Leukotriene Inhibitors in the Treatment of Allergy and Asthma



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Am Fam Physician. 2007 Jan 1;75(1):65-70.

ACF  This article exemplifies the AAFP 2007 Annual Clinical Focus on management of chronic illness.

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.

Approximately one third of all prescriptions for maintenance therapy in patients with persistent asthma are for leukotriene inhibitors; however, evidence of their effectiveness compared with other treatments is mixed. The popularity of this class of medications is likely because of convenient dosing, perceived ease of use, and concerns about side effects from long-term use of inhaled corticosteroids.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Leukotriene inhibitors are effective in the treatment of asthma but are less effective than inhaled corticosteroids.

A

6

Leukotriene inhibitors added to inhaled corticosteroids are less effective than long-acting beta2 agonists added to inhaled corticosteroids in the treatment of asthma.

A

7,9,11,12

Leukotriene inhibitors are alternative treatments in exercise-induced asthma and can be of benefit for children when oral therapy is preferred over inhalers.

B

12,13,1620

Leukotriene inhibitors are effective in the treatment of allergic rhinitis but are less effective than intranasal corticosteroids.

A

27,28,30


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 13 or http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Leukotriene inhibitors are effective in the treatment of asthma but are less effective than inhaled corticosteroids.

A

6

Leukotriene inhibitors added to inhaled corticosteroids are less effective than long-acting beta2 agonists added to inhaled corticosteroids in the treatment of asthma.

A

7,9,11,12

Leukotriene inhibitors are alternative treatments in exercise-induced asthma and can be of benefit for children when oral therapy is preferred over inhalers.

B

12,13,1620

Leukotriene inhibitors are effective in the treatment of allergic rhinitis but are less effective than intranasal corticosteroids.

A

27,28,30


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 13 or http://www.aafp.org/afpsort.xml.

Leukotrienes

Leukotrienes are synthesized in response to many triggers, including receptor activation, antigen-antibody interaction, physical stimuli such as cold, and any stimulation that increases intercellular calcium.1 These potent inflammatory mediators promote neutrophil-endothelial interactions, inducing bronchoconstriction and enhancing airway hyperresponsiveness. They also stimulate smooth muscle hypertrophy, mucus hypersecretion, and the influx of eosinophils into airway tissues2; therefore, inhibition of leukotrienes potentially plays an important role in the treatment of asthma and other allergic conditions such as allergic rhinitis, atopic dermatitis, and chronic urticaria.

Leukotriene-Inhibiting Drugs

Leukotriene inhibitors are either leukotriene receptor antagonists or leukotriene synthesis inhibitors, which act by blocking 5-lipoxygenase activity. The leukotriene receptor antagonists include zafirlukast (Accolate) and montelukast (Singulair); zileuton (Zyflo) is the only leukotriene synthesis inhibitor (Table 1).

Table 1

Leukotriene Inhibitors for the Treatment Of Allergy and Asthma

Drug Age and recommended oral dose Therapeutic issues Approximate monthly cost*

Montelukast (Singulair)

Adults: 10 mg before bed

Renal adjustments: none

Hepatic adjustments: in mild to moderate disease

$104.40 (4 mg, 5 mg, or 10 mg)

Children six to 14 years: 5 mg before bed

Children two to five years: 4 mg before bed

Zafirlukast (Accolate)

Patients older than 11 years: 20 mg twice daily

Renal adjustments: none

Hepatic adjustments: not defined

Monitor hepatic enzymes every two to three months

Administration with meals decreases bioavailability; take at least one hour before meals or two hours after

Inhibits metabolism of warfarin (Coumadin), increasing prothrombin time

$88.10 (10 mg or 20 mg)

Children seven to 11 years: 10 mg twice daily

Zileuton (Zyflo)

Patients older than 12 years: 600 mg four times daily

Can inhibit metabolism of warfarin, theophylline, and propranolol (Inderal)

Monitor hepatic enzymes every two to three months

$273.75 (600 mg)


*—Estimated cost to the pharmacist based on average wholesale prices in Red Book. Montvale, N.J.: Medical Economics Data, 2006. Cost to the patient will be higher, depending on prescription filling fee.

