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Zafirlukast is an oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It is available as a tablet and is usually dosed twice daily. Another leukotriene receptor antagonist is montelukast (Singulair), taken once daily. Zileuton (Zyflo), also used in the treatment of asthma via its inhibition of 5-lipoxygenase, is taken four times per day.

Zafirlukast blocks the action of the cysteinyl leukotrienes on the CysLT1 receptors, thus reducing constriction of the airways, build-up of mucus in the lungs and inflammation of the breathing passages.

Zafirlukast is marketed by Astra Zeneca with the brand names Accolate, Accoleit, and Vanticon. It was the first LTRA to be marketed in the USA and is now approved in over 60 countries, including the UK, Japan, Taiwan, Italy, Spain, Canada, Brazil, China and Turkey.

Pharmacokinetics

Healthy young men who received a single oral 40 mg dose attained peak plasma zafirlukast concentrations that averaged 607 μg/L at 3.4 hours. The elimination half-life ranged from 12 to 20 hours. In another study involving a 20 mg single oral dose in healthy men, the elimination half-life averaged 5.6 hours.^[1]^[2]

Special warnings

A letter was submitted to the FDA by Zeneca Pharmaceuticals on July 22, 1997, notifying them of a change in product labeling that includes the following potential reaction in patients undergoing a dosage reduction of oral steroids who are currently taking zafirlukast:

PRECAUTIONS-Eosinophilic Conditions: The reduction of the oral steroid dose, in some patients on ACCOLATE therapy, has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg–Strauss syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with ACCOLATE has not been established, caution is required when oral steroid reduction is being considered.¹

References

^ Fischer JD, Song MH, Suttle AB, Heizer WD, Burns CB, Vargo DL, Brouwer KL. Comparison of zafirlukast (Accolate) absorption after oral and colonic administration in humans. Pharmaceut. Res. 17: 154-159, 2000.
^ Bharathi DV, Naidu A, Jagadeesh B, Laxmi KN, Laxmi PR, Reddy PR, Mullangi R. Development and validation of a sensitive LC-MS/MS method with electrospray ionization for quantitation of zafirlukast, a selective leukotriene antagonist in human plasma: application to a clinical pharmacokinetic study. Biomed. Chromatogr. 22: 645-653, 2008.

External links

Zafirlukast (U.S. National Library of Medicine)

UpToDate Contents

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1. 喘息の治療において5-リポキシゲナーゼ経路に影響する薬剤 agents affecting the 5 lipoxygenase pathway in the treatment of asthma
2. 思春期および成人における中等度持続型喘息の治療 treatment of moderate persistent asthma in adolescents and adults
3. 思春期および成人における間欠型喘息および軽症持続型喘息の治療 treatment of intermittent and mild persistent asthma in adolescents and adults
4. 慢性蕁麻疹：標準的なマネージメントおよび患者教育 chronic urticaria standard management and patient education
5. 妊娠中の喘息のマネージメント management of asthma during pregnancy

English Journal

Adverse drug reactions associated with asthma medications in children: systematic review of clinical trials.

Aagaard L1, Hansen EH.Author information 1Faculty of Health Sciences, Institute of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark, laagaard@health.sdu.dk.AbstractBackground Respiratory medications are frequently prescribed for use in children. Several studies have reported information on the safety of asthma medications in clinical studies in adults, but information about safety in children is scarce. Objective To review published clinical trials on the occurrence and characteristics of adverse drug reactions (ADRs) in children, reported for asthma medications licensed for paediatric use. Methods We systematically reviewed the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. PubMed, Embase, Cochrane Library, PsycINFO, IPA, and CINAHLs databases were searched from origin until July 2013 for studies reporting ADRs for beta2-receptor agonists, inhaled corticosteroids, leukotriene receptor antagonists and combination products in children from birth to age 17. Information on ADR reporting rates, age and gender, type and seriousness of ADRs, design, setting, observation period, type of assessors, and funding sources was extracted from the articles. Results Literature searches resulted in 162 potential relevant articles. However only 12 of these studies were included in this review as they reported information about ADR rates from use of salmeterol, formoterol, fluticasone, montelukast, zafirlukast and budesonide/formoterol in children. The total population was approximately 3,000 children; the majority was 6- to 11-year-olds and two thirds of these were boys. The observation period varied from 1 to 22 months. The most frequently reported ADRs were exacerbation of asthma, respiratory tract infection, cough, fever and headache. Only few ADRs were rated as being serious, however a number of children dropped out of the clinical trials due to serious ADRs, and, therefore, the real number of serious ADRs is probably higher. Conclusions Few clinical trials reporting ADRs from use of asthma medications in children were identified in the literature. These studies reported only a few types of ADRs, the majority being non-serious.
International journal of clinical pharmacy.Int J Clin Pharm.2014 Feb 23. [Epub ahead of print]
Background Respiratory medications are frequently prescribed for use in children. Several studies have reported information on the safety of asthma medications in clinical studies in adults, but information about safety in children is scarce. Objective To review published clinical trials on the occu
PMID 24562976

Pranlukast inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase.

