Antileukotriene

Antileukotrienes
Drug class
Class identifiers
Mechanism of action  • Enzyme inhibition
 • Receptor antagonism
Biological target  • Enzymes: 5-LOX; FLAP
 • Receptors: CysLTRs

An antileukotriene is a drug which functions as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leukotriene receptors) and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD.[1] Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.

Leukotriene receptor antagonists, such as montelukast, zafirlukast, and pranlukast, and 5-lipoxygenase inhibitors, like zileuton and hypericum perforatum,[2][3][4][5] can be used to treat these diseases.[1] They are less effective than corticosteroids for treating asthma,[6] but more effective for treating certain mast cell disorders.[7]

Approaches

There are two main approaches to block the actions of leukotrienes.[1]

Inhibition of the 5-lipoxygenase pathway

Drugs that inhibit the 5-lipoxygenase enzyme will inhibit the synthetic pathway of leukotriene metabolism;[2][3] drugs such as MK-886 that block the 5-lipoxygenase activating protein (FLAP) inhibit functioning of the 5-lipoxygenase enzyme and may help in treating atherosclerosis.[8]

Examples of 5-LOX inhibitors include drugs, such as meclofenamate sodium[9] and zileuton.[9][2]

Some chemicals found in trace amounts in food, and some dietary supplements, also have been shown in inhibit 5-LOX, such as baicalein,[9] caffeic acid,[9] curcumin,[9] hyperforin[3][4][5] and St John's wort.[3][4][5]

Antagonism of cysteinyl-leukotriene type 1 receptors

Agents such as montelukast and zafirlukast block the actions of cysteinyl leukotrienes at the CysLT1 receptor on target cells such as bronchial smooth muscle via receptor antagonism.

These modifiers have been shown to improve asthma symptoms, reduce asthma exacerbations and limit markers of inflammation such as eosinophil counts in the peripheral blood and bronchoalveolar lavage fluid. This demonstrates that they have anti-inflammatory properties.

See also

References

  1. 1 2 3 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.
  2. 1 2 3 "Zyflo (Zileuton tablets)" (PDF). United States Food and Drug Administration. Cornerstone Therapeutics Inc. June 2012. p. 1. Retrieved 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.
  3. 1 2 3 4 "Enzymes". Hyperforin. Human Metabolome Database. 3.6. University of Alberta. 30 June 2013. Retrieved 12 December 2014. Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions (PMID 17696442 , 21751836 , 12725578 , 12018529 )
    1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
    2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity
  4. 1 2 3 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.
  5. 1 2 3 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.
  6. ↑ Fanta CH (March 2009). "Asthma". N Engl J Med 360 (10): 1002–14. doi:10.1056/NEJMra0804579. PMID 19264689.
  7. ↑ Frieri M (2015). "Mast Cell Activation Syndrome". Clin Rev Allergy Immunol. doi:10.1007/s12016-015-8487-6. PMID 25944644.
  8. ↑ 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.
  9. 1 2 3 4 5 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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