The role of the long-duration response to levodopa in Parkinson’s disease

Abstract

The long-duration response (LDR) to levodopa is an important component of the therapeutic response to the drug in Parkinson's disease (PD). Some characteristics are peculiar: it is independent from peripheral pharmacokinetics of levodopa, but it is dependent on the intervals between doses and on the size of each dose. Once the LDR fully develops, it is stable and maximal. After stopping treatment, the decay rate is inversely related to the severity of PD; when the LDR decreases over time, the patients present a fluctuating motor response. Therapeutic strategies based on the development and maintenance of the LDR should be sought to maximize the clinical benefit induced by levodopa and to avoid the appearance of motor complications.

The missing, the short, and the long: Levodopa responses and dopamine actions

“…6 13 . The LDR is present in more advanced PD but diminishes with disease progression, with the SDR becoming a more important treatment component.…”

“…6 13 . The pharmacokinetic hypothesis postulated the existence of a brain reservoir that accumulates L-dopa and slowly releases dopamine.…”

“…By various measures, the LDR accounts for 30 to 50% of the total (SDR 1 LDR) response to L-dopa and is responsible for much of the sustained-uniform response to L-dopa in patients with early PD. 6,13 The LDR is present in more advanced PD but diminishes with disease progression, with the SDR becoming a more important treatment component. 9,11,[14][15][16] In a longitudinal study following PD subjects over a 4-year interval, Nutt et al used their rigorous LDR evaluation protocol and documented more rapidly declining LDRs with disease progression.…”

“…Two broad categories of LDR mechanisms were considered: pharmacokinetic and pharmacodynamic. 6,13 The pharmacokinetic hypothesis postulated the existence of a brain reservoir that accumulates L-dopa and slowly releases dopamine. A plausible hypothesis was that surviving nigrostriatal terminals were a central reservoir of dopamine synthesized from exogenous L-dopa and the decline of the LDR with disease progression could be explained by gradual loss of residual nigrostriatal terminals.…”

“…By various measures, the LDR accounts for 30 to 50% of the total (SDR + LDR) response to L‐dopa and is responsible for much of the sustained‐uniform response to L‐dopa in patients with early PD . The LDR is present in more advanced PD but diminishes with disease progression, with the SDR becoming a more important treatment component .…”