Effect of Long-term Therapy on the Pharmacodynamics of Levodopa

Nutt, John G.; Woodward, William R.; Carter, Julie H.; Gancher, Stephen T.

doi:10.1001/archneur.1992.00530350037016

Cited by 118 publications

(84 citation statements)

References 24 publications

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“…2,3 After years of levodopa therapy, dyskinesia and the antiparkinsonian response occur together, 2,3 e-Pub ahead of print on March 10, 2010, at www.neurology.org. …”

Section: Discussionmentioning

confidence: 99%

“…The fact that anti-bradykinesia effects and dyskinesia were elicited together with microstimulation of the dorsal globus pallidus interna sites would support this reasoning. 7,8 A widely accepted observation is that sensitivity for the antiparkinsonian response and for dyskinesia are similar in more advanced patients 2,3 and in nonhuman primates. 9 This observation of identical sensitivities for the desired motor effects and for dyskinesia in more advanced patients would have to be considered a coincidence if there were different dose response curves for the antiparkinsonian response and for dyskinesia.…”

Section: Dyskinesia and Antiparkinsonian Responsementioning

confidence: 99%

“…A larger magnitude response has also been suggested in earlier studies. 2,3,16 These apparent changes in sensitivity are incorporated in figure 1B. The shorter latency and increased magnitude of responses to a drug are characteristics of behavioral supersensitivity.…”

Section: Dyskinesia and Antiparkinsonian Responsementioning

confidence: 99%

“…However, little data exist for the intermediate period, when the antiparkinsonian response and dyskinesia are supposedly dissociated. 2,3 We investigated the onset and offset of dyskinesia and the antiparkinsonian response as measures of sensitivity to levodopa when dyskinesia first appeared during long-term therapy to examine the temporal dissociation of the 2 responses. Further, we examined the changes in latencies and magnitudes of responses, indices of sensitization, during the first 4 years of therapy to determine if the evolution of the 2 responses would suggest that they originated from different mechanisms.…”

mentioning

confidence: 99%

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Dyskinesia and the antiparkinsonian response always temporally coincide

Nutt

Chung²,

Holford

2010

Neurology

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Objective: To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops.Methods: Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on longterm levodopa with dyskinesia and motor fluctuations. Results:The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa. Conclusions:The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered. Neurology Levodopa-induced dyskinesia is postulated to result from repeated pulsatile dopaminergic stimulation which progressively lowers the threshold for dyskinesia by sensitization.1 At the beginning of levodopa therapy, the threshold for dyskinesia is much higher than the peak plasma levodopa concentrations. Conversely, the threshold for the antiparkinsonian response is envisioned to be lower than that for dyskinesia. The hypothesized different thresholds allow dissociation of the antiparkinsonian response and dyskinesia. Continued levodopa therapy lowers the threshold for dyskinesia and dyskinesia occurs briefly at peak concentrations. Eventually, similar concentrations produce dyskinesia and the antiparkinsonian response, making the responses inseparable ( figure 1A). This hypothesis assumes 1) the antiparkinsonian response and dyskinesia have distinctly different dose responses and 2) they are altered differently during long-term levodopa therapy.Evidence for this hypothesized scenario is from temporal extremes. Initial levodopa therapy rarely produces dyskinesia, consistent with a high threshold for dyskinesia.2,3 After years of levodopa therapy, dyskinesia and the antiparkinsonian response occur together, 2,3 e-Pub ahead of print on March 10, 2010, at www.neurology.org.

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“…2,3 After years of levodopa therapy, dyskinesia and the antiparkinsonian response occur together, 2,3 e-Pub ahead of print on March 10, 2010, at www.neurology.org. …”

Section: Discussionmentioning

confidence: 99%

Section: Dyskinesia and Antiparkinsonian Responsementioning

confidence: 99%

Section: Dyskinesia and Antiparkinsonian Responsementioning

confidence: 99%

mentioning

confidence: 99%

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Dyskinesia and the antiparkinsonian response always temporally coincide

Nutt

Chung²,

Holford

2010

Neurology

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“…Tapping tasks represent such fast and robust bedside tests, which are therefore frequently used for clinical routine purposes [5, 6,10,11,12]. …”

Section: Discussionmentioning

confidence: 99%

Impact of Subthalamic Stimulation and Medication on Proximal and Distal Bradykinesia in Parkinson’s Disease

Wenzelburger¹,

Deuschl²,

Volkmann³

2009

Eur Neurol

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Objective: To evaluate the usefulness of a new instrument for bedside testing of proximal arm and distal finger tapping performance in patients with Parkinson’s disease (PD). Methods: Twenty healthy controls and 25 PD patients with subthalamic nucleus deep brain stimulation were investigated in different treatment conditions using three different tapping paradigms: (1) the standard tapping task of the CAPSIT-PD-protocol; (2) alternate pressing of two buttons on the new board by moving the arm at the elbow and shoulder (proximal tapping), and (3) alternate pressing of two closely collocated buttons on the new board by moving only the index finger (distal tapping) for 30 s. Results: The new tapping board was as sensitive as the standard board to distinguish untreated PD patients from controls. The relative improvements in tapping scores from the off treatment condition were largest for the proximal tapping task. The treatment effects of high frequency stimulation of the subthalamic nucleus or medication alone were comparable, whereas the combined treatment induced significantly higher tapping scores. Conclusion: The new tapping board represents a quick and easy to use bedside test, which may be routinely used to probe the efficacy of treatments on different aspects of motor control.

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