Istradefylline for Parkinson's disease patients experiencing motor fluctuations: Results of the KW-6002-US-018 study

Pourcher, Emmanuelle; Fernández, Hubert H.; Stacy, Mark; Mori, Akihisa; Ballerini, Rocco; Chaikin, Philip

doi:10.1016/j.parkreldis.2011.09.023

Cited by 105 publications

(61 citation statements)

References 11 publications

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“…As a result of this direct A 2A R-D 2 R interaction [29], antagonists for A 2A R have emerged as new targets for non-dopaminergic antiparkinsonian treatments [30]. Indeed, several clinical trials have shown that the administration of istradefylline (or KW-6002), an A 2A R antagonist, ameliorates the dyskinesias induced by chronic levodopa treatment of PD patients [31][32][33][34][35][36][37][38]. Similarly, since A 2A R levels have been shown to be increased in the putamen of some PD patients [5][6][7][8][9], it seems likely that ADORA2A repression would be an alternative therapy to reduce A 2A R activity.…”

Section: Resultsmentioning

confidence: 99%

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Villar-Menéndez

Núñez

Díaz-Sánchez

et al. 2014

Purinergic Signalling

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Adenosine A 2A receptor (A 2A R) is a G proteincoupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A 2A R expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A 2A R expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A 2A R messenger RNA (mRNA) and protein content as well as A 2A R-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5′UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A 2A R expression could be established. Overall, we concluded that striatal A 2A R functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A 2A R expression.

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Section: Resultsmentioning

confidence: 99%

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Villar-Menéndez

Núñez

Díaz-Sánchez

et al. 2014

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…Seven RCTs were identified. After reading each article, only five [18][19][20][21][22] of them fulfilled the inclusion criteria ( Fig. 1).…”

Section: Search Resultsmentioning

confidence: 99%

“…Table 1 contains the basic information on randomization methods, sample sizes, ITT, intervention, and follow-up. Two studies [20,21] pointed out that the randomization was done with a randomization schedule. Double-blind trials were described in all studies.…”

Section: Search Resultsmentioning

confidence: 99%

Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: A meta-analysis

Chen

Wang

Wei

et al. 2013

Journal of the Neurological Sciences

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“…However, despite the initial optimism based on the early studies, subsequent phase III clinical trials have yielded conflicting results. Two studies demonstrated a significant reduction in daily off time with an increased incidence of dyskinesias [22,23], but istradefylline did not affect off time in another trial [24]. In the latter study, motor function in the on state was improved compared with placebo, and a large placebo response may account for the negative effect on off time [24].…”

Section: Adenosinementioning

confidence: 94%

“…Two studies demonstrated a significant reduction in daily off time with an increased incidence of dyskinesias [22,23], but istradefylline did not affect off time in another trial [24]. In the latter study, motor function in the on state was improved compared with placebo, and a large placebo response may account for the negative effect on off time [24]. Although the US Food and Drug Administration issued a not approvable letter for istradefylline based on available data in 2008 [25], the drug was later approved for use in Japan as adjunctive treatment for PD [26], and phase III clinical development recently resumed in North America [27].…”

Section: Adenosinementioning

confidence: 98%

Treatment of Parkinson's Disease: What's in the Non-dopaminergic Pipeline?

Hung

Schwarzschild

2014

Neurotherapeutics

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Dopamine depletion resulting from degeneration of nigrostriatal dopaminergic neurons is the primary neurochemical basis of the motor symptoms of Parkinson's disease (PD). While dopaminergic replacement strategies are effective in ameliorating these symptoms early in the disease process, more advanced stages of PD are associated with the development of treatment-related motor complications and dopamine-resistant symptoms. Other neurotransmitter and neuromodulator systems are expressed in the basal ganglia and contribute to the extrapyramidal refinement of motor function. Furthermore, neuropathological studies suggest that they are also affected by the neurodegenerative process. These non-dopaminergic systems provide potential targets for treatment of motor fluctuations, levodopa-induced dyskinesias, and difficulty with gait and balance. This review summarizes recent advances in the clinical development of novel pharmacological approaches for treatment of PD motor symptoms. Although the non-dopaminergic pipeline has been slow to yield new drugs, further development will likely result in improved treatments for PD symptoms that are induced by or resistant to dopamine replacement.

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Istradefylline for Parkinson's disease patients experiencing motor fluctuations: Results of the KW-6002-US-018 study

Cited by 105 publications

References 11 publications

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: A meta-analysis

Treatment of Parkinson's Disease: What's in the Non-dopaminergic Pipeline?

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