオーダーの粒子からマイクロオーダーの粒子まで幅広いサイズの粒子を認めたが、湿式破砕処理で粒子サイズが1μm以下と、粒子サイズの分布はナノ領域となったが、破砕処理後に色調の変化を認め、回収率は58%であった。添加物としてMCを用い、1.0%MC添加により色調に変化はみられず、湿式破砕処理後の平均粒子径は206nm、回収率は67%であった。ピレノキシンナノ懸濁液は市販ピレノキシン点眼液と比較し、人工涙液への溶解速度が高く、見かけの溶解速度定数は2.1倍であった。ピレノキシンナノ懸濁液では市販ピレノキシン点眼液に比べ薬物分散安定性が高く、調製2週間後においても採取位置における薬物濃度の低下はみられなかった。市販ピレノキシン点眼液とピレノキシンナノ懸濁液の一滴量(重量)は、それぞれ38.8±1.3mg、40.4±1.3mgであった。
  • ナノ化技術が可能としたドラック・リポジショニング ニルバジピンナノ結晶点眼製剤による糖尿病網膜症治療, 上野 祥奈, 出口 粧央里, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集, 137年会, 4, 201, 201,   2017 03
  • 納豆による高血圧予防効果の解明 納豆菌酵素発酵代謝物は本態性高血圧の発症を抑制する, 長井 紀章, 真野 裕, 船上 仁範, 緒方 文彦, 伊藤 吉將, 後藤 和子, 川崎 直人, 日本薬学会年会要旨集, 137年会, 3, 204, 204,   2017 03
  • 納豆による高血圧予防効果の解明:納豆菌酵素発酵代謝物は本態性高血圧の発症を抑制する, 長井紀章, 真野裕, 船上仁範, 緒方文彦, 伊藤吉將, 後藤和子, 川崎直人, 日本薬学会年会要旨集(CD-ROM), 137th, 3, ROMBUNNO.26PB‐am120, 204,   2017 03 , http://jglobal.jst.go.jp/public/201702282312281858
  • 水晶体の加齢性変化 水晶体中アミロイドβ量の加齢性変化, 長井 紀章, 日本眼科学会雑誌, 121, 臨増, 23, 23,   2017 03
  • 納豆菌酵素発酵代謝(NFE)エキスがSHRおよびSHR-SPラットの血圧へ与える影響, 長井 紀章, 真野 裕, 船上 仁範, 緒方 文彦, 伊藤 吉將, 後藤 和子, 川崎 直人, 医療薬学, 43, 2, 72, 79,   2017 02 , 10.5649/jjphcs.43.72
    Summary:有効成分としてポリアミンおよびレバンを含有する市販品納豆菌酵素発酵代謝(NFE)エキスを用いた。5週齢のWKYラット、高血圧自然発症ラット(SHRラット)、5週齢の脳卒中易発症高血圧自然発症ラット(SHR-SPラット)を用いた。WKY、SHRおよびSHR-SPラットのいずれにおいても、NFEエキスの投与にかかわらず摂食量と体重に有意差は見られなかった。WKYラットではNFEエキス投与および非投与群間で収縮期および拡張期血圧に差は見られなかった。SHRおよびSHR-SPラットはともに、NFEエキス投与により収縮期および拡張期血圧が有意に抑制された。NFEエキスによる高血圧自然発症ラットの高血圧上昇抑制には、拍出量増加や末梢血管抵抗性の軽減が関与しているものと示唆された。NFEエキスの血圧降下作用は、SHRラット種の血圧の上昇遅延に起因しているものと示唆された。NFEエキスの特異的な成分として、プトレシン、スペルミジン、スペルミンといったポリアミンとレバンを認めた。
  • 【点眼薬2017】 薬理学からみた点眼による全身への影響, 伊藤 吉將, 長井 紀章, 獣医眼科プラクティス, 1, 2, 53, 56,   2017 02
  • Evaluation of retinal function in streptozotocin-induced diabetic rats by using the electroretinography and immunohistochemistry methods, Noriko Hiramatsu, Saori Deguchi, Chiaki Yoshioka, Hiroko Otake, Naoki Yamamoto, Noriaki Nagai, Yakugaku Zasshi, 137, 9, 1169, 1175,   2017 , 10.1248/yakushi.17-00115
    Summary:Streptozotocin-induced diabetic rat (STZ rat) was used in many studies for the diabetic mellitus. In this study, we demonstrated whether the electroretinograms (ERG) was changed in the retina of STZ rats. In addition, we investigated the histopathological alteration in the retina of STZ rats by using the immunological method. The 