Leukotriene receptor antagonists (LTRA) and inhibitors of leukotriene synthesis (5-lipoxygenase inhibitor) have become available in the last decade. These leukotriene modifiers, as a class, have been shown effective in the treatment of chronic asthma and exercise-induced bronchoconstriction. Currently, the LTRAs are recommended as first-line preventer agents and second-line controller agents in the treatment of chronic asthma. However, the leukotriene modifiers are being used clinically for other disease processes that involve leukotriene synthesis. Diseases such as allergic rhinitis, atopic dermatitis, chronic urticaria, and chronic obstructive lung disease have been treated with leukotriene modifiers. This presentation will briefly review the leukotriene modifiers’ molecular actions and their indications for asthma therapy. A detailed review of the literature for uses beyond asthma will follow.

Leukotrienes serve as inflammatory cell mediators with actions that include bronchoconstriction by smooth muscle contraction, bronchial hyper-responsiveness, inflammatory cell accumulation and chemotaxis, mucus hypersecretion, neuronal stimulation, and increased microvascular permeability.¹ Leukotriene modifiers, therefore, possess both anti-inflammatory and bronchodilator properties. Historically, leukotrienes were referred to as the slow-reacting-substances of anaphylaxis. Leukotrienes are products of arachidonic acid metabolism in activated inflammatory cells such as mast cells, eosinophils, and macrophages. Arachidonic acid cleaved from the phospholipid membrane is converted by the enzyme 5-lipoxygenase into leukotriene A4. Leukotriene A4 is an unstable intermediate product that is transformed into leukotriene C4, D4, and E4, which are transported extracellularly. Leukotriene C4, D4, and E4 are referred to as the cysteinyl leukotrienes. Leukotriene B4 is produced by a separate pathway.²

LTRAs block leukotriene D4 binding to the cysteinyl leukotriene receptor. This effectively also blocks the activity of leukotriene C4 and E4. Leukotriene synthesis inhibitors block leukotriene synthesis from arachidonic acid by inactivating the 5-lipoxygenase enzyme protein. This inhibition prevents the production of both the cysteinyl leukotrienes and leukotriene B4, as well as other inflammatory molecules that require 5-lipoxygenase for their production. The leukotriene synthesis inhibitors’ site of action is within the inflammatory cell, whereas LTRAs intervene within the extracellular space.¹

Currently, Zileuton (Zyflo) is the only FDA approved leukotriene synthesis inhibitor. Montelukast (Singulair) and zafirlukast (Accolate) are leukotriene receptor antagonists both approved by the FDA. The indication by the FDA for these drugs is chronic asthma therapy. Pranlukast (Ultair) is another LTRA not currently marketed in the United States. Montelukast dosing for adults is 10mg once a day with an average wholesale price (AWP) of $71.17 per month. Zafirlukast has an AWP of $62.16 per month for 20mg twice a day. The bioavailability of zafirlukast is reduced by 40% when taken with food. Zileuton is dosed 600mg, four times a day at an AWP of $90.90 per month.^3,4

Leukotriene receptor antagonists are approved for the treatment of chronic asthma by the FDA. The LTRAs are a hybrid between a preventer of inflammation by antagonism of the proinflammatory activities of leukotrienes and a bronchodilator by antagonism of leukotriene-induced smooth muscle bronchoconstriction. The National Heart, Lung, and Blood Institute Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report 2 did not address the use of leukotriene modifiers.⁵ Modified guidelines by Busse⁴¹ in JAMA recommends LTRAs as alternative monotherapy for mild persistent asthma and as add-on therapy for moderate or severe persistent asthma. LTRAs may permit reducing or tapering steroid-based controller agents for asthma. Leukotriene modifiers are a valuable treatment for the 10% of chronic asthmatics who have aspirin-sensitive asthma for which over-expression of leukotriene C4 synthetase has been implicated.^6,7

