Advance

NAGAI Noriaki

    Department of Pharmacy　Professor
Last Updated :2024/04/23

Researcher Information

URL

J-Global ID

Research Interests

  • 角膜   点眼製剤   経皮吸収製剤   ナノパーティクル（ナノ医薬品）   網膜   水晶体   酸化ストレス   ミトコンドリアDNA   白内障   一酸化窒素   

Research Areas

  • 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

Academic & Professional Experience

  • 2023/04 - Today  近畿大学 薬学部 教授
  • 2017 - Today  Kindai UniversityFaculty of Pharmacy准教授
  • 2013/04 - 2017  Kindai UniversityFaculty of Pharmacy講師

Published Papers

  • Noriaki Nagai; Fumihiko Ogata; Reita Kadowaki; Saori Deguchi; Hiroko Otake; Yosuke Nakazawa; Manju Misra; Naohito Kawasaki
    Journal of oleo science 73 (4) 563 - 571 2024 
    The solubility and permeability of the Biopharmaceutics Classification System (BCS) class IV drugs, such as furosemide (FUR), are low. Thus, the oral bioavailability of these drugs needs to be augmented. Here, we aimed to design orally disintegrating tablets containing FUR nanoparticles to improve bioavailability after oral administration. The FUR nanoparticles were generated by bead-milling in water containing 0.5% methylcellulose and 0.5% 2-hydroxypropyl-β-cyclodextrin (w/w%). Particle size was approximately 47-350 nm (mean particle size, 188 nm). An orally disintegrating tablet (FUR-NP tablet) comprising FUR nanoparticles (1%) was successfully produced by employing suspensions outlined above that incorporated additives (4% D-mannitol, 0.4% polyvinylpyrrolidone, and 16% gum Arabic, w/w%), followed by freeze-drying. The FUR-NP tablet disaggregated after only 5 s in water, liberating nano-sized FUR particles (172 nm). Experiments using rats showed the absorption of the FUR-NP tablet was significantly improved by comparison with a FUR tablet containing microparticles. In summary, the orally disintegrating tablet containing FUR nanoparticles markedly enhanced the bioavailability of FUR. We anticipate this formulation will also improve the bioavailability of other BCS class IV drugs.
  • Fumihiko Ogata; Noriaki Nagai; Yugo Uematsu; Yuhei Kobayashi; Nanako Kitamura; Chalermpong Saenjum; Naohito Kawasaki
    RSC Sustainability 2024 
    Fine Na-type zeolite grains (ZE) were prepared by dry milling treatment (D-ZE) or wet milling treatment (W-ZE). Then, the prepared samples were characterized. The effective parameters of adsorption capacities including the initial concentration, adsorption temperature, pH, and contact time for lead-ion adsorption were determined. The results revealed that the adsorption capacity of lead ions was in the order of ZE (32.7 mg g-1) < D-ZE (70.7 mg g-1) < W-ZE (166.9 mg g-1). The results of the adsorption processes exhibited increased adsorption temperature, an increased pH of up to 5.0, and increased contact time. Pseudo-second-order model kinetic was observed, and the lead adsorbent isotherm followed the Langmuir and Freundlich models. Finally, one of the adsorption mechanisms was elucidated by analyzing the binding energy of lead (Pb) and lead (Pb) distribution before and after adsorption. Thus, the results serve as useful information for the adsorption of lead ions from aqueous solutions using ZE samples.
  • Yuri Doki; Yosuke Nakazawa; Miyu Sukegawa; Rosica S Petrova; Yuki Ishida; Shin Endo; Noriaki Nagai; Naoki Yamamoto; Megumi Funakoshi-Tago; Paul J Donaldson
    Experimental eye research 237 109719 - 109719 2023/12 
    Presbyopia is caused by age-related lenticular hardening, resulting in near vision loss, and it occurs in almost every individual aged ≥50 years. The lens experiences mechanical pressure during for focal adjustment to change its thickness. As lenticular stiffening results in incomplete thickness changes, near vision is reduced, which is known as presbyopia. Piezo1 is a mechanosensitive channel that constantly senses pressure changes during the regulation of visual acuity, and changes in Piezo1 channel activity may contribute to presbyopia. However, no studies have reported on Piezo1 activation or the onset of presbyopia. To elucidate the relevance of Piezo1 activation and cross-linking in the development of presbyopia, we analysed the function of Piezo1 in the lens. The addition of Yoda1, a Piezo1 activator, induced an increase in transglutaminase 2 (TGM2) mRNA expression and activity through the extra-cellular signal-regulated kinase (ERK) 1/2 and c-Jun-NH2-terminal kinase1/2 pathways. In ex vivo lenses, Yoda1 treatment induced γ-crystallin cross-linking via TMG2 activation. Furthermore, Yoda1 eye-drops in mice led to lenticular hardening via TGM2 induction and activation in vivo, suggesting that Yoda1-treated animals could serve as a model for presbyopia. Our findings indicate that this presbyopia-animal model could be useful for screening drugs for lens-stiffening inhibition.
  • Saori Deguchi; Ayusa Iwakami; Mizuki Tujigiwa; Hiroko Otake; Yu Mano; Naoki Yamamoto; Yosuke Nakazawa; Manju Misra; Noriaki Nagai
    Journal of pharmaceutical health care and sciences 9 (1) 44 - 44 2023/11 
    BACKGROUND: Gastrointestinal injuries caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is a serious side effect in patients with rheumatoid arthritis (RA). However, effective therapeutic strategies have yet to be established. In this study, we investigated the therapeutic effects of teprenone (TEP), a gastric mucosal protective drug, on NSAID-induced gastrointestinal injuries in rats with RA (AA rats). METHODS: Gastrointestinal injury was induced by oral administration of indomethacin (IMC), a typical NSAID. TEP was orally administered after IMC-induced gastrointestinal bleeding, and the stomach, jejunum, and ileum were excised. RESULTS: On day 14 of IMC administration, lesion areas in the stomach, jejunum, and ileum were significantly larger in AA rats than in normal rats. When TEP was orally administered to AA rats, the lesion areas in the stomach, jejunum, and ileum significantly decreased compared with those in control rats (IMC-induced AA rats). Therefore, we measured NOS2 mRNA and NO levels, which were significantly decreased in rats with IMC-induced AA after treatment with TEP. CONCLUSIONS: These results suggest that the oral administration of TEP may be useful for the treatment of NSAID-induced gastrointestinal injuries in patients with RA.
  • Yuya Otaka; Kazutaka Kanai; Daiki Okada; Noriaki Nagai; Yohei Yamashita; Yoichiro Ichikawa; Kazuki Tajima
    International journal of molecular sciences 24 (17) 2023/08 
    The metabolism of 5-aminolevulinic acid (ALA) is more efficient when combined with sodium ferrous citrate (SFC). Our previous study revealed that oral administration of ALA, which has anti-inflammatory properties, and SFC (ALA/SFC) immediately before lipopolysaccharide (LPS) inoculation suppressed endotoxin-induced uveitis (EIU) in rats. However, the therapeutic effect of ALA/SFC post-administration remains unexplored. Hence, this study aimed to evaluate the therapeutic efficacy of ALA/SFC on EIU in rats, which were administered with a gastric gavage of ALA/SFC (100/157 mg/kg) or prednisolone (Pred, 10 mg/kg) after 4 h of LPS inoculation. The treatment groups showed ameliorated clinical scores, inflammatory cells, protein levels in the aqueous humor (AqH), and histopathologic evaluation 24 h after LPS inoculation. Furthermore, the treatment groups had reduced tumor necrosis factor-α, nitric oxide, prostaglandin E2, and interleukin-6 levels in the AqH. ALA/SFC demonstrated an anti-inflammatory effect equivalent to that demonstrated by Pred. These findings indicate that ALA/SFC exerts a therapeutic effect on EIU in rats, indicating its clinical usefulness in uveitis treatment.
  • Kana Aihara; Yosuke Nakazawa; Shun Takeda; Natsuko Hatsusaka; Takanori Onouchi; Noriko Hiramatsu; Mayumi Nagata; Noriaki Nagai; Megumi Funakoshi-Tago; Naoki Yamamoto; Hiroshi Sasaki
    Medical molecular morphology 56 (4) 274 - 287 2023/07 
    Regulation of ion and water microcirculation within the lens is tightly controlled through aquaporin channels and connexin junctions. However, cataracts can occur when the lens becomes cloudy. Various factors can induce cataracts, including diabetes which is a well-known cause. The most common phenotype of diabetic cataracts is a cortical and/or posterior subcapsular opacity. In addition to the three main types and two subtypes of cataracts, a vacuole formation is frequently observed; however, their origin remains unclear. In this study, we focused on the aquaporins and connexins involved in diabetes-induced cataracts and vacuoles in Nile grass type II diabetes. The results showed that the expression of aquaporin 0 and aquaporin 5 increased, and that of connexin 43 decreased in diabetic rat lenses. Additionally, aquaporin 0 and 5 were strongly localized in peripheral of vacuoles, suggesting that aquaporins are involved in vacuoles formation. Transillumination photography revealed large vacuoles at the tip of the Y-suture in the anterior capsule of the diabetic lens, and several small vacuoles were observed in the posterior capsule. Within the vacuoles, cytoplasmic degradation and aggregation of fibrous material were observed. Our findings suggest that aquaporins are potential candidate proteins for preventing vacuole formation.
  • Reita Kadowaki; Fumihiko Ogata; Aoi Fushiki; Saki Daimyo; Saori Deguchi; Hiroko Otake; Mayumi Nagata; Hiroshi Sasaki; Naohito Kawasaki; Noriaki Nagai
    Journal of pharmaceutical health care and sciences 9 (1) 20 - 20 2023/06 
    BACKGROUND: It is important to design an effective formulation to enhance the skin penetration, and nanotechnologies have been used in dermal and transdermal drug delivery. In this study, we prepared formulations (gels) containing l-menthol and felbinac (FEL) solid nanoparticles (FEL-NP gel) for topical application, and investigated the local and systemic absorption of the prepared FEL-NP gel. METHODS: FEL solid nanoparticles were obtained by bead milling of FEL powder (microparticles), and a topical formulation (FEL-NP gel) consisting of 1.5% FEL solid nanoparticles), 2% carboxypolymethylene, 2% l-menthol, 0.5% methylcellulose, and 5% 2-hydroxypropyl-β-cyclodextrin (w/w %) were prepared. RESULTS: The particle size of FEL nanoparticles was 20-200 nm. The released FEL concentration from FEL-NP gel was significantly higher than that from FEL gel without bead mill treatment (carboxypolymethylene gel in which FEL microparticles (MPs) instead of FEL nanoparticles were incorporated, FEL-MP gel), and FEL was released as nanoparticles from the gel. Moreover, both transdermal penetration and percutaneous absorption of FEL-NP gel were significantly increased compared with those of FEL-MP gel, and the area under the FEL concentration-time curve (AUC) of FEL-NP gels was 1.52- and 1.38-fold of commercially available FEL ointment and FEL-MP gel, respectively. In addition, after 24 h of treatment, the FEL content in rat skin treated with FEL-NP gels was 1.38- and 2.54-fold higher than that when treated with commercially available FEL ointment and FEL-MP gel, respectively. Moreover, the enhanced skin penetration of FEL-NP gels was significantly attenuated by inhibition of energy-dependent endocytosis, such as clathrin-mediated endocytosis. CONCLUSIONS: We successfully prepared a topically applied carboxypolymethylene gel containing FEL nanoparticles. In addition, we observed that the endocytosis pathway was mainly related to the high skin penetration of FEL nanoparticles, and FEL-NP gel application resulted in high local tissue concentration and systemic absorption of FEL. These findings provide useful information for the design of topically applied nanoformulations against inflammation by providing local and systemic effects.
  • Yuya Otaka; Kazutaka Kanai; Arisa Mori; Daiki Okada; Noriaki Nagai; Yohei Yamashita; Yoichiro Ichikawa; Kazuki Tajima
    International Journal of Molecular Sciences MDPI AG 24 (10) 8653 - 8653 2023/05 
    Sodium ferrous citrate (SFC) is involved in the metabolism of 5-aminolevulinic acid (5-ALA) and enhances its anti-inflammatory effects. The effects of 5-ALA/SFC on inflammation in rats with endotoxin-induced uveitis (EIU) have yet to be elucidated. In this study, during lipopolysaccharide injection, 5-ALA/SFC (10 mg/kg 5-ALA plus 15.7 mg/kg SFC) or 5-ALA (10 or 100 mg/kg) was administered via gastric gavage, wherein we saw that 5-ALA/SFC ameliorated ocular inflammation in EIU rats by suppressing clinical scores; by infiltrating cell counts, aqueous humor protein, and inflammatory cytokine levels; and by improving histopathological scores to the same extent as 100 mg/kg 5-ALA. Immunohistochemistry showed that 5-ALA/SFC suppressed iNOS and COX-2 expression, NF-κB activation, IκB-α degradation, and p-IKKα/β expression, and activated HO-1 and Nrf2 expression. Therefore, this study has investigated how 5-ALA/SFC reduces inflammation and revealed the pathways involved in EIU rats. 5-ALA/SFC is shown to inhibit ocular inflammation in EIU rats by inhibiting NF-κB and activating the HO-1/Nrf2 pathways.
  • Yuri Doki; Yosuke Nakazawa; Naoki Morishita; Shin Endo; Noriaki Nagai; Naoki Yamamoto; Hiroomi Tamura; Megumi Funakoshi-Tago
    Molecular medicine reports 27 (5) 2023/05 
    Advanced glycation end products (AGEs) in lens proteins increase with aging, thus inducing cataracts and/or presbyopia. Hesperetin (Hst), which is an abundant plant flavanone largely derived from citrus species, and its derivatives attenuate cataracts and presbyopia in vivo and in vitro; however, no reports have described its effects on AGE formation in lens proteins. The present study demonstrated that AGEs in lens proteins increase with age in mice. Additionally, it showed that Hst can prevent AGEs and N(ε)‑carboxymethyl‑lysine generation and modification of lens proteins using in vitro in human lens epithelial cell lines and ex vivo in mouse lens organ cultures. Furthermore, treatment with Hst prevented lens hardening and decreased chaperone activity in lens proteins. These results suggested that Hst and its derivatives are good candidates for the prevention of presbyopia and cataracts.
  • Yuya Otaka; Kazutaka Kanai; Daiki Okada; Noriaki Nagai; Yohei Yamashita; Yoichiro Ichikawa; Kazuki Tajima
    Veterinary sciences 10 (3) 2023/03 
    This study aimed to investigate the anti-inflammatory effect of 5-aminolevulinic acid (5-ALA) on endotoxin-induced uveitis (EIU) in rats. EIU was induced in male Sprague Dawley rats by the subcutaneous injection of lipopolysaccharide (LPS). During LPS injection, 5-ALA diluted with saline was administered via gastric gavage. After 24 h, clinical scores were assessed after which aqueous humor (AqH) samples were obtained. The number of infiltrating cells, protein concentration, and levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), and prostaglandin E2 (PGE2) in AqH were measured. For histological examination, both eyes of some rats were enucleated. In vitro, a mouse macrophage cell line (RAW264.7 cells) was stimulated by LPS with or without 5-ALA. Western blot was used to analyze the expression of inducible NO synthase (iNOS) and cyclooxygenase-2. 5-ALA suppressed the EIU clinical scores, infiltrating cell number, and protein concentration while improving the histopathologic scores. In particular, 100 mg/kg 5-ALA reduced the concentrations of NO, PGE2, TNF-α, and IL-6 in AqH, similar to 1 mg/kg prednisolone. In addition, 5-ALA suppressed iNOS upregulation in LPS-stimulated RAW264.7 cells. Therefore, 5-ALA has an anti-inflammatory effect on EIU through the inhibition of the upregulation of inflammatory mediators.
  • Fumihiko Ogata; Yugo Uematsu; Noriaki Nagai; Ibuki Kobata; Ayako Tabuchi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Heliyon 9 (3) e14503  2023/03 
    In this study, waste biomass adsorbents produced from mangosteen shells (MGS) were prepared (denoted as MGS500 and MGS1000). The physical and chemical characteristics, such as scanning electron microscopy, thermogravimetric-differential thermal analysis, specific surface area, pore volumes, surface functional groups, and point of zero charge of the prepared MGS samples were determined, and the adsorption capacity of cadmium ions from aqueous media was assessed. The effects of pH, adsorption time, temperature, and coexistence on adsorption were carefully assessed using an inductively coupled plasma optical emission spectrometer under several experimental conditions. The adsorption capacity decreased in the order, MGS < MGS500 < MGS1000. The optimal pH for cadmium ion removal was 5.0. The amount of cadmium ions adsorbed gradually increased with time, and adsorption equilibrium was achieved within 24 h after adsorption. Additionally, the amount of adsorbed cadmium ions increased with increasing adsorption temperature. To elucidate the adsorption mechanism in detail, the elemental distribution and X-ray photoelectron spectra of the prepared adsorbents were analyzed. Finally, desorption solutions such as HNO3, H2O, and NaOH were used to desorb the absorbed cadmium ions from MGS1000. Under our experimental conditions, the desorption percentage of cadmium ions was approximately 98.8% using HNO3. In conclusion, MGS1000 exhibited a good adsorption capacity of 12.0 mg/g for adsorbing cadmium ions from aqueous media and desorption capacity with HNO3 at 1000 mmol/L.
  • Mayu Kawaguchi; Kana Matsumoto; Joji Yoshitomi; Hiroko Otake; Kanta Sato; Atsushi Taga; Tatsuji Sasabe; Kenji Nobuhara; Akira Matsubara; Noriaki Nagai
    PloS one 18 (10) e0292447  2023 
    N,N-diethyl-meta-toluamide (DEET) is a widely used insect repellent, with minimal skin permeation and sustained repellent activity in the superficial layers of the skin. In this study, we prepared a 10% DEET formulation consisting of 40% ethanol with or without 2% poly(oxyethylene)/poly(oxypropylene) butyl ether (POE-POP), an amphiphilic random copolymer. Further, we demonstrated the effects of POE-POP on tensile stress (stickiness), hydrophobicity, skin retention, permeation, and repellent activity of DEET. Stickiness was measured in male ICR mice (7-week old), and skin retention and permeation were evaluated in male Wistar rats (7-week old). In addition, female Aedes albopictus were used to measure the repellent action of DEET. The addition of POE-POP did not affect stickiness, volatility, and degradability but decreased logP and increased viscosity of DEET. Next, we demonstrated the behavior of DEET formulations in the rat skin. POE-POP prolonged the retention of DEET in the superficial layers of the rat skin (skin surface and stratum corneum) and decreased the penetration of DEET into rat skin tissues (epithelium and dermis). The repellent effect of DEET was also enhanced by the addition of POE-POP. However, severe skin damage was not observed after repetitive treatment with DEET formulations containing POE-POP for one month (twice a day). In conclusion, we demonstrated that a 10% DEET formulation consisting of 40% ethanol and 2% POE-POP attenuated the skin penetration and prolonged the repellent action of DEET without causing stickiness and skin damage. We conclude that the combination of ethanol and POE-POP is useful as a safe and effective delivery system for the development of insect repellent formulations containing DEET.
  • Fumihiko Ogata; Kazuki Sugimura; Noriaki Nagai; Chalermpong Saenjum; Keiji Nishiwaki; Naohito Kawasaki
    RSC Sustainability 2023 
    This research aims to evaluate waste cotton and polyester as effective potential adsorbents for the removal of crystal violet (CV) from aqueous phases. Carbonaceous materials (VCP1000 or VC1000) from waste cotton and polyester were prepared at different calcination temperatures, and their characteristics were assessed using scanning electron microscopy, pHpzc, surface functional groups, and specific surface areas. The values of the parameters of VCP1000 or VC1000 were greater than those of other adsorbents. Additionally, adsorption experiments were performed in batch mode, and various parameters, including initial concentration, adsorption temperature, contact time, and pH, were demonstrated in this study. The amount of CV adsorbed onto VCP1000 and/or VC1000 was higher than those onto other VCP and/or VC adsorbents. The adsorption equilibrium of CV was achieved within 24 h. These data were fitted to the pseudo-second-order model (correlation coefficient: 0.991-0.995). The adsorption capacity increased with increasing adsorption temperatures (7 °C < 25 °C < 45 °C). The adsorption isotherm data were fitted to both the Langmuir and Freundlich models as well. The adsorption of CV using VCP1000 or VC1000 was significantly influenced by pH under our experimental conditions. Finally, elemental distribution and binding energy analyses were conducted to elucidate the adsorption mechanisms of CV. The obtained results indicate that the adsorbed CV was presented onto the VCP1000 and/or VC1000 surface. Collectively, these obtained results show that VCP1000 or VC1000 holds promise for the removal of CV from aqueous phases.
  • Fumihiko Ogata; Ayako Tabuchi; Noriaki Nagai; Megumu Toda; Masashi Otani; Chalermpong Saenjum; Naohito Kawasaki
    Chemical & pharmaceutical bulletin 71 (8) 661 - 664 2023 
    A colloidal silicate granulated nickel-aluminum-zirconium (CSG-NAZ) was prepared, and the chromium(VI) (Cr(VI)) ions recovery capacity was evaluated using a sodium sulfate solution in a column experiment. The amount adsorbed and breakthrough time were enhanced by decreasing the flow rate (flow rate is in the order of 3.0 > 2.0 > 0.5 mL). The breakthrough curves and model parameters were estimated using the Thomas and Yoon-Nelson models. The obtained data confirmed to fit both the Yoon-Nelson model (0.858-0.906) and the Thomas model (0.813-0.906). Additionally, Cr(VI) ions that adsorbed onto CSG-NAZ could be desorbed using a sodium sulfate solution in a column experiment. The total recovery percentage of Cr(VI) ions was 80.9% after six repetitions of adsorption/desorption. Finally, the obtained results revealed that CSG-NAZ was a candidate adsorbent for the recovery of Cr(VI) ions owing to its applicability toward a continuous system.
  • Shuya Masuda; Saori Deguchi; Fumihiko Ogata; Joji Yoshitomi; Hiroko Otake; Kazutaka Kanai; Naohito Kawasaki; Noriaki Nagai
    International journal of nanomedicine 18 5685 - 5699 2023 
    PURPOSE: We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF). METHODS: MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice. RESULTS: The particle size range of MF prepared with the bead mill treatment was 80-200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions. CONCLUSION: We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.
  • Reita Kadowaki; Fumihiko Ogata; Miku Nishida; Miri Komatsu; Hiroko Otake; Yosuke Nakazawa; Naoki Yamamoto; Naohito Kawasaki; Noriaki Nagai
    Drug design, development and therapy 17 3349 - 3361 2023 
    PURPOSE: Medical therapies, such as the use of anti-inflammatory agents, are commonly used for the treatment of oral mucositis (OM). However, these treatments have limited efficacy in treating severe cases of OM. In this study, we aimed to develop a carbopol gel incorporating troxipide (TRO) nanoparticles and methylcellulose (TRO-NP gel) and demonstrate its efficacy in accelerating wound healing in a hamster model of OM (OM model) induced by acetic acid injection. METHODS: TRO nanoparticles were prepared using bead milling. The crystalline form was determined by powder X-ray diffraction, and the particle size was measured using a NanoSight LM10 instrument. The drug release was determined using a Franz diffusion cell, and the hamsters injected with acetic acid were selected to evaluate the therapeutic effect of OM. RESULTS: After preparing TRO nanoparticles, we observed a mixture of crystals and amorphous TRO, and the particle size of TRO in the TRO-NP gel ranged from 50 to 280 nm. The TRO-NP gel exhibited a more uniform TRO distribution and viscosity compared to the Carbopol gel containing TRO microparticles (TRO-MP gel). However, the solubility of TRO was comparable in both TRO-MP and TRO-NP gels. The TRO-NP gel released a higher amount of TRO than that from the TRO-MP gel, with detectable release of TRO nanoparticles. TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were higher than those treated with TRO-MP gel. The increased TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were attenuated by treatment with 40 μM dynasore, an inhibitor of clathrin-dependent endocytosis (CME). Moreover, the therapeutic effect of the TRO-NP gel was superior to that of the TRO-MP gel in the hamster model of OM. CONCLUSION: We have designed a TRO-NP gel, and this gel showed excellent TRO delivery into the cheek pouch tissue through the CME pathway. Moreover, the TRO-NP gel treatment enhanced wound healing after acetic acid injection.
  • Yuya OTAKA; Kazutaka KANAI; Aoi TOMATSU; Riyo SANGU; Daiki OKADA; Noriaki NAGAI; Yohei YAMASHITA; Yoichiro ICHIKAWA; Aki SAKAI; Kazuki TAJIMA
    Journal of Veterinary Medical Science Japanese Society of Veterinary Science 85 (12) 1257 - 1260 0916-7250 2023 
    This study investigated the preventive effect of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) on blood-aqueous barrier (BAB) breakdown induced after anterior chamber paracentesis (ACP) in beagles. 5-ALA/SFC (1/0.64 mg/kg or 3/1.92 mg/kg) or carprofen (4.0 mg/kg) was orally administered daily for 7 days prior to ACP. Then, a sample of the aqueous humor (AH) was collected from one eye via ACP (first sample) and again 60 min later (second sample). The protein and prostaglandin E2 (PGE2) concentrations in both samples were measured. Compared with the control group, high-dose 5-ALA/SFC and carprofen significantly reduced the AH protein and PGE2 concentrations in the second sample. Our findings suggest that 5-ALA/SFC suppresses BAB breakdown in dogs.
  • Noriaki Nagai; Fumihiko Ogata; Reita Kadowaki; Saori Deguchi; Hiroko Otake; Yosuke Nakazawa; Mayumi Nagata; Hiroshi Sasaki; Naohito Kawasaki
    Frontiers in bioengineering and biotechnology 11 1167291 - 1167291 2023 
    The permeability of the Biopharmaceutics Classification System (BCS) class III drugs are low, and their oral bioavailability needs to be improved. In this study, we attempted to design oral formulations containing famotidine (FAM) nanoparticles to overcome the limitations of BCS class III drugs. Dispersions containing FAM nanoparticles with a particle size of approximately 50-220 nm were produced by the bead-milling treatment. Moreover, we succeeded in preparing an orally disintegrating tablet containing FAM nanoparticles using the dispersions described above, additives (D-mannitol, polyvinylpyrrolidone, and gum arabic), and freeze-dry treatment (FAM-NP tablet). The FAM-NP tablet was disaggregated 3.5 s after addition to purified water, and the FAM particles in the redispersion of the FAM-NP tablet stored for 3 months were nano-sized (141 ± 6.6 nm). The ex-vivo intestinal penetration and in vivo absorption of FAM in rats applied with the FAM-NP tablet were significantly higher than those in rats applied with the FAM tablet containing microparticles. In addition, enhanced intestinal penetration of the FAM-NP tablet was attenuated by an inhibitor of clathrin-mediated endocytosis. In conclusion, the orally disintegrating tablet containing FAM nanoparticles improved low mucosal permeability and low oral bioavailability and overcame these issues of BCS class III drugs as oral formulations.
  • Hiroko Otake; Yu Mano; Saori Deguchi; Fumihiko Ogata; Naohito Kawasaki; Noriaki Nagai
    Biological & pharmaceutical bulletin 46 (5) 707 - 712 2023 
    Wound-healing deficits of the skin, one of the most common complications in patients with diabetes, delay wound healing, significantly reducing the patient's QOL. Therefore, the topical treatment of wound areas with drug-containing ointments and dressings is important. In this study, we investigated the effect of various ointment bases on skin wound healing in normal and streptozotocin-induced diabetic rats (STZ rats). Three ointment bases were used: white ointment (oil-based), absorbent cream (emulsion-based, w/o), and macrogol ointment (water-based). Skin wound healing in STZ rats was delayed compared with that in normal rats. Each of the three ointment bases was applied to the skin wound area in normal rats, and there was no difference in the therapeutic effect. The therapeutic effect of both white ointment and absorbent cream was higher in the STZ rats group than that in the non-treated group, and delayed wound healing was observed in STZ rats treated with macrogol ointment. In conclusion, skin wound healing in STZ rats is affected by the properties of the ointment base, and it is important to use an ointment base that controls the drying of the wound area in STZ rats. These findings provide information for the selection of ointment bases useful for application to skin wounds in patients with diabetes.
  • Shun Takeda; Naoki Yamamoto; Noriaki Nagai; Noriko Hiramatsu; Saori Deguchi; Natsuko Hatsusaka; Eri Kubo; Hiroshi Sasaki
    Molecular medicine reports 27 (1) 2023/01 
    Enhancement of density via human lens epithelium (HLE) cell proliferation is the underlying cause of nuclear cataracts. Moreover, our previous epidemiological study demonstrated that the risk of nuclear cataract development is significantly higher under elevated environmental temperatures compared with under lower temperatures. The present study investigated the relationship between temperature and cell proliferation in terms of mitochondrial function, which is a nuclear cataract‑inducing risk factor, using two different HLE cell lines, SRA01/04 and immortalized human lens epithelial cells NY2 (iHLEC‑NY2). Cell proliferation was significantly enhanced under the high‑temperature condition (37.5˚C) in both cell lines. The cell growth levels of SRA01/04 and iHLEC‑NY2 cells cultured at 37.5˚C were 1.20‑ and 1.16‑fold those in the low‑temperature cultures (35.0˚C), respectively. Moreover, the levels of cytochrome c oxidase mRNA (mitochondrial genome, cytochrome c oxidase‑1‑3) and its activity in SRA01/04 and iHLEC‑NY2 cells cultured at 37.5˚C were higher compared with those in cells cultured at 35.0˚C. In addition, adenosine‑5'‑triphosphate (ATP) levels in SRA01/04 and iHLEC‑NY2 cells were also significantly higher at 37.5˚C compared with those at 35.0˚C. By contrast, no significant differences in Na+/K+‑ATPase or Ca2+‑ATPase activities were observed between HLE cells cultured at 35.0 and 37.5˚C. These results suggested that expression of the mitochondrial genome was enhanced in high‑temperature culture, resulting in a sufficient ATP content and cell proliferation for lens opacity. Therefore, elevated environmental temperatures may increase the risk of nuclear cataracts caused by HLE cell proliferation via mitochondrial activation.
  • Fumihiko Ogata; Yugo Uematsu; Noriaki Nagai; Misaki Nakamura; Ayako Tabuchi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Bioresource Technology Reports Elsevier BV 20 101238 - 101238 2589-014X 2022/12
  • Noriaki Nagai; Hiroko Otake
    Advanced drug delivery reviews 191 114582 - 114582 2022/12 
    Dry eye disease (DED) is a frequently observed eye complaint, which has recently attracted considerable research interest. Conventional therapy for DED involves the use of artificial tear products, cyclosporin, corticosteroids, mucin secretagogues, antibiotics and nonsteroidal anti-inflammatory drugs. In addition, ocular drug delivery systems based on nanotechnology are currently the focus of significant research effort and several nanotherapeutics, such as nanoemulsions, nanosuspensions, microemulsions, liposomes and nanomicelles, are in clinical trials and some have FDA approval as novel treatments for DED. Thus, there has been remarkable progress in the design of nanotechnology-based approaches to overcome the limitations of ophthalmic formulations for the management of anterior eye diseases. This review presents research results on diagnostic methods for DED, current treatment options, and promising pharmaceuticals as future therapeutics, as well as new ocular drug delivery systems.
  • Noriko Hiramatsu; Naoki Yamamoto; Mahito Ohkuma; Noriaki Nagai; Ei-Ichi Miyachi; Kumiko Yamatsuta; Kazuyoshi Imaizumi
    Medical molecular morphology 55 (4) 292 - 303 2022/12 