100 mg/kg of STZ was injected continuously for 2 d (100 mg/kg×2). The insulin level was decreased, and the glucose level was enhanced 14 d after the injection of STZ. Moreover, the levels of a-wave, b-wave and OP amplitude were decreased in the rat at 14 d after the injection of STZ. Although, the damage and apoptosis was not observed in the retinal ganglion cell of STZ rats by the immunological experiment using the phospho-H2A.X and cleaved caspase-3, the distance between cell and cell was increased in both of outer- and inner- nuclear (granule) layer in retina of STZ rats. In conclusion, we showed that the enhanced thickening in retina was caused by the injection of excessive STZ. The thickening in retina of STZ rats may lead to the dysfunction of retina, resulting in the decrease in ERG. These findings provide significant information that can be used in the design of a model of diabetic retinopathy.
  • 薬物ナノ結晶を用いた新規点眼システムの確立と緑内障治療への応用, 長井 紀章, 薬学雑誌, 136, 10, 1385, 1390,   2016 10 , 10.1248/yakushi.16-00089
    Summary:緑内障を始めとする眼領域治療において、角膜傷害性が少なく、薬物の効力を最大限に引き出すことが可能なドラッグデリバリーシステムの開発が切望されている。近年、製剤の品質と機能の向上に著しく貢献するであろうと期待されている、ナノ技術を基盤とした新しい点眼システム「ナノ結晶点眼製剤」の調製法について概説し、これらナノ結晶点眼製剤の薬物動態、細胞毒性および緑内障への有用性に関する知見について述べた。
  • 乾式遊星ボールミル・湿式ビーズミル法の組み合わせによるナノ医薬品の創製:シロスタゾールナノ結晶からなる注射用製剤は脳虚血を抑制する, 上野祥奈, 長井紀章, 松田茅裕, 岩前亜弥, 伊藤吉將, 船上仁範, 西川裕之, 川畑篤史, 日本油化学会年会講演要旨集, 55th, 294,   2016 09 07 , http://jglobal.jst.go.jp/public/201602226670659667
  • 点眼用添加物EDTAが種々保存剤の抗菌力および角膜傷害性へ与える影響, 長井 紀章, 田辺 航, 辻 朗子, 勝井 結美, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, あたらしい眼科, 33, 6, 857, 861,   2016 06
    Summary:今回筆者らは、一般的な点眼用添加剤である安定化剤エチレンジアミン四酢酸(EDTA)が、各種保存剤の抗菌力および角膜傷害性に与える影響について検討を行った。保存剤はベンザルコニウム塩化物(BAC)、パラオキシ安息香酸メチル(MP)、パラオキシ安息香酸プロピル(PP)、亜塩素酸ナトリウム(SC)およびクロルヘキシジングルコン酸塩(CHG)の計5種を用いた。また、抗菌力および角膜傷害性の確認には大腸菌(E.coli,ATCC 8739)、ヒト角膜上皮細胞(HCE-T)を用いた。その結果、EDTA併用下において、BACの抗菌力上昇が認められたが、細胞傷害性に変化はみられなかった。一方、他の4剤の保存剤では、EDTAとの併用により抗菌力および細胞傷害性の低下がみられた。以上、点眼薬処方におけるEDTA使用は、保存剤の抗菌力や細胞傷害性に影響を与えることを明らかとした。本研究成果は、点眼薬処方設計の一つの指標になるものと考える。(著者抄録)
  • 表面麻酔薬オキシブプロカイン塩酸塩点眼液の角膜傷害性評価, 長井 紀章, 真野 裕, 辰巳 賀陽子, 川崎 真緒, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, あたらしい眼科, 33, 6, 863, 866,   2016 06
