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Tomoyuki Kanda - One of the best experts on this subject based on the ideXlab platform.
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A Pooled Analysis From Phase 2b and 3 Studies in Japan of Istradefylline in Parkinson's Disease.
Movement disorders : official journal of the Movement Disorder Society, 2020Co-Authors: Nobutaka Hattori, Tomoyuki Kanda, Hiroki Kitabayashi, Takanobu Nomura, Keizo Toyama, Akihisa MoriAbstract:Background Characterization of patient factors associated with Istradefylline efficacy may facilitate personally optimized treatment. Objectives We aimed to examine which patient factors are associated with favorable Istradefylline treatment outcomes in PD patients with motor complications. Methods We performed a pooled analysis of data from two identical phase 2b and 3 Japanese studies of Istradefylline. Logistic regression models were used to assess the association of 12 patient characteristics with favorable outcomes. Results Off time reduction and increased good on time with Istradefylline provided a significantly favorable response in patients aged ≥65 years. Off time reduction was more favorable in patients with ≥8-hour daily off time at baseline. Improvement in UPDRS Part III was favorable in patients with UPDRS Part III baseline score ≥ 20. Conclusions Several patient factors influenced the effect of Istradefylline on motor fluctuations, motor function, activities of daily living, and clinical impression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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The adenosine A2A receptor antagonist, Istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets.
European journal of pharmacology, 2015Co-Authors: Shinichi Uchida, Akihisa Mori, Peter Jenner, Kazuhiro Soshiroda, Eri Okita, Mika Kawai-uchida, Tomoyuki KandaAbstract:The adenosine A2A receptor antagonist, Istradefylline improves motor function in patients with advanced Parkinson's disease (PD) optimally treated with a combination of L-DOPA and a dopamine agonist without increasing the risk of troublesome dyskinesia. However, the effects of Istradefylline on motor function when administered in combination with low dose of L-DOPA and dopamine agonists as occurs in early PD are unknown. We investigated whether Istradefylline enhances the combined anti-parkinsonian effects of a suboptimal dose of L-DOPA and a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Threshold doses of ropinirole (0.025-0.075 mg/kg p.o.) and pergolide (0.01 mg/kg p.o.) produced a weak anti-parkinsonian effect. Co-administration of a suboptimal dose of L-DOPA (2.5mg/kg p.o.) with threshold doses of the dopamine agonists enhanced their anti-parkinsonian effect that led to increased 'ON' time without dyskinesia appearing. Administering Istradefylline (10mg/kg p.o.) with the threshold doses of dopamine agonists and the suboptimal dose of L-DOPA in a triple combination caused a further enhancement of the anti-parkinsonian response but dyskinesia was still absent. In early PD, dopamine agonists are often used as first-line monotherapy, but efficacy is usually lost within a few years, at which time L-DOPA is added but with the risk of dyskinesia appearance. These results show that Istradefylline is effective in improving motor function in combination with low dose dopaminergic drug treatment without provoking dyskinesia.
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The adenosine A2A receptor antagonist, Istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets
European journal of pharmacology, 2014Co-Authors: Shinichi Uchida, Akihisa Mori, Peter Jenner, Kazuhiro Soshiroda, Eri Okita, Mika Kawai-uchida, Tomoyuki KandaAbstract:Abstract The adenosine A 2A receptor antagonist, Istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson׳s disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged ‘OFF’ periods. In contrast, the effects of Istradefylline on motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether Istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Both ropinirole (0.01–0.1 mg/kg p.o.) and pergolide (0.003–0.1 mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of ropinirole (0.025–0.075 mg/kg p.o.) and pergolide (0.01–0.075 mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of Istradefylline (10 mg/kg p.o.) alone resulted in a decrease in motor disability and increase in ‘ON’ time but dyskinesia was not observed. Combined administration of pergolide or ropinirole with Istradefylline resulted in an increase in the reversal of motor disability and increase in ‘ON’ time compared to that produced by either treatment alone but dyskinesia was still not observed. These results show that Istradefylline is effective in improving motor function when combined with low dose dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting.
