ParkinsonCanadaV1, PascalFrancis, Corpus, bibRecord, 000796

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 : 000796 ( PascalFrancis/Corpus ); précédent : 000795; suivant : 000797

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

Auteurs : Susan H. Fox ; Anthony E. Lang ; Jonathan M. Brotchie

Source :

Movement disorders [ 0885-3185 ] ; 2006.

RBID : Pascal:06-0538573

Descripteurs français

Pascal (Inist)
- Système nerveux pathologie, Dyskinésie, Parkinson maladie, Traitement, Lévodopa, Primates, Noyau gris central, Modèle animal, Pharmacologie.

English descriptors

KwdEn :
- Animal model, Basal ganglion, Dyskinesia, Levodopa, Nervous system diseases, Parkinson disease, Pharmacology, Primates, Treatment.

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, istradefyl-line, 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 Ila 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 Ila trials.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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Format Inist (serveur)

NO :	PASCAL 06-0538573 INIST
ET :	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
AU :	FOX (Susan H.); LANG (Anthony E.); BROTCHIE (Jonathan M.)
AF :	Movement Disorders Clinic, Toronto Western Hospital/Ontario/Canada (1 aut., 2 aut.); Toronto Western Research Institute, Toronto Western Hospital/Ontario/Canada (2 aut., 3 aut.)
DT :	Publication en série; Niveau analytique
SO :	Movement disorders; ISSN 0885-3185; Etats-Unis; Da. 2006; Vol. 21; No. 10; Pp. 1578-1594; Bibl. 152 ref.
LA :	Anglais
EA :	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, istradefyl-line, 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 Ila 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 Ila trials.
CC :	002B17; 002B02U01; 002B17F
FD :	Système nerveux pathologie; Dyskinésie; Parkinson maladie; Traitement; Lévodopa; Primates; Noyau gris central; Modèle animal; Pharmacologie
FG :	Mammalia; Vertebrata; Extrapyramidal syndrome; Mouvement involontaire; Trouble neurologique; Encéphale pathologie; Maladie dégénérative; Système nerveux central pathologie; Système nerveux central
ED :	Nervous system diseases; Dyskinesia; Parkinson disease; Treatment; Levodopa; Primates; Basal ganglion; Animal model; Pharmacology
EG :	Mammalia; Vertebrata; Extrapyramidal syndrome; Involuntary movement; Neurological disorder; Cerebral disorder; Degenerative disease; Central nervous system disease; Central nervous system
SD :	Sistema nervioso patología; Disquinesia; Parkinson enfermedad; Tratamiento; Levodopa; Primates; Núcleo basal; Modelo animal; Farmacología
LO :	INIST-20953.354000158877800030
ID :	06-0538573

