Pramipexole
Clinical data
Pronunciation/ˌpræmɪˈpɛksoʊl/
Trade namesMirapex, Mirapexin, Sifrol, others
AHFS/Drugs.comMonograph
MedlinePlusa697029
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability>90%
Protein binding15%
Elimination half-life8–12 hours
ExcretionUrine (90%), Feces (2%)
Identifiers
  • (S)-N 6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.124.761 Edit this at Wikidata
Chemical and physical data
FormulaC10H17N3S
Molar mass211.33 g·mol−1
3D model (JSmol)
  • n1c2c(sc1N)C[C@@H](NCCC)CC2
  • InChI=1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m0/s1 checkY
  • Key:FASDKYOPVNHBLU-ZETCQYMHSA-N checkY
  (verify)

Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS).[6] In Parkinson's disease it may be used alone or together with levodopa.[6] It is taken by mouth.[6] Pramipexole is a dopamine agonist of the non-ergoline class.[6]

Pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders"[7] such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviours.[8][9][10] There have also been reported detrimental side effects related to impulse-control disorders resulting from off-label use of pramipexole or other dopamine agonists in treating clinical depression.[11] The incidence and severity of impulse-control disorders for those taking the drug for depression is not fully understood because the drug has not been approved for the treatment of depression and the first major studies of its efficacy in treating anhedonic depression were conducted in 2022. There have been anecdotal reports of abrupt and severe personality changes related to impulsivity and loss of self-control in a minority of patients regardless of the condition being treated, although the incidence of these side effects is not yet fully known.[11]

Pramipexole was approved for medical use in the United States in 1997.[6] Use in pregnancy and breastfeeding is of unclear safety.[1] It is available as a generic medication.[12] In 2020, it was the 193rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[13][14]

Medical uses

Pramipexole is used in the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS).[6] Use in pregnancy and breastfeeding is of unclear safety.[1]

It is occasionally prescribed off-label for depression. Its effectiveness as an antidepressant may be a product of its strong partial agonistic activity on and preferential occupation of dopamine D3 receptors at low doses (see table below); as well, the drug has been shown to desensitize the inhibitory D22 autoreceptors but not the postsynaptic D2 receptors, leading to an increase in dopamine and serotonin levels in the prefrontal cortex.[15] Chronic administration of pramipexole may also result in desensitization of D3 autoreceptors, leading to reduced dopamine transporter function, "We show that prolonged administration of pramipexole (0.1mg/kg/day, 6 to 21 days) [equivalent to a low ~0.5 mg/day human dose], a preferential D3R agonist, leads to a decrease in DA [dopamine] uptake in mouse striatum that reflects a reduction in DAT [dopamine transporter] affinity for DA in the absence of any change in DAT density or subcellular distribution ... These observations provide novel insights into the long-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists".[16]

As summarized in the following commentary, trials have shown mixed results, "Dopamine agonists, such as pramipexole—a relatively selective dopamine D3 receptor agonist—are thus potential treatments for depression, especially anhedonic depression. D3 receptors are found in the mesolimbic system, which in turn has been implicated in the motoric and hedonic deficits in depression ... The first randomized controlled trial in patients with non-treatment-resistant major depressive disorder, by Corrigan et al., evaluated three dosages of pramipexole. The lowest dosage (0.375 mg/day) did not differentiate from placebo. The efficacy of the highest dosage (5.0 mg/day) was not evaluable, because of a 58% attrition rate. The third dosage (1.0 mg/day) was more effective than placebo ... Cusin et al. compared adjunctive adjunctive pramipexole with placebo in an 8-week randomized double-blind trial with 60 outpatients with major depression for whom at least one adequate antidepressant medication trial (mean, two trials) had failed. Although a modest statistically significant benefit of pramipexole over placebo was detected, neither the response rates (40% compared with 33%) nor the remission rates (27% compared with 23%) differed significantly between groups. Dosages were modest (mean=1.35 mg/day; maximum=2.0 mg/day) ... To our knowledge, this is the first case series of adjunctive pramipexole in patients with treatment-resistant depression for whom at least four previous treatments in the current episode had failed. Overall, 76% of the patients showed a meaningful clinical response that persisted, while 24% were intolerant or nonresponsive to pramipexole. Effective pramipexole dosages ranged from 0.75 to 5.0 mg/day. The mean effective dosage of pramipexole in responders and remitters (N=32) was 2.46 mg/day".[17]

