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To clarify the way in which the clinical response to levodopa changes with the progression of Parkinson's disease, a longitudinal study was performed to quantify motor response characteristics to single doses of levodopa by mouth over three years in 23 patients with fluctuating motor function. A significant increase in motor disability in "on" (time of peak motor improvement) and "off" (before levodopa dose) phases occurred and "on" phase dyskinesia increased by 24%, though the amplitude of motor response was conserved. There was no evidence of progressive loss of response of certain motor deficits affecting axial muscles and gait. The mean duration of motor response decreased by 17%. Both shortening of response duration and increase in "off" phase disability contribute to the development of motor fluctuations. A short response time to the levodopa test dose was not an invariable finding in patients with severe fluctuations, whereas all had large response amplitudes and high "off" phase disability scores. Patients who have developed motor fluctuations may continue to respond to dopaminergic treatment until late in the disease course, despite the unstable nature of their responses.

Diurnal differences in duration and quality of motor response to levodopa are frequently described by patients. The quality and duration of motor responses were objectively assessed to morning and afternoon oral levodopa doses in five patients with Parkinsonian motor fluctuations who complained of diurnal variation in response to their normal levodopa medication. Results suggest that under controlled conditions which eliminated the effects of diet and overlapping levodopa effects the response to levodopa remained unchanged throughout the day, and that the duration of response could be predicted by plasma levodopa levels.

The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.

Apomorphine a dopamine receptor agonist was given subcutaneously to 57 levodopa treated parkinsonian patients with refractory off-period disabilities for a median period of 16 months. In 30 given intermittent suprathreshold injections the mean number of hours spent in a disabling off state fell from 6.9 to 2.9. Similar benefit was observed in 21 patients receiving continuous infusions with additional boluses on demand by mini-pump (mean reduction of hours off from 9.9 to 4.5). Twelve patients have been treated for over two years without tachyphylaxis or loss of response. The incidence of neuropsychiatric side-effects has been low (7%). Six patients failed to show a sustained worthwhile response; severe disabilities during "on" periods being the major problem. Subcutaneous apomorphine is proposed as an effective treatment for patients with incapacitating "off" period disabilities refractory to oral medication and should be considered before experimental implantation procedures.

To assess the relative influence of central pharmacodynamic and peripheral pharmacokinetic factors on the duration of motor response to levodopa, the relationship between motor function and plasma levodopa levels was studied in 31 Parkinsonian patients. Duration of benefit from single levodopa doses while fasting depended on the degree to which the plasma levodopa level had declined over four hours; wearing off occurred when the plasma levodopa level had fallen to approximately 50% of peak concentration, irrespective of the duration of the motor response. Whilst the amplitude of motor response to levodopa is likely to be modified by alternations in dopamine receptor stimulation and sensitivity as the disease progresses, it is proposed that the duration of response is primarily determined by levodopa peripheral pharmacokinetics rather than by central pharmacodynamic factors associated with dopamine storage capacity.

Four patients with levodopa induced fluctuations in motor performance were studied during the constant intraduodenal infusion of levodopa. The results confirm that steady plasma levodopa levels with stable motor control can be achieved. However, when patients were given oral protein loads, motor performance declined despite maintenance of plasma levodopa levels. These findings suggest that competition for levodopa carrier mediated transport by amino acids, is more important at the blood-brain barrier than across the gut mucosa; thereby possibly limiting the efficacy of long-term direct intraduodenal administration of levodopa.