Use Of Montelukast Research Articles

Review of recent results of montelukast use as a monotherapy in children with mild asthma

Background: Asthma is a chronic disease with a heterogeneous phenotype that is often associated with allergic sensitization in childhood. The earliest definable form of asthma is mild (intermittent or persistent), a severity level that may be characteristic of a majority of children with asthma. Several asthma controllers are indicated for use in children. International guidelines recommend the use of inhaled corticosteroids as the preferred controller therapy in mild persistent asthma. Objective: This article reviewed recent results from randomized, double-blind studies of children with mild asthma treated with montelukast, a leukotriene receptor antagonist that is approved for the treatment of asthma and allergic rhinitis in children and adults. Methods: A literature search of MEDLINE was conducted to gather relevant, English-language articles using search terms such as randomized controlled studies, double-blind studies, montelukast, leukotriene receptor antagonist, pediatric asthma, mild asthma, exercise-induced asthma, and bronchoconstriction. Recent articles (since 1998) that described the use of montelukast as a monotherapy were chosen for this review. Results: Releevant studies included a 48-week, placebo-controlled study of 2- to 5-year-old mild intermittent asthmatics (N = 549); a 12-week, placebo-controlled study of 2- to 5-year-old mild persistent asthmatics (N = 689); an analysis of a mild persistent asthmatic cohort (N = 138) from an 8-week, placebo-controlled study of 6- to 14-year-old asthmatics; a 12-month study comparing montelukast with fluticasone in 6- to 14-year-old mild persistent asthmatics (N = 949); and 3 placebo-controlled studies in children with exercise-induced asthma (N = 123). The results from these studies, encompassing end points measuring lung function and symptoms, found that montelukast provided effective and beneficial asthma control to children aged 2 to 14 years with mild asthma. Conclusion: The evidence suggests that montelukast is an effective monotherapy controller in children with mild asthma.

A double‐blind, placebo‐controlled trial of montelukast in adult atopic eczema

Montelukast is an antagonist of cys-leukotriene receptors used mainly in the treatment of asthma- and seasonal-allergic rhinitis. Initial reports concerning the use of montelukast in atopic dermatitis (AD) have been encouraging, although not consistent. We have undertaken a randomized, double-blind, parallel-group, placebo-controlled trial to investigate further the efficacy of montelukast in the treatment of atopic eczema. Following a screening visit, subjects received placebo treatment for 2 weeks in a single-blind phase, followed after visit 2 by an 8-week, double-blind period of treatment with montelukast 10 mg daily or placebo. Subjects were patients aged 16-60 years under our care for treatment of AD of moderate severity, defined by a six-area, six-sign atopic dermatitis (SASSAD) score in the range 12-50. Response to treatment was assessed by investigators and by subjects using a seven-point scale, with response defined as marked improvement or better. In addition, the SASSAD score was used to monitor the severity of clinical signs. The proportion of skin involved was estimated and visual analogue scales were used to record the severity of pruritus and sleep disturbance. Topical corticosteroid usage was recorded using a five-point scale. Adverse events were recorded. Sixty subjects were recruited and 54 completed the study. The treatment groups were well matched for disease severity at baseline (SASSAD scores were 25 and 29 in the montelukast and placebo groups, respectively). There were no significant differences between the treatment groups in any of the parameters used to assess treatment response. The improvement in mean SASSAD score from baseline (visit 2) to the end of treatment was marginally superior in the placebo group, 1.41 points on montelukast vs. 1.76 on placebo, a difference of 0.35 (95% confidence interval -6.1 to 6.8). Adverse events were generally of a mild nature except for a brief septicaemic illness in one subject receiving montelukast. The data do not support previous reports of efficacy of montelukast in treatment of AD.

Visual Vignette

A 36-year-old woman was referred to the endocrinology clinic for further evaluation of acne, abdominal striae, and cushingoid features. Other problems included depression, hypothyroidism, connective tissue disease, mild type 2 diabetes, and bronchial asthma that had been controlled by use of montelukast and inhalers (including a corticosteroid inhaler). She was not receiving systemic or other forms of corticosteroids. She was taking levothyroxine, metformin, and other medications for her fibromyalgia and depression. Physical examination confirmed the presence of acne, abdominal striae, and cushingoid features. An abdominal computed tomographic scan (Fig. 1) had been performed before her current consultation. What is the structure to which the arrow points? What is the diagnosis?

