Istradefylline as monotherapy for Parkinson disease: Results of the 6002-US-051 trial

Fernández, Hubert H.; Greeley, David; Zweig, Richard M.; Wojcieszek, Joanne; Mori, Akihisa; Sussman, Neil M.

doi:10.1016/j.parkreldis.2009.06.008

Cited by 111 publications

(58 citation statements)

References 13 publications

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“…Recent trials of istradefylline and preladenant have demonstrated modest (1-1.2 hour) reductions in off time, and modest (1.1 to 3.2 points) improvements in UPDRS part III. 6,7,33,34 Although methodologic and patient population differences preclude direct comparison to our results, the effects of these newer antagonists upon UPDRS appear to be broadly similar to what we found with caffeine. Given caffeine's dramatically lower cost and wellestablished long-term safety profile, the advantage of the newer A2A antagonists relative to caffeine remains to be established.…”

Section: Caffeine and Edssupporting

confidence: 76%

Caffeine for treatment of Parkinson disease

et al. 2012

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Objective: Epidemiologic studies consistently link caffeine, a nonselective adenosine antagonist, to lower risk of Parkinson disease (PD). However, the symptomatic effects of caffeine in PD have not been adequately evaluated. Methods:We conducted a 6-week randomized controlled trial of caffeine in PD to assess effects upon daytime somnolence, motor severity, and other nonmotor features. Patients with PD with daytime somnolence (Epworth Ͼ10) were given caffeine 100 mg twice daily ϫ3 weeks, then 200 mg twice daily ϫ3 weeks, or matching placebo. The primary outcome was the Epworth Sleepiness Scale score. Secondary outcomes included motor severity, sleep markers, fatigue, depression, and quality of life. Effects of caffeine were analyzed with Bayesian hierarchical models, adjusting for study site, baseline scores, age, and sex.Results: Of 61 patients, 31 were randomized to placebo and 30 to caffeine. On the primary intention-to-treat analysis, caffeine resulted in a nonsignificant reduction in Epworth Sleepiness Scale score (Ϫ1.71 points; 95% confidence interval [CI] Ϫ3.57, 0.13). However, somnolence improved on the Clinical Global Impression of Change (ϩ0.64; 0.16, 1.13, intention-to-treat), with significant reduction in Epworth Sleepiness Scale score on per-protocol analysis (Ϫ1.97; Ϫ3.87, Ϫ0.05). Caffeine reduced the total Unified Parkinson's Disease Rating Scale score (Ϫ4.69 points; Ϫ7.7, Ϫ1.6) and the objective motor component (Ϫ3.15 points; Ϫ5.50, Ϫ0.83).Other than modest improvement in global health measures, there were no changes in quality of life, depression, or sleep quality. Adverse events were comparable in caffeine and placebo groups. Conclusions:Caffeine provided only equivocal borderline improvement in excessive somnolence in PD, but improved objective motor measures. These potential motor benefits suggest that a larger long-term trial of caffeine is warranted.

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Section: Caffeine and Edssupporting

confidence: 76%

Caffeine for treatment of Parkinson disease

et al. 2012

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“…The results of the first clinical trials with istradefylline have recently become available. [24][25][26][27][28] While the drug has shown to improve "off " time in patients with advanced PD, it has not shown an antidyskinetic effect. In fact, when istradefylline was administered as an adjunct therapy to levodopa, it caused an increase in LIDs, which required a reduction of the levodopa dose, though this was not evident in MPTP-treated nonhuman primates.…”

Section: Discussionmentioning

confidence: 99%

Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease

Ramlackhansingh¹,

Bose²,

Ahmed³

et al. 2011

Neurology

154

110

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Objective: To investigate striatal adenosine A2A receptor availability in patients with Parkinson disease (PD) with and without levodopa-induced dyskinesias (LIDs). While providing effective relief from the motor symptoms of PD, chronic levodopa use is associated with development of LIDs. A2A receptors are expressed on the bodies of indirect pathway medium spiny striatal neurons and on dopamine terminals and play a role in modulating dopamine transmission. A2A antagonists have antiparkinsonian activity by boosting levodopa efficacy. We aimed to study A2A receptor availability in patients with PD with and without LIDs using PET and [ 11 C]SCH442416, an A2A antagonist. Methods:Six patients with PD with and 6 without LIDs were studied withdrawn 12 hours from medication. Their PET findings were compared with 6 age-matched healthy controls. Using spectral analysis, [ 11 C]SCH442416 regional volumes of distribution (V T ) were computed for the caudate, putamen, and thalamus and binding potentials (BP ND ) reflecting the ratio of specific: nonspecific uptake were compared between groups.Results: A2A binding in the caudate and putamen of subjects with PD with LIDs was far higher (p ϭ 0.026 and p ϭ 0.036, respectively) than that of subjects with PD without LIDs, which lay within the control range. Thalamic A2A availability was similar for all 3 groups. Conclusion:Patients with PD with LIDs show increased A2A receptor availability in the striatum.This finding is compatible with altered adenosine transmission playing a role in LIDs and provides a rationale for a trial of A2A receptor agents in the treatment of these motor complications.

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“…In the clinic, when the A 2A antagonist Istradefylline was given as monotherapy (i.e. without L-Dopa) to de-novo PD patients, it did not produce statistically significant benefits [22]. However, when combined with L-Dopa, Istradefylline, and other A 2A antagonists, demonstrated significant efficacy [23][24][25].…”

Section: Introductionmentioning

confidence: 99%