montelukast and zileuton

The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, whereas small pilots using zileuton did have some clinically significant improvement. There are several agents in development that target leukotrienes and/or prostaglandins as well, including OC000459, Q301, and ZPL-521. In atopic dermatitis, OC000459 did not demonstrate efficacy in clinical trials, and the efficacy of the other 2 agents remains to be seen. Should these medications prove promising, these topical agents may play a future role in chronic maintenance therapy and flare prophylaxis in atopic dermatitis, as antileukotriene therapy does in asthma.

Topics: Acetates; Adult; Animals; Cyclopropanes; Dermatitis, Atopic; Female; Forecasting; Humans; Hydroxyurea; Leukotriene Antagonists; Male; Molecular Targeted Therapy; Prostaglandin Antagonists; Quinolines; Severity of Illness Index; Sulfides; Treatment Outcome

The US FDA has issued safety alerts and required manufacturers of leukotriene-modifying agents (LTMAs), including montelukast, zafirlukast and zileuton, to include suicide and neuropsychiatric events as a precaution in the drug label. This paper reviews the existing evidence on the potential association between the LTMAs and suicidal behaviour. We conducted a literature search of MEDLINE, EMBASE and International Pharmaceutical Abstracts from 1995 to 2010 (inclusive) to identify pertinent studies and reports. We also examined data obtained from the FDA adverse event reporting system. To date, there are no well conducted, comparative, observational studies of this association, and the safety alerts are based primarily on case reports. While the FDA safety alerts apply to all three LTMAs, montelukast (known by its trade name Singulair®) is by far the most widely used of these drugs and most of the reports to date regarding suicide pertain to montelukast. From 1998 to 2009 there were 838 suicide-related adverse events associated with leukotrienes reported to the FDA, of which all but five involved montelukast. Nearly all cases were reported in 2008 and 2009 (96.1%) after the FDA warnings. LTMAs are approved for use in asthma and allergic rhinitis, and are effective drugs. Both of these diseases are also associated with suicide, making confirmation of the association more difficult. Given the lack of good evidence, we recommend that a large observational cohort or case-control study be conducted to quantify the association between LTMAs and suicide. Until then, when prescribing LTMAs, clinicians should consider the potential for suicide and monitor patients who may be at elevated risk carefully for suicidal ideation or psychiatric symptoms associated with suicidal behaviour.

Topics: Acetates; Adverse Drug Reaction Reporting Systems; Cyclopropanes; Drug Labeling; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Suicide; Sulfides; Sulfonamides; Tosyl Compounds; United States; United States Food and Drug Administration

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Albuterol; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Child; Cyclopropanes; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Hydroxyurea; Leukotriene Antagonists; Quality of Life; Quinolines; Randomized Controlled Trials as Topic; Respiratory Function Tests; Salmeterol Xinafoate; Sulfides; Treatment Failure

Leukotriene inhibitors are the first new class of medications for the treatment of persistent asthma that have been approved by the U.S. Food and Drug Administration in more than two decades. They also have been approved for the treatment of allergic rhinitis. Prescriptions of leukotriene inhibitors have outpaced the evidence supporting their use, perhaps because of perceived ease of use compared with other asthma medications. In the treatment of persistent asthma, randomized controlled trials have shown leukotriene inhibitors to be more effective than placebo but less effective than inhaled corticosteroids. The use of leukotriene inhibitors has not consistently shown an inhaled-steroid-sparing effect, a reduction in need for systemic steroid treatment, or a cost savings. For exercise-induced asthma, leukotriene inhibitors are as effective as long-acting beta2-agonist bronchodilators and are superior to placebo; they have not been compared with short-acting bronchodilators. Leukotriene inhibitors are as effective as antihistamines but are less effective than intranasal steroids for the treatment of allergic rhinitis. The use of leukotriene inhibitors in treating atopic dermatitis, aspirin-intolerant asthma, and chronic idiopathic urticaria appears promising but has not been studied thoroughly. Leukotriene inhibitors have minimal side effects and are well tolerated in most populations.

Topics: Acetates; Anti-Asthmatic Agents; Asthma; Asthma, Exercise-Induced; Cyclopropanes; Dermatitis, Atopic; Humans; Hydroxyurea; Hypersensitivity; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sulfides; Sulfonamides; Tosyl Compounds

Twenty five years after the structure elucidation of slow reacting substance of anaphylaxis, antileukotrienes are established as a new therapeutic modality in asthma. The chapter reviews the biochemistry and pharmacology of leukotrienes and antileukotrienes with particular focus on the different usage of antileukotrienes for treatment of asthma and rhinitis in Europe and the US. Further research needs and new areas for leukotriene involvement in respiratory diseases are also discussed.