    When regenerated tissue is generated from induced pluripotent stem cells (iPSCs), it is necessary to track and identify the transplanted cells. Fluorescently-labeled iPSCs synthesize a fluorescent substance that is easily tracked. However, the expressed protein should not affect the original genome sequence or pluripotency. To solve this problem, we created a cell tool for basic research on iPSCs. Iris tissue-derived cells from GFP fluorescence-expressing mice (GFP-DBA/2 mice) were reprogrammed to generate GFP mouse iris-derived iPSCs (M-iris GFP iPSCs). M-iris GFP iPSCs expressed cell markers characteristic of iPSCs and showed pluripotency in differentiating into the three germ layers. In addition, when expressing GFP, the cells differentiated into functional recoverin- and calbindin-positive cells. Thus, this cell line will facilitate future studies on iPSCs.
  • Noriaki Nagai; Fumihiko Ogata; Saori Deguchi; Aoi Fushiki; Saki Daimyo; Hiroko Otake; Naohito Kawasaki
    Pharmaceutics 14 (11) 2022/11 
    We aimed to investigate which base was suitable for preparing transdermal formulations incorporating tulobuterol (TUL) nanoparticles (30-180 nm) in this study. Three bases (water-soluble, absorptive, and aqueous ionic cream) were selected to prepare the transdermal formulations, and TUL nanoparticles were prepared with a bead-milling treatment. In the drug release study, the TUL release from the water-soluble ointment was higher than that from the other two ointments. Moreover, the addition of l-menthol enhanced TUL nanoparticle release from the ointment, and the rat skin penetration of the TUL water-soluble ointment was also significantly higher than that of the other two ointments. In addition, the drug penetration of the TUL water-soluble ointment with l-menthol sustained zero-order release over 24 h, and the skin permeability of TUL increased with TUL content in the ointment. On the other hand, this penetration was significantly inhibited by treatment with a caveolae-mediated endocytosis inhibitor (nystatin). In conclusion, we found that the water-soluble base incorporating TUL nanoparticles and l-menthol was the best among those assessed in this study. Furthermore, the pathway using caveolae-mediated endocytosis was related to the skin penetration of TUL nanoparticles in the TUL water-soluble ointment with l-menthol. These findings are useful for the design of a transdermal sustained-release formulation based on TUL nanoparticles.
  • Manisha Choudhari; Kritika Nayak; Noriaki Nagai; Yosuke Nakazawa; Dignesh Khunt; Manju Misra
    International ophthalmology 43 (4) 1153 - 1167 2022/09 
    PURPOSE: The aim of the present study was to investigate increase in delivery of drug upon formulation as mucoadhesive microemulsion system and further to investigate possibility of any cytotoxic effects using such formulation. MATERIAL AND METHODS: Considering hydrophilic and small molecular nature of the drug, it was attempted to be formulated as microemulsion, by using pseudo ternary phase diagram method. Thus, three types of microemulsions were prepared; oil in water, water in oil type and chitosan-coated microemulsion. These microemulsions were characterized for several physicochemical properties like size, zeta potential, Polydispersity index, and compared for in vitro cell viability and ex vivo corneal irritation study. RESULTS: All three microemulsions were quite stable, transparent and homogenous systems. They showed similar drug release pattern, but highest ex vivo goat corneal permeation was observed with Chitosan coated microemulsion when compared with ganciclovir solution. CONCLUSION: All microemulsions were found to be non-irritant in in vitro cell viability assay and ex vivo corneal irritation study, indicating the potential of using such systems for delivery of drug to eye.
  • Noriko Hiramatsu; Naoki Yamamoto; Yu Kato; Noriaki Nagai; Sumito Isogai; Kazuyoshi Imaizumi
    Experimental and therapeutic medicine 24 (2) 539 - 539 2022/08 
    Induced pluripotent stem (iPS) cells are widely used as a research tool in regenerative medicine and embryology. In studies related to lens regeneration in the eye, iPS cells have been reported to differentiate into lens epithelial cells (LECs); however, to the best of our knowledge, no study to date has described their formation of three-dimensional cell aggregates. Notably, in vivo studies in newts have revealed that iris cells in the eye can dedifferentiate into LECs and regenerate a new lens. Thus, as basic research on lens regeneration, the present study investigated the differentiation of human iris tissue-derived cells and human iris tissue-derived iPS cells into LECs and their formation of three-dimensional cell aggregates using a combination of two-dimensional culture, static suspension culture and rotational suspension culture. The results revealed that three-dimensional cell aggregates were formed and differentiated into LECs expressing αA-crystallin, a specific marker protein for LECs, suggesting that the cell-cell interaction facilitated by cell aggregation may have a critical role in enabling highly efficient differentiation of LECs. However, the present study was unable to achieve transparency in the cell aggregates; therefore, we aim to continue to investigate the degradation of organelles and other materials necessary to make the interior of the formed cell aggregates transparent. Furthermore, we aim to expand on our current work to study the regeneration of the lens and ciliary body as a whole in vitro, with the aim of being able to restore focusing function after cataract surgery.
  • Saori Deguchi; Reita Kadowaki; Hiroko Otake; Atsushi Taga; Yosuke Nakazawa; Manju Misra; Naoki Yamamoto; Hiroshi Sasaki; Noriaki Nagai
    Pharmaceutics 14 (7) 2022/07 
    It has recently been reported that lanosterol (LAN) plays a preventive role against lens opacification through the reversal of crystalline aggregation. However, the effect of LAN is not sufficient to restore lens transparency. In this study, we designed ophthalmic nanosuspensions (LAN-ONSs and NIL-ONSs) based on LAN and nilvadipine (NIL), which can counteract cataract-related factors (e.g., enhanced Ca2+ and calpain levels), and investigated whether the combination of LAN-ONSs and NIL-ONSs can restore the nuclear lens opacity in sodium-selenite-induced cataractic rats (cataractic rats). The mean particle sizes of the LAN-ONSs and NIL-ONSs were 108.8 nm and 89.0 nm, respectively. The instillation of the LAN-ONSs or NIL-ONSs successfully delivered the drugs (LAN or NIL) into the lenses of the rats, although the instillation of LAN-ONSs or NIL-ONSs alone did not increase lens transparency in the cataractic rats. On the other hand, the cataract-related factors (enhanced Ca2+ and calpain levels) were significantly alleviated by the combination of LAN-ONSs and NIL-ONSs; furthermore, the perinuclear refractile ring in the lens nucleus and enhanced number of swollen fibers were attenuated by the LAN-ONS and NIL-ONS combination. Moreover, the opacity levels in the cataractic rats were reduced after treatment with the combination of LAN-ONSs and NIL-ONSs. It is possible that the combination of LAN and NIL will be useful for the treatment of lens opacification in the future.
  • レバミピド懸濁点眼液とMPCポリマーの併用処理によるドライアイ治療効果の有用性評価
    後藤 涼花; 勢力 諒太朗; 渡辺 彩花; 油納 美和; 大竹 裕子; 櫻井 俊輔; 原田 英治; 長井 紀章
    あたらしい眼科 (株)メディカル葵出版 39 (7) 982 - 987 0910-1810 2022/07 
    本研究では市販ドライアイ治療薬であるレバミピド懸濁点眼液(REB点眼液)と生体適合性MPCポリマー(MPCP)を併用処理した際のドライアイに対する治癒効果について検討した。REB点眼液点眼5分後にMPCPを処理することで、涙液中REB濃度の滞留性向上が確認され、そのREB眼表面滞留時間の延長はREB点眼液単独処理群と比較し有意に高値であった。次に、N-アセチルシステイン処理ウサギ(眼表面ムチン被覆障害モデル)を用い、REB点眼液とMPCP併用処理時のドライアイに対する治療効果を検討したところ、併用処理により、眼表面ムチン被覆障害モデルの涙液層破壊とムチン量低下は改善され、その効果はREB点眼液単独処理群に比べ高値であった。以上、MPCP併用により、REBの涙液中薬物滞留性が高まるとともに、ムチン被覆改善作用が向上する可能性が示唆された。(著者抄録)
  • Noriaki Nagai; Mayu Kawaguchi; Misa Minami; Kana Matsumoto; Tatsuji Sasabe; Kenji Nobuhara; Akira Matsubara
    Molecules (Basel, Switzerland) MDPI 27 (10) 2022/05 
    N,N-diethyl-3-toluamide (DEET) is one of the most widely used insect repellents in the world. It was reported that a solution containing 6-30% cyclodextrin (CD) as a solvent instead of ethanol (EtOH) provided an enhancement of the repellent action time duration of the DEET formulation, although the high-dose CD caused stickiness. In order to overcome this shortcoming, we attempted to prepare a 10% DEET formulation using EtOH containing low-dose CDs (β-CD, 2-hydroxypropyl-β-CD (HPβCD), methyl-β-CD, and sulfobutylether-β-CD) as solvents (DEET/EtOH/CD formulations). We determined the CD concentration to be 0.1% in the DEET/EtOH/CD formulations, since the stickiness of 0.1% CDs was not felt (approximately 8 × 10-3 N). The DEET residue on the skin superficial layers was prolonged, and the drug penetration into the skin tissue was decreased by the addition of 0.1% CD. In particular, the retention time and attenuated penetration of DEET on the rat skin treated with the DEET/EtOH/HPβCD formulation was significantly higher in comparison with that of the DEET/EtOH formulation without CD. Moreover, the repellent effect of DEET was more sustained by the addition of 0.1% HPβCD in the study using Aedes albopictus. In conclusion, we found that the DEET/EtOH/HPβCD formulations reduced the skin penetration of DEET and prolonged the repellent action without stickiness.
  • Fumihiko Ogata; Noriaki Nagai; Mamiko Funaki; Ayako Tabuchi; Yuhei Kobayashi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Chemical and Pharmaceutical Bulletin 70 (5) 400 - 407 0009-2363 2022/05 
    Coal fly ash (FA) was treated by hydrothermal activation with sodium hydroxide solution at different concentrations to optimize the conversion method. Zeolite of the sodium type is prepared from coal FA by 1, 1.5, and 3 mol/L sodium hydroxide solutions (ZE1, ZE1.5, and ZE3). These adsorbents?morphology, crystal structure, scanning electron microscopy, Fourier transform (FT)-IR spectra, cation exchange capacity (CEC), specific surface area and pore volumes, and pHpzc were determined. An adsorption experiment was performed to evaluate the effects of contact time, pH, temperature, and coexistence. From the results, the values of CEC and specific surface area of prepared samples was in the order ZE3 < ZE1.5 < ZE1. The similar trends were observed in lead ions adsorption. In addition, our obtained data elucidate that the ion exchange with sodium ions in the interlayer ZE1 is one of the adsorption mechanisms of Pb2_ from water layer. Finally, lead ions adsorbed on ZE1 could be desorbed using a hydrochloric acid solution, showing that ZE1 could be reused as a water purification agent.
  • Fumihiko Ogata; Noriaki Nagai; Chihiro Ito; Yuhei Kobayashi; Mizuki Yamaguchi; Ayako Tabuchi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    WATER SCIENCE AND TECHNOLOGY IWA PUBLISHING 85 (10) 2827 - 2839 0273-1223 2022/05 
    To increase the adsorption capability of Hg2+ from aqueous media, we prepared sodium-type fine zeolite grains with various particle sizes (denoted as ZE1, ZE2 and ZE3). The particle sizes of ZE1, ZE2 and ZE3 were 16.363 +/- 0.365, 1.454 +/- 0.357 and 0.607 +/- 0.377 mu m, respectively. Moreover, the CEC, specific surface area and pore volume were in the order ZE1 (42 mmol/g and 23.5 m(2)/g) < ZE2 (72 mmol/g and 67.1 m(2)/g) < ZE3 (135 mmol/g and 176.6 m(2)/g). Subsequently, the Hg2+ adsorption capability was investigated. The performance of tested agents on Hg2+ adsorbed was in the order ZE1 (5.0 mg/g) < ZE2 (9.4 mg/g) < ZE3 (20.2 mg/g). It was concluded that fine crystalline zeolite was important in enhancing the adsorption capability of Hg2+. In addition, the mechanism of adsorption of Hg2+ on the ZE samples was evaluated. Our results suggested that Hg2+ was exchanged with sodium ions in the interlayers of ZE samples with correlation coefficients of 0.966-0.979. Our findings revealed that these ZE samples constitute potential agents for the adsorption of Hg2+ from aqueous media.
  • Fumihiko Ogata; Noriaki Nagai; Mamiko Funaki; Ayako Tabuchi; Yuhei Kobayashi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 70 (5) 400 - 407 0009-2363 2022/05 
    Coal fly ash (FA) was treated by hydrothermal activation with sodium hydroxide solution at different concentrations to optimize the conversion method. Zeolite of the sodium type is prepared from coal FA by 1, 1.5, and 3 mol/L sodium hydroxide solutions (ZE1, ZE1.5, and ZE3). These adsorbents' morphology, crystal structure, scanning electron microscopy, Fourier transform (FT)-IR spectra, cation exchange capacity (CEC), specific surface area and pore volumes, and pH(pz)(e) were determined. An adsorption experiment was performed to evaluate the effects of contact time, pH, temperature, and coexistence. From the results, the values of CEC and specific surface area of prepared samples was in the order ZE3 < ZE1.5 < ZE1. The similar trends were observed in lead ions adsorption. In addition, our obtained data elucidate that the ion exchange with sodium ions in the interlayer ZE1 is one of the adsorption mechanisms of Pb2+ from water layer. Finally, lead ions adsorbed on ZE1 could be desorbed using a hydrochloric acid solution, showing that ZE1 could be reused as a water purification agent.
  • Fumihiko Ogata; Noriaki Nagai; Chihiro Ito; Yuhei Kobayashi; Mizuki Yamaguchi; Ayako Tabuchi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Water science and technology : a journal of the International Association on Water Pollution Research 85 (10) 2827 - 2839 2022/05 
    To increase the adsorption capability of Hg2+ from aqueous media, we prepared sodium-type fine zeolite grains with various particle sizes (denoted as ZE1, ZE2 and ZE3). The particle sizes of ZE1, ZE2 and ZE3 were 16.363 ± 0.365, 1.454 ± 0.357 and 0.607 ± 0.377 μm, respectively. Moreover, the CEC, specific surface area and pore volume were in the order ZE1 (42 mmol/g and 23.5 m2/g) < ZE2 (72 mmol/g and 67.1 m2/g) < ZE3 (135 mmol/g and 176.6 m2/g). Subsequently, the Hg2+ adsorption capability was investigated. The performance of tested agents on Hg2+ adsorbed was in the order ZE1 (5.0 mg/g) < ZE2 (9.4 mg/g) < ZE3 (20.2 mg/g). It was concluded that fine crystalline zeolite was important in enhancing the adsorption capability of Hg2+. In addition, the mechanism of adsorption of Hg2+ on the ZE samples was evaluated. Our results suggested that Hg2+ was exchanged with sodium ions in the interlayers of ZE samples with correlation coefficients of 0.966-0.979. Our findings revealed that these ZE samples constitute potential agents for the adsorption of Hg2+ from aqueous media.
  • Yoshihiro Oaku; Akinari Abe; Yohei Sasano; Fuka Sasaki; Chika Kubota; Naoki Yamamoto; Tohru Nagahama; Noriaki Nagai
    Pharmaceutics MDPI 14 (5) 2022/04 
    We previously found that 1% minoxidil (MXD) nanoparticles prepared using a bead mill method led to an increase I n hair follicle delivery and hair growth in C57BL/6 mice. In the present study, we designed a nanoparticle formulation containing 5% MXD (MXD-NPs) using the bead mill method and investigated the hair-growth effect of MXD-NPs and a commercially available MXD solution (CA-MXD). Hair growth and in vivo permeation studies were conducted using C57BL/6 mice. Moreover, we examined the MXD contents in the upper (hair bulge) and the lower hair follicle (hair bulb) and observed the hair follicle epithelial stem cells (HFSC) by immunohistochemical staining using the CD200 antibody. The mean particle size of the MXD in the MXD-NPs was 139.8 nm ± 8.9 nm. The hair-growth effect of the MXD-NPs was higher than that of CA-MXD, and the MXD content in the hair bulge of mice treated with MXD-NPs was 7.4-fold that of the mice treated with CA-MXD. In addition, the activation of HFSC was observed around the bulge in the MXD-NPs-treated mice. We showed that MXD-NPs enable the accumulation of MXD in the upper hair follicles more efficiently than CA-MXD, leading the activation of HFSC and the hair growth.
  • 眼科検査・治療の低侵襲化 糖尿病網膜症診療の低侵襲化への挑戦
    長岡 泰司; 横田 陽匡; 花栗 潤哉; 渡部 昌久; 朝生 浩; 花崎 浩継; 秋山 彩香; 大野 皓; 高瀬 公陽; 山上 聡; 櫛山 暁史; 櫛山 櫻; 長井 紀章; 中神 啓徳; 林 宏樹; 相原 一; 本庄 恵; 蔵野 信; 矢冨 裕; 五十嵐 浩二
    日本眼科学会雑誌 (公財)日本眼科学会 126 (3) 358 - 387 0029-0203 2022/03
  • Noriaki Nagai; Fumihiko Ogata; Ayari Ike; Yurisa Shimomae; Hanano Osako; Yosuke Nakazawa; Naoki Yamamoto; Naohito Kawasaki
    Pharmaceutics MDPI 14 (2) 2022/02 
    We previously reported that the bioavailability (BA) of irbesartan (IRB), a BSC class II drug, was improved by preparing nanocrystalline suspensions. However, nanocrystalline suspensions have chemical and physical instabilities and must be converted into tablets through drying approaches in order to overcome such instabilities. In this study, we attempted to design a molded tablet based on nanocrystalline IRB suspensions (IRB-NP tablet) and investigated the effects of this IRB-NP tablet on blood pressure (BP) in a stroke-prone spontaneously hypertensive (SHR-SP) rat. The IRB-NP tablet (with a hardness of 42.6 N) was developed by combining various additives (methylcellulose, 2-hydroxypropyl-β-cyclodextrin HPβCD, D-mannitol, polyvinylpyrrolidone, and gum arabic) followed by bead-milling and freeze-drying treatments. The mean particle size in the redispersions of the IRB-NP tablet was approximately 118 nm. The solubility and intestinal absorption of IRB in the IRB-NP tablet were significantly enhanced in comparison with the microcrystalline IRB tablet (IRB-MP tablet), and both solubility and clathrin-dependent endocytosis helped improve the low BA of the IRB. In addition, the BP-reducing effect of the IRB-NP tablet was significantly higher than that of the IRB-MP tablet. These results provide useful information for the preservation of nanocrystalline suspensions of BCS class II drugs, such as IRB.
  • Junya Hanaguri; Noriaki Nagai; Harumasa Yokota; Akifumi Kushiyama; Masahisa Watanabe; Satoru Yamagami; Taiji Nagaoka
    Pharmaceutics 14 (2) 2022/02 
    We investigated the effect of fenofibrate nano-eyedrops (FenoNano) on impaired retinal blood flow regulation in type 2 diabetic mice. Six-week-old db/db mice were randomly divided into an untreated group (n = 6) and treated group, which received FenoNano (n = 6). The longitudinal changes in retinal neuronal function and blood flow responses to systemic hyperoxia and flicker stimulation were evaluated every 2 weeks in diabetic db/db mice treated with FenoNano (n = 6) or the vehicle (n = 6) from ages 8-14 weeks. The retinal blood flow was assessed using laser speckle flowgraphy. We also evaluated the expressions of vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), and aquaporin 4 (AQP4) and the phosphorylation of peroxisome proliferator-activated receptor alpha (PPAR-α) by immunofluorescence. In db/db mice treated with FenoNano, both responses were restored from 8 to 14 weeks of age compared with the diabetic mice treated with the vehicle. At 14 weeks of age, the impaired regulation of retinal blood flow during systemic hyperoxia and flicker stimulation improved to about half of that in the db/db mice treated with FenoNano compared with the db/m control group (n = 5). FenoNano prevented the activation of VEGF and GFAP expression and increased the AQP4 expression and the phosphorylation of PPAR-α detected by immunofluorescence compared with the diabetic mice treated with the vehicle eyedrop. Our results suggested that the fenofibrate nano-eyedrops prevent retinal glial dysfunction via the phosphorylation of PPAR-α and improves the retinal blood flow dysregulation in type 2 diabetic mice.
  • Ryoka Goto; Yoshihiro Oaku; Fuka Sasaki; Chika Kubota; Saori Deguchi; Reita Kadowaki; Akinari Abe; Tohru Nagahama; Noriaki Nagai
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 142 (9) 1015 - 1020 2022 
    We previously designed the formulation containing minoxidil (MXD) nanoparticles (MXD-NPs), and found that the MXD-NPs can mainly deliver MXD into hair bulbs via hair follicles pathway, and that the therapeutic efficiency for hair growth is higher in comparison with the formulation containing dissolved MXD. In this study, we investigated whether the skin environmental changes by the treatment of steam towel, ethanol, l-menthol and commercially available (CA) carpronium affect the drug behavior in the MXD-NPs-applied mice. The steam towel, ethanol, l-menthol and CA-carpronium were pre-treated 3 min before MXD-NPs application, and the MXD content in the hair bulge, bulb, skin tissue and blood of mice were measured 4 h after MXD-NPs application. No significant difference of MXD levels in the blood was observed by the pre-treatment of steam towel, ethanol, l-menthol and CA-carpronium. On the other hand, the pre-treatment of steam towel and l-menthol enhanced the MXD levels in hair bulge and/or bulb. Although, the MXD levels in hair bulge and bulb were not changed by the pre-treatment of ethanol, the MXD levels in skin tissue was higher than that of saline-pre-treated group (control). The MXD levels in hair bulge, bulb and skin tissue of mice pre-treated with CA-carpronium were remarkably higher in comparison with control. In conclusion, we showed that the changes in skin environment by the steam towel, ethanol, l-menthol and CA-carpronium affected the absorption of MXD-NPs, and these increased MXD levels in the hair bulb and blood by the combination may enhance the therapeutic efficiency without side effects.
  • Tokio Obata; Saori Deguchi; Jyoji Yoshitomi; Kazunori Inaba; Yoko Urashima; Takuro Kobori; Kouichi Hosomi; Noriaki Nagai; Yuichiro Nakada
    PloS one 17 (11) e0277311  2022 
    In this study, we focused on the storage conditions and investigated the effects of low-temperature storage (10°C) on the dispersibility of active components in three formulations of fluorometholone (FLU) suspension eye-drops (one original drug and two generic drugs, P1-P3). For all three eye-drop products, before shaking by hand, white sediment anticipated to be the principal active component was seen at the vial base. In the ordinary-temperature storage group, the FLU contents per drop after shaking by hand were 0.076% in P1, 0.023% in P2, and 0.100% in P3, and the content in P2 was significantly lower than that in P1 and P3. In contrast, almost no dispersion was observed in the low-temperature group. The results after sufficient shaking of these samples with a vortex, in contrast, were such that the FLU contents per drop were 0.063% in P1, 0.086% in P2, and 0.088% in P3; the content in P1 was significantly lower than that in P2 and P3, and there was no difference between P2 and P3. Moreover, we evaluated the dispersibility according to the evaluation "Vs / (ρg - ρf) g." In both the low- and ordinary-temperature storage groups, the value of Vs / (ρg - ρf) g, proportional to the terminal velocity, decreased in the following order: P3 > P1 ≫ P2, and each value in the ordinary-temperature was higher than that in low temperature. The zeta potential decreased in the following order: P2 > P3 ≫ P1. In conclusion, when FLU suspension eye drops are stored at low temperatures until use, such as in a refrigerator, ordinary shaking does not help achieve dispersion to the specified concentration, and even with vigorous shaking with some formulations, the specified concentration cannot be achieved.
  • Fumihiko Ogata; Noriaki Nagai; Mamiko Funaki; Ayako Tabuchi; Yuhei Kobayashi; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Chemical & pharmaceutical bulletin 70 (5) 400 - 407 2022 
    Coal fly ash (FA) was treated by hydrothermal activation with sodium hydroxide solution at different concentrations to optimize the conversion method. Zeolite of the sodium type is prepared from coal FA by 1, 1.5, and 3 mol/L sodium hydroxide solutions (ZE1, ZE1.5, and ZE3). These adsorbents' morphology, crystal structure, scanning electron microscopy, Fourier transform (FT)-IR spectra, cation exchange capacity (CEC), specific surface area and pore volumes, and pHpzc were determined. An adsorption experiment was performed to evaluate the effects of contact time, pH, temperature, and coexistence. From the results, the values of CEC and specific surface area of prepared samples was in the order ZE3 < ZE1.5 < ZE1. The similar trends were observed in lead ions adsorption. In addition, our obtained data elucidate that the ion exchange with sodium ions in the interlayer ZE1 is one of the adsorption mechanisms of Pb2+ from water layer. Finally, lead ions adsorbed on ZE1 could be desorbed using a hydrochloric acid solution, showing that ZE1 could be reused as a water purification agent.
  • Yuki Sugiyama; Yosuke Nakazawa; Toko Sakagami; Sara Kawata; Noriaki Nagai; Naoki Yamamoto; Megumi Funakoshi-Tago; Hiroomi Tamura
    Experimental eye research ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD 213 108840 - 108840 0014-4835 2021/12 
    Posterior capsule opacification (PCO), the most common complication of cataract surgery occurring in 20-50% of patients after 2-5 years of cataract surgery, is a major problem in the aging society. The epithelial-mesenchymal transition (EMT) of lens epithelial cells after cataract surgery has been proposed as a major cause of PCO. Capsaicin, widely used as a food additive and analgesic agent, is a major pungent ingredient in red pepper. Although the effect of capsaicin on EMT has been reported in cancer cells, the biological reaction of capsaicin was unique in each cell type, and there have been no reports describing its effects on EMT earlier. In this study, we demonstrated that treatment with capsaicin inhibited TGFβ2-induced EMT in vitro lens epithelial cells and ex vivo explant lens epithelial cells. Furthermore, eye drops of capsaicin inhibited the PCO model mice in vivo. Finally, we showed that capsaicin inhibited non-canonically induced Smad2/3 activation via suppression of EGFR activation and ERK phosphorylation. Our findings indicate that capsaicin and its derivatives are good candidate compounds for preventing PCO after cataract surgery.
  • Hiroko Otake; Misa Minami; Mizuki Yamaguchi; Sawako Akiyama; Kazunori Inaba; Noriaki Nagai
    Experimental and therapeutic medicine SPANDIDOS PUBL LTD 22 (6) 1353 - 1353 1792-0981 2021/12 
    The inhalation performance of a dry powder inhaler (DPI) depends on the inhalation patterns of patients, inhalation particle characteristics and inhalation devices. In capsule-based DPIs, the capsule plays an important role in the dispersion of inhalation particles. The present study investigated the effects of inner physical properties of capsules on drug release from capsules-based DPIs with high resistance device. Atomic force microscopy (AFM) was used to evaluate the capsule physical properties, such as the capsule inner structure and surface potential, of three capsules with different compositions (G-Cap, PEG/G-Cap, and HPMC-Cap). As a model dry powder for capsule-based DPIs, the dry powder in Spiriva® Inhalation Capsules containing tiotropium bromide was used. Inhalation performance was evaluated using a twin-stage liquid impinge and Handihaler® (flow rate 30 l/min). The results indicated that the capsule inner surface presented with numerous valleys and mountains, regardless of the capsule type. Furthermore, the valley and mountain areas on the capsule inner surface showed a significantly higher or lower surface potential. Following inhalation of capsule-based DPIs, the drug remained in the valleys on the capsule inner surface; however, no significant difference was observed in the drug release from capsule and lung drug delivery. Therefore, inhalation performance in capsule-based DPIs when a high resistance device, such as Handihaler®, is used at an appropriately flow rate is not markedly affected by the physical properties of the capsule inner surface due to capsule composition.
  • Ryoka Goto; Shigehiro Yamada; Hiroko Otake; Yosuke Nakazawa; Mikako Oka; Naoki Yamamoto; Hiroshi Sasaki; Noriaki Nagai
    Pharmaceutics 13 (12) 2021/11 
    We developed ophthalmic formulations based on nilvadipine (NIL) nanocrystals (NIL-NP dispersions; mean particle size: 98 nm) by using bead mill treatment and investigated whether the instillation of NIL-NP dispersions delivers NIL to the lens and prevents lens opacification in hereditary cataractous Shumiya cataract rats (SCRs). Serious corneal stimulation was not detected in either human corneal epithelial cells or rats treated with NIL-NP dispersions. The NIL was directly delivered to the lens by the instillation of NIL-NP dispersions, and NIL content in the lenses of rats instilled with NIL-NP dispersions was significantly higher than that in the ophthalmic formulations based on NIL microcrystals (NIL-MP dispersions; mean particle size: 21 µm). Moreover, the supply of NIL prevented increases in Ca2+ content and calpain activity in the lenses of SCRs and delayed the onset of cataracts. In addition, the anti-cataract effect in the lens of rats instilled with NIL-NP dispersions was also significantly higher than that in NIL-MP dispersions. NIL-NPs could be used to prevent lens opacification.
  • Yosuke Nakazawa; Rosica S Petrova; Yuki Sugiyama; Noriaki Nagai; Hiroomi Tamura; Paul J Donaldson
    International journal of molecular sciences MDPI 22 (23) 2021/11 
    Lens water transport generates a hydrostatic pressure gradient that is regulated by a dual-feedback system that utilizes the mechanosensitive transient receptor potential vanilloid (TRPV) channels, TRPV1 and TRPV4, to sense changes in mechanical tension and extracellular osmolarity. Here, we investigate whether the modulation of TRPV1 or TRPV4 activity dynamically affects their membrane trafficking. Mouse lenses were incubated in either pilocarpine or tropicamide to alter zonular tension, exposed to osmotic stress, or the TRPV1 and TRPV4 activators capsaicin andGSK1016790A (GSK101), and the effect on the TRPV1 and TRPV4 membrane trafficking in peripheral fiber cells visualized using confocal microscopy. Decreases in zonular tension caused the removal of TRPV4 from the membrane of peripheral fiber cells. Hypotonic challenge had no effect on TRPV1, but increased the membrane localization of TRPV4. Hypertonic challenge caused the insertion of TRPV1 and the removal of TRPV4 from the membranes of peripheral fiber cells. Capsaicin caused an increase in TRPV4 membrane localization, but had no effect on TRPV1; while GSK101 decreased the membrane localization of TRPV4 and increased the membrane localization of TRPV1. These reciprocal changes in TRPV1/4 membrane localization are consistent with the channels acting as mechanosensitive transducers of a dual-feedback pathway that regulates lens water transport.
  • Mizuki Kita; Kazutaka Kanai; Hisaya K Ono; Yuya Otaka; Daiki Okada; Noriaki Nagai; Rina Kudo; Yohei Yamashita; Shiori Hino; Toru Matsunaga; Kazuki Tajima
    Veterinary sciences MDPI AG 8 (10) 238 - 238 2021/10 
    This study aimed to compare the in vitro and in vivo retention, bacterial adhesion, and biofilm formation between anionic and zwitterionic bandage contact lenses (BCLs) in healthy canines. BCL retention and tolerance were evaluated in 10 healthy canines via a single-masked, crossover study for 7 days. To compare in vitro bacterial adhesion and biofilm formation, four Staphylococcus strains were incubated with the BCLs at 37 °C for 2 or 24 h, and the bacterial colony forming units (CFUs) adhering to the BCLs were counted. Next, to compare in vivo bacterial adhesion, the CFUs of bacteria adhering to the BCLs worn by canines for 24 h were counted. Anionic lenses significantly retained and reduced in vitro bacterial adhesion than in the zwitterionic lenses. However, the amount of in vitro biofilm formation was more likely to be higher on anionic lenses than on zwitterionic lenses. In vivo bacterial adhesion was not significantly different between the two types of BCLs. Nevertheless, both BCLs were well-tolerated by the canines; thus, their short-term use in dogs can be recommended as safe.
  • Misa Minami; Hiroko Otake; Yosuke Nakazawa; Norio Okamoto; Naoki Yamamoto; Hiroshi Sasaki; Noriaki Nagai
    Pharmaceutics 13 (9) 2021/09 
