Istradefylline (KW-6002) is a selective adenosine A2A receptor (A2AR) antagonist with Ki of 2.2 nM. Oral administration of Istradefylline improves motor disability in MPTP-treated parkinsonian marmosets in a dose-dependent manner without provoking dyskinesia. Combination of Istradefylline with a low dose of L-DOPA or with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produces an additive improvement in motor disability but not dyskinesia in MPTP-treated common marmosets. Blockade of A2AR by Istradefylline treatment rescues locomotor impairment in dopamine D2 receptor-deficient mice, with the level of expression of enkephalin and substance P reestablished to normal levels. Istradefylline treatment potentiates rotational behavior induced by dopaminergic drugs in hemi-Parkinsonian rats. Istradefylline treatment alone causes an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly alters the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, Istradefylline does not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. Treatment with Istradefylline prevents the loss of dopaminergic striatal terminals and nigral cell bodies and inhibits the nigral microglia activation in MPTP treated mice. A Phase II study of Istradefylline (monotherapy) and a Phase III study of Istradefylline in combination with levodopa for the treatment of Parkinson's disease have been completed.
|Animal models||Common marmosets (Callithrix jacchus) with MPTP treatment|
|Formulation||Suspended in 0.3% Tween-80 and 10% sucrose solution|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
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|CGS 21680 hydrochloride
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