Topics: Acetates; Animals; Asthma; Clinical Trials as Topic; Cyclopropanes; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipoxygenase Inhibitors; Membrane Proteins; Quinolines; Receptors, Leukotriene; Respiratory System; Rhinitis; Sulfides

In the paper a review is presented of current literature on the use of antileukotrienes in the treatment of allergic diseases in children. Recent reports suggest a role of cysteinyl leukotrienes in the development of inflammatory reaction in the airways, including bronchial remodelling.

Topics: Acetates; Asthma; Child; Cyclopropanes; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Quinolines; Receptors, Leukotriene; Sulfides

Asthma is a chronic inflammatory disease of the airways that affects approximately 100 million people worldwide. In order to reduce symptoms, improve pulmonary function, and decrease morbidity, current treatment guidelines emphasize the importance of controlling the underlying inflammation in patients with asthma. Leukotrienes are leukocyte-generated lipid mediators that promote airway inflammation. Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for the treatment of asthma to become available in 25 years. Controlled clinical trials with the four currently used leukotriene modifiers (montelukast, zafirlukast, and zileuton in the US and pranlukast in Japan) have established their efficacy in improving pulmonary function, reducing symptoms, decreasing night-time awakenings, and decreasing the need for rescue medications. They exert anti-inflammatory effects that attenuate cellular infiltration and bronchial hyperresponsiveness and complement the anti-inflammatory properties of inhaled corticosteroids. In patients with moderate and severe asthma, they permit tapering of the corticosteroid dose. In patients with exercise-induced asthma, leukotriene modifiers limit the decline in and quicken the recovery of pulmonary functions without the tolerance issues seen with chronic long-acting beta(2)-adrenoceptor agonist use. In patients with aspirin (acetylsalicylic acid)-induced asthma, they improve pulmonary function and shift the dose response curve to the right, reducing the patient's response to aspirin. In patients with seasonal allergic rhinitis, with or without concomitant asthma, they improve nasal, eye, and throat symptoms as well as quality of life. Leukotriene modifiers are generally safe and well tolerated with adverse effect profiles similar to that of placebo. The one safety issue raised with leukotriene modifiers, Churg-Strauss Syndrome, appears to be the unmasking of an already present syndrome that is manifested when the leukotriene modifiers permit corticosteroid doses to be reduced. Although current treatment guidelines recommend their use in patients with mild persistent asthma, these guidelines were developed just as leukotriene modifiers were coming to the market, before much of the clinical efficacy data were published. Because asthma is a heterogeneous disease, the different asthma phenotypes respond differently to therapies; conseque

Topics: Acetates; Administration, Inhalation; Adolescent; Adult; Asthma; Child; Child, Preschool; Chromones; Controlled Clinical Trials as Topic; Cyclopropanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydroxyurea; Leukotriene Antagonists; Male; Middle Aged; Peak Expiratory Flow Rate; Quinolines; Respiratory Function Tests; Severity of Illness Index; Sulfides; Treatment Outcome

Cysteinyl leukotrienes (Cys-LTs) are mediators released in asthma and virus-induced wheezing. Corticosteroids appear to have little or no effect on this release in vivo. Cys-LTs are both direct bronchoconstrictors and proinflammatory substances that mediate several steps in the pathophysiology of chronic asthma, including inflammatory cell recruitment, vascular leakage, and possibly airway remodeling. Blocking studies show that Cys-LTs are pivotal mediators in the pathophysiology of asthma. Cys-LTs are key components in the early and late allergic airway response and also contribute to bronchial obstruction after exercise and hyperventilation of cold, dry air in asthmatics. LT modifiers reduce airway eosinophil numbers and exhaled nitric oxide levels. Together these findings support an important role for the Cys-LTs in the asthma airway inflammation. Cys-LT receptor antagonists (Cys-LTRA) are generally well-tolerated. Phase III randomized, controlled clinical trials (RCT) show that LT modifiers are moderately effective, apparently with a particular between-patient variability in their clinical response. The clinical effects of LT modifiers are additive to those of beta-agonists and corticosteroids. The onset of action of LT modifiers is within 1 to several days, and not rapid enough to make them useful as rescue treatment. Although LT modifiers possess some antiinflammatory activity, they cannot substitute for corticosteroids for inflammation control. LT modifiers are alternatives to long-acting beta-agonists as complementary treatment to inhaled corticosteroids in pediatric asthma management because they provide bronchodilation and bronchoprotection without development of tolerance, and complement the antiinflammatory activity unchecked by steroids. In addition, the Cys-LTRA montelukast has been shown to ameliorate asthmatic symptoms and provide bronchoprotection in asthmatic preschool children from 2 years of age, which is of particular importance in this difficult-to-manage group of asthmatics. Given their efficacy, antiinflammatory activity, oral administration, and safety, LT modifiers will play an important role in the treatment of asthmatic children.