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the adenosine a2a receptor antagonist Istradefylline enhances the motor response of l dopa without worsening dyskinesia in mptp treated common marmosets
Journal of Pharmacological Sciences, 2014Co-Authors: Shinichi Uchida, Akihisa Mori, Peter Jenner, Tomomi Tashiro, Mika Kawaiuchida, Tomoyuki KandaAbstract:Abstract The adenosine A2A-receptor antagonist Istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with submaximal doses of l -DOPA. However, the effects of combining Istradefylline with sub-optimal l -DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of Istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to l -DOPA. In these animals, single dose acute oral administration of Istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of l -DOPA (2.5 mg/kg). The chronic co-administration of Istradefylline (10 mg/kg) with l -DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that Istradefylline can be used to potentiate the effects of sub-optimal doses of l -DOPA in the treatment of Parkinson’s disease without causing or worsening dyskinesia.
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Antidepressant activity of the adenosine A2A receptor antagonist, Istradefylline (KW-6002) on learned helplessness in rats.
Psychopharmacology, 2014Co-Authors: Koji Yamada, Akihisa Mori, Minoru Kobayashi, Peter Jenner, Shizuo Shiozaki, Teruko Ohta, Tomoyuki KandaAbstract:Rationale Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson’s disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests.
Akihisa Mori - One of the best experts on this subject based on the ideXlab platform.
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A Pooled Analysis From Phase 2b and 3 Studies in Japan of Istradefylline in Parkinson's Disease.
Movement disorders : official journal of the Movement Disorder Society, 2020Co-Authors: Nobutaka Hattori, Tomoyuki Kanda, Hiroki Kitabayashi, Takanobu Nomura, Keizo Toyama, Akihisa MoriAbstract:Background Characterization of patient factors associated with Istradefylline efficacy may facilitate personally optimized treatment. Objectives We aimed to examine which patient factors are associated with favorable Istradefylline treatment outcomes in PD patients with motor complications. Methods We performed a pooled analysis of data from two identical phase 2b and 3 Japanese studies of Istradefylline. Logistic regression models were used to assess the association of 12 patient characteristics with favorable outcomes. Results Off time reduction and increased good on time with Istradefylline provided a significantly favorable response in patients aged ≥65 years. Off time reduction was more favorable in patients with ≥8-hour daily off time at baseline. Improvement in UPDRS Part III was favorable in patients with UPDRS Part III baseline score ≥ 20. Conclusions Several patient factors influenced the effect of Istradefylline on motor fluctuations, motor function, activities of daily living, and clinical impression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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A Pooled Analysis for Eight Randomized Controlled Trials of Istradefylline, an Adenosine A2A Receptor Antagonist: Efficacy as Adjunct to Levodopa in Parkinson’s Disease (PD) (P3.8-030)
Neurology, 2019Co-Authors: Stuart Isaacson, Akihisa Mori, Marc Cantillon, Nobutaka Hattori, Keizo Toyama, Marco Onofrj, Phyllis M. Salzman, Eri Ohta, Peter A LewittAbstract:Objective: Pooled efficacy analyses of eight randomized, placebo-controlled studies of Istradefylline combined with levodopa in patients with PD and motor fluctuations. Background: Istradefylline, a well-tolerated selective adenosine A2A receptor antagonist, acts via the indirect basal ganglia outflow pathway. In 2013, doses of 20 and 40mg/day were approved in Japan as adjunctive treatment to levodopa-containing products in patients with PD experiencing wearing-off phenomena. Design/Methods: Istradefylline was evaluated in patients with PD who concomitantly received levodopa with