The Selective Mu-Opioid Receptor Antagonist ADL5510 Reduces Levodopa-Induced Dyskinesia Without Affecting Antiparkinsonian Action in MPTP-Lesioned Macaque Model of Parkinson's Disease
Identifieur interne : 000305 ( PascalFrancis/Corpus ); précédent : 000304; suivant : 000306The Selective Mu-Opioid Receptor Antagonist ADL5510 Reduces Levodopa-Induced Dyskinesia Without Affecting Antiparkinsonian Action in MPTP-Lesioned Macaque Model of Parkinson's Disease
Auteurs : James B. Koprich ; Susan H. Fox ; Tom H. Johnston ; Allan Goodman ; Bertrand Le Bourdonnec ; Roland E. Dolle ; Robert N. Dehaven ; Diane L. Dehaven-Hudkins ; Patrick J. Little ; Jonathan M. BrotchieSource :
- Movement disorders [ 0885-3185 ] ; 2011.
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- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (L-dopa). Given the prominent role of the opioid system in basal ganglia function, non-selective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established L-dopa-induced dyskinesia (LID) received acute challenges with L-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of L-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/ kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by L-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61 % reductions with 1 and 3 mg/kg, respectively, compared with L-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of L-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD.
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| NO : | PASCAL 11-0321195 INIST |
|---|---|
| ET : | The Selective Mu-Opioid Receptor Antagonist ADL5510 Reduces Levodopa-Induced Dyskinesia Without Affecting Antiparkinsonian Action in MPTP-Lesioned Macaque Model of Parkinson's Disease |
| AU : | KOPRICH (James B.); FOX (Susan H.); JOHNSTON (Tom H.); GOODMAN (Allan); LE BOURDONNEC (Bertrand); DOLLE (Roland E.); DEHAVEN (Robert N.); DEHAVEN-HUDKINS (Diane L.); LITTLE (Patrick J.); BROTCHIE (Jonathan M.) |
| AF : | Toronto Western Research Institute, Toronto Western Hospital, University Health Network/Toronto, Ontario/Canada (1 aut., 3 aut., 10 aut.); Atuka Ltd./Toronto, Ontario/Canada (1 aut., 3 aut., 10 aut.); Division of Neurology, University of Toronto and Movement Disorders Clinic, Toronto Western Hospital, University Health Network/Toronto, Ontario/Canada (2 aut.); Adolor Corp./Exton, Pennsylvania/Etats-Unis (4 aut., 5 aut., 6 aut., 7 aut., 8 aut., 9 aut.) |
| DT : | Publication en série; Niveau analytique |
| SO : | Movement disorders; ISSN 0885-3185; Etats-Unis; Da. 2011; Vol. 26; No. 7; Pp. 1225-1233; Bibl. 48 ref. |
| LA : | Anglais |
| EA : | In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (L-dopa). Given the prominent role of the opioid system in basal ganglia function, non-selective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri dine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established L-dopa-induced dyskinesia (LID) received acute challenges with L-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of L-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/ kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by L-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61 % reductions with 1 and 3 mg/kg, respectively, compared with L-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of L-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD. |
| CC : | 002B17; 002B17G |
| FD : | Dyskinésie; Maladie de Parkinson; Pathologie du système nerveux; Récepteur opiacé; Lévodopa; Singe; Modèle; Homme |
| FG : | Primates; Mammalia; Vertebrata; Syndrome extrapyramidal; Mouvement involontaire; Trouble neurologique; Pathologie de l'encéphale; Maladie dégénérative; Pathologie du système nerveux central |
| ED : | Dyskinesia; Parkinson disease; Nervous system diseases; Opioid receptor; Levodopa; Monkey; Models; Human |
| EG : | Primates; Mammalia; Vertebrata; Extrapyramidal syndrome; Involuntary movement; Neurological disorder; Cerebral disorder; Degenerative disease; Central nervous system disease |
| SD : | Disquinesia; Parkinson enfermedad; Sistema nervioso patología; Receptor opiáceo; Levodopa; Mono; Modelo; Hombre |
| LO : | INIST-20953.354000190480410060 |
| ID : | 11-0321195 |
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Brotchie</name><affiliation><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Atuka Ltd.</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0321195</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0321195 INIST</idno><idno type="RBID">Pascal:11-0321195</idno><idno type="wicri:Area/PascalFrancis/Corpus">000305</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">The Selective Mu-Opioid Receptor Antagonist ADL5510 Reduces Levodopa-Induced Dyskinesia Without Affecting Antiparkinsonian Action in MPTP-Lesioned Macaque Model of Parkinson's Disease</title><author><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name><affiliation><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Atuka Ltd.</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><affiliation><inist:fA14 i1="03"><s1>Division of Neurology, University of Toronto and Movement Disorders Clinic, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>2 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><affiliation><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Atuka Ltd.