    Summary:本研究では、表面麻酔薬オキシブプロカイン塩酸塩点眼液の角膜傷害性について評価を行った。実験にはベノキシール点眼液0.4%(先発品)とオキシブプロカイン塩酸塩点眼液0.4%「ニットー」(ジェネリック医薬品、以下GE)を用いた。角膜傷害性は、ヒト角膜上皮細胞と1次速度式から算出した急性、慢性毒性にて評価した。また、ラット角膜上皮剥離モデルを用い、オキシブプロカイン塩酸塩点眼液点眼が角膜治癒へ与える影響についても検討した。GEの急性毒性は、先発品と比較し低値であった。一方、慢性毒性は、先発品とGE間で差は認められず、ラット角膜上皮剥離モデルを用いた系においても、GE点眼群の角膜傷害治癒速度は先発品のそれと同程度であった。以上、市販オキシブプロカイン塩酸塩点眼液の角膜傷害性を明らかにした。本研究結果は、眼に優しい表面麻酔薬開発への一つの指標になるものと考える。(著者抄録)
  • 【白内障の予防と治療】 白内障予防効果の向上を目指して 薬物ナノ結晶製剤の有用性, 長井 紀章, 伊藤 吉將, 日本白内障学会誌, 28, 1, 52, 55,   2016 06 , 10.14938/cataract.08-016
  • In Vitro and Vivo Evaluation of Corneal Damage Caused by Commercially Available Oxybuprocaine Eyedrops, using Human and Rat Corneal Epithelial Cells, 長井 紀章, 真野 裕, 辰巳 賀陽子, 川﨑 真緒, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, あたらしい眼科, 33, 6, 863, 866,   2016 06 , http://ci.nii.ac.jp/naid/40020888984
  • Effect of EDTA on Antimicrobial Activity and Corneal Toxicity of Various Eyedrop Preservatives, 長井 紀章, 田辺 航, 辻 朗子, 勝井 結美, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, あたらしい眼科, 33, 6, 857, 861,   2016 06 , http://ci.nii.ac.jp/naid/40020888948
  • シロスタゾール結晶多形間におけるナノ化製剤の安定性の比較, 吉岡 千晶, 長井 紀章, 伊藤 吉将, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集, 136年会, 2, 250, 250,   2016 03
  • トラニラストナノ結晶を用いた新規経眼瞼適用剤の開発とその涙液移行性評価, 上野 祥奈, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集, 136年会, 4, 64, 64,   2016 03
  • 点眼による網膜治療を目指した新規ナノ結晶点眼製剤の開発 シロスタゾールを用いた糖尿病網膜症治療, 田辺 航, 古瀬 のぞみ, 出口 粧央里, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集, 136年会, 4, 65, 65,   2016 03
  • 水溶性薬物の角膜透過性向上を可能とする新技術"ミネラルナノキャリア"の開発, 長井 紀章, 山岡 咲絵, 真野 裕, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集, 136年会, 4, 70, 70,   2016 03
  • カルシウム欠乏卵巣摘出ラットを用いた永久硬水および一時硬水の骨形成効果に関する基礎研究, 緒方文彦, 長井紀章, 伊藤吉將, 川崎直人, 日本薬学会年会要旨集(CD-ROM), 136th, 3, ROMBUNNO.29AB-AM380, 235,   2016 03 , http://jglobal.jst.go.jp/public/201602245568660411
  • New Developments to Break the Limitations of the Integrated Program-Inclusive Reform of Teaching and Learning by the Jigsaw Method- Foreword, Noriko Kodama, Noriaki Nagai, Tomohisa Yasuhara, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 136, 3, 359, 360,   2016 03 , 10.1248/yakushi.15-00231-F, http://ci.nii.ac.jp/naid/130005131258
  • Study on Enhancing the Anti-Cataract Effect —Usefulness of the Nanoparticle Formulation—, Nagai Noriaki, Ito Yoshimasa, The Journal of The Japanese Society for Cataract Research, 28, 1, 52, 55,   2016 , 10.14938/cataract.08-016, http://ci.nii.ac.jp/naid/130005162888