Sparing Effect by Montelukast Treatment for Chronic Graft Versus Host Disease: A Pilot Study

Chronic graft versus host disease (GvHD) is a major complication after allogeneic stem cell transplantation (SCT), which is usually progression from acute GvHD. Chronic GvHD is the main cause of severe morbidity and mortality in long-term survivors after SCT. The cysteinyl leukotrienes (cysLTs) and eosinophils play an important role in the pathogenesis of GvHD, which is the rationale for the combined use of montelukast (Mk) in the treatment of this illness. Mk was administrated to 19 eligible patients with refractory chronic GvHD, in addition to their standard immunosuppressive regimens. Mk was given orally (10 mg once daily) for a mean period of 10 months (range, 2-21 months). Organ-specific response was determined by the new scoring criteria established by the National Institutes of Health consensus project. Based on organ involvements endpoints, overall response to the combined therapy with Mk was observed in 15 of 19 (79%) patients. Significant improvement of skin liver and gastrointestinal was observed in 53%, 62%, and 46%, respectively. Generally, Mk was notably beneficial in milder stages of GvHD, which lead to earlier withdrawal of other immunosuppressive agents. Side effects of Mk administration were not documented, nor were cases of relapse of the basic disease. Our preliminary prospective investigation supports the potential efficacy of Mk as a safe and toxicity-sparing supplement to standard therapy for patients with chronic GvHD. Future clinical studies are necessary to establish the optimal dose of Mk and its role in the symptomatic and prophylactic treatment of acute and chronic GvHD.

Montelukast in the Treatment of Allergic Rhinitis

Cysteinyl-leukotrienes (CysLTs) are endogenous mediators of inflammation and play an important role in allergic airway disease by stimulating bronchoconstriction, mucus production, mucosal oedema and inflammation, airway infiltration by eosinophils, and dendritic cell maturation that prepares for future allergic response. Montelukast inhibits these actions by blocking type 1 CysLT receptors found on immunocytes, smooth muscle and endothelium in the respiratory mucosa. Initially developed as a treatment for asthma, montelukast has more recently found use in the treatment of allergic rhinitis (AR). We conducted a systematic review of studies that have evaluated montelukast in the treatment of seasonal AR (SAR) and perennial AR (PAR), with and without concomitant asthma. Primary consideration was given to large, randomised, placebo-controlled, double-blind clinical trials in which AR endpoints were assessed and the use of concurrent treatments for AR was excluded. Eight such studies were found in the literature. The primary endpoint in these was daytime nasal symptom severity represented by a composite score derived from individual self-ratings of nasal congestion, rhinorrhoea, nasal pruritus and sneezing. Secondary endpoints have included these individual nasal symptom scores, additional scores for eye, ear and throat symptoms, the impact of rhinitis on quality of sleep, global evaluations of outcome by patients and physicians, and measures of the severity of concomitant asthma. A general outcome was that patients treated with montelukast had significantly greater improvements in their symptoms of SAR and PAR than did patients who were given a placebo. As monotherapy, montelukast exhibited efficacy similar to that of loratadine, but less than that of the intranasally administered corticosteroid fluticasone propionate. The use of montelukast in combination with antihistamines such as loratadine or cetirizine has generally resulted in greater efficacy than when these agents were used alone, and in some studies has produced results comparable with intranasally applied corticosteroids. In patients with AR comorbid with asthma, montelukast treatment has resulted in significant improvements in both, compared with placebo. Montelukast is well tolerated and has a favourable safety profile; adverse events have occurred at similar frequencies in patients taking either montelukast or placebo. Montelukast provides an effective and well tolerated oral treatment for allergic airway inflammation in patients with SAR or PAR without asthma, and in patients in whom AR is comorbid with asthma.