Topics: Acetates; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Child; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Sulfides; Sulfonamides; Tosyl Compounds

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulairtrade mark, Merck) and zafirlukast (Accolatetrade mark, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflotrade mark, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.

Topics: Acetates; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Asthma; Bronchoconstriction; Child; Clinical Trials as Topic; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Phenylcarbamates; Phosphodiesterase Inhibitors; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds; Treatment Outcome

Leukotrienes are key mediators in asthma. Over the last 5 years, several antileukotrienes, including three receptor antagonists (montelukast, pranlukast and zafirlukast) and one 5-lipoxygenase inhibitor (zileuton), have been marketed and, to date, this class of drugs is being used widely. Still, their definite place in the asthma treatment algorithm is not yet established. These novel drugs have not yet all been evaluated in the same depth, but they have all been shown to possess anti-inflammatory properties and to be effective in chronic asthma treatment. Zafirlukast and montelukast are particularly efficacious in exercise-induced asthma and zileuton appears valuable for treating aspirin-intolerant asthmatics. Clinical comparisons to other anti-asthma drugs are still sparse. The corticosteroid-sparing effect of antileukotrienes is fairly well established except for zileuton, even though this drug has been evaluated most thoroughly in terms of its anti-inflammatory effects. Montelukast is the antileukotriene most extensively evaluated in children and zafirlukast has recently been approved for use in children in the USA, although not yet in Europe. Therapeutic regimes are quite variable depending on the drug, but all of the antileukotrienes marketed to date are taken orally; hence, compliance is usually greater than that with inhaled medication. Response to antileukotrienes appears to depend on the individual patients' characteristics, in particular on genetic polymorphisms related to leukotriene metabolism. All drugs of this class are well tolerated and only in the case of zileuton is there potential for hepatic adverse effects. The diagnosis of Churg-Strauss syndrome made among patients taking antileukotrienes seems to be more related to the withdrawal of corticosteroids than to the antileukotrienes themselves.

Topics: Acetates; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Chromones; Clinical Trials as Topic; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotrienes; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds

Cysteinyl leukotriene (CysLT) C4, D4, and E4 play key roles in asthma. CysLTs are newly generated after cellular activation and are produced by eosinophils, mast cells, alveolar macrophages, and neutrophils. Pharmacological actions of CysLTs include potent bronchoconstriction, increased microvascular leakage and mucus secretion, chemoattraction of eosinophils, acceleration of eosinophil apoptosis, and proliferation of human airway smooth muscle. Recent studies demonstrated that CysLT1 receptors are distributed on CD34+ stem cells, eosinophils, monocytes, macrophages, basophils, and B cells in addition to airway smooth muscle. Because of these wide variety of distribution, Cys LTs may have another important roles in airway inflammation. CysLT1 receptor antagonist is widely used and found to be beneficial for the chronic management of asthma especially to symptomatic patients who had already been treated with moderate to high doses of inhaled corticosteroids and also to mild to moderate steroid-naive asthmatic patients.

Topics: Acetates; Asthma; Chromones; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotrienes; Lipoxygenase Inhibitors; Membrane Proteins; Phenylcarbamates; Practice Guidelines as Topic; Quinolines; Receptors, Leukotriene; Sulfides; Sulfonamides; Tosyl Compounds

Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Lipoxygenase Inhibitors; Patient Compliance; Phenylcarbamates; Quinolines; Safety; Steroids; Sulfides; Sulfonamides; Tosyl Compounds; Treatment Outcome

The three leukotriene (LT) modifiers approved for use in the United States, zileuton, zafirlukast, and montelukast, are the first new class of therapeutic agents to be introduced in 20 years for the treatment of asthma. These agents are referred to as leukotriene modifiers and have clearly demonstrated the ability to ameliorate bronchoconstriction and indices of airway edema and abnormal mucus production as observed in clinical trials. These agents have been shown to improve airflow, reduce the need for an inhaled bronchodilator, and improve nocturnal awakenings and asthma symptom scores appreciably. When combined with inhaled corticosteroid therapy, they may either provide additional improvement in efficacy or permit the reduction of the dose of inhaled corticosteroid necessary for effective therapy. Physicians should be familiar with these agents and consider them for use in their practice, in conjunction with current asthma management guidelines.

Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Asthma, Exercise-Induced; Cyclopropanes; Drug Evaluation; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds; Treatment Outcome

Over recent years it has become widely accepted that asthma is a chronic persistent inflammatory condition regulated by a variety of inflammatory cells and mediators such as leukotrienes. It has been shown that there are increased levels of cysteinyl leukotrienes in biological fluids from patient with chronic asthma and in acute bronchospasm experimentally induced by allergen or other stimuli. The evidence suggests that blocking the formation or action of cysteinyl leukotrienes may be benefit in the treatment of chronic inflammatory diseases. In this article the leukotriene pathway, the biological role of these lipid mediators and their antagonists are widely characterised. There are three groups of leukotriene inhibitors: 5-lipooxygenase inhibitors, FLAP (activating protein) inhibitors and Cys-Lt1 receptor antagonists. On Polish market two representative drugs are currently: montelukast and zafirlukast, both leukotriene receptor antagonists. They bind competitively and selectively to Cys-Lt1 receptors blocking the pro-inflammatory effects of the cysteinyl leukotrienes. They offer protection against cold, dry air or exercise-induced bronchoconstriction significantly greater than placebo. These agents produce a modest improvement in lung function, symptom control and reduce the need for short acting inhaled beta2-agonist therapy. Some guidelines suggest that they may be considered as an alternative treatment to low dose inhaled corticosteroid therapy and cromones therapy of mild persistent asthma. It seems likely that aspirin-sensitive asthmatic patients may be benefited by LTD4-antagonists. These drugs have the great advantage of efficacy by oral administration and they do not appear any class-specific side effects. Also some basic information about zileuton--5-lipooxygenase inhibitor are given. Due to its induction of hepatic enzyme activity zileuton is not available in Poland, but it is important agent in evaluation of the leukotriene inhibitors in some models of inflammation. The introduction of leukotriene antagonists is undoubtedly an important breakthrough in asthma therapy.

Topics: Acetates; Arachidonate 5-Lipoxygenase; Asthma; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotrienes; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds

The antileukotriene agents are the first new category of asthma medications introduced in the past two decades. Leukotriene synthesis inhibitors block the production of leukotrienes whereas leukotriene receptor antagonists block the effects of leukotrienes at the receptor level. Leukotriene synthesis inhibitors are further classified as either 5-lipoxygenase inhibitors or 5-lipoxygenase-activating protein inhibitors. Zafirlukast, montelukast, and pranlukast are leukotriene receptor antagonists whereas zileuton is a 5-lipoxygenase inhibitor. Antileukotrienes have been shown to be relatively safe and effective in chronic mild to moderate asthma. Studies are ongoing to determine how they compare with inhaled steroids, which remain the drug of choice for anti-inflammatory therapy.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Asthma; Chromones; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Lipoxygenase Inhibitors; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds

Topics: Acetates; Asthma; Bronchi; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase Inhibitors; Membrane Proteins; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Rhinitis; Sinusitis; Sulfides; Sulfonamides; Tosyl Compounds

Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.

Topics: Acetates; Anti-Asthmatic Agents; Asthma; Cohort Studies; Cyclopropanes; Gene-Environment Interaction; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Hydroxyurea; Leukotrienes; Phenotype; Polymorphism, Single Nucleotide; Quinolines; Sulfides

The two classes of leukotriene modifiers work by inhibiting different portions of the same pathway. We hypothesized that single nucleotide polymorphisms (SNPs) in genes associated with response to montelukast (a cys-leukotriene receptor antagonist) would also be associated with response to zileuton (a 5-lipoxygenase inhibitor). We genotyped 26 SNPs that had previously been interrogated for association with montelukast response in five candidate genes (ABCC1, ALOX5, CYSLTR1, LTA4H, LTC4S) in a population of 577 asthmatics who participated in a clinical trial comparing intermittent and continuous-release zileuton to placebo. After adjusting for age and sex, six SNPs in three genes were associated with longitudinal forced expiratory volume at 1 s in response to zileuton (P values 0.005-0.05). After adjusting for age and sex, six SNPs in three genes were associated with longitudinal forced expiratory volume at 1 s in response to zileuton (P values 0.005-0.05), including two SNPs (ALOX5 rs2115819 and ABCC1 rs119774) that we had previously reported as associated with FEV1 response to montelukast. Thus, the lung function response to zileuton is modulated by several of the loci that also influence montelukast response.

Topics: Acetates; Adult; Anti-Asthmatic Agents; Asthma; Cyclopropanes; Cysteine; Female; Forced Expiratory Volume; Genotype; Humans; Hydroxyurea; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Middle Aged; Polymorphism, Single Nucleotide; Quinolines; Receptors, Leukotriene; Sulfides

