Chemistry:Istradefylline

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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.[1][2][3] Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa.[1] 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.[1]

Relatively common side effects include involuntary muscle movements (dyskinesia), constipation, hallucinations, dizziness, and, much like its parent molecule caffeine, nausea and sleeplessness.[1]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[4]

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).[5][6]

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.[7] 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).[8]

History

It was first approved in Japan in 2013.[9]

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.[1][2]

It was approved for medical use in the United States in 2019.[1][2][10] and approval was granted to Kyowa Kirin, Inc.[1]

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 A2A receptor.[11][12] There is preliminary clinical evidence that istradefylline has wakefulness-promoting effects similarly to caffeine.[11][12]

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.[13][14][11][15] Selective adenosine A2A receptor antagonists like istradefylline and preladenant may be useful in the treatment of motivational disorders in humans.[13][14]

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.[16] However, development for these indications was discontinued.[16]

See also

  • KW-6356, an adenosine A2A receptor inverse agonist intended to supersede Istradefylline.[17]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "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.
  2. ↑ 2.0 2.1 2.2 "Drug Trials Snapshots: Nourianz". 23 September 2019. https://www.fda.gov/drugs/drug-trials-snapshots-nourianz.  Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ "Contemporary Options for the Management of Motor Complications in Parkinson's Disease: Updated Clinical Review". Drugs 79 (6): 593–608. April 2019. doi:10.1007/s40265-019-01098-w. PMID 30905034. 
  4. ↑ "New Drug Therapy Approvals 2019". 31 December 2019. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019.  Public Domain This article incorporates text from this source, which is in the public domain.
  5. ↑ "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. October 2021. doi:10.1016/j.parkreldis.2021.09.015. PMID 34583302. 
  6. ↑ "A long-term study of istradefylline safety and efficacy in patients with Parkinson disease". Clinical Neuropharmacology 38 (2): 41–46. 2015. doi:10.1097/WNF.0000000000000073. PMID 25768849. 
  7. ↑ "Mechanism of Action". https://www.nourianzhcp.com/mechanism-of-action. 
  8. ↑ "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. December 2018. doi:10.1089/caff.2018.0017. PMID 30596206. 
  9. ↑ "Istradefylline: first global approval". Drugs 73 (8): 875–882. June 2013. doi:10.1007/s40265-013-0066-7. PMID 23700273. 
  10. ↑ "Drug Approval Package: Nourianz". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022075Orig1s000TOC.cfm. 
  11. ↑ 11.0 11.1 11.2 "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. November 2020. doi:10.1016/j.parkreldis.2020.09.022. PMID 33349577. 
  12. ↑ 12.0 12.1 "Adenosine and Sleep". Sleep-Wake Neurobiology and Pharmacology. Handbook of Experimental Pharmacology. 253. 2019. pp. 359–381. doi:10.1007/164_2017_36. ISBN 978-3-030-11270-7. 
  13. ↑ 13.0 13.1 "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev 70 (4): 747–762. October 2018. doi:10.1124/pr.117.015107. PMID 30209181. 
  14. ↑ 14.0 14.1 "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Anhedonia: Preclinical, Translational, and Clinical Integration. Current Topics in Behavioral Neurosciences. 58. 2022. pp. 325–353. doi:10.1007/7854_2022_355. ISBN 978-3-031-09682-2. "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." 
  15. ↑ "Anhedonia in Neurodegenerative Diseases". Anhedonia: Preclinical, Translational, and Clinical Integration. Current Topics in Behavioral Neurosciences. 58. 2022. pp. 255–277. doi:10.1007/7854_2022_352. ISBN 978-3-031-09682-2. "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." 
  16. ↑ 16.0 16.1 "Istradefylline". 5 November 2023. https://adisinsight.springer.com/drugs/800006318. 
  17. ↑ "The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson's disease". Purinergic Signalling 16 (2): 167–174. June 2020. doi:10.1007/s11302-020-09694-2. PMID 32236790. 

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