carbidopa or benserazide and experienced motor-response fluctuations (n=3245 randomized). Eight 12- or 16-week randomized, placebo-controlled, double-blind Phase 2b/3 clinical studies were conducted globally; change in OFF-time in daily, patient-completed 24-hour ON/OFF diaries provided the primary endpoint. Seven of eight studies shared common methodology. Pooled analysis results from once-daily oral Istradefylline (20 and 40mg/day) and placebo, evaluated using a mixed-model repeated-measures approach (including study as a variable), are presented. Results: The pooled analysis included 2719 treated patients (placebo, n=992; 20 mg/day, n=848; 40 mg/day, n=879). At week 12, OFF-hours/day with 20 and 40mg Istradefylline was reduced (LS mean difference from placebo in reduction from baseline [95%CI], −0.38 [−0.61, −0.15] and −0.45 [−0.68, −0.22], respectively). ON-hours/day without troublesome dyskinesia increased from baseline with Istradefylline compared with placebo (LS mean difference from placebo [95%CI], 20mg, 0.40 [0.15, 0.66]; 40mg, 0.33 [0.08, 0.59]). Istradefylline was well-tolerated, with an average completion rate of 89% across all studies. Dyskinesia was the most frequent AE (8% higher incidence with Istradefylline than placebo). Five studies showed statistical improvement with Istradefylline over placebo for OFF-time; additional analysis of these five studies and other secondary outcomes will be presented. Conclusions: Istradefylline offers an adenosine A2A receptor-mediated, nondopaminergic mechanism for patients with PD on levodopa with motor fluctuations. Istradefylline significantly improved OFF-time and ON-time without troublesome dyskinesia in the pooled analysis of eight studies, as well as in five individual trials. Disclosure: Dr. Isaacson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbvie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Avid, Axovant, AZTherapies, Biogen, Britannia, Eisai, Eli Lilly, Enterin, GE Healthcare, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, NeuroDerm, NINDS/NIH, Parkinson Study Group, Pfizer, Pharma Two B, Roche, Sanofi, Sunovion, Teva, UCB, US WorldMeds, and Zambon. Dr. Isaacson has received research support from Abbvie, Acadia, Acorda, Adamas, Amarantus, Axovant, AZ Therapies, Benevolent, Biogen, Cavion, Eli Lilly, Enterin, Impax, Intec Pharma, Jazz, Ipsen, Kyowa, Lundbeck, Michael J. Fox Foundation, Neuroderm, Parkinson Study Group, Pfizer, Pharma2B, Roche, Sanofi, Sunovion, Teva, UCB, US WorldMeds. Dr. Hattori has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dai-Nippon Sumitomo Pharma Co.,Ltd., Otsuka Pharmaceutical, Co.,Ltd, Takeda Pharmaceutical Co.,Ltd. Kyowa Hakko-Kirin Co.,Ltd., Sanofi K.K., Dai-Nippon Sumitomo Pharma Co.,Ltd, Meiji Seika Pharma, Biogen Japan Ltd., Hisamitsu Pharmaceutical Co.,Inc, Biogen Japan Ltd, Mitsubishi Tanabe Pharma Corporation, AbbVie GK, Alexion Pharmaceuticals, FP Pharmaceutical Corporation, Otsuka Pharmaceutical, Co.Ltd, Kyowa Hakko-Kirin Co.,Ltd., Daiichi Sankyo Co., Dai-Nippon Sumitomo Pharma Co.,Ltd, Takeda Pharmaceutical Co.,Ltd, Nippon Boehringer Ingelheim,Co.,Ltd, Medtronic, Inc., MSD K.K., Novartis Pharma K.K., Pfizer Japan Inc., Boston Scientific Corporation, Mylan N.V, Medtronic, Inc., Lund Beck Japan. Dr. Hattori has received research support from Astellas Pharma Inc., FP Pharmaceutical Corporation, Daiichi Sankyo Co., Takeda Pharmaceutical Co.,Ltd., Dai-Nippon Sumitomo Pharma Co.,Ltd, Medtronic, Inc., Boston Scientific Corporation, Kyowa Hakko-Kirin Co.,Ltd, Nippon Boehringer Ingelheim,Co.,Ltd, AbbVie GK, FP Pharmaceutical Corporation, Dai-Nippon Sumitomo Pharma Co.,Ltd,, Otsuka Pharmaceutical, Co.,Ltd, Nihon Medi-physics Co.,Ltd., Eisai Co.,Ltd., Mitsubishi Tanabe Pharma Corporation, Nihon Pharmaceutical Co., Ltd., OHARA Pharmaceutical Co.,Ltd., MiZ Co., Ltd., Ono Pharmaceutical Co., Ltd., Asahi Kasei Medical Co. Ltd.. Dr. Onofrj has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GlaxoSmithKline, Novartis, Lundbeck, Eisai, Valeant, MedTronic, and Newron, Zambon, the World Parkinson