Effect of co‐administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat

A combination of Angelicae Dahuricae Radix and Acori Tatarinowii Rhizoma has been widely used as the herb pair in traditional Chinese medicine to treat stroke, migraine, and epilepsy. However, the underlying synergistic mechanism of the herb pair remains unknown. This study was aimed at investigatin...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of separation science 2020-06, Vol.43 (12), p.2349-2362
Hauptverfasser: Shi, Baimei, Liu, Jianghong, Zhang, Qian, Wang, Shixiang, Jia, Pu, Bian, Liujiao, Zheng, Xiaohui
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2362
container_issue 12
container_start_page 2349
container_title Journal of separation science
container_volume 43
creator Shi, Baimei
Liu, Jianghong
Zhang, Qian
Wang, Shixiang
Jia, Pu
Bian, Liujiao
Zheng, Xiaohui
description A combination of Angelicae Dahuricae Radix and Acori Tatarinowii Rhizoma has been widely used as the herb pair in traditional Chinese medicine to treat stroke, migraine, and epilepsy. However, the underlying synergistic mechanism of the herb pair remains unknown. This study was aimed at investigating the effects of Acori Tatarinowii Rhizoma volatile oil on the pharmacokinetic parameters of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat, and in vitro absorption behavior of the three compounds using rat everted gut sac, in situ single‐pass intestinal perfusion, and Caco‐2 cell monolayer models. The pharmacokinetic study exhibited clear changes in the key pharmacokinetic parameters of the three main coumarins through co‐administering with Acori Tatarinowii Rhizoma volatile oil (50 mg/kg), the area under curve and the maximum plasma concentration of xanthotoxol increased 1.36 and 1.31 times; the area under curve, the maximum plasma concentration, mean residence time, half‐life of elimination, and the time to reach peak concentration of oxypeucedanin hydrate increased by 1.35, 1.18, 1.24, 1.19 and 1.49 times, respectively; the area under curve, mean residence time, half‐life of elimination, and time to reach peak concentration of byakangelicin climbed 1.29, 1.27, 1.37, and 1.28 times, respectively. The three coumarin components were absorbed well in the jejunum and ileum in the intestinal perfusion model, when co‐administered with Acori Tatarinowii Rhizoma volatile oil (100 μg/mL). The in vivo and in vitro experiments showed good relevance and consistency. The results demonstrated that the three coumarin compounds from Angelicae Dahuricae Radix were absorbed through the active transportation, and Acori Tatarinowii Rhizoma volatile oil could promote the intestinal absorption and transport of these compounds by inhibiting P‐glycoprotein (P‐gp)‐mediated efflux.
doi_str_mv 10.1002/jssc.201901250
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2414212852</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2414212852</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4058-427d1cc8a1582f2483ed2f92e425860b2c233da22f2a365106311a321fe07c6e3</originalsourceid><addsrcrecordid>eNqFkc1uEzEQx1eIipbClSOyxLVJ7fHuxjlGaYGiSkhtOa8m_mCd7trB9tIsJx6BJ-JheJI6pOSKL56P3_xHmn9RvGF0yiiF83WMcgqUzSmDij4rTljNqsmcs_L5Iab1cfEyxjWlbCbm9EVxzCE_yquT4velMVom4g2R_s_PX6h662xMAZP1bldeSB8sucOEwTr_YC25ae0P3yP57rtMdZp425EMb1oMPUp_b51OVhKDSe8UtuhS65Pf-u6M-O240YPUCp11pB1V3qTPCDpFViPeo_uqOytzywTfk8U-RU0usB3C3-gGld2STOTJV8WRwS7q10__afHl_eXd8uPk-vOHq-XieiJLWolJCTPFpBTIKgEGSsG1AjMHXUIlaroCCZwrhNxDXleM1pwx5MCMpjNZa35avNvrboL_NuiYmrUfgssrGyhZCQxEBZma7ikZfIxBm2YTbI9hbBhtdnY1O7uag1154O2T7LDqtTrg__zJQLkHHvKdx__INZ9ub5e1AMEfAWbepOw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2414212852</pqid></control><display><type>article</type><title>Effect