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.
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