Montelukast with desloratadine or levocetirizine for the treatment of persistent allergic rhinitis

Montelukast sodium is approved as a treatment for intermittent and persistent allergic rhinitis (AR), but it has not been evaluated as combined therapy with antihistamines for persistent AR. To investigate the effects of 6 weeks of treatment of persistent AR with desloratadine, levocetirizine, or montelukast alone or in combination. A randomized, double-blind, placebo-controlled crossover study was performed. Patients were assigned to 2 arms: 20 received montelukast, 10 mg/d, desloratadine, 5 mg/d, or both or placebo and 20 received montelukast, levocetirizine, or both, 5 mg/d, or placebo. The treatment periods were separated by 2-week washout periods. Symptom scoring, skin prick tests, spirometry, rhinometry, and nasal lavage were performed the day before and the last days of the treatment periods. Eosinophil cationic protein levels were evaluated by means of nasal lavage. The mean +/- SD total baseline nasal symptom score was 7.7 +/- 0.49 before treatment, 3.74 +/- 0.54 after desloratadine use, 3.6 +/- 0.48 after montelukast use, and 3.04 +/- 0.4 after montelukast-desloratadine use. The mean +/- SD baseline nasal symptom score was 7.95 +/- 0.68 before treatment, 3.02 +/- 0.64 after levocetirizine use, 3.44 +/- 0.55 after montelukast use, and 2.14 +/- 0.39 after montelukast-levocetirizine use. The greatest improvement in nasal symptoms occurred after combination treatment. Decreases in the level of eosinophil cationic protein were greater after the combined use of montelukast and antihistamine than after each agent given alone. For persistent AR, the combination of montelukast and either desloratadine or levocetirizine is more effective than monotherapy with these agents.

Montelukast, Compared With Fluticasone, for Control of Asthma Among 6- to 14-Year-Old Patients With Mild Asthma: The Mosaic Study

Purpose of the Study. Per current asthma guidelines, montelukast is considered a suitable alternative to inhaled corticosteroids (ICSs) for the treatment of mild persistent asthma, and this study was conducted to evaluate the use of oral montelukast compared with inhaled fluticasone in children with mild asthma. Study Population. Children (aged 6–14 years) with mild persistent asthma participating in the Montelukast Study of Asthma in Children (MOSAIC) study. Methods. In this 12-month, multicenter, randomized, double-blind, noninferiority comparison study, patients were randomly assigned to receive oral montelukast 5 mg once a day (n = 495) or inhaled fluticasone 100 μg twice a day (n = 499) after an appropriate run-in period. After baseline evaluations, patients were evaluated at 4-month intervals with spirometry and review of an asthma diary card. The primary end point, the percentage of asthma rescue-free days (RFDs), included days with no rescue-medication use and no asthma-related primary care or urgent care visits or hospitalizations. Secondary end points included forced expiratory volume in 1 second (FEV1), use of additional asthma medications, asthma attacks, β-agonist use, and peripheral blood eosinophil levels. Results. The mean percentage of RFDs was 84% in the montelukast group compared with 86.7% in the fluticasone group. The least-squares means difference was −2.8% (95% confidence interval: −4.7% to −0.9%), which represents a difference of <1 day/month. Both montelukast and fluticasone were associated with improvement in FEV1 (percent predicted) from baseline as well as reduction in the percentage of days with β-agonist use, reduction in blood eosinophils, and improvement in patient-perceived asthma control and asthma quality-of-life scores; however, fluticasone was significantly favored in terms of FEV1, β-agonist use, asthma control, and quality of life. Montelukast was associated with the increased use of systemic corticosteroids (17.8% vs 10.5%; P ≤ .001) and a higher percentage of patients with an asthma attack (32.2% vs 25.6%) compared with fluticasone. Conclusions. Montelukast was not inferior to fluticasone in terms of asthma RFDs; however, the use of montelukast was associated with more asthma attacks and more systemic steroid use. FEV1, β-agonist use, and quality of life improved significantly better for those in the fluticasone group. Reviewer Comments. This study represents the first direct comparison between montelukast and an ICS measuring differences in multiple parameters of asthma control in children with mild persistent asthma. This study establishes the noninferiority of montelukast compared with fluticasone in terms of RFDs; however, in terms of FEV1, systemic corticosteroid use, number of asthma attacks and β-agonist use, fluticasone was significantly superior to montelukast. This study underscores the fact that asthma control cannot be determined with just one measure and confirms the role of montelukast as an alternative to ICSs as suggested by the current guidelines. The role of montelukast in future asthma guidelines is currently under investigation. Future studies are needed for evidence-based clinical application.

Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children With Intermittent Asthma

Purpose of the Study. To evaluate the role of montelukast in prevention of viral-induced asthma exacerbations among 2- to 5-year-old children with a history of intermittent asthma. Study Population. A total of 549 children aged 2 to 5 years (from 68 sites in 23 countries) with a history of intermittent wheezing associated with upper respiratory infections. Methods. This was a multicenter, double-blind, parallel-group randomized trial comparing once-daily oral montelukast (4- or 5-mg chewable tablets) with placebo for 12 months. Subjects were required to have been free of symptoms and β-agonist use in a typical week over the 3 months before enrollment. An asthma exacerbation was defined as any 3 consecutive days with daytime symptoms and at least 2 β-agonist treatments per day; rescue use of oral/inhaled corticosteroids during ≥1 days; or a hospitalization because of asthma. The primary efficacy end point was number of exacerbation episodes over 1 year. Numerous secondary outcomes were also measured. Results. Patients in the montelukast group experienced a mean of 1.60 asthma-exacerbation episodes, compared with 2.34 in the placebo group, for a 31.9% rate reduction (P ≤ .001). Other end points with significant differences favoring the montelukast group included time to first exacerbation (median: 206 vs 147 days; P = .0024), rate of inhaled corticosteroid use (39.8% rate reduction; P = .027), and proportion of patients with asthma episodes (45% vs 56%; P = .008). There were no statistically significant differences in rates of oral corticosteroid use, average duration and severity of exacerbations, or proportion of patients who missed time from day care or school. Both groups experienced more exacerbations in the fall and fewer in the summer. Montelukast was well tolerated, and no patient discontinued therapy because of a drug-related adverse event. Conclusions. The authors concluded that once-daily montelukast significantly reduces asthma exacerbations secondary to respiratory tract infections compared with placebo among 2- to 5-year-old children with intermittent asthma and also reduces time to first exacerbation and need for β-agonist or inhaled corticosteroid therapy. There was no difference in severity or duration of episodes, although the authors argue that the study was not specifically designed to detect differences in these end points. Reviewer Comments. This study attempts to address the question of whether a controller medication may be useful in young children who wheeze with colds but are otherwise categorized as mild intermittent or even symptom-free. Asthma guidelines do not endorse use of preventive medications for such children, yet this study suggests that daily montelukast during the respiratory viral season may be useful to reduce exacerbations (although it did not reduce oral steroid use or severity of exacerbations). Montelukast during specified times might be a good option for many young children with intermittent asthma, but the cost/benefit ratio of chronic use is unclear, because the number of wheezing episodes per child was low even in the placebo group. Investigation of episodic use of montelukast with upper respiratory infections would be of interest.

Update on the use of montelukast in pediatric asthma

Cysteinyl leukotrienes are inflammatory bioactive lipids produced by various cells. They are present in increased amounts in airway secretions of all different asthma phenotypes and can induce all the inflammatory changes observed in the airways of asthmatic patients. For this reason, an attempt to inhibit the actions of these mediators through the use of cysteinyl receptor antagonists appears rational. Montelukast belongs to this new class of drugs, which has been proved effective in asthmatic children and its safety profile is comparable with that of placebo. The major advantages of this drug are its once-daily oral administration, which increases adherence to the therapeutic regimen; its long-term persistent efficacy in the prevention of exercise-induced bronchoconstriction; its possible preventive activity on viral-induced asthma exacerbations; and its complementary and additive effects when used with inhaled corticosteroids. As established for all drugs commonly used in the treatment of asthma, there is an interindividual variability also in response to montelukast. Therefore, it is important that caregivers evaluate treatment effect objectively in every asthmatic child to provide the single patient with a therapeutic regimen allowing the best quality of life.

Montelukast Treatment of Urticaria

To review clinical trial data to determine the benefits of using montelukast alone or as combination therapy in the treatment of urticaria. MEDLINE (1966-March 2006) and International Pharmaceutical Abstracts (1970-October 2005) were searched to find clinical trial publications that addressed the use of montelukast in urticaria. Six clinical trials were identified. Montelukast was compared alone and as combination therapy with nonsedating histamine1-receptor antagonists to determine efficacy and safety. Patients had chronic or physical urticaria. The results were mixed. Some studies demonstrated that montelukast can decrease urticarial symptoms with minimal adverse effects, while others found no differences. Large-scale, controlled trials are needed to determine which patients would likely benefit from treatment with montelukast.

