Istradefylline: Difference between revisions

{{Short description|Chemical compound}}

{{Use dmy dates|date=October 2019}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| verifiedrevid = 443805396

| drug_name =

| INN =

| type = <!-- empty -->

| image = Istradefylline structure.svg

| width = 250px

| alt =

<!-- Clinical data -->

| pronounce =

| tradename = Nouriast, Nourianz

| Drugs.com = {{Drugs.com|monograph|nourianz}}

| MedlinePlus =

| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->

| licence_EU = <!-- EMA uses INN (or special INN_EMA) -->

| DailyMedID = Istradefylline

| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| class =

| ATCvet =

| ATC_prefix = N04

| ATC_suffix = CX01

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref>{{cite web | title=Nourianz- istradefylline tablet, film coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a7d008cb-b273-4049-a5d2-9c6902910d58 | access-date=4 January 2021}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound = 98%

| metabolism = Mainly [[CYP1A1]], [[CYP3A4]], and [[CYP3A5]]

| metabolites =

| onset =

| elimination_half-life = 64–69 hrs

| duration_of_action =

| excretion = 68% faeces, 18% urine

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_supplemental =

| IUPHAR_ligand = 5608

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB11757

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4470574

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 2GZ0LIK7T4

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D04641

| ChEBI =

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 431770

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = KW-6002

<!-- Chemical and physical data -->

| IUPAC_name = 8-[(''E'')-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1''H''-purine-2,6-dione

| SMILES = O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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+

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = IQVRBWUUXZMOPW-PKNBQFBNSA-N

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical use -->

'''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.<ref name=FDA2019>{{cite press release | title=FDA approves new add-on drug to treat off episodes in adults with Parkinson's disease | website=U.S. [[Food and Drug Administration]] (FDA) | date=27 August 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-add-drug-treat-episodes-adults-parkinsons-disease | archive-url=https://web.archive.org/web/20190904020914/https://www.fda.gov/news-events/press-announcements/fda-approves-new-add-drug-treat-episodes-adults-parkinsons-disease | archive-date=4 September 2019 | url-status=live | access-date=29 August 2019}} {{PD-notice}}</ref><ref name="FDA Snapshot">{{cite web | title=Drug Trials Snapshots: Nourianz | website=U.S. [[Food and Drug Administration]] (FDA) | date=23 September 2019 | url=https://www.fda.gov/drugs/drug-trials-snapshots-nourianz | archive-url=https://web.archive.org/web/20191120053608/https://www.fda.gov/drugs/drug-trials-snapshots-nourianz | archive-date=20 November 2019 | url-status=live | access-date=19 November 2019}} {{PD-notice}}</ref><ref>{{cite journal | vauthors = Cabreira V, Soares-da-Silva P, Massano J | title = Contemporary Options for the Management of Motor Complications in Parkinson's Disease: Updated Clinical Review | journal = Drugs | volume = 79 | issue = 6 | pages = 593–608 | date = April 2019 | pmid = 30905034 | doi = 10.1007/s40265-019-01098-w | s2cid = 85456263 }}</ref> Istradefylline reduces "off" periods resulting from long-term treatment with the [[Management of Parkinson's disease#Medication|antiparkinson drug]] [[levodopa]].<ref name=FDA2019/> 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.<ref name=FDA2019 />

Relatively common side effects include involuntary muscle movements ([[dyskinesia]]), constipation, hallucinations, dizziness and, much like its parent molecule [[caffeine]], nausea and sleeplessness.<ref name=FDA2019/>

The U.S. [[Food and Drug Administration]] (FDA) considers it to be a [[first-in-class medication]].<ref>{{cite web | title=New Drug Therapy Approvals 2019 | website=U.S. Food and Drug Administration | date=31 December 2019 | url=https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019 | access-date=15 September 2020}} {{PD-notice}}</ref>

==Mechanism of action==

Istradefylline is a selective [[receptor antagonist|antagonist]] at the [[Adenosine A2a receptor|adenosine A_2A receptor]] (A2AR), but the precise mechanism by which it exerts its therapeutic effect in Parkinson's disease is unknown.<ref>{{Cite web|title=Mechanism of Action|url=http://www.nourianzhcp.com/mechanism-of-action |access-date=2020-12-27}}</ref> However, it is known that [[Protein dimer|dimers]] of these receptors form [[heterotetramer]]s with the dimers of [[Dopamine receptor D2|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).<ref>{{cite journal | vauthors = Ferré S, Díaz-Ríos M, Salamone JD, Prediger RD | title = New Developments on the Adenosine Mechanisms of the Central Effects of Caffeine and Their Implications for Neuropsychiatric Disorders | journal = Journal of Caffeine and Adenosine Research | volume = 8 | issue = 4 | pages = 121–131 | date = December 2018 | pmid = 30596206 | pmc = 6306650 | doi = 10.1089/caff.2018.0017 }}</ref>

