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Pramipexole (Mirapex, Mirapexin, Sifrol) is a dopamine agonist of the non-ergoline class indicated for treating Parkinson's disease (PD)^[1] and restless legs syndrome (RLS).^[2]

Pharmacology

Pramipexole acts as a partial/full agonist at the following receptors:^[3]^[4]

D_2S receptor (K_i = 3.9 nM; IA = 130%)
D_2L receptor (K_i = 2.2 nM; IA = 70%)
D₃ receptor (K_i = 0.5 nM; IA = 70%)
D₄ receptor (K_i = 5.1 nM; IA = 42%)

Pramipexole also possesses low/insignificant affinity (500–10,000 nM) for the 5-HT_1A, 5-HT_1B, 5-HT_1D, and α₂-adrenergic receptors.^[3]^[5] It has negligible affinity (>10,000 nM) for the D₁, D₅, 5-HT₂, α₁-adrenergic, β-adrenergic, H₁, and mACh receptors.^[3]^[5] All sites assayed were done using human tissues.^[3]^[4]

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 interrogate the role of D₃ receptor function in rodent models and tasks for neuropsychiatric disorders.^[6] 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.^[7]

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.

Bipolar depression

In a single controlled study of twenty one patients, pramipexole was found to be highly effective in the treatment of bipolar depression. Treatment was initiated at 0.125 mg three times a day and increased at a rate of 0.125 mg three times a day to a limit of 4.5 mg daily until the patients' condition satisfactorily responded to the medication or they could not abide the side effects. The final average dosage was 1.7 ± 0.9 mg daily. The incidence of hypomania in the treatment group was no greater than in the control group, although the size of the study is too small to determine risks for manic switch.^[8]

Unipolar depression

In one controlled study, pramipexole was shown to be efficacious in the treatment of unipolar depression.^[9]^{cited in}^[8]

Side effects

Common side effects of pramipexole may include:^[10]^[11]

Headache
Peripheral edema (Tan EK, Ondo W. Clinical characteristics of pramipexole-induced peripheral edema. Arch Neurol. 2000;57:729-732.)
Hyperalgesia (body aches and pains)
Nausea and vomiting
Sedation and somnolence
Decreased appetite and subsequent weight loss
Orthostatic hypotension (resulting in dizziness, lightheadedness, and possibly fainting, especially when standing up)
Insomnia
Hallucinations (seeing, hearing, smelling, tasting or feeling things that are not there)
Twitching, twisting, or other unusual body movements
Unusual tiredness or weakness

Several unusual adverse effects of pramipexole (and related D₃-preferring dopamine agonist medications such as ropinirole) may include compulsive gambling, punding, hypersexuality, and overeating,^[12] even in patients without any prior history of these behaviours.^[13]

Research

Pramipexole has been evaluated for the treatment of cluster headache^{[citation needed]} and to counteract problems with sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants.^[14] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.^[8]^[15]^[16] It is also being investigated for the treatment of clinical depression and fibromyalgia.^[17]^[18]^[19]

References

^ "Once-daily MIRAPEX ER now approved by FDA for both early and advanced Parkinson’s disease". Boehringer Ingelheim Pharmaceuticals, Inc. Retrieved 19 December 2013.
^ National Prescribing Service (2009). "Pramipexole for Parkinson's Disease". Medicines Update. Available at http://www.nps.org.au/consumers/publications/medicine_update/issues/Pramipexole_for_Parkinsons_disease
^ ^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): 1065–78. doi:10.1016/j.clinthera.2006.08.004. PMID 16982285.
^ ^a ^b Newman-Tancredi A, Cussac D, Audinot V, et al. (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): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667.
^ ^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.
^ Weber, M; Chang W; 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". Behav Pharmacol 19 (8): 786–795. doi:10.1097/FBP.0b013e32831c3b2b. PMC 3255557. PMID 19020413.
^ Chang, W; 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 Res 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMID 22227455.
^ ^a ^b ^c Zarate CA, Payne JL, Singh J, et al. (July 2004). "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study". Biol. Psychiatry 56 (1): 54–60. doi:10.1016/j.biopsych.2004.03.013. PMID 15219473.
^ Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000): Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11:58 –65.
^ "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. Archived from the original on 2006-09-26. Retrieved 2006-09-27.
^ "FDA Prescribing Information: Mirapex (pramipexole dihydrochloride)" (PDF). Food and Drug Administration (United States). Retrieved 2008-12-31.
^ Wolters ECh, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". J. Neurol. 255 Suppl 5: 48–56. doi:10.1007/s00415-008-5010-5. PMID 18787882.
^ 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 Clin. Proc. 84 (4): 310–6. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.
^ DeBattista C, Solvason HB, Breen JA, Schatzberg AF. (2000). "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression.". J Clin Psychopharmacol. 20 (2): 274–275. doi:10.1097/00004714-200004000-00029. PMID 10770475.
^ 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.". American Journal of Psychiatry 161 (3): 161:564–566. doi:10.1176/appi.ajp.161.3.564. PMID 14992985.
^ Guy M. Goodwina, A. Martinez-Aranb, David C. Glahn c, Eduard Vieta b (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.
^ Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A, Battistini G, Bassi A, Abelli M, Cassano GB. (2002). "Pramipexole in treatment-resistant depression: a 16-week naturalistic study.". Bipolar Disord. 4 (5): 307–314. doi:10.1034/j.1399-5618.2002.01171.x. PMID 12479663.
^ 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.
^ Holman AJ, Myers RR. (2005). "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.". Arthritis Rheum. 52 (8): 2495–2505. doi:10.1002/art.21191. PMID 16052595.