Montelukast in pediatric asthma management

Leukotriene modifiers (receptor antagonist and biosynthesis inhibitor) represent the first mediator specific therapeutic option for asthma. Montelukast, a leukotriene receptor antagonist is the only such agent approved for use in pediatric patients. Montelukast modifies action of leukotrienes, which are the most potent bronchoconstrictors, by blocking Cysteinyl leukotriene receptors. Systemic drug like mountelukast can reach lower airways and improves the peripheral functions which play a crucial role in the evolution of asthma. Review of existing literature showed that montelukast compared to placebo has proven clinical efficacy in better control of day time asthma symptoms, percentage of symptom free days, need for rescue drugs and improvement in FEV 1. Studies also demonstrated improvement in airway inflammation as indicated by reduction in fractional exhaled nitric oxide, a marker of inflammation. Studies comparing low dose inhaled corticosteroids (ICS) with montelukast are limited in children and conclude that it is not superior to ICS. For moderate to severe persistent asthma, montelukast has been compared with long acting beta agonists (LABA) as an add-on therapy to ICS, montelukast was less efficacious and less cost-effective. It has beneficial effects in exercise induced asthma and aspirin-sensitive asthma. Montelukast has onset of action within one hour. Patient satisfaction and compliance was better with montelukast than inhaled anti-inflammatory agents due to oral, once a day administration. The recommended doses of montelukast in asthma are- children 1-5 years: 4 mg chewable tablet, children 6-14 years: 5mg chewable tablet, 10mg tablet; administered once daily. The drug is well tolerated. Based on the presently available data montelukast may be an alternative treatment for mild persistent asthma as monotherapy where ICS cannot be administered. It is also an alternative to LABA as an add-on therapy to ICS for moderate to severe persistent asthma. The other indications for use of montelukast include: allergic rhinitis, exercise induced bronchoconstriction and aspirin-induced asthma.

Eosinophilic gastroenteritis in a young girl – long term remission under Montelukast

BackgroundEosinophilic gastrointestinal disorders are an emerging disease entity characterized by eosinophilic infiltration of the intestinal wall. Oral steroids can be still considered as first line treatment. Unfortunately relapses are quite common. Usually long term low-dose prednisone or immunosuppressive therapy is required, which is especially problematic in young patients. Thus a reliable steroid sparing agent with low side effects suitable for long term use is needed. There are strong hints to a similar pathophysiology of eosinophilic gastrointestinal disorders to that of asthma. Indeed leukotriene D4 plays an important role in the recruitment of eosinophils into the intestinal tissue causing damage. This patho-mechanism provides the rationale for the treatment with a leukotriene D4 receptor antagonist. Recently there have been first reports about successful short term use of Montelukast in eosinophilic gastrointestinal disorders.Case presentationWe report the case of a 17 year old girl with a long history of severe abdominal complaints leading to several hospitalizations in the past. Mimicking the picture of an intestinal tuberculosis she received an anti mycobacterial treatment without any success. Marked eosinophilia in blood, ascites and tissue samples of the intestinal tract finally lead to the diagnosis eosinophilic gastroenteritis. Tapering off prednisone caused another severe episode of abdominal pain. At that point leukotriene antagonist Montelukast was started at a dose of 10 mg once daily. Steroids could be tapered off completely within six weeks. The patient has been free of symptoms for over two years by now. Routine examinations, blood tests and endoscopy have rendered regular results. So far no side effects were noted.ConclusionHere report about successful long term remission of eosinophilic gastroenteritis under Montelukast. Further randomized control trials are required to asses the full benefits of Montelukast therapy in the whole spectrum of eosinophilic gastrointestinal disorders.

Pregnancy outcome following gestational exposure to montelukast: A prospective cotrolled study

