Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/06 23:36:00」(JST)

wiki en

Ropinirole (INN; trade names Requip, Repreve, Ronirol, Adartrel) is a dopamine agonist of the non-ergoline class of medications. It is manufactured by GlaxoSmithKline (GSK), Cipla, Dr. Reddy's Laboratories and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease and restless legs syndrome (RLS). Ropinirole is one of three medications approved by the FDA to treat RLS, the other two being pramipexole (Mirapex) and gabapentin enacarbil (Horizant). The discovery of the drug's utility in RLS has been used as an example of successful drug repurposing.^[2]

Ropinirole's patent expired in May 2008, and the drug is now available in generic form.^[3]

Medical uses

Ropinirole is prescribed for mainly Parkinson's disease, RLS and extrapyramidal symptoms. It can also reduce the side effects caused by selective serotonin reuptake inhibitors, including Parkinsonism syndrome as well as sexual dysfunction and erectile dysfunction caused by either SSRIs^[4] or antipsychotics.

Dosage

Ropinirole in the Requip form is available in various preparations, ranging from a 0.25 mg tablet to a 5 mg tablet. The primary reason is dose titration. This implies that the person taking Requip has to closely interact and communicate with the primary care physician with regard to how much should actually be taken by the patient.

For Parkinson's disease, the maximum recommended dose is 24 mg per day, taken in three separate doses spread throughout the day. The maximum dose recommendations of ropinirole for subjects with end stage renal disease (ESRD) should be reduced by 25% compared with those recommended for subjects with normal renal function. A 25% dose reduction represents a more straightforward dosage regimen in terms of available tablet strength, compared with a 30% dose reduction.^[5]

For RLS, the maximum recommended dose is 4 mg per day, taken 1 to 3 hours before bedtime. A 52-week open label study had a mean dosage of 1.90 mg, once daily 1 to 3 hours before bedtime.^[6]

Pharmacology

Ropinirole acts as a D₂, D₃, and D₄ dopamine receptor agonist with highest affinity for D₂. It is weakly active at the 5-HT₂, and α₂ receptors and is said to have virtually no affinity for the 5-HT₁, GABA, mAChRs, α₁, and β-adrenoreceptors.^[7]

Ropinirole is metabolized primarily by cytochrome P450 CYP1A2 to form two metabolites; SK&F-104557 and SK&F-89124, both of which are renally excreted,^[5] and at doses higher than clinical, is also metabolized by CYP3A4. At doses greater than 24 mg, CYP2D6 may be inhibited, although this has only been tested in vitro.^[1]

Side effects

Ropinirole can cause nausea, dizziness, hallucinations, orthostatic hypotension, and sudden sleep attacks during the daytime. Unusual side effects specific to D₃ agonists such as ropinirole and pramipexole can include hypersexuality, punding and compulsive gambling, even in patients without a history of these behaviours.^[8]

Lawsuits

In November 2012, GlaxoSmithKline was ordered by a Rennes appeals court to pay Frenchman Didier Jambart 197,000 euros ($255,824); Jambart had taken ropinirole from 2003 to 2010 and exhibited risky hypersexual behavior and gambled excessively until stopping the Parkinson's treatment.^[9]

Synthesis

Ropinirole synthesis: G. Gallagher, Jr., U.S. Patent 4,452,808 (1984 to Smithkline Beckman Corporation); idem et al., ^[10]

The sequence for preparing this agent starts with the homologation of the carboxylic acid in (). The acid is thus reduced to the carbinol () by means of diborane. The hydroxyl is thus next converted to the mesylate in the usual way and that displaced with cyanide. Hydrolysis of the resulting nitrile gives the resulting arylacetic acid (). The acid chloride from that acid is then taken on to the amide () by rxn with dipropylamine. Reduction of the amide with diborane completes the synthesis of the sidechain, affording the amine (). Condensation of the transient anion, from removal of a benzylic proton, with ethyl oxalate gives the chain-extented glyoxylate ester (). Saponification of the ester with NaOH followed by decarboxylation of the resulting α-ketoacid gives (). The nitro group is hydrogenated to give the transient amine (). Intramolecular cyclization of the amine and acid function then occurs to give the indolone lactam, ropinirole.

