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Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors., Patients and Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC., Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks., Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC., (©2022 The Authors; Published by the American Association for Cancer Research.)

As an adenosine receptor A2A antagonist, istradefylline is used as an adjunctive agent of levodopa to improve motor symptoms in advanced Parkinson's disease (PD) patients. In this study, we re-evaluated the effects of istradefylline on treating the motor symptoms of PD patients. We performed a literature search up to November 2021 from electronic databases. Eligible studies were synthesized for efficacy, tolerability, OFF time, Unified Parkinson's Disease Rating Scale part III score, ON state with dyskinesia, and the incidence of treatment-emergent adverse events. As a result, nine clinical studies with 2727 subjects on istradefylline treatment for PD patients were included. Our results showed that compared to placebo, istradefylline exhibited a statically significant difference in efficacy (1.39 [1.15 to 1.69]; p = 0.001), decreasing OFF time (-0.58 [-1.01 to - 0.16]; p = 0.007), and improving ON state with dyskinesia (0.69 [0.02 to 1.37]; p = 0.043). For tolerability, UPDRS III, and adverse effects, there was no significant difference between istradefylline and placebo. In conclusion, the results suggest that istradefylline exhibits an efficient and well-tolerated role in treating PD patients. Randomized controlled trials and long-term studies are still required to investigate the effects of istradefylline on motor and non-motor symptoms of PD in future research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background : Gait disorders are common in Parkinson's disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A 2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A 2A receptor antagonist with benefits for motor complications associated with Parkinson's disease. Research design and methods : This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson's disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed. Results : MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4-12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients. Conclusions : Istradefylline improved gait disorders in Parkinson's disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified. Trial registration : UMIN-CTR (UMIN000020288).

Adenosine and its analogs are of particular interest as potential therapeutic agents for treatment of cardiovascular diseases (CVDs). A2 adenosine receptor subtypes (A2a and A2b) are extensively expressed in cardiovascular system, and modulation of these receptors using A2 adenosine receptor agonists or antagonists regulates heart rate, blood pressure, heart rate variability, and cardiovascular toxicity during both normoxia and hypoxia conditions. Regulation of A2 adenosine receptor signaling via specific and novel pharmacological regulators is a potentially novel therapeutic approach for a better understanding and hence a better management of CVDs. This review summarizes the role of pharmacological A2 adenosine receptor regulators in the pathogenesis of CVDs., (© 2018 Wiley Periodicals, Inc.)

In recent years, inactivation of A 2A adenosine receptors has been emerged as a novel strategy for treatment of several neurodegenerative diseases. Although numerous studies have shown the beneficial effects of A 2A receptors blockade on spatial memory, the impacts of selective adenosine A 2A receptors on memory performance has not yet been examined in the context of demyelination. In the present study, we evaluated the effect of A 2A receptor antagonist SCH58261 on spatial memory and myelination in an experimental model of focal demyelination in rat fimbria. Demyelination was induced by local injection of lysolecithin (LPC) 1% (2 μl) into the hippocampus fimbria. SCH58261 (20 μg/0.5 μl or 40 μg/0.5 μl) was daily injected intracerebroventricularly (i.c.v.) for 10 days post LPC injection. The Morris water maze test was used to assess the spatial learning and memory on day 6 post lesion. Myelin staining and immunostaining against astrocytes/microglia were carried out 10 days post LPC injection. The administration of adenosine A 2A receptor antagonist prevented the spatial memory impairment in LPC receiving animals. Myelin staining revealed that application of SCH58261 reduces the extent of demyelination areas in the fimbria. Furthermore, the level of astrocytes and microglia activation was attenuated following administration of A 2A receptor antagonist. Collectively, the results of this study suggest that A 2A receptor blockade can improve the spatial memory and protect myelin sheath, which might be considered as a novel therapeutic approach for multiple sclerosis disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adenosine A 2A receptor antagonists are an alternative treatment strategy for Parkinson's disease. Several randomized placebo controlled studies have tested the effect of A 2A receptor antagonist istradefylline, and more robust evidence has been acquired. This meta-analysis aimed to provide evidence for its efficacy and safety on patients with Parkinson's disease. After a systematic literature search, we calculated the pooled standardized mean difference and risk ratio for continuous and dichotomous variables, respectively. Further, sensitivity analyses were performed to confirm the effect estimated by meta-analyses. Publication bias was assessed by funnel plot and deviation of intercept. Six studies satisfied our inclusion criteria. Istradefylline (40 mg/day) decreased off time and improved motor symptoms of Parkinson's disease in homogeneous studies. Istradefylline at 20 mg/day decreased off time and improved motor symptoms, but heterogeneity was found in the analysis of the former among studies. There was a significant effect of istradefylline on dyskinesia in homogeneous studies. Publication bias, however, was observed in the comparison of dyskinesia. Other adverse events showed no significant difference. The present meta-analysis suggests that istradefylline at 40 mg/day could alleviate off time and motor symptoms derived from Parkinson's disease. Dyskinesia might be worsened, but publication bias prevents this from being clear.