Background Asthma is the most common respiratory crisis complicating pregnancy. Montelukast is prescribed orally for chronic treatment of asthma. Although animal reproductive studies show no evidence of teratogenic effects, there are no human studies assessing possible effects on the developing fetus with in utero exposure. Despite known risks associated with poorly controlled asthma, lack of safety data prevents women from using montelukast in pregnancy. Our aim is to evaluate pregnancy outcomes following gestational exposure to montelukast. Methods This prospective controlled study enrolls pregnant women who contact Motherisk about exposure to montelukast. These women are followed up using standardized data collection forms. Montelukast-exposed women are compared to a disease-matched group using inhalers for similar indications and a group of women exposed to known non-teratogens. Rates of major anomalies and other adverse outcomes are compared between groups. Results To date, 64 women exposed to montelukast during 1st trimester have been enrolled, of which 24 have used it throughout pregnancy. Outcomes of this group include: 62 (96.9%) live births, 2 (3.1%) SA and 2 (3.1%) major malformations. Upon comparison to controls, no statistical differences are apparent in these or any other endpoints of interest. Conclusions Data collected thus far in this ongoing study appear to suggest no increased risk for major malformations above baseline of 1–3%, following use of montelukast in pregnancy. Clinical Pharmacology & Therapeutics (2005) 77, P30–P30; doi: 10.1016/j.clpt.2004.12.005

Outcomes Associated with Initiation of Different Controller Therapies in a Medicaid Asthmatic Population: A Retrospective Data Analysis

Background. Outcomes in asthmatic patients may vary depending on the controller medication used. Observational studies of outcomes of asthma therapy are needed to understand the implications of choice of controller in different populations. Objectives. To determine whether there are differences in health care use and costs of asthma treatment in asthma patients treated with montelukast compared with fluticasone proponiate 44 µg. Method. Using data from the North Carolina Medicaid program, we compared continuously enrolled asthmatic patients starting either fluticasone propionate 44 µg (FP44), an inhaled corticosteroid (ICS) (n = 312), or montelukast 5 and 10 mg, an oral leukotriene modifier (LM) (n = 398) between the years 1998 and 1999. A secondary analysis compared continuously enrolled asthmatic patients already using ICS as controller therapy initiating either salmeterol (long-acting β-agonist) (n = 97) or montelukast (n = 101) in the year 1998. Patients were followed for 1 year pre- and postcontroller or additional controller initiation for health care service use, medication refill patterns, and costs. Results. There were no significant differences in the adjusted asthma-related health care costs between the montelukast and FP44 groups. In both groups, physician visits were significantly higher in year 2 (p < 0.01) than in year 1. We found montelukast users to be more adherent with prescription refills (using measures of medication possession) even after allowing for a wider adherence range for FP (RR = 2.53; 95% CI = 1.50–4.26), although patients using montelukast were more likely than patients with fluticasone to switch controller pharmacotherapy (RR = 1.53; 95% CI = 1.12–2.09). Similarly, there were no differences in health care service use and costs between the montelukast and salmeterol groups, with the exception of a 33% reduction (p < 0.01) in number of inhaled corticosteroid refills in the second year in the salmeterol group. Conclusion. There were no cost and major health care use differences between the two primary or secondary controller therapies in the postinitiation year. Although FP was associated with lower rate of controller switch, montelukast use was associated with significantly better treatment adherence in patients with treatment persistence in this population of Medicaid-enrolled asthmatic patients. The addition of salmeterol as additional controller was associated with a significant decrease in inhaled corticosteroid use, suggesting decreased adherence in patients on the two-drug regimen.

The national montelukast survey

Randomized controlled trials have demonstrated the efficacy of montelukast for treating asthma; whether this can be extrapolated to clinical effectiveness in routine practice has yet to be established. To examine the use, effectiveness, and tolerability of montelukast in clinical practice for treating asthma and to explore prognostic factors that could predict a favorable response to the drug. This was a retrospective, cross-sectional, observational study of clinical outcomes seen in patients prescribed montelukast for asthma that used routinely collected clinical information. Data were collected on all consenting patients who had been prescribed montelukast for asthma irrespective of the continuation or duration of treatment. Independent observers, treating physicians, and patients assessed certain outcomes after the initiation of montelukast, including the general asthma response and changes in activity-related symptoms. Fifty-six centers in the United Kingdom (20 primary care and 36 secondary care) participated. The analysis was based on 1351 eligible patients for whom essential data were available. Eight hundred thirty patients (66.4%; 95% CI, 63.8% to 69.0%) were recorded as having shown an improvement in their asthma control, and 103 (8.2%; 95% CI, 6.8% to 9.9%) experienced a dramatic improvement. The greatest proportion of patients responding was seen in those with mild to moderate asthma. Montelukast was well tolerated; no new adverse events were recorded. Montelukast is an effective, well-tolerated treatment for asthma in routine practice. The overall response rate and tolerability seen in this survey are similar to those reported in randomized clinical trials.

