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 : 000797Translation 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. BrotchieSource :
- Movement disorders [ 0885-3185 ] ; 2006.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
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.
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Pour connaître la documentation sur le format Inist Standard.
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Format Inist (serveur)
NO : | PASCAL 06-0538573 INIST |
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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:06-0538573Le 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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<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>
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