Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial
Aims Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation. Methods This study consisted of single‐dose and multi...
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| Veröffentlicht in: | British journal of clinical pharmacology 2018-10, Vol.84 (10), p.2393-2404 |
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| creator | Kumagai, Yuji Amano, Hideki Sasaki, Yoshinobu Nakagawa, Chie Maeda, Mika Oikawa, Ichiro Furuie, Hidetoshi |
| description | Aims
Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.
Methods
This study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.
Results
Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P |
| doi_str_mv | 10.1111/bcp.13698 |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6138487</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>BCP13698</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4818-3efd8cd3dd25f8c7a857b4cd74b41e62c46e7b279976f45a7d0b7a3a2617c6c63</originalsourceid><addsrcrecordid>eNp1kctO3TAQhi3UCg6XBS9QeVuJQJzEl3RRiR5xqYTULmBt-RbOIB87skNbeA1eGIcDqF3Um5E133xj-UfokNTHpJwTbcZj0rJebKFFqbRqSEM_oEXd1qyiDSU7aDfnu7omLWF0G-00fU97LvgCPZ0NgzMTjgPOEG69wypYvL73E4zlYmN2eW46HzX8Aa2mo0Jg8E55rGHmDVg8JRXyGNPkEoawAg1TTEc4BmxWKQYw2MSQi1NNEMMXfIrLgI1reHR2bk0peu9mDyi_jz4Oymd38Fr30M352fXysrr6cfF9eXpVmU4QUbVusMLY1tqGDsJwJSjXnbG80x1xrDEdc1w3vO85GzqquK01V61qGOGGGdbuoa8b73iv184aV56hvBwTrFV6kFGB_LcTYCVv4y_JSCs6wYvg80ZgUsw5ueF9ltRyTkaWZORLMoX99Peyd_ItigKcbIDf5Vcf_m-S35Y_N8pnfluc5A</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Kumagai, Yuji ; Amano, Hideki ; Sasaki, Yoshinobu ; Nakagawa, Chie ; Maeda, Mika ; Oikawa, Ichiro ; Furuie, Hidetoshi</creator><creatorcontrib>Kumagai, Yuji ; Amano, Hideki ; Sasaki, Yoshinobu ; Nakagawa, Chie ; Maeda, Mika ; Oikawa, Ichiro ; Furuie, Hidetoshi</creatorcontrib><description>Aims
Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.
Methods
This study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.
Results
Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.
Conclusions
Elobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.13698</identifier><identifier>PMID: 29959787</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>Administration, Oral ; Adult ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - metabolism ; Cholestenones - blood ; Cholesterol, LDL - blood ; Chronic Disease - drug therapy ; Constipation - blood ; Constipation - drug therapy ; Constipation - pathology ; Cross-Over Studies ; Defecation - drug effects ; Dipeptides - pharmacology ; Dipeptides - therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Female ; Food-Drug Interactions ; gastroenterology ; Humans ; Ileum - drug effects ; Ileum - metabolism ; Ileum - pathology ; Male ; Membrane Glycoproteins - antagonists & inhibitors ; Membrane Glycoproteins - metabolism ; Middle Aged ; Original ; pharmacodynamics ; pharmacokinetics ; phase I ; Placebos - administration & dosage ; Placebos - adverse effects ; randomized controlled trial ; Sex Factors ; Tablets ; Thiazepines - pharmacology ; Thiazepines - therapeutic use ; Treatment Outcome ; Young Adult</subject><ispartof>British journal of clinical pharmacology, 2018-10, Vol.84 (10), p.2393-2404</ispartof><rights>2018 EA Pharma Co., Ltd. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4818-3efd8cd3dd25f8c7a857b4cd74b41e62c46e7b279976f45a7d0b7a3a2617c6c63</citedby><cites>FETCH-LOGICAL-c4818-3efd8cd3dd25f8c7a857b4cd74b41e62c46e7b279976f45a7d0b7a3a2617c6c63</cites><orcidid>0000-0002-8256-0516 ; 0000-0001-8628-2843</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbcp.13698$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcp.13698$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29959787$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumagai, Yuji</creatorcontrib><creatorcontrib>Amano, Hideki</creatorcontrib><creatorcontrib>Sasaki, Yoshinobu</creatorcontrib><creatorcontrib>Nakagawa, Chie</creatorcontrib><creatorcontrib>Maeda, Mika</creatorcontrib><creatorcontrib>Oikawa, Ichiro</creatorcontrib><creatorcontrib>Furuie, Hidetoshi</creatorcontrib><title>Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims
Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.
Methods
This study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.
Results
Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.