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Pascal:06-0538573

Le document en format XML

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<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, istradefyl-line, 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 Ila 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 Ila trials.</div>
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<s5>03</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Traitement</s0>
<s5>09</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Treatment</s0>
<s5>09</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Tratamiento</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>Primates</s0>
<s2>NS</s2>
<s5>11</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Primates</s0>
<s2>NS</s2>
<s5>11</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Primates</s0>
<s2>NS</s2>
<s5>11</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Noyau gris central</s0>
<s5>12</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>Basal ganglion</s0>
<s5>12</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA"><s0>Núcleo basal</s0>
<s5>12</s5>
</fC03>
<fC03 i1="08" i2="X" l="FRE"><s0>Modèle animal</s0>
<s5>13</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG"><s0>Animal model</s0>
<s5>13</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Modelo animal</s0>
<s5>13</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE"><s0>Pharmacologie</s0>
<s5>14</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG"><s0>Pharmacology</s0>
<s5>14</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA"><s0>Farmacología</s0>
<s5>14</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Mammalia</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Vertebrata</s0>
<s2>NS</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Extrapyramidal syndrome</s0>
<s5>37</s5>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Extrapyramidal syndrome</s0>
<s5>37</s5>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Extrapiramidal síndrome</s0>
<s5>37</s5>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Mouvement involontaire</s0>
<s5>38</s5>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Involuntary movement</s0>
<s5>38</s5>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Movimiento involuntario</s0>
<s5>38</s5>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Trouble neurologique</s0>
<s5>39</s5>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Neurological disorder</s0>
<s5>39</s5>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Trastorno neurológico</s0>
<s5>39</s5>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Encéphale pathologie</s0>
<s5>40</s5>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Cerebral disorder</s0>
<s5>40</s5>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Encéfalo patología</s0>
<s5>40</s5>
</fC07>
<fC07 i1="07" i2="X" l="FRE"><s0>Maladie dégénérative</s0>
<s5>41</s5>
</fC07>
<fC07 i1="07" i2="X" l="ENG"><s0>Degenerative disease</s0>
<s5>41</s5>
</fC07>
<fC07 i1="07" i2="X" l="SPA"><s0>Enfermedad degenerativa</s0>
<s5>41</s5>
</fC07>
<fC07 i1="08" i2="X" l="FRE"><s0>Système nerveux central pathologie</s0>
<s5>42</s5>
</fC07>
<fC07 i1="08" i2="X" l="ENG"><s0>Central nervous system disease</s0>
<s5>42</s5>
</fC07>
<fC07 i1="08" i2="X" l="SPA"><s0>Sistema nervosio central patología</s0>
<s5>42</s5>
</fC07>
<fC07 i1="09" i2="X" l="FRE"><s0>Système nerveux central</s0>
<s5>43</s5>
</fC07>
<fC07 i1="09" i2="X" l="ENG"><s0>Central nervous system</s0>
<s5>43</s5>
</fC07>
<fC07 i1="09" i2="X" l="SPA"><s0>Sistema nervioso central</s0>
<s5>43</s5>
</fC07>
<fN21><s1>353</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
</standard>
<server><NO>PASCAL 06-0538573 INIST</NO>
<ET>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</ET>
<AU>FOX (Susan H.); LANG (Anthony E.); BROTCHIE (Jonathan M.)</AU>
<AF>Movement Disorders Clinic, Toronto Western Hospital/Ontario/Canada (1 aut., 2 aut.); Toronto Western Research Institute, Toronto Western Hospital/Ontario/Canada (2 aut., 3 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Movement disorders; ISSN 0885-3185; Etats-Unis; Da. 2006; Vol. 21; No. 10; Pp. 1578-1594; Bibl. 152 ref.</SO>
<LA>Anglais</LA>
<EA>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, istradefyl-line, 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 Ila 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 Ila trials.</EA>
<CC>002B17; 002B02U01; 002B17F</CC>
<FD>Système nerveux pathologie; Dyskinésie; Parkinson maladie; Traitement; Lévodopa; Primates; Noyau gris central; Modèle animal; Pharmacologie</FD>
<FG>Mammalia; Vertebrata; Extrapyramidal syndrome; Mouvement involontaire; Trouble neurologique; Encéphale pathologie; Maladie dégénérative; Système nerveux central pathologie; Système nerveux central</FG>
<ED>Nervous system diseases; Dyskinesia; Parkinson disease; Treatment; Levodopa; Primates; Basal ganglion; Animal model; Pharmacology</ED>
<EG>Mammalia; Vertebrata; Extrapyramidal syndrome; Involuntary movement; Neurological disorder; Cerebral disorder; Degenerative disease; Central nervous system disease; Central nervous system</EG>
<SD>Sistema nervioso patología; Disquinesia; Parkinson enfermedad; Tratamiento; Levodopa; Primates; Núcleo basal; Modelo animal; Farmacología</SD>
<LO>INIST-20953.354000158877800030</LO>
<ID>06-0538573</ID>
</server>
</inist>
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	La maladie de Parkinson au Canada (serveur d'exploration)
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La maladie de Parkinson au Canada (serveur d'exploration)

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

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

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