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Brief Review |
Address correspondence to Graziano Riccioni, M.D., via S. Moffa 61, CP 188, 71016 San Severo (FG), Italy; tel 39 333 636 6661; fax 39 882 371 735; e-mail: griccioni{at}hotmail.com.
Abstract
Evidence from clinical trials and experience derived from managing patients with asthma justify a broader role for leukotriene (LT) blockers in asthma management than that recommended by the National Asthma Education and Prevention Program and the NIH Heart, Lung and Blood Institute treatment guidelines. Many published clinical trials, reviews, and case reports have suggested important new applications of LT blockers (ie, montelukast, zafirlukast, pranlukast, and zileuton) in several diseases in which leukotrienes play a pathogenic role. These include paranasal sinus disease, allergic fungal sinusitis, migraine, chronic urticaria, atopic dermatitis, chronic obstructive pulmonary disease, allergic conjunctivitis, mastocytosis, bronchiolitis, idiopathic pulmonary fibrosis, interstitial cystitis, and irritable bowel syndrome. Although double-blind, randomized, placebo-controlled trials are needed to confirm the effects that these drugs may have in these diseases, the aim of this short review is to delineate the future roles that these drugs may have in the management of these conditions.
(received 28 August 2004; accepted 15 September 2004)
Keywords: leukotriene, leukotriene receptor antagonists, sinusitis, migraine, urticaria, atopic dermatitis, chronic obstructive pulmonary disease, allergic conjunctivitis, mastocytosis, idiopathic pulmonary fibrosis, interstitial cystitis, irritable bowel syndrome
Introduction
The leukotrienes (LTs) are lipoxygenase products derived from arachidonic acid (AA) metabolism that can be grouped into 2 classes based on the presence or absence of a thioether-linked peptide. The cysteinyl-LTs (Cys-LTs) contain a thioether linkage: glutathione in LTC4, cysteinyl-glycine in LTD4, and cysteine in LTE4. In contrast, LTB4, a dihydroxy derivative, is devoid of a thioether-linked peptide. These mediators are produced via the 5-lypoxy-genase (5-LO) pathway of AA by a variety of cells in response to allergic or other cellular stimuli that cause cell activation [1,2].
Two general approaches have been used successfully to regulate LTs actions: LTs synthesis inhibition and LTs receptor antagonism. The LTs synthesis inhibitors block key steps in the biosynthetic pathway (ie, 5-LO or 5-LO activating protein) to inhibit production of both Cys-LTs and LTB4, whereas the LT receptor antagonists (LTRAs) selectively block the Cys-LT1 receptor on target cells.
Leukotriene Modifier Drugs
Members of both types of LT blockers have been approved for use in the USA, Europe, and other nations (eg, Japan). The US Food and Drug Administration approved zileuton, a 5-LO inhibitor, in 1996, and two LTs blockers, zafirlukast and montelukast, in 1996 and 1998 respectively; pranlukast was approved in Japan in 1995.
The efficacy of montelukast, zafirlukast, pranlukast, and zileuton on bronchial asthma has been established in numerous randomized, controlled, multicenter clinical trials. LTs modifiers reduce asthma symptoms, short-acting ß2-agonist (SABA) use, and asthma exacerbations, and improve all indexes of pulmonary function, as measured by the increases in forced expiratory flow at one sec (FEV1), peak expiratory flow (PEF), quality of life (QoL), and indices of bronchial inflammation (blood eosinophils, inflammatory cells in the bronchial mucosa, exhaled nitric oxide, substance P, neurokinin A, eosinophil cationic protein, and serum myeloperoxidase)[3,4].
Leukotriene Receptor Antagonist Drugs
Montelukast. Montelukast is an orally bioavailable Cys-LTRA that is usually administered once daily. This drug has been approved for long-term treatment of asthma in adults (10 mg/day) and children age 2 to 14 yr (using lower dosages, depending on the age of the child). Therapeutic concentrations do not inhibit cytochrome P450 isoenzymes. The most common adverse effects observed in adults at the 10 mg daily dosage were comparable to placebo, and included headache (18.4% vs 18.1%), abdominal pain (2.9% vs 2.5%), and cough (2.7% vs 2.4%). Elevations in liver enzymes occurred at a frequency that was generally comparable with placebo. The most common adverse effects that occurred in children at an incidence of 2% were slightly (but not significantly) higher than placebo. These included diarrhea, laryngitis, pharyngitis, nausea, otitis, sinusitis, and viral infections. The adverse event profile did not change with prolonged montelukast treatment [5–8].