Congress, the Movement Disorder Society, and the Atypical Dementias congress; was an invited guest and lecturer for the Mental Disorders in Parkinson Disease Congress, Boehringer/Inghelheim, GlaxoSmithKline, UCB, and Zambon. Dr. Onofrj has received personal compensation in an editorial capacity for Medicine. Dr. Onofrj has received research support from Italian Ministry of Health and the Italian Ministry of Education. . Dr. Mori has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Kyowa Hakko Kirin Co., Ltd. Dr. Toyama has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Kyowa Hakko Kirin Co., Ltd. Dr. Salzman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Kyowa Kirin Pharmaceutical Development, Inc.. Dr. Cantillon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Reviva, Lundbeck, Takeda, Allergan. Dr. Ohta has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Kyowa Kirin Pharmaceutical Development, Inc. Dr. LeWitt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda Therapeutics, Adamas Pharmaceuticals, Britannia, Intec Pharma, Jazz Pharmaceuticals, Lundbeck, Acadia Pharmaceuticals, Merz, NeuroDerm Ltd, Pfizer, Prexton, Sage Therapeutics, Scion, Sunovion Pharmaceuticals, SynAgile, and US WorldMeds. Dr. LeWitt has received research support from Bioelectron Technology Corporation, Biotie Therapies, Intec Pharma, Lundbeck, Michael J. Fox Foundation for Parkinson’s Research, Parkinson Study Group, Sunovion, and US WorldMeds.
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safety and effectiveness of Istradefylline in patients with parkinson s disease interim analysis of a post marketing surveillance study in japan
Expert Opinion on Pharmacotherapy, 2018Co-Authors: Makio Takahashi, Mayumi Saki, Masaki Fujita, Naoko Asai, Akihisa MoriAbstract:Background: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A2A receptor antagonist for the treatment of Parkinson’s disease (PD) in patients experiencing the wearing-off ...
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Safety and effectiveness of Istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan
Expert opinion on pharmacotherapy, 2018Co-Authors: Makio Takahashi, Mayumi Saki, Masaki Fujita, Naoko Asai, Akihisa MoriAbstract:Background: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A2A receptor antagonist for the treatment of Parkinson’s disease (PD) in patients experiencing the wearing-off ...
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Safety and effectiveness of Istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan
2018Co-Authors: Makio Takahashi, Mayumi Saki, Masaki Fujita, Naoko Asai, Akihisa MoriAbstract:Background: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A2A receptor antagonist for the treatment of Parkinson’s disease (PD) in patients experiencing the wearing-off phenomenon with levodopa (L-DOPA). The authors present an interim report from a post-marketing surveillance (PMS) evaluating the safety and effectiveness of long-term Istradefylline in a real-world setting. Research design and methods: Istradefylline safety was assessed by the incidence of adverse events (AE) and adverse drug reactions (ADRs). Effectiveness was assessed using the physician’s assessment of off-time, off-time symptoms and motor dysfunction, unified PD rating scale (UPDRS) Part III score, and the physician’s global assessment. Results: This analysis evaluated 476 patients. Istradefylline was generally well tolerated, despite dyskinesia and hallucination being the most common ADRs. Reduction in off-time was observed in 38.2% of patients, off-time symptoms were improved or markedly improved in 44.7%, and motor dysfunction was improved or markedly improved in 48.5%. The mean UPDRS Part III score decreased from 33.7 to 30.3 at the end of the study. The physician’s global assessment rated the drug as effective in 61.3% of patients. Conclusions: This PMS provides useful safety and effectiveness data for long-term treatment with Istradefylline in a real-world setting for patients with PD exhibiting the wearing-off phenomenon with L-DOPA.
