Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells
A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). Compound 25b inhibited ROS production from HUVECs with an IC 50 of 140 nM. and also exhibited low CYP2D6 inhibit...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (22), p.6861-6866 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 6866 |
|---|---|
| container_issue | 22 |
| container_start_page | 6861 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 21 |
| creator | Onda, Kenichi Narazaki, Fumie Ishibashi, Naoki Nakanishi, Keita Sawada, Yuki Imamura, Ken-ichiro Momose, Kazuhiro Furukawa, Shigetada Shimada, Yoshiaki Moriguchi, Hiroyuki Yuda, Masamichi Kayakiri, Hiroshi Ohta, Mitsuaki |
| description | A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). Compound
25b inhibited ROS production from HUVECs with an IC
50 of 140
nM. and also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.
Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1
H)-one (25b), inhibited ROS production from HUVECs with an IC
50 of 140
nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life. |
| doi_str_mv | 10.1016/j.bmcl.2011.09.015 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_904499422</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X11012509</els_id><sourcerecordid>900629626</sourcerecordid><originalsourceid>FETCH-LOGICAL-c441t-e77891fdd1ec2967f6129b7641291dc6fab39d81cbe6287f7d8539bc557a9df3</originalsourceid><addsrcrecordid>eNqNkcFu1DAQhi0EotvCC3AAXxCnBDuxnVjigioolSpxoEjcLMced71K7K2drOgj8NY47AI3xGkk-5uZX_Mh9IKSmhIq3u7qYTJj3RBKayJrQvkjtKFMsKplhD9GGyIFqXrJvp2h85x3hFBGGHuKzhoqRSt7vkE_ri2E2Ttv9OxjwNFhVt0vPsQxBsAWkj-UnwNkrDP2YesHP8eUVzCBNusXjt8f7iDgvAfjC7hP0S7m1ziX4oS3y6QDXqbBj2XNiA_gA4Zg47yF0ZcHA-OYn6EnTo8Znp_qBbr9-OH28lN18_nq-vL9TWUYo3MFXddL6qylYBopOidoI4dOsFKoNcLpoZW2p2YA0fSd62zPWzkYzjstrWsv0Jvj2JLyfoE8q8nnNYAOEJesZLmQlKxp_oMkoiRoRCGbI2lSzDmBU_vkJ50eFCVqVaV2alWlVlWKSFVUlaaXp_HLMIH90_LbTQFenwCdy9lc0sH4_JfjvJdC9IV7deScjkrfpcJ8_VI28eK75Zy3hXh3JKDc9eAhqVxEBQPWJzCzstH_K-lPxUa-Rw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>900629626</pqid></control><display><type>article</type><title>Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Onda, Kenichi ; Narazaki, Fumie ; Ishibashi, Naoki ; Nakanishi, Keita ; Sawada, Yuki ; Imamura, Ken-ichiro ; Momose, Kazuhiro ; Furukawa, Shigetada ; Shimada, Yoshiaki ; Moriguchi, Hiroyuki ; Yuda, Masamichi ; Kayakiri, Hiroshi ; Ohta, Mitsuaki</creator><creatorcontrib>Onda, Kenichi ; Narazaki, Fumie ; Ishibashi, Naoki ; Nakanishi, Keita ; Sawada, Yuki ; Imamura, Ken-ichiro ; Momose, Kazuhiro ; Furukawa, Shigetada ; Shimada, Yoshiaki ; Moriguchi, Hiroyuki ; Yuda, Masamichi ; Kayakiri, Hiroshi ; Ohta, Mitsuaki</creatorcontrib><description>A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). Compound
25b inhibited ROS production from HUVECs with an IC
50 of 140
nM. and also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.
Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1
H)-one (25b), inhibited ROS production from HUVECs with an IC
50 of 140
nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.09.015</identifier><identifier>PMID: 21963985</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>4-Quinolones ; 4-Quinolones - chemistry ; 4-Quinolones - pharmacokinetics ; 4-Quinolones - pharmacology ; Animals ; atherosclerosis ; bioavailability ; Biological and medical sciences ; Cytochrome P-450 CYP2D6 - metabolism ; Cytochrome P-450 CYP2D6 Inhibitors ; half life ; human umbilical vein endothelial cells ; Human Umbilical Vein Endothelial Cells - drug effects ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; HUVECs ; inhibitory concentration 50 ; Medical sciences ; Oxidative stress ; Oxidative Stress - drug effects ; pharmacokinetics ; Pharmacology. Drug treatments ; Rats ; Rats, Sprague-Dawley ; Reactive oxygen species ; Reactive Oxygen Species - antagonists & inhibitors ; Reactive Oxygen Species - metabolism ; solubility</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-11, Vol.21 (22), p.6861-6866</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-e77891fdd1ec2967f6129b7641291dc6fab39d81cbe6287f7d8539bc557a9df3</citedby><cites>FETCH-LOGICAL-c441t-e77891fdd1ec2967f6129b7641291dc6fab39d81cbe6287f7d8539bc557a9df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11012509$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25589668$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21963985$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Onda, Kenichi</creatorcontrib><creatorcontrib>Narazaki, Fumie</creatorcontrib><creatorcontrib>Ishibashi, Naoki</creatorcontrib><creatorcontrib>Nakanishi, Keita</creatorcontrib><creatorcontrib>Sawada, Yuki</creatorcontrib><creatorcontrib>Imamura, Ken-ichiro</creatorcontrib><creatorcontrib>Momose, Kazuhiro</creatorcontrib><creatorcontrib>Furukawa, Shigetada</creatorcontrib><creatorcontrib>Shimada, Yoshiaki</creatorcontrib><creatorcontrib>Moriguchi, Hiroyuki</creatorcontrib><creatorcontrib>Yuda, Masamichi</creatorcontrib><creatorcontrib>Kayakiri, Hiroshi</creatorcontrib><creatorcontrib>Ohta, Mitsuaki</creatorcontrib><title>Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). Compound
25b inhibited ROS production from HUVECs with an IC
50 of 140
nM. and also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.
Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1
H)-one (25b), inhibited ROS production from HUVECs with an IC
50 of 140
nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.</description><subject>4-Quinolones</subject><subject>4-Quinolones - chemistry</subject><subject>4-Quinolones - pharmacokinetics</subject><subject>4-Quinolones - pharmacology</subject><subject>Animals</subject><subject>atherosclerosis</subject><subject>bioavailability</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Cytochrome P-450 CYP2D6 Inhibitors</subject><subject>half life</subject><subject>human umbilical vein endothelial cells</subject><subject>Human Umbilical Vein Endothelial Cells - drug effects</subject><subject>Human Umbilical Vein Endothelial Cells - metabolism</subject><subject>Humans</subject><subject>HUVECs</subject><subject>inhibitory concentration 50</subject><subject>Medical sciences</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - antagonists & inhibitors</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>solubility</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFu1DAQhi0EotvCC3AAXxCnBDuxnVjigioolSpxoEjcLMced71K7K2drOgj8NY47AI3xGkk-5uZX_Mh9IKSmhIq3u7qYTJj3RBKayJrQvkjtKFMsKplhD9GGyIFqXrJvp2h85x3hFBGGHuKzhoqRSt7vkE_ri2E2Ttv9OxjwNFhVt0vPsQxBsAWkj-UnwNkrDP2YesHP8eUVzCBNusXjt8f7iDgvAfjC7hP0S7m1ziX4oS3y6QDXqbBj2XNiA_gA4Zg47yF0ZcHA-OYn6EnTo8Znp_qBbr9-OH28lN18_nq-vL9TWUYo3MFXddL6qylYBopOidoI4dOsFKoNcLpoZW2p2YA0fSd62zPWzkYzjstrWsv0Jvj2JLyfoE8q8nnNYAOEJesZLmQlKxp_oMkoiRoRCGbI2lSzDmBU_vkJ50eFCVqVaV2alWlVlWKSFVUlaaXp_HLMIH90_LbTQFenwCdy9lc0sH4_JfjvJdC9IV7deScjkrfpcJ8_VI28eK75Zy3hXh3JKDc9eAhqVxEBQPWJzCzstH_K-lPxUa-Rw</recordid><startdate>20111115</startdate><enddate>20111115</enddate><creator>Onda, Kenichi</creator><creator>Narazaki, Fumie</creator><creator>Ishibashi, Naoki</creator><creator>Nakanishi, Keita</creator><creator>Sawada, Yuki</creator><creator>Imamura, Ken-ichiro</creator><creator>Momose, Kazuhiro</creator><creator>Furukawa, Shigetada</creator><creator>Shimada, Yoshiaki</creator><creator>Moriguchi, Hiroyuki</creator><creator>Yuda, Masamichi</creator><creator>Kayakiri, Hiroshi</creator><creator>Ohta, Mitsuaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20111115</creationdate><title>Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells</title><author>Onda, Kenichi ; Narazaki, Fumie ; Ishibashi, Naoki ; Nakanishi, Keita ; Sawada, Yuki ; Imamura, Ken-ichiro ; Momose, Kazuhiro ; Furukawa, Shigetada ; Shimada, Yoshiaki ; Moriguchi, Hiroyuki ; Yuda, Masamichi ; Kayakiri, Hiroshi ; Ohta, Mitsuaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-e77891fdd1ec2967f6129b7641291dc6fab39d81cbe6287f7d8539bc557a9df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>4-Quinolones</topic><topic>4-Quinolones - chemistry</topic><topic>4-Quinolones - pharmacokinetics</topic><topic>4-Quinolones - pharmacology</topic><topic>Animals</topic><topic>atherosclerosis</topic><topic>bioavailability</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 CYP2D6 - metabolism</topic><topic>Cytochrome P-450 CYP2D6 Inhibitors</topic><topic>half life</topic><topic>human umbilical vein endothelial cells</topic><topic>Human Umbilical Vein Endothelial Cells - drug effects</topic><topic>Human Umbilical Vein Endothelial Cells - metabolism</topic><topic>Humans</topic><topic>HUVECs</topic><topic>inhibitory concentration 50</topic><topic>Medical sciences</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - antagonists & inhibitors</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>solubility</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Onda, Kenichi</creatorcontrib><creatorcontrib>Narazaki, Fumie</creatorcontrib><creatorcontrib>Ishibashi, Naoki</creatorcontrib><creatorcontrib>Nakanishi, Keita</creatorcontrib><creatorcontrib>Sawada, Yuki</creatorcontrib><creatorcontrib>Imamura, Ken-ichiro</creatorcontrib><creatorcontrib>Momose, Kazuhiro</creatorcontrib><creatorcontrib>Furukawa, Shigetada</creatorcontrib><creatorcontrib>Shimada, Yoshiaki</creatorcontrib><creatorcontrib>Moriguchi, Hiroyuki</creatorcontrib><creatorcontrib>Yuda, Masamichi</creatorcontrib><creatorcontrib>Kayakiri, Hiroshi</creatorcontrib><creatorcontrib>Ohta, Mitsuaki</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Onda, Kenichi</au><au>Narazaki, Fumie</au><au>Ishibashi, Naoki</au><au>Nakanishi, Keita</au><au>Sawada, Yuki</au><au>Imamura, Ken-ichiro</au><au>Momose, Kazuhiro</au><au>Furukawa, Shigetada</au><au>Shimada, Yoshiaki</au><au>Moriguchi, Hiroyuki</au><au>Yuda, Masamichi</au><au>Kayakiri, Hiroshi</au><au>Ohta, Mitsuaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-11-15</date><risdate>2011</risdate><volume>21</volume><issue>22</issue><spage>6861</spage><epage>6866</epage><pages>6861-6866</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). Compound
25b inhibited ROS production from HUVECs with an IC
50 of 140
nM. and also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.
Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1
H)-one (25b), inhibited ROS production from HUVECs with an IC
50 of 140
nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21963985</pmid><doi>10.1016/j.bmcl.2011.09.015</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-11, Vol.21 (22), p.6861-6866 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_904499422 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 4-Quinolones 4-Quinolones - chemistry 4-Quinolones - pharmacokinetics 4-Quinolones - pharmacology Animals atherosclerosis bioavailability Biological and medical sciences Cytochrome P-450 CYP2D6 - metabolism Cytochrome P-450 CYP2D6 Inhibitors half life human umbilical vein endothelial cells Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Humans HUVECs inhibitory concentration 50 Medical sciences Oxidative stress Oxidative Stress - drug effects pharmacokinetics Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Reactive oxygen species Reactive Oxygen Species - antagonists & inhibitors Reactive Oxygen Species - metabolism solubility |
| title | Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-19T04%3A56%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%204-quinolone%20derivatives%20as%20inhibitors%20of%20reactive%20oxygen%20species%20production%20from%20human%20umbilical%20vein%20endothelial%20cells&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Onda,%20Kenichi&rft.date=2011-11-15&rft.volume=21&rft.issue=22&rft.spage=6861&rft.epage=6866&rft.pages=6861-6866&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2011.09.015&rft_dat=%3Cproquest_cross%3E900629626%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=900629626&rft_id=info:pmid/21963985&rft_els_id=S0960894X11012509&rfr_iscdi=true |