Istradefylline

Last updated

Istradefylline
Istradefylline structure.svg
Clinical data
Trade names Nouriast, Nourianz
Other namesKW-6002
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 98%
Metabolism Mainly CYP1A1, CYP3A4, and CYP3A5
Elimination half-life 64–69 hrs
Excretion 68% faeces, 18% urine
Identifiers
  • 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 InfoCard 100.230.117 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H24N4O4
Molar mass 384.436 g·mol−1
3D model (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+ Yes check.svgY
  • Key:IQVRBWUUXZMOPW-PKNBQFBNSA-N Yes check.svgY
   (verify)

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]

Contents

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]

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 A2A 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 A2A 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]

Related Research Articles

<span class="mw-page-title-main">Bromocriptine</span> Dopamine agonist medication

Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.

<span class="mw-page-title-main">Adenosine receptor</span> Class of four receptor proteins to the molecule adenosine

The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Dihydroergocryptine</span> Chemical compound

Dihydroergocryptine (DHEC), sold under the brand names Almirid and Cripar among others, is a dopamine agonist of the ergoline group that is used as an antiparkinson agent in the treatment of Parkinson's disease. It is taken by mouth.

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

Adenosine A<sub>2A</sub> receptor Cell surface receptor found in humans

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.

<span class="mw-page-title-main">SCH-58261</span> Chemical compound

SCH-58261 is a drug which acts as a potent and selective antagonist for the adenosine receptor A2A, with more than 50x selectivity for A2A over other adenosine receptors. It has been used to investigate the mechanism of action of caffeine, which is a mixed A1 / A2A antagonist, and has shown that the A2A receptor is primarily responsible for the stimulant and ergogenic effects of caffeine, but blockade of both A1 and A2A receptors is required to accurately replicate caffeine's effects in animals. SCH-58261 has also shown antidepressant, nootropic and neuroprotective effects in a variety of animal models, and has been investigated as a possible treatment for Parkinson's disease.

<span class="mw-page-title-main">Parkinson's disease</span> Long-term neurodegenerative disease

Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease of mainly the central nervous system that affects both the motor and non-motor systems of the body. The symptoms usually emerge slowly, and, as the disease progresses, non-motor symptoms become more common. Usual symptoms include tremors, slowness of movement, rigidity, and difficulty with balance, collectively known as parkinsonism. Parkinson's disease dementia, falls and neuropsychiatric problems such as sleep abnormalities, psychosis, mood swings, or behavioral changes may also arise in advanced stages.

<span class="mw-page-title-main">Preladenant</span> Chemical compound

Preladenant is a drug that was developed by Schering-Plough which acted as a potent and selective antagonist of the adenosine A2A receptor. It was being researched as a potential treatment for Parkinson's disease. Positive results were reported in Phase II clinical trials in humans, but it did not prove itself to be more effective than a placebo during Phase III trials, and so was discontinued in May 2013.

Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.

<span class="mw-page-title-main">Wakefulness-promoting agent</span>

A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal. They are similar to but distinct from psychostimulants, which not only promote wakefulness but also produce other central nervous system effects, such as improved mood, energy, and motivation. Wakefulness-promoting agents are used to treat narcolepsy and hypersomnia as well as to promote wakefulness and increase performance in healthy people.

Adenosine A2A receptor antagonists are a class of drugs that blocks adenosine at the adenosine A2A receptor. Notable adenosine A2A receptor antagonists include caffeine, theophylline and istradefylline.

<span class="mw-page-title-main">MRZ-9547</span> Dopamine reuptake inhibitor that was under development for fatigue in Parkinsons disease

MRZ-9547, also known as (R)-phenylpiracetam, (R)-phenotropil, or (R)-fonturacetam, is a selective dopamine reuptake inhibitor (IC50Tooltip half-maximal inhibitory concentration = 14.5 μM) that was developed by Merz Pharma. It is the (R)-enantiomer of the racetam and nootropic phenylpiracetam (phenotropil; fonturacetam).

A pro-motivational agent is a drug which increases motivation. They can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD), as well as in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, for instance due to stroke, traumatic brain injury, or neurodegenerative diseases. They are also used non-medically by healthy people to increase motivation and productivity, for instance in educational contexts.

CT-005404, or CT-5404, is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It shows pro-motivational effects in animals and reverses motivational deficits induced by tetrabenazine and interleukin-1β. CT-005404 is described as being orally active in animals and having a long duration of action. It is under development by Chronos Therapeutics for treatment of motivational disorders. The drug was first described by 2018.

<span class="mw-page-title-main">Lu AA47070</span> An adenosine A2A receptor antagonist for Parkinsons disease that was abandoned

Lu AA47070 is a selective adenosine A2A receptor antagonist that was under development for the treatment of Parkinson's disease but was never marketed. It has been found to reverse some of the effects of dopamine D2 receptor antagonists like pimozide and haloperidol, for instance tremulous jaw movements, catalepsy, locomotor suppression, and other anti-motivational effects, in animals. The drug is a prodrug of Lu AA41063. It was discontinued in phase 1 clinical trials because it lacked the intended pharmacological properties in humans. Lu AA47070 was first described by 2008.

<span class="mw-page-title-main">MSX-3</span> Selective adenosine A2A receptor antagonist used in scientific research

MSX-3 is a selective adenosine A2A receptor antagonist used in scientific research. Similarly to MSX-4, it is a water-soluble ester prodrug of MSX-2.

<span class="mw-page-title-main">3-Chlorostyrylcaffeine</span> A selective adenosine A2A receptor antagonist and MAO-B inhibitor used in scientific research

3-Chlorostyrylcaffeine (CSC), or 8-(3-chlorostyryl)caffeine (8-CSC), is a potent and selective adenosine A2A receptor antagonist which is used in scientific research.

<span class="mw-page-title-main">MSX-2</span> A selective adenosine A2A receptor antagonist

MSX-2 is a selective adenosine A2A receptor antagonist used in scientific research. It is a xanthine and a derivative of the non-selective adenosine receptor antagonist caffeine.

<span class="mw-page-title-main">Lu AA41063</span> A selective adenosine A2A receptor antagonist

Lu AA41063 is a selective adenosine A2A receptor antagonist. Structurally, it is a non-xanthine.

References

  1. ↑ "Nourianz- istradefylline tablet, film coated". DailyMed. Retrieved 4 January 2021.
  2. 1 2 3 4 5 6 7 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  3. 1 2 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.PD-icon.svg 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.PD-icon.svg 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. 1 2 3 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. 1 2 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. 1 2 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. 1 2 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. 1 2 "Istradefylline". AdisInsight. 5 November 2023. Retrieved 16 September 2024.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.