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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
Since cyclooxygenase blockade did not alleviate colonic inflammation in patients, attention shifted to the lipoxygenase pathway of arachidonic acid metabolism [13]. Azulfidine and 5-ASA inhibit both 5-lipoxygenase- and lipoxygenase-activating protein (FLAP) [14,15]. This action blocks the production of leukotrienes, which function as chemotactic factors for neutrophils. In particular, mucosal levels of leukotriene B4 directly correlate with active inflammation in inflammatory bowel disease patients. Preliminary animal and human trials with lipoxygenase inhibitors were promising, but subsequent prospective randomized double-blinded clinical trials have not demonstrated a significant clinical response (see Section VII. D) [16–18].
Acetylcholine
Published in Geoffrey Burnstock, Susan G. Griffith, Nonadrenergic Innervation of Blood Vessels, 2019
The multiple actions of many drugs have also confused the search for the nature of EDRF. For example, despite diverse actions, the common property of many EDRF inhibitors is the ability to act as an antioxidant.75 In fact, perfusion experiments suggest that these inhibitors act by chemical interaction with EDRF in transit rather than interacting with EDRF production or its smooth muscle site of action. These studies suggest that lipoxygenase inhibitors are only effective if they also possess antioxidant properties and that EDRF is not a free radical.75 While some clues as to the chemical nature of EDRF have been obtained,75 its characteristics remain unknown at this time.
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].
Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Sahar A. Ali, Samir Mohamed Awad, Ahmed Mohammed Said, Shahenda Mahgoub, Heba Taha, Naglaa Mohamed Ahmed
The mechanism of action of antioxidants can be through various pathways such as free radical scavengers (preventive oxidants) and as lipoxygenase inhibitors (pro-oxidative enzymes)36,37. 15-Lipoxygenases (15-LOXes)38,39 are a unique class of non-heme iron containing enzymes that catalyse the peroxidation of polyunsaturated fatty acids such as arachidonic acid (AA) and linoleic acid to their related hydroperoxides. In addition, 15-LOXes are involved in various human diseases. 15-lipoxygenase-1 (15-LOX-1) has been recently documented as a target for reduction of the biosynthesis of eoxines, pro-inflammatory mediator40 and cancer promoter41. Also, it was reported that 15-LOX participates in the oxidative modification of low-density lipoproteins (LDLs) that leads to the progress of atherosclerosis42. Moreover, human 15-LOX-1 is one of the key mediators in neurodegenerative diseases such as Alzheimer’s disease43. There has been some literature work targeting 15-LOX-1. It was reported that 3,4,5-trisubstituted pyrazole (A) was found to work as a potent rabbit 15-LOX-1 inhibitor44. Recently, oxazole derivative (ML351) (B) showed novel 15- LOX inhibition with potent activity against human 15-LOX-1 in both a cellular and an in vivo model of stroke45 (Figure 3).
Adult atopic dermatitis: new and emerging therapies
Published in Expert Review of Clinical Pharmacology, 2018
Maddalena Napolitano, Claudio Marasca, Gabriella Fabbrocini, Cataldo Patruno
The role of LTs and PGs in the development of atopy has been established in studies of asthma pathogenesis [53]. The pathway begins with a stimulus that induces cytosolic phospholipase A2 (cPLA2) to cleave phospholipids present in the cell membrane and convert them to arachidonic acid, the precursor molecule. From arachidonic acid, there are divergent pathways that produce numerous different eicosanoids [53]. Biosynthesis of LTs occurs first from the production of LTA4 from arachidonic acid by the enzyme 5-lipoxygenase [53,54]. The interactions of LTs and PGs in the pathogenesis of AD are complex, and broad down-regulation of the arachidonic acid pathway would certainly lead to a reduction in skin inflammation [55]. Two topical drugs targeting the arachidonic acid pathway have been investigated in phase II clinical trials. Q301, a 5-lipoxygenase inhibitor, has been administered topically twice a day for 8 consecutive weeks. The randomized, double-blind, vehicle-controlled, parallel-group comparison study evaluated the safety and efficacy of Q301 cream versus vehicle in 57 adults aged > 18 years with moderate-to-severe AD (NCT02426359). The study ended in 2016, but the results are not yet available [53].