Istradefylline – a first generation adenosine A_2A antagonist for the treatment of Parkinson’s disease

Abstract

Introduction It is now accepted that Parkinson's disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. Adenosine A 2A receptor antagonists represent a new way forward in the symptomatic treatment of PD. Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A 2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A 2A antagonist currently in clinical use. Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a 'levodopa sparing' strategy in earlier PD would seem warranted.

How Are Adenosine and Adenosine A2A Receptors Involved in the Pathophysiology of Amyotrophic Lateral Sclerosis?

“…Higher levels in mast cells, eosinophils [34,35,47] Since it was first cloned in the late 1980s [48], the A 2A R has been of particular interest in movement disorders such as PD because of their selective expression in the brain regions involved in regulating motor control (i.e., the basal ganglia) and the pathogenesis of symptomatic motor dysfunction [42]. The adenosine A 2A R antagonist istradefylline (formerly known as KW-6002) is the first adenosinergic antiparkinsonian agent to be approved (Japan and USA) as a symptomatic treatment for PD [49]. The journey through research and development provides a good example of translational research, where the evidence base was carefully constructed according to the following: i.…”

“…Proof-of-concept clinical studies in PD patients, translating A 2A R antagonist pharmacology into clinical manifestation [49,59]. vii.…”

Istradefylline: A novel agent in the treatment of “off” episodes associated with levodopa/carbidopa use in Parkinson disease

“…Clinical experience with istradefylline will help identify its efficacy profile in relation to disease stage, patient population, and signs and symptoms of PD. 29 Finally, although istradefylline has potential benefits in terms of neuropsychiatric functioning of PD patients, more studies are needed to establish its role in this regard. 14 , 30 …”

Redefining the strategy for the use of COMT inhibitors in Parkinson’s disease: the role of opicapone

“…However, dopamine agonists bring other potentially significant adverse events (such as hallucinations, confusion and impulse control disorders) into the risk-benefit equation and are therefore not usually employed in an older (>65-70 years old) PD population [29]. Recently, nondopaminergic approaches to altering basal ganglia function have been suggested as effective in improving wearing-off such as the adenosine A 2A antagonist, istradefylline [30] and the NMDA antagonist, amantadine [31]. As with the dopamine agonists, while these non-dopaminergic approaches usually reduce the severity of fluctuations, they do not affect the pharmacokinetic profile of levodopa and therefore do not address the underlying problem of pulstaility.…”