A selective peroxisome proliferator-activated receptor alpha agonist, CP-900691, improves plasma lipids, lipoproteins, and glycemic control in diabetic monkeys
Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemi...
Gespeichert in:
Veröffentlicht in: | The Journal of pharmacology and experimental therapeutics 2010-06, Vol.333 (3), p.844-853 |
---|---|
Hauptverfasser: | , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 853 |
---|---|
container_issue | 3 |
container_start_page | 844 |
container_title | The Journal of pharmacology and experimental therapeutics |
container_volume | 333 |
creator | Wagner, Janice D Shadoan, Melanie K Zhang, Li Ward, Gina M Royer, Lori J Kavanagh, Kylie Francone, Omar L Auerbach, Bruce J Harwood, Jr, H James |
description | Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations. |
doi_str_mv | 10.1124/jpet.110.166736 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_733279802</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>733279802</sourcerecordid><originalsourceid>FETCH-LOGICAL-c296t-e4afe69aab8913656eb267a42fce6ad26ecf095054833e75c5e1454922343c863</originalsourceid><addsrcrecordid>eNo9UU1P3DAQtapWZaE994Z862UD_s7miFYUKiHBAc7RrDPZGpw4tb2r7q_pX60DW07z3sybNyM9Qr5xdsG5UJfPE-aCCjOmluYDWXAteMU4kx_JgjEhKqmNPiGnKT0zxpUy8jM5EYw3M1uQv1c0oUeb3R7phDH8cSkMBcbgXY8RcogVzGPI2NGIFqfSouCnX0BhG0aX8pKuH6piaBq-pG4ou3tMdPKQBqDeTa5Ly7mGMsnoxsJg7OjWHywOzlIbxlzuUTfSzsEGc-kNYXzBQ_pCPvXgE3491jPy9OP6cX1b3d3f_Fxf3VVWNCZXqKBH0wBsVg2XRhvcCFODEr1FA50waHvWaKbVSkqstdXIlVaNEFJJuzLyjHx_8y0v_t5hyu3gkkXvYcSwS20tpaibFRNFefmmtDGkFLFvp-gGiIeWs3YOpZ1DKaiw11DKxvnRe7cZsHvX_09B_gMq84rI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>733279802</pqid></control><display><type>article</type><title>A selective peroxisome proliferator-activated receptor alpha agonist, CP-900691, improves plasma lipids, lipoproteins, and glycemic control in diabetic monkeys</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Wagner, Janice D ; Shadoan, Melanie K ; Zhang, Li ; Ward, Gina M ; Royer, Lori J ; Kavanagh, Kylie ; Francone, Omar L ; Auerbach, Bruce J ; Harwood, Jr, H James</creator><creatorcontrib>Wagner, Janice D ; Shadoan, Melanie K ; Zhang, Li ; Ward, Gina M ; Royer, Lori J ; Kavanagh, Kylie ; Francone, Omar L ; Auerbach, Bruce J ; Harwood, Jr, H James</creatorcontrib><description><![CDATA[Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.]]></description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.110.166736</identifier><identifier>PMID: 20190014</identifier><language>eng</language><publisher>United States</publisher><subject>Adiponectin - blood ; Animals ; Area Under Curve ; Blood Glucose - metabolism ; C-Reactive Protein - metabolism ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - genetics ; Dose-Response Relationship, Drug ; Glucose Tolerance Test ; Hypoglycemic Agents - pharmacology ; Hypolipidemic Agents ; Insulin Resistance ; Lipids - blood ; Lipoproteins - blood ; Macaca fascicularis ; Piperidines - pharmacology ; PPAR alpha - agonists ; Propionates - pharmacology ; Weight Loss - drug effects</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2010-06, Vol.333 (3), p.844-853</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c296t-e4afe69aab8913656eb267a42fce6ad26ecf095054833e75c5e1454922343c863</citedby><cites>FETCH-LOGICAL-c296t-e4afe69aab8913656eb267a42fce6ad26ecf095054833e75c5e1454922343c863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20190014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wagner, Janice D</creatorcontrib><creatorcontrib>Shadoan, Melanie K</creatorcontrib><creatorcontrib>Zhang, Li</creatorcontrib><creatorcontrib>Ward, Gina M</creatorcontrib><creatorcontrib>Royer, Lori J</creatorcontrib><creatorcontrib>Kavanagh, Kylie</creatorcontrib><creatorcontrib>Francone, Omar L</creatorcontrib><creatorcontrib>Auerbach, Bruce J</creatorcontrib><creatorcontrib>Harwood, Jr, H James</creatorcontrib><title>A selective peroxisome proliferator-activated receptor alpha agonist, CP-900691, improves plasma lipids, lipoproteins, and glycemic control in diabetic monkeys</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description><![CDATA[Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.]]></description><subject>Adiponectin - blood</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Blood Glucose - metabolism</subject><subject>C-Reactive Protein - metabolism</subject><subject>Diabetes Mellitus, Type 2 - blood</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Dose-Response Relationship, Drug</subject><subject>Glucose Tolerance Test</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Hypolipidemic Agents</subject><subject>Insulin Resistance</subject><subject>Lipids - blood</subject><subject>Lipoproteins - blood</subject><subject>Macaca fascicularis</subject><subject>Piperidines - pharmacology</subject><subject>PPAR alpha - agonists</subject><subject>Propionates - pharmacology</subject><subject>Weight Loss - drug