Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit
Identifieur interne : 000604 ( Istex/Corpus ); précédent : 000603; suivant : 000605Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit
Auteurs : Karen L. Eskow Jaunarajs ; David G. Standaert ; Tacey X. Viegas ; Michael D. Bentley ; Zhihao Fang ; Bekir Dizman ; Kunsang Yoon ; Rebecca Weimer ; Paula Ravenscroft ; Tom H. Johnston ; Michael P. Hill ; Jonathan M. Brotchie ; Randall W. MoreadithSource :
- Movement Disorders [ 0885-3185 ] ; 2013-10.
Abstract
Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.
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DOI: 10.1002/mds.25625
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ISTEX:4F7894514D755826E1536555A418DCCAF9D2765ELe document en format XML
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Johnston</name><affiliation><mods:affiliation>Atuka Ltd., Ontario, Toronto, Canada</mods:affiliation></affiliation></author><author><name sortKey="Hill, Michael P" sort="Hill, Michael P" uniqKey="Hill M" first="Michael P." last="Hill">Michael P. Hill</name><affiliation><mods:affiliation>Atuka Ltd., Ontario, Toronto, Canada</mods:affiliation></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><affiliation><mods:affiliation>Atuka Ltd., Ontario, Toronto, Canada</mods:affiliation></affiliation></author><author><name sortKey="Moreadith, Randall W" sort="Moreadith, Randall W" uniqKey="Moreadith R" first="Randall W." last="Moreadith">Randall W. Moreadith</name><affiliation><mods:affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2013-10">2013-10</date><biblScope unit="volume">28</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1675">1675</biblScope><biblScope unit="page" to="1682">1682</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">4F7894514D755826E1536555A418DCCAF9D2765E</idno><idno type="DOI">10.1002/mds.25625</idno><idno type="ArticleID">MDS25625</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Karen L. Eskow Jaunarajs PhD</name><affiliations><json:string>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama‐Birmingham, Alabama, Birmingham, USA</json:string></affiliations></json:item><json:item><name>David G. Standaert MD, PhD</name><affiliations><json:string>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama‐Birmingham, Alabama, Birmingham, USA</json:string><json:string>E-mail: dstandaert@uab.edu</json:string></affiliations></json:item><json:item><name>Tacey X. Viegas PhD</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item><json:item><name>Michael D. Bentley PhD</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item><json:item><name>Zhihao Fang MS</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item><json:item><name>Bekir Dizman PhD</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item><json:item><name>Kunsang Yoon PhD</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item><json:item><name>Rebecca Weimer BS</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item><json:item><name>Paula Ravenscroft PhD</name><affiliations><json:string>Atuka Ltd., Ontario, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Tom H. Johnston PhD</name><affiliations><json:string>Atuka Ltd., Ontario, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Michael P. Hill PhD</name><affiliations><json:string>Atuka Ltd., Ontario, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Jonathan M. Brotchie PhD</name><affiliations><json:string>Atuka Ltd., Ontario, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Randall W. Moreadith MD, PhD</name><affiliations><json:string>Serina Therapeutics, Inc., Alabama, Huntsville, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>rotigotine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>6‐hydroxydopamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>rat</value></json:item></subject><articleId><json:string>MDS25625</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>reviewArticle</json:string></originalGenre><abstract>Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.</abstract><qualityIndicators><score>7.685</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 809.972 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1911</abstractCharCount><pdfWordCount>4685</pdfWordCount><pdfCharCount>30118</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>256</abstractWordCount></qualityIndicators><title>Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit</title><genre><json:string>review-article</json:string></genre><host><title>Movement 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PhD</roleName><email>dstandaert@uab.edu</email><affiliation>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama‐Birmingham, Alabama, Birmingham, USA</affiliation></author><author xml:id="author-3"><persName><forename type="first">Tacey X.</forename><surname>Viegas</surname></persName><roleName type="degree">PhD</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author><author xml:id="author-4"><persName><forename type="first">Michael D.</forename><surname>Bentley</surname></persName><roleName type="degree">PhD</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author><author xml:id="author-5"><persName><forename type="first">Zhihao</forename><surname>Fang</surname></persName><roleName type="degree">MS</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author><author xml:id="author-6"><persName><forename type="first">Bekir</forename><surname>Dizman</surname></persName><roleName type="degree">PhD</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author><author xml:id="author-7"><persName><forename type="first">Kunsang</forename><surname>Yoon</surname></persName><roleName type="degree">PhD</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author><author xml:id="author-8"><persName><forename type="first">Rebecca</forename><surname>Weimer</surname></persName><roleName type="degree">BS</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author><author xml:id="author-9"><persName><forename type="first">Paula</forename><surname>Ravenscroft</surname></persName><roleName type="degree">PhD</roleName><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation></author><author xml:id="author-10"><persName><forename type="first">Tom H.