of co‐administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Shi, Baimei ; Liu, Jianghong ; Zhang, Qian ; Wang, Shixiang ; Jia, Pu ; Bian, Liujiao ; Zheng, Xiaohui</creator><creatorcontrib>Shi, Baimei ; Liu, Jianghong ; Zhang, Qian ; Wang, Shixiang ; Jia, Pu ; Bian, Liujiao ; Zheng, Xiaohui</creatorcontrib><description>A combination of Angelicae Dahuricae Radix and Acori Tatarinowii Rhizoma has been widely used as the herb pair in traditional Chinese medicine to treat stroke, migraine, and epilepsy. However, the underlying synergistic mechanism of the herb pair remains unknown. This study was aimed at investigating the effects of Acori Tatarinowii Rhizoma volatile oil on the pharmacokinetic parameters of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat, and in vitro absorption behavior of the three compounds using rat everted gut sac, in situ single‐pass intestinal perfusion, and Caco‐2 cell monolayer models. The pharmacokinetic study exhibited clear changes in the key pharmacokinetic parameters of the three main coumarins through co‐administering with Acori Tatarinowii Rhizoma volatile oil (50 mg/kg), the area under curve and the maximum plasma concentration of xanthotoxol increased 1.36 and 1.31 times; the area under curve, the maximum plasma concentration, mean residence time, half‐life of elimination, and the time to reach peak concentration of oxypeucedanin hydrate increased by 1.35, 1.18, 1.24, 1.19 and 1.49 times, respectively; the area under curve, mean residence time, half‐life of elimination, and time to reach peak concentration of byakangelicin climbed 1.29, 1.27, 1.37, and 1.28 times, respectively. The three coumarin components were absorbed well in the jejunum and ileum in the intestinal perfusion model, when co‐administered with Acori Tatarinowii Rhizoma volatile oil (100 μg/mL). The in vivo and in vitro experiments showed good relevance and consistency. The results demonstrated that the three coumarin compounds from Angelicae Dahuricae Radix were absorbed through the active transportation, and Acori Tatarinowii Rhizoma volatile oil could promote the intestinal absorption and transport of these compounds by inhibiting P‐glycoprotein (P‐gp)‐mediated efflux.</description><identifier>ISSN: 1615-9306</identifier><identifier>EISSN: 1615-9314</identifier><identifier>DOI: 10.1002/jssc.201901250</identifier><identifier>PMID: 32222035</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Absorption ; Administration, Oral ; Angelica - chemistry ; Animals ; Araceae - chemistry ; byakangelicin ; Caco-2 Cells ; Coumarin ; Efflux ; Epilepsy ; Furocoumarins - administration &amp; dosage ; Furocoumarins - pharmacokinetics ; Glycoproteins ; Herbs ; Humans ; Intestinal Absorption - drug effects ; Male ; Mathematical models ; Migraine ; Oils, Volatile - administration &amp; dosage ; Oils, Volatile - pharmacokinetics ; oxypeucedanin hydrate ; Parameters ; Pharmacokinetics ; Pharmacology ; P‐glycoprotein ; Rats ; Rats, Sprague-Dawley ; Residence time distribution ; Traditional Chinese medicine ; xanthotoxol</subject><ispartof>Journal of separation science, 2020-06, Vol.43 (12), p.2349-2362</ispartof><rights>2020 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim</rights><rights>2020 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4058-427d1cc8a1582f2483ed2f92e425860b2c233da22f2a365106311a321fe07c6e3</citedby><cites>FETCH-LOGICAL-c4058-427d1cc8a1582f2483ed2f92e425860b2c233da22f2a365106311a321fe07c6e3</cites><orcidid>0000-0003-4271-0302 ; 0000-0002-9967-9302 ; 