effects</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UU1P3DAQtapWZaE994Z862UD_s7miFYUKiHBAc7RrDPZGpw4tb2r7q_pX60DW07z3sybNyM9Qr5xdsG5UJfPE-aCCjOmluYDWXAteMU4kx_JgjEhKqmNPiGnKT0zxpUy8jM5EYw3M1uQv1c0oUeb3R7phDH8cSkMBcbgXY8RcogVzGPI2NGIFqfSouCnX0BhG0aX8pKuH6piaBq-pG4ou3tMdPKQBqDeTa5Ly7mGMsnoxsJg7OjWHywOzlIbxlzuUTfSzsEGc-kNYXzBQ_pCPvXgE3491jPy9OP6cX1b3d3f_Fxf3VVWNCZXqKBH0wBsVg2XRhvcCFODEr1FA50waHvWaKbVSkqstdXIlVaNEFJJuzLyjHx_8y0v_t5hyu3gkkXvYcSwS20tpaibFRNFefmmtDGkFLFvp-gGiIeWs3YOpZ1DKaiw11DKxvnRe7cZsHvX_09B_gMq84rI</recordid><startdate>201006</startdate><enddate>201006</enddate><creator>Wagner, Janice D</creator><creator>Shadoan, Melanie K</creator><creator>Zhang, Li</creator><creator>Ward, Gina M</creator><creator>Royer, Lori J</creator><creator>Kavanagh, Kylie</creator><creator>Francone, Omar L</creator><creator>Auerbach, Bruce J</creator><creator>Harwood, Jr, H James</creator><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></search><sort><creationdate>201006</creationdate><title>A selective peroxisome proliferator-activated receptor alpha agonist, CP-900691, improves plasma lipids, lipoproteins, and glycemic control in diabetic monkeys</title><author>Wagner, Janice D ; Shadoan, Melanie K ; Zhang, Li ; Ward, Gina M ; Royer, Lori J ; Kavanagh, Kylie ; Francone, Omar L ; Auerbach, Bruce J ; Harwood, Jr, H James</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c296t-e4afe69aab8913656eb267a42fce6ad26ecf095054833e75c5e1454922343c863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adiponectin - blood</topic><topic>Animals</topic><topic>Area Under Curve</topic><topic>Blood Glucose - metabolism</topic><topic>C-Reactive Protein - metabolism</topic><topic>Diabetes Mellitus, Type 2 - blood</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Dose-Response Relationship, Drug</topic><topic>Glucose Tolerance Test</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Hypolipidemic Agents</topic><topic>Insulin Resistance</topic><topic>Lipids - blood</topic><topic>Lipoproteins - blood</topic><topic>Macaca fascicularis</topic><topic>Piperidines - pharmacology</topic><topic>PPAR alpha - agonists</topic><topic>Propionates - pharmacology</topic><topic>Weight Loss - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wagner, Janice D</creatorcontrib><creatorcontrib>Shadoan, Melanie K</creatorcontrib><creatorcontrib>Zhang, Li</creatorcontrib><creatorcontrib>Ward, Gina M</creatorcontrib><creatorcontrib>Royer, Lori J</creatorcontrib><creatorcontrib>Kavanagh, Kylie</creatorcontrib><creatorcontrib>Francone, Omar L</creatorcontrib><creatorcontrib>Auerbach, Bruce J</creatorcontrib><creatorcontrib>Harwood, Jr, H James</creatorcontrib><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><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wagner, Janice D</au><au>Shadoan, Melanie K</au><au>Zhang, Li</au><au>Ward, Gina M</au><au>Royer, Lori J</au><au>Kavanagh, Kylie</au><au>Francone, Omar L</au><au>Auerbach, Bruce J</au><au>Harwood, Jr, H James</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A selective peroxisome proliferator-activated receptor alpha agonist, CP-900691, improves plasma lipids, lipoproteins, and glycemic control in diabetic monkeys</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>2010-06</date><risdate>2010</risdate><volume>333</volume><issue>3</issue><spage>844</spage><epage>853</epage><pages>844-853</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><abstract><![CDATA[Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.]]></abstract><cop>United States</cop><pmid>20190014</pmid><doi>10.1124/jpet.110.166736</doi><tpages>10</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0022-3565 |
ispartof | The Journal of pharmacology and experimental therapeutics, 2010-06, Vol.333 (3), p.844-853 |
issn | 0022-3565 1521-0103 |
language | eng |
recordid | cdi_proquest_miscellaneous_733279802 |
source | MEDLINE; Alma/SFX Local Collection |
subjects | Adiponectin - blood Animals Area Under Curve Blood Glucose - metabolism C-Reactive Protein - metabolism Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - genetics Dose-Response Relationship, Drug Glucose Tolerance Test Hypoglycemic Agents - pharmacology Hypolipidemic Agents Insulin Resistance Lipids - blood Lipoproteins - blood Macaca fascicularis Piperidines - pharmacology PPAR alpha - agonists Propionates - pharmacology Weight Loss - drug effects |
title | A selective peroxisome proliferator-activated receptor alpha agonist, CP-900691, improves plasma lipids, lipoproteins, and glycemic control in diabetic monkeys |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T04%3A08%3A01IST&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=A%20selective%20peroxisome%20proliferator-activated%20receptor%20alpha%20agonist,%20CP-900691,%20improves%20plasma%20lipids,%20lipoproteins,%20and%20glycemic%20control%20in%20diabetic%20monkeys&rft.jtitle=The%20Journal%20of%20pharmacology%20and%20experimental%20therapeutics&rft.au=Wagner,%20Janice%20D&rft.date=2010-06&rft.volume=333&rft.issue=3&rft.spage=844&rft.epage=853&rft.pages=844-853&rft.issn=0022-3565&rft.eissn=1521-0103&rft_id=info:doi/10.1124/jpet.110.166736&rft_dat=%3Cproquest_cross%3E733279802%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=733279802&rft_id=info:pmid/20190014&rfr_iscdi=true |