Pathomthongtaweechai N1, Soodvilai S1, Chatsudthipong V1, Muanprasat C2.Author information 1Department of Physiology and Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama 6 Rd., Rajathevi, Bangkok 10400, Thailand.2Department of Physiology and Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Rama 6 Rd., Rajathevi, Bangkok 10400, Thailand. Electronic address: chatchai.mua@mahidol.ac.th.AbstractCysteinyl leukotriene receptor 1 (CysLT1 receptor) antagonists were found to inhibit chloride secretion in human airway epithelial cells. Since chloride secretion in renal epithelial cells, which shares common mechanisms with airway epithelial cells, plays important roles in renal cyst progression in polycystic kidney disease (PKD), this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms. Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney (MDCK) cyst models. Mechanisms of actions of CysLT1 receptor antagonists were determined using short-circuit current measurement, assays of cell viability and cell proliferation, and immunoblot analysis of signaling proteins. Of the three drugs acting as CysLT1 receptor antagonists (montelukast, pranlukast and zafirlukast) tested, pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability. Its effect was independent of the inhibition of CysLT1 receptors. Instead, it reduced cAMP-activated chloride secretion and proliferation of MDCK cells in an AMP-activated protein kinase (AMPK)-dependent manner and had no effect on CFTR protein expression. Interestingly, pranlukast enhanced AMPK activation via calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ) with consequent activation of acetyl-CoA carboxylase (ACC) and suppression of mammalian target of rapamycin (mTOR) pathway. These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting cAMP-activated chloride secretion and cell proliferation via CaMKKβ-AMPK-mTOR pathway. Therefore, pranlukast represents a class of known drugs that may have potential utility in PKD treatment.
European journal of pharmacology.Eur J Pharmacol.2014 Feb 5;724:67-76. doi: 10.1016/j.ejphar.2013.12.013. Epub 2013 Dec 17.
Cysteinyl leukotriene receptor 1 (CysLT1 receptor) antagonists were found to inhibit chloride secretion in human airway epithelial cells. Since chloride secretion in renal epithelial cells, which shares common mechanisms with airway epithelial cells, plays important roles in renal cyst progression i
PMID 24360935

Simple and Rapid Determination of Zafirlukast in Plasma by Ultra-performance Liquid Chromatography Tandem Mass Spectrometric Method: Application into Pharmacokinetic Study in Rabbits.

Iqbal M1, Ezzeldin E, Al-Rashood KA, Al-Khamees KI, Khan RM, Raish M, Anwer T.Author information 1Bioavailability Laboratory, College of Pharmacy, King Saud University, Riyadh, KSA.AbstractZafirlukast is a selective leukotriene receptor antagonist used for the prophylaxis and chronic treatment of asthma. The aim of the present study was to develop a simple sensitive ultra-performance liquid chromatography tandem mass spectroscopy method for rapid determination of zafirlukast in plasma. After a simple one step protein precipitation by acetonitrile, zafirlukast and montelukast (IS) were separated on Acquity UPLC BEHTM C18 column (50×2.1 mm, i.d. 1.7 µm, Waters, USA) using a mobile phase of acetonitrile:water containing 10 mM acetic acid (80:20, v/v) at a flow rate of 0.3 mL/min. Zafirlukast and IS were eluted at 0.51 and 1.1 min, respectively with a total run time of only 1.5 min. The mass spectrometric determination was carried out using an electrospray interface operated in the negative mode with multiple reactions monitoring mode. The precursor to product ion transitions of m/z 574.11>462.07 and m/z 584.2>472.1 were used to quantify zafirlukast and IS, respectively. The method was linear in the concentration range of 0.17-600 ng/mL with coefficients of determination greater than 0.996 and lower limit of quantitation of 0.17 ng/mL. Intra-day and inter-day accuracies were 88.3-113.9% and the precisions were ≤12.6%. Zafirlukast was found to stable under various storage and sample processing conditions as per guidelines of bio-analytical method validation. The method developed herein is simple and rapid, and was successfully applied for the pharmacokinetic study in rabbits.
Drug research.Drug Res (Stuttg).2013 Nov 20. [Epub ahead of print]
Zafirlukast is a selective leukotriene receptor antagonist used for the prophylaxis and chronic treatment of asthma. The aim of the present study was to develop a simple sensitive ultra-performance liquid chromatography tandem mass spectroscopy method for rapid determination of zafirlukast in plasma
PMID 24258705