Aspirin-exacerbated respiratory disease can be diagnosed with oral aspirin challenges and treated with aspirin desensitization.. To evaluate whether controller medications, particularly leukotriene modifier drugs, taken during oral aspirin challenges can reduce the risk of severe asthmatic responses.. The medical records of 676 patients who had undergone oral aspirin challenges, followed by aspirin desensitization, were reviewed. Asthmatic responses were stratified based on severity of bronchospastic response or lack of response. The effect of pretreatment with controller medications on the outcome of oral aspirin challenges was measured.. Leukotriene modifier drugs had the most significant effect in protecting the lower airways from severe reactions (P = .004). The protective effect of leukotriene modifier drugs was observed in patients already taking systemic corticosteroids, where the addition of leukotriene modifier drugs significantly shifted the response toward a milder asthmatic response (P < .001).. Protection from significant aspirin-induced bronchospasm during oral aspirin challenge can be accomplished with leukotriene modifier drugs. The use of a combination of inhaled corticosteroids, long-acting beta-agonists, systemic corticosteroids, and leukotriene modifier drugs stabilized underlying airways in preparation for a reasonably safe and accurate oral aspirin challenge. However, only pretreatment with leukotriene modifier drugs enhanced the safety of oral aspirin challenge in patients with aspirin-exacerbated respiratory disease by significantly decreasing the degree of asthmatic responses. Therefore, outpatient oral aspirin challenges in most well-selected patients appear to be a reasonable decision.

Topics: Acetates; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Asthmatic Agents; Aspirin; Asthma; Cyclopropanes; Desensitization, Immunologic; Drug Hypersensitivity; Female; Forced Expiratory Volume; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Middle Aged; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds; Treatment Outcome

Topics: Acetates; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Betacoronavirus; Coronavirus Infections; COVID-19; Cyclopropanes; Cytokine Release Syndrome; Humans; Hydroxyurea; Immunologic Factors; Indoles; Leukotrienes; Pandemics; Phenylcarbamates; Pneumonia, Viral; Quinolines; SARS-CoV-2; Severity of Illness Index; Sulfides; Sulfonamides; Tosyl Compounds

The aim of this study was to evaluate and compare the effects of 5-lipoxygenase enzyme (5-LO) inhibitor zileuton and cysteinyl leukotriene receptor (CysLT1R) antagonist montelukast in testicular torsion/detorsion (T/D) injury model in rats. Rats were anaesthetised with 75 mg kg(-1) ketamine hydrochloride and 8 mg kg(-1) xylazine intraperitoneal before the operation. Torsion was created by rotating the right testis 720° clockwise and maintained by fixing the testis. The rats were treated with CysLT1R antagonist montelukast (10 mg kg(-1); i.p.), 5-LO inhibitor zileuton (3 mg kg(-1); i.p.), and vehicle, at 30 min prior detorsion. After 1 h of torsion, the testis was counter-rotated to the natural position and replaced into the scrotum. Malondialdehyde (MDA) level was measured in testicular tissue after 3 h of reperfusion. Histological examination was performed after 24 h of reperfusion. T/D caused a significant increase in MDA level and histopathological injury in testes. Montelukast and zileuton treatments prevented the T/D-induced augmentation in MDA levels. Only zileuton treatment significantly reduced the T/D-induced histopathological injury. In this study, we demonstrated for the first time that zileuton had protective effects on testicular T/D injury. We have also found that zileuton is more effective than montelukast on histopathological injury.

Topics: Acetates; Animals; Cyclopropanes; Hydroxyurea; Male; Malondialdehyde; Quinolines; Rats; Rats, Wistar; Spermatic Cord Torsion; Sulfides

The abundant expression of leukotrienes (LTs) and their receptors in adenotonsillar tissues of children with obstructive sleep apnea (OSA) suggest that LT antagonists could be useful in treating OSA.. The effects of LTD4 and of LT receptor antagonists zileuton, montelukast, and BAY u9773 were examined on mixed cell cultures prepared from dissociated tonsils or adenoids harvested intraoperatively from children with polysomnographically diagnosed OSA. Proliferation was assessed by (3)[H]-thymidine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-8, IL-10, and IL-12) was assessed in supernatants using enzyme-linked immunosorbent assay.. LTD4 elicited dose-dependent increases in adenotonsillar cell proliferation (p < 0.001; n = 12). All LT antagonists exhibited dose-dependent reductions in adenotonsillar cellular proliferation rates, with montelukast more than BAY u9773 more than zileuton (n = 14/group; p < 0.001). However, BAY u9773 showed partial agonist effects and increased cellular proliferation at higher concentrations (10(-4) mmol/L; p < 0.01; n = 12). LTD4 effects were partially blocked by montelukast and BAY u9773 but not by zileuton. All three antagonists reduced TNF-alpha, IL-6, and IL-12 concentrations, with selective changes in IL-8 and no effects on IL-10 levels.. LT pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of this disease.