0000-0003-0738-4943</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjssc.201901250$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjssc.201901250$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32222035$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shi, Baimei</creatorcontrib><creatorcontrib>Liu, Jianghong</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Wang, Shixiang</creatorcontrib><creatorcontrib>Jia, Pu</creatorcontrib><creatorcontrib>Bian, Liujiao</creatorcontrib><creatorcontrib>Zheng, Xiaohui</creatorcontrib><title>Effect of co‐administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat</title><title>Journal of separation science</title><addtitle>J Sep Sci</addtitle><description>A combination of Angelicae Dahuricae Radix and Acori Tatarinowii Rhizoma has been widely used as the herb pair in traditional Chinese medicine to treat stroke, migraine, and epilepsy. However, the underlying synergistic mechanism of the herb pair remains unknown. This study was aimed at investigating the effects of Acori Tatarinowii Rhizoma volatile oil on the pharmacokinetic parameters of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat, and in vitro absorption behavior of the three compounds using rat everted gut sac, in situ single‐pass intestinal perfusion, and Caco‐2 cell monolayer models. The pharmacokinetic study exhibited clear changes in the key pharmacokinetic parameters of the three main coumarins through co‐administering with Acori Tatarinowii Rhizoma volatile oil (50 mg/kg), the area under curve and the maximum plasma concentration of xanthotoxol increased 1.36 and 1.31 times; the area under curve, the maximum plasma concentration, mean residence time, half‐life of elimination, and the time to reach peak concentration of oxypeucedanin hydrate increased by 1.35, 1.18, 1.24, 1.19 and 1.49 times, respectively; the area under curve, mean residence time, half‐life of elimination, and time to reach peak concentration of byakangelicin climbed 1.29, 1.27, 1.37, and 1.28 times, respectively. The three coumarin components were absorbed well in the jejunum and ileum in the intestinal perfusion model, when co‐administered with Acori Tatarinowii Rhizoma volatile oil (100 μg/mL). The in vivo and in vitro experiments showed good relevance and consistency. The results demonstrated that the three coumarin compounds from Angelicae Dahuricae Radix were absorbed through the active transportation, and Acori Tatarinowii Rhizoma volatile oil could promote the intestinal absorption and transport of these compounds by inhibiting P‐glycoprotein (P‐gp)‐mediated efflux.</description><subject>Absorption</subject><subject>Administration, Oral</subject><subject>Angelica - chemistry</subject><subject>Animals</subject><subject>Araceae - chemistry</subject><subject>byakangelicin</subject><subject>Caco-2 Cells</subject><subject>Coumarin</subject><subject>Efflux</subject><subject>Epilepsy</subject><subject>Furocoumarins - administration &amp; dosage</subject><subject>Furocoumarins - pharmacokinetics</subject><subject>Glycoproteins</subject><subject>Herbs</subject><subject>Humans</subject><subject>Intestinal Absorption - drug effects</subject><subject>Male</subject><subject>Mathematical models</subject><subject>Migraine</subject><subject>Oils, Volatile - administration &amp; dosage</subject><subject>Oils, Volatile - pharmacokinetics</subject><subject>oxypeucedanin hydrate</subject><subject>Parameters</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>P‐glycoprotein</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Residence time distribution</subject><subject>Traditional Chinese