Side effects

Common side effects of pramipexole may include:[18][2][3]

Pharmacology

The activity profile of pramipexole at various sites has been characterized as follows:

Activities of pramipexole at various sites[28][29][30][31][32]
Site Affinity (Ki, nM) Efficacy (Emax, %) Action
D2S 3.3 130 Full agonist
D2L 3.9 70 Partial agonist
D3 0.5 70 Partial agonist
D4 3.9 42 Partial agonist
Notes: Pramipexole also possesses lower affinity (500–10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors.[28][33] It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors.[28][33] All sites were assayed using human materials.[28][29]

While pramipexole is used clinically (see below), its D3-preferring receptor binding profile has made it a popular tool compound for preclinical research. For example, pramipexole has been used (in combination with D2- and or D3-preferring antagonists) to discover the role of D3 receptor function in rodent models and tasks for neuropsychiatric disorders.[34] Of note, it appears that pramipexole, in addition to having effects on dopamine D3 receptors, may also affect mitochondrial function via a mechanism that remains less understood. A pharmacological approach to separate dopaminergic from non-dopaminergic (e.g. mitochondrial) effects of pramipexole has been to study the effects of the R-stereoisomer of pramipexole (which has much lower affinity to the dopamine receptors when compared to the S-isomer) side by side with the effects of the S-isomer.[35]

Parkinson's disease is a neurodegenerative disease affecting the substantia nigra, a component of the basal ganglia. The substantia nigra has a high quantity of dopaminergic neurons, which are nerve cells that release the neurotransmitter known as dopamine. When dopamine is released, it may activate dopamine receptors in the striatum, which is another component of the basal ganglia. When neurons of the substantia nigra deteriorate in Parkinson's disease, the striatum no longer properly receives dopamine signals. As a result, the basal ganglia can no longer regulate body movement effectively and motor function becomes impaired. By acting as an agonist for the D2, D3, and D4 dopamine receptors, pramipexole may directly stimulate the underfunctioning dopamine receptors in the striatum, thereby restoring the dopamine signals needed for proper functioning of the basal ganglia.

Society and culture

Brand names

Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Glepark, and Oprymea.[citation needed]

Research

Pramipexole has been evaluated for the treatment of sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants.[36] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.[37][38][39] It is also being investigated for the treatment of clinical depression and fibromyalgia.[40][41][42]

Derivatives

Derivatives of pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639,[43] D-264, D-440,[44] and D-512.[44]

Notes

  1. ^ The term "augmentation" has different meanings depending on the context. In the context of the pharmacological management of psychiatric disorders, for example, it means enhancing treatment effects by adding a second drug (or other treatment intervention). In the present context, augmentation has the meaning given above (in the body of the article).