Topics: Acetates; Adenoids; Apoptosis; Cell Proliferation; Cells, Cultured; Child; Child, Preschool; Cyclopropanes; Dose-Response Relationship, Drug; Humans; Hydroxyurea; Immunohistochemistry; Interleukins; Leukotriene Antagonists; Leukotriene D4; Palatine Tonsil; Polysomnography; Quinolines; Sleep Apnea, Obstructive; SRS-A; Sulfides

Inflammatory mediators and drugs which affect inflammation can influence the healing of injured tissues. Leukotrienes are potent inflammatory mediators, and similar to prostaglandins, are metabolites of arachidonic acid which can have positive or negative effects on bone and cartilage tissues. Here we tested the hypothesis that blocking the negative regulation of leukotrienes, would lead to enhanced endochondral bone formation during fracture repair. A closed femoral fracture was created in mice. Animals were divided into three groups for treatment with either montelukast sodium, a cysteinyl leukotriene type 1 receptor antagonist (trade name Singulair), zileuton, a 5-lipoxygenase enzyme inhibitor (trade name Zyflo), or carrier alone. The fractures were analyzed using radiographs, quantitative gene expression, histology and histomorphometry, and immunohistochemistry. Both the montelukast sodium group and the zileuton group exhibited enhanced fracture repair when compared with controls. Both treatment groups exhibited increased callous size and earlier bone formation when compared to controls as early as day 7. Gene expression analysis of treatment groups showed increased markers of chondrocyte proliferation and differentiation, and increased early bone formation markers when compared with controls. Treatment with montelukast sodium directly targeted the cysteinyl leukotriene type 1 receptor, leading to increased chondrocyte proliferation at early time points. These novel findings suggests a potential mechanism by which the cysteinyl leukotriene type 1 receptor acts as a negative regulator of chondrocyte proliferation, with important and previously unrecognized implications for both fracture repair, and in a broader context, systemic chondrocyte growth and differentiation.

Topics: Acetates; Animals; Arachidonate 5-Lipoxygenase; Cell Proliferation; Chondrocytes; Cyclopropanes; Fracture Healing; Fractures, Bone; Gene Expression Regulation; Hydroxyurea; Hypertrophy; Leukotriene Antagonists; Leukotriene B4; Mice; Models, Biological; Osteogenesis; Quinolines; Radiography; Receptors, Leukotriene; Sulfides

Nasal polyposis is a chronic inflammatory disease of the upper respiratory tract that affects around 2% of the population and almost 67% of patients with aspirin-intolerant asthma. Polyps are rich in mast cells and eosinophils, resulting in high levels of the proinflammatory cysteinyl leukotrienes.. To better understand the role of the proinflammatory leukotrienes in nasal polyposis, we asked the following questions: (1) How do nasal polyps produce leukotriene C(4) (LTC(4))? (2) Can LTC(4) feed back in a paracrine way to maintain mast cell activation? (3) Could a combination therapy targeting the elements of this feed-forward loop provide a novel therapy for allergic disease?. We have used immunohistochemistry, enzyme immunoassay, and cytoplasmic calcium ion (Ca(2+)) imaging to address these questions on cultured and acutely isolated human mast cells from patients with polyposis.. Ca(2+) entry through store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels in polyps produced LTC(4) in a manner dependent on protein kinase C. LTC(4) thus generated activated mast cells through cysteinyl leukotriene type I receptors. Hence Ca(2+) influx into mast cells stimulates LTC(4) production, which then acts as a paracrine signal to activate further Ca(2+) influx. A combination of a low concentration of both a CRAC channel blocker and a leukotriene receptor antagonist was as effective at suppressing mast cell activation as a high concentration of either antagonist alone.. A drug combination directed against CRAC channels and leukotriene receptor antagonist suppresses the feed-forward loop that leads to aberrant mast cell activation. Hence our results identify a new potential strategy for combating polyposis and mast cell-dependent allergies.

Topics: Acetates; Arachidonate 5-Lipoxygenase; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Cyclopropanes; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Mast Cells; Nasal Polyps; Quinolines; Receptors, Leukotriene; Sulfides; Thapsigargin

5-lipoxygenase (5-LO) is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA). Here, we examined the role of the 5-LO-product, cysteinyl-LT (Cys-LT), with a 5-LO inhibitor (zileuton) and a Cys-LT, receptor antagonist (montelukast), in the inflammatory response and tissue injury associated with spinal cord injury (SCI).. SCI was induced in mice by the application of vascular clips to the dura via a two-level T6 to T7 laminectomy for 1 min. Cord inflammation was assessed histologically and by measuring inflammatory mediators (ELISA) and apoptosis by annexin V, TUNEL, Fas ligand staining and Bax and Bcl-2 expression (immunohistochemistry and western blots). Motor function in hindlimbs was assessed by a locomotor rating scale, for 10 days after cord injury.. SCI in mice resulted in tissue damage, oedema, neutrophil infiltration, apoptosis, tumour necrosis-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) expression, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) production, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in injured tissue. Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury, neutrophil infiltration, TNF-alpha, COX-2 and pERK1/2 expression, PGE(2) and LTB(4) production, and apoptosis. In separate experiments, zileuton or montelukast significantly improved the recovery of limb function over 10 days.. Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI. Our data underline the important role of 5-LO and Cys-LT in neurotrauma.

