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The Role of Plant-Based Natural Compounds in Inflammation
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Marcela Dvorakova, Premysl Landa, Lenka Langhansova
The production of pro-inflammatory leukotrienes (LTs) from AA is catalyzed by 5-LOX. LTs stimulate processes such as smooth muscle contraction, phagocyte chemotaxis and increased vascular permeability (Gilbert et al., 2011; Radmark and Samuelsson, 2009); thus, LTs are involved in inflammatory diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, psoriasis, atherosclerosis, rheumatoid arthritis, ischemic renal failure and inflammatory bowel diseases (Jo-Watanabe et al., 2019; Ghosh et al., 2016). Moreover, 5-LOX metabolites are involved in central nervous system diseases (Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, brain ischemia, etc.), type 2 diabetes and several types of cancer (Moore and Pidgeon, 2017; Ghosh et al., 2016). Currently, the only 5-LOX inhibitor used commercially, Zileuton, is approved for asthma treatment for oral use. However, it has a short half-life and may cause hepatotoxicity (Fiorucci et al., 2001; Bruno et al., 2018; Wood et al., 2020).
Respiratory Diseases
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Aref T. Senno, Ryan K. Brannon
Limited human data are available on the use of LTRA during pregnancy. Several small studies have not shown an increase in the rate of major malformations in offspring of women who took LTRA during pregnancy [30, 31]. Mean birth weight was lower, and risk of low birthweight and fetal distress was higher in the montelukast-exposed group, a difference that may have been related to asthma severity rather than drug effect. In nonpregnant individuals, these drugs are less effective than inhaled corticosteroids, and do not add much benefit to women already on inhaled steroids. They do not reduce the risk of exacerbation requiring systemic steroids, and are associated with modest improvement in PEF, with very modest decrease in use of rescue SABAs [32]. These drugs may be considered during pregnancy for women who had a good response to them prior to pregnancy, but they are not a preferred option when initiating therapy. Montelukast and zafirlukast are safe in pregnancy [33, 34]. Zileuton, a 5-lipoxygenase inhibitor, has been advised against in pregnancy based on animal data: Human data are lacking [19].
Immunomodulating Agents in Gastrointestinal Disease
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Samir A. Shah, Athos Bousvaros, A. Christopher Stevens
Zileuton is a new drug that has been studied in the treatment of asthma. It acts to inhibit 5-lipoxygenase, thus preventing leukotriene synthesis. Findings of recent studies in patients with UC are conflicting. One study found a 25% remission rate with Zileuton 600 mg four times a day compared with only 7% for placebo [244], However, another study found Zileuton slightly more effective than placebo but not as effective as 5-ASA in maintenance of remission in patients with ulcerative colitis [245]. Further evaluation of this agent is needed before any conclusions can be drawn.
The pharmacological management of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS)
Published in Expert Opinion on Pharmacotherapy, 2020
Timothy E. Albertson, James A. Chenoweth, Skyler J. Pearson, Susan Murin
The advantages and disadvantages of using an oral LRA compared to a leukotriene synthesis inhibitor have been discussed [113] and explain the large-scale use of LRA agents. A comparison of the oral 5-lipoxygenase inhibitor (5-LOi) zileuton, the oral LRA montelukast and placebo in a randomized placebo-controlled, double-blind trial in adult asthmatics with acute asthma symptoms found that the leukotriene synthesis inhibitor provided significantly better lung function improvement and reduction in inhaled rescue SABA use than did the LRA monteleukast or placebo [114]. A slow or extended release version of zileuton requires only twice a day dosing. It has demonstrated efficacy in asthma, exercise-induced asthma and aspirin-intolerant asthma [115–117]. One of the major limitations in the use of the 5-LOi zileuton has come from its effects on liver transaminase with patients demonstrating liver transaminase elevations in randomized, placebo-controlled trials of 1.9% for zileuton and 0.2% for placebo-treated subjects [117]. Neuropsychiatric complications with leukotriene-modifying agents (zileuton, zafirlukast, and montelukast) in asthma patients have been evaluated in a systematic review of 33 trials [118]. Four observational trials did not note any suicidal or neuropsychiatric events while ten specific ‘pharmacovigilance’ studies using global databases did note a neuropsychiatric adverse events signal. The authors called for high-quality prospective data to better define the extent of neuropsychiatric adverse events in asthmatic patients treated with leukotriene-modifying drugs [118].
Asthma pharmacotherapy: an update on leukotriene treatments
Published in Expert Review of Respiratory Medicine, 2019
Hoang Kim Tu Trinh, So-Hee Lee, Thi Bich Tra Cao, Hae-Sim Park
Blockade of 5-LO enzymatic activity is beneficial for reducing LT synthesis, which induces vascular permeability and bronchoconstriction as well as LTB4-dependent pathway [33]. Nevertheless, it is unclear whether 5-LO inhibitors blocked the production of anti-inflammatory metabolites such as lipoxins. To date, among 5-LO inhibitors such as atreleuton (VIA-2291), MK-0633, PF-4,191,834, naproxen and flavocoxid, only zileuton is approved in clinical trials. Zileuton inhibits 5-hydroxyeicosatetranenoic acid synthesis, neutrophils and LTB4 biosynthesis, but it showed hepatic toxicity and adverse pharmacokinetic effects [34]. In patients with bronchial asthma, the robust effect of zileuton occurs 2 days after drug administration, but not immediately [11]. With increasing LTRA use, there is the need to develop novel 5-LO inhibitors.
Depression symptoms and quality of life among individuals with aspirin-exacerbated respiratory disease
Published in Journal of Asthma, 2019
Jonathan M. Feldman, Ariel E. Zeigler, Krista Nelson, Esperanza Morales-Raveendran, Teresa Pelletier, Gigia Roizen, Zhen Ren, Elina Jerschow
It is possible that biological factors may also influence the relationship between AERD and depression symptoms. Patients with AERD have been shown to have high levels of leukotrienes [43]. Leukotriene receptor antagonist (LTRA) and 5-lypoxygenase (5-LO) inhibitors are sometimes used as treatments for AERD patients. Montelukast, a commonly prescribed LTRA medication, may have a possible side effect of increasing psychiatric symptoms including feelings of depression and suicidality [44, 45]. Zileuton, a 5-LO inhibitor, may also have side effects of behavioral disturbance [46]. Beside respiratory tissue, leukotriene receptors are also expressed in the brain [47, 48]. Therefore, it is possible that the lower level of depression symptoms reported in AERD patients may be linked with higher leukotriene levels at baseline, which warrants further research in future studies.