ABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Prostatic Neoplasms, Castration-Resistant , Male , Humans , B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung/drug therapy , Adenosine A2 Receptor Antagonists/adverse effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/etiology , Purinergic P1 Receptor Antagonists/therapeutic use , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/therapeutic use , Lung Neoplasms/drug therapy , Adenosine , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokineticsABSTRACT
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.
Subject(s)
Dyskinesias , Parkinson Disease , Adenosine A2 Receptor Antagonists/adverse effects , Antiparkinson Agents/adverse effects , Humans , Levodopa/adverse effects , Parkinson Disease/drug therapy , Purines , Treatment OutcomeSubject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Antiparkinson Agents/therapeutic use , Parkinson Disease/drug therapy , Purines/therapeutic use , Adenosine A2 Receptor Antagonists/administration & dosage , Adenosine A2 Receptor Antagonists/adverse effects , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/adverse effects , Carbidopa/administration & dosage , Carbidopa/adverse effects , Carbidopa/therapeutic use , Clinical Trials as Topic , Drug Administration Schedule , Humans , Levodopa/adverse effects , Levodopa/therapeutic use , Purines/administration & dosage , Purines/adverse effectsABSTRACT
Background: Gait disorders are common in Parkinson's disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A2A 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).
Subject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Parkinson Disease/drug therapy , Purines/therapeutic use , Adenosine A2 Receptor Antagonists/adverse effects , Administration, Oral , Aged , Drug Administration Schedule , Dyskinesias/etiology , Female , Gait/physiology , Gait Disorders, Neurologic/complications , Gait Disorders, Neurologic/drug therapy , Humans , Male , Middle Aged , Parkinson Disease/complications , Prospective Studies , Purines/adverse effects , Quality of Life , Treatment OutcomeABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Agonists/therapeutic use , Adenosine A2 Receptor Antagonists/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular System/drug effects , Receptors, Adenosine A2/drug effects , Signal Transduction/drug effects , Adenosine A2 Receptor Agonists/adverse effects , Adenosine A2 Receptor Antagonists/adverse effects , Animals , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Cardiovascular System/metabolism , Cardiovascular System/physiopathology , Humans , Molecular Targeted Therapy , Receptors, Adenosine A2/metabolism , Treatment OutcomeABSTRACT
In recent years, inactivation of A2A adenosine receptors has been emerged as a novel strategy for treatment of several neurodegenerative diseases. Although numerous studies have shown the beneficial effects of A2A receptors blockade on spatial memory, the impacts of selective adenosine A2A receptors on memory performance has not yet been examined in the context of demyelination. In the present study, we evaluated the effect of A2A 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⯵l) into the hippocampus fimbria. SCH58261 (20⯵g/0.5⯵l or 40⯵g/0.5⯵l) was daily injected intracerebroventricularly (i.c.v.) for 10â¯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 10â¯days post LPC injection. The administration of adenosine A2A 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 A2A receptor antagonist. Collectively, the results of this study suggest that A2A receptor blockade can improve the spatial memory and protect myelin sheath, which might be considered as a novel therapeutic approach for multiple sclerosis disease.
Subject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Lysophosphatidylcholines , Memory Disorders/etiology , Pyrimidines/therapeutic use , Receptor, Adenosine A2A , Spatial Memory/drug effects , Triazoles/therapeutic use , Adenosine A2 Receptor Antagonists/adverse effects , Animals , Astrocytes/drug effects , Demyelinating Diseases/pathology , Hippocampus/pathology , Injections, Intraventricular , Macrophage Activation/drug effects , Male , Maze Learning/drug effects , Memory Disorders/psychology , Microglia/drug effects , Pyrimidines/adverse effects , Rats , Rats, Wistar , Triazoles/adverse effectsABSTRACT
Adenosine A2A receptor antagonists are an alternative treatment strategy for Parkinson's disease. Several randomized placebo controlled studies have tested the effect of A2A 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.
Subject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Antiparkinson Agents/therapeutic use , Dyskinesia, Drug-Induced/etiology , Parkinson Disease/drug therapy , Purines/therapeutic use , Adenosine A2 Receptor Antagonists/adverse effects , Antiparkinson Agents/adverse effects , Humans , Purines/adverse effects , Treatment OutcomeABSTRACT
γ-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of Aß which is associated with Alzheimer's disease (AD). Here we identified that an anti-Parkinson's disease drug, Istradefylline, could enhance Aß generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of Aß42 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 Aß production. These effects of Istradefylline were reduced by the knockdown of A2AR but independent of A2AR-mediated G protein- or ß-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 Aß generation and γ-secretase activity. Thus, our study implies that the association of A2AR could modulate γ-secretase activity. Istradefylline enhance Aß 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).
Subject(s)
Adenosine A2 Receptor Antagonists/adverse effects , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Protein Precursor/genetics , Neurons/drug effects , Neuroprotective Agents/adverse effects , Purines/adverse effects , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/agonists , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Endosomes/drug effects , Endosomes/metabolism , Gene Expression Regulation , Humans , Mice , Mice, Transgenic , Neurons/cytology , Neurons/metabolism , Peptide Fragments/agonists , Peptide Fragments/genetics , Peptide Fragments/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Primary Cell Culture , Receptor, Adenosine A2A/deficiency , Receptor, Adenosine A2A/genetics , Signal Transduction , beta-Arrestins/genetics , beta-Arrestins/metabolismABSTRACT
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.