We present the case of a 77-year-old man with a 10-year history of Parkinson disease (PD), who developed posterior reversible encephalopathy syndrome (PRES). We diagnosed the case as PRES based on clinical features and MRI findings. He experienced orthostatic hypotension and supine hypertension, including nocturnal hypertension. PRES may result from marked supine/nocturnal hypertension and fluctuation in blood pressure. In addition, exacerbated factors could be representative of neuroleptic malignant syndrome. The hypertensive effect of istradefylline should also not be excluded. We believe this is the first case report of a patient with PD developing PRES without vasopressor use.

γ-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of Aβ which is associated with Alzheimer's disease (AD). Here we identified that an anti-Parkinson's disease drug, Istradefylline, could enhance Aβ generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of Aβ42 was detected in the cortex of APP/PS1 mouse after chronic treatment with Istradefylline. Istradefylline promoted the activity of γ-secretase which could lead to increased Aβ production. These effects of Istradefylline were reduced by the knockdown of A2AR but independent of A2AR-mediated G protein- or β-arrestin-dependent signal pathway. We further observed that A2AR colocalized with γ-secretase in endosomes and physically interacted with the catalytic subunit presenilin-1 (PS1). Interestingly, Istradefylline attenuated the interaction in time- and dosage-dependent manners. Moreover the knockdown of A2AR which in theory would release PS1 potentiated both Aβ generation and γ-secretase activity. Thus, our study implies that the association of A2AR could modulate γ-secretase activity. Istradefylline enhance Aβ generation and γ-secretase activity possibly via modulating the interaction between A2AR and γ-secretase, which may bring some undesired effects in the central nervous system (CNS)., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Antagonism of the A2A receptor improves motor behavior in patients with Parkinson's disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline , has the longest half-life out of the available A2A receptor antagonists. Istradefylline easily crosses the blood-brain barrier and shows a high affinity to the human A2A receptor., Areas Covered: This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug portfolio for the treatment of PD patients., Expert Opinion: Istradefylline was safe and well tolerated in clinical trials, which have focused on l-DOPA-treated PD patients. The future of istradefylline as a complementary drug for modulation of the dopaminergic neurotransmission also relies on its potential to act like an l-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of predominant l-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istradefylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.

Adenosine A2A receptor antagonist istradefylline has been approved this year for manufacturing and marketing in Japan. We, therefore, did this meta-analysis to systematically assess the efficacy and safety of istradefylline as augmentation to levodopa in patients with Parkinson's disease (PD). We systematically review the relative randomized controlled trials (RCTs) up to March 2014, which compared istradefylline to placebo for the short course of treatment for PD in adults. The primary outcome was daily OFF time and secondary outcome was UPDRS Part III score (on state). Data were obtained from seven RCTs, including 2205 patients. Compared to placebo on primary and secondary outcome, istradefylline group both showed significant reductions (WMD -0.60, p = 0.0001; WMD -1.07, p = 0.002). Subgroup analysis suggested that istradefylline 20, 40, and 60 mg/day in both group showed significant reductions on the two outcomes. Based on these results, Istradefylline could be an efficacy and safety augmentation drug added on to levodopa or other existing anti-Parkinsonian therapies. Limited by the number of studies, future large-scale studies are needed to verify these results, assess the long-term effect of istradefylline and the effect of istradefylline as monotherapy, and find the most effective dose of istradefylline.

Parkinson's disease is a neurodegenerative disease characterized by the motor symptoms of bradykinesia, tremor, and rigidity. Current therapies are based mainly on dopaminergic replacement strategies by administration of either dopamine agonists or dopamine precursor levodopa (L-Dopa). These treatments provide symptomatic relief without slowing or stopping the disease progression, and long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinisia. Unfortunately, there had been few novel treatments developed in the past decades. Among nondopaminergic strategies for the treatment of Parkinson's disease, antagonism of the adenosine A2A receptor has emerged to show great potential. Here we report the optimization of a new chemical scaffold, which achieved exceptional receptor binding affinity and ligand efficiency against adenosine A2A receptor. The leading compounds demonstrated excellent efficacy in the haloperidol induced catalepsy model for Parkinson's disease.