References

^ ^a ^b ^c ^d Tompson, Debra J. et al. (2007). "Steady-State Pharmacokinetic Properties of a 24-Hour Prolonged-Release Formulation of Ropinirole: Results of Two Randomized Studies in Patients with Parkinson’s Disease". Clinical Pharmacokinetics 29 (12): 2654–66. doi:10.1016/j.clinthera.2007.12.010. PMID 18201581.
^ Lipp, Elizabeth (2008-08-01). "Novel Approaches to Lead Optimization". Genetic Engineering & Biotechnology News. Drug Discovery 28 (14) (Mary Ann Liebert). p. 20. ISSN 1935-472X. Retrieved 2008-09-28. Note: The opinion that ropinirole's use in RLS was a successful example of drug repurposes was reported as being that of Josef Scheiber, a post-doctoral fellow at the Novartis Institutes for BioMedical Research.
^ New pharmaceutical products: Ceftriaxon-Rocephin, Granisetron-Kytril, Ipratropium-Albuterol
^ Clinical trial number NCT00334048 at ClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"
^ ^a ^b An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole | Authors: Debra J. Tompson, Deborah Hewens, Nancy Earl, David Oliveira, Jorg Taubel, Suzanne Swan, Luigi Giorgi | 13th International Congress of Parkinson’s Disease and Movement Disorders, Paris, France, June 7–11, 2009
^ Garcia-Borreguero D, Grunstein R, Sridhar G et al. (November 2007). "A 52-week open-label study of the long-term safety of ropinirole in patients with restless leg syndrome". Sleep Med. 8 (7–8): 742–52. doi:10.1016/j.sleep.2006.09.009. PMID 17512789.
^ Eden, R. J. et al. (1991). "Preclinical Pharmacology of Ropinirole (SK&F 101468-A) a Novel Dopamine D 2 Agonist". Pharmacology Biochemistry & Behavior 38: 147–154. doi:10.1016/0091-3057(91)90603-Y.
^ Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings 84 (4): 310–6. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.
^ Wong, Curtis (2012-11-29). "Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict". Huffington Post.
^ Gallagher, G.; Lavanchy, P. G.; Wilson, J. W.; Hieble, J. P.; Demarinis, R. M. (1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: A prejunctional dopamine receptor agonist". Journal of Medicinal Chemistry 28 (10): 1533. doi:10.1021/jm00148a028. PMID 4045928.

External links

Requip for RLS
Requip for PD
Requip - Clinical Pharmacology

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

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. パーキンソン病に対する神経保護療法 neuroprotective therapy for parkinson disease
3. パーキンソン病の薬理学的治療 pharmacologic treatment of parkinson disease
4. 多系統萎縮症：予後および治療 multiple system atrophy prognosis and treatment
5. パーキンソン病における症状の変動およびジスキネジア motor fluctuations and dyskinesia in parkinson disease

English Journal

Metabolic changes in de novo Parkinson's disease after dopaminergic therapy: A proton magnetic resonance spectroscopy study.

Ciurleo R1, Bonanno L1, Di Lorenzo G1, Bramanti P1, Marino S2.
Neuroscience letters.Neurosci Lett.2015 Jul 10;599:55-60. doi: 10.1016/j.neulet.2015.05.044. Epub 2015 May 22.
The aim of this study was to assess metabolic changes in the motor cortex in de novo Parkinson's disease (PD) patients before and after therapy with ropinirole. Twenty de novo drug-naïve PD patients and 15 healthy controls underwent conventional magnetic resonance imaging and proton magnetic resona
PMID 26007705

Dopamine agonists can improve pure apathy associated with lesions of the prefrontal-basal ganglia functional system.

Blundo C1, Gerace C.
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology.Neurol Sci.2015 Jul;36(7):1197-201. doi: 10.1007/s10072-014-2061-5. Epub 2015 Jan 21.
Apathy is a common neurobehavioral symptom of other syndromes or a syndrome per se which occurs in a variety of neuropsychiatric disorders. Apathy depends on disruption of emotional, cognitive, and behavioral functions. Six brain-damaged patients were assessed, including five patients with unilatera
PMID 25876742

Nano-ropinirole for the management of Parkinsonism: blood-brain pharmacokinetics and carrier localization.

Mustafa G1, Ahuja A, Al Rohaimi AH, Muslim S, Hassan AA, Baboota S, Ali J.
Expert review of neurotherapeutics.Expert Rev Neurother.2015 Jun;15(6):695-710. doi: 10.1586/14737175.2015.1036743. Epub 2015 May 8.
AIM: The aim of this study was to investigate the brain targeting potential of chitosan-coated oil in water nanoemulsions (CSNE(ROP)) delivered intranasally in haloperidol-induced Parkinson's disease rat models.METHODS: Chitosan-coated nanoemulsion (CSNE(ROP)) was developed through aqueous titration
PMID 25955028

Japanese Journal

A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea

Nakamura Katsuya,Sekijima Yoshiki,Nagamatsu Kiyoshiro,Yoshida Kunihiro,Ikeda Shu-ichi
JOURNAL OF THE NEUROLOGICAL SCIENCES 313(1-2), 189-192, 2012-02-15
… The dopamine agonist, ropinirole hydrochloride, reduced her choreic movements, suggesting that levodopa and/or dopamine agonists may compensate for underdeveloped dopaminergic pathways in this disorder. …
NAID 120005248139

