MovDisordV3, Main, Exploration, bibRecord, 000678

ABT-089 and ABT-894 Reduce L-Dopa-Induced Dyskinesias in a Monkey Model of Parkinson’s Disease

Identifieur interne : 000678 ( Main/Exploration ); précédent : 000677; suivant : 000679

ABT-089 and ABT-894 Reduce L-Dopa-Induced Dyskinesias in a Monkey Model of Parkinson’s Disease

Auteurs : Danhui Zhang [États-Unis] ; Tanuja Bordia [États-Unis] ; Matthew Mcgregor [États-Unis] ; J. Michael Mcintosh [États-Unis] ; Michael W. Decker [États-Unis] ; Maryka Quik [États-Unis]

Source :

Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2014.

RBID : PMC:3990279

English descriptors

KwdEn :
- Animals, Antiparkinson Agents (adverse effects), Antiparkinson Agents (therapeutic use), Dyskinesia, Drug-Induced (drug therapy), Female, Levodopa (adverse effects), Levodopa (therapeutic use), MPTP Poisoning (drug therapy), Male, Nicotinic Agonists (therapeutic use), Pyridines (therapeutic use), Pyrrolidines (therapeutic use), Saimiri, Treatment Outcome.
MESH :
- chemical , adverse effects : Antiparkinson Agents, Levodopa.
- chemical , therapeutic use : Antiparkinson Agents, Levodopa, Nicotinic Agonists, Pyridines, Pyrrolidines.
- drug therapy : Dyskinesia, Drug-Induced, MPTP Poisoning.
- Animals, Female, Male, Saimiri, Treatment Outcome.

Abstract

Background

L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson’s disease for which there is little treatment. Accumulating evidence shows that nicotine and nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here we examined the effect of two β2 nAChR agonists, ABT-089 and ABT-894, previously approved for phase 2 clinical trials for other indications.

Methods

Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered L-dopa/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Each set had a vehicle-treated, a nAChR agonist-treated and a nicotine-treated group, as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), while Set B monkeys were initially nAChR drug-naïve.

Results

Both sets were administered the partial agonist ABT-089 (0.01-1.0 mg/kg) orally 5 d/week twice daily 30 min before L-dopa with each dose given for 1-5 weeks. ABT-089 decreased LIDs 30-50% compared to vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks washout, the effect of the full agonist ABT-894 (0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT-089 was 30-60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (3-4 months). NAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed.

Conclusion

ABT-894 and ABT-089 appear good candidate nAChR drugs for the management of LIDs in Parkinson’s disease.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990279

DOI: 10.1002/mds.25817
PubMed: 24515328
PubMed Central: 3990279

Affiliations:

États-Unis
Californie, Illinois, Utah

Le document en format XML

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<term>Levodopa (adverse effects)</term>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title>
<p id="P1">L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson’s disease for which there is little treatment. Accumulating evidence shows that nicotine and nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here we examined the effect of two β2 nAChR agonists, ABT-089 and ABT-894, previously approved for phase 2 clinical trials for other indications.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered L-dopa/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Each set had a vehicle-treated, a nAChR agonist-treated and a nicotine-treated group, as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), while Set B monkeys were initially nAChR drug-naïve.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">Both sets were administered the partial agonist ABT-089 (0.01-1.0 mg/kg) orally 5 d/week twice daily 30 min before L-dopa with each dose given for 1-5 weeks. ABT-089 decreased LIDs 30-50% compared to vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks washout, the effect of the full agonist ABT-894 (0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT-089 was 30-60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (3-4 months). NAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed.</p>
</sec>
<sec id="S4"><title>Conclusion</title>
<p id="P4">ABT-894 and ABT-089 appear good candidate nAChR drugs for the management of LIDs in Parkinson’s disease.</p>
</sec>
</div>
</front>
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<name sortKey="Bordia, Tanuja" sort="Bordia, Tanuja" uniqKey="Bordia T" first="Tanuja" last="Bordia">Tanuja Bordia</name>
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Movement Disorders (revue)

ABT-089 and ABT-894 Reduce L-Dopa-Induced Dyskinesias in a Monkey Model of Parkinson’s Disease

ABT-089 and ABT-894 Reduce L-Dopa-Induced Dyskinesias in a Monkey Model of Parkinson’s Disease

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English descriptors

Abstract

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