Table 1   Leukotriene Inhibitors for the Treatment Of Allergy and Asthma

View Table

Table 1

Leukotriene Inhibitors for the Treatment Of Allergy and Asthma

Drug Age and recommended oral dose Therapeutic issues Approximate monthly cost*

Montelukast (Singulair)

Adults: 10 mg before bed

Renal adjustments: none

Hepatic adjustments: in mild to moderate disease

$104.40 (4 mg, 5 mg, or 10 mg)

Children six to 14 years: 5 mg before bed

Children two to five years: 4 mg before bed

Zafirlukast (Accolate)

Patients older than 11 years: 20 mg twice daily

Renal adjustments: none

Hepatic adjustments: not defined

Monitor hepatic enzymes every two to three months

Administration with meals decreases bioavailability; take at least one hour before meals or two hours after

Inhibits metabolism of warfarin (Coumadin), increasing prothrombin time

$88.10 (10 mg or 20 mg)

Children seven to 11 years: 10 mg twice daily

Zileuton (Zyflo)

Patients older than 12 years: 600 mg four times daily

Can inhibit metabolism of warfarin, theophylline, and propranolol (Inderal)

Monitor hepatic enzymes every two to three months

$273.75 (600 mg)


*—Estimated cost to the pharmacist based on average wholesale prices in Red Book. Montvale, N.J.: Medical Economics Data, 2006. Cost to the patient will be higher, depending on prescription filling fee.

MONTELUKAST

Montelukast is administered orally once daily and is approved for treatment of asthma in patients two years or older. The bioavailability is similar regardless of patient age, and absorption is not affected by food. No drug interactions have been documented. Side effects in adults are similar to those found with placebo; they occurred in less than 2 percent of patients six to 14 years of age. Montelukast is classified by the U.S. Food and Drug Administration (FDA) as pregnancy category B.3

ZAFIRLUKAST

Zafirlukast is approved for treatment of asthma in patients seven years or older. The most common adverse effects are pharyngitis, headache, rhinitis, and gastritis. Transient reversible increases in liver enzymes and reports of rare but significant liver dysfunction (including liver failure) have prompted recommendations against prescribing this drug to patients with hepatic dysfunction and recommendations to monitor liver enzymes every two to three months. Zafirlukast is FDA pregnancy category B.4

ZILEUTON

Zileuton is approved for treatment of chronic asthma in patients 12 years or older. Because it is metabolized by the cytochrome P450 isoenzyme system of the liver, zileuton may affect other drugs metabolized by these enzymes such as warfarin (Coumadin), theophylline, and propranolol (Inderal). Approximately 5 percent of patients receiving zileuton had increases in liver enzymes that resolved with discontinuation.5 The manufacturer of zileuton recommends monitoring liver enzymes before initiation of treatment, once a month for three months, and once every two to three months thereafter. Other adverse effects of zileuton include dyspepsia, abdominal pain, and nausea. It is FDA pregnancy category C.5

Leukotriene Inhibitors in the Treatment of Asthma

Many studies have compared leukotriene inhibitors with other asthma treatments. Two Cochrane Reviews evaluated research comparing leukotriene inhibitors with inhaled corticosteroids in the management of recurrent and persistent asthma in children and adults.6,7 Patients with persistent asthma who received leukotriene inhibitors were 65 percent more likely to experience an exacerbation requiring systemic steroids than patients receiving inhaled corticosteroids. This equates to one out of every 26 patients treated with a leukotriene inhibitor rather than an inhaled corticosteroid experiencing an exacerbation.6 The addition of leukotriene inhibitors to inhaled corticosteroids did not result in a statistically significant reduction in the need for systemic steroids.7

Leukotriene inhibitors also have been evaluated as inhaled-steroid–sparing agents. In these studies, the addition of a leukotriene inhibitor to inhaled corticosteroids did not result in a lower inhaled corticosteroid dose; however, it did result in fewer withdrawals caused by poor control (relative risk = 0.63; 95% confidence interval, 0.42 to 0.95).7 In contrast, the use of long-acting beta2 agonists in patients treated with inhaled fluticasone (Flovent) 250 mcg can be steroid sparing with the addition of inhaled salmeterol (Serevent), allowing for a 60 percent reduction in fluticasone to 100 mcg while still maintaining overall asthma control.8

A recent Cochrane Review summarized the addition of a long-acting beta2 agonist compared with a leukotriene receptor agonist in patients receiving inhaled steroids.9 This study concluded that in adults with asthma inadequately controlled by low-dose inhaled steroids, the addition of a long-acting beta2 agonist was superior in preventing exacerbations requiring systemic steroids.