External links

Mirapex.com - Manufacturer's website

UpToDate Contents

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1. 成人におけるレストレスレッグ症候群の治療 treatment of restless legs syndrome in adults
2. 成人における初期治療の効果がない線維筋痛症の治療 treatment of fibromyalgia in adults not responsive to initial therapies
3. 小児におけるむずむず脚（レストレスレッグス）症候群と周期性四肢運動障害 restless legs syndrome and periodic limb movement disorder in children
4. パーキンソン病に対する神経保護療法 neuroprotective therapy for parkinson disease
5. 成人における単極性うつ病：難治性うつ病の治療 unipolar depression in adults treatment of resistant depression

English Journal

Risk of Gambling Disorder and Impulse Control Disorder With Aripiprazole, Pramipexole, and Ropinirole: A Pharmacoepidemiologic Study.

Etminan M1, Sodhi M, Samii A, Procyshyn RM, Guo M, Carleton BC.
Journal of clinical psychopharmacology.J Clin Psychopharmacol.2017 Feb;37(1):102-104. doi: 10.1097/JCP.0000000000000634.
BACKGROUND: Recently, the US Food and Drug Administration issued a warning regarding the potential risk of gambling disorder, but large epidemiologic studies are lacking.METHODS: We used a large health claims database from the United States and conducted a nested case-control study. Cases were defin
PMID 27930495

Pramipexole in Treatment Resistant-Depression, Possible Role of Inflammatory Cytokines.

Escalona R1,2, Fawcett J1.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.Neuropsychopharmacology.2017 Jan;42(1):363. doi: 10.1038/npp.2016.217.
PMID 27909317

Immediate resolution of acute, choreatic hyperkinesias following intravenous fentanyl.

Finsterer J1, Rettensteiner J1.
Nigerian journal of clinical practice.Niger J Clin Pract.2017 Jan;20(1):119-122. doi: 10.4103/1119-3077.195542.
Acute hyperkinesia after discontinuation of tramadol in a patient with chronic pain using citalopram and pramipexole for restless legs syndrome (RLS) has not been reported. An 81-year-old female was admitted for increasing hyperkinesias of the whole body after she had discontinued tramadol 300 mg (t
PMID 27958259

Japanese Journal

Dyskinesia-hyperpyrexia syndromeを合併したパーキンソン病の1例

田口宗太郎,丹羽淳一,衣斐達,道勇学
臨床神経学 55(3), 182-184, 2015
症例は70歳の女性である．13年前にパーキンソン病（Parkinsons disease; PD）を発症，L-Dopa合剤，塩酸セレギリン，プラミペキソールを内服していた．プラミペキソールを等価量で徐放化した1ヵ月後に高熱をともない四肢のジスキネジアと幻視が出現した．全身の発汗が亢進し，見当識障害をともなっていたが，脳神経と感覚系に異常なく，筋強剛もなかった．血液検査では白血球増多と血清CK高値を …
NAID 130004921327

Effects of Bupropion and Pramipexole on Cell Proliferation in the Hippocampus of Adrenocorticotropic Hormone-Treated Rats

Onoue Yuka,Kuwatsuka Keiko,Miyazaki Ikuko [他]
Biological & pharmaceutical bulletin 37(2), 327-330, 2014-02
NAID 40019957206

健康成人被験者で高含量の向精神薬の生物学的同等性試験を行うことの妥当性:―クエチアピンおよびプラミペキソールでの検討―

松木俊二,名取和一,小川幸司,松井隆,松隈京子,坂本慶,木村美由紀,神田英里,米納誠,伊藤一弥,鄭恩希,白源正成,入江伸
臨床薬理 45(4), 151-159, 2014
… The aims of the present study were (1) to determine the maximum tolerated doses of quetiapine and pramipexole when given to healthy Japanese male subjects using gradually increasing single doses; … For pramipexole, 18 participants received 0.125 mg in the first stage, and then received 0.25 mg, 0.375 mg, or 0.5 mg in the second stage in the same manner as quetiapine. … In the group receiving 0.5 mg of pramipexole, three mild and five moderate adverse events were reported from five subjects. …
NAID 130004679400

Related Pictures

Pramipexole Oral : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD Mirapex 0.125 mg : Abana tablets 60 Pillbox - National Library of Medicine Pramipex (Pramipexole Dihydrochloride) - United Pharmacies Pramipexole (Mirapex, Mirapexin, Sifrol) Liquid Sale

