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Hospital Pharmacy Nov 2015This feature is extracted from a publication available from Wolters Kluwer Health. is a practitioner-oriented resource for information about specific drug uses that...
This feature is extracted from a publication available from Wolters Kluwer Health. is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding to [email protected].
PubMed: 27729674
DOI: 10.1310/hpj5010-873 -
Toxicology and Applied Pharmacology Dec 2020Atherosclerosis (AS), a common arterial disease, is one of the main pathological roots of cardiovascular disease. The formation and accumulation of foam cells is an...
Atherosclerosis (AS), a common arterial disease, is one of the main pathological roots of cardiovascular disease. The formation and accumulation of foam cells is an important event in early AS. An imbalance between cholesterol uptake and efflux is the primary cause of foam cell formation. Although research has focused on preventing the formation of foam cells, a safe and effective therapy has to be found. Zafirlukast is a widely useful type 1 cysteinyl leukotriene receptor (CysLT1R) antagonist with a good safety profile. Zafirlukast is the most used for the treatment of asthma and allergic rhinitis. However, the effect of zafirlukast on preventing the formation of foam cells has not been determined. The aim of this study was to investigate whether zafirlukast prevented macrophages from transforming into foam cells. Our data show that zafirlukast reduced the expression of CD36 and lipoprotein receptor-1 (LOX-1), which are responsible for lipid uptake. In addition, zafirlukast enhanced the activity of ATP-Binding Cassette A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), leading to the acceleration of cholesterol efflux. Furthermore, zafirlukast influenced the activity of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, which mediates the expression of ABCA1 and ABCG1. In summary, our data indicate that zafirlukast might be a potential treatment strategy for AS by mediating lipid metabolism and preventing the formation of foam cells.
Topics: ATP-Binding Cassette Transporters; Animals; Atherosclerosis; Biological Transport; Cell Line; Foam Cells; Indoles; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Mice; Phenylcarbamates; RAW 264.7 Cells; Signal Transduction; Sulfonamides; Tosyl Compounds
PubMed: 33096109
DOI: 10.1016/j.taap.2020.115295 -
Drugs 2001Zafirlukast is a selective and competitive orally administered inhibitor of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The drug is indicated for the prophylaxis and... (Review)
Review
UNLABELLED
Zafirlukast is a selective and competitive orally administered inhibitor of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The drug is indicated for the prophylaxis and treatment of chronic asthma, and has been developed in response to mounting evidence indicating the importance of the cysteinyl leukotrienes in the pathogenesis of this disorder. The efficacy of zafirlukast 20 mg twice daily has been shown in double-blind placebo-controlled studies of up to 13 weeks' duration in patients aged > or = 12 years. Zafirlukast was consistently superior to placebo in improving objective measures of lung function and subjective measures such as symptom scores and use of as-required bronchodilator therapy. This dosage is also as effective when added to low-dosage inhaled corticosteroid therapy as doubling of corticosteroid dosages. Recent studies indicate superior efficacy over zafirlukast of twice-daily inhaled fluticasone propionate 88 microg or salmeterol 42 microg, although zafirlukast was nevertheless associated with clinical improvement. Data also show zafirlukast 40 mg to be of similar efficacy to pranlukast 225 mg (both twice daily). Overall, preliminary pharmacoeconomic data suggest that healthcare costs are reduced by zafirlukast therapy, although superior cost effectiveness has been reported with inhaled fluticasone propionate. and further studies are needed. Data are available to show improvements in patient-rated quality of life, and preference for and high rates of compliance with zafirlukast. In clinical trials, zafirlukast has shown an adverse event profile similar to that of placebo. Isolated reports of hepatic dysfunction in a small number of individuals receiving the drug have been received, and recommendations for monitoring of patients are in place. Although no causal relationship has been established between zafirlukast and Churg-Strauss Syndrome, patients undergoing corticosteroid dosage reductions require careful surveillance.