    We previously designed ophthalmic formulations (nTRA) containing tranilast nanoparticles (Tra-NPs) with high uptake into ocular tissues. In this study, we used in situ gel (ISG) bases comprising combinations of pluronic F127 (F127) and methylcellulose (MC/F127), pluronic F68 (F68/F127), and Carbopol (Car/F127), and we developed in situ gels incorporating Tra-NPs (Tra-NP-incorporated ISNGs) such as nTRA-F127, nTRA-MC/F127, nTRA-F68/F127, and nTRA-Car/F127. Moreover, we demonstrated the therapeutic effect on conjunctival inflammation using lipopolysaccharide-induced rats. Each Tra-NP-incorporated ISNG was prepared by the bead mill method, the particle size was 40-190 nm, and the tranilast release and diffusion from formulation were nTRA > nTRA-F127 > nTRA-F68/F127 > nTRA-Car/F127 > nTRA-MC/F127. In the Tra-NP-incorporated ISNGs, the tranilast residence time in the lacrimal fluid, cornea, and conjunctiva was prolonged, although the Cmax was attenuated in comparison with nTRA. On the other hand, no significant difference in conjunctival inflammation between non- and nTRA-F127-instilled rats was found; however, the nTRA-F68/F127, nTRA-Car/F127, and nTRA-MC/F127 (combination-ISG) attenuated the vessel leakage, nitric oxide, and tumor necrosis factor-α expression. In particular, nTRA-F68/F127 was significant in preventing the conjunctival inflammation. In conclusion, we found that the combination-ISG base prolonged the residence time of Tra-NPs; however, Tra-NP release from the formulation was attenuated, and the Tmax was delayed longer than that in nTRA. The balance of drug residence and diffusion in lacrimal fluid may be important in providing high ocular bioavailability in formulations containing solid nanoparticles.
  • Saori Deguchi; Fumihiko Ogata; Masaki Watanabe; Hiroko Otake; Naoki Yamamoto; Naohito Kawasaki; Noriaki Nagai
    Pharmaceutics 13 (9) 2021/09 
    We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines.
  • Tomonori Hayashi; Tomoyoshi Miyamoto; Noriaki Nagai; Atsufumi Kawabata
    Scientific reports 11 (1) 17157 - 17157 2021/08 
    To identify risk factors for the prognosis of prostate cancer (PC), we retrospectively analyzed the impact of lifestyle-related disorders as well as PC characteristics at initial diagnosis on the progression to castration-resistant PC (CRPC) in PC patients undergoing hormone therapy. Of 648 PC patients, 230 who underwent hormone therapy and met inclusion criteria were enrolled in this study. CRPC developed in 48 patients (20.9%). Univariate analysis using Cox proportional hazard model indicated that newly developed diabetes mellitus (DM) following hormone therapy (postDM), but not preexisting DM, as well as PC characteristics at initial diagnosis including prostate-specific antigen (PSA) ≥ 18 were significantly associated with the progression to CRPC. A similar tendency was also observed in the relationship between newly developed hypertension following hormone therapy and CRPC progression. On the other hand, neither dyslipidemia nor hyperuricemia, regardless the onset timing, exhibited any association with CRPC progression. In multivariate analysis, postDM and PSA ≥ 18 were extracted as independent risk factors for CRPC progression (adjusted hazard ratios, 3.38 and 2.34; p values, 0.016 and 0.019, respectively). Kaplan-Meier analysis and log-rank test clearly indicated earlier progression to CRPC in PC patients who developed postDM or had relatively advanced initial PC characteristics including PSA ≥ 18. Together, the development of lifestyle-related disorders, particularly DM, following hormone therapy, as well as advanced PC characteristics at initial diagnosis is considered to predict earlier progression to CRPC and poor prognosis in PC patients undergoing hormone therapy.
  • Mizuki Kita; Kazutaka Kanai; Hiroki Mitsuhashi; Tomoki Noguchi; Noriaki Nagai; Mizuki Yamaguchi; Yuya Otaka; Rina Kudo; Yohei Yamashita; Kazuki Tajima
    Veterinary sciences 8 (8) 2021/08 
    Timolol maleate (TM), a beta-adrenergic receptor antagonist, is widely used for canine antiglaucoma eye drops; however, its bioavailability is <5%. Our previous study revealed that magnesium hydroxide nanoparticles (nMH) have potency in improving the bioavailability of fixed-combined TM in rodent models. This study aimed to investigate whether the fixed combination with nMH improves the ocular hypotensive effect of TM and affects pupil size (PS), heart rate (HR), and mean arterial pressure (MAP) in clinically healthy dogs. Five clinically healthy dogs were administered topical saline, commercial 0.5% TM, and a 0.01% or 0.1% nMH-0.5% TM fixed combination (0.01% or 0.1% nMH-TM) twice daily in one eye for 7 days with at least a 28-day interval. The changes from baseline were calculated and were statistically analyzed for each drug. IOP was significantly reduced in both 0.01% and 0.1% nMH-TM-treated-dogs compared with saline- and TM-treated dogs. Meanwhile, 0.01% and 0.1% nMH did not exacerbate the side effects of TM. From these results, nMH improved the ocular hypotensive effect of TM without enhancing side effects. Topical nMH-TM is potentially more effective for canine ocular hypotensive eye drops than TM.
  • Irene Vorontsova; James E Hall; Thomas F Schilling; Noriaki Nagai; Yosuke Nakazawa
    Cells MDPI 10 (8) 2021/08 
    Aquaporin 0 (AQP0) is the most abundant lens membrane protein, and loss of function in human and animal models leads to cataract formation. AQP0 has several functions in the lens including water transport and adhesion. Since lens optics rely on strict tissue architecture achieved by compact cell-to-cell adhesion between lens fiber cells, understanding how AQP0 contributes to adhesion would shed light on normal lens physiology and pathophysiology. We show in an in vitro adhesion assay that one of two closely related zebrafish Aqp0s, Aqp0b, has strong auto-adhesive properties while Aqp0a does not. The difference appears to be largely due to a single amino acid difference at residue 110 in the extracellular C-loop, which is T in Aqp0a and N in Aqp0b. Similarly, P110 is the key residue required for adhesion in mammalian AQP0, highlighting the importance of residue 110 in AQP0 cell-to-cell adhesion in vertebrate lenses as well as the divergence of adhesive and water permeability functions in zebrafish duplicates.
  • Yugo Uematsu; Fumihiko Ogata; Noriaki Nagai; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Heliyon ELSEVIER SCI LTD 7 (7) e07644  2021/07 
    Raw and calcined basil seeds (BS and BS1000, respectively) were evaluated for their ability to remove herbicides such as paraquat and diquat. The physicochemical properties of BS and BS1000 were determined and the effects of contact time and initial concentration on paraquat and diquat adsorption were assessed. After calcination treatment, the number of pores in BS increased, and the specific surface area was increased from 0.265 to 86.902 m2 g-1. The quantity of herbicides adsorbed using BS1000 was greater than that using either BS or medicinal-grade carbon. Additionally, the adsorption quantity increased with the increase in contact time and initial concentration of herbicide. Therefore, BS1000 is a potential resource for the removal of herbicides. Moreover, BS and BS1000 exhibited the capacity for herbicide adsorption in simulated intestinal fluid.
  • 中田 雄一郎; 山口 瑞季; 出口 粧央里; 稲葉 一訓; 長井 紀章
    薬学雑誌 (公社)日本薬学会 141 (6) 869 - 876 0031-6903 2021/06 
    異なる期間保管した際の懸濁点眼剤の物理的な安定性(再分散性および粒子径)を評価するとともに、混和後の初回1滴中のフルオロメトロン(FML)の濃度変化について検討した。先発品1種と後発品4種(A-D)の計5種のFML 0.1を選択し、研究室の保管棚に未開封の状態で4ヵ月(短期保管)および40ヵ月間(長期保管)正立静置保存し、その後の懸濁粒子の状態を評価した。いずれの点眼薬においても、短期・長期保管後、容器の底に白濁沈殿物が生じ、手振り(混和)回数の増加に従い沈殿物量の減少が認められた。また、短期保管および長期保管後のFML 0.1における初回1滴中薬物濃度の変化では、すべての製品において混和回数の増加に従い初回の1滴中濃度は高まり、先発品において1滴あたりの薬物濃度は10回混和で規格値の約70%程度であり、後発品Bでは濃度は30%に満たなかった。
  • Hiroko Otake; Mizuki Yamaguchi; Fumihiko Ogata; Saori Deguchi; Naoki Yamamoto; Hiroshi Sasaki; Naohito Kawasaki; Noriaki Nagai
    International journal of molecular sciences MDPI 22 (10) 2021/05 
    We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79-216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs' skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.
  • Hiroko Otake; Mizuki Yamaguchi; Fumihiko Ogata; Saori Deguchi; Naoki Yamamoto; Hiroshi Sasaki; Naohito Kawasaki; Noriaki Nagai
    Nanomaterials (Basel, Switzerland) MDPI 11 (4) 2021/04 
    Cilostazol (CIL) exerted a protective effect by promoting blood-brain barrier integrity as well as improving the status of neurological dysfunctions following cerebral ischemia/reperfusion (I/R) injury. We attempted to design a 0.5% CIL carbopol gel using solid nanoparticles (CIL-Ngel), and then investigated the relationships between energy-dependent endocytosis and the skin penetration of CIL-Ngel in this study. In addition, we evaluated whether the CIL-Ngel attenuated I/R-induced brain injury in a middle cerebral artery occlusion (MCAO)/reperfusion model mouse. The particle size of CIL was decreased using a bead mill, and the CIL particles (14.9 × 1014 particles/0.3 g) in the CIL-Ngel were approximately 50-180 nm. The release of CIL in the CIL-Ngel was higher than that in gel containing CIL powder (CIL-Mgel), and the CIL particles were released from the CIL-Ngel as nanoparticles. In addition, the percutaneous absorption of CIL from the CIL-Ngel was higher in comparison with that from CIL-Mgel, and clathrin-dependent endocytosis and caveolae-dependent endocytosis were related to the enhanced skin penetration of CIL-NPs. In the traditional (oral administration of CIL powder, 3 mg/kg) and transdermal administration (CIL-Ngel, 0.3 g) for 3 days (once a day), the area under the plasma CIL concentration-time curves (AUC) was similar, although the CIL supplied to the blood by the CIL-Ngel was more sustained than that via oral administration of CIL powder. Furthermore, the CIL-Ngel attenuated the ischemic stroke. In conclusion, we designed a gel using solid CIL-NPs, and we showed that the sustained release of CIL by CIL-Ngel provided an effective treatment for ischemic stroke in MCAO/reperfusion model mice. These findings induce the possibilities of developing novel applications of CIL solid nanoparticles.
  • Naoki Yamamoto; Noriko Hiramatsu; Mahito Ohkuma; Natsuko Hatsusaka; Shun Takeda; Noriaki Nagai; Ei-Ichi Miyachi; Masashi Kondo; Kazuyoshi Imaizumi; Masayuki Horiguchi; Eri Kubo; Hiroshi Sasaki
    Cells MDPI 10 (4) 2021/03 
    Regenerative medicine in ophthalmology that uses induced pluripotent stem cells (iPS) cells has been described, but those studies used iPS cells derived from fibroblasts. Here, we generated iPS cells derived from iris cells that develop from the same inner layer of the optic cup as the retina, to regenerate retinal nerves. We first identified cells positive for p75NTR, a marker of retinal tissue stem and progenitor cells, in human iris tissue. We then reprogrammed the cultured p75NTR-positive iris tissue stem/progenitor (H-iris stem/progenitor) cells to create iris-derived iPS (H-iris iPS) cells for the first time. These cells were positive for iPS cell markers and showed pluripotency to differentiate into three germ layers. When H-iris iPS cells were pre-differentiated into neural stem/progenitor cells, not all cells became positive for neural stem/progenitor and nerve cell markers. When these cells were pre-differentiated into neural stem/progenitor cells, sorted with p75NTR, and used as a medium for differentiating into retinal nerve cells, the cells differentiated into Recoverin-positive cells with electrophysiological functions. In a different medium, H-iris iPS cells differentiated into retinal ganglion cell marker-positive cells with electrophysiological functions. This is the first demonstration of H-iris iPS cells differentiating into retinal neurons that function physiologically as neurons.
  • Saori Deguchi; Fumihiko Ogata; Takumi Isaka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki; Noriaki Nagai
    Pharmaceutics 13 (3) 2021/03 
    Postprandial hyperglycemia, a so-called blood glucose spike, is associated with enhanced risks of diabetes mellitus (DM) and its complications. In this study, we attempted to design nanoparticles (NPs) of protamine zinc insulin (PZI) by the bead mill method, and prepare ophthalmic formulations based on the PZI-NPs with (nPZI/P) or without polyacrylic acid (nPZI). In addition, we investigated whether the instillation of the newly developed nPZI and nPZI/P can prevent postprandial hyperglycemia in a rabbit model involving the oral glucose tolerance test (OGTT). The particle size of PZI was decreased by the bead mill to a range for both nPZI and nPZI/P of 80-550 nm with no observable aggregation for 6 d. Neither nPZI nor nPZI/P caused any noticeable corneal toxicity. The plasma INS levels in rabbits instilled with nPZI were significantly higher than in rabbits instilled with INS suspensions (commercially available formulations, CA-INS), and the plasma INS levels were further enhanced with the amount of polyacrylic acid in the nPZI/P. In addition, the rapid rise in plasma glucose levels in OGTT-treated rabbits was prevented by a single instillation of nPZI/P, which was significantly more effective at attenuating postprandial hyperglycemia (blood glucose spike) in comparison with nPZI. In conclusion, we designed nPZI/P, and show that a single instillation before OGTT attenuates the rapid enhancement of plasma glucose levels. These findings suggest a better management strategy for the postprandial blood glucose spike, which is an important target of DM therapy.
  • Yosuke Nakazawa; Miki Aoki; Yuri Doki; Naoki Morishita; Shin Endo; Noriaki Nagai; Megumi Funakoshi-Tago; Hiroomi Tamura
    Biochemistry and biophysics reports ELSEVIER 25 100885 - 100885 2405-5808 2021/03 
    Presbyopia is one of the most well-known diseases of the eye, predominantly affecting the adult population after 50 years'. Due to hardening of the lens and failure of accommodative change, patients lose the ability to focus on near objects. This eye symptom is reported to be an early symptom of age-related nuclear cataract, and we have previously reported that hesperetin treatment could delay the onset of nuclear cataractogenesis induced by sodium selenite. In this study, we examined whether oral intake of α-glucosyl-hesperidin (G-Hsd), which has greater water solubility than hesperetin, could delay the onset of presbyopia. G-Hsd treatment protected lens elasticity, upregulated the mRNA expression of anti-oxidative enzymes like glutathione reductase and thioredoxin reductase 1 in the plasma and lens, and prevented premature cataract symptoms in selenite-induced cataract rat lens. Thus, the anti-presbyopic effects of G-Hsd were attributed, at least in part, to its antioxidant effects. G-Hsd represents the first oral treatment agent with anti-presbyopia and/or anti-cataract properties.
  • Yosuke Nakazawa; Yuri Doki; Yuki Sugiyama; Ryota Kobayashi; Noriaki Nagai; Naoki Morisita; Shin Endo; Megumi Funakoshi-Tago; Hiroomi Tamura
    Cells MDPI 10 (2) 2021/02 
    Presbyopia is characterized by a decline in the ability to accommodate the lens. The most commonly accepted theory for the onset of presbyopia is an age-related increase in the stiffness of the lens. However, the cause of lens sclerosis remains unclear. With age, water microcirculation in the lens could change because of an increase in intracellular pressure. In the lens, the intracellular pressure is controlled by the Transient Receptor Potential Vanilloid (TRPV) 1 and TRPV4 feedback pathways. In this study, we tried to elucidate that administration of α-glucosyl-hesperidin (G-Hsd), previously reported to prevent nuclear cataract formation, affects lens elasticity and the distribution of TRPV channels and Aquaporin (AQP) channels to meet the requirement of intracellular pressure. As a result, the mouse control lens was significantly toughened compared to both the 1% and 2% G-Hsd mouse lens treatments. The anti-oxidant levels in the lens and plasma decreased with age; however, this decrease could be nullified with either 1% or 2% G-Hsd treatment in a concentration- and exposure time-dependent manner. Moreover, G-Hsd treatment affected the TRPV4 distribution, but not TRPV1, AQP0, and AQP5, in the peripheral area and could maintain intracellular pressure. These findings suggest that G-Hsd has great potential as a compound to prevent presbyopia and/or cataract formation.
  • トラニラストナノ結晶を用いた結膜炎治療薬の開発 メチルセルロースは超微粒子の滞留性を高める
    南 実沙; 山崎 由夏; 大竹 裕子; 金井 一享; 長井 紀章
    日本眼薬理学会プログラム・抄録集 日本眼薬理学会 40回 42 - 42 2021/02
  • 眼科領域における生体適合性ポリマーの応用性 MPCポリマーはベンザルコニウム塩化物の角膜傷害性を軽減する
    長井 紀章; 南 実沙; 山崎 由夏; 大竹 裕子; 櫻井 俊輔; 原田 英治
    日本眼薬理学会プログラム・抄録集 日本眼薬理学会 40回 46 - 46 2021/02
  • Fumihiko Ogata; Noriaki Nagai; Ayako Tabuchi; Megumu Toda; Masashi Otani; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    WATER MDPI 13 (4) 2021/02 
    To evaluate the feasibility of nickel-aluminum (the Ni2+:Al3+ molar ratios of 1.0:1.0 and 1.0:2.0 are denoted as NA11 and NA12, respectively) and nickel-aluminum-zirconium type (the Ni2+:Al3+:Zr4+ molar ratios of 0.9:1.0:0.09 and 0.9:2.0:0.09 are denoted as NAZ1 and NAZ2, respectively) hydroxides for Cr(VI) removal from aqueous media, the adsorption capability and adsorption mechanism of Cr(VI) using the above-mentioned adsorbents were investigated in this study. The quantity of Cr(VI) adsorbed onto NA11, NA12, NAZ1, and NAZ2 was 25.5, 25.6, 24.1, and 24.6 mg g(-1), respectively. However, the quantity of aluminum (base metal) released from NA11 (approximately 0.14 mg g(-1)) was higher than that from NAZ1 (approximately 1.0 mu g g(-1)), indicating that NAZ1 was more suitable for Cr(VI) removal than NA11. In addition, the effects of pH, contact time, and temperature on the adsorption of Cr(VI) were evaluated. Moreover, to elucidate the adsorption mechanism of Cr(VI) using NA11 and NAZ1, the elemental distribution, X-ray photoelectron spectrometry spectra, and ion exchange capability were also determined. Cr(VI) adsorbed onto the NAZ1 surface was easily desorbed using a sodium hydroxide solution under our experimental conditions. The information regarding this study can be useful for removing Cr(VI) from aqueous media.
  • Noriaki Nagai; Shunsuke Sakurai; Ryotaro Seiriki; Misa Minami; Mizuki Yamaguchi; Saori Deguchi; Eiji Harata
    Pharmaceutics 13 (2) 2021/01 
    The polymer that includes 2-methacryloyloxy ethyl phosphorylcholine (MPC) is well-known as an effectively hydrating multifunction agent. In this study, we prepared an MPC polymer (MPCP) using radical polymerization with co-monomers-MPC/Stearyl Methacrylate/N,N-dimethylacrylamide-and evaluated the MPCP's usefulness for dry eye treatment using a rabbit model treated with N-acetylcysteine. The MPCP particle size was 50-250 nm, and the form was similar to that of micelles. The MPCP viscosity (approximately 0.95 mPa·s) was 1.17-fold that of purified water, and a decrease in the transepithelial electrical resistance value (corneal damage) was not observed in the immortalized human corneal epithelial cell line HCE-T cell (HCE-T cell layer). The MPCP enhanced the water maintenance on the cornea, and the instillation of MPCP increased the lacrimal fluid volume and prolonged the tear film breakup time without an increase in total mucin contents in the lacrimal fluid of the normal rabbits. The therapeutic potential of the MPCP for dry eye was evaluated using an N-acetylcysteine-treated rabbit model, and, in our investigation, we found that MPCP enhanced the volume of lacrimal fluid and promoted an improvement in the tear film breakup levels. These findings regarding the creation and characteristics of a novel MPCP will provide relevant information for designing further studies to develop a treatment for dry eyes.
  • Noriko Hiramatsu; Noriaki Nagai; Masashi Kondo; Kazuyoshi Imaizumi; Hiroshi Sasaki; Naoki Yamamoto
    Medical molecular morphology 54 (3) 216 - 226 2021/01 
    The incidence rate of post-cataract surgery posterior capsule opacification (PCO) and lens turbidity is about 20% in 5 years. Soemmering's ring, which is a type of PCO also called a regenerated lens with similar tissue structure to that of a human lens, is an important proxy for elucidating the mechanism of lens regeneration and maintenance of transparency. The authors created new human immortalized crystalline lens epithelial cells (iHLEC-NY1s) with excellent differentiation potential, and as a result of culturing the cells by static and rotation-floating methods, succeeded in producing a three-dimensional cell structure model (3D-iHLEC-NY1s) which is similar to Soemmering's ring in tissue structure and expression characteristics of αA-crystalline, βB2-crystalline, vimentin proteins. 3D-iHLEC-NY1s is expected to be a proxy in vitro experimental model of Soemmering's ring to enable evaluation of drug effects on suppression of cell aggregate formation and transparency. By further improving the culture conditions, we aim to control the cell sequence and elucidate the mechanism underlying the maintenance of lens transparency.
  • Yosuke Nakazawa; Noriaki Nagai
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan PHARMACEUTICAL SOC JAPAN 141 (12) 1305 - 1306 0031-6903 2021
  • Fumihiko Ogata; Noriaki Nagai; Shouko Iijima; Megumu Toda; Masashi Otani; Takehiro Nakamura; Naohito Kawasaki
    Chemical & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 69 (8) 789 - 795 0009-2363 2021 
    In this study, the effect of contact time, temperature, pH, and coexistences on the adsorption of phosphate ions using the complex nickel-aluminum-zirconium hydroxide (NAZ) was evaluated. Moreover, the recovery of adsorbed phosphate ions from NAZ using desorption solution with different concentrations was demonstrated. The results showed that the quantity of phosphate ions adsorbed gradually increased with time, and the adsorption equilibrium was achieved within 24 h after adsorption. This kinetic data could be well described by the pseudo-second-order model with the correlation coefficient in the value of 0.997. Additionally, the quantity of phosphate which was adsorbed increased as temperature increased, and these results corresponded well with both the Langmuir, the correlation coefficient ranged from 0.920-0.949, and Freundlich models, the correlation coefficient ranged from 0.863-0.995. These results showed that the adsorption of phosphate ion was monolayer adsorption onto the NAZ surface. The optimal pH for removal of phosphate ions from aqueous media was during 4-8. In addition, chloride, nitrate, and sulfate ions did not significantly affect to the adsorption capability of phosphate ions in the complex solution system. Finally, the phosphate ions which were adsorbed onto NAZ could be recovered using sodium sulfate solution (recovery percentage: approx. 50% using sodium sulfate solution at 1000 mmol/L). These results highlight the potential of using NAZ as the cost-effectiveness adsorbent for phosphate ions removal from aqueous media.
  • Hiroko Otake; Ryoka Goto; Fumihiko Ogata; Takumi Isaka; Naohito Kawasaki; Shinichiro Kobayakawa; Toru Matsunaga; Noriaki Nagai
    International journal of nanomedicine DOVE MEDICAL PRESS LTD 16 5343 - 5356 1178-2013 2021 
    Purpose: The multi-instillation of three commercially available (CA) eye drops [fluorometholone (FL)-, bromfenac (BF)- and levofloxacin (LV)-eye drops] has been used to manage pain and inflammation post-intraocular surgery. However, the multi-instillation of these three eye drops causes corneal damage, and the FL drops have the disadvantage of low ocular bioavailability. To overcome these problems, we prepared fixed-combination eye drops based on FL nanoparticles (FL-NPs) and BF/LV solution (nFBL-FC), and evaluated the corneal toxicity and transcorneal penetration of the nFBL-FC eye drops. Methods: FL powder was mixed in 2-hydroxypropyl-β-cyclodextrin solution containing benzalkonium chloride, mannitol and methylcellulose, and milled with a Bead Smash 12 (5500 rpm for 30 s×30 times). The BF/LV solution was then added to the milled-dispersions to be used as nFBL-FC. The FL, BF and LV concentrations were measured by HPLC methods, and transcorneal penetration was evaluated in rabbits. Results: The FL particle size in nFBL-FC was 40-150 nm, with only 0.0018% in liquid form. No aggregation of FL particles in the nFBL-FC was observed for 1 month. The viability of human corneal epithelial cells treated with nFBL-FC was remarkably higher than that of cells subjected to the multi-instillation of the corresponding three CA-eye drops. In addition, the corneal penetrations (AUC) of the FL, BF and LV in nFBL-FC were 4.9-, 1.8-, and 7.1-fold those of the corresponding CA-eye drops, respectively. Moreover, the caveolae-dependent endocytosis (CavME) inhibitor (nystatin) significantly prevented the transcorneal penetration of these drugs. Conclusion: We prepared fixed-combination eye drops based on FL-NPs and BF/LV solution (nFBL-FC), and show that high levels of FL-NPs and dissolved BF/LV (liquid drugs) can be delivered into the aqueous humor by the instillation of nFBL-FC. Further, we show that CavME is mainly related to the enhancement of transcorneal penetration of both the solid (NPs) and liquid drugs.
  • Noriaki Nagai
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 141 (1) 47 - 53 2021 
    The use of eye drops is a well-established practice in the treatment of ophthalmic diseases, although the bioavailability of traditional eye drops, which are either solutions or suspensions, is insufficient, as the corneal barrier and dilution by lacrimation prevent the transcorneal penetration of drugs. Additionally, frequent instillation may cause undesirable systemic side effects and local corneal toxicity. To overcome these problems, micro- and nanoparticles, hydrogels, and viscous solutions have been tested, and solid nanoparticles are also expected to be applied. This review examines the usefulness of ophthalmic formulations based on solid nanoparticles, by using the specific example of indomethacin (IMC). Ophthalmic formulations based on solid IMC nanoparticles (IMC-NP dispersions) have been prepared using various additives (benzalkonium chloride, mannitol, methylcellulose, and cyclodextrin) and a rotation/revolution pulverizer (NP-100), to produce particles of 50-220 nm in size. The solubility of IMC in IMC-NP dispersions was 4.18-fold higher than that in the suspensions containing IMC microparticles (IMC-MP suspensions), and IMC-NP dispersions were better tolerated than commercially available NSAIDs eye drops, such as IMC, pranoprofen, diclofenac, bromfenac, and nepafenac eyedrops, in human corneal epithelial cells. Moreover, the corneal penetration in IMC-NP dispersions was higher than that in commercially available IMC and IMC-MP suspensions, and three energy-dependent endocytosis pathways (clathrin-dependent endocytosis, caveolae-dependent endocytosis, and macropinocytosis) were related to the high ophthalmic bioavailability of IMC-NP dispersions. This information can be used to support future studies aimed at designing novel ophthalmic formulations.
  • Yuichiro Nakada; Mizuki Yamaguchi; Saori Deguchi; Kazunori Inaba; Noriaki Nagai
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan PHARMACEUTICAL SOC JAPAN 141 (6) 869 - 876 0031-6903 2021 
    Quality changes associated with physical changes in suspended eye drops are difficult to predict. In this study, we attempted to evaluate the aggregation and redispersability in commercially available suspended eye drops (fluorometholone ophthalmic solutions). The 0.1% fluorometholone ophthalmic solutions (the original product and 4 generic products) were gently mixed by hand after short-term (4 months) or long-term (40 months) storage, and the drug concentration in the first drop and physical stability (redispersability and particle size) were measured. All eye drops produced a cloudy precipitate on the bottom surface of the container, and the amount of precipitate decreased with mixing time. The drug concentration per drop in the original product was approximately 70% of the labeled value after mixing 10 times, and the drug particle size was approximately 4 μm. After mixing the generic products stored short-term 10 times, the concentration ranged from less than 50% to almost 100%. In addition, some generic products after long-term storage had a reduced redispersion ability and labeled concentration. These results suggested that at least 10 mixing were required before the using of fluorometholone original product. In addition, some generic products may not provide sufficient drug exposure even when mixed in the same manner as the original products.
  • Naoki Yamamoto; Shun Takeda; Natsuko Hatsusaka; Noriko Hiramatsu; Noriaki Nagai; Saori Deguchi; Yosuke Nakazawa; Takumi Takata; Sachiko Kodera; Akimasa Hirata; Eri Kubo; Hiroshi Sasaki
    Cells MDPI 9 (12) 2020/12 
    The prevalence of nuclear cataracts was observed to be significantly higher among residents of tropical and subtropical regions compared to those of temperate and subarctic regions. We hypothesized that elevated environmental temperatures may pose a risk of nuclear cataract development. The results of our in silico simulation revealed that in temperate and tropical regions, the human lens temperature ranges from 35.0 °C to 37.5 °C depending on the environmental temperature. The medium temperature changes during the replacement regularly in the cell culture experiment were carefully monitored using a sensor connected to a thermometer and showed a decrease of 1.9 °C, 3.0 °C, 1.7 °C, and 0.1 °C, after 5 min when setting the temperature of the heat plate device at 35.0 °C, 37.5 °C, 40.0 °C, and 42.5 °C, respectively. In the newly created immortalized human lens epithelial cell line clone NY2 (iHLEC-NY2), the amounts of RNA synthesis of αA crystallin, protein expression, and amyloid β (Aβ)1-40 secreted into the medium were increased at the culture temperature of 37.5 °C compared to 35.0 °C. In short-term culture experiments, the secretion of Aβ1-40 observed in cataracts was increased at 37.5 °C compared to 35.0 °C, suggesting that the long-term exposure to a high-temperature environment may increase the risk of cataracts.
  • Fumihiko Ogata; Noriaki Nagai; Eri Nagahashi; Natsumi Kadowaki; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    WATER SUPPLY IWA PUBLISHING 20 (7) 2815 - 2825 1606-9749 2020/11 
    In this study, metal complex hydroxide materials containing magnesium to iron in molar ratios of 3:1 and 5:1, referred to in this study as Mg-Fe-CH3.0 and Mg-Fe-CH5.0, respectively, were prepared, and their adsorption capability with respect to fluoride ions was investigated. The physicochemical characteristics of adsorbents were determined using scanning electron microscopy and X-ray diffraction, and specific surface area and the number of hydroxyl groups were calculated. The adsorption behaviors and mechanism of fluoride ions were assessed. The adsorption capability of fluoride ions using Mg-Fe-CH3.0 was greater than that using Mg-Fe-CH5.0. In addition, the amount adsorbed depended on the adsorption temperatures; the adsorption was comparatively less at 5 degrees C than at 25 degrees C. Adsorption mechanism of fluoride ions was evaluated by elemental distribution analysis and binding energy. The binding energy of fluorine onto Mg-Fe-CH3.0 and Mg-Fe-CH5.0 could be detected after adsorption. Additionally, it was clear that one of the adsorption mechanisms was related to the ion exchange between fluoride ions and chloride ions in the interlayer space of the Mg-Fe-CH3.0 and Mg-Fe-CH5.0 (correlation coefficient 0.923-0.965). This study illustrates that both Mg-Fe-CH3.0 and Mg-Fe-CH5.0 have a high potential for fluoride ion adsorption from the aqueous phase.
  • Noriaki Nagai; Takumi Isaka; Saori Deguchi; Misa Minami; Mizuki Yamaguchi; Hiroko Otake; Norio Okamoto; Yosuke Nakazawa
    International journal of molecular sciences 21 (19) 2020/09 
    We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50-150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5-10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.
  • Saori Deguchi; Fumihiko Ogata; Mizuki Yamaguchi; Misa Minami; Hiroko Otake; Kazutaka Kanai; Naohito Kawasaki; Noriaki Nagai
    Cells 9 (10) 2020/09 
    We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80-250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.
  • 池西 政幸; 石井 康世; 雪矢 良輔; 緒方 文彦; 川崎 直人; 長井 紀章; 大鳥 徹; 奥野 智之
    Medical Nutritionist of PEN Leaders (有)フジメディカル出版 4 (2) 136 - 140 2432-5678 2020/09 
    中心静脈栄養療法施行中の患者で市販微量元素製剤投与の結果、鉄を除いた製剤の院内調製が必要となった。そこで、他施設の情報(マンガン・亜鉛・銅・ヨウ素/4成分注)を基に調製するも、微量・微小の浮遊物が多いなどの問題が判明したことから、その調製方法を検討し、機器的手法により品質を評価した。すなわち、4成分注を1成分注(銅)と3成分注(マンガン・亜鉛・ヨウ素)の2種類の製剤に分けて調製し、含量試験および微粒子試験を行ったところ、3製剤ともに必要量の微量元素が均一性を維持した状態で調製されていたものの、1成分注と3成分注では、4成分注に比較して微粒子数が減少し、これまでの目視による異物検査の判定に対応した結果が得られた。以上より、4成分配合微量元素製剤を2種類に分ける調製方法は、調製する薬剤師のみならず、投薬する患者においても、より安全で安心かつ適正に提供し、用いることができる改良法の一つであると考える。(著者抄録)
  • Kanta Sato; Noriaki Nagai; Tetsushi Yamamoto; Kuniko Mitamura; Atsushi Taga
    International journal of molecular sciences MDPI 21 (14) 2020/07 [Refereed]
     