Background: Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa., Methods: We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594., Findings: Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1·1 h, 95% CI -1·8 to -0·5; p=0·0006), the tozadenant 120 mg twice-daily group (-1·1 h, -1·8 to -0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (-1·2 h, -1·9 to -0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients)., Interpretation: Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted., Funding: Biotie Therapies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatology. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates. The development of new highly selective adenosine A2A receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clinical research regarding A2A antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivatives in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compounds have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A2A antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. In addition, early findings suggest that A2A antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacological and clinical data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.

Purpose: Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization., Methods: This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5., Results: The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID., Conclusions: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR₅) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.

Introduction: Recent experimental and clinical research has shown that A2A adenosine receptor antagonism can bring about an improvement in the motor behavior of patients with Parkinson's disease. Istradefylline , a xanthine derivative, has the longest half-life of all the currently available A2A adenosine receptor antagonists; it can successfully permeate through the blood-brain barrier and has a high human A2A adenosine receptor affinity., Areas Covered: In this article, the author discusses the potential role of A2A adenosine receptor antagonists in the treatment of Parkinson's disease through the evaluation of istradefylline. Specifically, the article reviews the clinical and pharmacokinetic information available to elucidate its therapeutic potential., Expert Opinion: A2A adenosine receptor antagonists are efficacious in combination with l-dopa. l-dopa has a complex pharmacokinetic behavior and causes long-term behavioral and metabolic side effects. Future research on A2A adenosine receptor antagonism should consider compounds like istradefylline as l-dopa and/or dopamine agonist-sparing treatment alternatives, since their clinical handling, safety and side-effect profile are superior to l-dopa and/or dopamine agonists. The current focus to demonstrate a specific dyskinesia-ameliorating efficacy of A2A adenosine receptor antagonism in clinical trials is risky, since the presentation of dyskinesia varies on a day-to-day basis and is considerably influenced by peripheral l-dopa metabolism. The demonstration of an antidyskinetic effect may convince authorities, but this is far less relevant in clinical practice as patients generally better tolerate dyskinesia than other phenomena and dopaminergic side effects.

Objectives: To assess the efficacy and safety of istradefylline as an adjunct to levodopa in patients with Parkinson's Disease (PD)., Methods: In this study, we searched the Cochrane Library, MEDLINE, Embase, China Academic Journal Full-text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Scientific Journals Database (VIP), and Wanfang Database. The quality of included studies was strictly evaluated. Data analyses were performed by the Cochrane Collaboration's RevMan5.0 software., Results: Five randomized controlled trials (RCTs) were included. The result showed a significant reduction of the awake time per day spent in the OFF state and improvement of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III in the ON state when receiving istradefylline compared with patients receiving placebo. There was no significant difference between the istradefylline 20mg and the istradefylline 40 mg groups in the UPDRS Part III in the ON state (WMD=1.27, 95% CI [-0.40, 2.95]). The results showed significant differences in dyskinesia (RR=1.63, 95% CI [1.16, 2.29]) compared to istradefylline 40 mg with placebo. There was no significant statistical difference with regard to other adverse events., Conclusions: The present study showed that istradefylline is safe and effective as an adjunct to levodopa in patients with PD. Future large-scale, higher-quality, long-treatment, and placebo-controlled trials are needed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This model-based analysis quantifies the population pharmacokinetic-pharmacodynamic efficacy and safety/tolerability relationships of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy participants and patients with Parkinson disease. Data from 6 phase 2/3 clinical trials comprised the population database, with 1760 and 1798 patients contributing to the efficacy and safety/tolerability analyses, respectively. The relationship between istradefylline area under the curve at steady state and percentage OFF time was described by a nonlinear model (Emax) based on time for the disease progression/placebo response component and an Emax model for the effect of istradefylline. The typical maximum decrease in percentage OFF time due to istradefylline exposure would be 5.79% (95% confidence interval = 4.09%-7.49%) with one-half of the maximum effect reached at an exposure of 1690 ng × hr/mL (95% confidence interval = 199-3180 ng × hr/mL). The pharmacokinetic-pharmacodynamic relationships for dyskinesia and dizziness were described by an Emax model, and for nausea, a power model was used. The probabilities of dyskinesia and dizziness are expected to plateau at a dose of 40 mg/d, and the probability of nausea is expected to continually rise as the dose is increased. Collectively, these results support a starting istradefylline dose of 20 to 40 mg/d.