Randomized controlled trials have shown zafirlukast reduces the risk of asthma exacerbations in mild to moderate asthmatics.^8,9,10 Montelukast also has been shown effective as monotherapy in mild asthma.¹¹ Near maximum response to montelukast is achieved after the first few doses. In general, most studies have found inhaled corticosteroids superior to LTRAs as monotherapy controller agents.^12,13 Montelukast has been shown to provide additional asthma control when combined with inhaled corticosteroids as in the Montelukast/Beclomethasone Additivity Group Study, and currently is being studied in the Investigation of Montelukast as a Partner Agent for Complementary Therapy (IMPACT) trial versus salmeterol.^14,15 A previous 4-week randomized, double-blind, multicenter clinical trial found salmeterol superior to zafirlukast as concurrent therapy to inhaled corticosteroids for asthma control.¹⁶

Montelukast additionally has been extensively investigated for prevention of exercise-induced bronchoconstriction. The Exercise Study Group was a randomized, double-blind comparison trial of montelukast versus salmeterol for prevention of exercise-induced bronchoconstriction. The 8-week trial showed superior prevention of FEV1 reduction by montelukast over salmeterol.¹⁷

Authors have argued that the pathophysiology of asthma and allergic rhinitis are related based on the concept of "one linked airway disease."¹⁸ Subsequently, leukotriene inhibitors have been prescribed for allergic rhinitis.

Allergic rhinitis affects approximately 20% of the population. Symptoms such as nasal congestion, sneezing, rhinorrhea, and nasal itching characterize the disease. Allergen exposure to the allergic patient causes chemical mediator release by mast cells, basophils, and eosinophils. Two of the most abundant and potent mediators are histamine and cysteinyl leukotrienes. Several studies have identified increased levels of leukotrienes in nasal lavages after allergen challenges.¹⁹

Nasal obstruction of the upper airways is predominately vascular in origin by engorgement of venous sinusoids within the turbinates that obstructs flow. Nasal airway resistance can be measured quantitatively by rhinomanometry. Direct nasal challenge studies with leukotrienes (LTC4 and LTD4) have consistently identified no effect on nasal pruritis or sneezing, in contrast to histamine challenges. The major leukotriene effect appears to be on the nasal vasculature inducing nasal congestion and plasma protein exudation.²

• Knapp- First Human Trial of 5-lipoxygenase Inhibitor Effect On Nasal Congestion

The first clinical study showing reduced leukotriene synthesis reduces nasal congestion was published in The New England Journal of Medicine in 1990 using an orally active 5-lipoxygenase inhibitor (A-64077).²⁰ Eight persons with history of allergic rhinitis caused by ragweed, grasses, or cat dander were studied. None had taken allergy medications for at least one month. Patients were randomized into a double-blind, placebo-controlled study after a positive nasal-provocation screen. Each underwent two allergen challenges at least two weeks apart. The participants were dosed either with 800mg of A-64077 or placebo and exposed to allergen three hours later. The subjects assessed nasal congestion on a scale of 0 to 5  (0 = no congestion, 5 = total occlusion), and the number of sneezes were recorded.

Results: Seven of eight subjects correctly noted when they received active drug, because their allergen-induced congestion response was similar to that of their screening test on one occasion and markedly reduced on the other. There was a statistically significant difference (p < 0.02) between treatment groups for congestion scores (4.6 vs. 3.6).

• Donnelly et al.- LTRA to Treat Acute Seasonal Allergic Rhinitis

In 1995, "the walk in the park" study compared zafirlukast vs. placebo for relieving symptoms of acute seasonal allergic rhinitis.²¹ In this study, 185 persons with documented ragweed allergy by skin prick test spent 8 hours a day for two consecutive days in an outdoor park during peak ragweed season in Iowa. Subjects were assessed hourly for major allergic rhinitis symptoms: nasal congestion, sneezing, rhinorrhea, itchy nose, throat or palate, as well as eye symptoms. The symptoms were rated as none (0); slight, but not bothersome (1); mild, noticeable with mild discomfort (2); moderate, noticeable and uncomfortable (3); and severe, interfering with daily activities (4). Subjects with sufficient symptoms during a 3-hour baseline period on day 1 were randomized to treatment with a single daily dose of 10, 20, 40, or 100mg zafirlukast or placebo. Symptoms were recorded at hourly intervals in the park and two-hour intervals at home. At the end of day two, a global efficacy evaluation to rate allergy symptom control was completed based on a scale of (1) good or substantial, (2) fair or moderate, (3) doubtful or minor, (4) none, and (5) aggravated symptoms.