    The authors wish to make the following corrections to this paper [...].
  • Noriaki Nagai; Kazuki Umachi; Hiroko Otake; Mikako Oka; Noriko Hiramatsu; Hiroshi Sasaki; Naoki Yamamoto
    Pharmaceutics 12 (7) 2020/07 [Refereed]
     
    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.
  • Noriaki Nagai; Ryotaro Seiriki; Saori Deguchi; Hiroko Otake; Noriko Hiramatsu; Hiroshi Sasaki; Naoki Yamamoto
    Pharmaceutics 12 (6) 2020/06 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Megumu Toda; Masashi Otani; Chalermpong Saenjum; Takehiro Nakamura; Naohito Kawasaki
    Water (Switzerland) MDPI 12 (6) 2020/06 [Refereed]
     
    © 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.
  • メロキシカムナノ製剤の開発とその消化管吸収機構の解明
    山口 瑞季; 池田 瑠璃; 渡辺 雅輝; 大竹 裕子; 長井 紀章
    日本薬剤学会年会講演要旨集 (公社)日本薬剤学会 35年会 148 - 148 2020/05
  • 経眼瞼適用レバミピドナノゲル製剤によるドライアイ治療
    南 実沙; 石井 美有; 勢力 諒太朗; 大竹 裕子; 平松 範子; 山本 直樹; 長井 紀章
    日本薬剤学会年会講演要旨集 (公社)日本薬剤学会 35年会 148 - 148 2020/05
  • トラニラストの超微細化と肺内投与による肺線維化抑制効果
    大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章
    日本薬剤学会年会講演要旨集 (公社)日本薬剤学会 35年会 163 - 163 2020/05
  • Yu Mano; Hiroko Otake; Teppei Shibata; Eri Kubo; Hiroshi Sasaki; Noriaki Nagai
    Biomedicines 8 (4) 2020/04 [Refereed]
     
    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.
  • Misa Minami; Ryotaro Seiriki; Hiroko Otake; Yosuke Nakazawa; Kazutaka Kanai; Tadatoshi Tanino; Noriaki Nagai
    Materials (Basel, Switzerland) 13 (7) 2020/04 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Naohito Kawasaki
    Pharmaceutics 12 (4) 2020/04 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Ryo Itami; Takehiro Nakamura; Naohito Kawasaki
    JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING ELSEVIER SCI LTD 8 (2) 2213-2929 2020/04 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Naohito Kawasaki
    Pharmaceutics 12 (4) 2020/04 [Refereed]
     
    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.
  • Yosuke Nakazawa; Miki Aoki; Sho Ishiwa; Naoki Morishita; Shin Endo; Noriaki Nagai; Naoki Yamamoto; Megumi Funakoshi-Tago; Hiroomi Tamura
    Molecular medicine reports SPANDIDOS PUBL LTD 21 (3) 1258 - 1266 1791-2997 2020/03 [Refereed]
     
    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.
  • Noriaki Nagai; Miyu Ishii; Ryotaro Seiriki; Fumihiko Ogata; Hiroko Otake; Yosuke Nakazawa; Norio Okamoto; Kazutaka Kanai; Naohito Kawasaki
    Pharmaceutics 12 (2) 2020/02 [Refereed]
     
    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.
  • Noriaki Nagai; Yuya Fukuoka; Kanta Sato; Hiroko Otake; Atsushi Taga; Mikako Oka; Noriko Hiramatsu; Naoki Yamamoto
    International journal of molecular sciences 21 (3) 2020/02 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Akane Soeda; Kaito Yamashiro; Takehiro Nakamura; Chalermpong Saenjum; Naohito Kawasaki
    Bioresource Technology Reports 9 2020/02 [Refereed]
     
    © 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.
  • Tomonori Hayashi; Hinako Kawaguchi; Tsumugi Eifuku; Hiroshi Matsuoka; Atsufumi Kawabata; Noriaki Nagai
    Chemical & pharmaceutical bulletin 68 (9) 879 - 884 2020 
    The percutaneous absorption of a fentanyl (FEN)-patch is affected by various external factors including the volume of sebum secretion, which causes changes in the skin surface environment. In this study, we prepared a lard-based sebum-like secretion (SLS), and applied it to investigate the effect of different skin surface conditions on the drug penetration of a FEN-patch. In vitro work to test drug release using the Franz diffusion cell indicated that drug release was significantly suppressed by treatment with 5% SLS, which is equivalent to the amount of daily human sebum secretion. Conversely, in ex vivo experiments using rat skin, the amount of FEN that accumulated in the skin tissue of the 5% SLS-treated rats was higher in comparison with the non-SLS treated group. Furthermore, in vivo experiments indicated that the plasma FEN concentration in rats treated with the FEN-patch was significantly increased by treatment with 5% SLS. These results suggest that the sebum affected the release, accumulation, and absorption of FEN from the FEN-patch, and the FEN concentration in the blood was reflected by the balance of the suppression of drug release and the enhancement of drug accumulation in the skin with SLS.
  • Kazunori Inaba; Misa Minami; Mizuki Yamaguchi; Ryoka Goto; Hiroko Otake; Takeshi Kotake; Noriaki Nagai
    Chemical & pharmaceutical bulletin 68 (11) 1069 - 1073 2020 
    Ophthalmic preservatives are indispensable in eye drop formulations, but may be toxic to corneal structures. Corneal damage necessitates the discontinuation of treatment with ophthalmic solutions. Therefore, the development of a new and safe preservative system without corneal toxicity is needed. The present study investigated the effects of mannitol on the antimicrobial activities and corneal toxicities of various preservatives using Escherichia coli and a human corneal epithelial cell line (HCE-T cells). The following preservatives were examined: boric acid (BA), benzalkonium chloride (BAC), methyl parahydroxybenzoate (MP), propyl parahydroxybenzoate (PP), sodium chlorite (SC), and zinc chloride (ZC). The antimicrobial activities and HCE-T-cell toxicities of 50 µg/mL BA, MP, PP, SC, and ZC were reduced by a co-treatment with mannitol (0-300 µg/mL). The suppressed antimicrobial activities of BA, MP, PP, and SC by the co-treatment with mannitol were restored by the application of a mannitol content higher than 500 µg/mL. In contrast to these 5 preservatives, the addition of mannitol did not affect the antimicrobial activity of BAC and attenuated its HCE-T cell toxicity. Therefore, the balance between the contents of mannitol and preservatives is important in co-treatments. The present results will serve as a guide for the future development of eye drop formulations without corneal toxicity.
  • Yosuke Nakazawa; Teppei Shibata; Noriaki Nagai; Eri Kubo; Hiroomi Tamura; Hiroshi Sasaki
    Open medicine (Warsaw, Poland) DE GRUYTER POLAND SP Z O O 15 (1) 1163 - 1171 2391-5463 2020 
    Cataracts are mainly classified into three types: cortical cataracts, nuclear cataracts, and posterior subcapsular cataracts. In addition, retrodots and waterclefts are cataract subtypes that cause decreased visual function. To maintain an orderly and tightly packed arrangement to minimize light scattering, adhesion molecules such as connexins and aquaporin 0 (AQP0) are highly expressed in the lens. We hypothesized that some main and/or subcataract type(s) are correlated with adhesion molecule degradation. Lens samples were collected from cataract patients during cataract surgery, and mRNA and protein expression levels were measured by real-time RT-PCR and western blotting, respectively. The mRNA levels of adhesion molecules were not significantly different among any cataract types. Moreover, AQP0 and connexin 46 protein expressions were unchanged among patients. However, connexin 50 protein level was significantly decreased in the lens of patients with WC cataract subtype. P62 and LC3B proteins were detected in the WC patients' lenses, but not in other patients' lenses. These results suggest that more research is needed on the subtypes of cataracts besides the three major types of cataract for tailor-made cataract therapy.
  • Hiroyo Okamoto; Tomohiro Yoshikawa; Kenta Takeuchi; Saori Deguchi; Yuto Hatakenaka; Hiroshi Matsuoka; Atsufumi Kawabata; Noriaki Nagai
    Chemical & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 68 (6) 516 - 519 0009-2363 2020 [Refereed]
     