An anti-Parkinson drug ropinirole depletes orexin from rat hypothalamic slice culture

Neuroscience Research 68(4), 315-321, 2010-12
… Non-ergot-type dopamine receptor agonists such as ropinirole are used for the treatment of Parkinson disease, but they occasionally show serious side effects including sleep attacks and daytime sleepiness. … Because narcolepsy is thought to result from deficiency of a hypothalamic neuropeptide orexin, we examined whether ropinirole affected the integrity of orexin-containing neurons, using organotypic slice culture of rat hypothalamus. …
NAID 80021430682

脳卒中の高次機能障害に対する薬物療法の試み

卜蔵浩和,豊田元哉,河野直人,山口修平
脳卒中 31(6), 448-452, 2009-11-25
NAID 10027053617

Related Pictures

★リンクテーブル★

リンク元	「ロピニロール」
拡張検索	「ropinirole hydrochloride」

「ロピニロール」

Ropinirole
Systematic (IUPAC) name
	4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
Clinical data
Trade names	Requip
AHFS/Drugs.com	monograph
MedlinePlus	a698013
Pregnancy; category	C;
Legal status	℞ (Prescription only);
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	50%
Metabolism	Hepatic (CYP1A2)
Biological half-life	5-6 hours
Identifiers
CAS Registry Number	91374-21-9
ATC code	N04BC04
PubChem	CID: 5095
IUPHAR/BPS	7295
DrugBank	DB00268
ChemSpider	4916
UNII	030PYR8953
KEGG	D08489
ChEBI	CHEBI:8888
ChEMBL	CHEMBL589
Chemical data
Formula	C16H24N2O
Molecular mass	260.375 g/mol
	SMILES O=C2Nc1cccc(c1C2)CCN(CCC)CCC ;
	InChI InChI=1S/C16H24N2O/c1-3-9-18(10-4-2)11-8-13-6-5-7-15-14(13)12-16(19)17-15/h5-7H,3-4,8-12H2,1-2H3,(H,17,19) ; Key:UHSKFQJFRQCDBE-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: ropinirole
化: 塩酸ロピニロール ropinirole hydrochloride
商: レキップCR、レキップ
関: 抗パーキンソン剤

「ropinirole hydrochloride」

　　[★]

塩酸ロピニロール

関: ropinirole

[TompsonD-1] Tompson, Debra J. et al. (2007). "Steady-State Pharmacokinetic Properties of a 24-Hour Prolonged-Release Formulation of Ropinirole: Results of Two Randomized Studies in Patients with Parkinson’s Disease". Clinical Pharmacokinetics 29 (12): 2654–66. doi:10.1016/j.clinthera.2007.12.010. PMID 18201581.

[Lipp_GEN2008-2] Lipp, Elizabeth (2008-08-01). "Novel Approaches to Lead Optimization". Genetic Engineering & Biotechnology News. Drug Discovery 28 (14) (Mary Ann Liebert). p. 20. ISSN 1935-472X. Retrieved 2008-09-28. Note: The opinion that ropinirole's use in RLS was a successful example of drug repurposes was reported as being that of Josef Scheiber, a post-doctoral fellow at the Novartis Institutes for BioMedical Research.

[3] New pharmaceutical products: Ceftriaxon-Rocephin, Granisetron-Kytril, Ipratropium-Albuterol

[4] Clinical trial number NCT00334048 at ClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"

[RPL-5] An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole | Authors: Debra J. Tompson, Deborah Hewens, Nancy Earl, David Oliveira, Jorg Taubel, Suzanne Swan, Luigi Giorgi | 13th International Congress of Parkinson’s Disease and Movement Disorders, Paris, France, June 7–11, 2009

[52wkOpenLabel-6] Garcia-Borreguero D, Grunstein R, Sridhar G et al. (November 2007). "A 52-week open-label study of the long-term safety of ropinirole in patients with restless leg syndrome". Sleep Med. 8 (7–8): 742–52. doi:10.1016/j.sleep.2006.09.009. PMID 17512789.

[RopPharmacology-7] Eden, R. J. et al. (1991). "Preclinical Pharmacology of Ropinirole (SK&F 101468-A) a Novel Dopamine D 2 Agonist". Pharmacology Biochemistry & Behavior 38: 147–154. doi:10.1016/0091-3057(91)90603-Y.

[8] Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings 84 (4): 310–6. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.

[9] Wong, Curtis (2012-11-29). "Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict". Huffington Post.

[10] Gallagher, G.; Lavanchy, P. G.; Wilson, J. W.; Hieble, J. P.; Demarinis, R. M. (1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: A prejunctional dopamine receptor agonist". Journal of Medicinal Chemistry 28 (10): 1533. doi:10.1021/jm00148a028. PMID 4045928.

匿名

検索

案内

案内

ropinirole