Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson’s Disease: A Pooled Analysis of 8 Phase 2b/3 Trials

Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.

Effect of Adenosine A2a Receptor Antagonist In Haloperidol Induced Model of Parkinson’s Disease.

One of the major causes of neurological disorders is degeneration of neurons which is commonly termed as Neurodegeneration. It is well documented that two of the neurodegenerative disorders i.e., Alzheimer’s Disease & Parkinson Disease comes in top fifteen causes of deaths in United States of America. Due to the neuroprotective property of adenosine A2a receptor antagonists (ZM241385) was evaluated in haloperidol mouse model of Parkinson’s disease. Our results reveal significant antidopaminergic effects of adenosine A2A receptor antagonist that support its utilization as a new treatment approach in Parkinson’s diseases.

Enhancement of Ketone Supplements-Evoked Effect on Absence Epileptic Activity by Co-Administration of Uridine in Wistar Albino Glaxo Rijswijk Rats

Both uridine and exogenous ketone supplements decreased the number of spike-wave discharges (SWDs) in a rat model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It has been suggested that alleviating influence of both uridine and ketone supplements on absence epileptic activity may be modulated by A1 type adenosine receptors (A1Rs). The first aim was to determine whether intraperitoneal (i.p.) administration of a specific A1R antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 0.2 mg/kg) and a selective adenosine A2A receptor antagonist (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine) (SCH 58261; 0.5 mg/kg) have a modulatory influence on i.p. 1000 mg/kg uridine-evoked effects on SWD number in WAG/Rij rats. The second aim was to assess efficacy of a sub-effective dose of uridine (i.p. 250 mg/kg) combined with beta-hydroxybutyrate salt + medium chain triglyceride (KSMCT; 2.5 g/kg, gavage) on absence epilepsy. DPCPX completely abolished the i.p. 1000 mg/kg uridine-evoked alleviating effect on SWD number whereas SCH 58261 was ineffective, confirming the A1R mechanism. Moreover, the sub-effective dose of uridine markedly enhanced the effect of KSMCT (2.5 g/kg, gavage) on absence epileptic activity. These results demonstrate the anti-epilepsy benefits of co-administrating uridine and exogenous ketone supplements as a means to treat absence epilepsy.

Istradefylline to Treat Patients with Parkinson’s Disease Experiencing “Off” Episodes: A Comprehensive Review

Parkinson’s disease (PD) is a common neurodegenerative disorder that leads to significant morbidity and disability. PD is caused by a loss of dopaminergic, cholinergic, serotonergic, and noradrenergic neurons in the central nervous system (CNS), and peripherally; the syndromic parkinsonism symptoms of movement disorder, gait disorder, rigidity and tremor are mostly driven by the loss of these neurons in the basal ganglia. Unfortunately, a significant proportion of patients taking levodopa, the standard of care treatment for PD, will begin to experience a decrease in effectiveness at varying times. These periods, referred to as “off episodes”, are characterized by increased symptoms and have a detrimental effect on quality of life and disability. Istradefylline, a novel adenosine A2A receptor antagonist, is indicated as a treatment addition to levodopa/carbidopa in patients experiencing “off episodes”. It promotes dopaminergic activity by antagonizing adenosine in the basal ganglia. This review will discuss istradefylline as a treatment for PD patients with off episodes.