- |||||||||| Zyflo (zileuton) / Chiesi
Biomarker, Clinical, Journal: Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers. (Pubmed Central) - Jun 25, 2022
Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.
- |||||||||| Journal: Participation of 5-lipoxygenase and LTB4 in liver regeneration after partial hepatectomy. (Pubmed Central) - Nov 7, 2020
Non-parenchymal cells (NPCs) from zileuton-treated PH-rats displayed higher apoptosis than NPCs from PH control rats. In conclusion, the present work provides evidences that 5-LOX activation and its product LTB4 are involved in the initial signaling events for liver regeneration after PH and the pharmacological inhibition of this enzyme can delay the initial time course of the phenomenon.
- |||||||||| atreleuton (A 85761) / AbbVie, VIA Pharma, setileuton (MK-0633) / Merck (MSD), zileuton extended release tablets / Generic mfg.
Review, Journal: 5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. (Pubmed Central) - Sep 24, 2020
So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.
- |||||||||| zileuton extended release tablets / Generic mfg.
Journal: Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms. (Pubmed Central) - Sep 18, 2020
The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways).
- |||||||||| zileuton extended release tablets / Generic mfg., zafirlukast / Generic mfg.
Journal: In brief: Neuropsychiatric events with montelukast. (Pubmed Central) - Sep 16, 2020
Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways). No abstract available
- |||||||||| remdesivir / Generic mfg., dexamethasone / Generic mfg., zileuton extended release tablets / Generic mfg.
Journal: A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes. (Pubmed Central) - Aug 28, 2020
Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair).
- |||||||||| aspirin / Generic mfg., epinephrine / Generic mfg., zileuton extended release tablets / Generic mfg.
Review, Journal: Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management. (Pubmed Central) - Jul 29, 2020
Acute episodes of mast cell activation require epinephrine, and prolonged episodes may be addressed with corticosteroids. Patients with clonal mast cell syndromes may need a reduction in the number of mast cells to prevent severe symptoms including anaphylaxis and/or progression to aggressive diseases.
- |||||||||| zileuton extended release tablets / Generic mfg., celecoxib oral / Generic mfg.
Preclinical, Journal: In vitro cytotoxicity of montelukast in HAPI and SH-SY5Y cells. (Pubmed Central) - Jun 25, 2020
The results of the current study show the capability of montelukast to directly induce toxicity and inflammation in HAPI cells, possibly through the involvement of PGE and ROS, and toxicity in undifferentiated SH-SY5Y neuroblastoma cells. The current study highlights the importance of consideration between benefit and risk of montelukast usage and provides references for future investigation on decreasing montelukast-related NEs.
- |||||||||| zileuton extended release tablets / Generic mfg.
Journal: Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. (Pubmed Central) - May 19, 2020
Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.-Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.
- |||||||||| zileuton extended release tablets / Generic mfg.
Journal: HMGB1 enhances AGE-mediated VSMC proliferation via an increase in 5-LO-linked RAGE expression. (Pubmed Central) - May 7, 2020
Both of these effects were markedly attenuated in cells pretreated with zileuton (1-10 μM), a 5-LO inhibitor, as well as in cells transfected with 5-LO siRNA, suggesting a potential involvement of 5-LO signaling in HMGB1-mediated RAGE expression in VSMCs...Taken together, our results suggest that HMGB1-induced increase in 5-LO expression enhances RAGE expression in VSMCs, which stimulates AGE-mediated VSMC proliferation. Thus, the 5-LO-RAGE signaling axis in VSMCs might serve as a potential therapeutic target for vascular remodeling in the injured vasculature.
- |||||||||| zileuton extended release tablets / Generic mfg.
Journal: Inhibition of 5-Lipoxygenase Decreases Renal Fibrosis and Progression of Chronic Kidney Disease. (Pubmed Central) - Jan 1, 2020
Zileuton, a US Food and Drug Administration-approved antagonist of 5-LO, significantly reduced fibrosis at 7 and 14 days after UUO; these findings were confirmed using a genetically modified [5-LO-associated protein-knockout ( Alox5ap)] mouse strain...In contrast, using the folate nephropathy model, we found that both Ltc4s-/- and Lta4h-/- mice had reduced fibrosis and improved renal function. In summary, our studies suggest that manipulation of the 5-LO pathway may represent a novel treatment approach for chronic kidney disease.