Regadenoson (REG) is a A2a receptor selective pharmacologic SPECT imaging agent. Its safety in unselected chronic obstructive pulmonary disease (COPD) or asthma (AM) undergoing SPECT imaging has not been well evaluated. We retrospectively identified 228 patients (COPD n = 126 and AM n = 102, Grp 1) undergoing REG SPECT from Jan to Nov 2009 and compared to 1,142 patients without COPD and AM (control, Grp 2). A standard 400 μg REG bolus was used and gated Tc-99 m tetrofosmin SPECT done. Patient demographics, REG SPECT data, side effects, arrhythmia occurrences, and any exacerbation of COPD or AM leading to treatment, hospitalization or death were evaluated. The side effect profile of Grp 1 was also compared to a historical cohort who underwent intravenous dipyridamole thallium-201 imaging and adenosine SPECT. Both groups were comparable with regards to baseline characteristics. There was 0% incidence of clinical exacerbation of COPD or AM after REG. COPD patients had more non-significant arrhythmias (58.3% vs. Grp 2, 43%, P = 0.004). There was 0% incidence of any atrio-ventricular block and only 2 instances of brief supraventricular tachycardia. When compared to the historical cohort of COPD who underwent IV dipyridamole thallium imaging, COPD in Grp 1, had more dyspnea and flushing and when compared to COPD/AM patients who underwent adenosine SPECT, Grp 1 pts had more of flushing and headache (24.9% vs. 2.8%, P = <0.001) but less of bronchospasm (1.3% vs. 6.9%, P = 0.022) and AV block (0% vs. 4.2%, P = 0.014). REG SPECT can be safely performed in COPD and AM population.

The A2(A) receptor agonist, regadenoson, is increasingly used as a vasodilator during nuclear myocardial perfusion imaging. Regadenoson is administered as a single, fixed dose. Given the frequency of obesity in patients with symptoms of heart disease, it is important to know whether the fixed dose of regadenoson produces maximal coronary hyperemia in subjects of widely varying body size. Thirty subjects (12 female, 18 male, mean BMI 30.3 ± 6.5, range 19.6-46.6) were imaged on a 3T magnetic resonance scanner. Imaging with a saturation recovery radial turboFLASH sequence was done first at rest, then during adenosine infusion (140 μg/kg/min) and 30 min later with regadenoson (0.4 mg/5 ml bolus). A 5 cc/s injection of Gd-BOPTA was used for each perfusion sequence, with doses of 0.02, 0.03 and 0.03 mmol/kg, respectively. Analysis of the upslope of myocardial time-intensity curves and quantitative processing to obtain myocardial perfusion reserve (MPR) values were performed for each vasodilator. The tissue upslopes for adenosine and regadenoson matched closely (y = 1.1x + 0.03, r = 0.9). Mean MPR was 2.3 ± 0.6 for adenosine and 2.4 ± 0.9 for regadenoson (p = 0.14). There was good agreement between MPR measured with adenosine and regadenoson (y = 1.1x - 0.06, r = 0.7). The MPR values measured with both agents tended to be lower as BMI increased. There were no complications during administration of either agent. Regadenoson produced fewer side effects. Fixed dose regadenoson and weight adjusted adenosine produce similar measures of MPR in patients with a wide range of body sizes. Regadenoson is a potentially useful vasodilator for stress MRI studies.

Single-photon emission computerized tomography for myocardial perfusion imaging (MPI) is a non-invasive technique. MPI is performed by subjecting the patient to exercise or by using a pharmacological stress agent. Regadenoson is a selective A 2A adenosine receptor agonist used when MPI with exercise is contraindicated. It binds to the A 2A receptor and stimulates adenylate cyclase, resulting in increased cAMP, which phosphorylates protein kinase A thereby opening the ATP-dependant potassium channels leading to hyperpolarization in the coronary vascular smooth muscle. After a single bolus dose of regadenoson 400 μg, a peak plasma concentration (C max) of 13.6 ng/mL is attained in 1-4 min, with a terminal half-life of 2 h. It has a quick onset, short duration sufficient enough for hyperemic response, with comparable efficacy to adenosine, but with fewer side-effects. The adverse effects of this drug are dyspnea, headache, flushing, chest pain and atrioventricular block. Regadenoson is used for MPI in patients with co-morbid conditions like mild-to-moderate reactive airway disease, obstructive lung disease and renal impairment.