</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Goodman, Allan" sort="Goodman, Allan" uniqKey="Goodman A" first="Allan" last="Goodman">Allan Goodman</name><affiliation><inist:fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Le Bourdonnec, Bertrand" sort="Le Bourdonnec, Bertrand" uniqKey="Le Bourdonnec B" first="Bertrand" last="Le Bourdonnec">Bertrand Le Bourdonnec</name><affiliation><inist:fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Dolle, Roland E" sort="Dolle, Roland E" uniqKey="Dolle R" first="Roland E." last="Dolle">Roland E. Dolle</name><affiliation><inist:fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Dehaven, Robert N" sort="Dehaven, Robert N" uniqKey="Dehaven R" first="Robert N." last="Dehaven">Robert N. Dehaven</name><affiliation><inist:fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Dehaven Hudkins, Diane L" sort="Dehaven Hudkins, Diane L" uniqKey="Dehaven Hudkins D" first="Diane L." last="Dehaven-Hudkins">Diane L. Dehaven-Hudkins</name><affiliation><inist:fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Little, Patrick J" sort="Little, Patrick J" uniqKey="Little P" first="Patrick J." last="Little">Patrick J. Little</name><affiliation><inist:fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></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><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Atuka Ltd.</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14></affiliation></author></analytic><series><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Dyskinesia</term><term>Human</term><term>Levodopa</term><term>Models</term><term>Monkey</term><term>Nervous system diseases</term><term>Opioid receptor</term><term>Parkinson disease</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Dyskinésie</term><term>Maladie de Parkinson</term><term>Pathologie du système nerveux</term><term>Récepteur opiacé</term><term>Lévodopa</term><term>Singe</term><term>Modèle</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (<sub>L</sub>-dopa). Given the prominent role of the opioid system in basal ganglia function, non-selective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established <sub>L</sub>-dopa-induced dyskinesia (LID) received acute challenges with <sub>L</sub>-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of <sub>L</sub>-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/ kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by <sub>L</sub>-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61 % reductions with 1 and 3 mg/kg, respectively, compared with <sub>L</sub>-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of <sub>L</sub>-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0885-3185</s0></fA01><fA03 i2="1"><s0>Mov. disord.</s0></fA03><fA05><s2>26</s2></fA05><fA06><s2>7</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>The Selective Mu-Opioid Receptor Antagonist ADL5510 Reduces Levodopa-Induced Dyskinesia Without Affecting Antiparkinsonian Action in MPTP-Lesioned Macaque Model of Parkinson's Disease</s1></fA08><fA11 i1="01" i2="1"><s1>KOPRICH (James B.)</s1></fA11><fA11 i1="02" i2="1"><s1>FOX (Susan H.)</s1></fA11><fA11 i1="03" i2="1"><s1>JOHNSTON (Tom H.)</s1></fA11><fA11 i1="04" i2="1"><s1>GOODMAN (Allan)</s1></fA11><fA11 i1="05" i2="1"><s1>LE BOURDONNEC (Bertrand)</s1></fA11><fA11 i1="06" i2="1"><s1>DOLLE (Roland E.)</s1></fA11><fA11 i1="07" i2="1"><s1>DEHAVEN (Robert N.)</s1></fA11><fA11 i1="08" i2="1"><s1>DEHAVEN-HUDKINS (Diane L.)</s1></fA11><fA11 i1="09" i2="1"><s1>LITTLE (Patrick J.)</s1></fA11><fA11 i1="10" i2="1"><s1>BROTCHIE (Jonathan M.)</s1></fA11><fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="02"><s1>Atuka Ltd.</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="03"><s1>Division of Neurology, University of Toronto and Movement Disorders Clinic, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>2 aut.</sZ></fA14><fA14 i1="04"><s1>Adolor Corp.</s1><s2>Exton, Pennsylvania</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></fA14><fA20><s1>1225-1233</s1></fA20><fA21><s1>2011</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>20953</s2><s5>354000190480410060</s5></fA43><fA44><s0>0000</s0><s1>© 2011 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>48 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>11-0321195</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Movement disorders</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (<sub>L</sub>-dopa). Given the prominent role of the opioid system in basal ganglia function, non-selective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established <sub>L</sub>-dopa-induced dyskinesia (LID) received acute challenges with <sub>L</sub>-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of <sub>L</sub>-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/ kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by <sub>L</sub>-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61 % reductions with 1 and 3 mg/kg, respectively, compared with <sub>L</sub>-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of <sub>L</sub>-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD.</s0></fC01><fC02 i1="01" i2="X"><s0>002B17</s0></fC02><fC02 i1="02" i2="X"><s0>002B17G</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Dyskinésie</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Dyskinesia</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Disquinesia</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Maladie de Parkinson</s0><s2>NM</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Parkinson disease</s0><s2>NM</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Parkinson enfermedad</s0><s2>NM</s2><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Pathologie du système nerveux</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Nervous system diseases</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Sistema nervioso patología</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Récepteur opiacé</s0><s5>09</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Opioid receptor</s0><s5>09</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Receptor