  • カルシウム欠乏卵巣摘出ラットを用いた永久硬水および一時硬水の骨形成効果に関する基礎研究, 緒方 文彦, 長井 紀章, 伊藤 吉將, 川崎 直人, 臨床環境医学, 24, 2, 94, 101,   2015 12
    Summary:本研究では、卵巣摘出ラットを用いてミネラル水飲水量と骨粗鬆症との関連性について基礎的検討を実施した。給餌方法は、低カルシウム食と精製水(PW群)、低カルシウム食と永久硬水(PH群)および低カルシウム食と一時硬水(HT群)の3種類とした。実験開始3ヵ月後、PH群およびTH群の骨密度は、PW群のそれと比較し、高値を示した(p<0.05)。これらのことから、永久硬水および一時硬水は、骨量の維持に寄与していることが明らかとなった。さらに、実験開始3ヵ月後のPW群においては、実験開始直後と比較し、骨中および血中のカルシウムおよびマグネシウム濃度は減少傾向を示した。一方、PH群およびHT群では、骨中および血中のカルシウムおよびマグネシウム濃度を維持していた。PH群およびTH群では骨量の維持が可能であることが示唆された。また、PW群、PH群およびTH群間において血清カルカリフォスファターゼに有意な差は認められなかった。(著者抄録)
  • The Proper Storage of Non-Steroidal Anti-Inflammatory Drugs Cataplasm: Risk of Contamination by the Combination Storage of Cataplasm and Hemorrhoid Ointment, Kotake Takeshi, Matsumoto Yurika, Tsukamoto Ayumi, Inoue Tomomi, Ishiwata Syunji, Kusanagi Mika, Sakano Tika, Ozato Yasuyuki, Ito Yoshimasa, Nagai Noriaki, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 41, 11, 786, 792,   2015 11 , 10.5649/jjphcs.41.786, http://ci.nii.ac.jp/naid/130005279279
    Summary:We investigated whether the component in cataplasm transmitted into hemorrhoid ointment in the combined storage of hemorrhoid ointment and non-steroidal anti-inflammatory drugs (NSAIDs) cataplasm. The NSAIDs cataplasm was used as a commercially available methyl salicylate (MS reishippu "TAIHO", MS cataplasm) and indomethacin (Catlep<sup>®</sup>, IMC cataplasm) cataplasm. In addition, the hemorrhoid ointment was in a polyethylene container with (Neriproct<sup>®</sup> ointment, DFV-L ointment) or without aluminum laminate (Posterisan<sup>®</sup> forte, HC ointment). As for the methyl salicylate, 5.68 mg / pieces in HC ointment were detected at 40 weeks of combined storage with MS cataplasm. The methyl salicylate concentration in DFV-L ointment was lower than that in HC ointment under the same conditions. On the other hand, no contamination of indomethacin in HC and DFV-L ointment was observed in the combined storage with IMC cataplasm. These results show that the methyl salicylate in cataplasm passed the polyethylene container, and provide significant information on the risk of contamination by the combined storage of cataplasm and hemorrhoid ointment.