CONCLUSIONS
zafirlukast is an effective and well tolerated agent for preventive monotherapy in mild to moderate persistent asthma. Emerging data indicate benefit of the drug when added to low-dosage inhaled corticosteroids and show that it may be a viable alternative to inhaled adjunctive treatments and increased corticosteroid dosages in some patients. Although inhaled fluticasone propionate and salmeterol have been associated with greater clinical improvement than zafirlukast in clinical studies, compliance considerations and the confirmed clinical efficacy relative to placebo of the drug denote zafirlukast as an effective alternative in treatment programmes based on individualised therapy. As experience with zafirlukast accumulates, it is expected that the drug will be positioned more definitively in national and international treatment guidelines.
Topics: Administration, Inhalation; Adolescent; Adult; Aged; Albuterol; Anti-Asthmatic Agents; Asthma; Child; Child, Preschool; Chromones; Humans; Indoles; Leukotriene Antagonists; Middle Aged; Phenylcarbamates; Salmeterol Xinafoate; Sulfonamides; Tosyl Compounds
PubMed: 11270943
DOI: 10.2165/00003495-200161020-00012 -
Drugs of Today (Barcelona, Spain : 1998) Apr 1998Cysteinyl-leukotrienes are important mediators in the pathogenesis of asthma. Zafirlukast is a selective and competitive leukotriene receptor antagonist that has been...
Cysteinyl-leukotrienes are important mediators in the pathogenesis of asthma. Zafirlukast is a selective and competitive leukotriene receptor antagonist that has been developed for the treatment of asthma. It inhibits exercise-induced asthma, both the early- and late-phase response after allergen challenge in asthmatic subjects, and aspirin-induced asthma in aspirin-sensitive asthmatic patients. Published data indicate that zafirlukast 20 mg twice daily causes an improvement in lung function (FEV(1) and peak expiratory flow measurements) and symptom control, together with a reduction in the use of short-acting beta-agonist inhaled therapy in patients with mild to moderate asthma. Studies presented in abstract form have shown that zafirlukast 20 mg twice daily had similar efficacy as sodium cromoglycate aerosol or dry powder inhalation; in one of the studies, no advantage of the active drugs was reported over placebo. Compared to inhaled beclomethasone dipropionate therapy (200-250 microg b.i.d.), improvements in morning peak flow, FEV(1) and daytime symptom score were significantly less with zafirlukast 20 mg twice daily than with inhaled steroids. A steroid-sparing effect of zafirlukast (20 mg b.i.d.) was not observed in studies of 12-20 weeks duration in patients on inhaled steroid therapy. A significant improvement in lung function and symptom control was observed on addition of zafirlukast 80 mg twice daily in symptomatic patients maintained on high-dose inhaled steroid therapy. Meta-analysis of 5 large studies indicate that there is a significant reduction in the number of asthma exacerbations compared to placebo. Zafirlukast at 20 mg twice daily dosage appears to be well-tolerated comparable to placebo. High doses of 80 mg twice daily have been associated with reports of elevated liver enzymes. Zafirlukast is a useful addition to existing antiasthma therapies. It may be used in combination with inhaled or oral corticosteroid therapy. Further investigation of its efficacy and antiinflammatory effects will clarify its use as a first-line antiinflammatory agent in mild asthma. Zafirlukast is administered orally and may therefore be useful in patients poorly compliant with inhaled steroid therapy and with a poor inhaler technique.
