Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit.
Identifieur interne : 000787 ( Main/Exploration ); précédent : 000786; suivant : 000788Rotigotine polyoxazoline conjugate SER-214 provides robust and sustained antiparkinsonian benefit.
Auteurs : Karen L. Eskow Jaunarajs [États-Unis] ; 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 : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Antiparkinson Agents (administration & dosage), Antiparkinson Agents (pharmacokinetics), Antiparkinson Agents (therapeutic use), Disease Models, Animal, Dopamine Agonists (administration & dosage), Dopamine Agonists (pharmacokinetics), Dopamine Agonists (therapeutic use), Drug Delivery Systems, Female, Male, Motor Activity (drug effects), Parkinsonian Disorders (drug therapy), Rats, Rats, Sprague-Dawley, Tetrahydronaphthalenes (administration & dosage), Tetrahydronaphthalenes (pharmacokinetics), Tetrahydronaphthalenes (therapeutic use), Thiophenes (administration & dosage), Thiophenes (pharmacokinetics), Thiophenes (therapeutic use), Treatment Outcome.
- MESH :
- chemical , administration & dosage : Antiparkinson Agents, Dopamine Agonists, Tetrahydronaphthalenes, Thiophenes.
- chemical , pharmacokinetics : Antiparkinson Agents, Dopamine Agonists, Tetrahydronaphthalenes, Thiophenes.
- chemical , therapeutic use : Antiparkinson Agents, Dopamine Agonists, Tetrahydronaphthalenes, Thiophenes.
- drug effects : Motor Activity.
- drug therapy : Parkinsonian Disorders.
- Animals, Disease Models, Animal, Drug Delivery Systems, Female, Male, Rats, Rats, Sprague-Dawley, Treatment Outcome.
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.
DOI: 10.1002/mds.25625
PubMed: 24014074
Affiliations:
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Bentley</name></author><author><name sortKey="Fang, Zhihao" sort="Fang, Zhihao" uniqKey="Fang Z" first="Zhihao" last="Fang">Zhihao Fang</name></author><author><name sortKey="Dizman, Bekir" sort="Dizman, Bekir" uniqKey="Dizman B" first="Bekir" last="Dizman">Bekir Dizman</name></author><author><name sortKey="Yoon, Kunsang" sort="Yoon, Kunsang" uniqKey="Yoon K" first="Kunsang" last="Yoon">Kunsang Yoon</name></author><author><name sortKey="Weimer, Rebecca" sort="Weimer, Rebecca" uniqKey="Weimer R" first="Rebecca" last="Weimer">Rebecca Weimer</name></author><author><name sortKey="Ravenscroft, Paula" sort="Ravenscroft, Paula" uniqKey="Ravenscroft P" first="Paula" last="Ravenscroft">Paula Ravenscroft</name></author><author><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H" last="Johnston">Tom H. Johnston</name></author><author><name sortKey="Hill, Michael P" sort="Hill, Michael P" uniqKey="Hill M" first="Michael P" last="Hill">Michael P. Hill</name></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name></author><author><name sortKey="Moreadith, Randall W" sort="Moreadith, Randall W" uniqKey="Moreadith R" first="Randall W" last="Moreadith">Randall W. Moreadith</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiparkinson Agents (administration & dosage)</term><term>Antiparkinson Agents (pharmacokinetics)</term><term>Antiparkinson Agents (therapeutic use)</term><term>Disease Models, Animal</term><term>Dopamine Agonists (administration & dosage)</term><term>Dopamine Agonists (pharmacokinetics)</term><term>Dopamine Agonists (therapeutic use)</term><term>Drug Delivery Systems</term><term>Female</term><term>Male</term><term>Motor Activity (drug effects)</term><term>Parkinsonian Disorders (drug therapy)</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Tetrahydronaphthalenes (administration & dosage)</term><term>Tetrahydronaphthalenes (pharmacokinetics)</term><term>Tetrahydronaphthalenes (therapeutic use)</term><term>Thiophenes (administration & dosage)</term><term>Thiophenes (pharmacokinetics)</term><term>Thiophenes (therapeutic use)</term><term>Treatment Outcome</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antiparkinson Agents</term><term>Dopamine Agonists</term><term>Tetrahydronaphthalenes</term><term>Thiophenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Antiparkinson Agents</term><term>Dopamine Agonists</term><term>Tetrahydronaphthalenes</term><term>Thiophenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiparkinson Agents</term><term>Dopamine Agonists</term><term>Tetrahydronaphthalenes</term><term>Thiophenes</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Motor Activity</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinsonian Disorders</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Drug Delivery Systems</term><term>Female</term><term>Male</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Treatment Outcome</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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><affiliations><list><country><li>États-Unis</li></country><region><li>Alabama</li></region></list><tree><noCountry><name sortKey="Bentley, Michael D" sort="Bentley, Michael D" uniqKey="Bentley M" first="Michael D" last="Bentley">Michael D. Bentley</name><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Dizman, Bekir" sort="Dizman, Bekir" uniqKey="Dizman B" first="Bekir" last="Dizman">Bekir Dizman</name><name sortKey="Fang, Zhihao" sort="Fang, Zhihao" uniqKey="Fang Z" first="Zhihao" last="Fang">Zhihao Fang</name><name sortKey="Hill, Michael P" sort="Hill, Michael P" uniqKey="Hill M" first="Michael P" last="Hill">Michael P. Hill</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H" last="Johnston">Tom H. Johnston</name><name sortKey="Moreadith, Randall W" sort="Moreadith, Randall W" uniqKey="Moreadith R" first="Randall W" last="Moreadith">Randall W. Moreadith</name><name sortKey="Ravenscroft, Paula" sort="Ravenscroft, Paula" uniqKey="Ravenscroft P" first="Paula" last="Ravenscroft">Paula Ravenscroft</name><name sortKey="Standaert, David G" sort="Standaert, David G" uniqKey="Standaert D" first="David G" last="Standaert">David G. Standaert</name><name sortKey="Viegas, Tacey X" sort="Viegas, Tacey X" uniqKey="Viegas T" first="Tacey X" last="Viegas">Tacey X. Viegas</name><name sortKey="Weimer, Rebecca" sort="Weimer, Rebecca" uniqKey="Weimer R" first="Rebecca" last="Weimer">Rebecca Weimer</name><name sortKey="Yoon, Kunsang" sort="Yoon, Kunsang" uniqKey="Yoon K" first="Kunsang" last="Yoon">Kunsang Yoon</name></noCountry><country name="États-Unis"><region name="Alabama"><name sortKey="Eskow Jaunarajs, Karen L" sort="Eskow Jaunarajs, Karen L" uniqKey="Eskow Jaunarajs K" first="Karen L" last="Eskow Jaunarajs">Karen L. Eskow Jaunarajs</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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