</forename><surname>Johnston</surname></persName><roleName type="degree">PhD</roleName><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation></author><author xml:id="author-11"><persName><forename type="first">Michael P.</forename><surname>Hill</surname></persName><roleName type="degree">PhD</roleName><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation></author><author xml:id="author-12"><persName><forename type="first">Jonathan M.</forename><surname>Brotchie</surname></persName><roleName type="degree">PhD</roleName><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation></author><author xml:id="author-13"><persName><forename type="first">Randall W.</forename><surname>Moreadith</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2013-10"></date><biblScope unit="volume">28</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1675">1675</biblScope><biblScope unit="page" to="1682">1682</biblScope></imprint></monogr><idno type="istex">4F7894514D755826E1536555A418DCCAF9D2765E</idno><idno type="DOI">10.1002/mds.25625</idno><idno type="ArticleID">MDS25625</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2013-08-02</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Parkinson's disease</term></item><item><term>dopamine</term></item><item><term>rotigotine</term></item><item><term>6‐hydroxydopamine</term></item><item><term>rat</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2013-04-02">Received</change><change when="2013-06-14">Registration</change><change when="2013-08-02">Created</change><change when="2013-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/4F7894514D755826E1536555A418DCCAF9D2765E/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en" xml:id="mds25625"><header><publicationMeta level="product"><doi origin="wiley" registered="yes">10.1002/(ISSN)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="short">Mov Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="120"><doi>10.1002/mds.v28.12</doi><copyright ownership="thirdParty">© 2013 Movement Disorder Society</copyright><numberingGroup><numbering type="journalVolume" number="28">28</numbering><numbering type="journalIssue">12</numbering></numberingGroup><coverDate startDate="2013-10">October 2013</coverDate></publicationMeta><publicationMeta level="unit" position="140" type="reviewArticle" status="forIssue" accessType="open"><doi>10.1002/mds.25625</doi><idGroup><id type="unit" value="MDS25625"></id></idGroup><countGroup><count type="pageTotal" number="8"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">© 2013 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2013-04-02"></event><event type="manuscriptRevised" date="2013-05-24"></event><event type="manuscriptAccepted" date="2013-06-14"></event><event type="xmlCreated" agent="Cenveo Publisher Services" date="2013-08-02"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.2.6 mode:FullText" date="2013-10-25"></event><event type="publishedOnlineEarlyUnpaginated" date="2013-09-03"></event><event type="firstOnline" date="2013-09-03"></event><event type="publishedOnlineFinalForm" date="2013-10-25"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.6.4 mode:FullText" date="2015-10-01"></event></eventGroup><numberingGroup><numbering type="pageFirst">1675</numbering><numbering type="pageLast">1682</numbering></numberingGroup><correspondenceTo><b>Correspondence to:</b> Dr. David Standaert, Department of Neurology, University of Alabama at Birmingham, 1719 6th Ave South, CIRC 516, Birmingham, AL 35294‐0021, USA; <email>dstandaert@uab.edu</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS25625.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit</title><title type="short">Continuous Dopaminergic Tone with Poz‐Rotigotine</title><title type="shortAuthors">Eskow Jaunarajs et al.</title></titleGroup><creators><creator creatorRole="author" xml:id="mds25625-cr-0001" affiliationRef="#mds25625-aff-0001"><personName><givenNames>Karen L.</givenNames><familyName>Eskow Jaunarajs</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0002" affiliationRef="#mds25625-aff-0001" corresponding="yes"><personName><givenNames>David G.</givenNames><familyName>Standaert</familyName><degrees>MD, PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0003" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Tacey X.</givenNames><familyName>Viegas</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0004" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Michael D.</givenNames><familyName>Bentley</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0005" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Zhihao</givenNames><familyName>Fang</familyName><degrees>MS</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0006" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Bekir</givenNames><familyName>Dizman</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0007" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Kunsang</givenNames><familyName>Yoon</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0008" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Rebecca</givenNames><familyName>Weimer</familyName><degrees>BS</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0009" affiliationRef="#mds25625-aff-0003"><personName><givenNames>Paula</givenNames><familyName>Ravenscroft</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0010" affiliationRef="#mds25625-aff-0003"><personName><givenNames>Tom H.</givenNames><familyName>Johnston</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0011" affiliationRef="#mds25625-aff-0003"><personName><givenNames>Michael P.</givenNames><familyName>Hill</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0012" affiliationRef="#mds25625-aff-0003"><personName><givenNames>Jonathan M.