scholarly journals Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig

2021 ◽  
Vol 22 (10) ◽  
pp. 5137
Author(s):  
Hiroko Otake ◽  
Mizuki Yamaguchi ◽  
Fumihiko Ogata ◽  
Saori Deguchi ◽  
Naoki Yamamoto ◽  
...  
Keyword(s):  
Skin Penetration ◽  
The Other ◽  
Skin Tissue ◽  
Significant Information ◽  
Detailed Mechanism ◽  
Carbopol Gel ◽  
Göttingen Minipig ◽  
Bead Mill ◽  
Transdermal Penetration ◽  
Energy Dependent

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.

scholarly journals Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles

2018 ◽  
Vol 19 (7) ◽  
pp. 2138 ◽  
Author(s):  
Noriaki Nagai ◽  
Fumihiko Ogata ◽  
Miyu Ishii ◽  
Yuya Fukuoka ◽  
Hiroko Otake ◽  
...  
Keyword(s):  
Skin Penetration ◽  
Cytochalasin D ◽  
Significant Information ◽  
Bead Mill ◽  
Penetration Mechanism ◽  
Auc Value ◽  
The Mean ◽  
Transdermal Penetration ◽  
Energy Dependent ◽  
Transdermal Formulation

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.

scholarly journals Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles

2019 ◽  
Vol 20 (15) ◽  
pp. 3644 ◽  
Author(s):  
Noriaki Nagai ◽  
Fumihiko Ogata ◽  
Mizuki Yamaguchi ◽  
Yuya Fukuoka ◽  
Hiroko Otake ◽  
...  
Keyword(s):  
Percutaneous Absorption ◽  
Skin Penetration ◽  
Particle Characterization ◽  
Transdermal Drug Delivery System ◽  
Franz Diffusion Cell ◽  
Bead Mill ◽  
Transdermal Penetration ◽  
Energy Dependent

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).

scholarly journals In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals

2020 ◽  
Vol 21 (19) ◽  
pp. 7083
Author(s):  
Noriaki Nagai ◽  
Takumi Isaka ◽  
Saori Deguchi ◽  
Misa Minami ◽  
Mizuki Yamaguchi ◽  
...  
Keyword(s):  
Pluronic F127 ◽  
Significant Information ◽  
Corneal Permeability ◽  
Enhanced Absorption ◽  
Bead Mill ◽  
Resident Time ◽  
Energy Dependent ◽  
Corneal Permeation ◽  
In Situ Gelling

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.

scholarly journals Nanocrystalline Suspensions of Irbesartan Enhance Oral Bioavailability by Improving Drug Solubility and Leading Endocytosis Uptake into the Intestine

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1404
Author(s):  
Saori Deguchi ◽  
Fumihiko Ogata ◽  
Masaki Watanabe ◽  
Hiroko Otake ◽  
Naoki Yamamoto ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Intestinal Absorption ◽  
Antihypertensive Effect ◽  
The Other ◽  
Drug Solubility ◽  
Inclusion Complex Formation ◽  
Significant Information ◽  
Spontaneously Hypertensive ◽  
Bead Mill ◽  
The Mean

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.

Mining Bug Report Repositories to Identify Significant Information for Software Bug Fixing

2021 ◽  
Author(s):  
Bancha Luaphol ◽  
Jantima Polpinij ◽  
Manasawee Kaenampornpan
Keyword(s):  
The Other ◽  
Problem Domain ◽  
Significant Information ◽  
Bug Reports ◽  
Bug Fixing ◽  
Classification Technique ◽  
Bug Report ◽  
Multiple Issues ◽  
Improved Accuracy ◽  
Software Bug