Topics: Acetates; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Cyclooxygenase 2; Cyclopropanes; Cysteine; Dinoprostone; Disease Models, Animal; Gene Expression Regulation; Hydroxyurea; Inflammation; Leukotrienes; Lipoxygenase Inhibitors; Male; Mice; Neutrophil Infiltration; Quinolines; Recovery of Function; Spinal Cord Injuries; Sulfides; Tumor Necrosis Factor-alpha

Pain is commonly associated with inflammation. Several mediators including prostaglandins have been implicated in pain and inflammation. However, the recent reports indicated the role of leukotrienes as signaling molecules in pain. The present study was aimed to evaluate the effect of 5-LOX inhibitor, zileuton in nociceptive paradigms including inflammatory pain. Acetic acid-induced writhing, tail flick and hot plate tests to assess pain response were used. The effect on carrageenan-induced mechanical hyperalgesia, and acetic acid-induced vascular permeability was also determined. Zileuton (ED50=31.81 mg/kg p.o.), zafirlukast (ED50=6.19 mg/kg p.o.), montelukast (ED50=7.17 mg/kg p.o.) inhibited acetic acid-induced writhing in mice. Further, zileuton and ZK 158252, leukotriene B4 receptor antagonist did not alter basal response against tail flick and hot plate assays. Acetic acid-induced vascular permeability was significantly inhibited by zileuton. Oral administration of zileuton showed efficacy against carrageenan-induced mechanical hyperalgesia and also reversed histological changes in paw biopsies. These data suggest that zileuton, a 5-LOX inhibitor, exhibited antinociceptive effect in paradigms of inflammatory pain.

Topics: Acetates; Acetic Acid; Analgesics; Animals; Capillary Permeability; Carrageenan; Cyclopropanes; Dose-Response Relationship, Drug; Female; Hindlimb; Hydroxyurea; Hyperalgesia; Indoles; Inflammation; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Mice; Pain; Pain Measurement; Phenylcarbamates; Quinolines; Rats; Rats, Wistar; Receptors, Leukotriene B4; Sulfides; Sulfonamides; Tosyl Compounds

The introduction of leukotriene modifiers, the first novel class of medications for asthma in more than 2 decades, provided an opportunity to evaluate the clinical context in which patients receive new treatments. Because milder asthma is usually controllable with more familiar medications, we hypothesized that adults with asthma would receive leukotriene modifiers for more severe disease.. We conducted a prospective, longitudinal, 18-month cohort study of 349 patients with asthma. We evaluated the association of baseline self-reported medication use and measures of asthma severity. We also examined the impact of baseline measurement of asthma severity on incident leukotriene modifier use at follow-up.. At baseline, 39 (11%) of 349 patients reported leukotriene modifier use during the previous 2 weeks (95% confidence interval [CI], 8%-15%). Adults with asthma who reported recent use of leukotriene modifiers were more likely to indicate use of other long-term controller medications for asthma, such as inhaled corticosteroids (80% vs 57%;P =.007). Leukotriene modifier use was also associated with poorer severity-of-asthma scores (mean score difference, 3.6 points; 95% CI, 1.7-5.2 points) and asthma-specific health-related quality of life (mean score difference, 8.1 points; 95% CI, 3.4-12.8 points). Leukotriene modifier users were also more likely to indicate a recent emergency department visit (odds ratio [OR], 2.3; 95% CI, 0.9-5.6) or hospitalization for asthma (OR, 4.1; 95% CI, 1.4-11.4). Greater baseline asthma severity was associated with an increased probability of new-onset leukotriene modifier use during 18-month follow-up. Poorer baseline severity-of-asthma scores and asthma-specific quality-of-life scores were related to a greater likelihood of leukotriene modifier use at follow-up (OR per SD-sized score increment, 2.0; 95% CI, 1.4-2.7; OR, 1.8; 95% CI, 1.3-2.5; respectively). Recent hospitalization for asthma at baseline was also associated with a greater likelihood of leukotriene modifier use at follow-up (OR, 4.9; 95% CI, 1.6-14.8).. Adults with asthma who receive leukotriene modifiers have more severe asthma.

Topics: Acetates; Adult; Anti-Asthmatic Agents; Asthma; Cyclopropanes; Female; Health Status Indicators; Hospitalization; Humans; Hydroxyurea; Leukotriene Antagonists; Logistic Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Quinolines; Sulfides

Hepatorenal syndrome (HRS) is a peculiar form of progressive renal failure complicating the course of cirrhosis and ascites. The renal impairment of HRS is merely functional and potentially reversible. Notwithstanding, in spite of several encouraging attempts, a satisfactory medical treatment for HRS is still expected. Several pathophysiological mechanisms are active in HRS. Arachidonate metabolism derangements are among these, and prostaglandins and thromboxane antagonists have been tried with variable outcomes. Also leukotrienes (LT) appear to be involved in HRS. Three drugs (zileuton, montelukast and zafirlukast) interfering with LT synthesis and receptor binding are currently available, but they have not yet been tried in HRS. Accordingly, the author would like to suggest physicians engaged in care of these critical patients to consider a trial with these drugs-as well as with any future innovative agent active on the arachidonate-derived metabolic pathways.