★リンクテーブル★

リンク元	「プラミペキソール」
拡張検索	「pramipexole hydrochloride hydrate」

「プラミペキソール」

Pramipexole
Systematic (IUPAC) name
	(S)-N 6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
Clinical data
Trade names	Mirapex, Mirapexin, Sifrol
AHFS/Drugs.com	monograph
MedlinePlus	a697029
Pregnancy; category	AU: B3; US: C (Risk not ruled out); ;
Routes of; administration	Oral
Legal status	℞ (Prescription only);
Pharmacokinetic data
Bioavailability	>90%
Protein binding	15%
Biological half-life	8–12 hours
Excretion	Urine (90%), Feces (2%)
Identifiers
CAS Number	104632-26-0
ATC code	N04BC05 (WHO)
PubChem	CID 119570
IUPHAR/BPS	953
DrugBank	DB00413
ChemSpider	106770
UNII	83619PEU5T
KEGG	D05575
ChEBI	CHEBI:8356
ChEMBL	CHEMBL301265
Chemical data
Formula	C10H17N3S
Molar mass	211.324 g/mol
	SMILES n1c2c(sc1N)C[C@@H](NCCC)CC2 ;
	InChI 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 ; Key:FASDKYOPVNHBLU-ZETCQYMHSA-N ;
(verify)

　　[★]

英: pramipexole
化: 塩酸プラミペキソール水和物, pramipexole hydrochloride hydrate
関: ビ・シフロール、ミラペックス
関: 抗パーキンソン剤

パーキンソン病の治療薬である。
非麦角系のドパミン受容体作用薬である。
ドパミンD2受容体に対する親和性とドパミンD2受容体刺激作用有する。
組成：(ミラペックス 0.375mgの場合)

1錠中、プラミペキソール塩酸塩水和物　0.375mg、添加物：ヒプロメロース、トウモロコシデンプン、カルボキシビニルポリマー、軽質無水ケイ酸、ステアリン酸マグネシウム

「pramipexole hydrochloride hydrate」

　　[★] プラミペキソール。塩酸プラミペキソール水和物

[Boehringer2010-1] "Once-daily MIRAPEX ER now approved by FDA for both early and advanced Parkinson’s disease". Boehringer Ingelheim Pharmaceuticals, Inc. Retrieved 19 December 2013.

[2] National Prescribing Service (2009). "Pramipexole for Parkinson's Disease". Medicines Update. Available at http://www.nps.org.au/consumers/publications/medicine_update/issues/Pramipexole_for_Parkinsons_disease

[pmid16982285-3] Kvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clinical Therapeutics 28 (8): 1065–78. doi:10.1016/j.clinthera.2006.08.004. PMID 16982285.

[pmid12388667-4] Newman-Tancredi A, Cussac D, Audinot V, et al. (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): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667.

[pmid12388666-5] 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.

[6] Weber, M; Chang W; 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". Behav Pharmacol 19 (8): 786–795. doi:10.1097/FBP.0b013e32831c3b2b. PMC 3255557. PMID 19020413.

[7] Chang, W; 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 Res 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMID 22227455.

[BiDep-8] Zarate CA, Payne JL, Singh J, et al. (July 2004). "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study". Biol. Psychiatry 56 (1): 54–60. doi:10.1016/j.biopsych.2004.03.013. PMID 15219473.

[9] Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000): Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11:58 –65.

[10] "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. Archived from the original on 2006-09-26. Retrieved 2006-09-27.

[fda-11] "FDA Prescribing Information: Mirapex (pramipexole dihydrochloride)" (PDF). Food and Drug Administration (United States). Retrieved 2008-12-31.

[12] Wolters ECh, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". J. Neurol. 255 Suppl 5: 48–56. doi:10.1007/s00415-008-5010-5. PMID 18787882.

[13] 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 Clin. Proc. 84 (4): 310–6. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.

[pmid10770475-14] DeBattista C, Solvason HB, Breen JA, Schatzberg AF. (2000). "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression.". J Clin Psychopharmacol. 20 (2): 274–275. doi:10.1097/00004714-200004000-00029. PMID 10770475.

[15] 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.". American Journal of Psychiatry 161 (3): 161:564–566. doi:10.1176/appi.ajp.161.3.564. PMID 14992985.

[16] Guy M. Goodwina, A. Martinez-Aranb, David C. Glahn c, Eduard Vieta b (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.

[pmid12479663-17] Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A, Battistini G, Bassi A, Abelli M, Cassano GB. (2002). "Pramipexole in treatment-resistant depression: a 16-week naturalistic study.". Bipolar Disord. 4 (5): 307–314. doi:10.1034/j.1399-5618.2002.01171.x. PMID 12479663.

[pmid15549689-18] 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.

[pmid16052595-19] Holman AJ, Myers RR. (2005). "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.". Arthritis Rheum. 52 (8): 2495–2505. doi:10.1002/art.21191. PMID 16052595.

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pramipexole