Neil M. Sussman - One of the best experts on this subject based on the ideXlab platform.
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Istradefylline as monotherapy for Parkinson disease: Results of the 6002-US-051 trial
Parkinsonism & related disorders, 2009Co-Authors: Hubert H. Fernandez, D.r. Greeley, Richard M. Zweig, Joanne Wojcieszek, A. Mori, Neil M. SussmanAbstract:Abstract Objective 6002-US-051 was a 12-week, double-blind study evaluating the safety and efficacy of Istradefylline, a selective A2A adenosine receptor antagonist, as monotherapy in patients with Parkinson's disease (PD). Methods Patients with Hoehn–Yahr stages 1–2.5 who had not received dopaminergic drugs in the past 30 days or levodopa for >30 days at anytime were randomized to 40 mg/day Istradefylline or placebo. The primary efficacy outcome was the change from Baseline to Endpoint in the Unified Parkinson's Disease Rating Scale (UPDRS) Subscale III score. Safety was assessed by physical examination, laboratory tests, electrocardiograms, and adverse event monitoring. Results 176 patients comprised the intent-to-treat population. Although Istradefylline showed numerically greater improvements in UPDRS Subscale III at each time point and reached statistical significance at Week 2 (LS mean difference = −1.47), it did not show statistically significant improvement from placebo for the primary endpoint (least square [LS] mean difference = −1.11). Similar proportions of patients in each group experienced treatment-emergent adverse events (63% Istradefylline, 65% placebo). Conclusions Istradefylline, as monotherapy in patients with PD, is safe and well tolerated. However, efficacy in improving motor symptoms in early PD was not statistically demonstrated by this study.
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Study of Istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations
Movement disorders : official journal of the Movement Disorder Society, 2008Co-Authors: Robert A. Hauser, Akihisa Mori, Lisa M. Shulman, Joel M. Trugman, John W. Roberts, Rocco Ballerini, Neil M. SussmanAbstract:The objective of this study was to evaluate the efficacy, safety, and tolerability of Istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of Istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to Istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between Istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) Istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with Istradefylline than placebo. We conclude that Istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.
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adenosine a2a receptor antagonist Istradefylline kw 6002 reduces off time in parkinson s disease a double blind randomized multicenter clinical trial 6002 us 005
Annals of Neurology, 2008Co-Authors: Akihisa Mori, Peter A Lewitt, Mark Guttman, James W Tetrud, Paul J Tuite, P Chaikin, Neil M. SussmanAbstract:Objective Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A2A receptor antagonist, Istradefylline, shows promise for the treatment of PD. Methods Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of Istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake “off” time, recorded by subjects using a patient PD diary. Secondary end points evaluated “on” time (including “on time with dyskinesia”), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression–Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake “off” time for Istradefylline was a mean (± standard deviation) of −10.8 ± 16.6% (95% confidence interval, −13.46 to −7.52) and for placebo, −4.0 ± 15.7% (95% confidence interval, −7.73–0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake “off” time of −1.8 ± 2.8 hours for Istradefylline and −0.6 ± 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with Istradefylline were generally mild. Interpretation Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in “off” time without increased troublesome dyskinesia. Ann Neurol 2008
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Adenosine A2A receptor antagonist Istradefylline (KW‐6002) reduces “off” time in Parkinson's disease: A double‐blind, randomized, multicenter clinical trial (6002‐US‐005)
Annals of neurology, 2008Co-Authors: Peter A Lewitt, Akihisa Mori, Philip Chaikin, Mark Guttman, James W Tetrud, Paul J Tuite, Neil M. SussmanAbstract:Objective Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A2A receptor antagonist, Istradefylline, shows promise for the treatment of PD. Methods Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of Istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake “off” time, recorded by subjects using a patient PD diary. Secondary end points evaluated “on” time (including “on time with dyskinesia”), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression–Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake “off” time for Istradefylline was a mean (± standard deviation) of −10.8 ± 16.6% (95% confidence interval, −13.46 to −7.52) and for placebo, −4.0 ± 15.7% (95% confidence interval, −7.73–0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake “off” time of −1.8 ± 2.8 hours for Istradefylline and −0.6 ± 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with Istradefylline were generally mild. Interpretation Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in “off” time without increased troublesome dyskinesia. Ann Neurol 2008
