The Role of Leukotrienes Inhibitors in the Management of Chronic Inflammatory Diseases

Abstract

Background: Leukotrienes are powerful mediators of inflammation and interact with specific receptors in target cell membrane to initiate an inflammatory response. Thus, Leukotrienes (LTs) are considered to be potent mediators of inflammatory diseases including allergic rhinitis, inflammatory bowel disease and asthma. Leukotriene B4 and the series of cysteinyl leukotrienes (C4, D4, and E4) are metabolites of arachidonic acid metabolism that cause inflammation. The cysteinyl LTs are known to increase vascular permeability, bronco-constriction and mucus secretion. Objectives: To review the published data for leukotriene inhibitors of plant origin and the recent patents for leukotriene inhibitors, as well as their role in the management of inflammatory diseases. Methods: Published data for leukotrienes antagonists of plant origin were searched from 1938 to 2019, without language restrictions using relevant keywords in both free text and Medical Subject Headings (MeSH terms) format. Literature and patent searches in the field of leukotriene inhibitors were carried out by using numerous scientific databases including Science Direct, PubMed, MEDLINE, Google Patents, US Patents, US Patent Applications, Abstract of Japan, German Patents, European Patents, WIPO and NAPRALERT. Finally, data from these information resources were analyzed and reported in the present study. Results: Currently, numerous anti-histaminic medicines are available including chloropheneremine, brompheniramine, cetirizine, and clementine. Furthermore, specific leukotriene antagonists from allopathic medicines are also available including zileuton, montelukast, pranlukast and zafirlukast and are considered effective and safe medicines as compared to the first generation medicines. The present study reports leukotrienes antagonistic agents of natural products and certain recent patents that could be an alternative medicine in the management of inflammation in respiratory diseases. Conclusion: The present study highlights recent updates on the pharmacology and patents on leukotriene antagonists in the management of inflammation respiratory diseases.

Novel aerosol treatment of airway hyper-reactivity and inflammation in a murine model of asthma with a soluble epoxide hydrolase inhibitor

“…First, pro-inflammatory lipid mediators via the LOX pathway (i.e., LTs) were decreased following OVA+TPPU exposure compared to OVA alone. This finding reflected a reduction in bronchoconstriction [ 31 ]. Studies of a different sEHI, trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid ( t -TUCB), yielded similar results to the present study on TPPU in preventing the influx of inflammatory cells into lung tissues and BALF of asthmatic mice.…”

“…PG deficiencies in airways after TPPU treatment may improve airway remodeling and chronic inflammation [ 49 ]. Likewise, a reduction in LTB4 has been shown to alleviate vascular permeability and mucus production in a murine asthma model [ 31 ]. The increased LXs observed with TPPU exposure in the present study suggest that LXs might also contribute to the benefits of sEHI administration.…”

“…Preliminary investigations (unpublished data) suggest that sEHIs synergize with the 5-lipoxygenase activating protein (FLAP) inhibitor, MK886, to reduce airway inflammation in the ovalbumin (OVA)-induced murine model. MK886 inhibits the biosynthesis of inflammatory LTs [ 30 ] that cause bronchoconstriction and excess mucus formation inherent to asthma [ 31 ]. Several sEHIs have been developed for the treatment of hypertension, Type-2 diabetes [ 10 , 11 ], and chronic pain [ 12 ] and subsequently moved into human clinical trials [ 32 ].…”

Increased expressions of CD123, CD63, CD203c, and Fc epsilon receptor I on blood leukocytes of allergic asthma

“…LTC4 elevated CD63 + cells in CD123 + KU812 cells at 2 and 16 h ( Figure 7Ba , t -test, p = 0.0001, 0.0030) and the MFI of CD63 expression on CD123 + KU812 cell at 2 h following challenge ( Figure 7Bb , t -test, p = 0.0309). LTC4 also increased the proportion of FcεRI + CD123 + KU812 cells at 16 h, which was clearly reduced by Mon, an LTC4 receptor antagonist ( Meshram et al, 2020 ) ( Figure 7Ca , t -test, p = 0.0006, 0.0421). Likewise, histamine and PGD2 at 2 and 16 h following incubation enhanced proportions of FcεRI + CD123 + KU812 cells ( Figure 7Ca , t -test, p = 0.0040, 0.0045, 0.0013, 0.0003) and MFI of FcεRI expression on CD123 + KU812 cell at 2 h following challenge ( Figure 7Cb , t -test, p = 0.0006, 0.0258).…”

Characteristics of allergen profile, sensitization patterns and Allergic Rhinitis in SouthEast Asia

“…In addition, the symptoms of allergic rhinitis, such as sneezing, itching, coughing, runny or stuffy nose, headache, etc., can vary, depending on the severity of allergies [7,8]. During allergen exposure, the early phase allergic responses are initiated by allergen crosslinking of IgE bound to the IgE receptor leading to activation of mast cells and subsequent degranulation and release of a variety of pre-and newly synthesized mediators including cysteinyl leukotrienes, prostaglandins, histamine, tumor necrosis factor a (TNF-a), cytokines/ chemokines [9,10]. In addition, histamine acting through H1 receptors, as well as through H2, H3, and H4 receptors, might further increase the production of proinflammatory cytokines and mediators, leading to further infiltration and activation of inflammatory cells in the late phase allergic response [11].…”