PubMed: 15010725
DOI: 10.1358/dot.1998.34.4.472184 -
Drugs Jan 1998Zafirlukast is a competitive and selective leukotriene receptor antagonist indicated for the prophylaxis and treatment of chronic asthma. The rationale for the... (Review)
Review
Zafirlukast is a competitive and selective leukotriene receptor antagonist indicated for the prophylaxis and treatment of chronic asthma. The rationale for the development of leukotriene antagonists was based on in vitro and in vivo data demonstrating the extensive role of the cysteinyl leukotrienes C4 (LTC4), D4 (LTD4) and E4 (LTE4) in the pathogenesis of asthma. Initial data have demonstrated an improvement in pulmonary function and symptom control and a reduction in the use of short-acting inhaled beta 2-adrenoceptor agonist therapy in patients with mild to moderate asthma treated with oral zafirlukast at the recommended dosage of 20 mg twice daily. Available data also suggest that zafirlukast may significantly reduce the incidence of asthma exacerbations. Data on the comparative efficacy of zafirlukast and existing antiasthma medications are limited. Results from 2 double-blind randomised studies comparing zafirlukast 20 mg twice daily with sodium cromoglycate aerosol or dry powder inhalation reported similar efficacy for both drugs. In a comparison with inhaled beclomethasone dipropionate (0.2 to 0.25 mg twice daily), improvements in morning peak expiratory flow rate, forced expiratory volume in 1 second and daytime symptom score were significantly less with zafirlukast 20 mg twice daily for 6 weeks. However, available data suggest that patient compliance and patient preference may be greater with oral zafirlukast 20 mg twice daily than with twice-daily inhaled corticosteroid therapy. Confounding results from 2 studies preclude any clear conclusions regarding the potential steroid-sparing effect of zafirlukast at the recommended dosage of 20 mg twice daily. Furthermore, Churg-Strauss syndrome has been reported in 6 patients who were being withdrawn from oral corticosteroid therapy while receiving treatment with oral zafirlukast. It is, therefore, recommended that zafirlukast-treated patients who require a reduction in their oral corticosteroid therapy are closely monitored. Zafirlukast is generally well tolerated. Reports of elevated liver enzymes in patients receiving high dosages of zafirlukast (80 mg twice daily) preclude the use of dosages exceeding 40 mg twice daily. Careful monitoring is necessary in zafirlukast-treated patients receiving concomitant therapy with drugs such as warfarin, terfenadine and erythromycin because of the potential for drug interactions. Thus, zafirlukast is a potentially useful addition to current antiasthma therapies in patients with mild to moderate asthma. Because zafirlukast is administered orally, it may be particularly beneficial in patients poorly compliant with asthma therapy as a result of poor inhaler technique. Further investigation of the efficacy of zafirlukast is expected to more clearly define its position in the management of asthma.
Topics: Anti-Asthmatic Agents; Asthma; Clinical Trials as Topic; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Sulfonamides; Tosyl Compounds
PubMed: 9463793
DOI: 10.2165/00003495-199855010-00008 -
Clinical Pharmacokinetics 2002Zafirlukast is a cysteinyl leukotriene type 1 receptor antagonist that causes bronchodilation and has anti-inflammatory properties. Clinical efficacy has been... (Review)
Review
Zafirlukast is a cysteinyl leukotriene type 1 receptor antagonist that causes bronchodilation and has anti-inflammatory properties. Clinical efficacy has been demonstrated when using oral doses of 20 to 40 mg twice daily. The pharmacokinetics of zafirlukast are best described by a two-compartment model. Maximum plasma concentrations (Cmax) were achieved 3 hours after a single oral dose of 20 or 40 mg to healthy volunteers. The absolute bioavailability of zafirlukast is unknown. However, coadministration of zafirlukast with food reduces bioavailability by approximately 40%. The drug binds to plasma proteins (>99%), predominantly to albumin, and has a mean terminal elimination half-life of approximately 10 hours in both healthy volunteers and patients with asthma. Zafirlukast undergoes extensive hepatic metabolism. Hydroxylation by cytochrome P450 (CYP) 2C9 is the major biotransformation pathway. The metabolites of zafirlukast contribute little to its overall activity. Zafirlukast is mainly eliminated in the faeces, while urinary excretion accounts for <10% of an orally administered dose. Because of its primarily hepatic metabolism, the clearance of zafirlukast is reduced in patients with hepatic impairment. In patients with stable alcoholic cirrhosis, Cmax and area under the plasma concentration-time curve for zafirlukast were increased by 50 to 60% compared with healthy volunteers. Asymptomatic elevations of serum liver enzymes have been reported with high dosages of zafirlukast (80 mg twice daily), returning to normal after cessation of the drug. Inhibition of the CYP2C9 and CYP3A isoenzymes by zafirlukast has been reported in vitro. Zafirlukast interacts with warfarin and produces a clinically significant increase in the prothrombin time, but it does not alter the pharmacokinetics of terfenadine carboxylate, the active metabolite of terfenadine. Plasma concentrations of zafirlukast decreased when the drug was administered concomitantly with erythromycin, terfenadine or theophylline, and increased when it was coadministered with aspirin (acetylsalicylic acid). Theophylline metabolism is unchanged in most cases by zafirlukast, but there is a report of one patient with increased theophylline plasma concentrations when zafirlukast was coadministered. Recently, cases of Churg-Strauss syndrome have been described in patients with asthma receiving zafirlukast treatment. This occurrence in patients being withdrawn from corticosteroid therapy while receiving zafirlukast has been attributed to a previously undiagnosed presence of this syndrome in these patients.
