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Lancet (London, England) Aug 1996
Review
Topics: Arthritis, Rheumatoid; Asthma; Humans; Hydroxyurea; Lipoxygenase Inhibitors
PubMed: 8757156
DOI: 10.1016/S0140-6736(95)12297-4 -
Pulmonary Pharmacology & Therapeutics Feb 2020Zileuton, a 5-lipoxygenase (5LPO) inhibitor exerts a broad influence in the arachidonic acid (AA) pathway by blocking upstream molecules that otherwise would lead to...
UNLABELLED
Zileuton, a 5-lipoxygenase (5LPO) inhibitor exerts a broad influence in the arachidonic acid (AA) pathway by blocking upstream molecules that otherwise would lead to production of an array of inflammatory leukotrienes (LT) A4-E4. Hence, it has the potential to be a drug suitable to treat complicated asthmatics. Studies have shown modest response rates for zileuton in asthmatics.
OBJECTIVE
We sought to study our hypothesis that response to zileuton varies across specific asthmatic phenotypes.
METHODS
We retrospectively analyzed data from 129 patients with asthma that were prescribed zileuton at the University of Pittsburgh's Comprehensive Lung Clinic. A total of 75 patients from the above population had requisite lung function data and zileuton usage that would help assess a drug response effect. A zileuton responder was defined as having at least or greater than 5% annualized increase in post-bronchodilator FEV1% from baseline. Using a multivariate logistic regression analysis, we determined the association between responder status and the underlying phenotypic characteristics.
RESULTS
Using generalized estimating equations (GEE) analysis of 331 individual lung function test data-points as well as logistic regression analysis for predictors of 5% or more annualized increase in FEV1%, 21 of 75 patients (28%) met criteria for having a differential response to zileuton. Severe asthma was associated less often with responder status (OR 0.12; p 0.004). Obesity was less often associated with responder status, however did not reach significance (OR 0.46; p 0.15).
CONCLUSION
In this retrospective study, zileuton response varies across asthmatics, with poorer response rates being associated with those with severe asthma and possibly obesity. Although prescription trends for zileuton may predominate amongst severe asthmatics, this tendency does not seem to mirror the actual likelihood to respond. As against the trivial role for zileuton per current GINA algorithms, our study brings forward a notion that zileuton may well be considered along with LTRAs (like montelukast) for non-severe asthma.
Topics: Adult; Aged; Anti-Asthmatic Agents; Asthma; Female; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Lung; Male; Middle Aged; Phenotype; Respiratory Function Tests; Retrospective Studies; Severity of Illness Index
PubMed: 31841698
DOI: 10.1016/j.pupt.2019.101872 -
Cancer Chemotherapy and Pharmacology Dec 2021Inhibitors of arachidonate lipoxygenase 5 (ALOX5) exhibit anticancer activity. Zileuton is an FDA-approved drug for treating asthma and an ALOX5 inhibitor. This study...
BACKGROUND
Inhibitors of arachidonate lipoxygenase 5 (ALOX5) exhibit anticancer activity. Zileuton is an FDA-approved drug for treating asthma and an ALOX5 inhibitor. This study evaluated the efficacy of zileuton in cervical cancer, determined the molecular mechanism of action, and assessed ALOX5 expression in cervical cancer patients.
METHODS
The effects of zileuton were evaluated using cervical cancer cell lines and xenograft mouse models. Loss-of-function analysis of ALOX5 was performed using siRNA. The levels of ALOX5 and 5-HETE were determined using immunohistochemistry and ELISA.
RESULTS
Zileuton resulted in cell proliferation inhibition and apoptosis induction in a dose-dependent manner, regardless of cellular origin or HPV infection. In two independent cervical cancer xenograft mouse models, zileuton at nontoxic doses significantly prevented tumor formation and decreased tumor growth. Zileuton acts on cervical cancer cells by inhibiting the ALOX5-5-HETE axis. Of note, ALOX5-5-HETE was significantly upregulated in cervical cancer compared with normal tissue. Inhibition of ALOX5 via the siRNA approach mimics the inhibitory effects of zileuton and confirms the roles of ALOX5 in cervical cancer.
CONCLUSIONS
Our work demonstrates that the ALOX5-5-HETE axis is activated in cervical cancer, with important roles in growth and survival, and this can be therapeutically targeted by zileuton. Our findings also provide preclinical evidence to assess the efficacy of zileuton in cervical cancer in clinical settings.
Topics: Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Cell Proliferation; Disease Models, Animal; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Mice; Mice, SCID; Tumor Cells, Cultured; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays
PubMed: 34477945
DOI: 10.1007/s00280-021-04343-w -
The Annals of Pharmacotherapy 1996To introduce and review zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma. (Comparative Study)
Comparative Study Review
OBJECTIVE
To introduce and review zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma.
DATA SOURCES
A MEDLINE search (from 1966 to December 1995) was performed to identify pertinent English-language literature.
STUDY SELECTION
Basic science studies on the pharmacokinetics of zileuton, its pathophysiologic effects on asthma, and clinical efficacy trials were reviewed.