References

  1. ^ a b c "Pramipexole Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  2. ^ a b "Mirapex- pramipexole dihydrochloride tablet". DailyMed. 1 March 2020. Retrieved 17 October 2020.
  3. ^ a b "Mirapex ER- pramipexole dihydrochloride tablet, extended release". DailyMed. 5 February 2020. Retrieved 17 October 2020.
  4. ^ "Sifrol EPAR". European Medicines Agency. 17 September 2018. Retrieved 17 October 2020.
  5. ^ "Mirapexin EPAR". European Medicines Agency. 17 September 2018. Retrieved 17 October 2020.
  6. ^ a b c d e f "Pramipexole Dihydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019.
  7. ^ Napier TC, Kirby A, Persons AL (August 2020). "The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 102: 109942. doi:10.1016/j.pnpbp.2020.109942. PMID 32272129. S2CID 215237629. ... features of ICSDs [impulsive-compulsive spectrum disorders] during D2/D3R treatment are consistent with the pharmacological profile of the drugs, the known role of D2/D3R in these behaviors, and the neuroanatomical substrates of D2/D3R-expressing brain systems of ICSDs as shown by modern human imaging studies. While we pose that D2/D3R agonist treatment is sufficient to mediate ICSDs, there likely are many factors that overlay this profile, e.g., genetic vulnerabilities, brain disease state, and maladaptations to the chronic therapy.
  8. ^ Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (April 2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings. 84 (4): 310–316. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.
  9. ^ Moore TJ, Glenmullen J, Mattison DR (December 2014). "Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs". JAMA Internal Medicine. 174 (12): 1930–1933. doi:10.1001/jamainternmed.2014.5262. PMID 25329919.
  10. ^ Wolters EC, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". Journal of Neurology. 255 Suppl 5: 48–56. doi:10.1007/s00415-008-5010-5. PMID 18787882. S2CID 24531331.
  11. ^ a b Elliott, Carl. "The Degradation Drug". The American Scholar. Retrieved 15 September 2022.
  12. ^ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 417–418. ISBN 9780857113382.
  13. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  14. ^ "Pramipexole - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  15. ^ Chernoloz O, El Mansari M, Blier P (February 2012). "Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain". Journal of Psychiatry & Neuroscience. 37 (2): 113–121. doi:10.1503/jpn.110038. PMC 3297071. PMID 22023785.
  16. ^ Castro-Hernández J, Afonso-Oramas D, Cruz-Muros I, Salas-Hernández J, Barroso-Chinea P, Moratalla R, et al. (February 2015). "Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake". Neurobiology of Disease. 74: 325–335. doi:10.1016/j.nbd.2014.12.007. PMID 25511804. S2CID 25373392.
  17. ^ Fawcett J, Rush AJ, Vukelich J, Diaz SH, Dunklee L, Romo P, et al. (February 2016). "Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression". The American Journal of Psychiatry. 173 (2): 107–111. doi:10.1176/appi.ajp.2015.15060788. PMID 26844792.
  18. ^ "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. Archived from the original on 26 September 2006. Retrieved 27 September 2006.
  19. ^ Tan EK, Ondo W (May 2000). "Clinical characteristics of pramipexole-induced peripheral edema". Archives of Neurology. 57 (5): 729–732. doi:10.1001/archneur.57.5.729. PMID 10815140.
  20. ^ Napier TC, Kirby A, Persons AL (August 2020). "The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 102: 109942. doi:10.1016/j.pnpbp.2020.109942. PMID 32272129. S2CID 215237629. ... features of ICSDs [impulsive-compulsive spectrum disorders] during D2/D3R treatment are consistent with the pharmacological profile of the drugs, the known role of D2/D3R in these behaviors, and the neuroanatomical substrates of D2/D3R-expressing brain systems of ICSDs as shown by modern human imaging studies. While we pose that D2/D3R agonist treatment is sufficient to mediate ICSDs, there likely are many factors that overlay this profile, e.g., genetic vulnerabilities, brain disease state, and maladaptations to the chronic therapy.
  21. ^ Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (April 2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings. 84 (4): 310–316. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.
  22. ^ Moore TJ, Glenmullen J, Mattison DR (December 2014). "Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs". JAMA Internal Medicine. 174 (12): 1930–1933. doi:10.1001/jamainternmed.2014.5262. PMID 25329919.
  23. ^ Wolters EC, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". Journal of Neurology. 255 Suppl 5: 48–56. doi:10.1007/s00415-008-5010-5. PMID 18787882. S2CID 24531331.