One randomized controlled trial (RCT) of 889 patients with incomplete control of asthma symptoms on inhaled budesonide (Rhinocort) found that adding montelukast was clinically equivalent to doubling the dose of budesonide.10

As recently as 2002, the National Asthma Education and Prevention Program (NAEPP) and other academic organizations placed leukotriene inhibitors as a third-line add-on agent when intermittent short-acting inhaled beta2 agonists are insufficient; the addition of inhaled corticosteroids was first-line, and long-acting beta2 agonists were second-line agents to short-acting beta2 agonists.1113 The NAEPP expert panel report states that leukotriene inhibitors should not be considered a preferred therapy for the treatment of mild persistent asthma but rather an alternative.13 Leukotriene inhibitors may also be used in combination with inhaled corticosteroids in the treatment of moderate persistent asthma. This recommendation was based on only modest evidence of benefit.12  The NAEPP expert panel report also included recommendations for managing asthma using the stepwise approach (Table 2).13

TABLE 2

Stepwise Approach For Asthma Management In Infants And Young Children*

Step/Severity Symptom occurrence Medications

Step 1 Mild intermittent

Two or less days per week

Short-acting beta2 agonists as needed†

Two or less nights per month

Step 2 Mild persistent

More than two days per week; less than once per day

Step 1 and low-dose inhaled corticosteroids† or inhaled cromoglycate or leukotriene modifier or theophylline or nedocromil (Tilade)

More than two nights per month

Step 3 Moderate persistent

Daily

Step 1 and low- to medium-dose inhaled corticosteroids and long-acting inhaled beta2 agonists† or increased dose inhaled corticosteroid or low- to medium-dose inhaled corticosteroid and either a leukotriene modifier or theophylline

More than one night per week

Step 4 Severe persistent

Continual or frequent

Step 1 and high-dose inhaled corticosteroid and long-acting inhaled beta2 agonists† and, if needed, systemic corticosteroids


*—Five years or younger.

†—Preferred treatment.

Adapted from the National Institute of Health. National Asthma Education and Prevention Program. NAEPP expert panel report. Guidelines for the diagnosis and management of asthma—update on selected topics 2002. NIH publication no. 97-4051. Accessed March 23, 2006, at: http://www.nhlbi.nih.gov/guidelines/asthma/execsumm.pdf.

TABLE 2   Stepwise Approach For Asthma Management In Infants And Young Children*

View Table

TABLE 2

Stepwise Approach For Asthma Management In Infants And Young Children*

Step/Severity Symptom occurrence Medications

Step 1 Mild intermittent

Two or less days per week

Short-acting beta2 agonists as needed†

Two or less nights per month

Step 2 Mild persistent

More than two days per week; less than once per day

Step 1 and low-dose inhaled corticosteroids† or inhaled cromoglycate or leukotriene modifier or theophylline or nedocromil (Tilade)

More than two nights per month

Step 3 Moderate persistent

Daily

Step 1 and low- to medium-dose inhaled corticosteroids and long-acting inhaled beta2 agonists† or increased dose inhaled corticosteroid or low- to medium-dose inhaled corticosteroid and either a leukotriene modifier or theophylline

More than one night per week

Step 4 Severe persistent

Continual or frequent

Step 1 and high-dose inhaled corticosteroid and long-acting inhaled beta2 agonists† and, if needed, systemic corticosteroids


*—Five years or younger.

†—Preferred treatment.

Adapted from the National Institute of Health. National Asthma Education and Prevention Program. NAEPP expert panel report. Guidelines for the diagnosis and management of asthma—update on selected topics 2002. NIH publication no. 97-4051. Accessed March 23, 2006, at: http://www.nhlbi.nih.gov/guidelines/asthma/execsumm.pdf.

Leukotriene inhibitors have been shown to have significant benefit over placebo in the prevention of viral-induced asthma exacerbations in children with a history of intermittent asthma. In a study of children two to five years of age with intermittent asthma, montelukast reduced the frequency of upper respiratory infection–induced exacerbation of asthma (number needed to treat [NNT] = 9).14 No studies have compared leukotriene inhibitors with inhaled corticosteroids for this indication.

Leukotriene inhibitors may have a role in the treatment of acute asthma. High doses of zafirlukast (160 mg) given to patients upon arrival in the emergency department reduced the number of patients who had an extended stay of longer than four hours (NNT = 20). Continuing the drug at a dose of 20 mg twice daily for 28 days also improved outcomes (NNT to prevent one relapse = 20).15

Most of these studies have shown that leukotriene inhibitors, when used alone, are more effective than placebo for the treatment of asthma; however, they are less effective than inhaled corticosteroids or long-acting beta2 agonists.6,7 Two studies of overall treatment costs showed that the combination of salmeterol and fluticasone (Advair Diskus) was more cost-effective than montelukast plus fluticasone.16,17 It may be reasonable to add leukotriene inhibitor therapy in some situations, such as in children if there is concern about side effects from increasing doses of inhaled corticosteroids. However, leukotriene inhibitors should not be substituted for inhaled corticosteroids when the latter are clinically indicated.