Zafirlukast. Zafirlukast is a Cys-LTRA that is approved for the treatment of asthma in children age 7 yr or older. It is administered orally twice daily and is metabolized by the liver; hepatic cytochrome P450 is inhibited by therapeutic concentrations. Therefore, there is a risk of drug interactions, and transient elevations of liver enzymes have been reported. The most common adverse effects that were comparable in incidence to placebo included headache (12.9% vs 11.7%), infections (3.5% vs 3.4%), nausea (3.1% vs 2.0%), and diarrhea (2.8% vs 2.1%). Other common adverse effects (eg, pharyngitis, rhinitis, flush syndrome, and increased cough) occurred at incidences identical to or lower than placebo [6,9–12].
Pranlukast. Pranlukast is an orally administered Cys-LTRA that is indicated for prophylactic treatment of chronic bronchial asthma in pediatric and adult patients. In clinical trials, pranlukast was well tolerated with an adverse event profile similar to that of the placebo. Gastrointestinal events and hepatic function abnormalities were the most common reported adverse effects, but were not significantly different from other LTRAs [6,13–18].
Zileuton. Zileuton is the only marketed drug with a specific effect on Cys-LTs synthesis via inhibition of the 5-LO enzyme. It is administered orally 4 times daily and is approved for treatment of asthma in patients 12 yr and older. It is metabolized by the cytochrome P450 isoenzymes and may, therefore, interact with other drugs metabolized by these enzymes, such as theophylline and warfarin. The use of zileuton is hampered by the dosing regimen and the requirement that liver enzymes be monitored. The adverse event profile in controlled clinical trials was generally similar to LTRAs. The most common adverse effects compared to placebo included headache (24.6% vs 24.0%), dyspepsia (8.2% vs 2.9%), unspecified pain (7.8% vs 5.3%), nausea (5.5% vs 3.7%), abdominal pain (4.6% vs 2.4%), and asthenia (3.8% vs 2.4%). Unlike the LTRAs, therapy with zileuton is associated with hepatotoxicity, and liver function enzymes should be monitored during treatment. Elevations of liver function tests may progress, remain unchanged, or resolve during continued treatment. At a dosage of 600 mg, 4 times daily, zileuton carries a pregnancy category C classification because of abnormalities noted in rabbit and rat fetuses [6,19–25].
Recent Clinical Applications
Paranasal sinus disease. LTs are inflammatory mediators that have an important role in paranasal sinus disease (PSD) and the formation of nasal polyps (NP). Cys-LTs are overproduced in asthmatic subjects with chronic hyperplastic rhinosinusistis (CHR) and NP [26]. In view of the fact that these agents lead to symptoms in asthmatics patients, the use of LTRAs, particularly montelukast and zafirlukast, seems appropriate [27,28]. A number of studies have indicated their role in inhibiting nasal symptoms in asthmatic patients. In addition, it has been suggested that many aspirin-intolerant asthma patients have NP and that treatment with the LTRAs results in improvement and resolution of the NP [29–32]. The LTRAs might be good alternatives to the long-term administration of oral steroids, in view of their systemic anti-inflammatory effects and acceptable safety profiles [33–37].
Allergic fungal sinusitis. Allergic fungal sinusitis (AFS) is a non-invasive form of highly recurrent, chronic, allergic, hypertrophic rhinosinusitis that can be distinguished clinically, histopatologically, and prognostically from the other forms of chronic fungal rhinosinusitis. There are characteristic presenting symptoms, physical examination findings, and laboratory tests (eg, elevated total serum IgE and positive inhalant allergy skin tests). Treatment involves sinus surgery, topical and systemic corticosteroids, antihistamines, and LTRAs [38–40]. Ongoing studies are elucidating the pathophysiological relationships and treatment options for AFS and other forms of CHR [41,42].
Migraine. Migraine (M) is a paroxysmal disorder characterized by recurrent attacks of headache, with or without associated visual and gastrointestinal disturbances. M can be classified in two main groups: common and classic. There is evidence that confirms the important roles of AA, prostaglandins, and LTs in the pathogenesis of M, based on measurements of this substances in biological fluids during and after the attack [43–45]. Non-steroidal anti-inflammatory agents (NSAIDs) have been widely used for treating M. A 2-mo, open-label study evaluated montelukast (10 or 20 mg/day) for prophylaxis of M and showed its potential as an effective, well-tolerated, prophylactic agent [46]. The pathogenesis of M is not well understood and there is need for prophylactic medications. Inhibition of mast cells release of anti-LT and other vasoactive molecules may be such an approach [47,48].