- |||||||||| Zyflo CR (zileuton) / Vectura
Journal: Comprehensive Quality by Design Approach for Stable Nanocrystalline Drug Products. (Pubmed Central) - Nov 24, 2019
The novelty of the present research is application of a comprehensive quality by design (QbD) approach to minimize errors in product optimization and validation for the development of a stable nanocrystalline zileuton (BCS class II drug) formulation...Drug release from the formulations followed a particle size dependent dissolution trend. Additionally, pH switch dissolution testing indicated that complete drug release from the nanoformulations was observed at intestinal pH (pH 6.8) within 1-2 h of the shift from the stomach pH (pH 1.2).
- |||||||||| Zyflo CR (zileuton) / Vectura
Journal: Effect of zileuton on osteoporotic bone and its healing, expression of bone and brain genes in rats. (Pubmed Central) - Nov 11, 2019
Here, we describe for the first time, the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in crosstalk between bones and brain and may be a potent drug for further examination in estrogen deficiency-related dysfunction(s).
- |||||||||| triamcinolone acetonide / Generic Mfg., Atarax (hydroxyzine hydrochloride) / Alliance, Zyflo CR (zileuton) / Vectura
GRANULOMATOUS CHEILITIS IN A WOMAN RECEIVING HIV ANTIRETROVIRAL THERAPY (Monitor 4) - Nov 9, 2019 - Abstract #ACAAI2019ACAAI_761;
CD4+ lymphocyte counts since presentation ranged from 900-1400 cells/cmm.The Challenge: Angioedema did not resolve with multiple courses of oral prednisone or oral and intravenous antihistamines prior to referral...Symptoms were initially attributed to idiopathic angioedema but did not improve with Cetirizine 10mg twice daily, Ranitidine 150mg twice daily, Zileuton 600mg twice daily, Montelukast 10mg daily, and Hydroxyzine 25mg at night...Subsequent referral to otolaryngology resulted in surgical lip reduction and maintenance Triamcinolone acetonide 40mg intralesional injections every 6-8 weeks...Recurrence of symptoms at the same site may be indicative of a localized disease process rather than a systemic disorder. Patients receiving ART who do not respond to treatment for idiopathic angioedema may benefit from biopsy.
- |||||||||| Zyflo CR (zileuton) / Vectura
NADPH Oxidase Controls Neutrophil Infiltration in the Lung in Early Response to Fungal Cell Walls Via LTB4 (W315, Level 3 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_1579;
Cluster formation was abrogated by inhibiting LTB4 synthesis with the 5-lipoxygenase (5-LO) inhibitor zileuton or by the BLT1 receptor antagonist U75302, demonstrating that cluster formation was LTB4 and BLT1 dependent...This study is the first to implicate LTB4 in promoting neutrophilic lung inflammation in response to fungal cell walls in CGD, likely by an amplified feed-forward loop involving increased production of LTB4 by CGD PMN . LTB4 could be a potential therapeutic target to ameliorate CGD hyperinflammation.
- |||||||||| Zyflo CR (zileuton) / Vectura, celecoxib oral / Generic Mfg.
Journal: Design, synthesis, biological evaluation and docking study of novel indole-2-amide as anti-inflammatory agents with dual inhibition of COX and 5-LOX. (Pubmed Central) - Nov 6, 2019
The most promising compound 10b was exhibited the highest selectivity for COX-2 (selectivity index (COX-1/COX-2) = 17.45) and moderate 5-LOX inhibitory activity (IC = 66 nM), which comparable to positive controlled zileuton (IC = 38.91 nM)...Further, at the active sites of the COX-1, COX-2 co-crystals, 3b and 4l showed higher binding forces in the molecular docking study, which consistent with the results of in vitro experiments. These results demonstrated that these compounds had dual inhibitory activity of COX/5-LOX, providing clues for further searching for safer and more effective anti-inflammatory drugs.
- |||||||||| Zyflo CR (zileuton) / Vectura
Journal: Chalcone-Thiazole Hybrids: Rational Design, Synthesis, and Lead Identification against 5-Lipoxygenase. (Pubmed Central) - Oct 18, 2019
In vitro biological evaluation showed that most of the compounds were better 5-LOX inhibitors than the positive control, Zileuton (IC = 1.05 ± 0.03 μM)...Further, 4k has redox (noncompetitive) while 4n and 4v act through a competitive inhibition mechanism. SAR indicated that the presence of methoxy/methyl either in the vicinity of chalcone or both thiazole and chalcone contributed to the synergistic inhibitory effect.