EXERCISE-INDUCED ASTHMA

Traditionally, pretreatment with a short-acting beta2 agonist has been used for prevention of exercise-induced asthma. Long-acting beta2 agonists sometimes are used instead to lengthen the duration of protection.18 Short-acting beta2 agonists provide protection for up to two hours, whereas long-acting beta2 agonists protect for up to 12 hours. Both montelukast19 and zafirlukast20 have shown significant beneficial effects in treatment of exercise-induced bronchospasm when compared with placebo. A single dose of leukotriene inhibitors within one hour before exercise was equal to a long-acting beta2 agonist in preventing exercise-induced asthma.21

Notably, over an eight-week study period, the tolerance that some patients developed to long-acting beta2 agonists did not occur in patients receiving leukotriene inhibitors.22 One review suggests that using leukotriene inhibitors may be preferable to increasing the dose of beta2 agonists.23 Leukotriene inhibitors can provide a useful alternative in preventing exercise-induced asthma, especially in young children for whom the use of an inhaler may be difficult, or for persons who receive incomplete protection from short-acting beta2 agonists.

ASPIRIN-INTOLERANT ASTHMA

A double-blind, placebo-controlled RCT of 80 patients has shown that montelukast was more beneficial than placebo in improving forced expiratory volume in one second, improving symptoms, decreasing exacerbations, and providing one more night per week of uninterrupted sleep in patients with aspirin-induced or aspirin-intolerant asthma.24 Two smaller randomized trials (eight and 40 patients) involving zileuton also support the clinical effectiveness of leukotriene inhibitors in bronchoconstriction induced by aspirin or nonsteroidal anti-inflammatory drugs, as well as for asthma control in patients receiving oral or inhaled steroids.25,26

Leukotriene Inhibitors in the Treatment of Allergic Rhinitis

The FDA has approved montelukast for the treatment of allergic rhinitis. Studies show that montelukast was more beneficial than placebo and equally as effective as loratadine (Claritin) for the treatment of seasonal allergic rhinitis. There was only a marginal benefit in adding montelukast to loratadine, and neither montelukast nor loratadine were as effective as intranasal steroids.27,28 In addition, a recent study comparing montelukast with pseudoephedrine showed equal benefit with no difference in side effects.29

A systematic review and meta-analysis compared intranasal steroids, leukotriene inhibitors, and antihistamines in the treatment of allergic rhinitis.30 Intranasal corticosteroids showed a 12 percent absolute improvement over leukotriene inhibitors on a weighted mean difference of a composite nasal symptom score. Leukotriene inhibitors were not statistically different from antihistamines for nasal symptoms but were significantly less effective than antihistamines as rated by a score measuring quality of life. Although the combination of leukotriene inhibitors with antihistamines was significantly more effective for nasal symptoms than either alone, this combination was not statistically significant using a score measuring quality of life. There was no statistically significant difference between intranasal corticosteroids and the combination of leukotriene inhibitors plus antihistamines for nasal symptoms, but there was a 3 percent nonsignificant trend supporting intranasal steroid use.30

Even if the combination was clinically equivalent to intranasal steroids, the cost of two drugs (leukotriene inhibitor and an antihistamine) would exceed the cost of intranasal steroids alone. Thus, intranasal corticosteroids remain the treatment of choice. The availability of generic second-generation antihistamines argues for the addition of an antihistamine if intranasal steroids do not sufficiently control symptoms.

Leukotriene Inhibitors in the Treatment of Atopic Dermatitis

Experimental data have suggested that leukotrienes may be involved in the pathogenesis of atopic dermatitis. Because the majority of children with atopic dermatitis later develop allergic rhinitis and asthma, it is conceivable that early leukotriene inhibitor use could not only treat atopic dermatitis but also modify the disease course of allergic rhinitis and asthma in children. However, there are only a few small studies of the use of leukotriene inhibitors in the treatment of atopic dermatitis, most of which are either case reports or small randomized crossover trials. Two studies showed small but significant improvements in atopic dermatitis with the use of these agents.31,32 Another study on the use of either montelukast or zafirlukast in seven patients in a nonrandomized, no-control, add-on usage trial showed that leukotriene inhibitors did not lead to a sustained benefit for extensive atopic dermatitis.33 The role of leukotriene inhibitors in atopic dermatitis has yet to be defined.