    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.
  • Noriaki Nagai; Misa Minami; Saori Deguchi; Hiroko Otake; Hiroshi Sasaki; Naoki Yamamoto
    Frontiers in bioengineering and biotechnology 8 764 - 764 2020 [Refereed]
     
    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.
  • Hiroko Otake; Tetushi Yamamoto; Saori Deguchi; Atushi Taga; Noriaki Nagai
    Molecular medicine reports SPANDIDOS PUBL LTD 21 (1) 379 - 386 1791-2997 2020/01 [Refereed]
     
    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.
  • Kanta Sato; Noriaki Nagai; Tetsushi Yamamoto; Kuniko Mitamura; Atsushi Taga
    International journal of molecular sciences MDPI 20 (20) 2019/10 [Refereed]
     
    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.
  • Noriaki Nagai; Ryusuke Sakamoto; Seiji Yamamoto; Saori Deguchi; Hiroko Otake; Tadatoshi Tanino
    International journal of molecular sciences 20 (20) 2019/10 [Refereed]
     
    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.
  • Shinsuke Ide; Akira Ganaha; Tetsuya Tono; Takashi Goto; Noriaki Nagai; Keiji Matsuda; Minako Azuma; Toshinori Hirai
    International journal of pediatric otorhinolaryngology 124 34 - 38 2019/09 [Refereed]
     
    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.
  • Kazuaki Sato; Kiwako Iwasaki; Noriaki Nagai; Yohei Yamashita; Seishiro Chikazawa; Fumio Hoshi; Kazutaka Kanai
    Veterinary ophthalmology WILEY 22 (5) 607 - 613 1463-5216 2019/09 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Mizuki Yamaguchi; Yuya Fukuoka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki
    International journal of molecular sciences 20 (15) 2019/07 [Refereed]
     
    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).
  • Noriaki Nagai; Yu Mano; Hiroko Otake; Teppei Shibata; Eri Kubo; Hiroshi Sasaki
    Molecular medicine reports 19 (6) 5464 - 5472 1791-2997 2019/06 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshie Iwai; Saori Deguchi; Hiroko Otake; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura
    Nanomaterials (Basel, Switzerland) 9 (5) 2019/05 [Refereed]
     
    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.
  • Kazuaki Sato; Kazutaka Kanai; Maiko Ozaki; Takaaki Kagawa; Mizuki Kita; Yohei Yamashita; Noriaki Nagai; Kazuki Tajima
    The Journal of veterinary medical science JAPAN SOC VET SCI 81 (4) 573 - 576 0916-7250 2019/04 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Mao Kishida; Takehiro Nakamura; Naohito Kawasaki
    JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING ELSEVIER SCI LTD 7 (1) 2213-2929 2019/02 [Refereed]
     
    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.
  • Ogata Fumihiko; Nagai Noriaki; Kishida Mao; Nakamura Takehiro; Kawasaki Naohito
    JOURNAL OF ENVIRONMENTAL CHEMICAL ENGINEERING 7 (1) 2213-3437 2019/02 [Refereed]
  • Yosuke Nakazawa; Nana Ishimori; Jun Oguchi; Noriaki Nagai; Masaki Kimura; Megumi Funakoshi-Tago; Hiroomi Tamura
    Experimental and therapeutic medicine SPANDIDOS PUBL LTD 17 (2) 1420 - 1425 1792-0981 2019/02 [Refereed]
     
    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.
  • Miyu Ishii; Yuya Fukuoka; Saori Deguchi; Hiroko Otake; Tadatoshi Tanino; Noriaki Nagai
    International journal of molecular sciences 20 (3) 1422-0067 2019/01 [Refereed]
     
    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.
  • Noriaki Nagai; Yuka Yamasaki; Tsubasa Nakamura; Hiroko Otake; Naoya Okamoto
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 139 (1) 123 - 130 0031-6903 2019 [Refereed]
     
    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.
  • Kazunori Inaba; Toshiharu Oie; Hiroko Otake; Takeshi Kotake; Noriaki Nagai
    Chemical & pharmaceutical bulletin 67 (2) 120 - 124 0009-2363 2019 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki
    International journal of nanomedicine 14 1213 - 1227 1176-9114 2019 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Megumu Toda; Masashi Otani; Takehiro Nakamura; Naohito Kawasaki
    Chemical & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 67 (5) 487 - 492 0009-2363 2019 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Takehiro Nakamura; Naohito Kawasaki
    Chemical & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 67 (10) 1168 - 1170 0009-2363 2019 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshie Iwai; Akane Sakamoto; Hiroko Otake; Yoshihiro Oaku; Akinari Abe; Tohru Nagahama
    International journal of nanomedicine 14 7921 - 7931 1176-9114 2019 [Refereed]
     
    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).
  • Tadatoshi Tanino; Toru Bando; Yukie Nojiri; Yuna Okada; Noriaki Nagai; Yukari Ueda; Eiichi Sakurai
    Biochemical pharmacology PERGAMON-ELSEVIER SCIENCE LTD 158 318 - 326 0006-2952 2018/12 [Refereed]
     
    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.
  • Tetsushi Yamamoto; Hiroko Otake; Noriko Hiramatsu; Naoki Yamamoto; Atsushi Taga; Noriaki Nagai
    International journal of molecular sciences MDPI 19 (11) 1422-0067 2018/11 [Refereed]
     
    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.
  • 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  1661-6596 2018/07 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Miyu Ishii; Yuya Fukuoka; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki
    International journal of molecular sciences 19 (7) 1422-0067 2018/07 [Refereed]
     
    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.
  • Yosuke Nakazawa; Martin Pauze; Kazuya Fukuyama; Noriaki Nagai; Megumi Funakoshi-Tago; Takeshi Sugai; Hiroomi Tamura
    Molecular medicine reports Spandidos Publications 18 (1) 1043 - 1050 1791-3004 2018/07 [Refereed]
     
    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.
  • Nagai Noriaki; Deguchi Saori; Ishii Miyu; Fukuoka Yuya; Otake Hiroko; Nakazawa Yosuke
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 59 (9) 0146-0404 2018/07 [Refereed]
  • Noriaki Nagai; Yuya Fukuoka; Miyu Ishii; Hiroko Otake; Tetsushi Yamamoto; Atsushi Taga; Norio Okamoto; Yoshikazu Shimomura
    International journal of molecular sciences MDPI AG 19 (4) 1422-0067 2018/04 [Refereed]
     
    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.
  • 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 (株)北隆館 33 (4) 371 - 373 0919-8237 2018/04 
    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)
  • Chiaki Yoshioka; Yoshimasa Ito; Noriaki Nagai
    Experimental and therapeutic medicine SPANDIDOS PUBL LTD 15 (4) 3501 - 3508 1792-0981 2018/04 [Refereed]
     
    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.
  • 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 122 (1) 61 - 62 2018/01
  • Noriaki Nagai; Sakie Yamaoka; Yuya Fukuoka; Miyu Ishii; Hiroko Otake; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura
    International journal of molecular sciences 19 (1) 1422-0067 2018/01 [Refereed]
     
    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.
  • Noriaki Nagai; Akina Ueno; Miyu Ishii; Yuya Fukuoka; Hiroko Otake
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 138 (8) 1111 - 1117 0031-6903 2018 [Refereed]
     
    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.
  • Chiaki Yoshioka; Yoshimasa Ito; Noriaki Nagai
    Experimental and therapeutic medicine SPANDIDOS PUBL LTD 15 (1) 454 - 460 1792-0981 2018/01 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Erimi Ueta; Takehiro Nakamura; Naohito Kawasaki
    Chemical & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 66 (3) 295 - 302 0009-2363 2018 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Yukine Kariya; Eri Nagahashi; Yuhei Kobayashi; Takehiro Nakamura; Naohito Kawasaki
    Chemical & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 66 (4) 458 - 465 0009-2363 2018 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Yosuke Nakazawa; Naohito Kawasaki
    International journal of nanomedicine 13 5215 - 5229 1176-9114 2018 [Refereed]
     
    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.
  • Saori Deguchi; Hiroko Otake; Yosuke Nakazawa; Noriko Hiramatsu; Naoki Yamamoto; Noriaki Nagai
    International Journal of Molecular Sciences MDPI AG 18 (12) 1422-0067 2017/12 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Hiroko Otake; Naohito Kawasaki; Yosuke Nakazawa; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura
    EXPERIMENTAL EYE RESEARCH ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD 165 118 - 124 0014-4835 2017/12 [Refereed]
     
    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.
  • Noriaki Nagai; Tetsushi Yamamoto; Kuniko Mitamura; Atsushi Taga
    Biomedical Reports Spandidos Publications 7 (5) 445 - 450 2049-9442 2017/11 [Refereed]
     
    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.
  • Yosuke Nakazawa; Noriaki Nagai; Nana Ishimori; Jun Oguchi; Hiroomi Tamura
    BIOMEDICINE & PHARMACOTHERAPY ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER 95 137 - 143 0753-3322 2017/11 [Refereed]
     
    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.
  • 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 (株)北隆館 32 (11) 1099 - 1101 0919-8237 2017/10 
    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)
  • Noriaki Nagai; Saori Deguchi; Hiroko Otake; Noriko Hiramatsu; Naoki Yamamoto
    International Journal of Molecular Sciences MDPI AG 18 (9) 1422-0067 2017/09 [Refereed]
     
    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.
  • Noriaki Nagai; Saori Deguchi; Hiroko Otake; Noriko Hiramatsu; Naoki Yamamoto
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES MDPI AG 18 (9) 1422-0067 2017/09 [Refereed]
     
    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.
  • Noriko Hiramatsu; Saori Deguchi; Chiaki Yoshioka; Hiroko Otake; Naoki Yamamoto; Noriaki Nagai
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 137 (9) 1169 - 1175 0031-6903 2017/09 [Refereed]
     
    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.
  • Noriaki Nagai; Yosuke Nakazawa; Yoshimasa Ito; Kazutaka Kanai; Norio Okamoto; Yoshikazu Shimomura
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 40 (7) 1055 - 1062 0918-6158 2017/07 [Refereed]
     
    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.
  • Noriaki Nagai; Akina Ueno; Tadatoshi Tanino; Mikako Oka; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 40 (6) 910 - 915 0918-6158 2017/06 [Refereed]
     
    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.
  • Noriaki Nagai; Yu Mano; Hiroko Otake; Teppei Shibata; Eri Kubo; Hiroshi Sasaki
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE ASSOC RESEARCH VISION OPHTHALMOLOGY INC 58 (7) 3294 - 3302 0146-0404 2017/06 [Refereed]
     
    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.
  • Akina Ueno; Sakie Yamaoka; Yoshimasa Ito; Takeshi Kotake; Yosuke Nakazawa; Noriaki Nagai
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 137 (5) 635 - 641 0031-6903 2017/05 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Teppei Shibata; Eri Kubo; Hiroshi Sasaki
    TOXICOLOGY ELSEVIER IRELAND LTD 381 19 - 30 0300-483X 2017/04 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Saori Deguchi; Akina Ueno; Naohito Kawasaki; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 40 (4) 444 - 450 0918-6158 2017/04 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Naohito Kawasaki
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 65 (3) 268 - 275 0009-2363 2017/03 [Refereed]
     
    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.
  • Noriaki Nagai; Sachiyo Kotani; Yu Mano; Akina Ueno; Yoshimasa Ito; Toshio Kitaba; Takumi Takata; Noriko Fujii
    BIOMED RESEARCH INTERNATIONAL HINDAWI LTD 2017 5343010  2314-6133 2017 [Refereed]
     
    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.
  • Ogata F; Nagai N; Kawasaki N
    Chemical & pharmaceutical bulletin 65 (3) 268 - 275 0009-2363 2017 [Refereed]
  • Noriaki Nagai; Tadatoshi Tanino; Yoshimasa Ito
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 65 (12) 1045 - 1053 1345-8957 2016/12 [Refereed]
     
    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.
  • Noriaki Nagai; Yu Mano; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 39 (11) 1881 - 1887 0918-6158 2016/11 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    EXPERIMENTAL EYE RESEARCH ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD 151 47 - 53 0014-4835 2016/10 [Refereed]
     
    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.
  • Noriaki Nagai
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 136 (10) 1385 - 1390 0031-6903 2016/10 [Refereed]
     
    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.
  • 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 日本眼薬理学会 36回 49 - 49 2016/09
  • 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 (公社)日本薬学会 136年会 (4) 70 - 70 0918-9823 2016/03
  • Noriko Kodama; Noriaki Nagai; Tomohisa Yasuhara
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 136 (3) 359 - 360 0031-6903 2016/03 [Refereed]
  • Noriko Kodama; Noriaki Nagai; Tomohisa Yasuhara
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 136 (3) 359 - 360 0031-6903 2016/03 [Refereed]
  • Noriaki Nagai; Yoshimasa Ito; Hiroshi Sasaki
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE ASSOC RESEARCH VISION OPHTHALMOLOGY INC 57 (3) 1408 - 1417 0146-0404 2016/03 [Refereed]
     
    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.
  • Nagai Noriaki; Tsukamoto Ayumi; Kotake Takeshi; Ito Yoshimasa; Okamoto Norio; Shimomura Yoshikazu
    Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) Japanese Society of Pharmaceutical Health Care and Sciences 42 (9) 645 - 650 2016 

    Studies in rabbits have been performed to evaluate the intraocular pressure (IOP)-reducing effect of various anti-glaucoma eye drops and eye drops of latanoprost (LP), which is a selective agonist of prostaglandin F receptor (FP). However, the sensitivity and localization of FP receptors in the rabbit eye are different from those in humans, and studying the relationship between IOP regulation and FP receptors in rabbits is important for the evaluation of antiglaucoma eye drops. In this study, we investigated whether stimulation of FP receptors in rabbits affects the regulation of aqueous humour production via β receptors by using the LP and the β-blocker timolol (TM). Ocular hypertension was induced in the rabbits by the infusion of a 5％ glucose solution (15 mL/kg). Although no reduction in IOP was observed after the instillation of saline and 0.005％ LP, 0.5％ TM eye drops significantly reduced IOP. The IOP-reducing effect, as measured by area under the curve (AUC∆IOP) in rabbits treated with TM eye drops, was 81.3％ that of LP 0.005％/TM 0.5％ fixed combination (LTFC) eye drops, and the TM concentration in the aqueous humour following the instillation of LTFC eye drops was similar to that of TM eye drops. These results show that the stimulation of FP receptors affects the production of aqueous humour via β receptors in rabbits, meaning the rabbit model is not suitable for the evaluation of anti-glaucoma eye drops with FP receptor activity, since this drug effect was not observed in humans.

  • Noriaki Nagai; Fumihiko Ogata; Naohito Kawasaki; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 39 (1) 138 - 142 0918-6158 2016/01 [Refereed]
     
    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.
  • Noriaki Nagai; Chiaki Yoshioka; Tadatoshi Tanino; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    CURRENT EYE RESEARCH TAYLOR & FRANCIS INC 41 (4) 532 - 542 0271-3683 2016 [Refereed]
     
    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.
  • Noriaki Nagai; Aya Iwamae; Shion Tanimoto; Chiaki Yoshioka; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 38 (12) 1918 - 1924 0918-6158 2015/12 [Refereed]
     
    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.
  • Noriaki Nagai; Chiaki Yoshioka; Yoshimasa Ito; Yoshinori Funakami; Hiroyuki Nishikawa; Atsufumi Kawabata
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES MDPI AG 16 (12) 29329 - 29344 1422-0067 2015/12 [Refereed]
     
    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.
  • Noriaki Nagai; Tadatoshi Tanino; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 38 (10) 1580 - 1590 0918-6158 2015/10 [Refereed]
     
    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.
  • Tadatoshi Tanino; Yoshinori Funakami; Noriaki Nagai; Yoshihisa Kato
    JOURNAL OF PHARMACY AND PHARMACOLOGY WILEY-BLACKWELL 67 (10) 1406 - 1415 0022-3573 2015/10 [Refereed]
     
    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.
  • Tadatoshi Tanino; Noriaki Nagai; Yoshinori Funakami
    JOURNAL OF PHARMACY AND PHARMACOLOGY WILEY 67 (10) 1457 - 1465 0022-3573 2015/10 [Refereed]
     
    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.
  • Noriaki Nagai; Fumihiko Ogata; Naohito Kawasaki; Yoshimasa Ito; Yoshinori Funakami; Norio Okamoto; Yoshikazu Shimomura
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 38 (7) 1063 - 1069 0918-6158 2015/07 [Refereed]
     
    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.
  • Noriaki Nagai; Chiaki Yoshioka; Tadatoshi Tanino; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 64 (7) 743 - 750 1345-8957 2015/07 [Refereed]
     
    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.
  • 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 (5) 1 - 11 2015/05 [Refereed]
  • Noriaki Nagai; Yoshimasa Ito; Tadatoshi Tanino
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 38 (4) 601 - 610 0918-6158 2015/04 [Refereed]
     
    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.
  • 長井 紀章; 真野 裕; 松平 有加
    あたらしい眼科 メディカル葵出版 32 (4) 545 - 549 0910-1810 2015/04
  • NAGAI NORIAKI
    日本眼科学会雑誌 119 26  0029-0203 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
    真野 裕; 谷本 紫苑; 中屋 仁美; 長井 紀章; 伊藤 吉將
    日本薬学会年会要旨集 (公社)日本薬学会 135年会 (4) 127 - 127 0918-9823 2015/03
  • 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 6 (4) online  2015/03 [Refereed]
  • 長井 紀章; 吉岡 千晶; 森 愛里
    あたらしい眼科 メディカル葵出版 32 (3) 419 - 424 0910-1810 2015/03
  • Noriaki Nagai; Chiaki Yoshioka; Yu Mano; Wataru Tnabe; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    EXPERIMENTAL EYE RESEARCH ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD 132 115 - 123 0014-4835 2015/03 [Refereed]
     
    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.
  • Noriaki Nagai; Tetsushi Yamamoto; Wataru Tanabe; Yoshimasa Ito; Satoshi Kurabuchi; Kuniko Mitamura; Atsushi Taga
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 64 (3) 331 - 335 1345-8957 2015/03 [Refereed]
     
    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.
  • Noriaki Nagai; Chiaki Yoshioka; Yoshimasa Ito
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 64 (3) 337 - 346 1345-8957 2015/03 [Refereed]
     
    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.
  • Noriaki Nagai; Chiaki Yoshioka; Yu Mano; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    CURRENT EYE RESEARCH TAYLOR & FRANCIS INC 40 (10) 990 - 1000 0271-3683 2015 [Refereed]
     
    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 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 (20) 1 - 11 2014/10 [Refereed]
  • NAGAI NORIAKI; FUJITA HIROMI; ITO YOSHIMASA; OKAMOTO NORIO; SHIMOMURA YOSHIKAZU
    眼薬理 28 (1) 41 - 44 0914-1405 2014/08
  • Noriaki Nagai; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 37 (7) 1109 - 1118 0918-6158 2014/07 [Refereed]
     
    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.
  • 長井 紀章; 藤田 裕美; 伊藤 吉將
    あたらしい眼科 メディカル葵出版 31 (5) 729 - 732 0910-1810 2014/05
  • Noriaki Nagai; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    TOXICOLOGY ELSEVIER IRELAND LTD 319 (1) 53 - 62 0300-483X 2014/05 [Refereed]
     
    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.
  • Fumihiko Ogata; Noriaki Nagai; Yoshimasa Ito; Naohito Kawasaki
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 134 (5) 679 - 685 0031-6903 2014/05 [Refereed]
     
    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)
  • NAGAI NORIAKI; ITO YOSHIMASA
    薬局 65 (5) 1731-1737,1712  0044-0035 2014/04
  • 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 38 (2) 75 - 80 2014/03 [Refereed]
  • Noriaki Nagai; Hikaru Ono; Miho Hashino; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 63 (2) 177 - 186 1345-8957 2014/02 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito
    TOXICOLOGY ELSEVIER IRELAND LTD 315 (1) 55 - 64 0300-483X 2014/01 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 37 (1) 96 - 104 0918-6158 2014/01 [Refereed]
     
    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.
  • 長井 紀章; 緒方 文彦; 塚本 あゆみ
    薬局薬学 日本薬局学会 6 (1) 22 - 27 1884-3077 2014
  • Nagai Noriaki; Kim Yusei; Matzno Sumio; Matsuyama Kenji; Otori Toru
    Jpn.J.Drug Inform. Japanese Society of Drug Informatics 16 (3) 137 - 142 1345-1464 2014 
    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.
  • Nagai Noriaki
    The Journal of The Japanese Society for Cataract Research The Japanese Society for Cataract Research 26 (1) 13 - 19 0915-4302 2014 
    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.
  • Nagai N; Ito Y
    World journal of diabetes 6 4 (6) 282 - 289 2013/12 [Refereed]
  • 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 Japanese Society of Drug Informatics 15 (3) 124 - 132 1345-1464 2013/11 
    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.
  • 岡本 紀夫; 日下 俊次; 長井 紀章
    眼科臨床紀要 眼科臨床紀要会 6 (11) 903 - 905 1882-5176 2013/11
  • NAGAI NORIAKI; OGATA FUMIHIKO; FUNAKAMI YOSHINORI; ITO YOSHIMASA; KAWASAKI NAOHITO
    あたらしい眼科 メディカル葵出版 30 (11) 1623 - 1627 0910-1810 2013/11
  • NAGAI NORIAKI; ITO YOSHIMASA; OKAMOTO NORIO; SHIMOMURA YOSHIKAZU
    眼薬理 27 (1) 27 - 29 0914-1405 2013/09
  • Noriaki Nagai; Yoshimasa Ito; Atsushi Taga
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 62 (9) 737 - 743 1345-8957 2013/09 [Refereed]
     
    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.
  • NAGAI Noriaki; OE Kyouhei; MORI Airi; ITO Yoshimasa; OKAMOTO Norio; SHIMOMURA Yoshikazu
    あたらしい眼科 = Journal of the eye メディカル葵出版 30 (7) 1023 - 1028 0910-1810 2013/07
  • NAGAI NORIAKI; OE KYOHEI; MORI AIRI; ITO YOSHIMASA; OKAMOTO NORIO; SHIMOMURA YOSHIKAZU
    あたらしい眼科 メディカル葵出版 30 (7) 1023 - 1028 0910-1810 2013/07
  • Yoshimasa Ito; Noriaki Nagai; Norio Okamoto; Yoshikazu Shimomura; Kunio Nakanishi; Ryuichiro Tanaka
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 36 (6) 1017 - 1023 0918-6158 2013/06 [Refereed]
     
    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.
  • NAGAI Noriaki; TAKEDA Atsushi; ITO Yoshimasa
    日本白内障学会誌 25 51 - 55 0915-4302 2013/06
  • Noriaki Nagai; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 62 (3) 159 - 166 1345-8957 2013/03 [Refereed]
     
    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.
  • NAGAI NORIAKI; TAKEDA ATSUSHI; ITO YOSHIMASA
    あたらしい眼科 メディカル葵出版 30 (1) 97 - 101 0910-1810 2013/01
  • Noriaki Nagai; Yoshimasa Ito
    Journal of Oleo Science 6 62 (6) 403 - 408 1345-8957 2013 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura; Haruki Okamura
    Journal of Oleo Science 7 62 (7) 513 - 523 1345-8957 2013 [Refereed]
     
    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.
  • 大鳥 徹; 長井 紀章; 橋本 佳幸
    薬局薬学 日本薬局学会 5 (2) 107 - 115 1884-3077 2013
  • NAGAI Noriaki; TAKEDA Atsushi; ITO Yoshimasa
    あたらしい眼科 メディカル葵出版 30 (1) 97 - 101 0910-1810 2013/01
  • Nagai Noriaki; Ogata Fumihiko; Hayashi Tomonori; Nishiura Saori; Matsuoka Hiroshi; Kawasaki Naohito; Ito Yoshimasa
    Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) Japanese Society of Pharmaceutical Health Care and Sciences 39 (1) 33 - 38 1346-342X 2013 
    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.
  • Noriaki Nagai; Atsushi Takeda; Yuri Itanami; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 35 (12) 2230 - 2237 0918-6158 2012/12 [Refereed]
     