Japanese Journal

高齢者気管支喘息患者における追加治療法の選択 : ロイコトリエン受容体拮抗薬(ザフィルルカスト)と吸入ステロイド薬(フルチカゾンプロピオネート)との比較検討

長島修,熱田了,原田紀宏 [他],牧野文彦,伊藤潤,梶山雄一郎,十合晋作,高橋和久,福地義之助
順天堂医学 = Juntendo medical journal 55(3), 303-308, 2009-09-30
NAID 10029497363

高齢者気管支喘息患者における追加治療法の選択:-ロイコトリエン受容体拮抗薬 (ザフィルルカスト) と吸入ステロイド薬 (フルチカゾンプロピオネート) との比較検討-

長島修,熱田了,原田紀宏,牧野文彦,伊藤潤,梶山雄一郎,十合晋作,高橋和久,福地義之助
順天堂医学 55(3), 303-308, 2009
目的: 高齢者気管支喘息患者に対する追加治療としての吸入ステロイドの増量治療とロイコトリエン受容体拮抗薬の追加投与治療を比較検討する.対象・方法: 気道過敏性が亢進している中等症持続型気管支喘息患者に対して本検討を行った. 全例フルチカゾンプロピオネート (fluticasone propionate dry powderinhaler: FDP) 400μgが投与されており, 65歳以上の高齢者 …
NAID 130004712112

Montelukast Is a Potent and Durable Inhibitor of Multidrug Resistance Protein 2-Mediated Efflux of Taxol and Saquinavir

, , [他],
Biological and Pharmaceutical Bulletin 32(12), 2002-2009, 2009
… Using the MRP2 over-expressing Madin-Darby canine kidney cell line, MDCKII-MRP2, we evaluated whether the clinically approved LTRAs, e.g. montelukast (Singulair™) and zafirlukast (Accolate™), can similarly suppress MRP2-mediated efflux. … We compared the efficacy of increasing concentrations (20—100 μM) of MK-571, montelukast, and zafirlukast, in suppressing the efflux of calcein-AM, a fluorescent MRP substrate, and the radiolabeled [3H-] drugs, taxol and saquinavir. …
NAID 130000116986

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★リンクテーブル★

リンク元	「ザフィルルカスト」「accolate」

「ザフィルルカスト」

Zafirlukast
Systematic (IUPAC) name
	cyclopentyl 3-{2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl}-1-methyl-1H-indol-5-ylcarbamate
Clinical data
Trade names	Accolate
AHFS/Drugs.com	monograph
MedlinePlus	a697007
Pregnancy; category	B1 (Australia), B (United States);
Legal status	POM (UK);
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	Unknown
Protein binding	99%
Metabolism	Hepatic (CYP2C9-mediated)
Half-life	10 hours
Excretion	Biliary
Identifiers
CAS Registry Number	107753-78-6
ATC code	R03DC01
PubChem	CID: 5717
IUPHAR/BPS	3322
DrugBank	DB00549
ChemSpider	5515
UNII	XZ629S5L50
KEGG	D00411
ChEBI	CHEBI:10100
ChEMBL	CHEMBL603
Chemical data
Formula	C31H33N3O6S
Molecular mass	575.676 g/mol
	SMILES O=S(=O)(c1ccccc1C)NC(=O)c2ccc(c(OC)c2)Cc4c3cc(ccc3n(c4)C)NC(=O)OC5CCCC5;
	InChI InChI=1S/C31H33N3O6S/c1-20-8-4-7-11-29(20)41(37,38)33-30(35)22-13-12-21(28(17-22)39-3)16-23-19-34(2)27-15-14-24(18-26(23)27)32-31(36)40-25-9-5-6-10-25/h4,7-8,11-15,17-19,25H,5-6,9-10,16H2,1-3H3,(H,32,36)(H,33,35) ; Key:YEEZWCHGZNKEEK-UHFFFAOYSA-N ;
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