Leukotriene Inhibitors in the Treatment of Chronic Urticaria

Leukotriene inhibitors have been studied as monotherapy or for use in combination with the mainstay of oral antihistamine in the treatment of chronic idiopathic urticaria. One study did show that montelukast was more effective in reducing urticaria activity scores than placebo (P <.001) in the treatment of chronic idiopathic urticaria, with a statistically significant decrease in the use of antihistamines as well.34 Another randomized study comparing the antihistamine desloratadine (Clarinex) with montelukast in treating chronic idiopathic urticaria showed that montelukast was more effective than placebo but less effective than desloratadine.35 There was no benefit to adding montelukast to desloratadine. This study was limited by a high drop-out rate in the montelukast-only and placebo groups of the study. No leukotriene inhibitors are currently approved for use in chronic urticaria.

Data Sources: The data sources for this review included Medline searches using the key words leukotriene inhibitors, antagonists, receptor blockers and modifiers, asthma, allergic rhinitis, atopic dermatitis, and urticaria.

The Authors

DEAN THOMAS SCOW, M.D., is a faculty member at the St. Mary's Family Medicine Residency Program, Grand Junction, Colo. Dr. Scow received his medical degree from the University of Chicago (Ill.) Pritzker School of Medicine and completed a family practice residency at Naval Hospital Bremerton (Wash.).

GARY K. LUTTERMOSER, M.D., is assistant program director for the Penn State University/Good Samaritan Hospital Family and Community Medicine Residency Program in Lebanon, Pa., and a clinical assistant professor in the Department of Family and Community Medicine at Penn State College of Medicine in Hershey, Pa. He received his medical degree from the Medical University of Ohio at Toledo (now the University of Toledo) and completed a family practice residency at Akron (Ohio) City Hospital and a short-term faculty training fellowship at Michigan State University in East Lansing.

KEITH SCOTT DICKERSON, M.D., M.S., is a faculty physician at St. Mary's Family Medicine Residency Program. He received his medical degree from the Medical College of Pennsylvania in Philadelphia (now Drexel University College of Medicine) and completed a residency in family medicine at the University of New Mexico in Albuquerque.

Address correspondence to Dean Thomas Scow, M.D., St. Mary's Family Residency, 1160 Patterson Rd., Grand Junction, CO 81506 (e-mail: dean.scow@stmarygj.org). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Salvi SS, Krishna MT, Sampson AP, Holgate ST. The anti-inflammatory effects of leukotriene-modifying drugs and their use in asthma. Chest. 2001;119:1533–46.

2. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway [published correction appears in N Engl J Med 1999;340:663]. N Engl J Med. 1999;340:197–206.

3. Singulair (montelukast sodium). Product information. Whitehouse Station, N.J.: Merck & Co., 2006. Accessed March 23, 2006, at: http://www.singulair.com/singulair/shared/documents/english/singulair_prescribing_info.pdf.

4. Accolate (zafirlukast) [Product information]. Wilmington, Del.: Astra-Zeneca Pharmaceuticals, 2004. Accessed March 23, 2006, at: http://www.astrazenecaus.com/pi/accolate.pdf.

5. Zileuton for asthma. Med Lett Drugs Ther. 1997;39:18–9.

6. Ducharme FM, Di Salvio F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev. 2004;(1):CD002314.

7. Ducharme F, Schwartz Z, Kakuma R. Addition of antileukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2004;(1):CD003133.

8. Busse W, Koenig SM, Oppenheimer J, Sahn SA, Yancey SW, Reilly D, et al. Steroid-sparing effects of fluticasone propionate 100 microg and salmeterol 50 microg administered twice daily in a single product in patients previously controlled with fluticasone propionate 250 microg administered twice daily. J Allergy Clin Immunol. 2003;111:57–65.

9. Ram FS, Cates CJ, Ducharme FM. Long-acting beta2-agonists versusanti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2005;(1):CD003137.

10. Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, et al., for the Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax. 2003;58:211–6.

11. National Asthma Education and Prevention Program. Combination therapy: addition of other long-term-control medications to inhaled corticosteroids. J Allergy Clin Immunol. 2002;110(suppl 5):S16980.