Topics: Acetates; Arachidonic Acid; Cyclopropanes; Hepatorenal Syndrome; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotrienes; Liver; Phenylcarbamates; Protein Structure, Tertiary; Quinolines; Sulfides; Sulfonamides; Thromboxanes; Tosyl Compounds

This article presents information on the safety of zafirlukast, montelukast, and zileuton, three antileukotrienes (anti-LTs) approved in the United States for the prophylaxis and treatment of asthma. After reading this article, readers should have an understanding both of the general safety of anti-LTs and their specific adverse effects.. Relevant and appropriate controlled clinical studies on the safety of anti-LTs in asthma were used. Only literature in the English language was reviewed.. Material was taken from academic/scholarly journals and appropriate reviews.. Antiasthma agents, including corticosteroids, beta2-agonists, and methylxanthines, may be categorized into two classes: those used for the long-term control and prevention of persistent asthma and those used for the prompt relief of acute symptoms and exacerbations of the disease. Although most agents are safe and well tolerated when used properly, adverse effects may occur with use at higher dose levels. The anti-LTs, including zafirlukast, montelukast, and zileuton, are the first new pharmacologic class in the therapeutic armamentarium for asthma management to be approved in the United States in the past 20 years. Both zafirlukast and montelukast carry pregnancy category B classification whereas zileuton carries pregnancy category C classification. The most common adverse effects observed in clinical trials were headache, pharyngitis, abdominal pain, dyspepsia, and cough.. The results of clinical trials and real-world experience indicate that these agents are generally safe and well tolerated, with an incidence of adverse effects comparable with placebo.

Topics: Acetates; Asthma; Churg-Strauss Syndrome; Clinical Trials as Topic; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds

Topics: Acetates; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adult; Albuterol; Asthma; Bronchial Spasm; Child; Cromolyn Sodium; Cyclopropanes; Exercise; Female; Growth Disorders; Humans; Hydroxyurea; Indoles; Ipratropium; Lactation; Leukotriene Antagonists; Nebulizers and Vaporizers; Nedocromil; Phenylcarbamates; Pregnancy; Pregnancy Complications; Quinolines; Salmeterol Xinafoate; Sulfides; Sulfonamides; Theophylline; Tosyl Compounds

Topics: Abnormalities, Drug-Induced; Acetates; Administration, Inhalation; Administration, Intranasal; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Budesonide; Chlorpheniramine; Cyclopropanes; Ephedrine; Female; Histamine H1 Antagonists; Humans; Hydroxyurea; Hypersensitivity; Indoles; Ipratropium; Leukotriene Antagonists; Metaproterenol; Nasal Decongestants; Nebulizers and Vaporizers; Nedocromil; Phenylcarbamates; Pregnancy; Pregnancy Complications; Quinolines; Salmeterol Xinafoate; Sulfides; Sulfonamides; Terbutaline; Tosyl Compounds; Tripelennamine

Leukotriene-modifying drugs are novel agents introduced recently to treat asthma. Both 5-lipoxygenase inhibitors, such as zileuton, and leukotriene receptor antagonists, such as zafirlukast and montelukast, have proved effective in the treatment of asthma. To our knowledge, there have been no detailed reports regarding dermatologic manifestations of this class of drugs. This article describes an unusual case of erythema nodosum in a 46-year-old asthmatic man who received 2 different leukotriene modifiers.

Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Cyclopropanes; Diagnosis, Differential; Erythema Induratum; Humans; Hydroxyurea; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Middle Aged; Panniculitis, Nodular Nonsuppurative; Quinolines; Sulfides

Topics: Acetates; Administration, Inhalation; Administration, Oral; Adolescent; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Albuterol; Asthma; Bone Density; Bronchial Spasm; Bronchodilator Agents; Child; Child, Preschool; Choice Behavior; Cromolyn Sodium; Cyclopropanes; Exercise; Female; Growth; Humans; Hydroxyurea; Indoles; Infant, Newborn; Ipratropium; Lactation; Leukotriene Antagonists; Phenylcarbamates; Pregnancy; Pregnancy Complications; Quinolines; Salmeterol Xinafoate; Sulfides; Sulfonamides; Tachycardia; Theophylline; Tosyl Compounds

Topics: Acetates; Anti-Asthmatic Agents; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds; Treatment Outcome