SELECTIVE INHIBITION OF HUMAN CYTOCHROME P4502C8 BY MONTELUKAST

The leukotriene receptor antagonist montelukast was examined for its inhibition of the human drug-metabolizing enzyme cytochrome P4502C8 (CYP2C8). Montelukast was demonstrated to be a potent inhibitor of CYP2C8-catalyzed amodiaquine N-deethylase, rosiglitazone N-demethylase, and paclitaxel 6alpha-hydroxylase in human liver microsomes. Inhibition was also observed when the reaction was catalyzed by recombinant heterologously expressed CYP2C8. The mechanism of inhibition was competitive, with K(i) values ranging from 0.0092 to 0.15 microM. Inhibition potency was highly dependent on the microsomal protein concentration. Increasing the microsomal protein concentration by 80-fold yielded a 100-fold decrease in inhibition potency. Preincubation of montelukast with human liver microsomes and NADPH did not alter the inhibition potency, suggesting that montelukast is not a mechanism-based inactivator. Montelukast was a selective inhibitor for human CYP2C8; inhibition of other human cytochrome P450 enzymes was substantially less. These in vitro data support the use of montelukast as a selective CYP2C8 inhibitor that could be used to determine the contribution of this enzyme to drug metabolism reactions. These data also raise the possibility that montelukast could have an effect on the metabolic clearance of drugs possessing CYP2C8-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions.

Churg-Strauss Syndrome Development during Asthma Therapy with Leukotriene Receptor Antagonists: Just a Coincidental Association?

A report on our clinical experience based on 3 male patients who developed Churg-Strauss syndrome (CSS) after standard oral montelukast use. All patients affected by moderate asthma and chronic hyperplastic rhinosinusitis were treated with inhaled corticosteroids and ß2 agonists. Systemic corticosteroid treatment consisted in oral daily prednisone in case 1, in short courses of oral betamethasone in case 2, and in remote and isolated administrations of oral betamethasone and intramuscular methylprednisolone in case 3. Because of the improvement of the asthma symptoms after montelukast use, patient 1 decided to take half the dose of prednisone for 10 days and patient 2 decided to discontinue systemic and inhaled corticosteroids for 45 days. Overt CSS was heralded by vasculitic skin lesions and developed in each patient with severe organ damage, consisting in renal, myocardial and gastrointestinal involvement. Remission was obtained by standard CSS therapy after montelukast withdrawal. According to the unmasking hypothesis, antileukotriene treatment, by enabling the reduction in systemic corticosteroid therapy in case 1 and its discontinuation in case 2, might have only permitted the precipitation of the vasculitis. However antileukotriene-associated CSS reportedly occurred in systemic corticosteroid-naïve patients and relapsed in one patient after antileukotriene treatment. These observations lend support to the concept that the precipitation of the vasculitic phase may be associated with leukotriene modifier deleterious effects. In conclusion there is not enough evidence to prove that antileukotriene treatment plays a direct causative role in the pathogenesis of CSS. Further clinical and experimental research is required to clarify the antileukotriene associated CSS controversy.

The use of the leukotriene receptor antagonist montelukast (singulair®) in the management of dysmenorrhea in adolescents