medicine</subject><subject>xanthotoxol</subject><issn>1615-9306</issn><issn>1615-9314</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEQx1eIipbClSOyxLVJ7fHuxjlGaYGiSkhtOa8m_mCd7trB9tIsJx6BJ-JheJI6pOSKL56P3_xHmn9RvGF0yiiF83WMcgqUzSmDij4rTljNqsmcs_L5Iab1cfEyxjWlbCbm9EVxzCE_yquT4velMVom4g2R_s_PX6h662xMAZP1bldeSB8sucOEwTr_YC25ae0P3yP57rtMdZp425EMb1oMPUp_b51OVhKDSe8UtuhS65Pf-u6M-O240YPUCp11pB1V3qTPCDpFViPeo_uqOytzywTfk8U-RU0usB3C3-gGld2STOTJV8WRwS7q10__afHl_eXd8uPk-vOHq-XieiJLWolJCTPFpBTIKgEGSsG1AjMHXUIlaroCCZwrhNxDXleM1pwx5MCMpjNZa35avNvrboL_NuiYmrUfgssrGyhZCQxEBZma7ikZfIxBm2YTbI9hbBhtdnY1O7uag1154O2T7LDqtTrg__zJQLkHHvKdx__INZ9ub5e1AMEfAWbepOw</recordid><startdate>202006</startdate><enddate>202006</enddate><creator>Shi, Baimei</creator><creator>Liu, Jianghong</creator><creator>Zhang, Qian</creator><creator>Wang, Shixiang</creator><creator>Jia, Pu</creator><creator>Bian, Liujiao</creator><creator>Zheng, Xiaohui</creator><general>Wiley Subscription Services, Inc</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>7U5</scope><scope>8FD</scope><scope>L7M</scope><orcidid>https://orcid.org/0000-0003-4271-0302</orcidid><orcidid>https://orcid.org/0000-0002-9967-9302</orcidid><orcidid>https://orcid.org/0000-0003-0738-4943</orcidid></search><sort><creationdate>202006</creationdate><title>Effect of co‐administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat</title><author>Shi, Baimei ; Liu, Jianghong ; Zhang, Qian ; Wang, Shixiang ; Jia, Pu ; Bian, Liujiao ; Zheng, Xiaohui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4058-427d1cc8a1582f2483ed2f92e425860b2c233da22f2a365106311a321fe07c6e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Absorption</topic><topic>Administration, Oral</topic><topic>Angelica - chemistry</topic><topic>Animals</topic><topic>Araceae - chemistry</topic><topic>byakangelicin</topic><topic>Caco-2 Cells</topic><topic>Coumarin</topic><topic>Efflux</topic><topic>Epilepsy</topic><topic>Furocoumarins - administration &amp; dosage</topic><topic>Furocoumarins - pharmacokinetics</topic><topic>Glycoproteins</topic><topic>Herbs</topic><topic>Humans</topic><topic>Intestinal Absorption - drug effects</topic><topic>Male</topic><topic>Mathematical models</topic><topic>Migraine</topic><topic>Oils, Volatile - administration &amp; dosage</topic><topic>Oils, Volatile - pharmacokinetics</topic><topic>oxypeucedanin hydrate</topic><topic>Parameters</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>P‐glycoprotein</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Residence time distribution</topic><topic>Traditional Chinese medicine</topic><topic>xanthotoxol</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shi, Baimei</creatorcontrib><creatorcontrib>Liu, Jianghong</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Wang, Shixiang</creatorcontrib><creatorcontrib>Jia, Pu</creatorcontrib><creatorcontrib>Bian, Liujiao</creatorcontrib><creatorcontrib>Zheng, Xiaohui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Technology Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><jtitle>Journal of separation science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shi, Baimei</au><au>Liu, Jianghong</au><au>Zhang, Qian</au><au>Wang, Shixiang</au><au>Jia, Pu</au><au>Bian, Liujiao</au><au>Zheng, Xiaohui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of co‐administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat</atitle><jtitle>Journal of separation science</jtitle><addtitle>J Sep Sci</addtitle><date>2020-06</date><risdate>2020</risdate><volume>43</volume><issue>12</issue><spage>2349</spage><epage>2362</epage><pages>2349-2362</pages><issn>1615-9306</issn><eissn>1615-9314</eissn><abstract>A combination of Angelicae Dahuricae Radix and Acori Tatarinowii Rhizoma has been widely used as the herb pair in traditional Chinese medicine to treat stroke, migraine, and