Background: The safety and tolerability of regadenoson, a pharmacologic stress agent that is excreted primarily by the kidneys, were examined in subjects with chronic kidney disease (CKD)., Methods: This multicenter, double-blind, randomized, placebo-controlled study involved men and women, ≥18 years of age, with stage 3 or 4 [estimated glomerular filtration rate (eGFR) 30-59 mL/minute/1.73 m(2) and 15-29 mL/minute/1.73 m(2), respectively] CKD and known or suspected coronary artery disease. Subjects were randomized 2:1 to receive one 10-second intravenous injection of regadenoson 0.4 mg or placebo. The primary outcome measure was the frequency of serious adverse events over 24-h post-dose., Results: The study included 432 subjects with stage 3 (regadenoson n = 287; placebo n = 145) and 72 with stage 4 (regadenoson n = 47; placebo n = 25) CKD. No serious adverse events or deaths were reported over 24-h post-dose. The overall adverse event incidence was higher with regadenoson than placebo (62.6% vs 21.2%; P < .0001). Of the most common adverse events (≥5%) reported by subjects receiving regadenoson, headache (24.9% vs 7.1%), dyspnea (19.2% vs 0.6%), chest discomfort (14.7% vs 0.6%), nausea (14.7% vs 1.2%), flushing (12.0% vs 1.8%), and dizziness (9.6% vs 0.6%) occurred significantly more often (P < .0001) with regadenoson than placebo. There were no trends for clinically meaningful changes in eGFR from baseline to 24-h post-dose in subjects with stage 3 or 4 CKD., Conclusions: Regadenoson was not associated with any serious or unexpected adverse events in subjects with stage 3 or 4 CKD.

Introduction: Despite several available therapeutic options to treat the symptoms of Parkinson's disease (PD), there are currently no agents that halt or slow the progression of disease. Istradefylline is a selective adenosine A(2A) antagonist that is currently of interest for the treatment of motor complications in PD., Areas Covered: This paper reviews the limitations of currently available treatment options and discusses the results seen in both animal models and human clinical trials that have explored the benefits of istradefylline in PD., Expert Opinion: The studies outlined continue to suggest that istradefylline may be a promising non-dopaminergic therapy for the treatment of PD. It has not been proven to be more efficacious than other currently available dopaminergic drugs, nor has it been shown to be of significant benefit as monotherapy; however, it seems to be a safe and well-tolerated drug that may help with wearing-off fluctuations. Istradefylline is not yet an FDA-approved drug. At this time, the potential for approval in the US or through the European Medical Agency remains unknown.

Adenosine A(2a) receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A(2a) antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A(2a) antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.

Adenosine A(2A) receptor (A(2A)R) antagonists are being investigated as promising treatment strategy for Parkinson's disease (PD). To test whether A(2A)R antagonists are beneficial in early PD stages we used MitoPark mice, a genetic model with gradual degeneration of DA cells. Daily treatment of young MitoPark mice for eight weeks with the A(2A)R antagonist MSX-3 prevented the reduction of spontaneous locomotor activity observed in saline or L-DOPA treated animals. Chronic A(2A)R antagonist treatment neither induced desensitization of receptors nor accumulation of the drug in brain tissue. Despite beneficial effects on behavior, which are not improved upon addition of a low dose of L-DOPA, the characteristic decline of dopamine levels was not changed. Our results indicate that effective dosing with A(2A)R antagonists should be tested as monotherapy in early PD, and serves to remind us that positive behavioral effects of such treatment need not be reflected in rescue of striatal dopamine levels., (Copyright 2010 Elsevier Inc. All rights reserved.)

Adenosine A(2A) receptor antagonists exert antiparkinsonian effects in animal models and several drugs in this class are currently being assessed in clinical trials. Preladenant (SCH-420814) is an adenosine A(2A) receptor antagonist with a high affinity and very high selectivity for adenosine A(2A) receptors, which is being developed by Merck & Co Inc (following its acquisition of Schering-Plough Corp) for the potential treatment of Parkinson's disease. Preclinical studies in rodent and primate models of parkinsonism demonstrated that preladenant can reverse the motor impairments induced by dopamine depletion or antagonism. Phase I and II clinical trials indicated that preladenant was well tolerated. Moreover, preladenant met its major endpoints by reducing OFF time and increasing ON time in l-DOPA-treated patients with Parkinson's disease, without worsening dyskinesias. Therefore, preladenant may have considerable utility for the treatment of Parkinson's disease, as well as the parkinsonian side effects of dopamine D2 receptor antagonists. As research has suggested that adenosine A(2A) receptor antagonists are active in animal models of effort-based decision making, it is possible that preladenant could also be useful for treating energy-related symptoms, such as fatigue, psychomotor retardation and anergia in patients with parkinsonism or depression. At the time of publication, phase III clinical trials were recruiting patients with Parkinson's disease.