L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life.
We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4x daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia.
In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001).
Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group.
"The study recruited Parkinson patients in an early stage of the disease without motor complications. The results did not corroborate the primary expectations, and in fact under the additional application of entacapone patients presented rather with a higher rate of dyskinesias . In a post hoc analysis of the study data, using a complex model, the risk of developing dyskinesias was compared in four sub-groups each of which had been treated with different LDD. "
[Show abstract][Hide abstract] ABSTRACT: Numerous studies have shown that, among other factors, high DDL's constitute a significant risk for the early development of dyskinesias. In a recently published post-hoc analysis of material from the STRIDE-PD study high LDD's >400 mg per day were identified as risk factors for the development of dyskinesias and the question was presented for discussion as to whether daily doses >400 mg should therefore be principally avoided. The present paper reviews the consensus reached at the expert meeting from November, 2013, which critically debated on this recommendation. Evidence based on reliable work on the optimum levodopa dose is meager due to the lack of specifically controlled titration studies and is based mainly on indirect data from clinical comparative studies on levodopa vs. other dopaminergic agents: In early stages of the disease daily doses usually reached 400-600 mg/die, while 700-1400 mg/die were typical in advanced cases, but in all cases the variation was considerable. Seen in this light, the present authors hesitate to support the claim that LDD's should be limited to below 400 mg/die. This claim has not yet been corroborated sufficiently.
"AUC area under the curve value (peg insertion: s 9 450 min; UPDRS: scores 9 450 min), F F value of the repeated measures ANOVA, Peg insertion peg insertion sum score of both hands (s), UPDRS score of part motor examination of the Unified Parkinson's Disease Rating Scale * p \ 0.05; ** p \ 0.01; *** p \ 0.001 (p values of the post hoc analysis) significant comparisons between L-dopa/carbidopa and L-dopa/ carbidopa/entacapone ??? p \ 0.001 (p value of the post hoc analysis) significant comparison between L-dopa/carbidopa plus tolcapone and L-dopa/carbidopa/ entacapone S. Muhlack et al. 123 Author's personal copy additional COMT inhibition is performed. As consequence, it is no surprise that the STRIDE-PD trial failed with its strict design of enforced oral L-dopa intake every 3.5 h probably due to premature onset of peak dose dyskinesia (Stocchi et al. 2010). We confirm that higher 3-OMD bioavailability is present during L-dopa dosing only with a DDI compared to the combination with COMT inhibition. "
[Show abstract][Hide abstract] ABSTRACT: Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.
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