epilepsy. However, the underlying synergistic mechanism of the herb pair remains unknown. This study was aimed at investigating the effects of Acori Tatarinowii Rhizoma volatile oil on the pharmacokinetic parameters of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat, and in vitro absorption behavior of the three compounds using rat everted gut sac, in situ single‐pass intestinal perfusion, and Caco‐2 cell monolayer models. The pharmacokinetic study exhibited clear changes in the key pharmacokinetic parameters of the three main coumarins through co‐administering with Acori Tatarinowii Rhizoma volatile oil (50 mg/kg), the area under curve and the maximum plasma concentration of xanthotoxol increased 1.36 and 1.31 times; the area under curve, the maximum plasma concentration, mean residence time, half‐life of elimination, and the time to reach peak concentration of oxypeucedanin hydrate increased by 1.35, 1.18, 1.24, 1.19 and 1.49 times, respectively; the area under curve, mean residence time, half‐life of elimination, and time to reach peak concentration of byakangelicin climbed 1.29, 1.27, 1.37, and 1.28 times, respectively. The three coumarin components were absorbed well in the jejunum and ileum in the intestinal perfusion model, when co‐administered with Acori Tatarinowii Rhizoma volatile oil (100 μg/mL). The in vivo and in vitro experiments showed good relevance and consistency. The results demonstrated that the three coumarin compounds from Angelicae Dahuricae Radix were absorbed through the active transportation, and Acori Tatarinowii Rhizoma volatile oil could promote the intestinal absorption and transport of these compounds by inhibiting P‐glycoprotein (P‐gp)‐mediated efflux.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32222035</pmid><doi>10.1002/jssc.201901250</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-4271-0302</orcidid><orcidid>https://orcid.org/0000-0002-9967-9302</orcidid><orcidid>https://orcid.org/0000-0003-0738-4943</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 1615-9306
ispartof Journal of separation science, 2020-06, Vol.43 (12), p.2349-2362
issn 1615-9306
1615-9314
language eng
recordid cdi_proquest_journals_2414212852
source MEDLINE; Wiley Online Library Journals Frontfile Complete
subjects Absorption
Administration, Oral
Angelica - chemistry
Animals
Araceae - chemistry
byakangelicin
Caco-2 Cells
Coumarin
Efflux
Epilepsy
Furocoumarins - administration & dosage
Furocoumarins - pharmacokinetics
Glycoproteins
Herbs
Humans
Intestinal Absorption - drug effects
Male
Mathematical models
Migraine
Oils, Volatile - administration & dosage
Oils, Volatile - pharmacokinetics
oxypeucedanin hydrate
Parameters
Pharmacokinetics
Pharmacology
P‐glycoprotein
Rats
Rats, Sprague-Dawley
Residence time distribution
Traditional Chinese medicine
xanthotoxol
title Effect of co‐administration of Acori Tatarinowii Rhizoma volatile oil on pharmacokinetic fate of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T13%3A49%3A02IST&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=Effect%20of%20co%E2%80%90administration%20of%20Acori%20Tatarinowii%20Rhizoma%20volatile%20oil%20on%20pharmacokinetic%20fate%20of%20xanthotoxol,%20oxypeucedanin%20hydrate,%20and%20byakangelicin%20from%20Angelicae%20Dahuricae%20Radix%20in%20rat&rft.jtitle=Journal%20of%20separation%20science&rft.au=Shi,%20Baimei&rft.date=2020-06&rft.volume=43&rft.issue=12&rft.spage=2349&rft.epage=2362&rft.pages=2349-2362&rft.issn=1615-9306&rft.eissn=1615-9314&rft_id=info:doi/10.1002/jssc.201901250&rft_dat=%3Cproquest_cross%3E2414212852%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=2414212852&rft_id=info:pmid/32222035&rfr_iscdi=true