  24. ^ Winkelmann J, Allen RP, Högl B, Inoue Y, Oertel W, Salminen AV, et al. (July 2018). "Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§". Movement Disorders. 33 (7): 1077–1091. doi:10.1002/mds.27260. PMID 29756335. S2CID 21669996. … the specific goals of the current review were to … separately identify the RLS-specific side effect, which is augmentation.
  25. ^ "Pramipexole Monograph for Professionals". Drugs.com. Retrieved 11 December 2020. Augmentation of symptoms of restless legs syndrome (e.g., earlier onset of symptoms in the evening or afternoon, increase in symptoms, spread of symptoms to involve other extremities) reported; incidence increased with increasing duration of pramipexole treatment.
  26. ^ Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, et al. (December 2016). "Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology". Neurology. 87 (24): 2585–2593. doi:10.1212/WNL.0000000000003388. PMC 5206998. PMID 27856776.
  27. ^ Salminen AV, Winkelmann J (November 2018). "Restless Legs Syndrome and Other Movement Disorders of Sleep-Treatment Update". Current Treatment Options in Neurology. 20 (12): 55. doi:10.1007/s11940-018-0540-3. PMID 30411165. S2CID 53242049. … augmentation of the RLS symptoms is a major limitation of oral dopaminergic therapy.
  28. ^ a b c d Kvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clinical Therapeutics. 28 (8): 1065–1078. doi:10.1016/j.clinthera.2006.08.004. PMID 16982285.
  29. ^ a b Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 805–814. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
  30. ^ Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM (June 1995). "Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors". European Journal of Pharmacology. 290 (1): 29–36. doi:10.1016/0922-4106(95)90013-6. PMID 7664822.
  31. ^ "PDSP Ki Database Pramipexole Query". PDSP Ki Database. UNC. Retrieved 11 July 2022.
  32. ^ "Pramipexole dihydrochloride characteristics". Bio-techne. Retrieved 11 July 2022.
  33. ^ a b Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. S2CID 6200455.
  34. ^ Weber M, Chang WL, Breier M, Ko D, Swerdlow NR (December 2008). "Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation". Behavioural Pharmacology. 19 (8): 786–795. doi:10.1097/FBP.0b013e32831c3b2b. PMC 3255557. PMID 19020413.
  35. ^ Chang WL, Weber M, Breier MR, Saint Marie RL, Hines SR, Swerdlow NR (February 2012). "Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats". Brain Research. 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMC 3268831. PMID 22227455.
  36. ^ DeBattista C, Solvason HB, Breen JA, Schatzberg AF (April 2000). "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression". Journal of Clinical Psychopharmacology. 20 (2): 274–275. doi:10.1097/00004714-200004000-00029. PMID 10770475.
  37. ^ Zarate CA, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, et al. (July 2004). "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study". Biological Psychiatry. 56 (1): 54–60. doi:10.1016/j.biopsych.2004.03.013. PMID 15219473. S2CID 19613411.
  38. ^ Goldberg JF, Burdick KE, Endick CJ (March 2004). "Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression". The American Journal of Psychiatry. 161 (3): 564–566. doi:10.1176/appi.ajp.161.3.564. PMID 14992985.
  39. ^ Goodwin GM, Martinez-Aran A, Glahn DC, Vieta E (November 2008). "Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report". European Neuropsychopharmacology. 18 (11): 787–793. doi:10.1016/j.euroneuro.2008.07.005. PMID 18725178. S2CID 18520604.
  40. ^ Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, Houck PR, et al. (October 2002). "Pramipexole in treatment-resistant depression: a 16-week naturalistic study". Bipolar Disorders. 4 (5): 307–314. doi:10.1034/j.1399-5618.2002.01171.x. PMID 12479663.
  41. ^ Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano GB (2004). "Pramipexole in treatment-resistant depression: an extended follow-up". Depression and Anxiety. 20 (3): 131–138. doi:10.1002/da.20038. PMID 15549689. S2CID 23007562.
  42. ^ Holman AJ, Myers RR (August 2005). "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications". Arthritis and Rheumatism. 52 (8): 2495–2505. doi:10.1002/art.21191. PMID 16052595.
  43. ^ Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S (August 2011). "CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist". ACS Medicinal Chemistry Letters. 2 (8): 620–625. doi:10.1021/ml200100t. PMC 3224040. PMID 22125662.
  44. ^ a b Santra S, Xu L, Shah M, Johnson M, Dutta A (October 2013). "D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson's disease animal model". ACS Chemical Neuroscience. 4 (10): 1382–1392. doi:10.1021/cn400106n. PMC 3798991. PMID 23906010.

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