Conclusions
Elobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Carrier Proteins - metabolism</subject><subject>Cholestenones - blood</subject><subject>Cholesterol, LDL - blood</subject><subject>Chronic Disease - drug therapy</subject><subject>Constipation - blood</subject><subject>Constipation - drug therapy</subject><subject>Constipation - pathology</subject><subject>Cross-Over Studies</subject><subject>Defecation - drug effects</subject><subject>Dipeptides - pharmacology</subject><subject>Dipeptides - therapeutic use</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>Food-Drug Interactions</subject><subject>gastroenterology</subject><subject>Humans</subject><subject>Ileum - drug effects</subject><subject>Ileum - metabolism</subject><subject>Ileum - pathology</subject><subject>Male</subject><subject>Membrane Glycoproteins - antagonists & inhibitors</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Middle Aged</subject><subject>Original</subject><subject>pharmacodynamics</subject><subject>pharmacokinetics</subject><subject>phase I</subject><subject>Placebos - administration & dosage</subject><subject>Placebos - adverse effects</subject><subject>randomized controlled trial</subject><subject>Sex Factors</subject><subject>Tablets</subject><subject>Thiazepines - pharmacology</subject><subject>Thiazepines - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp1kctO3TAQhi3UCg6XBS9QeVuJQJzEl3RRiR5xqYTULmBt-RbOIB87skNbeA1eGIcDqF3Um5E133xj-UfokNTHpJwTbcZj0rJebKFFqbRqSEM_oEXd1qyiDSU7aDfnu7omLWF0G-00fU97LvgCPZ0NgzMTjgPOEG69wypYvL73E4zlYmN2eW46HzX8Aa2mo0Jg8E55rGHmDVg8JRXyGNPkEoawAg1TTEc4BmxWKQYw2MSQi1NNEMMXfIrLgI1reHR2bk0peu9mDyi_jz4Oymd38Fr30M352fXysrr6cfF9eXpVmU4QUbVusMLY1tqGDsJwJSjXnbG80x1xrDEdc1w3vO85GzqquK01V61qGOGGGdbuoa8b73iv184aV56hvBwTrFV6kFGB_LcTYCVv4y_JSCs6wYvg80ZgUsw5ueF9ltRyTkaWZORLMoX99Peyd_ItigKcbIDf5Vcf_m-S35Y_N8pnfluc5A</recordid><startdate>201810</startdate><enddate>201810</enddate><creator>Kumagai, Yuji</creator><creator>Amano, Hideki</creator><creator>Sasaki, Yoshinobu</creator><creator>Nakagawa, Chie</creator><creator>Maeda, Mika</creator><creator>Oikawa, Ichiro</creator><creator>Furuie, Hidetoshi</creator><general>John Wiley and Sons Inc</general><scope>24P</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>5PM</scope><orcidid>https://orcid.org/0000-0002-8256-0516</orcidid><orcidid>https://orcid.org/0000-0001-8628-2843</orcidid></search><sort><creationdate>201810</creationdate><title>Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial</title><author>Kumagai, Yuji ; Amano, Hideki ; Sasaki, Yoshinobu ; Nakagawa, Chie ; Maeda, Mika ; Oikawa, Ichiro ; Furuie, Hidetoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4818-3efd8cd3dd25f8c7a857b4cd74b41e62c46e7b279976f45a7d0b7a3a2617c6c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Carrier Proteins - antagonists & inhibitors</topic><topic>Carrier Proteins - metabolism</topic><topic>Cholestenones - blood</topic><topic>Cholesterol, LDL - blood</topic><topic>Chronic Disease - drug therapy</topic><topic>Constipation - blood</topic><topic>Constipation - drug therapy</topic><topic>Constipation - pathology</topic><topic>Cross-Over Studies</topic><topic>Defecation - drug effects</topic><topic>Dipeptides - pharmacology</topic><topic>Dipeptides - therapeutic use</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>Food-Drug Interactions</topic><topic>gastroenterology</topic><topic>Humans</topic><topic>Ileum - drug effects</topic><topic>Ileum - metabolism</topic><topic>Ileum - pathology</topic><topic>Male</topic><topic>Membrane Glycoproteins - antagonists & inhibitors</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Middle Aged</topic><topic>Original</topic><topic>pharmacodynamics</topic><topic>pharmacokinetics</topic><topic>phase I</topic><topic>Placebos - administration & dosage</topic><topic>Placebos - adverse effects</topic><topic>randomized controlled trial</topic><topic>Sex Factors</topic><topic>Tablets</topic><topic>Thiazepines - pharmacology</topic><topic>Thiazepines - therapeutic use</topic><topic>Treatment Outcome</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumagai, Yuji</creatorcontrib><creatorcontrib>Amano, Hideki</creatorcontrib><creatorcontrib>Sasaki, Yoshinobu</creatorcontrib><creatorcontrib>Nakagawa, Chie</creatorcontrib><creatorcontrib>Maeda, Mika</creatorcontrib><creatorcontrib>Oikawa, Ichiro</creatorcontrib><creatorcontrib>Furuie, Hidetoshi</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumagai, Yuji</au><au>Amano, Hideki</au><au>Sasaki, Yoshinobu</au><au>Nakagawa, Chie</au><au>Maeda, Mika</au><au>Oikawa, Ichiro</au><au>Furuie, Hidetoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2018-10</date><risdate>2018</risdate><volume>84</volume><issue>10</issue><spage>2393</spage><epage>2404</epage><pages>2393-2404</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><abstract>Aims
Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.
Methods
This study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.
Results
Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.
Conclusions
Elobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>29959787</pmid><doi>10.1111/bcp.13698</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-8256-0516</orcidid><orcidid>https://orcid.org/0000-0001-8628-2843</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Administration, Oral Adult Carrier Proteins - antagonists & inhibitors Carrier Proteins - metabolism Cholestenones - blood Cholesterol, LDL - blood Chronic Disease - drug therapy Constipation - blood Constipation - drug therapy Constipation - pathology Cross-Over Studies Defecation - drug effects Dipeptides - pharmacology Dipeptides - therapeutic use Dose-Response Relationship, Drug Double-Blind Method Drug Administration Schedule Female Food-Drug Interactions gastroenterology Humans Ileum - drug effects Ileum - metabolism Ileum - pathology Male Membrane Glycoproteins - antagonists & inhibitors Membrane Glycoproteins - metabolism Middle Aged Original pharmacodynamics pharmacokinetics phase I Placebos - administration & dosage Placebos - adverse effects randomized controlled trial Sex Factors Tablets Thiazepines - pharmacology Thiazepines - therapeutic use Treatment Outcome Young Adult |
| title | Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial |
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