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1.
Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration. 总被引:2,自引:0,他引:2
Hakon H Sigurdsson Einar Stefánsson Elínborg Gudmundsdóttir Thór Eysteinsson Margrét Thorsteinsdóttir Thorsteinn Loftsson 《Journal of controlled release》2005,102(1):255-262
Due to limited aqueous solubility of dorzolamide at physiologic pH, the pH of Trusopt eye drops (cont. 2% dorzolamide) has to be kept at about 5.65, and to increase the topical bioavailability of the drug from Trusopt the contact time of the drug with the eye surface is increased by increasing the viscosity of the eye drops to 100 cps. This low pH and high viscosity can lead to local irritation. In this study, dorzolamide hydrochloride was formulated as 2% and 4% low viscosity solutions (viscosity 3 to 5 cps) containing randomly methylated beta-cyclodextrin at pH 7.45. These formulations were evaluated in rabbits. The animals were sacrificed at various time points after topical administration of the drug and the dorzolamide concentration determined in the different parts of the eye. Trusopt was used as a reference standard. The topical availability of dorzolamide from the cyclodextrin-containing eye drops appeared to be comparable to that from Trusopt and the drug reached retina and optic nerve to give measurable concentrations for at least 8 h after administration of the eye drops. 相似文献
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R Whelan C Kim M Chen J Leiter M M Grunstein H Hakonarson 《The European respiratory journal》2004,24(4):559-567
Interleukin (IL)-1beta is a pleiotropic, pro-inflammatory cytokine that has been importantly implicated in driving the inflammatory response and resultant changes in airway smooth muscle (ASM) responsiveness in asthma. IL-1beta belongs to a family of molecules, known as the IL-1 axis, which exert both pro- and anti-inflammatory effects. Since dysregulation of IL-1 axis molecules may be critical in the pathobiology of asthma, the present study examined the expression and activation of both the inhibitory and stimulatory IL-1 axis molecules in human ASM cells and their roles in modulating cytokine and immunoglobulin (Ig)E immune complex (IgE cx)-mediated changes in rabbit ASM constrictor and relaxant responsiveness. The results demonstrate the following. 1) Pre-treatment of isolated rabbit tracheal rings with the inhibitory IL-1 axis members, IL-1 receptor antagonist and IL-1 type-II receptor abrogated both IL-5- and IgE cx-induced changes in ASM responsiveness. 2) Administration of IL-5, IL-1beta and IgE cxs to human ASM cells increased mRNA and protein expressions of both stimulatory and inhibitory IL-1 axis molecules. 3) The time course of IL-5-induced IL-1 axis molecule expression preceded that of both IL-1beta and IgE immune cxs. Collectively, these findings suggest that modulation at the level of the interleukin-1 axis of molecules may have significant therapeutic potential in the treatment of asthma. 相似文献
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Melody R. Palmer Daniel S. Kim David R. Crosslin Ian B. Stanaway Elisabeth A. Rosenthal David S. Carrell David J. Cronkite Adam Gordon Xiaomeng Du Yatong K. Li Marc S. Williams Chunhua Weng Qiping Feng Rongling Li Sarah A. Pendergrass Hakon Hakonarson David Fasel Sunghwan Sohn Patrick Sleiman Samuel K. Handelman Elizabeth Speliotes Iftikhar J. Kullo Eric B. Larson Gail P. Jarvik 《Genetic epidemiology》2021,45(1):4-15
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Mucus is a complex hydrogel, comprising glycoproteins, lipids, salts, DNA, enzymes and cellular debris, covering many epithelial surfaces in the human body. Once secreted, mucin forms a barrier to protect the underlying tissues against the extracellular environment. Mucus can therefore adversely affect the absorption or action of drugs administered by the oral, pulmonary, vaginal, nasal or other routes. Solubility and lipophilicity are key factors determining drug absorption, as a drug has to be soluble in the body fluids at the site of absorption and must also possess enough lipophilicity to permeate the biological membrane. Evidence has accumulated over the past 40 years indicating that poorly soluble drugs will interact with mucus glycoprotein. Studies of the permeability of native or purified mucous gels are important when it comes to understanding the relative importance of hindered diffusion versus drug binding in mucous layers. This review highlights the current understanding of the drug–mucin interaction and also examines briefly the interaction of polymers and particles with the mucus matrix. While the concept of mucoadhesion was thought to provide an intensified and prolonged contact to mucosal absorption sites, mucopenetrating properties are nowadays being discussed for (nano)particulate carriers to overcome the mucus as a barrier and enhance drug delivery through mucus. 相似文献
6.
