Antagonis reseptor leukotriena
Antileukotriena, juga dikenal sebagai pengubah leukotriena dan antagonis reseptor leukotriena (Bahasa Inggris: leukotrien receptor antagonist, disingkat LTRA) adalah obat yang berfungsi sebagai penghambat enzim terkait leukotriena (arakidonat 5-lipoksigenase), akibatnya menentang fungsi mediator inflamasi ini; leukotriena diproduksi oleh sistem imun dan berfungsi untuk meningkatkan bronkokonstriksi, inflamasi, permeabilitas mikrovaskular, dan sekresi mukus pada asma dan PPOK.[1] Antagonis reseptor leukotriena terkadang secara umum disebut sebagai "leukast".
| Antileukotriena | |
|---|---|
| Kelas obat-obatan | |
| Pengenal kelas | |
| Sinonim | Pengubah leukotriena; Antagonis reseptor leukotriena |
| Mekanisme aksi | • penghambatan enzim • Antagonis reseptor |
| Target biologis | • Enzim: 5-LOX; FLAP • Reseptor: CysLTRs |
| Dalam Wikidata | |
Antagonis reseptor leukotriena, seperti montelukast, zafirlukast, dan pranlukast,[2][3] dan penghambat 5-lipoksigenase seperti zileuton dan Hypericum perforatum,[4][5][6][7] dapat digunakan untuk mengobati penyakit ini.[1] Obat-obatan ini kurang efektif dibandingkan kortikosteroid untuk mengobati asma,[8] tetapi lebih efektif untuk mengobati gangguan sel mast tertentu.[9]
Pendekatan
suntingAda dua pendekatan utama untuk memblokir aksi leukotriena.[1]
Penghambatan jalur 5-lipoksigenase
suntingObat yang menghambat enzim 5-lipoksigenase akan menghambat jalur sintetis metabolisme leukotriena;[4][5] obat seperti MK-886 yang memblokir protein pengaktif 5-lipoksigenase (FLAP) menghambat fungsi 5-lipoksigenase dan dapat membantu dalam mengobati aterosklerosis.[10]
Contoh penghambat 5-LOX meliputi obat-obatan, seperti natrium meklofenamat dan zileuton.[11][4]
Beberapa zat kimia yang ditemukan dalam jumlah sedikit dalam makanan dan beberapa suplemen makanan juga telah terbukti menghambat 5-LOX seperti baikalein, asam kafeat, kurkumin,[11] hiperforin[5][6][7] dan Hypericum perforatum.[5][6][7]
Antagonisme reseptor sisteinil-leukotriena tipe 1
suntingAgen seperti montelukast dan zafirlukast memblokir aksi sisteinil leukotriena pada reseptor CysLT1 pada sel target seperti otot polos bronkus melalui antagonisme reseptor.
Pengubah ini telah terbukti memperbaiki gejala asma, mengurangi eksaserbasi asma, dan membatasi penanda peradangan seperti jumlah eosinofil dalam darah perifer dan cairan lavage bronkoalveolar. Ini menunjukkan bahwa mereka juga memiliki sifat antiinflamasi.
Referensi
sunting- ^ a b c Scott JP, Peters-Golden M (September 2013). "Antileukotriene agents for the treatment of lung disease". Am. J. Respir. Crit. Care Med. 188 (5): 538–544. doi:10.1164/rccm.201301-0023PP. PMID 23822826.
- ^ Singh, Rakesh Kumar; Tandon, Ruchi; Dastidar, Sunanda Ghosh; Ray, Abhijit (2013). "A review on leukotrienes and their receptors with reference to asthma". Journal of Asthma. 50 (9): 922–931. doi:10.3109/02770903.2013.823447. ISSN 0277-0903. PMID 23859232.
- ^ Al-Ahmad, Mona; Hassab, Mohammed; Al Ansari, Ali (2020-12-21). "Allergic and Non-allergic Rhinitis". Textbook of Clinical Otolaryngology. Cham: Springer International Publishing. hlm. 241–252. doi:10.1007/978-3-030-54088-3_22. ISBN 978-3-030-54087-6.
Antileukotrienes such as montelukast may be used in patients with asthma associated with allergic rhinitis.
- ^ a b c "Zyflo (Zileuton tablets)" (PDF). United States Food and Drug Administration. Cornerstone Therapeutics Inc. June 2012. hlm. 1. Diakses tanggal 12 December 2014.
Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.
- ^ a b c d "Enzymes". Hyperforin (HMDB0030463). Human Metabolome Database. 3.6. University of Alberta. 30 June 2013. Diakses tanggal 12 December 2014.
- ^ a b c de Melo MS, Quintans Jde S, Araújo AA, Duarte MC, Bonjardim LR, Nogueira PC, Moraes VR, de Araújo-Júnior JX, Ribeiro EA, Quintans-Júnior LJ (2014). "A systematic review for anti-inflammatory property of Clusiaceae family: a preclinical approach". Evid Based Complement Alternat Med. 2014: 960258. doi:10.1155/2014/960258
. PMC 4058220 . PMID 24976853. These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity.
- ^ a b c Wölfle U, Seelinger G, Schempp CM (February 2014). "Topical application of St. John's wort (Hypericum perforatum)". Planta Med. 80 (2–3): 109–20. doi:10.1055/s-0033-1351019 . PMID 24214835.
Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 μmol/L and 1.2 μmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 μmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.
- ^ Fanta CH (March 2009). "Asthma". N Engl J Med. 360 (10): 1002–14. doi:10.1056/NEJMra0804579. PMID 19264689.
- ^ Frieri M (2015). "Mast Cell Activation Syndrome". Clin Rev Allergy Immunol. 54 (3): 353–365. doi:10.1007/s12016-015-8487-6. PMID 25944644.
- ^ Jawien, J.; Gajda, M.; Rudling, M.; Mateuszuk, L.; Olszanecki, R.; Guzik, T. J.; Cichocki, T.; Chlopicki, S.; Korbut, R. (March 2006). "Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice". European Journal of Clinical Investigation. 36 (3): 141–146. doi:10.1111/j.1365-2362.2006.01606.x. PMID 16506957.
- ^ a b Bishayee K, Khuda-Bukhsh AR (September 2013). "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochim. Biophys. Sin. (Shanghai). 45 (9): 709–719. doi:10.1093/abbs/gmt064 . PMID 23752617.
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