Topics: Anti-Asthmatic Agents; Asthma; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Indoles; Phenylcarbamates; Sulfonamides; Tosyl Compounds
PubMed: 11888331
DOI: 10.2165/00003088-200241020-00003 -
The Annals of Pharmacotherapy Sep 1997To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of zafirlukast. Therapeutic issues regarding the use of a leukotriene-receptor... (Review)
Review
OBJECTIVE
To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of zafirlukast. Therapeutic issues regarding the use of a leukotriene-receptor antagonist as prophylactic antiinflammatory therapy for asthma are also discussed.
DATA SOURCES
A MEDLINE search was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Pharmacokinetic and dosing information were abstracted from the product labeling.
STUDY SELECTION
All available published articles describing double-blind, placebo-controlled trials of both oral and aerosol zafirlukast in patients with asthma or rhinitis were reviewed. These included single-dose studies with zafirlukast against exercise, allergen, leukotriene D4 (LTD4), and platelet-activating factor (PAF) challenges, and 6- and 13-week trials in patients with asthma. Studies describing clinical trials with long-term use or comparisons with other asthma medications as reported in abstracts are also included.
DATA EXTRACTION
Information on the safety and efficacy of zafirlukast from single- and multiple-dose studies was evaluated on the basis of statistical significance relative to placebo treatment.
DATA SYNTHESIS
Zafirlukast, a potent and selective antagonist of the cysteinyl leukotriene receptor, blocks leukotriene-mediated pathologic events in both experimental animal and clinical disease models. Zafirlukast antagonizes LTD4-, PAF-, and exercise-induced bronchoconstriction, and blocks both early- and late-phase responses following allergen provocation in patients with atopic asthma. Greater efficacy is noted following oral administration than with aerosol dosing, presumably because of the enhanced delivery of drug when ingested rather than inhaled.
CONCLUSIONS
Zafirlukast is the first orally active leukotriene-receptor antagonist approved by the Food and Drug Administration for the prophylactic and chronic treatment of asthma. Since the leukotrienes play an important role in the underlying inflammatory processes of asthma, zafirlukast represents a new antiinflammatory option available in an oral dosage form. It is clear that this agent has therapeutic activity in patients with asthma, but its effectiveness relative to other antiasthma medications still needs confirmation. Data from clinical studies support the use of zafirlukast as first-line therapy in patients with mild-to-moderate asthma. Further research is needed to establish its role as an add-on agent for patients with severe asthma, aspirin-sensitive asthma, and both allergies and asthma. In addition to having a favorable safety and efficacy profile, zafirlukast has the advantage of being an oral agent with twice-daily dosing; these attributes offer the potential for greater patient adherence to pharmacotherapy and, thereby, improved control of asthma symptoms.
Topics: Animals; Anti-Asthmatic Agents; Asthma; Clinical Trials as Topic; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Sulfonamides; Tosyl Compounds
PubMed: 9296243
DOI: 10.1177/106002809703100912