Subject(s)
Blood Pressure/physiology , Hypertension/complications , Hypertension/physiopathology , Hypotension, Orthostatic/complications , Hypotension, Orthostatic/physiopathology , Parkinson Disease/complications , Posterior Leukoencephalopathy Syndrome/etiology , Supine Position/physiology , Adenosine A2 Receptor Antagonists/adverse effects , Aged , Humans , Magnetic Resonance Imaging , Male , Neuroleptic Malignant Syndrome/etiology , Posterior Leukoencephalopathy Syndrome/diagnostic imaging , Purines/adverse effects , Severity of Illness IndexABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/adverse effects , Parkinson Disease/drug therapy , Purines/adverse effects , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/therapeutic use , Animals , Antiparkinson Agents/adverse effects , Antiparkinson Agents/pharmacology , Antiparkinson Agents/therapeutic use , Blood-Brain Barrier/metabolism , Dose-Response Relationship, Drug , Half-Life , Humans , Parkinson Disease/physiopathology , Purines/pharmacology , Purines/therapeutic useABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Parkinson Disease/drug therapy , Purines/pharmacology , Randomized Controlled Trials as Topic/methods , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/adverse effects , Adenosine A2 Receptor Antagonists/therapeutic use , Drug Synergism , Humans , Levodopa/therapeutic use , Purines/adverse effects , Purines/therapeutic useABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/adverse effects , Antiparkinson Agents/adverse effects , Benzothiazoles/adverse effects , Dyskinesia, Drug-Induced/diagnosis , Levodopa/adverse effects , Parkinson Disease/diagnosis , Parkinson Disease/drug therapy , Aged , Cross-Over Studies , Double-Blind Method , Dyskinesia, Drug-Induced/epidemiology , Female , Humans , Internationality , Male , Middle Aged , Parkinson Disease/epidemiologyABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Antiparkinson Agents/pharmacology , Pyrimidines/pharmacology , Adenosine A2 Receptor Antagonists/adverse effects , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/pharmacokinetics , Animals , Antiparkinson Agents/adverse effects , Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/pharmacokinetics , Brain/drug effects , Catalepsy , Dose-Response Relationship, Drug , Drug Interactions , HEK293 Cells , Haloperidol , Humans , Male , Mice , Microsomes, Liver/drug effects , Molecular Structure , Parkinsonian Disorders/drug therapy , Pyrimidines/adverse effects , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats, Wistar , Receptors, Adrenergic, alpha-2/metabolismABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Antiparkinson Agents/pharmacology , Parkinson Disease/drug therapy , Adenosine A2 Receptor Antagonists/adverse effects , Adenosine A2 Receptor Antagonists/chemistry , Animals , Antiparkinson Agents/adverse effects , Antiparkinson Agents/chemistry , Clinical Trials as Topic , Humans , Parkinson Disease/physiopathologyABSTRACT
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 ß-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.
Subject(s)
Antiparkinson Agents/therapeutic use , Gait Disorders, Neurologic/prevention & control , Molecular Targeted Therapy , Neurons/drug effects , Parkinson Disease/drug therapy , Serotonin Antagonists/therapeutic use , Tremor/prevention & control , Adenosine A2 Receptor Antagonists/adverse effects , Adenosine A2 Receptor Antagonists/therapeutic use , Animals , Antiparkinson Agents/adverse effects , Dopamine Agents/adverse effects , Drug Resistance , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/prevention & control , Gait Disorders, Neurologic/etiology , Humans , Levodopa/adverse effects , Mesencephalon/drug effects , Mesencephalon/metabolism , Monoamine Oxidase Inhibitors/adverse effects , Monoamine Oxidase Inhibitors/therapeutic use , Neurons/metabolism , Off-Label Use , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Serotonin Antagonists/adverse effects , Tremor/etiologyABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/adverse effects , Antiparkinson Agents/adverse effects , Long QT Syndrome/chemically induced , Pyrimidines/adverse effects , Triazoles/adverse effects , Adenosine A2 Receptor Antagonists/administration & dosage , Adenosine A2 Receptor Antagonists/pharmacology , Adolescent , Adult , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/pharmacology , Aza Compounds/administration & dosage , Aza Compounds/adverse effects , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Electrocardiography , Female , Fluoroquinolones , Humans , Male , Middle Aged , Moxifloxacin , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Quinolines/administration & dosage , Quinolines/adverse effects , Triazoles/administration & dosage , Triazoles/pharmacology , Young AdultABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/administration & dosage , Parkinson Disease/drug therapy , Purines/administration & dosage , Adenosine/antagonists & inhibitors , Adenosine/metabolism , Adenosine A2 Receptor Antagonists/adverse effects , Adenosine A2 Receptor Antagonists/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Disease Models, Animal , Dopamine Agonists/pharmacology , Dyskinesias/drug therapy , Half-Life , Humans , Levodopa/administration & dosage , Levodopa/adverse effects , Levodopa/pharmacokinetics , Purines/adverse effects , Purines/pharmacokinetics , Treatment OutcomeABSTRACT
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.
Subject(s)
Adenosine A2 Receptor Antagonists/therapeutic use , Parkinson Disease/drug therapy , Purines/therapeutic use , Adenosine A2 Receptor Antagonists/adverse effects , Aged , Antiparkinson Agents/therapeutic use , Drug Therapy, Combination , Female , Humans , Levodopa/therapeutic use , Male , Middle Aged , Purines/adverse effects , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
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.