The subacute levodopa test for evaluating long‐duration response in parkinson's disease

Abstract

The clinical relevance of a long-duration response (LDR) to levodopa therapy in Parkinson's disease (PD) has not been widely recognized. In 25 patients with moderate PD, we measured LDR on motor function after short periods of treatment with levodopa (subacute tests). Each subacute test lasted 15 days and consisted of the oral administration of levodopa at various interdose intervals (IDIs) of 48, 24, 12, 8, 6, and 5 hours. The goal for a subacute test was to achieve a satisfactory antiparkinsonian effect before the last levodopa dose (day 15), i.e., an LDR greater than 50% of the maximal response following an acute levodopa test (LDR-endpoint). Twenty-one patients (84%) reached the LDR-endpoint. The IDI at which levodopa was administered clearly differentiated patients who were otherwise clinically indistinguishable when evaluated at baseline off medication or after an acute levodopa test. The IDI schedule that produced a satisfactory LDR was specific for each patient, since longer DIs failed to produce the required LDR, and a shorter IDI schedule (resulting in larger cumulative dosage of levodopa) did not significantly enhance the response. Also, the LDR decay rate after discontinuation of treatment was individual for each patient and independent of the cumulative amount of levodopa administered. Both the IDI schedule and the LDR decay rate may reflect the ability of nigrostriatal neurons to store and to release dopamine formed from the exogenous precursor. The assessment of the LDR to levodopa by subacute tests is useful for establishing the appropriate dose of the drug, as well as for developing levodopa sparing strategies in PD patients.

Short‐ and long‐duration responses to levodopa during the first year of levodopa therapy

“…The improvement produced by the LDR was larger than the improvement produced by the SDR. This observation is in accord with observations of Quattrone and colleagues [8] that the LDR is a large portion of the response to levodopa during repetitive dosing. The LDR is not a prolonged SDR, because a clearly defined SDR superimposed on the LDR could be seen in many of the subjects.…”

Long-Duration Response to Levodopa in Patients With Advanced Parkinson Disease Treated With Subthalamic Deep Brain Stimulation

“…However, our estimate of LDR amplitude corresponds to those estimates reported in earlier phases of the disease, from one third of the total levodopa response (disability progression after drug withdrawal), 6 to more than 100% of the SDR by using tapping speed recordings. 20,21 Our results suggest that the LDR persists and is still of significant magnitude after a mean disease duration of more than 15 years in STN-DBS-treated patients with PD who do not require medication after surgery. This extends previous observations with no reduction in LDR magnitude during a 4-year period 8 and with similar LDR magnitude after 8 years of PD progression.…”

Entacapone potentiates the long-duration response but does not normalize levodopa-induced molecular changes

“…In addition, a beneficial effect of entacapone administration attenuating levodopa or DA agonist-induced dyskinesias in 6-OHDA-lesioned rats (Marin et al 2006) and in MPTP-treated monkeys (Smith et al 2003, Zubair et al 2007) has been already shown. Because it has been associated with levodopa, a presynaptic mechanism has been considered as one of the mechanisms involved in the LDR (Quattrone et al 1995;Nutt and Holford 1996).…”

“…The SDR is the basis for the clinical phenomenon of the motor fluctuation known as "wearing-off". However, the LDR is a sustained motor improvement that takes days to build up and lasts for many hours to days after levodopa discontinuation (Nutt et al 1995;Quattrone et al 1995;Zappia et al 1997). A study in the novo patients (the ELLDOPA trial) has shown that the LDR may actually last for several weeks after cessation of levodopa treatment (Parkinson Study Group 2004).…”