PurposePrevious studies have shown an increase in leukotrienes in the uterine tissue as well as in the menstrual flow of adult women with dysmenorrhea. An increase in leukotriene-E4, the major urinary leukotriene, was also reported in adolescent girls with dysmenorrhea, further suggesting a possible involvement of these potent vasoconstrictors and inflammatory mediators in generating dysmenorrhea symptoms. In the present study we examined whether blocking leukotrienes might alleviate symptoms of dysmenorrhea in adolescents. MethodsTwenty-five adolescents (age 16 ± 1 years, 4 ± 1 years post menarche, body mass index 23 ± 1) with dysmenorrhea participated in a randomized, double blind, crossover study. Thirteen girls received one tablet of montelukast (Singulair®, Merck, West Point, PA) 10 mg daily starting on day 21 of the cycle until the last day of the menstrual period for two menstrual cycles, followed by one tablet of placebo (Merck, West Point, PA) daily starting on day 21 of the cycle until the last day of the menstrual period for two additional menstrual cycles. The other 12 girls had a reverse schedule starting with placebo. Participants were instructed to use one or two 200-mg tablets of ibuprofen every 6 h in the event of continuing menstrual symptoms. The Cox Menstrual Symptom Scale was used to assess response to treatment. An intent-to-treat approach was used for data analysis. ResultsTwenty-two girls completed the study. Two girls were noncompliant with the study protocol, and one was withdrawn because of Helicobacter pylori infection. Compared with Cox menstrual score (mean ± SE) before study (46 ± 6), there was no significant change in menstrual symptoms during treatment with placebo (Cox score 42 ± 7) or during treatment with montelukast (Cox score 39 ± 7), and there was no significant difference between montelukast and placebo treatments as well. Likewise, there was no significant difference between the amount of ibuprofen tablets consumed during the menstrual periods before study (4 ± 1), while on placebo (3 ± 1), and while on montelukast (4 ± 1). ConclusionsThis study does not support the use of montelukast, in the current FDA-approved dose (for asthma) and commencing immediately before the menstrual period, for treatment of dysmenorrhea. It remains to be determined in further studies whether a higher dose or a prolonged daily use of montelukast may alleviate symptoms of dysmenorrhea in adolescents.

A Comparison of Cetirizine and Montelukast for Treating Childhood Perennial Allergic Rhinitis

The purpose of the present study was to compare the efficacy and safety of cetirizine and montelukast use for the treatment of pediatric perennial allergic rhinitis. To this end, 60 perennial allergic rhinitis patients suffering a mite allergy, and aged from 6 to 12 years old, were randomly assigned to one of three treatment groups for a period of 12 weeks; 20 were assigned to the cetirizine group (10 mg daily), 20 to the montelukast group (5 mg daily), and 20 to the placebo group. The effects of the three agents were compared with the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire and participants' nasal symptom score by daily diary card. Nasal peak expiratory flow rate and laboratory examinations were evaluated for members of the three groups. The results revealed that cetirizine and montelukast were efficacious for the total symptom score for weeks 4, 8, and 12 (p < 0.01). Cetirizine was more effective than montelukast for rhinorrhea, nasal congestion, sneezing, and red eyes. The Pediatric...

Preventive Therapy for Asthmatic Children Under Florida Medicaid: Changes During the 1990s

Background: In response to the increasing prevalence and severity of asthma in this country, the National Institutes of Health in 1991 published an expert consensus report Guidelines for the Diagnosis and Management of Asthma. An important aspect of the report included the recommendation that children with moderate asthma may benefit from daily treatment with anti‐inflammatory drugs such as inhaled corticosteroids and cromolyn. Objectives: The objective of this article is to examine changes in prescribing of daily anti‐inflammatory drugs for children covered by Florida Medicaid during two 2‐year periods, the first just after publication of the Guidelines and the second 7 years later; and to estimate adherence to treatment by children who received one of them. Design: The study groups for each of the two 2‐year periods included only children 2 to 18 years old who had medical or institutional claims to Medicaid for asthma and who were continuously covered during the period. From outpatient claims files, a record was assembled for each child containing the number of prescriptions in each category of asthma drugs during each interval. For each child who had received a prescription for any daily preventative drug, the number of such prescriptions and the time after the first were used to calculate availability of medication. Results: The proportion of children receiving at least one prescription for a preventive drug rose from 26.9 per cent of children in 1990–1992 to 52.6 per cent in 1997–1998. African‐American children were less likely to receive a preventive in the earlier period, but the difference narrowed by 1997. Assuming that one refill provided a month's supply of drug, the percentage of children who had enough drug dispensed to treat for more than half of the time following the initial prescription rose from 6.1 to 11.2 per cent. For children with the highest use of β‐agonist (11 or more prescriptions over 2 years), the percentage rose from 25.3 to 35.8; in those with 5 or more courses of a systemic steroid, the proportion rose from 36.6 to 40.2. During the second interval, adherence to use of oral montelukast was no better than to inhaled daily medications. Conclusion: In the 7 years after the publication of the NIH Guidelines, asthmatic children covered by Florida Medicaid had an approximate doubling in the proportion who received a prescription for a daily anti‐inflammatory drug. However, during both intervals the adherence to treatment once prescribed remained low even among those with the severest asthma. Effective strategies to improve adherence will be needed before these drugs can realize their potential.