- |||||||||| Zyflo CR (zileuton) / Vectura
POLYUNSATURATED FATTY ACIDS AND 5-LIPOXYGENASE IN NON-ALCOHOLIC FATTY LIVER DISEASE (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_1311;
Inhibition of 5-LOX negated negative effects of omega-6 fatty acid on hepatic steatosis and inflammation. These results warrant more in-depth investigation into effects of 5-lipoxygenase in non-alcoholic fatty liver disease.
- |||||||||| Zyflo CR (zileuton) / Vectura
Preclinical, Journal: BLTR1 in Monocytes Emerges as a Therapeutic Target For Vascular Inflammation With a Subsequent Intimal Hyperplasia in a Murine Wire-Injured Femoral Artery. (Pubmed Central) - Sep 22, 2019
In cultured primary bone marrow-derived cells (BMDCs) stimulated with HMGB1, the number of cells with macrophage-like morphology was markedly increased in association with an increased expression of CD11b/Mac-1, which were attenuated in cells pre-treated with Zileuton, a 5-LO inhibitor as well as in 5-LO-deficient BMDCs...In vivo, both macrophage infiltration and intimal hyperplasia in our wire-injured femoral artery were markedly attenuated in BLTR1-deficient mice as compared with wild-type controls, but these effects were reversed in BLTR1-deficient mice transplanted with monocytes from control mice. These results suggest that BLTR1 in monocytes is a pivotal player in MMD with subsequent macrophage infiltration into neointima, leading to vascular remodeling after vascular injury.
- |||||||||| Zyflo CR (zileuton) / Vectura
Preclinical, Journal: Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice. (Pubmed Central) - Sep 14, 2019
Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease-modifying therapeutic approach for tauopathy.
- |||||||||| Ultane (sevoflurane) / Generic Mfg.
Preclinical, Journal: Involvement of leukotriene pathway in the development of sevoflurane-induced pica in rats. (Pubmed Central) - Aug 17, 2019
Furthermore, we observed that sevoflurane significantly increased urinary leukotriene excretion and 5-lipoxygenase mRNA expression in the spleen, but not hypothalamus. These results suggest that the production of leukotriene may lead to the development of sevoflurane-induced pica in rats, and that inhibition of the leukotriene pathway could be potentially useful for the treatment of PONV.
- |||||||||| aspirin / generics
Clinical, Journal: Clinical updates in aspirin-exacerbated respiratory disease. (Pubmed Central) - Aug 3, 2019
Dietary modifications toward a diet that is high in omega-3 fatty acids and low in omega-6 fatty acids can reduce the production of the inflammatory leukotriene and prostaglandin D₂ lipids and help improve symptoms for patients with AERD. A lack of definitive understanding of the causative mechanisms of AERD and the absence of an AERD-specific patient-reported outcome measure are obstacles that remain in this field, but much progress has been made over the past decade.
- |||||||||| Zyflo CR (zileuton) / Vectura
Preclinical, Journal: Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway. (Pubmed Central) - Jul 13, 2019
...To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype...Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.
- |||||||||| Zyflo CR (zileuton) / Vectura, Miostat (carbachol) / Novartis
Preclinical, Journal: Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization. (Pubmed Central) - May 14, 2019
Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy.
- |||||||||| Zyflo CR (zileuton) / Vectura
Preclinical, Journal: Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction. (Pubmed Central) - Apr 11, 2019
To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs. 5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors.
- |||||||||| Zyflo (zileuton) / Chiesi
Trial primary completion date: Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers (clinicaltrials.gov) - Apr 14, 2015
P1/2, N=84, Completed,
5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors. Trial primary completion date: Sep 2011 --> Aug 2012
- |||||||||| zileuton extended release tablets / Generic mfg.
Trial completion: Single Dose Bronchodilatory Study in Asthma (clinicaltrials.gov) - Jul 10, 2013
P4, N=25, Completed,
Trial completion date: Dec 2013 --> Dec 2014 Recruiting --> Completed
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