Results: 164 of 169 persons who reported to the park were randomized to treatment. Five persons did not complete the study. There was no significant difference among demographics or baseline symptom scores between the treatment groups. Statistically significant reductions in nasal congestion, sneezing, and rhinorrhea were found for the 20mg and 40mg zafirlukast treatment groups during day and night based on mean symptom scores.

                                                        *p < 0.01         # p < 0.05

Conclusion: Both the 20mg and 40mg zafirlukast relieved symptoms of nasal congestion and rhinorrhea as predicted from the knowledge of leukotriene effects, and yet sneezing thought due to the effect of histamine was also reduced. This discrepancy may be due to the differences in artificial settings with laboratory instillation versus the milieu of released mediators of inflammation in real life. Also, 100mg dosing of zafirlukast showed no clinical effect. This may reflect a dose-response curve that differs from the upper airway compared to the lower airway where 100mg dosing was effective in asthma therapy. Improved baseline symptoms on day 2 may also suggest a prophylactic effect of zafirlukast on day 2. Interestingly, the onset of action for the treatment groups was within 2 hours of the first dose.

The limitations of the study include small population size, obviously short therapy period, and a purely subjective measure of benefit. Also, zafirlukast is usually dosed twice a day secondary to the half-life.

• Grossman et al.- Pranlukast Also Proven Beneficial in Seasonal Allergic Rhinitis

A second study of seasonal allergic rhinitis symptom relief was conducted with the leukotriene receptor antagonist pranlukast, commercially unavailable in the United States.²² Pranlukast (150mg and 300mg bid) was compared to 10mg loratadine in a 4-week double-blind, placebo-controlled parallel group trial in 484 patients with documented fall seasonal allergic rhinitis. At each 7-day visit interval, the average of the four highest daily summary symptom scores for that week was calculated. Rhinitis symptoms were significantly reduced compared to placebo in patients treated with pranlukast 150mg bid at weeks 1,3, and 4 [-9%, -23%, and -24% from baseline]. Statistical significance was reached at week one also for pranlukast 300mg bid. Loratadine showed symptom reduction at all time points. This abstract proposed that pranlukast is an effective and tolerated treatment for allergic rhinitis.

• Meltzer et al.- LTRA and Anti-histamine Compared for Allergic Rhinitis Treatment

The Montelukast Study Group published a randomized, placebo-controlled clinical trial of concomitant montelukast and loratadine treatment compared to monotherapy regiments. The data first was presented in abstract form in 1998 and published in 2000.^23,24 The 12 center randomized trial used 5 parallel treatment groups with a 1-week, single-blind, placebo run-in period and a 2-week, double-blind treatment period. Patients were randomly allocated at the third visit to receive 10mg montelukast, 20mg montelukast, 10mg loratadine, 10mg loratadine + 10mg montelukast, or placebo. A daily rhinitis diary card was maintained with a 4-point scale for both daytime and nighttime rhinitis symptoms. The daytime symptoms pertained to nasal congestion, nasal itch, sneezing, and rhinorrhea, as well as eye symptoms. The scale was not noticeable (0); mild symptoms, noticeable but not bothersome (1); moderate symptoms, noticeable and disturbing some of the time (2); severe symptoms, very disturbing some of the time and/or disturbing most of the time (3). The nighttime questions, which also used the four-point scale, pertained to severity of nasal congestion on awakening, difficulty going to sleep, and nighttime awakenings because of nasal symptoms. Patients had to have sufficient nasal symptoms during the 1-week placebo run-in period to be eligible for randomization. The patients also completed the Rhinoconjunctivitis Quality-of-Life Questionnaire at the time of randomization and the final visit. With a sample size of 80 patients per group, the trial had 80% power to detect a difference of .25 score change from baseline.

