Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer
Purpose The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain me...
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| Veröffentlicht in: | Pharmaceutical research 2018-02, Vol.35 (2), p.31-10, Article 31 |
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| creator | Mohammad, Afroz S. Griffith, Jessica I. Adkins, Chris E. Shah, Neal Sechrest, Emily Dolan, Emma L. Terrell-Hall, Tori B. Hendriks, Bart S. Lee, Helen Lockman, Paul R. |
| description | Purpose
The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect.
Methods
Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated.
Results
Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p |
| doi_str_mv | 10.1007/s11095-017-2278-0 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5884086</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A724212630</galeid><sourcerecordid>A724212630</sourcerecordid><originalsourceid>FETCH-LOGICAL-c537t-29acf8f50b77c838f8977c3a8d2566055d076bf1941bdf2fe9241ccfb2dfbd123</originalsourceid><addsrcrecordid>eNp1Ul1rFDEUHUSxtfoDfJGALxU6Ncl8JPNS2F2qFrYquIJvIZu52abMJGsys-jf85d5h639ECUPCfeee869NyfLXjJ6yigVbxNjtKlyykTOuZA5fZQdskoUeUPLb4-zQyp4mUtRsoPsWUrXlFLJmvJpdsCbopZcNofZr6XbhhR63ZGL6HwYwGhPZsaM_djpARJxnlzCoNOgB2fIEpILPp2QRQwpYXq4AjLvQmjz1diHSOY6RgeRHM9X8zcnRPuWfI6hC36TyJcx7twOpZATVc5_bCG6HvyAocvQQkeCJfOo7yQnBYytott2QD7CBpvYoWAEzJKF9gbi8-yJ1V2CFzf3Ufb13flq8SFffnp_sZgtc1MVYsh5o42VtqJrIYwspJUNPgotW17VNa2qlop6bXFBbN1abqHhJTPGrnlr1y3jxVF2tufdjuseWoN9R92pLY6g408VtFMPM95dqU3YqUrKksoaCY5vCGL4PkIaVO-Sga7THsKYFGsaxmQtqhKhr_-CXocxehxvQhVlUZaC3qE2ugPlvA2oayZSNcOv54zXxYQ6_QcKTwu9M8GDdRh_UMD2BWb64wj2dkZG1WQ8tTeeQuOpyXhqqnl1fzm3FX-chgC-ByRM-Q3EexP9l_U39UvlYw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1993434470</pqid></control><display><type>article</type><title>Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer</title><source>Springer Nature - Complete Springer Journals</source><creator>Mohammad, Afroz S. ; Griffith, Jessica I. ; Adkins, Chris E. ; Shah, Neal ; Sechrest, Emily ; Dolan, Emma L. ; Terrell-Hall, Tori B. ; Hendriks, Bart S. ; Lee, Helen ; Lockman, Paul R.</creator><creatorcontrib>Mohammad, Afroz S. ; Griffith, Jessica I. ; Adkins, Chris E. ; Shah, Neal ; Sechrest, Emily ; Dolan, Emma L. ; Terrell-Hall, Tori B. ; Hendriks, Bart S. ; Lee, Helen ; Lockman, Paul R.</creatorcontrib><description>Purpose
The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect.
Methods
Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated.
Results
Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle.
Conclusions
Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-017-2278-0</identifier><identifier>PMID: 29368289</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Biochemistry ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Blood ; Brain ; Brain cancer ; Breast cancer ; Central nervous system ; Controlled release ; Exposure ; Irinotecan ; Lesions ; Medical Law ; Metabolites ; Metastases ; Metastasis ; Permeability ; Pharmacology/Toxicology ; Pharmacy ; Research Paper ; Sustained release ; Toxicity ; Tumors</subject><ispartof>Pharmaceutical research, 2018-02, Vol.35 (2), p.31-10, Article 31</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2018</rights><rights>COPYRIGHT 2018 Springer</rights><rights>Pharmaceutical Research is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-29acf8f50b77c838f8977c3a8d2566055d076bf1941bdf2fe9241ccfb2dfbd123</citedby><cites>FETCH-LOGICAL-c537t-29acf8f50b77c838f8977c3a8d2566055d076bf1941bdf2fe9241ccfb2dfbd123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11095-017-2278-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11095-017-2278-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29368289$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mohammad, Afroz S.</creatorcontrib><creatorcontrib>Griffith, Jessica I.</creatorcontrib><creatorcontrib>Adkins, Chris E.</creatorcontrib><creatorcontrib>Shah, Neal</creatorcontrib><creatorcontrib>Sechrest, Emily</creatorcontrib><creatorcontrib>Dolan, Emma L.</creatorcontrib><creatorcontrib>Terrell-Hall, Tori B.</creatorcontrib><creatorcontrib>Hendriks, Bart S.</creatorcontrib><creatorcontrib>Lee, Helen</creatorcontrib><creatorcontrib>Lockman, Paul R.</creatorcontrib><title>Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>Purpose
The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect.
Methods
Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated.
Results
Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle.