Most studies relating to bug reports aims to automatically identify necessary information from bug reports for software bug fixing. Unfortunately, the study of bug reports focuses only on one issue, but more complete and comprehensive software bug fixing would be facilitated by assessing multiple issues concurrently. This becomes a challenge in this study, where it aims to present a method of identifying bug reports at severe level from a bug report repository, together with assembling their related bug reports to visualize the overall picture of a software problem domain. The proposed method is called “mining bug report repositories”. Two techniques of text mining are applied as the main mechanisms in this method. First, classification is applied for identifying severe bug reports, called “bug severity classification”, while “threshold-based similarity analysis” is then applied to assemble bug reports that are related to a bug report at severe level. Our datasets are from three opensource namely SeaMonkey, Firefox, and Core:Layout downloaded from the Bugzilla. Finally, the best models from the proposed method are selected and compared with two baseline methods. For identifying severe bug reports using classification technique, the results show that our method improved accuracy, F1, and AUC scores over the baseline by 11.39, 11.63, and 19% respectively. Meanwhile, for assembling related bug reports using threshold-based similarity technique, the results show that our method improved precision, and likelihood scores over the other baseline by 15.76, and 9.14% respectively. This demonstrate that our proposed method may help increasing chance to fix bugs completely.

Effects of pH on the Transformation of Gypsum to Carbonate Apatite in the Presence of Ammonium Hydrogen Phosphate

2006 ◽  
Vol 309-311 ◽  
pp. 199-202 ◽  
Author(s):  
Ishikawa Kunio ◽  
Yumiko Suzuki ◽  
Shigeki Matsuya ◽  
Masaharu Nakagawa ◽  
Kiyoshi Koyano
Keyword(s):  
The Other ◽  
Dicalcium Phosphate ◽  
Carbonate Apatite ◽  
Compositional Change ◽  
Hydrogen Phosphate ◽  
Detailed Mechanism ◽  
Effects Of Ph ◽  
Ammonium Hydrogen ◽  
Ammonium Hydrogen Phosphate ◽  
Ph Dependent

Effects of pH on the transformation of gypsum to apatite in the presence of ammonium hydrogen phosphate was studied using NH4H2PO4, (NH4)2HPO4 and (NH4)3PO4. When set gypsum was immersed to ammonium hydrogen phosphate, pH of the solution decreased regardless of the solution. Although pH of the solution decreased, no significant compositional change was observed when gypsum was immersed in NH4H2PO4. On the other hand, apatite and small amount of dicalcium phosphate anhydrous (CaHPO4) was formed when gypsum was immersed in (NH4)2HPO4 solution. Only apatite was formed when gypsum was immersed in (NH4)3PO4 solution. Although the detailed mechanism for the pH dependent products has not been clarified, one of the causes may be the different thermodynamical difference between gypsum and apatite. We would like to recommend the use of (NH4)3PO4 solution since this provides higher pH and thus larger thermodynamical difference between apatite and gypsum and resulting pure apatite block.

MAP UNITS IN CONTROLLED AND UNCONTROLLED LEGENDS ON SOME CANADIAN SOIL MAPS

1980 ◽  
Vol 60 (3) ◽  
pp. 511-516 ◽  
Author(s):  
K. W. G. VALENTINE ◽  
D. CHANG
Keyword(s):  
Small Proportion ◽  
The Other ◽  
Soil Maps ◽  
Land Area ◽  
Significant Information ◽  
Small Areas ◽  
Other Hand

The map index linkages (from CanSIS cartographic file) of seven soil maps were analyzed to find out how many map delineations represented each map unit and what proportion of the map they covered. Many map units were represented by only one or two delineations. This was more true for uncontrolled than controlled legends (51–85% of map units in uncontrolled legends versus 27–37% of map units in controlled legends). In both types of map the map units that had only one or two delineations covered only a small proportion of the land area. On the other hand, only a small proportion of the map units (between 14 and 31%) was needed to cover 75% of the land area in both types of maps. It proved possible to reduce the number of map units in one map with an uncontrolled legend from 193 to 91. This was done, firstly, by combining map units that represented only very small areas (or were represented by only one delineation) with larger map units that were very similar for the purpose of the survey. Secondly, map units were combined when more than 85% of the soils within them were the same. Controlled legends need not be very long and need not omit significant information.