DATA EXTRACTION
Clinical trials were emphasized. Studies from ex vivo or animal models of pharmacologic and pharmacodynamic effects were considered for review where no in vivo human data were available.
DATA SYNTHESIS
Zileuton has shown the ability to attenuate induced bronchospasm, produce some degree of bronchodilation, and provide antiinflammatory or steroid-sparing effects with both single doses (800 mg) and chronic treatment (400 and 600 mg qid). Zileuton has been studied in patients requiring daily inhaled beta-adrenergic agonist treatment; however, data from pediatric populations and comparisons with other asthma medications are limited at this time. Adverse effects include dyspepsia and elevated liver enzymes (incidence approximately 3%). One case of jaundice has been reported among the more than 5000 patients treated with zileuton. There is also some concern for drug interactions with hepatically cleared medications, such as theophylline.
CONCLUSIONS
Zileuton represents the first drug of a new treatment category for asthma, the 5-lipoxygenase inhibitors. Some people with asthma may receive considerable benefit, but as it is an entirely new drug entity, zileuton's final place in the hierarchy of asthma medications remains to be determined.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Clinical Trials as Topic; Drug Interactions; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Theophylline
PubMed: 8826571
DOI: 10.1177/106002809603000725 -
International Journal of Molecular... Apr 2022M1 microglia induce neuroinflammation-related neuronal death in animal models of spontaneous subarachnoid haemorrhage. Zileuton is a 5-lipoxygenase inhibitor that...
M1 microglia induce neuroinflammation-related neuronal death in animal models of spontaneous subarachnoid haemorrhage. Zileuton is a 5-lipoxygenase inhibitor that reduces the levels of downstream pro-inflammatory cytokines. This study aimed to investigate whether zileuton inhibits microglial activation and describe its underlying mechanisms. BV-2 cells were exposed to 1 mg/mL haemolysate for 30 min, followed by treatment with different concentrations (5, 10, 15, or 20 μM) of zileuton for 24 h. The cells were then assessed for viability, polarisation, and protein expression levels. Haemolysate increases the viability of BV-2 cells and induces M1 polarisation. Subsequent exposure to high concentrations of zileuton decreased the viability of BV-2 cells, shifted the polarisation to the M2 phenotype, suppressed the expression of 5-lipoxygenase, decreased tumour necrosis factor α levels, and increased interleukin-10 levels. Furthermore, high concentrations of zileuton suppressed the expression of myeloid differentiation primary response protein 88 and reduced the phosphorylated-nuclear factor-kappa B (NF-kB)/NF-kB ratio. Therefore, phenotype reversal from M1 to M2 is a possible mechanism by which zileuton attenuates haemolysate-induced neuroinflammation after spontaneous subarachnoid haemorrhage.
Topics: Animals; Hydroxyurea; Lipopolysaccharides; Lipoxygenase Inhibitors; Microglia; Myeloid Differentiation Factor 88; NF-kappa B; Signal Transduction; Subarachnoid Hemorrhage
PubMed: 35563304
DOI: 10.3390/ijms23094910 -
International Journal of Clinical... Apr 2007The 5-Lipoxygenase pathway results in the formation of leukotrienes, including leukotriene B(4) (LTB(4)), 5-oxo-6E,8Z,11Z,14Z-eicosatetranoic acid and the cysteinyl... (Review)
Review
The 5-Lipoxygenase pathway results in the formation of leukotrienes, including leukotriene B(4) (LTB(4)), 5-oxo-6E,8Z,11Z,14Z-eicosatetranoic acid and the cysteinyl leukotrienes (LTC(4), LTD(4) and LTE(4)) and activates all four leukotriene receptors, BLT1, BLT2, cysLT(1) and cysLT(2). Zileuton is the only commercially available inhibitor of the 5-Lipoxygenase pathway. In a number of clinical trials, zileuton has been shown to improve airway function and inflammation, asthma symptom control and quality of life in asthmatics. Given the important role that leukotrienes play in airway inflammation, zileuton provides an additional therapeutic option in the management of chronic, persistent asthma, particularly those asthmatics with more severe disease. In addition, zileuton has shown promise in a number of other conditions, including upper airway inflammatory conditions, dermatological disease and chronic obstructive pulmonary disease. The development of new formulations, including a controlled release tablet formulation for b.i.d. dosing and an intravenous preparation for acute asthma exacerbations may enhance clinical utility and expand therapeutic indications.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Asthma; Dermatitis, Atopic; Drug Administration Schedule; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Pulmonary Disease, Chronic Obstructive; Rhinitis
PubMed: 17394438
DOI: 10.1111/j.1742-1241.2007.01320.x -
Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model.The Journal of Antimicrobial... Oct 2023Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting...
OBJECTIVES
Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury.
METHODS
Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was also conducted to characterize the extent of kidney injury.
RESULTS
Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton.
CONCLUSIONS
Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.
Topics: Humans; Female; Rats; Male; Animals; Polymyxins; Polymyxin B; Aminoglycosides; Amikacin; Creatinine; Rats, Sprague-Dawley; Anti-Bacterial Agents; Acute Kidney Injury; Kidney; Models, Animal
PubMed: 37563789
DOI: 10.1093/jac/dkad246