  • 点眼用添加物EDTAが種々保存剤の抗菌効果及び角膜傷害性へ与える影響, 田辺 航, 長井 紀章, 辻 朗子, 勝井 結美, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 35回, 60, 60,   2015 09
  • 表面麻酔剤オキシブプロカイン塩酸塩点眼液の角膜傷害性評価, 真野 裕, 長井 紀章, 辰巳 賀陽子, 川崎 真緒, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 35回, 61, 61,   2015 09
  • トラニラストナノ粒子分散液によるリポポリサッカライド刺激RAW264.7細胞に対する抗炎症効果および作用機序の解明, 佐藤和昭, 荒井直紀, 金井一享, 伊藤吉將, 長井紀章, 山下洋平, 木村祐哉, 近澤征史朗, 堀泰智, 星史雄, 伊藤直之, 日本獣医学会学術集会講演要旨集, 158th, 402,   2015 08 30 , http://jglobal.jst.go.jp/public/201502206887479876
  • 薬物粒子径変更に伴うブリンゾラミド懸濁性点眼液の眼内薬物移行性評価, 長井 紀章, 真野 裕, 松平 有加, 山岡 咲絵, 吉岡 千晶, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 眼薬理, 29, 1, 33, 37,   2015 08
    Summary:本研究では、市販緑内障治療薬である炭酸脱水酵素阻害薬ブリンゾラミド(BLZ)懸濁性点眼液の薬物粒子径変更に伴う眼内薬物移行性について検討を行った。市販BLZ懸濁性点眼液(エイゾプト)の薬物粒子微細化には、ビーズミルによる水中破砕法を用いた。市販BLZ懸濁性点眼液の平均粒子径は7.05±0.416μmであったが、ビーズミル法を用いることで、平均粒子径0.423±0.221μmまで微細化でき、ナノオーダーの粒子径を有するBLZ分散液が調製できた(Milled-BLZ分散液)。これらMilled-BLZ分散液の眼内薬物移行性について評価したところ、薬物粒子径をナノオーダーにしたことで主薬の角膜透過性および薬物網膜到達量が有意に向上した。以上、微細化によりBLZ懸濁性点眼液の眼内薬物移行性が高まることが明らかとなった。本研究は、点眼用懸濁液の製剤設計およびバイオアベイラビリティー向上につながるものと考えられる。(著者抄録)
  • カルシウム欠乏卵巣摘出ラットを用いた高ミネラル水の骨形成促進効果に関する基礎研究, OGATA FUMIHIKO, NAGAI NORIAKI, ITO YOSHIMASA, KAWASAKI NAOHITO, 日本薬学会年会要旨集(CD-ROM), 135th, 3, ROMBUNNO.28PA-AM052, 221,   2015 03 , http://jglobal.jst.go.jp/detail.php?from=API&JGLOBAL_ID=201502289192020610
  • カルシウム欠乏卵巣摘出ラットを用いた高ミネラル水の骨形成促進効果に関する基礎研究, 緒方 文彦, 長井 紀章, 伊藤 吉將, 川崎 直人, 日本薬学会年会要旨集, 135年会, 3, 221, 221,   2015 03
  • トラニラストナノ粒子分散液による抗炎症効果の検証および作用機序の解明:in vitro試験, 佐藤和昭, 金井一享, 伊藤吉將, 長井紀章, 山下洋平, 山下洋平, 木村祐哉, 近澤征史朗, 堀泰智, 星史雄, 伊藤直之, 比較眼科学会年次大会講演要旨集, 35th, 45,   2015 , http://jglobal.jst.go.jp/public/201602203291114631
  • トラニラストナノ粒子分散点眼液のぶどう膜炎に対する抗炎症効果と機序の解明:in vivo試験, 二階堂寛, 金井一享, 能美君人, 伊藤吉將, 長井紀章, 山下洋平, 山下洋平, 近澤征史朗, 堀泰智, 星史雄, 伊藤直之, 比較眼科学会年次大会講演要旨集, 35th, 44,   2015 , http://jglobal.jst.go.jp/public/201602214669681698
  • 薬物粒子径変更に伴うブリンゾラミド懸濁性点眼液の角膜透過性向上, 真野 裕, 長井 紀章, 松平 有加, 山岡 咲絵, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 34回, 60, 60,   2014 09
  • ポリソルベート80またはEDTA併用使用が種々点眼用保存剤の効力に及ぼす影響, 田辺 航, 長井 紀章, 辻 朗子, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 34回, 61, 61,   2014 09
  • ベシル酸アムロジピン製剤を用いた簡易懸濁法適用時における吸着剤の影響, OGATA FUMIHIKO, NAGAI NORIAKI, HAYASHI TOMONORI, NISHIURA SAORI, MATSUOKA HIROSHI, ITO YOSHIMASA, KAWASAKI NAOTO, 日本薬学会年会要旨集(CD-ROM), 134th, 3, ROMBUNNO.28PML-103, 244,   2014 03 , http://jglobal.jst.go.jp/detail.php?from=API&JGLOBAL_ID=201402220771359142
  • メープルシュガーにおける血糖値上昇抑制効果, 多賀淳, 長井紀章, 山本哲志, 三田村邦子, 伊藤吉將, 日本薬学会年会要旨集(CD-ROM), 134th, ROMBUNNO.28AML-101,   2014 , http://jglobal.jst.go.jp/detail.php?from=API&JGLOBAL_ID=201402251488298822
