Istradefylline - a first generation adenosine A2A antagonist for the treatment of Parkinson's disease.

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 A2A 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 A2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A2A 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.

The challenge of developing adenosine A2A antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant.

Laboratory and clinical experience have pointed to the value of targeting motor pathways emerging from the striatum to treat problems arising in advanced Parkinson's disease (PD). These pathways are selectively populated with a subtype of adenosine binding sites (A2A receptors) that offer a target for improving PD symptomatology. Several compounds were developed that possess high selectivity and potency for blocking this receptor. Three of these compounds - istradefylline, preladenant, and tozadenant - were chosen for clinical development programs that culminated in Phase 3 multicenter randomized clinical trials. Each of these drugs exert virtually no off-target neurochemical effects. Clinical trials with these drugs focused upon reducing OFF time when administered adjunctly to levodopa and other antiparkinsonian medications. Despite promising Phase 2 data, preladenant did not show efficacy when tested in a randomized placebo-controlled Phase 3 clinical trial. Reports of hematological toxicity necessitated ceasing an ongoing Phase 3 investigation of tozadenant. Following a challenging approval process, based on the results of randomized clinical trials carried out in the U.S. and Japan, istradefylline received approval in these countries for treatment of OFF episodes.

Medical Management and Prevention of Motor Complications in Parkinson's Disease.

Levodopa is the most effective medication for the treatment of the motor symptoms of Parkinson's disease. However, over time, the clinical response to levodopa becomes complicated by a reduction in the duration and reliability of motor improvement (motor fluctuations) and the emergence of involuntary movements (levodopa-induced dyskinesia). Strategies that have been attempted in an effort to delay the development of these motor complications include levodopa sparing and continuous dopaminergic therapy. Once motor complications occur, a wide array of medical treatments is available to maximize motor function through the day while limiting dyskinesia. Here, we review the clinical features, epidemiology, and risk factors for the development of motor complications, as well as strategies for their prevention and medical management.