Long‐duration effect and the postsynaptic compartment: Study using a dopamine agonist with a short half‐life

Abstract

A possible reason why levodopa induces a sustained, stable motor benefit during the first months to years of therapy may be its long duration of action. This long-duration effect may be due either to a presynaptic storage mechanism or to postsynaptic pharmacodynamic changes. We previously reported that the dopamine agonist ropinirole induced a long-duration response (LDR) in levodopa-naive patients with Parkinson's disease. In this study, we investigated motor responses to the short half-life dopamine agonist lisuride in a group of levodopa naive parkinsonian patients. Once lisuride reached its maximum effect, it was substituted, in randomized order, with placebo. Neither investigators nor patients knew when the active drug was switched to placebo. When patients were switched from lisuride to placebo, their Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and tapping test and screw scores declined to baseline values within a mean 9.0 +/- 1.9 days. The results confirmed that, like ropinirole and levodopa, the short-acting dopamine agonist lisuride induces a long-duration response, probably due to postsynaptic changes.

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

“…Both levodopa and dopamine agonists have shown long duration effects on UPDRS, lasting for days and even weeks. So, the traditional 12 hours off medication for “off-state” assessment would not reflect the true dopaminergic deficit (Fahn et al, 2004; Stocchi et al, 2001). Nevertheless, this assessment is of value and the “off-state” motor UPDRS will be used as a secondary outcome measure once symptomatic treatment has been initiated.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…In the case of the FIRST-STEP study, perhaps a 39-week duration was too short to demonstrate an effect. Moreover, it would have been interesting to compare the administration of more Sokoloff et al, 1990, Newman-Tancredi et al, 1997, and Alachkar et al, 2010, whereas half-lives are from Taylor and Laverty, 1969, Cedarbaum, 1987, Gancher et al, 1987, Uitti and Ahlskog, 1996, Wright et al, 1997, Fariello, 1998, Kaye and Nicholls, 2000, Stocchi et al, 2001, and Cawello et al, 2009 178 frequent, smaller doses of L-DOPA/entacapone to the three and four times a day regimens that were used in both studies, as perhaps these administration paradigms did not allow sufficient continuous stimulation of dopamine receptors, although adherence to such more frequent regimens might have been complicated. Pulsatile L-DOPA delivery is also likely involved in the maintenance of the dyskinetic state once priming has occurred.…”

End-of-dose deterioration in non ergolinic dopamine agonist monotherapy of Parkinson’s disease

“…We conclude therefore that our report underlines the need to investigate other possible mechanisms of WO, including post-synaptic effects, like reduction of the Long Duration Response [34] or like changes in presynaptic autoreceptor regulation [4], and fosters further studies on DA kinetics and inter-individual differences.…”