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 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
(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 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

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]

Research

Wakefulness effects

The wakefulness-promoting effects of non-selective adenosine receptor antagonists like caffeine appear to be mediated specifically and exclusively by antagonism of the adenosine A_2A receptor.^[12][13] There is preliminary clinical evidence that istradefylline has wakefulness-promoting effects similarly to caffeine.^[12][13]

Motivational disorders

Istradefylline shows pro-motivational effects in animals and has been found to reduce apathy, fatigue, and anhedonia in people with Parkinson's disease.^{[14][15][12][16]} Selective adenosine A_2A receptor antagonists like istradefylline and preladenant may be useful in the treatment of motivational disorders in humans.^[14][15]

Other conditions

In addition to Parkinson's disease, istradefylline was under development for the treatment of major depressive disorder (MDD), restless legs syndrome, and substance-related disorders.^[17] However, development for these indications was discontinued.^[17]

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.
7. Ferré S, Díaz-Ríos M, Salamone JD, Prediger RD (December 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. Shimo Y, Maeda T, Chiu SW, Yamaguchi T, Kashihara K, Tsuboi Y, et al. (October 2021). "Influence of istradefylline on non-motor symptoms of Parkinson's disease: A subanalysis of a 1-year observational study in Japan (J-FIRST)". Parkinsonism & Related Disorders. 91: 115–120. doi:10.1016/j.parkreldis.2021.09.015. PMID 34583302. S2CID 238218741.
9. Kondo T, Mizuno Y (2015). "A long-term study of istradefylline safety and efficacy in patients with Parkinson disease". Clinical Neuropharmacology. 38 (2): 41–46. doi:10.1097/WNF.0000000000000073. PMID 25768849. S2CID 7309419.
10. Dungo R, Deeks ED (June 2013). "Istradefylline: first global approval". Drugs. 73 (8): 875–882. doi:10.1007/s40265-013-0066-7. PMID 23700273. S2CID 35937325.
11. "Drug Approval Package: Nourianz". U.S. Food and Drug Administration (FDA).
12. Jenner P, Mori A, Kanda T (November 2020). "Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?". Parkinsonism Relat Disord. 80 Suppl 1: S28–S36. doi:10.1016/j.parkreldis.2020.09.022. PMID 33349577.
13. Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB (2019). "Adenosine and Sleep". Handb Exp Pharmacol. 253: 359–381. doi:10.1007/164_2017_36. PMID 28646346.
14. Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC 6169368. PMID 30209181.
15. Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Curr Top Behav Neurosci. 58: 325–353. doi:10.1007/7854_2022_355. PMID 35505057. Adenosine A2A receptor antagonists have been studied for their potential antiparkinsonian effects (Ferré 1997; Morelli and Pinna 2002; Correa et al. 2004), and istradefylline (Nourianz) has been approved for use in several countries. Particularly relevant for the present review, drugs that act on adenosine A2A receptors induce substantial effects on instrumental behavior and effort-related choice. [...] Caffeine, theophylline, and several adenosine A2A receptor antagonists (MSX-3, MSX-4, Lu AA47070, istradefylline) can reverse the low-effort bias induced by systemically administered DA D2 antagonists (Farrar et al. 2007; Worden et al. 2009; Mott et al. 2009; Collins et al. 2012; Nunes et al. 2010; Santerre et al. 2012; Randall et al. 2012; Pardo et al. 2020), and MSX-3 and preladenant reverse the effects of TBZ (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018). [...] Furthermore, A2A receptor knockout mice are resistant to the effort-related effects of haloperidol (Pardo et al. 2012). [...] Along with adenosine A2A antagonists such as istradefylline and preladenant (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018), and D1 agonists (Yohn et al. 2015b), atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.
16. Turner V, Husain M (2022). "Anhedonia in Neurodegenerative Diseases". Curr Top Behav Neurosci. 58: 255–277. doi:10.1007/7854_2022_352. PMID 35435648. Recently, PD patients have been treated with istradefylline, an adenosine A2A receptor antagonist used for treatment of motor symptoms. The drug was given to 14 PD patients for 12 weeks, measuring anhedonia, apathy and depression using the SHAPS, Apathy Scale and BDI. On istradefylline, SHAPS, Apathy Scale and BDI scores significantly reduced from baseline scores at 4-, 8- and 12-weeks, with mean SHAPS scores at week 12 about 50% reduced from baseline scores, indicating that istradefylline reduces anhedonia (Nagayama et al. 2019). As apathy and depression rates dropped as well as anhedonia, this trial also provided evidence for the overlapping relationship between the three symptoms. [...] Taken together, there is some evidence that dopamine agonists such as pramipexole and piribedil, or the adenosine A2A receptor antagonist istradefylline can improve anhedonia and apathy in PD.
17. "Istradefylline". AdisInsight. 5 November 2023. Retrieved 16 September 2024.

External links

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