</givenNames><familyName>Brotchie</familyName><degrees>PhD</degrees></personName></creator><creator creatorRole="author" xml:id="mds25625-cr-0013" affiliationRef="#mds25625-aff-0002"><personName><givenNames>Randall W.</givenNames><familyName>Moreadith</familyName><degrees>MD, PhD</degrees></personName></creator></creators><affiliationGroup><affiliation xml:id="mds25625-aff-0001" countryCode="US" type="organization"><orgDiv>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology</orgDiv><orgName>University of Alabama‐Birmingham</orgName><address><city>Birmingham</city><countryPart>Alabama</countryPart><country>USA</country></address></affiliation><affiliation xml:id="mds25625-aff-0002" countryCode="US" type="organization"><orgName>Serina Therapeutics, Inc.</orgName><address><city>Huntsville</city><countryPart>Alabama</countryPart><country>USA</country></address></affiliation><affiliation xml:id="mds25625-aff-0003" countryCode="CA" type="organization"><orgName>Atuka Ltd.</orgName><address><city>Toronto</city><countryPart>Ontario</countryPart><country>Canada</country></address></affiliation></affiliationGroup><keywordGroup><keyword xml:id="mds25625-kwd-0001">Parkinson's disease</keyword><keyword xml:id="mds25625-kwd-0002">dopamine</keyword><keyword xml:id="mds25625-kwd-0003">rotigotine</keyword><keyword xml:id="mds25625-kwd-0004">6‐hydroxydopamine</keyword><keyword xml:id="mds25625-kwd-0005">rat</keyword></keywordGroup><abstractGroup><abstract type="main"><title type="main">ABSTRACT</title><p>Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐<i>off</i>” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="mds25625-note-0001"><p><b>Relevant Financial disclosures:</b> Serina Therapeutics, Inc. is a privately held pharmaceutical development company located in the Hudson Alpha Institute for Biotechnology in Huntsville, Alabama, USA. The employees of Serina Therapeutics (T.X.V., M.D.B., Z.F., B.D., K.Y., and R.W.M.) have ownership interest in the company. D.G.S. is a consultant for Serina Therapeutics, Inc. and has no stock ownership in the company. P.R., T.H.J., M.J.H., and J.M.B. received payments from and hold equity stakes in Atuka, Inc.</p></note><note xml:id="mds25625-note-0002"><p>Full financial disclosures and author roles may be found in the online version of this article.</p></note><note xml:id="mds25625-note-0009"><p>All financial disclosures are correct.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Continuous Dopaminergic Tone with Poz‐Rotigotine</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit</title></titleInfo><name type="personal"><namePart type="given">Karen L.</namePart><namePart type="family">Eskow Jaunarajs</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama‐Birmingham, Alabama, Birmingham, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David G.</namePart><namePart type="family">Standaert</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama‐Birmingham, Alabama, Birmingham, USA</affiliation><affiliation>E-mail: dstandaert@uab.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tacey X.</namePart><namePart type="family">Viegas</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael D.</namePart><namePart type="family">Bentley</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhihao</namePart><namePart type="family">Fang</namePart><namePart type="termsOfAddress">MS</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bekir</namePart><namePart type="family">Dizman</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kunsang</namePart><namePart type="family">Yoon</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rebecca</namePart><namePart type="family">Weimer</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paula</namePart><namePart type="family">Ravenscroft</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tom H.</namePart><namePart type="family">Johnston</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael P.</namePart><namePart type="family">Hill</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jonathan M.</namePart><namePart type="family">Brotchie</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Atuka Ltd., Ontario, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Randall W.</namePart><namePart type="family">Moreadith</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Serina Therapeutics, Inc., Alabama, Huntsville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="review-article" displayLabel="reviewArticle"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2013-10</dateIssued><dateCreated encoding="w3cdtf">2013-08-02</dateCreated><dateCaptured encoding="w3cdtf">2013-04-02</dateCaptured><dateValid encoding="w3cdtf">2013-06-14</dateValid><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.</abstract><subject><genre>keywords</genre><topic>Parkinson's disease</topic><topic>dopamine</topic><topic>rotigotine</topic><topic>6‐hydroxydopamine</topic><topic>rat</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov Disord.</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0885-3185</identifier><identifier type="eISSN">1531-8257</identifier><identifier type="DOI">10.1002/(ISSN)1531-8257</identifier><identifier type="PublisherID">MDS</identifier><part><date>2013</date><detail type="volume"><caption>vol.</caption><number>28</number></detail><detail type="issue"><caption>no.</caption><number>12</number></detail><extent unit="pages"><start>1675</start><end>1682</end><total>8</total></extent></part></relatedItem><identifier type="istex">4F7894514D755826E1536555A418DCCAF9D2765E</identifier><identifier type="DOI">10.1002/mds.25625</identifier><identifier type="ArticleID">MDS25625</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2013 Movement Disorder Society© 2013 Movement Disorder Society</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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