  • ウサギ赤血球を用いたベンザルコニウム塩化物の傷害性評価とセリシンによる保護効果, 長井 紀章, 藤田 裕美, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 33回, 46, 46,   2013 09
  • 糖尿病モデル動物OLETFラット網膜におけるIL-18の発現亢進, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 32回, 67, 67,   2012 09
  • ラット角膜上皮剥離モデルを用いた点眼薬の角膜傷害性評価 粘稠化剤メチルセルロース添加に伴うBAC角膜傷害性の変化, 長井 紀章, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本薬学会年会要旨集, 132年会, 4, 316, 316,   2012 03
  • 糖尿病モデル動物OLETFラット網膜におけるアミロイドβの発現, 長井 紀章, 竹田 厚志, 村尾 まゆみ, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 31回, 58, 58,   2011 09
  • Relationship between Lipid Peroxidation and Ca^<2+>-ATPase Activity in ICR/f Rat Lenses Stimulated by Hydrogen Peroxide, NAGAI Noriaki, MURAO Takatoshi, KONAKA Yoko, ITO Yoshimasa, TAKEUCHI Noriko, 日本白内障学会誌, 23, 51, 54,   2011 06 03 , http://ci.nii.ac.jp/naid/10029877893
  • 脳虚血モデルラットにおけるシロスタゾール・ナノ粒子分散液の脳血流改善効果, 村尾卓俊, 南部義徳, 井上晃博, 長井紀章, 伊藤吉將, 船上仁範, 市田成志, 岡本紀夫, 松山知弘, 日本薬学会年会要旨集, 131st, 4, 189,   2011 03 05 , http://jglobal.jst.go.jp/public/201102296661466037
  • 主たる点眼剤添加物が糖尿病モデル動物OLETFラット角膜傷害治癒へ与える影響, 長井 紀章, 村尾 卓俊, 伊藤 吉將, 岡本 紀夫, 下村 嘉一, 日本眼薬理学会プログラム・抄録集, 30回, 46, 46,   2010 10
  • Cilostazolナノ粒子分散液の静脈内投与の検討, 村尾卓俊, 長井紀章, 伊藤吉將, 岡本紀夫, 船上仁範, 市田成志, 日本薬学会年会要旨集, 130th, 4, 188,   2010 03 05 , http://jglobal.jst.go.jp/public/201002263713957180
  • チーム基盤型学習(TBL)を導入した薬学部・医学部連携教育, 木村健, 安原智久, 船上仁範, 長井紀章, 喜多綾子, 北小路学, 大鳥徹, 岩城正宏, 松尾理, 日本薬学会年会要旨集, 130th, 4, 334,   2010 03 05 , http://jglobal.jst.go.jp/public/201002282052543388
  • Pharmaceutical evaluation method between original and generic drugs by dissolution test using HPLC connected to micro-dialysis probe, 長井 紀章, 伊藤 吉將, Jasco report, 51, 1, 14, 18,   2009 09 25 , http://ci.nii.ac.jp/naid/40016867164
  • エンドトキシン誘発ぶどう膜炎モデルにおけるジスルフィラム経口投与の効果, 金井一享, 堀泰智, 伊藤直之, 星史雄, 伊藤吉將, 長井紀章, 樋口誠一, 日本獣医学会学術集会講演要旨集, 148th, 263,   2009 , http://jglobal.jst.go.jp/public/200902265676229499

Research Grants & Projects

  • Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for Scientific Research(若手研究(B)), Early prediction of senile cataract based on the elucidation of mitochondrial DNA, We demonstrated that the rapidly and high production of nitric oxide (NO) caused to the mitochondrial damage in the human lens epithelial cells, and the balance in sensitivity of mitochondria and cell membrane to NO were related the mitochondrial dysfunction. In addition, the recovery time for mitochondrial function is related to exposure time to NO in human lens epithelial cells. The repetition in temporary mitochondrial dysfunction may be caused the lens opacification.