Results: 460 patients of 834 screened were randomly allocated to the 5 treatment groups. A negative skin test to a panel of 8 tree and grass pollens was the most common reason for exclusion. On-going use of decongestants, antihistamines, or any form of steroids also excluded patients from the trial. Baseline characteristics were similar. Twenty-six patients did not complete the study, and 7 patients had incomplete data distributed equally among the 5 treatment groups.

Monotherapy with either montelukast 20mg or loratadine 10mg was not significantly different from placebo in the overall daytime nasal, daytime eye, nighttime, or composite day/night symptoms. Montelukast 10mg did show improvement over placebo in daytime eye, nighttime, and composite symptom scores. However, global evaluations of overall allergic rhinitis symptoms by the Rhinoconjunctivitis Quality-of-Life scores showed significant difference for both loratadine and montelukast monotherapy compared to placebo. Concomitant treatment with montelukast and loratadine significantly improved daytime nasal symptoms compared with placebo and monotherapy. All other endpoints also showed significant improvement with combination therapy.

                                P < 0.001*                                 (95% C.I. for the mean)
                                P < 0.050#

Conclusion: Only the combination therapy showed significant improvement in all symptom scores. This is contrary to other placebo-controlled trials showing efficacy of loratadine in allergic rhinitis. Interestingly, both montelukast and loratadine as monotherapy were found to improve Quality-of-Life scores, in comparison with placebo, despite their apparent lack of effect in reducing rhinitis symptom scores.

• Pullerits et al.- Comparison of LTRA to Nasal Glucocorticoid for Treatment of Allergic Rhinitis

The use of nasal glucocorticoids has been proven in the treatment of seasonal allergic rhinitis. A randomized, placebo-controlled study comparing LTRA and beclomethasone nasal spray was completed in 1999.²⁵ Thirty-three patients with a known history of allergic rhinitis during the grass pollen season had confirmatory positive skin prick test to three common grass pollen extracts. Prior to the study, all patients had nasal biopsies. Patients then were randomized to beclomethasone nasal spray 50ug, 2 sprays each nostril bid; zafirlukast 20mg bid; or matching nasal spray and capsules. Treatment was started three weeks prior to expected grass pollen season. During the whole treatment period, patients recorded their daily symptoms for sneezing, rhinorrhea, nasal itch, and nasal blockage using a score from 0 to 4. (0= symptom not present, 1= symptom present, no discomfort, 2= some discomfort, 3= marked discomfort, no interference with activities, 4= interference with daily activities) At the 6^th week, repeat nasal biopsy was performed. A secondary endpoint was counting the number of tissue EG2+ (which suggests activated cells) eosinophils per mm² of a transsection of the nasal mucosa biopsy. The treatment course was 50 days.

Results: The mean symptom score increased in all groups during the peak grass pollen season.

There was a significant difference between the placebo and the beclomethasone treated group (p=0.005), and the zafirlukast and the beclomethasone treated group (p=0.01); but no significant difference between placebo and the zafirlukast treated group (p=0.8). The increase in EG2+ cells was significantly lower for the beclomethasone treated group than the placebo group (p=0.015). There was not a significant difference between the placebo and zafirlukast group (p=0.4).

Conclusion: "This randomized, placebo-controlled study has shown that a leukotriene receptor antagonist is less effective than a nasal glucocorticoid in improving local symptoms in patients with seasonal allergic rhinitis during a grass pollen season. Furthermore, the leukotriene receptor antagonist did not protect against the increase in local eosinophilic inflammation induced by the pollen season, whereas the nasal glucocorticoid was effective in this respect." Like the previous RCT, this study shows no benefit of the use of a leukotriene receptor antagonist as monotherapy in seasonal allergic rhinitis. This study does not have the power however to detect small differences.

