The fluctuating response to L-DOPA in Parkinson's disease (""""""""on-off"""""""" phenomenon) is a common, disabling problem that occurs during chronic L-DOPA treatment and is resistant to current modes of therapeutic manipulation. Preliminary data suggest that fluctuating delivery of L-DOPA to its cerebral site of action, caused by rapidly changing plasma L-DOPA concentrations and vagaries in transport of L-DOPA from plasma to brain, may be the major cause of the problem. In animals L-DOPA has been shown to be transported by the large neutral amino acid (LNAA) transport system and its entry into the brain may be influenced by other LNAAs which compete for transport, by glucose which lowers plasma concentrations of LNAA and by 3-0-methyldopa (30MD), an L-DOPA metabolite which also competes with L-DOPA for blood-brain barrier transport. This proposal will explore the clinical importance of transport mechanisms for L-DOPA using patients with debilitating """"""""on-off"""""""" phenomenon. The moment to moment clinical status in these patients is a sensitive indicator of L-DOPA's action in the brain. Oscillations in plasma L-DOPA concentration are eliminated by constant intravenous administration of the drug, allowing examination of factors modifying transport from plasma to brain. Challenges with various amino acids, glucose or 30MD during constant infusion of L-DOPA will be used to assess their effects on the clinical response to L-DOPA. The role of these factors during oral dosing will be examined by evaluating the (L-DOPA)/(LNAA+30MD) ratio as a predictor of the clinical response. The effect of stabilizing the plasma LNAA concentrations by multiple small meals will be investigated as a method of reducing the fluctuating response to oral L-DOPA. Finally, prolonged infusions (up to 100 hours) will determine if maintenance of constant plasma concentrations of L-DOPA and amino acids is sufficient to produce a sustained, optimal clinical response. These studies assess the importance of absorption and transport of L-DOPA to the acute clinical response to the drug. This understanding is the foundation on which to design improved therapuetic strategies to treat Parkinson's disease and to minimize or prevent the """"""""on-off"""""""" phenomenon.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021062-03
Application #
3401833
Study Section
Neurology A Study Section (NEUA)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Holford, Nick H G; Nutt, John G (2011) Interpreting the results of Parkinson's disease clinical trials: time for a change. Mov Disord 26:569-77
Zampieri, Cris; Salarian, Arash; Carlson-Kuhta, Patricia et al. (2011) Assessing mobility at home in people with early Parkinson's disease using an instrumented Timed Up and Go test. Parkinsonism Relat Disord 17:277-80
Chung, Kathryn A; Lobb, Brenna M; Nutt, John G et al. (2010) Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 75:1263-9
Kay, D M; Stevens, C F; Hamza, T H et al. (2010) A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2. Neurology 75:1189-94
Chung, Kathryn A; Lobb, Brenna M; Nutt, John G et al. (2010) Objective measurement of dyskinesia in Parkinson's disease using a force plate. Mov Disord 25:602-8
Brodsky, Matthew A; Park, Byung S; Nutt, John G (2010) Effects of a dopamine agonist on the pharmacodynamics of levodopa in Parkinson disease. Arch Neurol 67:27-32
Nutt, John G; Chung, Kathy A; Holford, Nicholas H G (2010) Dyskinesia and the antiparkinsonian response always temporally coincide: a retrospective study. Neurology 74:1191-7
Gunzler, Steven A; Pavel, Misha; Koudelka, Caroline et al. (2009) Foot-tapping rate as an objective outcome measure for Parkinson disease clinical trials. Clin Neuropharmacol 32:97-102
Peterson, Amie L; Nutt, John G (2008) Treatment of Parkinson's disease with trophic factors. Neurotherapeutics 5:270-80
Holford, Nick; Nutt, John G (2008) Disease progression, drug action and Parkinson's disease: why time cannot be ignored. Eur J Clin Pharmacol 64:207-16

Showing the most recent 10 out of 68 publications