Martinus Richter Per-Henrik Agren Jean-Luc Besse Maria Coester Hakon Kofoed Nicola Maffulli Martijn Steultjens Amir Reza Vosoughi Milad Bahari 《Foot and Ankle Surgery》2021,27(5):496-500
BackgroundThe Score Committee of the European Foot and Ankle Society (EFAS) developed, validated, and published the EFAS Score in nine European languages (English, German, French, Italian, Polish, Dutch, Swedish, Finnish, Turkish). From other languages under validation, the Persian version finished data acquisition and underwent further validation.MethodsThe Persian version of the EFAS Score was developed and validated in three stages: 1) item (question) identification (completed during initial validation study), 2) item reduction and scale exploration (completed during initial validation study), 3) confirmatory analyses and responsiveness of Persian version (completed during initial validation study in nine other languages). The data were collected pre-operatively and post-operatively at a minimum follow-up of 3 months and mean follow-up of 6 months. Item reduction, scale exploration, confirmatory analyses and responsiveness were executed using classical test theory and item response theory.ResultsThe internal consistency was confirmed in the Persian version (Cronbach’s Alpha 0.82). The Standard Error of Measurement (SEM) was 0.38 and is similar to other language versions. Between baseline and follow-up, 97% of patients showed an improvement on their EFAS score, with excellent responsiveness (effect size 1.93).ConclusionsThe Persian EFAS Score version was successfully validated in patients with a wide variety of foot and ankle pathologies. All score versions are freely available at www.efas.co. 相似文献
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Martin Picard Jiangwen Zhang Saege Hancock Olga Derbeneva Ryan Golhar Pawel Golik Sean O’Hearn Shawn Levy Prasanth Potluri Maria Lvova Antonio Davila Chun Shi Lin Juan Carlos Perin Eric F. Rappaport Hakon Hakonarson Ian A. Trounce Vincent Procaccio Douglas C. Wallace 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(38):E4033-E4042
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Grant SF Glessner JT Bradfield JP Zhao J Tirone JE Berkowitz RI Hakonarson H Sondheimer N 《International journal of obesity (2005)》2012,36(1):80-83
Mitochondrial electron transport has a central role in regulating energy supply within a cell. We hypothesized that mitochondrial variants or increased levels of mitochondrial heteroplasmy could be associated with common childhood obesity through their effects on mitochondrial function. To investigate this question, we queried two genome-wide genotyped childhood obesity datasets, consisting of 1080 European-American (EA) obese children (defined as BMI ≥ 95th percentile) together with 2500 EA lean controls (defined as BMI<50th percentile) and 1479 African-American (AA) obese children and 1575 AA lean controls. Association was not observed between childhood obesity and any of the assayed mitochondrial polymorphisms in either ethnicity. We also found no observable differences in heteroplasmy between each obese and non-obese group. Finally, we analyzed the quantitative mitochondrial genotype cells generated, whether they exceeded the heteroplasmy threshold or not. With this more lenient test, we found six positions with a significant difference between EA cases and controls (P<1 × 10(-4)). However, when evaluating the AA data set, no differences were noted at these sites, suggesting that our initial observations were because of chance rather than a meaningful relationship to childhood obesity. As such, it is unlikely that common mitochondrial polymorphisms or heteroplasmy have a role in childhood obesity. 相似文献