scholarly journals Exposure of Agriculture Workers to Pesticides: The Effect of Heat on Protective Glove Performance and Skin Exposure to Dichlorvos

2019 ◽  
Vol 16 (23) ◽  
pp. 4798 ◽  
Author(s):  
Leigh Thredgold ◽  
Sharyn Gaskin ◽  
Chloe Quy ◽  
Dino Pisaniello
Keyword(s):  
Skin Penetration ◽  
Fold Increase ◽  
Organophosphate Insecticide ◽  
Temperature Dependent ◽  
Thermal Environments ◽  
Transdermal Penetration ◽  
Dermal Uptake ◽  
Chemical Permeation ◽  
Published Research ◽  
Kinetics Of

Dichlorvos is a toxic organophosphate insecticide that is used in agriculture and other insecticide applications. Dermal uptake is a known exposure route for dichlorvos and chemical protective gloves are commonly utilized. Chemical handling and application may occur in a variety of thermal environments, and the rates of both chemical permeation through gloves and transdermal penetration may vary significantly with temperature. There has been no published research on the temperature-dependent kinetics of these processes for dichlorvos and thus, this study reports on the effects of hot conditions for the concentrated and application strength chemical. Dichlorvos breakthrough times for non-disposable polyvinyl chloride (PVC) gloves at 60 °C were approximately halved compared to 25 °C for the concentrate (2 vs. 4 h) and more than halved at application strength (3 vs. >8 h). From permeation experiments covering 15–60 °C, there was a 460-fold increase in cumulative permeation over 8 h for the concentrated dichlorvos and the estimated activation energy halved. Elevated temperature was also shown to be a significant factor for human skin penetration increasing the cumulative penetration of concentrate dichlorvos from 179 ± 37 to 1315 ± 362 µg/cm2 (p = 0.0032) and application strength from 29.8 ± 5.7 to 115 ± 19 µg/cm2 (p = 0.0131). This work illustrates the important role temperature plays in glove performance and health risk via dermal exposure. As such, it is important to consider in-use conditions of temperature when implementing chemical hygiene programs.

Uptake of 3,5,3′-l-tri-iodothyronine in human erythrocytes

1989 ◽  
Vol 121 (3) ◽  
pp. 585-591 ◽  
Author(s):  
K. Yamauchi ◽  
R. Horiuchi ◽  
H. Takikawa
Keyword(s):  
Binding Sites ◽  
Binding Capacity ◽  
Human Erythrocytes ◽  
The Other ◽  
Transport Pathway ◽  
High Affinity ◽  
High Affinity Site ◽  
Maximum Binding Capacity ◽  
Energy Dependent ◽  
Dependent Pathway

ABSTRACT The mechanisms of 3,5,3′-l-tri-iodothyronine (T3) uptake into human erythrocytes were examined. Purified membranes of human erythrocytes were shown to have two classes of T3-binding sites with one being a high-affinity site (dissociation constant, 59·2±17·8 nmol/l; maximum binding capacity, 344·3 ± 95·5 fmol/μg protein). Furthermore, it was shown that there were two pathways for T3 uptake in human erythrocytes; one was saturable, stereospecific (T3»thyroxine > 3,5,3′-d-tri-iodothyronine), energydependent and dominant at 15 °C; the other was not displaced by unlabelled T3 and was energyindependent but did not occur by passive diffusion. The former pathway which, it is suggested, is a receptor-mediated transport pathway, was inhibited by monodansylcadaverine, phloretin or oligomycin at 15 or 37 °C, but the latter pathway was not inhibited by these inhibitors. Our results strongly suggest that uptake of T3 by the energy-independent pathway became predominant over the energy-dependent pathway at 37 °C and accounted for 83% of total T3 uptake of human erythrocytes. Journal of Endocrinology (1989) 121, 585–591

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