Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.
Identifieur interne : 001795 ( Ncbi/Merge ); précédent : 001794; suivant : 001796Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.
Auteurs : Susan H. Fox [Canada] ; Anthony E. Lang ; Jonathan M. BrotchieSource :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2006.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents (adverse effects), Antiparkinson Agents (therapeutic use), Basal Ganglia (drug effects), Clinical Trials, Phase II as Topic, Drug Evaluation, Preclinical, Drugs, Investigational (therapeutic use), Dyskinesia, Drug-Induced (drug therapy), Haplorhini, Humans, Treatment Failure.
- MESH :
- chemical , adverse effects : Antiparkinson Agents.
- chemical , therapeutic use : Antiparkinson Agents, Drugs, Investigational.
- chemical : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
- drug effects : Basal Ganglia.
- drug therapy : Dyskinesia, Drug-Induced.
- Animals, Clinical Trials, Phase II as Topic, Drug Evaluation, Preclinical, Haplorhini, Humans, Treatment Failure.
Abstract
Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.
DOI: 10.1002/mds.20936
PubMed: 16874752
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 002B43
- to stream PubMed, to step Curation: 002B43
- to stream PubMed, to step Checkpoint: 002A50
Links to Exploration step
pubmed:16874752Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.</title>
<author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name>
<affiliation wicri:level="1"><nlm:affiliation>Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario</wicri:regionArea>
<wicri:noRegion>Ontario</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</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>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2006">2006</date>
<idno type="doi">10.1002/mds.20936</idno>
<idno type="RBID">pubmed:16874752</idno>
<idno type="pmid">16874752</idno>
<idno type="wicri:Area/PubMed/Corpus">002B43</idno>
<idno type="wicri:Area/PubMed/Curation">002B43</idno>
<idno type="wicri:Area/PubMed/Checkpoint">002A50</idno>
<idno type="wicri:Area/Ncbi/Merge">001795</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.</title>
<author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name>
<affiliation wicri:level="1"><nlm:affiliation>Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario</wicri:regionArea>
<wicri:noRegion>Ontario</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</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>
</analytic>
<series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title>
<idno type="ISSN">0885-3185</idno>
<imprint><date when="2006" type="published">2006</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term>
<term>Animals</term>
<term>Antiparkinson Agents (adverse effects)</term>
<term>Antiparkinson Agents (therapeutic use)</term>
<term>Basal Ganglia (drug effects)</term>
<term>Clinical Trials, Phase II as Topic</term>
<term>Drug Evaluation, Preclinical</term>
<term>Drugs, Investigational (therapeutic use)</term>
<term>Dyskinesia, Drug-Induced (drug therapy)</term>
<term>Haplorhini</term>
<term>Humans</term>
<term>Treatment Failure</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Antiparkinson Agents</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiparkinson Agents</term>
<term>Drugs, Investigational</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Basal Ganglia</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesia, Drug-Induced</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Clinical Trials, Phase II as Topic</term>
<term>Drug Evaluation, Preclinical</term>
<term>Haplorhini</term>
<term>Humans</term>
<term>Treatment Failure</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.</div>
</front>
</TEI>
<pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">16874752</PMID>
<DateCreated><Year>2006</Year>
<Month>10</Month>
<Day>26</Day>
</DateCreated>
<DateCompleted><Year>2007</Year>
<Month>02</Month>
<Day>02</Day>
</DateCompleted>
<DateRevised><Year>2013</Year>
<Month>11</Month>
<Day>21</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Print">0885-3185</ISSN>
<JournalIssue CitedMedium="Print"><Volume>21</Volume>
<Issue>10</Issue>
<PubDate><Year>2006</Year>
<Month>Oct</Month>
</PubDate>
</JournalIssue>
<Title>Movement disorders : official journal of the Movement Disorder Society</Title>
<ISOAbbreviation>Mov. Disord.</ISOAbbreviation>
</Journal>
<ArticleTitle>Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.</ArticleTitle>
<Pagination><MedlinePgn>1578-94</MedlinePgn>
</Pagination>
<Abstract><AbstractText>Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Fox</LastName>
<ForeName>Susan H</ForeName>
<Initials>SH</Initials>
<AffiliationInfo><Affiliation>Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lang</LastName>
<ForeName>Anthony E</ForeName>
<Initials>AE</Initials>
</Author>
<Author ValidYN="Y"><LastName>Brotchie</LastName>
<ForeName>Jonathan M</ForeName>
<Initials>JM</Initials>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
<PublicationType UI="D016454">Review</PublicationType>
</PublicationTypeList>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Mov Disord</MedlineTA>
<NlmUniqueID>8610688</NlmUniqueID>
<ISSNLinking>0885-3185</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000978">Antiparkinson Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D015507">Drugs, Investigational</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>9P21XSP91P</RegistryNumber>
<NameOfSubstance UI="D015632">1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N" UI="D015632">1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D000818">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D000978">Antiparkinson Agents</DescriptorName>
<QualifierName MajorTopicYN="Y" UI="Q000009">adverse effects</QualifierName>
<QualifierName MajorTopicYN="N" UI="Q000627">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D001479">Basal Ganglia</DescriptorName>
<QualifierName MajorTopicYN="N" UI="Q000187">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="Y" UI="D017322">Clinical Trials, Phase II as Topic</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="Y" UI="D004353">Drug Evaluation, Preclinical</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D015507">Drugs, Investigational</DescriptorName>
<QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D004409">Dyskinesia, Drug-Induced</DescriptorName>
<QualifierName MajorTopicYN="Y" UI="Q000188">drug therapy</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D000882">Haplorhini</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D006801">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D017211">Treatment Failure</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<NumberOfReferences>152</NumberOfReferences>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year>
<Month>7</Month>
<Day>29</Day>
<Hour>9</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2007</Year>
<Month>2</Month>
<Day>3</Day>
<Hour>9</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2006</Year>
<Month>7</Month>
<Day>29</Day>
<Hour>9</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="doi">10.1002/mds.20936</ArticleId>
<ArticleId IdType="pubmed">16874752</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>Canada</li>
</country>
</list>
<tree><noCountry><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name>
<name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name>
</noCountry>
<country name="Canada"><noRegion><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Santé/explor/MovDisordV3/Data/Ncbi/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001795 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd -nk 001795 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Santé |area= MovDisordV3 |flux= Ncbi |étape= Merge |type= RBID |clé= pubmed:16874752 |texte= Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/RBID.i -Sk "pubmed:16874752" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd \ | NlmPubMed2Wicri -a MovDisordV3
![]() | This area was generated with Dilib version V0.6.23. | ![]() |