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Effectiveness and Tolerability of Istradefylline for the Treatment of Restless Legs Syndrome: An Exploratory Study in Five Female Patients
Current therapeutic research clinical and experimental, 2007Co-Authors: John Decerce, Lisa F. Smith, Walter Gonzalez, Neil M. SussmanAbstract:Background: Studies of Istradefylline (KW6002), an adenosine A2A-receptor antagonist, have provided evidence of its efficacy as a nondopaminergic antiparkinsonian drug. Antiparkinsonian drugs have also had efficacy in treating restless legs syndrome (RLS). Objectives: The aims of this study were to assess the effectiveness and tolerability of Istradefylline in the treatment of RLS. Methods: This was a single-center, multiparametric, prospective trial of Istradefylline as a treatment for moderate to severe idiopathic RLS. It was conducted at the Shands/Jacksonville Sleep Disorders Center, University of Florida, Jacksonville, Florida, from March 2003 to October 2003. Patients received a single PO 80-mg dose QD of Istradefylline in the late afternoon or early evening for 6 weeks. Appropriate tolerability evaluations (ie, vital assessments, physical examination, clinical laboratory tests, and electrocardiogram) were performed at screening, while on study drug, and after withdrawal of study drug. Results: Fifteen participants (mean [SD] age, 61 [7.1] years; range, 50-69 years) were screened for enrollment. The mean duration of RLS was 18 years. Of the 15 potential patients, 6 did not meet entry criteria, 2 withdrew consent, 1 had not completed baseline procedures at the time of study suspension, and 1 was excluded for administrative reasons. Therefore, a total of 5 patients received the study drug. Of these, 3 (60%) patients responded favorably to Istradefylline treatment. Improvement in the periodic limb movement index was observed in 3 patients compared with baseline (patients 2, 4, and 5 [index score: 6, 4, 9 vs 50, 35, 18, respectively]). Improvement in the International RLS Rating Scale scores was observed in 3 patients compared with baseline (patients 2, 4, and 5 [index score: 7, 23, 9 vs 35, 25, 20, respectively]). There was a return to baseline severity in 2 of the 3 patients after withdrawal of study drug. Improvement in RLS symptoms was observed in 3 patients treated with Istradefylline for 6 weeks. A clinical worsening of baseline insomnia was observed in 2 patients. Conclusions: Although we could not definitively conclude a beneficial effect based on this small exploratory trial, we found the data to be encouraging. The study drug was well tolerated. Further study of this compound in the treatment of RLS is justified.
Koji Yamada - One of the best experts on this subject based on the ideXlab platform.
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Antidepressant activity of the adenosine A2A receptor antagonist, Istradefylline (KW-6002) on learned helplessness in rats.
Psychopharmacology, 2014Co-Authors: Koji Yamada, Akihisa Mori, Minoru Kobayashi, Peter Jenner, Shizuo Shiozaki, Teruko Ohta, Tomoyuki KandaAbstract:Rationale Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson’s disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests.
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antidepressant like activity of the adenosine a2a receptor antagonist Istradefylline kw 6002 in the forced swim test and the tail suspension test in rodents
Pharmacology Biochemistry and Behavior, 2013Co-Authors: Koji Yamada, Akihisa Mori, Minoru Kobayashi, P Jenner, Tomoyuki KandaAbstract:Abstract Rationale Depression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist Istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects. Objective We have investigated whether Istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents. Results Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16 mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The Istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of Istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, Istradefylline (0.08 mg/kg and higher) decreased immobility time. Moreover, co-administration of Istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time. Conclusions Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic–pituitary–adrenal axis.