Chronic urticaria. Chronic urticaria (CU) is one of the most common and, in its chronic course, excruciating dermato-allergic diseases. Athough the pathogenesis of CU is not fully understood, recent studies have identified several important triggering factors. The dermal mast cells and their mediators play a central role in CU, which is a cutaneous autoimmune disorder mediated by autoantibodies to the high affinity IgE receptor on mast cells, with consequent production of various chemokines, cytokines, and LTs [49–52]. LTRAs might be effective for the treatment of CU [53,54]. Several studies documented that combined therapy with montelukast and zafirlukast produced significantly greater improvement than placebo or cetirizine monotherapy [55–57].
Atopic dermatitis. Atopic dermatitis (AD) is a chronic, relapsing, eczematous disorder of the skin that occurs in persons of all ages, but is more common in children. AD is associated with other atopic diseases such as allergic rhinoconjuntivitis and bronchial asthma. Nearly 80% of children with AD eventually develop allergic rhinitis or asthma. AD is classified as mixed (ie, cases associated with respiratory allergies) or pure, with intrinsic and extrinsic variants. In the extrinsic type, interleukin-4 (IL-4) is secreted by T-cells isolated from spontaneous lesions and skin-derived T-lymphocytes express more IL-13. There is evidence for enhanced LTs production in the pathogenesis of AD [58,59]. It has been suggested that LTRAs may be more successful for the treatment of the extrinsic subgroup of AD. In small clinical trials and case studies, montelukast was found to be a safe and effective alternative to steroid-sparing therapy in the management of patients with AD [59–62]. The same was true in pediatric patients treated with chewable montelukast day (5 mg/day for 24 wk) [63]. There are also supportive case reports [64].
Chronic obstructive pulmonary disease. LTs are involved in airway inflammation and mucus hyper-secretion, characteristically present in asthma and chronic obstructive pulmonary disease (COPD) [65]. Many studies have demonstrated selective increases of exhaled LTB4 and PGE2 in patients with COPD who may be relatively resistant to inhaled corticosteroid therapy [66]. In a randomized, double-blind, crossover, and placebo-controlled study of 23 patients with severe CODP, a single oral dose of 40 mg of zafirlukast demonstrated significant bronchodilator or antibronchoconstrictor effects compared to placebo [67], even in patients who are smokers [68].
A preliminary double-blind, randomized, placebo-controlled trial evaluated the effects of zileuton (500 mg twice/day), or placebo, on sputum LTB4 and myeloperoxidase (a marker of sputum neutrophil number and activation) concentrations in 17 patients with COPD and chronic bronchitis. This study suggested that the leukotriene synthesis inhibitor produced modest reductions in some measures of neutrophilic bronchial inflammation in patients with COPD [69]. A retrospective study documented that administration of montelukast (10 mg/day) to 20 patients with moderate to severe COPD produced significant improvement in shortness of breath, sputum production, wheezing, and nocturnal symptoms, as well as significant reductions in use of oral and inhaled corticosteroids, inhaled bronchodilators, and supplemental oxygen. There were also significant reductions in the number of visits to the emergency department, number of hospitalizations, and duration of hospitalizations for acute exacerbations of COPD [70].
Allergic conjunctivitis. Allergic conjuctivitis (AC) is the most frequent form of ocular allergy in patients who consult ophthalmologists and allergists [71,72]. The severity of the disease ranges from mild itching and redness, as seen in seasonal AC, to the serious, vision-threatening forms of ocular allergy that affect the cornea, such as atopic keratoconjunctivitis (AK). The pathogenesis of AC involves a complex mechanism that centers around IgE-mediated mast cell degranulation and release of multiple performed and newly formed inflammatory mediators. The diagnosis of AC is usually a clinical one that is made on a thorough history and careful examination [73]. Treatment of ocular allergy should begin with conservative measures including allergen avoidance, environmental control, ocular irrigation, and cold compresses [72]. Pharmacotherapy of AC consists of several classes of drugs: antihistamines, mast cell stabilizers, NSAIDs, topical steroids, and, in cases of AK, cyclosporine [71]. Many studies have evaluated the signs and symptoms of coexisting vernal keratoconjunctivitis in asthmatic patients treated with oral montelukast. There were significant and persistent reductions of ocular signs and symptoms in asthmatic patients with vernal keratoconjunctivitis who were treated for 15 days with montelukast. This points to a need for double-blind, placebo-controlled trials to evaluate the potential of this new treatment in patients with vernal keratoconjuctivitis [74,75].
Mastocytosis. Systemic mastocytosis (SM) is a rare, often misdiagnosed, condition characterized by the accumulation, abnormal proliferation, and activation of mast cells in various tissues. SM has been treated with various inhibitors of mast-cell mediators, including corticosteroids, antihistamines, and interferon [76,77]. A trial in young patients with SM showed that treatment with montelukast (0.25 mg/kg body wt) resulted in improvement of their symptoms and skin lesions [78].
