ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease.
Identifieur interne : 001399 ( PubMed/Corpus ); précédent : 001398; suivant : 001400ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease.
Auteurs : O. Rascol ; O. Blin ; C. Thalamas ; S. Descombes ; C. Soubrouillard ; P. Azulay ; N. Fabre ; F. Viallet ; K. Lafnitzegger ; S. Wright ; J H Carter ; J G NuttSource :
- Annals of neurology [ 0364-5134 ] ; 1999.
English descriptors
- KwdEn :
- Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Parkinson Disease (drug therapy), Prodrugs (adverse effects), Prodrugs (pharmacology), Prodrugs (therapeutic use), Pyridines (adverse effects), Pyridines (pharmacology), Pyridines (therapeutic use), Tetrahydronaphthalenes (adverse effects), Tetrahydronaphthalenes (pharmacology), Tetrahydronaphthalenes (therapeutic use).
- MESH :
- chemical , adverse effects : Prodrugs, Pyridines, Tetrahydronaphthalenes.
- drug therapy : Parkinson Disease.
- chemical , pharmacology : Prodrugs, Pyridines, Tetrahydronaphthalenes.
- chemical , therapeutic use : Prodrugs, Pyridines, Tetrahydronaphthalenes.
- Aged, Double-Blind Method, Female, Humans, Male, Middle Aged.
Abstract
Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.
PubMed: 10360765
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Soubrouillard</name></author><author><name sortKey="Azulay, P" sort="Azulay, P" uniqKey="Azulay P" first="P" last="Azulay">P. Azulay</name></author><author><name sortKey="Fabre, N" sort="Fabre, N" uniqKey="Fabre N" first="N" last="Fabre">N. Fabre</name></author><author><name sortKey="Viallet, F" sort="Viallet, F" uniqKey="Viallet F" first="F" last="Viallet">F. Viallet</name></author><author><name sortKey="Lafnitzegger, K" sort="Lafnitzegger, K" uniqKey="Lafnitzegger K" first="K" last="Lafnitzegger">K. Lafnitzegger</name></author><author><name sortKey="Wright, S" sort="Wright, S" uniqKey="Wright S" first="S" last="Wright">S. Wright</name></author><author><name sortKey="Carter, J H" sort="Carter, J H" uniqKey="Carter J" first="J H" last="Carter">J H Carter</name></author><author><name sortKey="Nutt, J G" sort="Nutt, J G" uniqKey="Nutt J" first="J G" last="Nutt">J G Nutt</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="1999">1999</date><idno type="RBID">pubmed:10360765</idno><idno type="pmid">10360765</idno><idno type="wicri:Area/PubMed/Corpus">001399</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001399</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease.</title><author><name sortKey="Rascol, O" sort="Rascol, O" uniqKey="Rascol O" first="O" last="Rascol">O. Rascol</name><affiliation><nlm:affiliation>Clinical Investigation Centre, Department of Pharmacology, INSERM U455, University Hospital, Toulouse, France.</nlm:affiliation></affiliation></author><author><name sortKey="Blin, O" sort="Blin, O" uniqKey="Blin O" first="O" last="Blin">O. Blin</name></author><author><name sortKey="Thalamas, C" sort="Thalamas, C" uniqKey="Thalamas C" first="C" last="Thalamas">C. Thalamas</name></author><author><name sortKey="Descombes, S" sort="Descombes, S" uniqKey="Descombes S" first="S" last="Descombes">S. Descombes</name></author><author><name sortKey="Soubrouillard, C" sort="Soubrouillard, C" uniqKey="Soubrouillard C" first="C" last="Soubrouillard">C. Soubrouillard</name></author><author><name sortKey="Azulay, P" sort="Azulay, P" uniqKey="Azulay P" first="P" last="Azulay">P. Azulay</name></author><author><name sortKey="Fabre, N" sort="Fabre, N" uniqKey="Fabre N" first="N" last="Fabre">N. Fabre</name></author><author><name sortKey="Viallet, F" sort="Viallet, F" uniqKey="Viallet F" first="F" last="Viallet">F. Viallet</name></author><author><name sortKey="Lafnitzegger, K" sort="Lafnitzegger, K" uniqKey="Lafnitzegger K" first="K" last="Lafnitzegger">K. Lafnitzegger</name></author><author><name sortKey="Wright, S" sort="Wright, S" uniqKey="Wright S" first="S" last="Wright">S. Wright</name></author><author><name sortKey="Carter, J H" sort="Carter, J H" uniqKey="Carter J" first="J H" last="Carter">J H Carter</name></author><author><name sortKey="Nutt, J G" sort="Nutt, J G" uniqKey="Nutt J" first="J G" last="Nutt">J G Nutt</name></author></analytic><series><title level="j">Annals of neurology</title><idno type="ISSN">0364-5134</idno><imprint><date when="1999" type="published">1999</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term><term>Double-Blind Method</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Parkinson Disease (drug therapy)</term><term>Prodrugs (adverse effects)</term><term>Prodrugs (pharmacology)</term><term>Prodrugs (therapeutic use)</term><term>Pyridines (adverse effects)</term><term>Pyridines (pharmacology)</term><term>Pyridines (therapeutic use)</term><term>Tetrahydronaphthalenes (adverse effects)</term><term>Tetrahydronaphthalenes (pharmacology)</term><term>Tetrahydronaphthalenes (therapeutic use)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Prodrugs</term><term>Pyridines</term><term>Tetrahydronaphthalenes</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Prodrugs</term><term>Pyridines</term><term>Tetrahydronaphthalenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Prodrugs</term><term>Pyridines</term><term>Tetrahydronaphthalenes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Double-Blind Method</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">10360765</PMID><DateCreated><Year>1999</Year><Month>06</Month><Day>24</Day></DateCreated><DateCompleted><Year>1999</Year><Month>06</Month><Day>24</Day></DateCompleted><DateRevised><Year>2012</Year><Month>11</Month><Day>15</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0364-5134</ISSN><JournalIssue CitedMedium="Print"><Volume>45</Volume><Issue>6</Issue><PubDate><Year>1999</Year><Month>Jun</Month></PubDate></JournalIssue><Title>Annals of neurology</Title><ISOAbbreviation>Ann. Neurol.</ISOAbbreviation></Journal><ArticleTitle>ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>736-41</MedlinePgn></Pagination><Abstract><AbstractText>Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rascol</LastName><ForeName>O</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Clinical Investigation Centre, Department of Pharmacology, INSERM U455, University Hospital, Toulouse, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blin</LastName><ForeName>O</ForeName><Initials>O</Initials></Author><Author ValidYN="Y"><LastName>Thalamas</LastName><ForeName>C</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Descombes</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Soubrouillard</LastName><ForeName>C</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Azulay</LastName><ForeName>P</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Fabre</LastName><ForeName>N</ForeName><Initials>N</Initials></Author><Author ValidYN="Y"><LastName>Viallet</LastName><ForeName>F</ForeName><Initials>F</Initials></Author><Author ValidYN="Y"><LastName>Lafnitzegger</LastName><ForeName>K</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Wright</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Carter</LastName><ForeName>J H</ForeName><Initials>JH</Initials></Author><Author ValidYN="Y"><LastName>Nutt</LastName><ForeName>J G</ForeName><Initials>JG</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016430">Clinical Trial</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016449">Randomized Controlled 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MajorTopicYN="N">Pyridines</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013764" MajorTopicYN="N">Tetrahydronaphthalenes</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>1999</Year><Month>6</Month><Day>9</Day></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>1999</Year><Month>6</Month><Day>9</Day><Hour>0</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate 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