Istradefylline

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]

Istradefylline
Clinical data
Trade namesNouriast, Nourianz
Other namesKW-6002
AHFS/Drugs.comMonograph
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding98%
MetabolismMainly CYP1A1, CYP3A4, and CYP3A5
Elimination half-life64–69 hrs
Excretion68% 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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.230.117
Chemical and physical data
FormulaC20H24N4O4
Molar mass384.436 g·mol−1
3D model (JSmol)
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
  (verify)

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

Istradefylline is a selective antagonist at the adenosine A2A 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]

History

It was first approved in Japan in 2013.[8]

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][9] and approval was granted to Kyowa Kirin, Inc.[2]

References
  1. "Nourianz- istradefylline tablet, film coated". DailyMed. Retrieved 4 January 2021.
  2. "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.
  3. "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.
  4. Cabreira V, Soares-da-Silva P, Massano J (April 2019). "Contemporary Options for the Management of Motor Complications in Parkinson's Disease: Updated Clinical Review". Drugs. 79 (6): 593–608. doi:10.1007/s40265-019-01098-w. PMID 30905034. S2CID 85456263.
  5. "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.
  6. "Mechanism of Action". Retrieved 27 December 2020.{{cite web}}: CS1 maint: url-status (link)
  7. Ferré S, et al. (2018). "New developments on the adenosine mechanisms of the central effects of caffeine and their implications for neuropsychiatric disorders". Journal of Caffeine and Adenosine Research. 8 (4): 121–131. doi:10.1089/caff.2018.0017. PMC 6306650. PMID 30596206.
  8. Dungo R, Deeks ED (June 2013). "Istradefylline: first global approval". Drugs. 73 (8): 875–82. doi:10.1007/s40265-013-0066-7. ISSN 1179-1950. PMID 23700273. S2CID 35937325.
  9. "Drug Approval Package: Nourianz". U.S. Food and Drug Administration (FDA).
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