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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/28 21:26:18」(JST)

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Ranolazine, sold under the trade name Ranexa by Gilead Sciences, is a drug to treat angina that was first approved in 2006.

Medical uses

Ranolazine is used to treat chronic angina.^[1]

Contraindications

Some contraindications for ranolazine are related to its metabolism and are described under Drug Interactions. Additionally, in clinical trials ranolazine slightly increased QT interval in some patients^[2] and the FDA label contains a warning for doctors to beware of this effect in their patients.^[3] The drug's effect on the QT interval is increased in the setting of liver dysfunction; thus it is contraindicated in persons with mild to severe liver disease.^[4]

Side effects

The most common side effects are dizziness (11.8%) and constipation (10.9%).^[1] Other side effects include headache and nausea.^[2]

Drug interactions

Ranolazine is metabolized by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6.^[3] For this reason, the doses of ranolazine and drugs that interact with those enzymes need to be adjusted when they are used by the same patient.

Ranolazine should not be used with drugs like ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A nor with drugs that activate CYP3A like rifampin and phenobarbital. ^[3]

For drugs that are moderate CYP3A inhibitors like diltiazem, verapamil, erythromycin, the dose of ranolazine should be reduced.^[3]

Drugs that are metabolized by CYP2D6 like digoxin and tricyclic antidepressants may need to be given at reduced doses when administered with ranolazine.^[3]

Mechanism of action

Ranolazine inhibits the late inward sodium current in heart muscle.^[5] Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.^[2]

Legal status

Ranolazine was approved by the FDA in January 2006, for the treatment of patients with chronic angina as a second-line treatment in addition to other drugs.^[2] In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.^[2] In April 2008 ranolazine was approved by the European EMEA for use in angina.^[6]

History

In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from Syntex, a subsidiary of Roche, which had discovered the drug and had developed it through Phase II trials in angina.^[7] In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.^[8] In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini.^[9] In 2009, Gilead acquired CV Therapeutics.^[10] In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.^[11]

References

^ ^a ^b Banon D et al. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. Am J Cardiol. 2014 Mar 15;113(6):1075-82. PMID 24462341
^ ^a ^b ^c ^d ^e Kloner RA, et al. Efficacy and safety of ranolazine in patients with chronic stable angina. Postgrad Med. 2013 Nov;125(6):43-52. PMID 24200760
^ ^a ^b ^c ^d ^e "Prescribing Information (2013)" (PDF). U.S. Food and Drug Administration.
^ "FDA Approves New Treatment for Chest Pain". FDA News. 2006-01-31. Retrieved 2011-03-02.
^ D Noble and P J Noble. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload Heart. Jul 2006; 92(Suppl 4): iv1–iv5. PMID 16775091 PMCID 1861316
^ EMEA Ranolazine page at the EMEA
^ CV Therapeutics press release. April 1, 1996 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.
^ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
^ Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa
^ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
^ Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries

UpToDate Contents

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1. 狭心症の新しい治療法 new therapies for angina pectoris
2. 心臓の虚血性再潅流障害 ischemic reperfusion injury of the heart
3. 終末期医療：特定の症状の評価へのアプローチ end of life care approach to assessment of specific symptoms
4. 急性心筋梗塞患者の心室性不整脈の臨床的特徴および治療 clinical features and treatment of ventricular arrhythmias during acute myocardial infarction
5. 安定狭心症の管理の概要 overview of the management of stable angina pectoris

English Journal

Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: A systematic review and meta-analysis.

Belsey J1, Savelieva I2, Mugelli A3, Camm AJ2.
European journal of preventive cardiology.Eur J Prev Cardiol.2015 Jul;22(7):837-48. doi: 10.1177/2047487314533217. Epub 2014 Apr 28.
AIMS: First-line medical management of stable angina generally involves a beta-blocker (BB) or calcium channel blocker (CCB), with other classes of medication being added if symptom control is inadequate. Evidence supporting the appropriate choice of a second-line agent is currently unclear. The obj
PMID 24776376

Effect of Ranolazine Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes.

