Contents

Istradefylline

Istradefylline

Clinical data
Trade names	Nouriast, Nourianz
Other names	KW-6002
AHFS/Drugs.com	Monograph
License data	US DailyMed: Istradefylline
Routes of administration	By mouth
ATC code	N04CX01 (WHO)
Legal status
Legal status	US: ℞-only[1]
Pharmacokinetic data
Protein binding	98%
Metabolism	Mainly CYP1A1, CYP3A4, and CYP3A5
Elimination half-life	64–69 hrs
Excretion	68% faeces, 18% urine
Identifiers
IUPAC name 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
CAS Number	155270-99-8 Y
PubChem CID	5311037
IUPHAR/BPS	5608
DrugBank	DB11757 Y
ChemSpider	4470574 Y
UNII	2GZ0LIK7T4
KEGG	D04641 Y
ChEMBL	ChEMBL431770 Y
CompTox Dashboard (EPA)	DTXSID7057652
ECHA InfoCard	100.230.117
Chemical and physical data
Formula	C20H24N4O4
Molar mass	384.436 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC
InChI InChI=1S/C20H24N4O4/c1-6-23-18-17(19(25)24(7-2)20(23)26)22(3)16(21-18)11-9-13-8-10-14(27-4)15(12-13)28-5/h8-12H,6-7H2,1-5H3/b11-9+ Y Key:IQVRBWUUXZMOPW-PKNBQFBNSA-N Y
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Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes.^[2][3][4] Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa.^[2] An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.^[2]

Relatively common side effects include involuntary muscle movements (dyskinesia), constipation, hallucinations, dizziness and, much like its parent molecule caffeine, nausea and sleeplessness.^[2]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[5]

Mechanism of action[edit]

Istradefylline is a selective antagonist at the adenosine A_2A receptor (A2AR), but the precise mechanism by which it exerts its therapeutic effect in Parkinson's disease is unknown.^[6] However, it is known that dimers of these receptors form heterotetramers with the dimers of dopamine D₂ receptors (D2R) within striatum. Adenosine acts as an endogenous A2AR agonist, but also as a negative allosteric modulator (NAM) within these tetramers towards D2Rs, thus inhibiting the D2R mediated effects of dopamine, an endogenous D2R agonist. Istradefylline is believed to bind an A2AR within an A2AR-D2R-tetramer and function as a NAM towards the other A2AR (instead of D2R), thus inhibiting the effects of adenosine and enhancing the movement (locomotion) promoting effects exerted by dopamine via D2R. However, at high istradefylline concentration, it causes locomotion depression akin to caffeine (which is a broad-spectrum adenosine receptor antagonist), and might do so by displacing adenosine, and working as a NAM towards D2R (instead of A2AR).^[7]

Adverse effects[edit]

The adverse effects of Istradefylline have only been studied in the context of treating "off" episodes in Parkinson's disease. The most common adverse effects of Istradefylline in clinical trials are dyskinesia exacerbation (roughly 9% increase relative to placebo), malaise, and nasopharyngitis (common cold).^[8][9]

History[edit]

It was first approved in Japan in 2013.^[10]

The effectiveness of Nourianz in treating "off" episodes in patients with Parkinson's disease who are already being treated with levodopa/carbidopa was shown in four 12-week placebo-controlled clinical studies that included a total of 1,143 participants. In all four studies, people treated with Nourianz experienced a statistically significant decrease from baseline in daily "off" time compared to patients receiving a placebo.^[2][3]

It was approved for medical use in the United States in 2019.^[2][3][11] and approval was granted to Kyowa Kirin, Inc.^[2]

References[edit]

1. ^ "Nourianz- istradefylline tablet, film coated". DailyMed. Retrieved 4 January 2021.

^ ^{a b c d e f g} "FDA approves new add-on drug to treat off episodes in adults with Parkinson's disease". U.S. Food and Drug Administration (FDA) (Press release). 27 August 2019. Archived from the original on 4 September 2019. Retrieved 29 August 2019. This article incorporates text from this source, which is in the public domain.

^ ^{a b c} "Drug Trials Snapshots: Nourianz". U.S. Food and Drug Administration (FDA). 23 September 2019. Archived from the original on 20 November 2019. Retrieved 19 November 2019. This article incorporates text from this source, which is in the public domain.

^ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Retrieved 15 September 2020. This article incorporates text from this source, which is in the public domain.

External links[edit]

• "Istradefylline". Drug Information Portal. U.S. National Library of Medicine.