| Antileukotrienes | |
|---|---|
| Drug class | |
| Class identifiers | |
| Synonyms | Leukotriene modifier; Leukotriene receptor antagonist |
| Mechanism of action | • Enzyme inhibition • Receptor antagonism |
| Biological target | • Enzymes:5-LOX;FLAP • Receptors:CysLTRs |
| Legal status | |
| In Wikidata | |
Anantileukotriene, also known asleukotriene modifier andleukotriene receptor antagonist, is a medication which functions as aleukotriene-relatedenzyme inhibitor (arachidonate 5-lipoxygenase) or leukotrienereceptor antagonist (cysteinyl leukotriene receptors) and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by theimmune system and serve to promotebronchoconstriction,inflammation,microvascular permeability, andmucus secretion inasthma andCOPD.[1] Leukotriene receptor antagonists are sometimes colloquially referred to asleukasts.
Leukotriene receptor antagonists, such asmontelukast,zafirlukast, andpranlukast,[2] and 5-lipoxygenase inhibitors, likezileuton andHypericum perforatum,[3][4][5][6] can be used to treat these diseases.[1] They are less effective thancorticosteroids for treating asthma,[7] but more effective for treating certainmast cell disorders.[8]
There are two main approaches to block the actions of leukotrienes.[1]
Drugs that inhibit the enzyme5-lipoxygenase will inhibit the synthetic pathway of leukotriene metabolism;[3][4] drugs such asMK-886 that block the5-lipoxygenase activating protein (FLAP) inhibit functioning of 5-lipoxygenase and may help in treatingatherosclerosis.[9]
Examples of 5-LOX inhibitors include drugs, such asmeclofenamate sodium[10] andzileuton.[10][3]
Some chemicals found in trace amounts in food, and some dietary supplements, also have been shown to inhibit 5-LOX, such asbaicalein,[10]caffeic acid,[10]curcumin,[10]hyperforin[4][5][6] andSt John's wort.[4][5][6]
Agents such asmontelukast andzafirlukast block the actions of cysteinyl leukotrienes at theCysLT1 receptor on target cells such as bronchialsmooth muscle viareceptor antagonism.[citation needed]
These modifiers have been shown to improve asthma symptoms, reduce asthma exacerbations and limit markers of inflammation such aseosinophil counts in the peripheral blood andbronchoalveolar lavage fluid. This demonstrates that they have anti-inflammatory properties.[citation needed]
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.
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.
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.