12. Agency for Healthcare Research and Quality. Management of chronic asthma. Evidence report/technology assessment: number 44. Accessed March 23, 2006, at: http://www.ahrq.gov/clinic/epcsums/asthmasum.htm.

13. National Institute of Health. National Asthma Education and Prevention Program. NAEPP expert panel report. Guidelines for the diagnosis and management of asthma—update on selected topics 2002. Accessed March 23, 2006, at: http://www.nhlbi.nih.gov/guidelines/asthma/execsumm.pdf.

14. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005;171:315–22.

15. Silverman RA, Nowak RM, Korenblat PE, Skobeloff E, Chen Y, Bonuccelli CM, et al. Zafirlukast treatment for acute asthma: evaluation in a randomized, double-blind, multicenter trial. Chest. 2004;126:1480–9.

16. Stempel DA, O'Donnell JC, Meyer JW. Inhaled corticosteroids plus salmeterol or montelukast: effects on resource utilization and costs. J Allergy Clin Immunol. 2002;109:433–9.

17. O'Connor RD, O'Donnell JC, Pinto LA, Wiener DJ, Legorreta AP. Two-year retrospective economic evaluation of three dual-controller therapies used in the treatment of asthma [published correction appears in Chest 2002;122:387]. Chest. 2002;121:1028–35.

18. Kemp JP, Dockhorn RJ, Busse WW, Bleecker ER, Van As A. Prolonged effect of inhaled salmeterol against exercise-induced bronchospasm. Am J Respir Crit Care Med. 1994;150:1612–5.

19. Vidal C, Fernandez-Ovide E, Pineiro J, Nunez R, Gonzalez-Quintela A. Comparison of montelukast vs. budesonide in the treatment of exercise-induced bronchoconstriction. Ann Allergy Asthma Immunol. 2001;86:655–8.

20. Dahlen B, Roquet A, Inman MD, Karlsson O, Naya I, Ansren G, et al. Influence of zafirlukast and loratadine on exercised-induced broncho-constriction. J Allergy Clin Immunol. 2002;109:789–93.

21. Coreno A, Skowronski M, Kotaru C, McFadden ER Jr. Comparative effects of long-acting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma. J Allergy Clin Immunol. 2000;106:500–6.

22. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, Ghannam AF, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Exercise Study Group. Ann Intern Med. 2000;132:97–104.

23. Anderson SD. Single-dose agents in the prevention of exercise-induced asthma: a descriptive review. Treat Respir Med. 2004;3:365–79.

24. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:9–14.

25. Israel E, Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Shapiro J, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis. 1993;148:1447–51.

26. Dahlen B, Nizankowska E, Szczeklik A, Zetterstrom O, Bochenek G, Kumlin M, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med. 1998;157:1187–94.

27. Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinsein SF, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol. 2000;105:917–22.

28. Pullerits T, Praks L, Ristioja V, Lotvall J. Comparison of a nasal gluco-corticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 2002;109:949–55.

29. Mucha SM, deTineo M, Naclerio RM, Baroody FM. Comparison of montelukast and pseudoephedrine in the treatment of allergic rhinitis. Arch Otolaryngol Head Neck Surg. 2006;132:164–72.

30. Wilson AM, O'Byrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med. 2004;116:338–44.

31. Carucci JA, Washenik K, Weinstein A, Shupack J, Cohen DE. The leukotriene antagonist zafirlukast as a therapeutic agent for atopic dermatitis. Arch Dermatol. 1998;134:785–6.

32. Yanase DJ, David-Bajar K. The leukotriene antagonist montelukast as a therapeutic agent for atopic dermatitis. J Am Acad Dermatol. 2001;44:89–93.

33. Silverberg NB, Paller AS. Leukotriene receptor antagonists are ineffective for severe atopic dermatitis. J Am Acad Dermatol. 2004;50:485–6.

34. Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J Allergy Clin Immunol. 2002;110:484–8.

35. Di Lorenzo G, Pacor ML, Mansueto P, Esposito Pellitteri M, Lo Bianco C, Ditta V, et al. Randomized placebo-controlled trial comparing desloratadine and montelukast in monotherapy and desloratadine plus montelukast in combined therapy for chronic idiopathic urticaria. J Allergy Clin Immunol. 2004;114:619–25.

Members of various family medicine departments develop articles for “Clinical Pharmacology.” This is one in a series coordinated by Allen F. Shaughnessy, Pharm.D., and Andrea E. Gordon, M.D., Tufts University Family Medicine Residency, Malden, Mass.



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