Atopic dermatitis is a chronic relapsing T-cell mediated inflammatory skin disorder that often affects those with a personal or family history of atopy. Patients usually exhibit eczematous changes in flexural distributions with a history of extreme pruritus. Although atopic dermatitis predominates in early childhood, twenty percent of childhood atopic dermatitis persists into adulthood. Current therapy options usually include topical corticosteroids, oral antihistamines, and antibiotics as needed for superinfections. Recalcitrant atopic dermatitis may be treated on experimental basis with interferon-gamma, cyclosporine, or topical tacrolimus. Some have proposed leukotriene inhibitors as "logical" choices for therapeutic agents to treat atopic dermatitis since asthma, allergic rhinitis, and atopic dermatitis have atopic basis of disease.²⁶ To date, only two published papers address the use of leukotriene inhibitors to treat atopic dermatitis. A series of four case reports by Carucci et al.²⁷ using zafirlukast observed subjective improvement of atopic dermatitis. A pilot study using zileuton has also been published.²⁶

Nine patients with atopic dermatitis who had been consistently symptomatic for 3 months were enrolled. All patients stopped previous atopic dermatitis medications one week before entering the trial. All patients were given zileuton 600mg PO qid. Office visits occurred at 0,2,4, and 6 weeks. At every visit, the patients rated their degree of pruritis on a 0 to 10 scale. Subjects also rated their degree of disease dissatisfaction on a scale of 0 (satisfied) to 10 (severely dissatisfied). Objective scoring of skin involvement in 20 equal body surface areas by an examiner was performed at each visit. The examiner was blinded to previous skin scores.

Two of the nine patients enrolled did not comply with the first follow-up visit. A third subject withdrew within the first two weeks secondary to gastrointestinal intolerance of zileuton. The remaining six patients completed the six week study. The baseline mean disease dissatisfaction score was 8, which improved to 4.4 (p = 0.03) after 6 weeks of treatment. All subjects indicated improvement, although one subject noted dramatic improvement from a dissatisfaction score of 10 to 1 after 6 weeks. The pruritis scores fell from a mean of 7.3 to 4.3 (p = 0.06) after 6 weeks of zileuton therapy. Skin scores were also reduced from a baseline mean of 24 (out of 60) to 14 (p = 0.03) after 6 weeks of therapy.

Although disease dissatisfaction scores and objective skin scores improved and the difference was statistically significant, this study has several weaknesses as acknowledged by the author. The study was quite small and the three subjects that dropped out of the trial were not included in the analysis. One subject appeared to have a much more dramatic response to therapy than the other five subjects. This makes the final analysis more favorable for promising results. The study was also open-labeled without a control to evaluate for placebo effect.

Recurrent urticaria of greater than 6 to 8 weeks duration is termed chronic urticaria. This syndrome is often idiopathic, with anti-histamines as the mainstay of therapy. No controlled clinical trials have been published to provide evidence as to whether leukotriene inhibitors have a role in chronic urticaria treatment. A retrospective chart review by Bensch and Borish identified 18 patients with the diagnosis of chronic urticaria who were treated with leukotriene modifiers.²⁸ Ten of these patients had dramatic improvement with the addition of leukotriene modifiers. Four patients received montelukast, five patients received zafirlukast, and one patient received both zafirlukast and zileuton. Improvement was seen within 1 week and resolution of the urticaria was within one month. All patients continued on antihistamines and various other treatment agents.

Case reports of successful treatment with leukotriene modifiers of chronic urticaria have also been published. Berkun and Shalit reported a case of successful treatment of steroid-dependent delayed pressure urticaria with montelukast.²⁹ Ellis reported two cases of successful treatment of chronic urticaria with zileuton.³⁰ One subject had more improvement with zileuton than zafirlukast. Norris and Sullivan reported that 9 of 15 steroid-requiring patients with chronic urticaria achieved control with zafirlukast.³¹ Chiu and Warren published a series of 15 subjects for which eight of the subjects responded to zafirlukast.³² Spector and Tan noted in a letter that two patients with chronic urticaria were controlled by leukotriene modifiers.³³ One subject was treated with zafirlukast, and the other subject treated with zileuton.