== 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 [[Common cold|nasopharyngitis]] (common cold).<ref>{{cite journal | vauthors = Shimo Y, Maeda T, Chiu SW, Yamaguchi T, Kashihara K, Tsuboi Y, Nomoto M, Hattori N, Watanabe H, Saiki H | title = Influence of istradefylline on non-motor symptoms of Parkinson's disease: A subanalysis of a 1-year observational study in Japan (J-FIRST) | journal = Parkinsonism & Related Disorders | volume = 91 | pages = 115–120 | date = October 2021 | pmid = 34583302 | doi = 10.1016/j.parkreldis.2021.09.015 | s2cid = 238218741 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kondo T, Mizuno Y | title = A long-term study of istradefylline safety and efficacy in patients with Parkinson disease | journal = Clinical Neuropharmacology | volume = 38 | issue = 2 | pages = 41–46 | date = 2015 | pmid = 25768849 | doi = 10.1097/WNF.0000000000000073 | s2cid = 7309419 }}</ref>

==History==

It was first approved in Japan in 2013.<ref>{{cite journal | vauthors = Dungo R, Deeks ED | title = Istradefylline: first global approval | journal = Drugs | volume = 73 | issue = 8 | pages = 875–882 | date = June 2013 | pmid = 23700273 | doi = 10.1007/s40265-013-0066-7 | s2cid = 35937325 }}</ref>

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.<ref name=FDA2019 /><ref name="FDA Snapshot" />

It was approved for medical use in the United States in 2019.<ref name=FDA2019/><ref name="FDA Snapshot" /><ref name="FDA approval">{{cite web | title=Drug Approval Package: Nourianz | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022075Orig1s000TOC.cfm }}</ref> and approval was granted to Kyowa Kirin, Inc.<ref name=FDA2019 />

== Research ==

=== Motivational disorders ===

Istradefylline shows [[pro-motivational agent|pro-motivational]] effects in animals and has been found to reduce [[apathy]], [[fatigue (medical)|fatigue]], and [[anhedonia]] in people with Parkinson's disease.<ref name="SalamoneCorreaFerrigno2018">{{cite journal | vauthors = Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE | title = The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation | journal = Pharmacol Rev | volume = 70 | issue = 4 | pages = 747–762 | date = October 2018 | pmid = 30209181 | pmc = 6169368 | doi = 10.1124/pr.117.015107 | url = }}</ref><ref name="TreadwaySalamone2022">{{cite journal | vauthors = Treadway MT, Salamone JD | title = Vigor, Effort-Related Aspects of Motivation and Anhedonia | journal = Curr Top Behav Neurosci | volume = 58 | issue = | pages = 325–353 | date = 2022 | pmid = 35505057 | doi = 10.1007/7854_2022_355 | url = | quote = 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.}}</ref><ref name="JennerMoriKanda2020">{{cite journal | vauthors = Jenner P, Mori A, Kanda T | title = Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease? | journal = Parkinsonism Relat Disord | volume = 80 Suppl 1 | issue = | pages = S28–S36 | date = November 2020 | pmid = 33349577 | doi = 10.1016/j.parkreldis.2020.09.022 | url = | doi-access = free }}</ref><ref name="TurnerHusain2022">{{cite journal | vauthors = Turner V, Husain M | title = Anhedonia in Neurodegenerative Diseases | journal = Curr Top Behav Neurosci | volume = 58 | issue = | pages = 255–277 | date = 2022 | pmid = 35435648 | doi = 10.1007/7854_2022_352 | url = | quote = 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.}}</ref> Selective adenosine A_2A receptor antagonists like istradefylline and [[preladenant]] may be useful in the treatment of [[motivational disorder]]s in humans.<ref name="SalamoneCorreaFerrigno2018" /><ref name="TreadwaySalamone2022" />

=== 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 misuse|substance-related disorder]]s.<ref name="AdisInsight">{{cite web | title=Istradefylline | website=AdisInsight | date=5 November 2023 | url=https://adisinsight.springer.com/drugs/800006318 | access-date=16 September 2024}}</ref> However, development for these indications was discontinued.<ref name="AdisInsight" />

== External links ==

* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/istradefylline | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Istradefylline }}

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