    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.
  • Noriaki Nagai; Nahoko Konishi; Tadahisa Nitta; Atsushi Taga; Yoshimasa Ito
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 132 (11) 1307 - 1316 0031-6903 2012/11 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito
    CURRENT EYE RESEARCH TAYLOR & FRANCIS INC 37 (10) 889 - 897 0271-3683 2012/10 [Refereed]
     
    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.
  • NAGAI NORIAKI; TAKEDA ATSUSHI; MURAO MAYUMI; ITO YOSHIMASA; OKAMOTO NORIO; SHIMOMURA YOSHIKAZU
    眼薬理 26 (1) 35 - 37 0914-1405 2012/08
  • Noriaki Nagai; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 132 (7) 837 - 843 0031-6903 2012/07 [Refereed]
     
    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.
  • NAGAI NORIAKI; ONO HIKARU; YAMATO MIKIE; HORINO TOMOMI; KITAKOJI MANABU; ITO YOSHIMASA; TAKADA MITSUTAKA
    医療薬学 Japanese Society of Pharmaceutical Health Care and Sciences 38 (2) 111 - 117 1346-342X 2012/02 
    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.
  • Kazutaka Kanai; Yoshimasa Ito; Noriaki Nagai; Naoyuki Itoh; Yasutomo Hori; Seishirou Chikazawa; Fumio Hoshi; Seiichi Higuchi
    CURRENT EYE RESEARCH INFORMA HEALTHCARE 37 (2) 124 - 131 0271-3683 2012/02 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Noriko Takeuchi
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 35 (2) 239 - 245 0918-6158 2012/02 [Refereed]
     
    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.
  • Shinya Hirahara; Keiji Matsuda; Katsuhiro Toyama; Yuki Nagano; Noriaki Nagai; Tetsuya Tono
    Journal of Otolaryngology of Japan Oto-Rhino-Laryngological Society of Japan Inc. 115 (6) 632 - 635 0030-6622 2012 [Refereed]
     
    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.
  • NAGAI NORIAKI; OE KYOHEI; ITO YOSHIMASA; OKAMOTO NORIO; SHIMOMURA YOSHIKAZU
    あたらしい眼科 メディカル葵出版 28 (9) 1331 - 1336 0910-1810 2011/09
  • Noriaki Nagai; Yoshimasa Ito; Noriko Takeuchi
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 34 (7) 1005 - 1010 0918-6158 2011/07 [Refereed]
     
    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.
  • NAGAI NORIAKI; MURAO TAKATOSHI; ITO YOSHIMASA; OKAMOTO NORIO; SHIMOMURA YOSHIKAZU
    あたらしい眼科 メディカル葵出版 28 (6) 855 - 859 0910-1810 2011/06
  • 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 23 (1) 51 - 54 0915-4302 2011/06
  • Noriaki Nagai; Takatoshi Murao; Yoshimasa Ito; Norio Okamoto; Haruki Okamura
    CURRENT EYE RESEARCH INFORMA HEALTHCARE 36 (6) 497 - 506 0271-3683 2011/06 [Refereed]
     
    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.
  • Noriaki Nagai; Takatoshi Murao; Kyouhei Oe; Yoshimasa Ito; Norio Okamoto; Yoshikazu Shimomura
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 131 (6) 985 - 991 0031-6903 2011/06 [Refereed]
     
    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.
  • NAGAI Noriaki; MURAO Takatoshi; KONAKA Yoko; ITO Yoshimasa; TAKEUCHI Noriko
    Journal of the eye メディカル葵出版 28 (4) 527 - 530 0910-1810 2011/04
  • Kazutaka Kanai; Naoyuki Itoh; Yoshimasa Ito; Noriaki Nagai; Yasutomo Hori; Seishirou Chikazawa; Fumio Hoshi; Seiichi Higuchi
    JOURNAL OF VETERINARY MEDICAL SCIENCE JAPAN SOC VET SCI 73 (4) 517 - 520 0916-7250 2011/04 [Refereed]
     
    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.
  • Noriaki Nagai; Takatoshi Murao; Rino Inubuse; Nahoko Konishi; Yoshimasa Ito
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 131 (4) 621 - 628 0031-6903 2011/04 [Refereed]
     
    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.
  • 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 (公社)日本薬学会 131年会 (4) 309 - 309 0918-9823 2011/03
  • 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 TAYLOR & FRANCIS INC 35 (10) 892 - 899 0271-3683 2010/10 [Refereed]
     
    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.
  • NAGAI NORIAKI; MURAO TAKATOSHI; ITO YOSHIMASA; OKAMOTO NORIO
    あたらしい眼科 メディカル葵出版 27 (9) 1299 - 1302 0910-1810 2010/09
  • NAGAI NORIAKI; MURAO TAKATOSHI; ITO YOSHIMASA; OKAMOTO NORIO
    あたらしい眼科 メディカル葵出版 27 (9) 1295 - 1298 0910-1810 2010/09
  • NAGAI NORIAKI; MURAO TAKATOSHI; ITO YOSHIMASA; OKAMOTO NORIO; MIMURA OSAMU
    眼薬理 24 (1) 52 - 54 0914-1405 2010/09
  • Yoshimasa Ito; Noriaki Nagai; Yoshikazu Shimomura
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 33 (9) 1574 - 1578 0918-6158 2010/09 [Refereed]
     
    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.
  • Norio Okamoto; Yoshimasa Ito; Noriaki Nagai; Takatoshi Murao; Yusuke Takiguchi; Takuji Kurimoto; Osamu Mimura
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 59 (8) 423 - 430 1345-8957 2010/08 [Refereed]
     
    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.
  • Noriaki Nagai; Takatoshi Murao; Norio Okamoto; Yoshimasa Ito
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 59 (8) 441 - 449 1345-8957 2010/08 [Refereed]
     
    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.
  • OKAMOTO Norio; ITO Yoshimasa; NAGAI Noriaki; HOSOTANI Yuka; MIMURA Osamu
    Folia japonica de ophthalmologica clinica 眼科臨床紀要会 3 (7) 649 - 652 1882-5176 2010/07
  • Hirokazu Kawano; Keiji Matsuda; Haruka Nakanishi; Katsuhiro Toyama; Noriaki Nagai; Tetsuya Tono
    EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY SPRINGER 267 (6) 875 - 879 0937-4477 2010/06 [Refereed]
     
    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.
  • 長井紀章
    日本眼科学会雑誌 114 79  0029-0203 2010/03
  • Noriaki Nagai; Takatoshi Murao; Norio Okamoto; Yoshimasa Ito
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 59 (3) 135 - 141 1345-8957 2010/03 [Refereed]
     
    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.
  • Noriaki Nagai; Takatoshi Murao; Yoshimasa Ito
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 129 (12) 1515 - 1521 0031-6903 2009/12 [Refereed]
     
    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.
  • Noriaki Nagai; Takatoshi Murao; Norio Okamoto; Yoshimasa Ito
    JOURNAL OF OLEO SCIENCE JAPAN OIL CHEMISTS SOC 58 (9) 485 - 490 1345-8957 2009/09 [Refereed]
     
    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.
  • Noriaki Nagai; Takatoshi Murao; Yoshimasa Ito; Norio Okamoto; Masahiro Sasaki
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 32 (9) 1594 - 1599 0918-6158 2009/09 [Refereed]
     
    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.
  • NAGAI Noriaki; ITO Yoshimasa; TAKEUCHI Noriko; USUI Shigeyuki; HIRANO Kazuyuki
    眼薬理 = Japanese journal of ocular pharmacology 23 (1) 45 - 50 0914-1405 2009/08
  • NAGAI Noriaki; ITO Yoshimasa; USUI Shigeyuki; HIRANO Kazuyuki
    Journal of the eye メディカル葵出版 26 (5) 709 - 713 0910-1810 2009/05
  • NAGAI NORIAKI; ITO YOSHIMASA; USUI SHIGEYUKI; HIRANO KAZUYUKI
    あたらしい眼科 メディカル葵出版 26 (5) 709 - 713 0910-1810 2009/05
  • NAGAI NORIAKI; ITO YOSHIMASA; TAKEUCHI NORIKO; USUI SHIGEYUKI; HIRANO KAZUYUKI
    あたらしい眼科 メディカル葵出版 26 (5) 675 - 680 0910-1810 2009/05
  • Noriaki Nagai; Takatoshi Murao; Yoshimasa Ito; Norio Okamoto; Masahiro Sasaki
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 32 (5) 933 - 936 0918-6158 2009/05 [Refereed]
     
    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.
  • OKAMOTO Norio; OONO Shinichirou; ITO Yoshimasa; NAGAI Noriaki; TAKAGI Kazuyuki; MIMURA Osamu
    Folia japonica de ophthalmologica clinica 眼科臨床紀要会 2 (4) 326 - 330 1882-5176 2009/04
  • OKAMOTO NORIO; ITO YOSHIMASA; ONO SHIN'ICHIRO; HARINO SEIYO; NAGAI NORIAKI; MIMURA OSAMU
    あたらしい眼科 メディカル葵出版 26 (2) 263 - 267 0910-1810 2009/02
  • Noriaki Nagai; Takashi Fukuhata; Yoshimasa Ito; Shigeyuki Usui; Kazuyuki Hirano
    TOXICOLOGY ELSEVIER IRELAND LTD 255 (3) 124 - 130 0300-483X 2009/01 [Refereed]
     
    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.
  • Noriaki Nagai; Takashi Fukuhata; Yoshimasa Ito; Shigeyuki Usui; Kazuyuki Hirano
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 32 (1) 116 - 120 0918-6158 2009/01 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Noriko Takeuchi; Shigeyuki Usui; Kazuyuki Hirano
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 31 (11) 1990 - 1995 0918-6158 2008/11 [Refereed]
     
    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.
  • NAGAI NORIAKI; ITO YOSHIMASA; TAKEUCHI NORIKO; KAMEI AKIRA
    眼薬理 22 (1) 54 - 56 0914-1405 2008/09
  • NAGAI NORIAKI; ITO YOSHIMASA; OKAMOTO NORIO; KAWAKAMI YOSHIMI
    あたらしい眼科 メディカル葵出版 25 (8) 1135 - 1138 0910-1810 2008/08
  • Noriaki Nagai; Mitsushi Inomata; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 31 (7) 1444 - 1448 0918-6158 2008/07 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Noriko Takeuchi
    TOXICOLOGY ELSEVIER IRELAND LTD 247 (2-3) 139 - 144 0300-483X 2008/05 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Noriko Takeuchi
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 31 (5) 981 - 985 0918-6158 2008/05 [Refereed]
     
    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.
  • NAGAI NORIAKI; ITO YOSHIMASA; OKAMOTO NORIO; KAWAKAMI YOSHIMI
    あたらしい眼科 メディカル葵出版 25 (4) 553 - 556 0910-1810 2008/04
  • 岡本 紀夫; 伊藤 吉將; 長井 紀章
    眼科 金原出版 50 (4) 455 - 459 0016-4488 2008/04
  • NAGAI Noriaki; SONG Yongbo; FUKUHATA Takashi; ITO Yoshimasa; OKAMURA Haruki
    日本白内障学会誌 19 (1) 815 - 818 0915-4302 2008/01
  • Noriaki Nagai; Tetsuya Tono; Keiji Matsuda; Katsuhiro Toyama; Hirokazu Kawano; Takao Kodama
    MEDITERRANEAN JOURNAL OF OTOLOGY MEDITERRANEAN SOC OTOLOGY & AUDIOLOGY 4 (3) 197 - 202 1305-5267 2008 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito
    Toxicology 1-3 242 (1-3) 7 - 15 0300-483X 2007/12 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Haruki Okamura
    JOURNAL OF BIOCHEMISTRY OXFORD UNIV PRESS 142 (5) 597 - 603 0021-924X 2007/11 [Refereed]
     
    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.
  • Noriaki Nagai; Tetsuya Tono; Keiji Matsuda; Katsuhiro Toyama; Hirokazu Kawano; Takao Kodama
    Journal of Otolaryngology of Japan 11 110 (11) 707 - 712 0030-6622 2007/11 [Refereed]
     
    [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.
  • Noriaki Nagai; Takashi Fukuhata; Yoshimasa Ito; Hideyuki Tai; Yoshihiro Hataguchi; Koji Nakagawa
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 30 (10) 1934 - 1937 0918-6158 2007/10 [Refereed]
     
    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.
  • FUKUHATA Takashi; NAGAI Noriaki; ITO Yoshimasa; TAI Hideyuki; HATAGUCHI Yoshihiro; UOZUMI Yoshinobu; NAKAGAWA Koji
    眼薬理 = Japanese journal of ocular pharmacology 21 (1) 37 - 40 0914-1405 2007/08
  • ITO YOSHIMASA; OKAMOTO NORIO; BESSHO MASASHI; KAWAKAMI YOSHIMI; MIMURA OSAMU; NAGAI NORIAKI
    あたらしい眼科 メディカル葵出版 24 (8) 1125 - 1127 0910-1810 2007/08
  • Noriaki Nagai; Maki Takeda; Yoshimasa Ito; Noriko Takeuchi; Akira Kamei
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 30 (8) 1529 - 1534 0918-6158 2007/08 [Refereed]
     
    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.
  • NAGAI NORIAKI; SONG YONGBO; FUKUHATA TAKASHI; ITO YOSHIMASA; OKAMURA HARUKI
    あたらしい眼科 メディカル葵出版 24 (6) 815 - 818 0910-1810 2007/06
  • FUKUHATA TAKASHI; NAGAI NORIAKI; ITO YOSHIMASA; TAI HIDEYUKI; HATAGUCHI YOSHIHIRO; UOZUMI YOSHINOBU; NAKAGAWA KOJI
    あたらしい眼科 メディカル葵出版 24 (6) 831 - 834 0910-1810 2007/06
  • 長井 紀章; 宋 永波; 福畠 孝史
    Journal of the eye メディカル葵出版 24 (6) 815 - 818 0910-1810 2007/06
  • Noriaki Nagai; Takashi Fukuhata; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 30 (1) 6 - 10 0918-6158 2007/01 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito
    CURRENT EYE RESEARCH TAYLOR & FRANCIS INC 32 (5) 439 - 445 0271-3683 2007 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Hideyuki Tai; Yoshihiro Hataguchi; Koji Nakagawa
    Journal of Oleo Science 1 56 (1) 29 - 33 1347-3352 2007 [Refereed]
     
    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.
  • Noriaki Nagai; Noriko Takeuchi; Akira Kamei; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 29 (12) 2367 - 2371 0918-6158 2006/12 [Refereed]
     
    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.
  • NAGAI Noriaki; FUKUHATA Takashi; LIU Ying; ITO Yoshimasa; KAWAKAMI Yoshimi; IKEDA Tomohiro; MIMURA Osamu; OKAMURA Haruki
    日本白内障学会誌 18 (1) 383 - 386 0915-4302 2006/10
  • Noriaki Nagai; Ying Liu; Takashi Fukuhata; Yoshimasa Ito
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 29 (10) 2077 - 2081 0918-6158 2006/10 [Refereed]
     
    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.
  • Noriaki Nagai; Yoshimasa Ito; Mitsushi Inomata; Seigo Shumiya; Hideyuki Tai; Yoshihiro Hataguchi; Koji Nakagawa
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 29 (6) 1234 - 1238 0918-6158 2006/06 [Refereed]
     
    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.
  • NAGAI Noriaki; FUKUHATA Takashi; LIU Ying; ITO Yoshimasa; KAWAKAMI Yoshimi; IKEDA Tomohiro; MIMURA Osamu; OKAMURA Haruki
    Journal of the eye メディカル葵出版 23 (3) 383 - 386 0910-1810 2006/03
  • Yoshimasa Ito; Noriaki Nagai; Hong Cai; Maki Takeda; Yuichi Koizumi
    Journal of Oleo Science 55 (1) 15 - 22 1347-3352 2006 [Refereed]
     
    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.

Books etc

  • 医薬品におけるDDS技術開発と製剤への応用
    長井紀章 (Contributor第1章 医薬品における投与形態の概要と課題．第5節 医薬品の点眼投与 p 75-81)㈱技術情報協会 2021/12
  • 長井, 紀章; 大竹, 裕子 京都廣川書店 2021/03 9784909197795 ix, 253p
  • 臨床製剤学
    長井紀章 (Contributorp. 272-305)南江堂 2021
  • 「製剤・包装の改良・工夫点と病院から選ばれる医薬品開発」第4章 剤型・投与経路開発による、病院から選ばれる医薬品開発
    長井紀章 (Contributor第5節 全身作用型貼付剤の薬物放出量のコントロールと製剤設計)㈱技術情報協会 2017
  • 眼科獣医プラクティス 特集 点眼薬2017. 薬理学から見た点眼による全身への影響 コラム
    長井紀章 (ContributorNo.2 pp 53 -56)ファームプレス 2017
  • 最新製剤学 第4版
    長井紀章 (Joint workpp. 145-167, 439-410)廣川書店 2016
  • コンプリヘンシブ基礎化学
    長井紀章 (Joint work)京都廣川書店 2016
  • 眼科 (GANKA. OPHTHALMOLOGY) 特集 薬剤性角膜上皮障害
    長井紀章 (Contributor薬剤性角膜上皮障害のメカニズムと前臨床評価法)金原出版株式会社 2015
  • 薬局 特集 徹底理解！点眼剤-眼科領域の薬物治療に活かすポイント-
    長井紀章 (ContributorVol. 65 No. 5, pp. 37-43)南山堂 2014
  • 注射剤に代わる新しい薬剤投与デバイスの開発
    長井紀章 (Others第3章 貼付剤における経皮デリバリー技術と製剤設計 第3節 薬物放出量のコントロール)㈱技術情報協会 2014

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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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  [Not invited]
    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
  • 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
  • NAGAI NORIAKI; MANO YU; KOTANI SACHIYO; ITO YOSHIMASA
    日本薬学会年会要旨集(CD-ROM)  2015/03
  • OGATA FUMIHIKO; NAGAI NORIAKI; ITO YOSHIMASA; KAWASAKI NAOHITO
    日本薬学会年会要旨集(CD-ROM)  2015/03
  • TANABE WATARU; HAYASHI MAHO; YAMAOKA TAIKI; NAGAI NORIAKI; ITO YOSHIMASA
    日本薬学会年会要旨集(CD-ROM)  2015/03
  • ITO YOSHIMASA; NAGAI NORIAKI; TADA NATSUMI; HAYASHI MAHO
    日本薬学会年会要旨集(CD-ROM)  2015/03
  • MANO YU; TANIMOTO SHION; NAKAYA HITOMI; NAGAI NORIAKI; ITO YOSHIMASA
    日本薬学会年会要旨集(CD-ROM)  2015/03
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • MANO YU; NAGAI NORIAKI; ITO YOSHIMASA
    生体機能と創薬シンポジウム要旨集  2014
  • 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
  • NAGAI NORIAKI; HIRATA MANA; TANABE WATARU; ITO YOSHIMASA
    日本薬学会年会要旨集(CD-ROM)  2014
  • TAGA ATSUSHI; NAGAI NORIAKI; YAMAMOTO TETSUSHI; MITAMURA KUNIKO; ITO YOSHIMASA
    日本薬学会年会要旨集(CD-ROM)  2014
  • 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
  • ITO YOSHIMASA; NAGAI NORIAKI; TADA NATSUMI; HAYASHI MAHO
    日本薬学会年会要旨集(CD-ROM)  2014
  • 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
  • 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
  • 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
  • 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
  • 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
  • 市販緑内障治療薬による角膜障害性のキネティクス解析  [Not invited]
    岡本 紀夫; 長井 紀章; 大江 恭平; 下村 嘉一; 伊藤 吉將
    第37回角膜カンファレンス・第29回日本角膜移植学会  2013/02  白浜  第37回角膜カンファレンス・第29回日本角膜移植学会
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • NAGAI Noriaki; MURAO Takatoshi; KONAKA Yoko; ITO Yoshimasa; TAKEUCHI Noriko
    日本白内障学会誌  2011/06
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • マイクロダイアリシス法による眼房水中一酸化窒素量の経時的測定の確立  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊
    第21回 マイクロダイアリシス研究会  2010/12  東京  第21回 マイクロダイアリシス研究会
  • 角膜透過を改善したピログルタミン酸点眼製剤の眼圧降下作用  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • 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  品川  第30回日本眼薬理学会
  • ヒト水晶体上皮細胞株SAR01/04における一酸化窒素過剰産生がCa2+制御機構へ与える影響  [Not invited]
    伊藤 吉將; 長井 紀章; 楠山 侑里; 村尾
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • ナノテクノロジーを利用したシロスタゾール経皮吸収製剤の設計  [Not invited]
    伊藤 吉將; 長井 紀章; 西口 宏一
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • セリシン含有抗緑内障薬による角膜上皮低侵襲性点眼療法の確立  [Not invited]
    伊藤 吉將; 長井 紀章; 関 菜穂子; 岡本 紀夫; 下村 嘉一
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • シロスタゾールナノ粒子分散液の安全な静脈投与量について  [Not invited]
    伊藤 吉將; 長井 紀章; 南部 義徳; 岡本 紀夫; 松山
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • 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
  • 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点眼液の局所投与効果  [Not invited]
    金井 一享; 伊藤 吉將; 長井 紀章; 伊藤 直之; 近澤; 征史朗; 堀; 泰智; 星; 史雄; 樋口 誠一
    第150回日本獣医学会学術集会  2010/09  帯広  第150回日本獣医学会学術集会
  • 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
  • 調剤薬局における薬剤師需要の動向予測に関する研究  [Not invited]
    長井 紀章; 川瀬 篤史; 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2010 第18回クリニカルファーマシーシンポジウム  2010/07  広島  医療薬学フォーラム2010 第18回クリニカルファーマシーシンポジウム
  • KINETIC ANALYSIS OF THE RATE OF CORNEAL WOUND HEAALING IN OLETF RATS, A MODEL OF TYPE 2 DIABETES MELLITUS  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    XIX International Congress of Eye Research  2010/07  Canada  XIX International Congress of Eye Research
  • INSTILLATION OF PYROGLUTAMIC ACID REDUCES THE ENHANCED OF INTRAOCULAR PRESSURE IN RABBIT  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    XIX International Congress of Eye Research  2010/07  Canada  XIX International Congress of Eye Research
  • ENHANCING EFFECTS OF SERICIN ON CORENAK WOUND HEALING IN OLETF RATS, A MODEL OF TYPE 2 DIABETES MELLITUS  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    XIX International Congress of Eye Research，Montrea  2010/07  Canada  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  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 小仲; 竹内 典子
    第49回日本白内障学会総会・第25回日本眼内レンズ屈折手術学会総会  2010/06  大阪  第49回日本白内障学会総会・第25回日本眼内レンズ屈折手術学会総会
  • 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
  • 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 シンポジウム「白内障・水晶体研究の最前線」  [Not invited]
    長井 紀章
    第114年回日本眼科学会総会  2010/04  名古屋  第114年回日本眼科学会総会
  • 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
  • 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  岡山  日本薬学会第130年会
  • 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  岡山  第130年回日本薬学会
  • 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  岡山  第130年回日本薬学会
  • セリシンを用いた低角膜障害薬物療法に関する研究  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    第130年回日本薬学会  2010/03  岡山  第130年回日本薬学会
  • 種々点眼薬含有添加物における角膜傷害性評価に関する研究  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    第34回角膜カンファレンス・第26回日本角膜移植学会  2010/02  仙台  第34回角膜カンファレンス・第26回日本角膜移植学会
  • セリシン及び抗緑内障薬併用がSV40不死化ヒト角膜上皮細胞増殖へ与える影響  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    第34回角膜カンファレンス・第26回日本角膜移植学会  2010/02  仙台  第34回角膜カンファレンス・第26回日本角膜移植学会
  • 種々遺伝性モデルラット水晶体における恒常性破綻機構の分類とその要因の探索 シンポジウム講演「水晶体研究への若手研究者の挑戦」  [Not invited]
    長井 紀章
    第36回 水晶体研究会  2010/01  東京  第36回 水晶体研究会
  • マイクロダイアリシス-HPLCを用いた新規溶出試験法によるニフェジピン製剤の評価  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊
    第20回 マイクロダイアリシス学会 記念大会  2009/12  東京  第20回 マイクロダイアリシス学会 記念大会
  • ビーズミルによるトラニラスト・ナノ粒子分散液の調製とその角膜透過性の改善  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    第59回 日本薬学会近畿支部総会・大会  2009/10  大阪  第59回 日本薬学会近畿支部総会・大会
  • Ⅱ型糖尿病モデル動物OLETFラットにおけるセリシン溶液点眼の角膜傷害治癒促進効果  [Not invited]
    伊藤 吉將; 長井 紀章; 村尾 卓俊; 岡本 紀夫
    第59回 日本薬学会近畿支部総会・大会  2009/10  大阪  第59回 日本薬学会近畿支部総会・大会
  • 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  鳥取  第148回日本獣医学会学術集会
  • 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  東京  第29回日本眼薬理学会
  • 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  [Not invited]
    伊藤 吉將; 長井 紀章
    第48回日本白内障学会総会・第24回日本眼内レンズ屈折手術学会総会・第45回日本眼光学学会総会・22 nd APACRS Annual Meeting 合同会議  2009/06  東京  第48回日本白内障学会総会・第24回日本眼内レンズ屈折手術学会総会・第45回日本眼光学学会総会・22 nd APACRS Annual Meeting 合同会議
  • 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
  • 長井紀章; 伊藤吉將
    日本薬学会年会要旨集  2009/03
  • 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
  • マイクロダイアリシス-HPLC法の溶出試験への応用  [Not invited]
    伊藤 吉將; 長井 紀章
    第129年回日本薬学会  2009/03  京都  第129年回日本薬学会
  • 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  大阪  第33回角膜カンファレンス・第25回日本角膜移植学会
  • BAC非含有プロスタグランジン製剤トラバタンズ点眼液の角膜障害性評価に関する研究  [Not invited]
    伊藤 吉將; 長井 紀章; 岡本 紀夫; 三
    第33回角膜カンファレンス・第25回日本角膜移植学会  2009/02  大阪  第33回角膜カンファレンス・第25回日本角膜移植学会
  • 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
  • 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
  • ヒト水晶体上皮細胞株SRA01/04における一酸化窒素過剰産生によるチトクロムcオキシダーゼ障害  [Not invited]
    伊藤 吉將; 長井 紀章
    第35回 水晶体研究会  2009/01  宇都宮  第35回 水晶体研究会
  • 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  神戸  第31回日本分子生物学会年会 第81回日本生化学会大会合同大会
  • 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  岡山  第28回日本眼薬理学会
  • PREPARATION OF CILOSTAZOL EYE DROPS AS AN ANTI-GLAUCOMA AGENT AND IMPROVEMENT FOR ITS PERMEABILITY THROUGH THE RABBIT CONEA  [Not invited]
    伊藤 吉將; 長井 紀章; 岡本 紀夫; 三
    XVIII International Congress of Eye Research  2008/09  CHINA  XVIII International Congress of Eye Research
  • MECHANISM FOR ANTI-CATARACT EFFECT OF DISULFIRAM TO ICR/F RAT AS A HEREDITARY CATARACT MODEL  [Not invited]
    伊藤 吉將; 長井 紀章; 竹内 典子
    XVIII International Congress of Eye Research  2008/09  CHINA，  XVIII International Congress of Eye Research
  • HP？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  [Not invited]
    伊藤 吉將; 長井 紀章; 竹内 典子
    第47回日本白内障学会総会・第23回日本眼内レンズ屈折手術学会総会 合同会議  2008/06  東京  第47回日本白内障学会総会・第23回日本眼内レンズ屈折手術学会総会 合同会議
  • 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
  • 遺伝性白内障ラット（ICR/f）における鉄の動態  [Not invited]
    伊藤 吉將; 長井 紀章; 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
    第128年会 日本薬学会  2008/04  横浜  第128年会 日本薬学会
  • 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
  • 長井紀章; 伊藤吉將; 竹内典子
    日本薬学会年会要旨集  2008/03  横浜  第128年会 日本薬学会
  • 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  横浜  第128年会 日本薬学会
  • 遺伝性白内障ICR/fラット水晶体での一酸化窒素量増大と水晶体混濁  [Not invited]
    伊藤 吉將; 長井 紀章; 竹内 典子
    第34回 水晶体研究会  2008/01  石川  第34回 水晶体研究会
  • 種々抗緑内障点眼薬単剤及び2剤併用がヒト角膜上皮細胞へ与える影響，  [Not invited]
    伊藤 吉將; 長井 紀章; 岡本 紀夫; 上; 吉美; 三村 治
    第57回 日本薬学会近畿支部総会・大会，  2007/10  大阪  第57回 日本薬学会近畿支部総会・大会，
  • 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  岐阜  第27回日本眼薬理学会
  • 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  岐阜  第18回日本緑内障学会
  • 遺伝性白内障ラットICR/fにおけるHP？CD包摂ジスルフィラム点眼液の抗白内障効果  [Not invited]
    伊藤 吉將; 長井 紀章; 竹内 典子; 亀
    第46回日本白内障学会総会・第22回日本眼内レンズ屈折手術学会総会 合同会議  2007/06  愛媛  第46回日本白内障学会総会・第22回日本眼内レンズ屈折手術学会総会 合同会議
  • 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  富山  第127年会 日本薬学会
  • 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  富山  第127年会 日本薬学会
  • 遺伝性白内障ラットSCR及びUPLラット間における水晶体中ゲノムDNA残存性とDLADの関連  [Not invited]
    伊藤 吉將; 長井 紀章; 福畠 孝史; 竹内 典子; 亀
    第32回水晶体研究会  2007/01  神奈川  第32回水晶体研究会
  • ヒト水晶体上皮由来細胞SRA01/04におけるマグネシウム欠乏による細胞内ATP量への影響  [Not invited]
    伊藤 吉將; 長井 紀章; 太井 秀行; 端口; 佳宏; 魚住; 嘉伸; 中川 光司
    第33回水晶体研究会  2007/01  淡路  第33回水晶体研究会
  • PREPARATION OF DISULFIRAM EYE DROP AS AN ANTI-GLAUCOMA AGENT USING 2-HYDROXYPROPYL-β-CYCLODEXTRIN  [Not invited]
    伊藤 吉將; 長井 紀章; 森下 大輔
    XVII International Congress of Eye Research  2006/10  Argentina  XVII International Congress of Eye Research
  • IS DNASE II-LIKE ACID DNASE IN LENS A KEY ENZEME FOR CATARACT DEVELOPMENT ?  [Not invited]
    伊藤 吉將; 長井 紀章; 福畠 孝史
    XVII International Congress of Eye Research  2006/10  Argentina  XVII International Congress of Eye Research
  • 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  [Not invited]
    伊藤 吉將; 長井 紀章; 福畠 孝史
    第26回日本眼薬理学会  2006/09  福井  第26回日本眼薬理学会
  • 遺伝性白内障UPLラットの白内障発症におけるインターロイキン18の関与  [Not invited]
    伊藤 吉將; 長井 紀章; 宋 永波; 福畠; 孝史; 岡村 春樹
    第45回日本白内障学会総会・第21回日本眼内レンズ屈折手術学会総会 合同会議  2006/06  東京  第45回日本白内障学会総会・第21回日本眼内レンズ屈折手術学会総会 合同会議
  • 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
  • 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
  • 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  仙台  第126年会 日本薬学会
  • 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  [Not invited]
    伊藤 吉將; 長井 紀章; 角谷 瑠里子; 畠; 孝史 宋 永波
    第126年会 日本薬学会  2006/03  仙台  第126年会 日本薬学会
  • 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  仙台  第126年会 日本薬学会
  • マグネシウムイオン投与の影響：アジュバント誘発関節炎ラットにおける足浮腫増大とインドメタシン消化管障害の相関性  [Not invited]
    伊藤 吉將; 長井 紀章; 福畠 孝史; 角野
    第55回日本薬学会近畿支部総会・大会  2005/10  兵庫  第55回日本薬学会近畿支部総会・大会
  • ヒト培養角膜上皮細胞単層膜におけるジスルフィラム透過性とALDH3A1発現の役割  [Not invited]
    伊藤 吉將; 長井 紀章; 中川 奈緒美; 畠
    第55回日本薬学会近畿支部総会・大会  2005/10  兵庫  第55回日本薬学会近畿支部総会・大会
  • ヒト水晶体上皮細胞株SRA01/04におけるiNOS遺伝子発現と細胞障害  [Not invited]
    伊藤 吉將; 長井 紀章; 福畠 孝史; 川上吉美; 池田; 誠宏; 三村 治
    2005/06
  • 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  東京  第125年会日本薬学会
  • 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  東京  第125年会日本薬学会
  • 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  東京  第125年会日本薬学会
  • Delay of cataract development in Shumiya cataract rat by administration of high mineral water  [Not invited]
    伊藤 吉將; 長井 紀章; 猪股 光司; 太井 秀行; 端口; 佳宏; 中川; 光司; 中島 宏; 正木 茂夫
    XVI International Congress of Eye Research  2004/09  Australia  XVI International Congress of Eye Research
  • 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
  • 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  大阪  第124年会日本薬学会
  • 高Mgイオン水投与による遺伝性白内障ラットSCR水晶体中Ca,Mg量及びDNA断片化への影響  [Not invited]
    伊藤 吉將; 長井 紀章; 正木 茂夫; 猪股 光司; 太井 秀行; 端口; 佳宏; 中川; 光司; 中島 宏
    第43回日本白内障学会・第30回水晶体研究会合同学会  2004/03  第43回日本白内障学会・第30回水晶体研究会合同学会
  • グルタミン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  [Not invited]
    伊藤 吉將; 長井 紀章; 高橋 知子; 中西 邦夫
    第124年会日本薬学会  2004/03  大阪  第124年会日本薬学会
  • 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  日本薬学会第123年会（長崎）
     