Eckel RH1, Henry RR2, Yue P3, Dhalla A4, Wong P5, Jochelson P3, Belardinelli L6, Skyler JS7.
Diabetes care.Diabetes Care.2015 Jun 6. pii: dc142629. [Epub ahead of print]
OBJECTIVE: Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosyla
PMID 26049552

Influence of trimetazidine and ranolazine on endothelial function in patients with ischemic heart disease.

Rehberger-Likozar A1, Šebeštjen M.
Coronary artery disease.Coron Artery Dis.2015 Jun 5. [Epub ahead of print]
OBJECTIVE: Endothelial dysfunction is an independent predictor of atherosclerosis progression and cardiovascular events in patients with ischemic heart disease. Ranolazine and trimetazidine are novel drugs that reduce angina symptoms in the above-mentioned patients. The aim of this study was to comp
PMID 26049922

Japanese Journal

Ranolazine Attenuates the Enhanced Reverse Na⁺-Ca²⁺ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

Wang Xiao-Jing,Wang Lei-Lei,Fu Chen [他]
Journal of pharmacological sciences 124(3), 365-373, 2014-03
NAID 40020026469

Ranolazine Attenuates the Enhanced Reverse Na+-Ca2+ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

Wang Xiao-Jing,Wang Lei-Lei,Fu Chen,Zhang Pei-Hua,Wu Ying,Ma Ji-Hua
Journal of Pharmacological Sciences 124(3), 365-373, 2014
… Ranolazine (RAN), a novel antianginal agent, inhibits the increased late sodium current (INa.L) under many pathological conditions. …
NAID 130003391493

Protective Effects of Ranolazine on Air Pollutant-Induced Ventricular Arrhythmia through Late INa Inhibition

Hwang HyeJin,Kim Jin-Bae,Pak Hui-Nam,Lee Moon-Hyoung,Joung Boyoung
Journal of Arrhythmia 27(Supplement), PE2_018, 2011
… The objective of this study is to examine whether ranolazine, a novel inhibitor of late INa, can reduce particulate matter (PM)-induced ventricular arrhythmia. … In Langendorff-perfused rat hearts, arrhythmic events were analyzed after diesel exhaust product (DEP) infusion and pretreatment with ranolazine. …
NAID 130002129978

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Ranolazine
Systematic (IUPAC) name
	(RS)-N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a606015
Licence data	EMA:Link, US FDA:link
Pregnancy; category	US: C (Risk not ruled out);
Legal status	US: ℞-only;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	35 to 50%
Protein binding	62%
Metabolism	Hepatic, CYP extensively involved
Biological half-life	7 hours
Excretion	Renal (75%) and fecal (25%)
Identifiers
CAS Registry Number	142387-99-3
ATC code	C01EB18
PubChem	CID: 56959
IUPHAR/BPS	7291
DrugBank	DB00243
ChemSpider	51354
UNII	A6IEZ5M406
ChEMBL	CHEMBL1404
Chemical data
Formula	C24H33N3O4
Molecular mass	427.537 g/mol
	SMILES O=C(Nc1c(cccc1C)C)CN3CCN(CC(O)COc2ccccc2OC)CC3 ;
	InChI InChI=1S/C24H33N3O4/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3/h4-10,20,28H,11-17H2,1-3H3,(H,25,29) ; Key:XKLMZUWKNUAPSZ-UHFFFAOYSA-N ;
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英: ranolazine
関: 狭心症

慢性狭心症治療薬

[Banon-1] Banon D et al. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. Am J Cardiol. 2014 Mar 15;113(6):1075-82. PMID 24462341

[Kloner-2] Kloner RA, et al. Efficacy and safety of ranolazine in patients with chronic stable angina. Postgrad Med. 2013 Nov;125(6):43-52. PMID 24200760

[Label-3] "Prescribing Information (2013)" (PDF). U.S. Food and Drug Administration.

[FDANews-2006-4] "FDA Approves New Treatment for Chest Pain". FDA News. 2006-01-31. Retrieved 2011-03-02.

[5] D Noble and P J Noble. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload Heart. Jul 2006; 92(Suppl 4): iv1–iv5. PMID 16775091 PMCID 1861316

[6] EMEA Ranolazine page at the EMEA

[7] CV Therapeutics press release. April 1, 1996 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.

[8] CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia

[9] Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa

[10] Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics

[11] Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries

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ranolazine