title: 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.
abstract: 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.
authors.affiliation: Central Nervous System Research Laboratories, Central Nervous System Research & Development Unit, Research & Development Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Research Core Function Laboratories, Research Functions Unit, Research & Development Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, 411-8731, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Soshiroda
authors.affiliation: Research Core Function Laboratories, Research Functions Unit, Research & Development Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, 411-8731, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Okita
authors.affiliation: Research Core Function Laboratories, Research Functions Unit, Research & Development Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, 411-8731, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kawai-Uchida
authors.affiliation: Strategic Product Portfolio Department, Kyowa Hakko Kirin Co., Ltd., Tokyo 100-8185, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mori
authors.affiliation: Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College, London SE1 1UL, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
authors.affiliation: Central Nervous System Research Laboratories, Central Nervous System Research & Development Unit, Research & Development Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. Electronic address: tomoyuki.kanda@kyowa-kirin.co.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kanda
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002144:Callithrix; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D007211:Indoles / Q000627:therapeutic use; D007980:Levodopa / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010479:Pergolide / Q000627:therapeutic use; D011687:Purines / Q000627:therapeutic use*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D007211:Indoles; D011687:Purines; C046649:ropinirole; D010479:Pergolide; C111599:istradefylline; D007980:Levodopa
keywords: Adenosine A(2A) receptor antagonist; Anti-parkinsonian; Dopamine agonist; Istradefylline (PubChem CID: 5311037); L-DOPA; L-DOPA (PubChem CID: 6047); MPTP; pergolide mesylate (PubChem CID: 47812); ropinirole HCl (PubChem CID: 68727)