    眼房水の調節には誘導型一酸化窒素合成酵素（iNOS）が産生するNOが働いていることが明らかとされている。ジスルフィラムの活性体であるジエチルジチオカルバミン酸はiNOSの阻害剤であり、緑内障で高まった房水産生量を低下させる可能性がある。本研究では、種々ジスルフィラム点眼薬製剤をウサギに点眼し実験的高眼圧を抑制することができた。

MISC

  • 武田 峻; 山本 直樹; 初坂 奈津子; 平松 範子; 長井 紀章; 出口 粧央里; 中澤 洋介; 高田 匠; 小寺 紗千子; 平田 晃正; 久保 江理; 佐々木 洋  金沢医科大学雑誌  48-  (2)  89  -89  2023/12
  • ジヒドロピリジン系カルシウム拮抗薬ニルバジピンのナノ結晶点眼液調製と水晶体硬化に対する有用性評価
    出口 粧央里; 門脇 玲太; 浅井 拓己; 大竹 裕子; 岡本 紀夫; 中澤 洋介; Misra Manju; 長井 紀章  日本眼薬理学会プログラム・抄録集  43回-  43  -43  2023/11
  • 複数分子標的に向けた抗がん抗体療法(Antibody-based cancer therapy toward multiple target molecules)
    沖田 鋼季; 山崎 晶貴; 富岡 佳久; 長井 紀章; 益子 高  日本癌学会総会記事  82回-  2063  -2063  2023/09
  • 長井 紀章  薬局  74-  (7)  1251  -1255  2023/06
  • 【水晶体透明化計画】水晶体再透明化をめざした薬物療法の可能性
    長井 紀章  日本白内障学会誌  35-  (1)  72  -74  2023/06
  • 2型糖尿病モデルマウスにおけるペマフィブラートナノ粒子点眼の網膜循環への影響
    花栗 潤哉; 横田 陽匡; 高瀬 公陽; 渡部 昌久; 櫛山 暁史; 長井 紀章; 山上 聡; 長岡 泰司  日本糖尿病眼学会誌  27-  119  -119  2023/05
  • 薬物封入コンタクトレンズの開発 トラニラストナノ粒子封入に伴う徐放性能の向上
    小早川 信一郎; 後藤 涼花; 衣川 美宇; 矢野 詩歩; 曽谷 月香; 松永 透; 檜野 栞; 長井 紀章  日本眼科学会雑誌  127-  (臨増)  244  -244  2023/03
  • 酸素誘導網膜症マウスモデルにおけるフェノフィブラートナノ粒子点眼の効果
    高瀬 公陽; 横田 陽匡; 長井 紀章; 花栗 潤哉; 杉山 瑠璃; 大野 皓; 櫛山 暁史; 山上 聡; 長岡 泰司  日本眼科学会雑誌  127-  (臨増)  252  -252  2023/03
  • 大高裕也; 岡田大輝; 田島一樹; 長井紀章; 山下洋平; 市川陽一郎; 酒井和紀; 金井一享  日本獣医学会学術集会講演要旨集  166th-  2023
  • 長井 紀章; 後藤 涼花; 渡辺 彩花; 油納 美和; 小坂 太陽; 大竹 裕子; 鷲見 梓; 笹木 友美子; 原 真佐夫; 原田 英治  医療薬学  48-  (12)  545  -550  2022/12
  • TRPVチャネルを介したEMT抑制メカニズムの解析
    中澤 洋介; 杉山 裕紀; 河田 沙礼; 長井 紀章; 山本 直樹; Rosica Petrova; Paul Donaldson; 多胡 めぐみ  日本眼薬理学会プログラム・抄録集  42回-  56  -56  2022/10
  • トラニラスト封入コンタクトレンズの眼表面における持続的な薬物放出の評価
    小早川 信一郎; 檜野 栞; 松永 透; 後藤 涼花; 矢野 詩歩; 長井 紀章  日本眼薬理学会プログラム・抄録集  42回-  61  -61  2022/10
  • シクロデキストリンとカチオン性基からなる共重合体CDQAポリマーはレバミピドの角膜含有量を高める
    長井 紀章; 門脇 玲太; 後藤 涼花; 出口 粧央里; 吉富 丈二; 大竹 裕子; 松田 将; 小林 滉; 原田 英治  日本眼薬理学会プログラム・抄録集  42回-  62  -62  2022/10
  • 後藤 涼花; 大阿久 佳宏; 佐々木 風歌; 久保田 ちか; 出口 粧央里; 門脇 玲太; 阿部 晃也; 長濱 徹; 長井 紀章  薬学雑誌  142-  (9)  1015  -1020  2022/09
  • 後藤 涼花; 大阿久 佳宏; 佐々木 風歌; 久保田 ちか; 出口 粧央里; 門脇 玲太; 阿部 晃也; 長濱 徹; 長井 紀章  薬学雑誌  142-  (9)  1015  -1020  2022/09
  • 後藤 涼花; 勢力 諒太朗; 渡辺 彩花; 油納 美和; 大竹 裕子; 櫻井 俊輔; 原田 英治; 長井 紀章  あたらしい眼科  39-  (7)  982  -987  2022/07
  • 長井 紀章  日本白内障学会誌  34-  (1)  35  -37  2022/06
  • 後藤 涼花; 山田 茂裕; 馬地 一稀; 竹中 晴菜; 平松 範子; 山本 直樹; 佐々木 洋; 長井 紀章  日本白内障学会誌  34-  (1)  61  -65  2022/06
  • 武田 峻; 山本 直樹; 長井 紀章; 出口 粧央里; 平松 範子; 初坂 奈津子; 永田 万由美; 松島 博之; 久保 江理; 佐々木 洋  日本白内障学会誌  34-  (1)  76  -82  2022/06
  • 長井 紀章  日本白内障学会誌  34-  (1)  35  -37  2022/06
  • 後藤 涼花; 山田 茂裕; 馬地 一稀; 竹中 晴菜; 平松 範子; 山本 直樹; 佐々木 洋; 長井 紀章  日本白内障学会誌  34-  (1)  61  -65  2022/06
  • 武田 峻; 山本 直樹; 長井 紀章; 出口 粧央里; 平松 範子; 初坂 奈津子; 永田 万由美; 松島 博之; 久保 江理; 佐々木 洋  日本白内障学会誌  34-  (1)  76  -82  2022/06
  • 低用量シクロデキストリンの配合は虫除け成分ディートの実用性を高める
    長井 紀章; 川口 麻由; 南 実沙; 松本 夏奈; 笹邉 達志; 延原 健二; 松原 晶  日本薬学会年会要旨集  142年会-  26S  -am09  2022/03
  • 口腔粘膜炎の早期治療を可能とするトロキシピドナノゲル製剤の開発
    出口 粧央里; 吉岡 涼; 西田 未来; 小松 美莉; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  142年会-  27H  -am03S  2022/03
  • ブリンゾラミドナノ点眼製剤化に伴う眼内薬物移行性の改善と緑内障治療効果の向上
    後藤 涼花; 衣川 美宇; 矢野 詩歩; 大竹 裕子; 岡本 紀夫; 長井 紀章  日本薬学会年会要旨集  142年会-  27L  -am09S  2022/03
  • 噴霧急速凍結乾燥法を用いたトラニラストナノ結晶懸濁液からの微粉末体作成と吸入製剤への応用性
    大竹 裕子; 辜 瓊雅; 福本 航; 長井 紀章  日本薬学会年会要旨集  142年会-  28F  -am10  2022/03
  • 芍薬甘草湯エキス顆粒における粗大・コロイド・分子分散体の同定とその消化管吸収性の評価
    吉富 丈治; 大竹 裕子; 遠藤 雄一; 小竹 武; 長井 紀章  日本薬学会年会要旨集  142年会-  28J  -am07S  2022/03
  • 低温下における保管はフルオロメトロン懸濁性点眼薬の再分散性を低下させる
    小畑 友紀雄; 出口 粧央里; 山口 瑞季; 稲葉 一訓; 長井 紀章; 中田 雄一郎  日本薬学会年会要旨集  142年会-  27PO1  -14  2022/03
  • BCSクラス3薬物を対象としたナノ結晶製剤の開発研究 再分散可能なファモチジンナノ固化成形体の調製
    門脇 玲太; 池 彩里; 下前 憂梨咲; 大迫 華乃; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  142年会-  27PO7  -05S  2022/03
  • コンタクトレンズへのトラニラスト封入とその薬物動態
    小早川 信一郎; 松永 透; 檜野 栞; 河西 晴子; 山口 瑞季; 長井 紀章  日本眼科学会雑誌  126-  (臨増)  236  -236  2022/03
  • コンタクトレンズへのトラニラスト封入とその薬物動態
    小早川 信一郎; 松永 透; 檜野 栞; 河西 晴子; 山口 瑞季; 長井 紀章  日本眼科学会雑誌  126-  (臨増)  236  -236  2022/03
  • 低用量シクロデキストリンの配合は虫除け成分ディートの実用性を高める
    長井 紀章; 川口 麻由; 南 実沙; 松本 夏奈; 笹邉 達志; 延原 健二; 松原 晶  日本薬学会年会要旨集  142年会-  26S  -am09  2022/03
  • 低温下における保管はフルオロメトロン懸濁性点眼薬の再分散性を低下させる
    小畑 友紀雄; 出口 粧央里; 山口 瑞季; 稲葉 一訓; 長井 紀章; 中田 雄一郎  日本薬学会年会要旨集  142年会-  27PO1  -14  2022/03
  • 長岡 泰司; 横田 陽匡; 花栗 潤哉; 渡部 昌久; 朝生 浩; 花崎 浩継; 秋山 彩香; 大野 皓; 高瀬 公陽; 山上 聡; 櫛山 暁史; 櫛山 櫻; 長井 紀章; 中神 啓徳; 林 宏樹; 相原 一; 本庄 恵; 蔵野 信; 矢冨 裕; 五十嵐 浩二  日本眼科学会雑誌  126-  (3)  358  -387  2022/03
  • 口腔粘膜炎の早期治療を可能とするトロキシピドナノゲル製剤の開発
    出口 粧央里; 吉岡 涼; 西田 未来; 小松 美莉; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  142年会-  27H  -am03S  2022/03
  • ブリンゾラミドナノ点眼製剤化に伴う眼内薬物移行性の改善と緑内障治療効果の向上
    後藤 涼花; 衣川 美宇; 矢野 詩歩; 大竹 裕子; 岡本 紀夫; 長井 紀章  日本薬学会年会要旨集  142年会-  27L  -am09S  2022/03
  • 噴霧急速凍結乾燥法を用いたトラニラストナノ結晶懸濁液からの微粉末体作成と吸入製剤への応用性
    大竹 裕子; 辜 瓊雅; 福本 航; 長井 紀章  日本薬学会年会要旨集  142年会-  28F  -am10  2022/03
  • 芍薬甘草湯エキス顆粒における粗大・コロイド・分子分散体の同定とその消化管吸収性の評価
    吉富 丈治; 大竹 裕子; 遠藤 雄一; 小竹 武; 長井 紀章  日本薬学会年会要旨集  142年会-  28J  -am07S  2022/03
  • BCSクラス3薬物を対象としたナノ結晶製剤の開発研究 再分散可能なファモチジンナノ固化成形体の調製
    門脇 玲太; 池 彩里; 下前 憂梨咲; 大迫 華乃; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  142年会-  27PO7  -05S  2022/03
  • 【眼科医のための薬理学のイロハ】点眼薬における保存剤の功と罪
    後藤 涼花; 長井 紀章  OCULISTA  (107)  11  -18  2022/02
  • ストレプトゾトシン誘発視機能障害に対するブリンゾラミドナノ点眼液の有用性評価
    南 実沙; 後藤 涼花; 櫻井 達真; 明和 亮伍; 衣川 美宇; 出口 粧央里; 大竹 裕子; 長井 紀章  日本眼薬理学会プログラム・抄録集  41回-  37  -37  2021/11
  • ストレプトゾトシン誘発視機能障害に対するブリンゾラミドナノ点眼液の有用性評価
    南 実沙; 後藤 涼花; 櫻井 達真; 明和 亮伍; 衣川 美宇; 出口 粧央里; 大竹 裕子; 長井 紀章  日本眼薬理学会プログラム・抄録集  41回-  37  -37  2021/11
  • 異なる材質のバンテージコンタクトレンズの眼保持性、細菌付着性に関する比較
    喜多 瑞樹; 小野 久弥; 田島 一樹; 大高 裕也; 岡田 大輝; 長井 紀章; 工藤 莉奈; 山下 洋平; 檜野 栞; 松永 透; 金井 一享  日本獣医学会学術集会講演要旨集  164回-  [HSO  -58]  2021/09
  • エンドトキシン誘発ぶどう膜炎ラットにおける5-アミノレブリン酸の効果
    大高 裕也; 岡田 大輝; 喜多 瑞樹; 田島 一樹; 長井 紀章; 工藤 莉奈; 山下 洋平; 酒井 和紀; 金井 一享  日本獣医学会学術集会講演要旨集  164回-  [HSO  -59]  2021/09
  • 2型糖尿病モデルマウスにおけるペマフィブラートナノ粒子点眼の網膜循環への影響
    花栗 潤哉; 横田 陽匡; 高瀬 公陽; 渡部 昌久; 櫛山 暁史; 長井 紀章; 山上 聡; 長岡 泰司  糖尿病合併症  35-  (Suppl.)  265  -265  2021/09
  • 長井 紀章  日本白内障学会誌  33-  (1)  32  -36  2021/06
  • 後藤 涼花; 南 実沙; 宇野 樹; 山口 瑞季; 稲葉 一訓; 竹本 晃佑; 中尾 元紀; 橋本 直文; 長井 紀章  医療薬学  47-  (5)  225  -233  2021/05
  • 自転・公転ミキサーの粉砕技術に基づく錠剤破砕と経管投与法への応用
    後藤 涼花; 南 実沙; 宇野 樹; 山口 瑞季; 稲葉 一訓; 竹本 晃佑; 中尾 元紀; 橋本 直文; 長井 紀章  医療薬学  47-  (5)  225  -233  2021/05
  • イルベサルタンナノ結晶を用いた経口用固形製剤の設計 固化成形体の調製と薬物吸収性評価
    南 実沙; 渡辺 雅輝; 池 彩里; 下前 憂梨咲; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  141年会-  29P01  -270S  2021/03
  • モメタゾンフランカルボン酸エステルのナノ粒子化と点鼻製剤への応用
    出口 粧央里; 吉富 丈治; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  141年会-  29P01  -277S  2021/03
  • フェノフィブラートナノ点眼薬の開発と眼後部への薬物送達能評価
    後藤 涼花; 長岡 泰司; 出口 粧央里; 森本 泰光; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  141年会-  29P01  -278S  2021/03
  • 透明・再生水晶体への挑戦 ラノステロールによる水晶体透明性の可能性(Possibility of cataract treatment by lanosterol)
    長井 紀章  日本眼科学会雑誌  125-  (臨増)  39  -39  2021/03
  • 新規ヒト不死化水晶体上皮細胞を用いた培養温度の違いによる水晶体蛋白質への影響
    山本 直樹; 長井 紀章; 中澤 洋介; 平松 範子; 高田 匠; 武田 峻; 桶本 孟; 石田 秀俊; 宮下 久範; 柴田 哲平; 初坂 奈津子; 平田 晃正; 久保 江理; 佐々木 洋  日本眼科学会雑誌  125-  (臨増)  224  -224  2021/03
  • 体温と白内障病型および水晶体エネルギー代謝との関係
    武田 峻; 山本 直樹; 長井 紀章; 出口 粧央里; 柴田 哲平; 初坂 奈津子; 平田 晃正; 久保 江理; 佐々木 洋  日本眼科学会雑誌  125-  (臨増)  246  -246  2021/03
  • 透明・再生水晶体への挑戦 ラノステロールによる水晶体透明性の可能性(Possibility of cataract treatment by lanosterol)
    長井 紀章  日本眼科学会雑誌  125-  (臨増)  39  -39  2021/03
  • 新規ヒト不死化水晶体上皮細胞を用いた培養温度の違いによる水晶体蛋白質への影響
    山本 直樹; 長井 紀章; 中澤 洋介; 平松 範子; 高田 匠; 武田 峻; 桶本 孟; 石田 秀俊; 宮下 久範; 柴田 哲平; 初坂 奈津子; 平田 晃正; 久保 江理; 佐々木 洋  日本眼科学会雑誌  125-  (臨増)  224  -224  2021/03
  • 体温と白内障病型および水晶体エネルギー代謝との関係
    武田 峻; 山本 直樹; 長井 紀章; 出口 粧央里; 柴田 哲平; 初坂 奈津子; 平田 晃正; 久保 江理; 佐々木 洋  日本眼科学会雑誌  125-  (臨増)  246  -246  2021/03
  • イルベサルタンナノ結晶を用いた経口用固形製剤の設計 固化成形体の調製と薬物吸収性評価
    南 実沙; 渡辺 雅輝; 池 彩里; 下前 憂梨咲; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  141年会-  29P01  -270S  2021/03
  • モメタゾンフランカルボン酸エステルのナノ粒子化と点鼻製剤への応用
    出口 粧央里; 吉富 丈治; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  141年会-  29P01  -277S  2021/03
  • フェノフィブラートナノ点眼薬の開発と眼後部への薬物送達能評価
    後藤 涼花; 長岡 泰司; 出口 粧央里; 森本 泰光; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  141年会-  29P01  -278S  2021/03
  • トラニラストナノ結晶を用いた結膜炎治療薬の開発 メチルセルロースは超微粒子の滞留性を高める
    南 実沙; 山崎 由夏; 大竹 裕子; 金井 一享; 長井 紀章  日本眼薬理学会プログラム・抄録集  40回-  42  -42  2021/02
  • 眼科領域における生体適合性ポリマーの応用性 MPCポリマーはベンザルコニウム塩化物の角膜傷害性を軽減する
    長井 紀章; 南 実沙; 山崎 由夏; 大竹 裕子; 櫻井 俊輔; 原田 英治  日本眼薬理学会プログラム・抄録集  40回-  46  -46  2021/02
  • 眞野裕; 眞野裕; 長井紀章; 石田茂伸; 多胡友絵; 星育子; 小泉祐一; 小泉祐一  日本医療薬学会年会講演要旨集(Web)  31-  2021
  • 長井 紀章  薬学雑誌  141-  (1)  47  -53  2021/01
  • 林友典; 宮本朋佳; 平田敦士; 長井紀章; 川畑篤史  日本薬理学雑誌  156-  (Supplement)  2021
  • 喜多瑞樹; 小野久弥; 田島一樹; 大高裕也; 岡田大輝; 長井紀章; 工藤莉奈; 山下洋平; 檜野栞; 松永透; 金井一享  日本獣医学会学術集会講演要旨集  164th (CD-ROM)-  [HSO  -58]  2021
  • 大高裕也; 岡田大輝; 喜多瑞樹; 田島一樹; 長井紀章; 工藤莉奈; 山下洋平; 酒井和紀; 金井一享  日本獣医学会学術集会講演要旨集  164th (CD-ROM)-  [HSO  -59]  2021
  • 喜多瑞樹; 金井一享; 田島一樹; 三橋洋貴; 埜口朋希; 長井紀章; 山口瑞季; 大高裕也; 工藤莉奈; 山下洋平  比較眼科学会年次大会講演要旨集  40th-  35  -35  2021
  • 長井 紀章  薬学雑誌  141-  (1)  47  -53  2021/01
  • 南 実沙; 山口 瑞季; 山崎 由夏; 大竹 裕子; 櫻井 俊輔; 原田 英治; 長井 紀章  あたらしい眼科  37-  (10)  1309  -1314  2020/10
  • 池西 政幸; 石井 康世; 雪矢 良輔; 緒方 文彦; 川崎 直人; 長井 紀章; 大鳥 徹; 奥野 智之  Medical Nutritionist of PEN Leaders  4-  (2)  136  -140  2020/09
  • 遺伝性白内障ラットSCRに対するラノステロールの有用性に関する検討
    稲葉 一訓; 山口 瑞季; 岡 美佳子; 長井 紀章  別冊Bio Clinica: 慢性炎症と疾患  9-  (1)  107  -109  2020/08
  • Clinical Academic Topics 薬物ナノ結晶と眼内薬物送達技術
    大竹 裕子; 長井 紀章  アレルギーの臨床  40-  (5)  385  -387  2020/05
  • 点眼治療戦略 点眼薬開発を支える基礎研究 安全性及び有用性の改善とその評価ツール
    長井 紀章  日本薬剤学会年会講演要旨集  35年会-  52  -52  2020/05
  • メロキシカムナノ製剤の開発とその消化管吸収機構の解明
    山口 瑞季; 池田 瑠璃; 渡辺 雅輝; 大竹 裕子; 長井 紀章  日本薬剤学会年会講演要旨集  35年会-  148  -148  2020/05
  • 経眼瞼適用レバミピドナノゲル製剤によるドライアイ治療
    南 実沙; 石井 美有; 勢力 諒太朗; 大竹 裕子; 平松 範子; 山本 直樹; 長井 紀章  日本薬剤学会年会講演要旨集  35年会-  148  -148  2020/05
  • トラニラストの超微細化と肺内投与による肺線維化抑制効果
    大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章  日本薬剤学会年会講演要旨集  35年会-  163  -163  2020/05
  • Clinical Academic Topics 薬物ナノ結晶と眼内薬物送達技術
    大竹 裕子; 長井 紀章  アレルギーの臨床  40-  (5)  385  -387  2020/05  [Refereed]
  • 今いちど、眼科領域の進歩を考える -基礎、臨床、そしてドラッグリポジショニングについて- 薬物ナノ結晶を基盤とした眼内薬物送達システム
    長井 紀章  日本薬学会年会要旨集  140年会-  S02  -4  2020/03
  • I-メントールによるインドメタシンナノ結晶製剤の経皮吸収促進効果とその透過機序の解明
    山口 瑞季; 福岡 侑也; 永福 紡; 川口 陽菜子; 原 雅紀; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  140年会-  26K  -am07S  2020/03
  • 食後高血糖の制御を目的とした新剤形の確立 インスリンナノ点眼薬は血糖値スパイクを抑制する
    長井 紀章; 畠中 優斗; 井阪 匠; 出口 粧央里; 大竹 裕子; 金井 一享; 岡本 紀夫; 下村 嘉一  日本薬学会年会要旨集  140年会-  26P  -pm169  2020/03
  • 院内における簡易デンプン細粒調製法の確立 調剤用賦形剤として実用性向上を目指して
    吉川 知宏; 岡本 広世; 竹内 健太; 松岡 寛; 川畑 篤史; 長井 紀章  日本薬学会年会要旨集  140年会-  27Y  -pm01  2020/03
  • ナノ結晶点眼製剤による新規結膜炎治療薬の確立 トラニラストナノ結晶点眼液の抗炎症効果
    南 実沙; 山崎 由夏; 蛭子 小春; 宇野 樹; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  140年会-  27Y  -pm15S  2020/03
  • ブレオマイシン誘発性肺線維症モデルマウスにおけるトラニラストナノ結晶分散液の肺内投与時における有用性評価
    大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章  日本薬学会年会要旨集  140年会-  28P  -pm082  2020/03
  • 今いちど、眼科領域の進歩を考える -基礎、臨床、そしてドラッグリポジショニングについて- 薬物ナノ結晶を基盤とした眼内薬物送達システム
    長井 紀章  日本薬学会年会要旨集  140年会-  S02  -4  2020/03
  • I-メントールによるインドメタシンナノ結晶製剤の経皮吸収促進効果とその透過機序の解明
    山口 瑞季; 福岡 侑也; 永福 紡; 川口 陽菜子; 原 雅紀; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  140年会-  26K  -am07S  2020/03
  • 食後高血糖の制御を目的とした新剤形の確立 インスリンナノ点眼薬は血糖値スパイクを抑制する
    長井 紀章; 畠中 優斗; 井阪 匠; 出口 粧央里; 大竹 裕子; 金井 一享; 岡本 紀夫; 下村 嘉一  日本薬学会年会要旨集  140年会-  26P  -pm169  2020/03
  • 院内における簡易デンプン細粒調製法の確立 調剤用賦形剤として実用性向上を目指して
    吉川 知宏; 岡本 広世; 竹内 健太; 松岡 寛; 川畑 篤史; 長井 紀章  日本薬学会年会要旨集  140年会-  27Y  -pm01  2020/03
  • ナノ結晶点眼製剤による新規結膜炎治療薬の確立 トラニラストナノ結晶点眼液の抗炎症効果
    南 実沙; 山崎 由夏; 蛭子 小春; 宇野 樹; 大竹 裕子; 長井 紀章  日本薬学会年会要旨集  140年会-  27Y  -pm15S  2020/03
  • ブレオマイシン誘発性肺線維症モデルマウスにおけるトラニラストナノ結晶分散液の肺内投与時における有用性評価
    大竹 裕子; 秋山 紗和子; 片山 理沙; 福本 航; 長井 紀章  日本薬学会年会要旨集  140年会-  28P  -pm082  2020/03
  • 山口 瑞季; 岡 美佳子; 長井 紀章  Precision Medicine  3-  (2)  143  -146  2020/02  [Refereed]
  • 稲葉 一訓; 本多 公貴; 大竹 裕子; 岡本 紀夫; 下村 嘉一; 小竹 武; 長井 紀章  医療薬学  46-  (2)  93  -99  2020/02
  • 南 実沙; 蛭子 小春; 山崎 由夏; 益田 佑輔; 北口 剛吉; 村田 久枝; 長井 紀章  医療薬学  46-  (1)  31  -37  2020/01  [Refereed]
  • 医薬品適正使用の取り組み セレン含有院内製剤の水剤から錠剤への剤型変更後の評価
    覚野 律; 大橋 香菜子; 桑原 明日香; 脇 啓子; 仲村 弥栄子; 田邨 保之; 森 惠子; 木原 理絵; 中村 明美; 都市 美晴; 川端 成佐; 中尾 元紀; 大竹 裕子; 松野 純男; 緒方 文彦; 川崎 直人; 長井 紀章  国立病院総合医学会講演抄録集  73回-  WS11  -4  2019/11
  • 一酸化窒素-アミロイドβポジティブフィードバックはヒト水晶体上皮細胞でのミトコンドリア障害を増悪する
    長井 紀章; 福岡 侑也; 石井 美有; 大竹 裕子; 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  39回-  43  -43  2019/09
  • 山本 哲志; 蛭子 小春; 三田村 邦子; 長井 紀章; 多賀 淳  JSBMS Letters  44-  (Suppl.)  110  -110  2019/08
  • 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]
  • 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]
  • 長井 紀章  日本白内障学会誌  31-  (1)  17  -19  2019/06  [Refereed]
  • 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]
  • 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]
  • 【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
  • インドメタシンナノ粒子に対する経皮吸収促進剤l-メントールの有用性評価
    福岡 侑也; 氏原 慎太郎; 梁 宇紀; 山口 瑞季; 大竹 裕子; 長井 紀章  日本薬剤学会年会講演要旨集  34年会-  158  -158  2019/05
  • レバミピドナノゲル製剤の開発と口腔粘膜炎治療への応用
    石井 美有; 勢力 諒太朗; 大竹 裕子; 平松 範子; 山本 直樹; 長井 紀章  日本薬剤学会年会講演要旨集  34年会-  161  -161  2019/05
  • トラニラストナノ結晶を用いた新規吸入剤の調製とその体内動態評価
    大竹 裕子; 秋山 紗和子; 片山 理沙; 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  34年会-  195  -195  2019/05
  • インドメタシンナノ製剤の開発とその消化管吸収機序の解明
    長井 紀章; 中村 翼; 池田 瑠璃; 渡辺 雅輝; 大竹 裕子  日本薬剤学会年会講演要旨集  34年会-  204  -204  2019/05
  • 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  [Refereed]
  • カプセル組成の変更に伴う吸入粉末剤の薬物放出制御に関する研究 カプセル表面の形状および電位差が薬物放出性に与える影響
    大竹 裕子; 片山 理沙; 秋山 紗和子; 石井 美有; 福岡 侑也; 長井 紀章  日本薬学会年会要旨集  139年会-  (4)  127  -127  2019/03
  • 眼科適用ラノステロールナノ製剤を用いた新規白内障治療法の確立を目指して
    福岡 侑也; 渡邉 菜摘; 大竹 裕子; 佐藤 完太; 多賀 淳; 岡 美佳子; 平松 範子; 山本 直樹; 長井 紀章  日本薬学会年会要旨集  139年会-  (4)  127  -127  2019/03
  • 就寝中に目を修復!持続性薬物供給システムの開発 ナノ結晶技術はドライアイを改善する
    長井 紀章; 石井 美有; 勢力 諒太朗; 大竹 裕子; 金井 一享; 岡本 紀夫; 下村 嘉一  日本薬学会年会要旨集  139年会-  (4)  128  -128  2019/03
  • 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
  • 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
  • 長井 紀章  獣医眼科プラクティス  3-  (2)  47  -54  2019/02
  • 眞野裕; 福岡侑也; 石井美有; 出口粧央里; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋; 長井紀章  日本白内障学会総会・水晶体研究会プログラム・講演抄録集  58th-45th-  2019
  • 大竹裕子; 石井美有; 福岡侑也; 眞野裕; 佐々木洋; 長井紀章  日本白内障学会総会・水晶体研究会プログラム・講演抄録集  58th-45th-  2019
  • 石井美有; 眞野裕; 福岡侑也; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋; 長井紀章  日本白内障学会総会・水晶体研究会プログラム・講演抄録集  58th-45th-  2019
  • 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
  • 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]
  • 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
  • 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
  • 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
  • 長井 紀章  医療薬学  44-  (10)  481  -490  2018/10  [Refereed]
  • 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
  • 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]
  • 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
  • 長井 紀章  日本白内障学会誌  30-  (1)  65  -67  2018/06
  • 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
  • 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
  • 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  138年会-  (3)  215  -215  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
  • 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
  • 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
  • 長井紀章; 真野裕; 福岡侑也; 石井美有; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋  日本白内障学会総会・水晶体研究会プログラム・講演抄録集  57th-44th-  2018
  • 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  37回-  43  -43  2017/09
  • Noriko Hiramatsu; Saori Deguchi; Chiaki Yoshioka; Hiroko Otake; Naoki Yamamoto; Noriaki Nagai  Yakugaku Zasshi  137-  (9)  1169  -1175  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  160回-  463  -463  2017/08
  • 岡 美佳子; 長井 紀章  日本白内障学会誌  29-  (1)  48  -49  2017/06
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 【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
  • 長井紀章; 真野裕; 大竹裕子; 柴田哲平; 久保江理; 佐々木洋  日本医療薬学会年会講演要旨集(Web)  27-  2017
  • 長井 紀章  薬学雑誌  136-  (10)  1385  -1390  2016/10
  • 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
  • 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
  • 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
  • 長井 紀章; 伊藤 吉將  日本白内障学会誌  28-  (1)  52  -55  2016/06
  • 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
  • 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
  • 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
  • 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
  • Noriko Kodama; Noriaki Nagai; Tomohisa Yasuhara  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN  136-  (3)  359  -360  2016/03
  • 長井紀章; 真野裕; 鬼池翔太; 上野祥奈; 山岡咲絵; 伊藤吉將; 岡本紀夫; 下村嘉一  日本白内障学会総会・水晶体研究会プログラム・講演抄録集  55th-  2016
  • 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・講演抄録集  36th-  2016
  • Nagai Noriaki; Ito Yoshimasa  The Journal of The Japanese Society for Cataract Research  28-  (1)  52  -55  2016
  • 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
  • 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
  • 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
  • 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
  • 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
  • 長井 紀章; 伊藤 吉將  眼科  57-  (7)  905  -909  2015/06
  • 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
  • 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
  • 伊藤吉將; 長井紀章; 松平有加; 山岡咲江; 真野裕; 岡本紀夫; 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  39th-31st-  2015
  • 長井紀章; 真野裕; 小谷幸代; 伊藤吉將  日本薬学会年会要旨集(CD-ROM)  135th-  2015
  • 長井紀章; 真野裕; 小谷幸代; 伊藤吉將; 柴田哲平; 久保江理; 佐々木洋  日本白内障学会総会・水晶体研究会プログラム・講演抄録集  54th-  2015
  • 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
  • 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
  • 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
  • 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
  • 真野裕; 長井紀章; 伊藤吉將  生体機能と創薬シンポジウム要旨集  2014-  2014
  • 長井紀章; 真野裕; 伊藤吉將; 柴田哲平; 久保江理; 佐々木洋  日本白内障学会総会プログラム・講演抄録集  53rd-  2014
  • 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
  • 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
  • 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  21-  314  -314  2011/09
  • 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
  • NAGAI Noriaki; MURAO Takatoshi; KONAKA Yoko; ITO Yoshimasa; TAKEUCHI Noriko  日本白内障学会誌  23-  51  -54  2011/06
  • 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
  • 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  131st-  (4)  2011
  • 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  19th-  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・抄録集  30回-  46  -46  2010/10
  • 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
  • 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
  • 長井 紀章; 伊藤 吉將  Jasco report  51-  (1)  14  -18  2009/09
  • 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