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In vitro pharmacological profile of the A_2A receptor antagonist Istradefylline
Naunyn-Schmiedeberg's Archives of Pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A_2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A_2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of Istradefylline as an A_2A receptor antagonist. Istradefylline exhibited high affinity for A_2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A_1, A_2B, and A_3) were lower than that for A_2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D_1, D_2, D_3, D_4, and D_5). In addition, Istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol- O -methyl transferase. A kinetic analysis indicated that Istradefylline reversibly binds to the human A_2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A_2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that Istradefylline is a potent, selective, and competitive A_2A receptor antagonist. The in vitro pharmacological profile of Istradefylline helps to explain the in vivo profile of Istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
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In vitro pharmacological profile of the A2A receptor antagonist Istradefylline.
Naunyn-Schmiedeberg's archives of pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of Istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, Istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that Istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that Istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro pharmacological profile of Istradefylline helps to explain the in vivo profile of Istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
Peter Jenner - One of the best experts on this subject based on the ideXlab platform.
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the story of Istradefylline the first approved a2a antagonist for the treatment of parkinson s disease
2015Co-Authors: Akihisa Mori, Peter A Lewitt, Peter JennerAbstract:Istradefylline is the first selective adenosine A2A receptor antagonist which has recently been approved in Japan for Parkinson’s disease therapy. Its launch followed a journey through drug development over a period of more than 20 years. This chapter details the progression of Istradefylline from identification of the receptor target for Parkinson’s disease therapy, to characterisation as a development candidate, to elucidation of its mechanism of action, and finally, to progression through clinical evaluation and eventual registration. Initially, Istradefylline was shown to be a highly selective antagonist for adenosine A2A receptors and to have a highly localised site of action linked to the indirect output pathway from the striatum. Subsequently, it was found to be effective at reversing motor impairments in rodent and primate models of Parkinson’s disease without provoking dyskinesia in primates. In clinical trials, Istradefylline (as an adjunct to L-DOPA therapy) decreased ‘OFF’ time without increasing troublesome dyskinesia. The latter findings were the basis for its registration as a treatment for ‘wearing off’ in Parkinson’s disease. However, this sequence of apparently logical events was interrupted by many challenges that had to be overcome—the topic of a still unfolding story. At this time, the development of Istradefylline in Parkinson’s disease is still incomplete and under further clinical investigation. Recently, the drug has shown effectiveness in experimental models of non-motor features of Parkinson’s disease. The latter findings and further experience from the clinical use of Istradefylline in Parkinson’s disease will provide future scope for the development of A2A antagonists in treating human disorders.
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The adenosine A2A receptor antagonist, Istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets.
European journal of pharmacology, 2015Co-Authors: Shinichi Uchida, Akihisa Mori, Peter Jenner, Kazuhiro Soshiroda, Eri Okita, Mika Kawai-uchida, Tomoyuki KandaAbstract:The adenosine A2A receptor antagonist, Istradefylline improves motor function in patients with advanced Parkinson's disease (PD) optimally treated with a combination of L-DOPA and a dopamine agonist without increasing the risk of troublesome dyskinesia. However, the effects of Istradefylline on motor function when administered in combination with low dose of L-DOPA and dopamine agonists as occurs in early PD are unknown. We investigated whether Istradefylline enhances the combined anti-parkinsonian effects of a suboptimal dose of L-DOPA and a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Threshold doses of ropinirole (0.025-0.075 mg/kg p.o.) and pergolide (0.01 mg/kg p.o.) produced a weak anti-parkinsonian effect. Co-administration of a suboptimal dose of L-DOPA (2.5mg/kg p.o.) with threshold doses of the dopamine agonists enhanced their anti-parkinsonian effect that led to increased 'ON' time without dyskinesia appearing. Administering Istradefylline (10mg/kg p.o.) with the threshold doses of dopamine agonists and the suboptimal dose of L-DOPA in a triple combination caused a further enhancement of the anti-parkinsonian response but dyskinesia was still absent. In early PD, dopamine agonists are often used as first-line monotherapy, but efficacy is usually lost within a few years, at which time L-DOPA is added but with the risk of dyskinesia appearance. These results show that Istradefylline is effective in improving motor function in combination with low dose dopaminergic drug treatment without provoking dyskinesia.
