Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits
To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using hum...
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| creator | Kida, Tetsuo Kozai, Seiko Takahashi, Hiroaki Isaka, Mitsuyoshi Tokushige, Hideki Sakamoto, Taiji |
| description | To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits.
The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits.
The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs.
Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases. |
| doi_str_mv | 10.1371/journal.pone.0096481 |
| format | Article |
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The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits.
The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs.
Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0096481</identifier><identifier>PMID: 24796327</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject><![CDATA[Administration, Topical ; Animals ; Anti-inflammatory agents ; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics ; Aqueous Humor - drug effects ; Aqueous Humor - metabolism ; Benzophenones - administration & dosage ; Benzophenones - chemistry ; Benzophenones - pharmacokinetics ; Biology and Life Sciences ; Blood ; Breakdown ; Bromobenzenes - administration & dosage ; Bromobenzenes - chemistry ; Bromobenzenes - pharmacokinetics ; Cataracts ; Choroid - drug effects ; Choroid - metabolism ; Chromatography ; Chromatography, Liquid ; Concanavalin A ; COX-2 inhibitors ; Cyclooxygenase 1 - chemistry ; Cyclooxygenase 2 - chemistry ; Cyclooxygenase Inhibitors - administration & dosage ; Cyclooxygenase Inhibitors - chemistry ; Cyclooxygenase Inhibitors - pharmacokinetics ; Cyclooxygenase-1 ; Cyclooxygenase-2 ; Diclofenac ; Diclofenac - administration & dosage ; Diclofenac - chemistry ; Diclofenac - pharmacokinetics ; Drug delivery systems ; Drugs ; Effectiveness ; Humans ; Inflammatory diseases ; Liquid chromatography ; Macular degeneration ; Male ; Mass spectrometry ; Mass spectroscopy ; Medicine and Health Sciences ; Metabolites ; Nepafenac ; Nonsteroidal anti-inflammatory agents ; Nonsteroidal anti-inflammatory drugs ; Pharmaceuticals ; Pharmacokinetics ; Pharmacology ; Phenylacetates - administration & dosage ; Phenylacetates - chemistry ; Phenylacetates - pharmacokinetics ; Proteins ; Rabbits ; Research and Analysis Methods ; Retina ; Simulators (Training equipment) ; Software ; Tandem Mass Spectrometry ; Tissues]]></subject><ispartof>PloS one, 2014-05, Vol.9 (5), p.e96481</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Kida et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Kida et al 2014 Kida et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-9a57ad5ead75ea3fac25be752426a051ed92292c8d0ec6acf53d0ad07d5229483</citedby><cites>FETCH-LOGICAL-c758t-9a57ad5ead75ea3fac25be752426a051ed92292c8d0ec6acf53d0ad07d5229483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010472/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010472/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24796327$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lewin, Alfred S.</contributor><creatorcontrib>Kida, Tetsuo</creatorcontrib><creatorcontrib>Kozai, Seiko</creatorcontrib><creatorcontrib>Takahashi, Hiroaki</creatorcontrib><creatorcontrib>Isaka, Mitsuyoshi</creatorcontrib><creatorcontrib>Tokushige, Hideki</creatorcontrib><creatorcontrib>Sakamoto, Taiji</creatorcontrib><title>Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits.
The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits.
The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs.
Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.</description><subject>Administration, Topical</subject><subject>Animals</subject><subject>Anti-inflammatory agents</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - administration & dosage</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</subject><subject>Aqueous Humor - drug effects</subject><subject>Aqueous Humor - metabolism</subject><subject>Benzophenones - administration & dosage</subject><subject>Benzophenones - chemistry</subject><subject>Benzophenones - pharmacokinetics</subject><subject>Biology and Life Sciences</subject><subject>Blood</subject><subject>Breakdown</subject><subject>Bromobenzenes - administration & dosage</subject><subject>Bromobenzenes - chemistry</subject><subject>Bromobenzenes - pharmacokinetics</subject><subject>Cataracts</subject><subject>Choroid - drug effects</subject><subject>Choroid - metabolism</subject><subject>Chromatography</subject><subject>Chromatography, Liquid</subject><subject>Concanavalin A</subject><subject>COX-2 inhibitors</subject><subject>Cyclooxygenase 1 - chemistry</subject><subject>Cyclooxygenase 2 - chemistry</subject><subject>Cyclooxygenase Inhibitors - administration & dosage</subject><subject>Cyclooxygenase Inhibitors - chemistry</subject><subject>Cyclooxygenase Inhibitors - pharmacokinetics</subject><subject>Cyclooxygenase-1</subject><subject>Cyclooxygenase-2</subject><subject>Diclofenac</subject><subject>Diclofenac - administration & dosage</subject><subject>Diclofenac - chemistry</subject><subject>Diclofenac - pharmacokinetics</subject><subject>Drug delivery systems</subject><subject>Drugs</subject><subject>Effectiveness</subject><subject>Humans</subject><subject>Inflammatory diseases</subject><subject>Liquid chromatography</subject><subject>Macular degeneration</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Medicine and Health Sciences</subject><subject>Metabolites</subject><subject>Nepafenac</subject><subject>Nonsteroidal anti-inflammatory agents</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Pharmaceuticals</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Phenylacetates - administration & dosage</subject><subject>Phenylacetates - chemistry</subject><subject>Phenylacetates - pharmacokinetics</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Research and Analysis Methods</subject><subject>Retina</subject><subject>Simulators (Training equipment)</subject><subject>Software</subject><subject>Tandem Mass Spectrometry</subject><subject>Tissues</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QLguDFjEmaNO2NsCx-DCys-HUbziTpTMY06SapOBf-d7NOd5mCggSScPKcN-HNWxRPMVriiuPXOz8GB3Y5eKeXCLU1bfC94hS3FVnUBFX3j_YnxaMYdwixqqnrh8UJobytK8JPi18ftxB6kP67cToZGUtwqtRdZyTIfem7Mvkh763dlzAM1mhVOu9i0sEbBTbjySyM6yz0PSQf9qUK4yaWxpUhCzovt35Ck4lx1IcjWK9Nio-LBx3YqJ9M61nx9d3bLxcfFpdX71cX55cLyVmTFi0wDoppUDxPVQeSsLXmjFBSA2JYq5aQlshGIS1rkB2rFAKFuGK5TpvqrHh-0B2sj2JyLgrMCGpbTinOxOpAKA87MQTTQ9gLD0b8KfiwERCyP1YLqhBjpGWNBE0BWEuw1opqVGmOcaey1pvptnHdayW1SwHsTHR-4sxWbPwPQRFGlJMs8GISCP46O5b-8eSJ2kB-Vf4Cn8Vkb6IU5xQ3HHFOUaaWf6HyULo3MmenM7k-a3g1a8hM0j_TBsYYxerzp_9nr77N2ZdH7FaDTdvo7ZhMjtMcpAdQBh9j0N2dcxiJm-jfuiFuoi-m6Oe2Z8eu3zXdZr36DaqsAkg</recordid><startdate>20140505</startdate><enddate>20140505</enddate><creator>Kida, Tetsuo</creator><creator>Kozai, Seiko</creator><creator>Takahashi, Hiroaki</creator><creator>Isaka, Mitsuyoshi</creator><creator>Tokushige, Hideki</creator><creator>Sakamoto, Taiji</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140505</creationdate><title>Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits</title><author>Kida, Tetsuo ; Kozai, Seiko ; Takahashi, Hiroaki ; Isaka, Mitsuyoshi ; Tokushige, Hideki ; Sakamoto, Taiji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-9a57ad5ead75ea3fac25be752426a051ed92292c8d0ec6acf53d0ad07d5229483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Administration, Topical</topic><topic>Animals</topic><topic>Anti-inflammatory agents</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - 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chemistry</topic><topic>Cyclooxygenase Inhibitors - pharmacokinetics</topic><topic>Cyclooxygenase-1</topic><topic>Cyclooxygenase-2</topic><topic>Diclofenac</topic><topic>Diclofenac - administration & dosage</topic><topic>Diclofenac - chemistry</topic><topic>Diclofenac - pharmacokinetics</topic><topic>Drug delivery systems</topic><topic>Drugs</topic><topic>Effectiveness</topic><topic>Humans</topic><topic>Inflammatory diseases</topic><topic>Liquid chromatography</topic><topic>Macular degeneration</topic><topic>Male</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Medicine and Health Sciences</topic><topic>Metabolites</topic><topic>Nepafenac</topic><topic>Nonsteroidal anti-inflammatory agents</topic><topic>Nonsteroidal anti-inflammatory drugs</topic><topic>Pharmaceuticals</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Phenylacetates - administration & dosage</topic><topic>Phenylacetates - chemistry</topic><topic>Phenylacetates - pharmacokinetics</topic><topic>Proteins</topic><topic>Rabbits</topic><topic>Research and Analysis Methods</topic><topic>Retina</topic><topic>Simulators (Training equipment)</topic><topic>Software</topic><topic>Tandem Mass Spectrometry</topic><topic>Tissues</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kida, Tetsuo</creatorcontrib><creatorcontrib>Kozai, Seiko</creatorcontrib><creatorcontrib>Takahashi, Hiroaki</creatorcontrib><creatorcontrib>Isaka, Mitsuyoshi</creatorcontrib><creatorcontrib>Tokushige, Hideki</creatorcontrib><creatorcontrib>Sakamoto, Taiji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kida, Tetsuo</au><au>Kozai, Seiko</au><au>Takahashi, Hiroaki</au><au>Isaka, Mitsuyoshi</au><au>Tokushige, Hideki</au><au>Sakamoto, Taiji</au><au>Lewin, Alfred S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-05-05</date><risdate>2014</risdate><volume>9</volume><issue>5</issue><spage>e96481</spage><pages>e96481-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits.
The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits.
The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs.
Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24796327</pmid><doi>10.1371/journal.pone.0096481</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-05, Vol.9 (5), p.e96481 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1520997441 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Administration, Topical Animals Anti-inflammatory agents Anti-Inflammatory Agents, Non-Steroidal - administration & dosage Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Aqueous Humor - drug effects Aqueous Humor - metabolism Benzophenones - administration & dosage Benzophenones - chemistry Benzophenones - pharmacokinetics Biology and Life Sciences Blood Breakdown Bromobenzenes - administration & dosage Bromobenzenes - chemistry Bromobenzenes - pharmacokinetics Cataracts Choroid - drug effects Choroid - metabolism Chromatography Chromatography, Liquid Concanavalin A COX-2 inhibitors Cyclooxygenase 1 - chemistry Cyclooxygenase 2 - chemistry Cyclooxygenase Inhibitors - administration & dosage Cyclooxygenase Inhibitors - chemistry Cyclooxygenase Inhibitors - pharmacokinetics Cyclooxygenase-1 Cyclooxygenase-2 Diclofenac Diclofenac - administration & dosage Diclofenac - chemistry Diclofenac - pharmacokinetics Drug delivery systems Drugs Effectiveness Humans Inflammatory diseases Liquid chromatography Macular degeneration Male Mass spectrometry Mass spectroscopy Medicine and Health Sciences Metabolites Nepafenac Nonsteroidal anti-inflammatory agents Nonsteroidal anti-inflammatory drugs Pharmaceuticals Pharmacokinetics Pharmacology Phenylacetates - administration & dosage Phenylacetates - chemistry Phenylacetates - pharmacokinetics Proteins Rabbits Research and Analysis Methods Retina Simulators (Training equipment) Software Tandem Mass Spectrometry Tissues |
| title | Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits |
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