A clinical observation of decreased migraine frequency was noted in asthmatics treated with leukotriene inhibitors. A number of studies implicate leukotrienes in the pathophysiology of migraine and cluster headaches. Sheftell et al. published a prospective open-label study evaluating montelukast as a prophylactic agent for migraines.³⁴ Seventeen patients diagnosed with migraines without aura were enrolled. Subjects kept headache calendars for a two-month baseline period and then a three-month open-label treatment phase. Montelukast was started at 10mg PO qd, and increased to 10mg bid if a patient was not responding at one month.

The results of the trial showed a statistically significant reduction in the number of severe headaches after treatment with montelukast was started from 2.78 per month to 1.31 per month (p<0.025). However, there was no significant change in mild or moderate headaches.

Headaches per Month [Mean Number]

The weaknesses of this study include the open-label design and the small sample size. Interestingly, the number of severe headaches was reduced, while mild headaches were increased in frequency. This may be a result of montelukast decreasing the severity of a headache as opposed to a complete elimination.

Case reports and letters have been published with regards to the use of leukotriene modifiers in sinonasal polyposis,³⁵ sinus symptoms of aspirin-triad disease,³⁶ eosinophilic lung diseases,³⁷ and eosinophilic gastroenteritis.³⁸ There are currently no trials investigating leukotriene modifiers in the treatment of chronic obstructive lung disease.

Leukotriene modifiers are being used for many conditions for which strong evidence supporting their efficacy is lacking. Leukotriene modifiers have been considered quite safe and well-tolerated. However, as their use has become more widespread, several toxic side-effects have been noted.

Montelukast had been prescribed to over 2 million persons including children over the age of 6 by the end of 1999. Initially, only dyspepsia was thought to be a major side-effect. However, cases of elevated liver transaminases have now been noted.¹

Zafirlukast has similar side-effect profile as montelukast.¹ About 5% of patients have reported increases in liver enzymes. Five-fold increases in liver enzymes were seen in patients receiving zafirlukast in doses greater than 20mg twice daily during trials. Recently, a report of three patients with severe hepatitis was published in the Annals of Internal Medicine.³⁹ All patients were dosing zafirlukast at 20mg twice a day. Patient 1 recovered spontaneously after discontinuation of the medicine. Patient 2 required liver transplant after subfulminant hepatic failure. Patient 3 developed severe hepatitis (ALT=20,184) that improved with steroid therapy. Both zafirlukast and montelukast are metabolized via the hepatic cytochrome p450 pathway. It is probably prudent to monitor liver enzymes in patients with a history of excessive alcohol intake, liver disease, or co-administered hepatotoxic medications.

Zafirlukast, pranlukast, and montelukast have been associated with patients developing Churg-Strauss-like syndromes (allergic angiitis and granulomatosis).^3,40 Most case reports occurred in steroid-dependent asthmatics who were reducing systemic corticosteroid therapy after initiating a leukotriene receptor antagonist. Authors have suggested an unmasking of the underlying condition by leukotriene antagonists. Reports of Churg-Strauss have also been noted in patients not on steroid therapy when the LTRA was started.⁴²

Zileuton has a reported 1 in 50 chance of hepatic transaminitis.²⁶ The FDA recommends baseline and 4 week monitoring of liver enzymes. Zileuton will also potentiate the effects of theophylline and warfarin.³ These concerns, as well as four times a day dosing, have limited the use of zileuton in the United States.

• Leukotriene Inhibitors for Asthma Therapy

• Leukotriene Inhibitors for Allergic Rhinitis Therapy

• Leukotriene Inhibitors for Treatment of Atopic Dermatitis

• Leukotriene Inhibitors for Treatment of Chronic Urticaria

• Leukotriene Inhibitors for Migraine Prophylaxis

• Other Uses for Leukotriene Inhibitors?

• Safety of Leukotriene Inhibitors

• Concluding Thoughts

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