Conclusions
Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.</description><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Blood</subject><subject>Brain</subject><subject>Brain cancer</subject><subject>Breast cancer</subject><subject>Central nervous system</subject><subject>Controlled release</subject><subject>Exposure</subject><subject>Irinotecan</subject><subject>Lesions</subject><subject>Medical Law</subject><subject>Metabolites</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Permeability</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Research Paper</subject><subject>Sustained release</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><recordid>eNp1Ul1rFDEUHUSxtfoDfJGALxU6Ncl8JPNS2F2qFrYquIJvIZu52abMJGsys-jf85d5h639ECUPCfeee869NyfLXjJ6yigVbxNjtKlyykTOuZA5fZQdskoUeUPLb4-zQyp4mUtRsoPsWUrXlFLJmvJpdsCbopZcNofZr6XbhhR63ZGL6HwYwGhPZsaM_djpARJxnlzCoNOgB2fIEpILPp2QRQwpYXq4AjLvQmjz1diHSOY6RgeRHM9X8zcnRPuWfI6hC36TyJcx7twOpZATVc5_bCG6HvyAocvQQkeCJfOo7yQnBYytott2QD7CBpvYoWAEzJKF9gbi8-yJ1V2CFzf3Ufb13flq8SFffnp_sZgtc1MVYsh5o42VtqJrIYwspJUNPgotW17VNa2qlop6bXFBbN1abqHhJTPGrnlr1y3jxVF2tufdjuseWoN9R92pLY6g408VtFMPM95dqU3YqUrKksoaCY5vCGL4PkIaVO-Sga7THsKYFGsaxmQtqhKhr_-CXocxehxvQhVlUZaC3qE2ugPlvA2oayZSNcOv54zXxYQ6_QcKTwu9M8GDdRh_UMD2BWb64wj2dkZG1WQ8tTeeQuOpyXhqqnl1fzm3FX-chgC-ByRM-Q3EexP9l_U39UvlYw</recordid><startdate>20180201</startdate><enddate>20180201</enddate><creator>Mohammad, Afroz S.</creator><creator>Griffith, Jessica I.</creator><creator>Adkins, Chris E.</creator><creator>Shah, Neal</creator><creator>Sechrest, Emily</creator><creator>Dolan, Emma L.</creator><creator>Terrell-Hall, Tori B.</creator><creator>Hendriks, Bart S.</creator><creator>Lee, Helen</creator><creator>Lockman, Paul R.</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180201</creationdate><title>Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer</title><author>Mohammad, Afroz S. ; Griffith, Jessica I. ; Adkins, Chris E. ; Shah, Neal ; Sechrest, Emily ; Dolan, Emma L. ; Terrell-Hall, Tori B. ; Hendriks, Bart S. ; Lee, Helen ; Lockman, Paul R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-29acf8f50b77c838f8977c3a8d2566055d076bf1941bdf2fe9241ccfb2dfbd123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Blood</topic><topic>Brain</topic><topic>Brain cancer</topic><topic>Breast cancer</topic><topic>Central nervous system</topic><topic>Controlled release</topic><topic>Exposure</topic><topic>Irinotecan</topic><topic>Lesions</topic><topic>Medical Law</topic><topic>Metabolites</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Permeability</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Research Paper</topic><topic>Sustained release</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mohammad, Afroz S.</creatorcontrib><creatorcontrib>Griffith, Jessica I.</creatorcontrib><creatorcontrib>Adkins, Chris E.</creatorcontrib><creatorcontrib>Shah, Neal</creatorcontrib><creatorcontrib>Sechrest, Emily</creatorcontrib><creatorcontrib>Dolan, Emma L.</creatorcontrib><creatorcontrib>Terrell-Hall, Tori B.</creatorcontrib><creatorcontrib>Hendriks, Bart S.</creatorcontrib><creatorcontrib>Lee, Helen</creatorcontrib><creatorcontrib>Lockman, Paul R.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Neurosciences Abstracts</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>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mohammad, Afroz S.</au><au>Griffith, Jessica I.</au><au>Adkins, Chris E.</au><au>Shah, Neal</au><au>Sechrest, Emily</au><au>Dolan, Emma L.</au><au>Terrell-Hall, Tori B.</au><au>Hendriks, Bart S.</au><au>Lee, Helen</au><au>Lockman, Paul R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2018-02-01</date><risdate>2018</risdate><volume>35</volume><issue>2</issue><spage>31</spage><epage>10</epage><pages>31-10</pages><artnum>31</artnum><issn>0724-8741</issn><eissn>1573-904X</eissn><abstract>Purpose
The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect.
Methods
Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated.
Results
Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle.
Conclusions
Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>29368289</pmid><doi>10.1007/s11095-017-2278-0</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | Springer Nature - Complete Springer Journals |
| subjects | Biochemistry Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Blood Brain Brain cancer Breast cancer Central nervous system Controlled release Exposure Irinotecan Lesions Medical Law Metabolites Metastases Metastasis Permeability Pharmacology/Toxicology Pharmacy Research Paper Sustained release Toxicity Tumors |
| title | Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer |
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