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Awards & Honors

  • 2023/02 参天製薬創業者記念眼科医学研究基金
     晶体混濁改善を目指したナノ結晶配合点眼薬の開発
  • 2022/08 World Congress on Oleo Science WCOS 2022 Select Lectures Award,
     
    受賞者: Noriaki Nagai
  • 2020/11 公益財団法人コーセーコスメトロジー研究財団 2020年度 コスメトロジー研究助成
     
    受賞者: 長井紀章
  • 2020/11 公益財団法人 持田記念医学薬学振興財団 2020 年度 持田記念研究助成
     
    受賞者: 長井紀章
  • 2020/04 公益財団法人 笹川保健財団 2020年度 笹川保健財団研究助成（研究）
     
    受賞者: 長井紀章
  • 2020/03 公益財団法人 薬学研究奨励財団 第40回 研究助成
     
    受賞者: 長井紀章
  • 2019/09 日本眼薬理学会 令和元年度（第一回）日本眼薬理学会奨励賞
     
    受賞者: 長井紀章
  • 2019/03 第139年会日本薬学会 一般学術発表ハイライト
     
    受賞者: 長井紀章
  • 2018/11 日本医療薬学会 平成30年度日本医療薬学会奨励賞
     
    受賞者: 長井紀章
  • 2018/07 日本白内障学会 ベストディスカッション賞
     
    受賞者: 長井紀章
  • 2018/03 第138年会日本薬学会 一般学術発表ハイライト
     
    受賞者: 長井紀章
  • 2018/03 平成29年度 ホソカワ粉体工学振興財団研究助成
     
    受賞者: 長井紀章
  • 2017/09 第44回 大和証券ヘルス財団 調査研究助成
     
    受賞者: 長井紀章
  • 2016/09 7th Journal of Oleo Science Award for Best Author
     
    受賞者: 長井紀章
  • 2016/07 第55回日本白内障学会・第42回水晶体研究会 セッション優秀賞
     
    受賞者: 長井紀章
  • 2016/01 日本薬学会近畿支部奨励賞（第二部門 物理系薬学）
     
    受賞者: 長井紀章
  • 2015/12 National Foundation for Eye Research, Alvira Reddy Award
     
    受賞者: 長井紀章
  • 2015/09 第54回日本白内障学会・第41回水晶体研究会 セッション優秀賞
     
    受賞者: 長井紀章
  • 2014/01 第40回水晶体研究会 セッション優秀賞
     
    受賞者: 長井紀章
  • 2013/06 日本薬学会 BPB Highlighted paper selected by Editor-in-Chief
     
    受賞者: 長井紀章
  • 2013/06 日本白内障学会 日本白内障学会学術賞
     
    受賞者: 長井紀章
  • 2013/02 日本角膜学会 内田賞
     
    受賞者: 伊藤吉將;長井紀章他
  • 2013/01 第39回水晶体研究会 優秀演題賞
     
    受賞者: 長井紀章

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2021/04 -2024/03 
    Author : 長井 紀章
     
    網膜疾患は中途失明の主たる原因であるが、現在の点眼薬では眼後部に位置する網膜に十分な薬物量を送達することが難しいのが現状である。本研究ではこれら課題を克服すべく、薬物ナノ結晶を装填したin situゲル化ナノ点眼液の処方設計を検討し、従来点眼液以上の眼内への薬物送達が可能であることを見出した。また、眼疾患モデルを用い、これら点眼製剤の有用性について評価した。
    １）In situゲル化ナノ点眼液の処方設計とその物性評価：各種添加物を用いたビーズミル法（乾式・水中破砕）にて、トラニラスト、イルベサルタン、ブリンゾラミド、ニルバジピン等数種のナノ結晶製剤の調製法を確立した。また、メチルセルロースやPluronic F-127及び68を始めとした温度応答性in situゲル基剤をナノ結晶製剤に適用した際の粘性変化や現表面での薬物滞留性を測定することで、ナノ結晶がゲルから持続的に放出できる最適な組成・濃度の設定を行った。 ２）In situゲル化ナノ点眼液の眼疾患治療への応用性：In situゲル化ナノ点眼液は従来の溶液型製剤と比較し、薬物眼表面滞留性、角膜透過性及び眼内組織（水晶体や網膜）への薬物移行性が高まることを明らかとした。また、今回調製した製剤の1つであるブリンゾラミドナノ点眼製剤点眼が糖尿病モデル動物の視機能改善に有効であることを明らかとした。
    以上、数種のin situゲル化ナノ点眼液を作成し、眼疾患に対する有用性について検討を行った。来年度は、今回作成したin situゲル化ナノ点眼液の薬効について病態モデルを用いて評価する予定である。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 山本 直樹; 平松 範子; 大熊 真人; 堀口 正之; 長井 紀章
     
    発生学的観点からin vivoにおいて多能性幹細胞から多様な細胞へ分化する過程では，細胞間の因子やシグナルが適切かつ必要な部位に作用する必要があるが，その機序は明らかではない。本研究では，ヒト虹彩由来iPS細胞から生理的機能を有する網膜神経細胞への分化において二次元培養の細胞間相互作用と三次元オルガノイド培養を中心とした網膜神経細胞の再生，およびそれらの細胞の移植時における拒絶反応に対する免疫抑制剤などの薬物送達と移植効率を検討する。 さらに，既に臨床で使用されている薬物の安全性や薬効評価について，iPS細胞から分化誘導後に不死化させた網膜前駆細胞および網膜神経細胞を用いた薬効評価を行う。 2020年度では，我々が初めて樹立することに成功したヒト虹彩由来iPS細胞の多分化能に関する検証実験を行い，さらにヒト虹彩由来iPS細胞を二次元培養系において，Recoverin陽性の網膜神経細胞，およびNeurofilament-MとBrn-3b陽性の網膜神経節細胞に分化誘導を行った。分化誘導した細胞について，電気生理学的機能の有無についてパッチクランプ法による検証を行い，Naチャネル（内向き電流）が検出された。TTXを添加することにより、Naチャネルは消失し、Wash outすることで再びNaチャネルが再検出されたことから、電気生理学的に機能する網膜神経細胞であることが確認された。 以上の結果より，ヒト虹彩由来iPS細胞を二次元培養系による分化誘導を行ったところ，電気生理学的な機能を有する網膜神経系細胞に分化できることがわかった。これらの結果をまとめて論文として報告した。
  • 毛根への薬物直接送達可能とするナノ結晶ハイドロゲルの開発
    公益財団法人コーセーコスメトロジー研究財団：2020年度 コスメトロジー研究助成 (素材、物性に関する分野)
    Date (from‐to) : 2021/04 -2023/03 
    Author : 長井 紀章
  • 超微細技術による薬物ナノパウダーの創製と吸入製剤化への応用展開
    公益財団法人 持田記念医学薬学振興財団：2020 年度 持田記念研究助成金
    Date (from‐to) : 2020/12 -2021/12 
    Author : 長井 紀章
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2018/04 -2021/03 
    Author : Nagai Noriaki
     
    Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. In this study, we prepared ophthalmic formulations containing nilvadipine nanoparticles (NIL-NPs), and demonstrated whether the instillation of NIL-NPs can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats). NIL-NPs was prepared by wet bead mill treatment, and the mean particle size was 77 nm. Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The instillation of NIL-NPs allowed the topical supplement of nilvadipine into the retina, and repetitive instillation of NIL-NPs (2 times/day for 1 week) attenuated the retinal disorders led by the excessive streptozotocin. An ophthalmic drug delivery system using drug nanoparticles may be useful the application for therapy of retinopathy.
  • 近畿大学学内研究助成金 SR01
    近畿大学：学内研究助成金
    Date (from‐to) : 2019/04 -2020/03
  • 眼深部組織を標的とした次世代型ナノ点眼製剤の開発と網膜症治療への応用
    文部科学省：科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2018 -2020 
    Author : 長井紀章
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : ITO Yoshimasa; NAGAI Noriaki
     
    We developed the transdermal drug delivery system for ophthalmic therapy by using drug nanoparticle technology (transdermal ophthalmic therapy). The “transdermal ophthalmic therapy” show non-stimulate, and can provide stable drug supply to lacrimal fluid via meibomian glands. This preparation may lead to an expansion of their usefulness for therapy in the ophthalmologic field.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015 -2017 
    Author : NAGAI Noriaki
     
    We designed new oral formulations containing nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam (MLX) solid nanoparticles, and investigate their usefulness by evaluating bioavailability and gastrointestinal lesions. The MLX solid nanoparticles were prepared using a bead mill method, and high quality dispersions containing MLX nanoparticles were prepared (MLXnano, particle size: 48 ± 138 nm, means± S.D.). The bioavailability in MLXnano was 4.3-fold higher in comparison with that in conventional MLX, and the MLX-induced gastrointestinal lesions in rats administered MLXnano, in consideration of bioavailability, were significantly less than for conventional MLX. An oral drug delivery system using drug nanoparticles may expand the usage of NSAIDs for therapy in the inflammatory field.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2013 -2014 
    Author : NAGAI Noriaki
     
    We attempted to establish a new method for preparing drug solid nanoparticles, and succeeded in preparing a high quality dispersion containing cilostazol (CLZ) nanoparticles. In addition, the instillation of the ophthalmic dispersions containing CLZ nanoparticles suppresses retinal vasoconstriction in endothelin-1-injected rats. It is possible that an ocular drug delivery system using drug nanoparticles may expand their usage as therapy in the glaucoma patient.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : ITO Yoshimasa; NAGAI Noriaki
     
    We demonstrated that the treatment of L-pyroglutamic acid decreased the enhanced intraocular pressure, and enhanced the survival of retinal ganglion cells after optic nerve transection in the in vivo study. In addition, we tried to develop the transdermal drug delivery system for ophthalmic therapy. It is possible that the transdermal ophthalmic therapy by using L-pyroglutamic acid provide the effective therapy for glaucoma patient.
  • Ministry of Education, Culture, Sports, Science and Technology：Grants-in-Aid for Scientific Research(若手研究(B))
    Date (from‐to) : 2011 -2012 
    Author : Noriaki NAGAI
     
    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.

Others

  • 2023/04 -2026/03  次世代型ナノ医薬品の製造処方の確立：超微細化に適した薬物 化学構造の把握と薬学・医学分野への応用性評価 
    近畿大学学内研究助成金 21 世紀研究開発奨励金【共同研究助成金】 KD2304 研究内容：20 nm～100 nmの薬物ナノ粒子を製造し、難溶性薬物の物性改善を目的とする。また、薬物破砕技術を専門とする企業と共同にて、これら薬物の超破砕化の効率化を模索する。

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