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 : 001173 ( Main/Exploration ); précédent : 001172; suivant : 001174Translation 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 [Canada] ; Jonathan M. Brotchie [Canada]Source :
- Movement Disorders [ 0885-3185 ] ; 2006-10.
English descriptors
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. © 2006 Movement Disorder Society
Url:
DOI: 10.1002/mds.20936
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><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>
</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">ISTEX</idno>
<idno type="RBID">ISTEX:0A0D942659CE14DBCB4EC170F0658094A6EB097E</idno>
<date when="2006" year="2006">2006</date>
<idno type="doi">10.1002/mds.20936</idno>
<idno type="url">https://api.istex.fr/document/0A0D942659CE14DBCB4EC170F0658094A6EB097E/fulltext/pdf</idno>
<idno type="wicri:Area/Main/Corpus">001103</idno>
<idno type="wicri:Area/Main/Curation">000F10</idno>
<idno type="wicri:Area/Main/Exploration">001173</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title level="a" type="main" 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"><country xml:lang="fr">Canada</country>
<wicri:regionArea>Movement Disorders Clinic, Toronto Western Hospital, 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>
<affiliation wicri:level="1"><country xml:lang="fr">Canada</country>
<wicri:regionArea>Movement Disorders Clinic, Toronto Western Hospital, Ontario</wicri:regionArea>
<wicri:noRegion>Ontario</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><country xml:lang="fr">Canada</country>
<wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, Ontario</wicri:regionArea>
<wicri:noRegion>Ontario</wicri:noRegion>
</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 wicri:level="1"><country xml:lang="fr">Canada</country>
<wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, Ontario</wicri:regionArea>
<wicri:noRegion>Ontario</wicri:noRegion>
</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>Wiley Subscription Services, Inc., A Wiley Company</publisher>
<pubPlace>Hoboken</pubPlace>
<date type="published" when="2006-10">2006-10</date>
<biblScope unit="volume">21</biblScope>
<biblScope unit="issue">10</biblScope>
<biblScope unit="page" from="1578">1578</biblScope>
<biblScope unit="page" to="1594">1594</biblScope>
</imprint>
<idno type="ISSN">0885-3185</idno>
</series>
<idno type="istex">0A0D942659CE14DBCB4EC170F0658094A6EB097E</idno>
<idno type="DOI">10.1002/mds.20936</idno>
<idno type="ArticleID">MDS20936</idno>
</biblStruct>
</sourceDesc>
<seriesStmt><idno type="ISSN">0885-3185</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease</term>
<term>animal models</term>
<term>basal ganglia</term>
<term>pharmacology</term>
</keywords>
</textClass>
<langUsage><language ident="en">en</language>
</langUsage>
</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. © 2006 Movement Disorder Society</div>
</front>
</TEI>
<affiliations><list><country><li>Canada</li>
</country>
</list>
<tree><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>
<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>
<name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001173 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 001173 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= ParkinsonV1 |flux= Main |étape= Exploration |type= RBID |clé= ISTEX:0A0D942659CE14DBCB4EC170F0658094A6EB097E |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 }}
This area was generated with Dilib version V0.6.23. |