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 : 003143 ( Main/Exploration ); précédent : 003142; suivant : 003144Translation 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.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Pharmacologie.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animal model, Animals, Antiparkinson Agents (adverse effects), Antiparkinson Agents (therapeutic use), Basal Ganglia (drug effects), Basal ganglion, Clinical Trials, Phase II as Topic, Drug Evaluation, Preclinical, Drugs, Investigational (therapeutic use), Dyskinesia, Dyskinesia, Drug-Induced (drug therapy), Haplorhini, Humans, Levodopa, Nervous system diseases, Parkinson disease, Parkinson's disease, Pharmacology, Primates, Treatment, Treatment Failure, animal models, basal ganglia, pharmacology.
- 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. © 2006 Movement Disorder Society
Url:
DOI: 10.1002/mds.20936
Affiliations:
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Le document en format XML
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<term>Nervous system diseases</term>
<term>Parkinson disease</term>
<term>Parkinson's disease</term>
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<term>pharmacology</term>
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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, 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>
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