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The Story of Istradefylline—The First Approved A2A Antagonist for the Treatment of Parkinson’s Disease
Current Topics in Neurotoxicity, 2015Co-Authors: Akihisa Mori, Peter A Lewitt, Peter JennerAbstract:Istradefylline is the first selective adenosine A2A receptor antagonist which has recently been approved in Japan for Parkinson’s disease therapy. Its launch followed a journey through drug development over a period of more than 20 years. This chapter details the progression of Istradefylline from identification of the receptor target for Parkinson’s disease therapy, to characterisation as a development candidate, to elucidation of its mechanism of action, and finally, to progression through clinical evaluation and eventual registration. Initially, Istradefylline was shown to be a highly selective antagonist for adenosine A2A receptors and to have a highly localised site of action linked to the indirect output pathway from the striatum. Subsequently, it was found to be effective at reversing motor impairments in rodent and primate models of Parkinson’s disease without provoking dyskinesia in primates. In clinical trials, Istradefylline (as an adjunct to L-DOPA therapy) decreased ‘OFF’ time without increasing troublesome dyskinesia. The latter findings were the basis for its registration as a treatment for ‘wearing off’ in Parkinson’s disease. However, this sequence of apparently logical events was interrupted by many challenges that had to be overcome—the topic of a still unfolding story. At this time, the development of Istradefylline in Parkinson’s disease is still incomplete and under further clinical investigation. Recently, the drug has shown effectiveness in experimental models of non-motor features of Parkinson’s disease. The latter findings and further experience from the clinical use of Istradefylline in Parkinson’s disease will provide future scope for the development of A2A antagonists in treating human disorders.
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The adenosine A2A receptor antagonist, Istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets
European journal of pharmacology, 2014Co-Authors: Shinichi Uchida, Akihisa Mori, Peter Jenner, Kazuhiro Soshiroda, Eri Okita, Mika Kawai-uchida, Tomoyuki KandaAbstract:Abstract The adenosine A 2A receptor antagonist, Istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson׳s disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged ‘OFF’ periods. In contrast, the effects of Istradefylline on motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether Istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Both ropinirole (0.01–0.1 mg/kg p.o.) and pergolide (0.003–0.1 mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of ropinirole (0.025–0.075 mg/kg p.o.) and pergolide (0.01–0.075 mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of Istradefylline (10 mg/kg p.o.) alone resulted in a decrease in motor disability and increase in ‘ON’ time but dyskinesia was not observed. Combined administration of pergolide or ropinirole with Istradefylline resulted in an increase in the reversal of motor disability and increase in ‘ON’ time compared to that produced by either treatment alone but dyskinesia was still not observed. These results show that Istradefylline is effective in improving motor function when combined with low dose dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting.
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the adenosine a2a receptor antagonist Istradefylline enhances the motor response of l dopa without worsening dyskinesia in mptp treated common marmosets
Journal of Pharmacological Sciences, 2014Co-Authors: Shinichi Uchida, Akihisa Mori, Peter Jenner, Tomomi Tashiro, Mika Kawaiuchida, Tomoyuki KandaAbstract:Abstract The adenosine A2A-receptor antagonist Istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with submaximal doses of l -DOPA. However, the effects of combining Istradefylline with sub-optimal l -DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of Istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to l -DOPA. In these animals, single dose acute oral administration of Istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of l -DOPA (2.5 mg/kg). The chronic co-administration of Istradefylline (10 mg/kg) with l -DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that Istradefylline can be used to potentiate the effects of sub-optimal doses of l -DOPA in the treatment of Parkinson’s disease without causing or worsening dyskinesia.
