Istradefylline

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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
  • 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
JSmol)
  • O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC
  • 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+ checkY
  • Key:IQVRBWUUXZMOPW-PKNBQFBNSA-N checkY
  (verify)

Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to

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

Istradefylline is a selective

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

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

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]

Possible use for the treatment of nAMD

ADORA2A inhibition with Istradefylline may be a therapeutic approach to treat subretinal fibrosis associated with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults.[12]

References

  1. ^ "Nourianz- istradefylline tablet, film coated". DailyMed. Retrieved 4 January 2021.
  2. ^ 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. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ 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. Public Domain This article incorporates text from this source, which is in the public domain.
  4. S2CID 85456263
    .
  5. ^ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Retrieved 15 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ^ "Mechanism of Action". Retrieved 27 December 2020.
  7. PMID 30596206
    .
  8. S2CID 238218741
    .
  9. S2CID 7309419
    .
  10. S2CID 35937325
    .
  11. ^ "Drug Approval Package: Nourianz". U.S. Food and Drug Administration (FDA).
  12. doi:10.1126/scitranslmed.adk3868

External links
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