Long-term use of L-DOPA in Parkinson’s disease results in motor complications and a progressive reduction in clinical efficacy. No new pharmacologic agents and treatment options have been able to deliver a more effective treatment than L-DOPA and therefore L-DOPA treatment strategies could offer improved clinical outcomes. This led to the hypothesis that L-DOPA, the current 'gold standard' pharmacotherapy for Parkinson’s disease can be improved by optimising its treatment strategies. Using validated animal models of Parkinson’s disease, behavioural studies were performed to test this hypothesis to evaluate if we could: (1) potentiate the clinical response of L-DOPA by maximising the efficiency of peripheral decarboxylase (DDC) inhibition, (2) enhance the clinical response of L-DOPA through prodrug delivery and (3) optimise L-DOPA's clinical therapeutic window through combination therapy with dopamine agonists. Firstly, it was shown that the efficiency of DDC inhibition could improve the L-DOPA response particularly when L-alpha-methyl dopa (L-AMD) was utilised. Secondly, the novel L-DOPA prodrug PRX 1354, induced improvement in L-DOPA motor function in MPTP treated marmosets but did not have the same positive effect on dyskinesia expression. Lastly, in the MPTP-treated common marmosets, L-DOPA combined with the dopamine agonist pramipexole resulted in improved motor function and a reduction of dyskinesia. In conclusion, manipulating L-DOPA treatment strategies can improve motor function while reducing dyskinesia expression. These results suggest that optimizing the treatment of Parkinson’s disease by improving L-DOPA treatment strategies could reduce the impact of dyskinesia in Parkinson’s disease patients.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:676936 |
| Date | January 2014 |
| Creators | Tayarani-Binazir, Kayhan Ashley |
| Contributors | Salvage, Sarah ; Jenner, Peter |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://kclpure.kcl.ac.uk/portal/en/theses/behavioural-investigation-into-whether-ldopa-the-current-gold-standard-pharmacotherapy-for-parkinsons-disease-can-be-improved-by-optimising-its-treatment-strategies(0b62fd27-f368-4ff3-aeb3-e28ef5deb0cb).html |
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