opiáceo</s0><s5>09</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Lévodopa</s0><s2>NK</s2><s2>FR</s2><s5>10</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Levodopa</s0><s2>NK</s2><s2>FR</s2><s5>10</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Levodopa</s0><s2>NK</s2><s2>FR</s2><s5>10</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Singe</s0><s5>11</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Monkey</s0><s5>11</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Mono</s0><s5>11</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Modèle</s0><s5>12</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Models</s0><s5>12</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Modelo</s0><s5>12</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Homme</s0><s5>13</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Human</s0><s5>13</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Hombre</s0><s5>13</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Primates</s0><s2>NS</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Primates</s0><s2>NS</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Primates</s0><s2>NS</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Mammalia</s0><s2>NS</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Mammalia</s0><s2>NS</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Mammalia</s0><s2>NS</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Vertebrata</s0><s2>NS</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Vertebrata</s0><s2>NS</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Vertebrata</s0><s2>NS</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Syndrome extrapyramidal</s0><s5>37</s5></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Extrapyramidal syndrome</s0><s5>37</s5></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Extrapiramidal síndrome</s0><s5>37</s5></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Mouvement involontaire</s0><s5>38</s5></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Involuntary movement</s0><s5>38</s5></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Movimiento involuntario</s0><s5>38</s5></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Trouble neurologique</s0><s5>40</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Neurological disorder</s0><s5>40</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Trastorno neurológico</s0><s5>40</s5></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Pathologie de l'encéphale</s0><s5>41</s5></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Cerebral disorder</s0><s5>41</s5></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Encéfalo patología</s0><s5>41</s5></fC07><fC07 i1="08" i2="X" l="FRE"><s0>Maladie dégénérative</s0><s5>42</s5></fC07><fC07 i1="08" i2="X" l="ENG"><s0>Degenerative disease</s0><s5>42</s5></fC07><fC07 i1="08" i2="X" l="SPA"><s0>Enfermedad degenerativa</s0><s5>42</s5></fC07><fC07 i1="09" i2="X" l="FRE"><s0>Pathologie du système nerveux central</s0><s5>43</s5></fC07><fC07 i1="09" i2="X" l="ENG"><s0>Central nervous system disease</s0><s5>43</s5></fC07><fC07 i1="09" i2="X" l="SPA"><s0>Sistema nervosio central patología</s0><s5>43</s5></fC07><fN21><s1>220</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard><server><NO>PASCAL 11-0321195 INIST</NO><ET>The Selective Mu-Opioid Receptor Antagonist ADL5510 Reduces Levodopa-Induced Dyskinesia Without Affecting Antiparkinsonian Action in MPTP-Lesioned Macaque Model of Parkinson's Disease</ET><AU>KOPRICH (James B.); FOX (Susan H.); JOHNSTON (Tom H.); GOODMAN (Allan); LE BOURDONNEC (Bertrand); DOLLE (Roland E.); DEHAVEN (Robert N.); DEHAVEN-HUDKINS (Diane L.); LITTLE (Patrick J.); BROTCHIE (Jonathan M.)</AU><AF>Toronto Western Research Institute, Toronto Western Hospital, University Health Network/Toronto, Ontario/Canada (1 aut., 3 aut., 10 aut.); Atuka Ltd./Toronto, Ontario/Canada (1 aut., 3 aut., 10 aut.); Division of Neurology, University of Toronto and Movement Disorders Clinic, Toronto Western Hospital, University Health Network/Toronto, Ontario/Canada (2 aut.); Adolor Corp./Exton, Pennsylvania/Etats-Unis (4 aut., 5 aut., 6 aut., 7 aut., 8 aut., 9 aut.)</AF><DT>Publication en série; Niveau analytique</DT><SO>Movement disorders; ISSN 0885-3185; Etats-Unis; Da. 2011; Vol. 26; No. 7; Pp. 1225-1233; Bibl. 48 ref.</SO><LA>Anglais</LA><EA>In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (<sub>L</sub>-dopa). Given the prominent role of the opioid system in basal ganglia function, non-selective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri dine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established <sub>L</sub>-dopa-induced dyskinesia (LID) received acute challenges with <sub>L</sub>-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of <sub>L</sub>-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/ kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by <sub>L</sub>-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61 % reductions with 1 and 3 mg/kg, respectively, compared with <sub>L</sub>-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of <sub>L</sub>-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD.</EA><CC>002B17; 002B17G</CC><FD>Dyskinésie; Maladie de Parkinson; Pathologie du système nerveux; Récepteur opiacé; Lévodopa; Singe; Modèle; Homme</FD><FG>Primates; Mammalia; Vertebrata; Syndrome extrapyramidal; Mouvement involontaire; Trouble neurologique; Pathologie de l'encéphale; Maladie dégénérative; Pathologie du système nerveux central</FG><ED>Dyskinesia; Parkinson disease; Nervous system diseases; Opioid receptor; Levodopa; Monkey; Models; Human</ED><EG>Primates; Mammalia; Vertebrata; Extrapyramidal syndrome; Involuntary movement; Neurological disorder; Cerebral disorder; Degenerative disease; Central nervous system disease</EG><SD>Disquinesia; Parkinson enfermedad; Sistema nervioso patología; Receptor opiáceo; Levodopa; Mono; Modelo; Hombre</SD><LO>INIST-20953.354000190480410060</LO><ID>11-0321195</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
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