싱귤레어정, 오논캡슐 [Leukotriene modifiers = antileukotriene agents] 천식과 비염 치료제

Montelukast (몬테루카스트, 싱귤레어), pranlukast (프란루카스트, 오논)은 천식, 비염, 다른 알레르기 질환에서 사용되는 약제입니다.

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류코트리엔 (leukotriene)은 주로 myeloid cells에서 생성되는 강력한 지질 염증 매개 물질입니다. 이것의 이름은 1979년 스웨덴 생화학자 Bengt Samuelsson에 의해 명명되었는데 leukocytes에서 기원하고 conjugated double bonds가 3개 있어 이름을 leuko + triene으로 하였습니다.

류코트리엔에는 4개의 double bond가 있고 이 중 3개는 conjugated double bonds입니다.

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Leukotriene modifiers

Source cells include mast cells, eosinophils, basophils, and macrophages. Zileuton inhibits 5-lipoxygenase (5-LO), while montelukast, zafirlukast, and pranlukast are antagonists of the CysLT1 receptor.

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PLA2: phospholipase A2; AA: arachidonic acid; 5-LO: 5-lipoxygenase; FLAP: 5-LO activating protein; LTA4: leukotriene A4; LTA4H: LTA4 hydrolase; LTC4S: LTC4 synthetase; LTB4: leukotriene B4 arises from the hydrolysis of LTA4 by LTA4 hydrolase; LTC4: leukotriene C4 arises from the conjugation of LTA4 with reduced glutathione by LTC4 synthetase; LTD4: leukotriene D4 arises from LTC4 by the rapid removal of glutamic acid in the extracellular microenvironment; LTE4: leukotriene E4 arises from LTD4 by the further removal of glycine in the extracellular microenvironment; BLT1: receptor for LTB4, no commercially available inhibitors; BLT2: receptor for LTB4, no commercially available inhibitors; CysLTS: cys-leukotrienes, LTC4, LTD4, LTE4; CysLT1: receptor for LTC4, LTD4, LTE4, inhibited by montelukast, pranlukast, and zafirlukast; CysLT2: receptor for LTC4, LTD4, LTE4, but not inhibited by montelukast, pranlukast, or zafirlukast.

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Mast cells, eosinophils, basophils, the principal effector cells of type 2 (eosinophil-rich) immunopathology 모두 LTC​4S를 표현하며 활성화되었을 때에 LTB4보다 LTC4를 표현합니다. Macrophages와 myeloid dendritic cells 또한 혈소판처럼 LTC4S를 표현합니다.

Once released, LTC4 is converted by a gamma glutamyl leukotrienase to LTD4 by removal of the glutamic acid residue from the glutathione adduct. LTD4 is extremely short lived due to its rapid conversion by extracellular dipeptidases to the stable metabolite, LTE4, by removal of glycine. LTE4 is excreted in the urine without further modification and is often used a marker of systemic production of CysLTs in clinical studies.

모든 3가지 CysLTs는 bioactive mediators로서 3개의 다른 유사한 G-protein coupled receptors를 자극합니다.

Type 1 CysLT receptor (CysLT1R)는 천식과 알레르기 비염 치료를 위해 승인된 receptor antagonists의 target입니다. 이 수용체는 LTD4에 높은 친화력이 있으며 기도와 혈관 평활근과 여러 면역 세포에서 표현됩니다. CysLT1R는 특정 타당한 면역 세포 (mast cells, innate group 2 lymphoid cells, T helper type 2 [Th2] cells)의 활성화뿐만 아니라 사람에서 CysLTs의 기관지 수축 효과를 담당합니다.

CysLT2R, expressed by endothelial cells, brain, cardiac Purkinje cells, and leukocytes, recognizes LTC4 and LTD4 with equal affinity, while CysLT3R (also known as GPR99) is expressed by epithelial cells of the airway and proximal convoluted tubule. Although animal models suggest that CysLT2R and CysLT3R both play important roles in allergic pulmonary inflammation, knowledge of their role in human asthma is limited by the absence of selectively targeted drugs.

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Type 1 CysLT receptor (CysLT1R)는 천식과 알레르기 비염 치료를 위해 승인된 receptor antagonists의 target입니다. 미국에서 3개의 antileukotriene agents (=leukotriene modifying agents)가 이용 가능합니다. Montelukast, Zafirlukast, Zileuton

 

Montelukast와 zafirlukast는 cysteinyl leukotriene (CysLT1) receptor antagonists이고 우리나라, 터키, 베네수엘라, 멕시코, 일본에서 사용되는 또 다른 약제로 pranlukast (프란루카스트, 오논캡슐)가 있습니다. 몬테루카스트는 하루 1회 투여하고 zafirlukast와 pranlukast는 하루 2회 투여합니다. Montelukast는 1세 이상 소아에서 승인되었고 zafirlukast는 5세 이상에서 승인되었습니다.

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Usual doses of antileukotriene agents in the management of persistent asthma

Medication	Preparations	Infant and small child	Pediatric	Adolescent and adult
Montelukast	Granules: 4 mg per packet Chewable tablets: 4 mg, 5 mg Tablet: 10 mg	12 months* to 5 years: 4 mg granules or chewable tablet once daily in evening	6 to 14 years: 5 mg chewable tablet once daily in evening	≥15 years and adult: 10 mg tablet once daily in evening
Zafirlukast¶	Tablets: 10 mg, 20 mg	(Not studied)	5 to 11 years: 10 mg twice per day	≥12 years and adult: 20 mg twice per day
Zileuton¶	Immediate-release tablet: 600 mg Extended-release tablet: 600 mg	(Not studied)	(Not studied)	≥12 years and adult: Immediate release: 600 mg four times per day Extended release: 1200 mg twice per day
PranlukastΔ	Capsules: 112.5 mg, 225 mg Granules: 50 mg, 70 mg, 100 mg per packet	24 months to 5 years: 7 to 10 mg/kg granules per day in two divided doses	6 to 11 years: 7 to 10 mg/kg per day granules in two divided doses (maximum 225 mg twice per day)	≥12 years and adult: 225 mg twice per day

* Approved for use in infants ≥6 months in some countries other than United States.

¶ Elevated transaminases and severe hepatoxicity have been reported.

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정리

1. Type 1 CysLT receptor (CysLT1R)는 천식과 알레르기 비염 치료를 위해 승인된 receptor antagonists의 target이다.
2. Montelukast와 zafirlukast는 cysteinyl leukotriene (CysLT1) receptor antagonists이고 우리나라, 일본에서 사용되는 또 다른 약제로 pranlukast (프란루카스트, 오논캡슐)가 있습니다.

네이버 지식백과

 

 

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