title: The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets.
abstract: The adenosine A2A 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 (0.01-0.1mg/kg p.o.) and pergolide (0.003-0.1mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of ropinirole (0.025-0.075mg/kg p.o.) and pergolide (0.01-0.075mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of istradefylline (10mg/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.
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 Centre, School of Health and Biomedical Sciences, 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: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002144:Callithrix; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D007211:Indoles / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010479:Pergolide / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D007211:Indoles; D011687:Purines; D043705:Receptor, Adenosine A2A; C046649:ropinirole; D010479:Pergolide; C111599:istradefylline; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Adenosine A(2A) receptor antagonist; Anti-parkinsonian; Dopamine agonist; Istradefylline (PubChem CID: 5311037); MPTP; Pergolide mesylate (PubChem CID: 47812); Ropinirole HCl (PubChem CID: 68727)