Bronchiolitis. Many published studies have documented increased LTE4 levels in patients with infectious diseases due to respiratory syncytial virus (RSV), such as bronchitis, pneumonia, and bronchiolitis, suggesting that LTs may be involved. Cys-LTs, in fact, are released during RSV infection and may contribute to the inflammatory state [79]. In a 36-mo, double-blind trial, 130 infants (median age 9 mo) who were hospitalized with acute RSV bronchiolitis were randomized into 2 parallel-comparison groups of 5-mg montelukast chewable tablets or matching placebo given for 28 days starting within 7 days after the onset of symptoms. Infants in the montelukast group were free of symptoms on 22% of the days and nights, which was significantly lower than the placebo group, and there were significant reductions in daytime coughing and clinical exacerbations compared to the placebo [80–84].
Irritable bowel syndrome. Irritable bowel syndrome (IBS) is a functional intestinal motor disorder clinically consisting of altered bowel habits, abdominal pain, and the absence of any detectable organic pathologic process [85]. The most used definition in epidemiological studies is represented by the revised ROME II criteria, where IBS is characterized by abdominal discomfort or pain that cannot be explained by structural or biochemical abnormalities and that has at least 2 of the following 3 features: (a) the pain is relieved by defecation; (b) the onset of symptoms is associated with altered frequency of bowel movements (diarrhea or constipation); and (c) the onset of symptoms is associated with an alteration in the form of the stool (loose, watery, or pellet-like) [85,86]. Beneficial effects of montelukast have been observed in humans with IBS [87] and in rats with experimental colitis [88]. Case reports of asthmatic patients with IBS and nontropical sprue documented improvement of symptoms (particularly diarrhea) after 1 wk of treatment with montelukast (10 mg/day) [87]. In a published study, 20% of patients with IBS had an partial case of sprue. These patients may benefit from treatment with LTRAs [89].
Idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF), also termed cryptogenic fibrosing alveolitis, is a clinicopathological syndrome characterised by cough, exertional dyspnea, basilar crackles, a restrictive defect on pulmonary function tests, honeycombing on high-resolution, thin-section, computed tomography (CAT) scans, and histological diagnosis of usual interstitial pneumonia on lung biopsy. The clinical course is indolent, but inexorable. The molecular processes that underlie the pulmonary fibrogenesis may provide targets for therapeutic intervention [90,91]. Current therapeutic strategies are aimed at suppressing inflammation. Patients with IPF have increased lung LTB4 and LTC4 levels, suggesting constitutive activation of the 5-LO pathway in this disorder [92]. Mice deficient in 5-lipoxygenase have reduced capacity to biosynthesize cys-LTs, reduced lung inflammation, and reduced lung fibrosis following intratracheal administration of bleomycin [93]. In 5-lipoxygenase-null mice there is increased production of an antifibrotic cytokine, interferon-
and of the antiinflammatory/antifibrotic eicosanoid, PGE2, suggesting that the 5-lipoxygenase pathway may influence the fibrotic response either directly via production of LTs or indirectly by modulating the biosynthesis of other protective mediators [93,94]. Clinical trials are currently underway or in the planning stages, and include drugs such as interferon-1b, pirfenidone, acetylcysteine, etanercept (a tumor necrosis factor 
-antagonist), bosentan (an endothelin-1 receptor antagonist), and zileuton [95,96]. Use of LTRAs may provide an alternative treatment approach to modulating this pathway in IPF [96].
Interstitial cystitis. Interstitial cystitis (IC) is a debilitating, chronic, bladder disease characterized by urinary urgency and frequency, with bladder and pelvic pain on bladder filling. The condition is easily confused with urinary tract infections that do not respond to antibiotic therapy. The diagnosis of IC is difficult and should be based on the patient’s history, the physical examination, and cystoscopy. The pathophysiology of IC is multimodal [97] and the most consistent pathological finding is a large number of activated bladder mast cells [98]. Numerous pharmacologic treatments have addressed this condition with limited success [99], including pentosan polysulfate, heparin, tricyclic anti-depressants, intravesical dimethyl sulfoxide, and bacille Calmette-Guerin [100–102]. The presence of LTD4 receptors in human detrusor myocytes and increased urinary LTE4 in patients with IC and detrusor mastocytosis implies a role for cysteinyl-containing LTs as proinflammatory mediators in this disease [103]. In 10 women with IC, who were diagnosed according to the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) criteria, treatment with montelukast (10 mg/day for 3 mo) resulted in significant mitigation of urinary frequency and pain [104].
Conclusions
Most of the long-term therapeutic experience with LTRAs comes from treating children with asthma [105]. However, these agents may also be useful for treating other chronic diseases, such as paranasal sinus disease, allergic fungal sinusitis, migraine, urticaria, atopic dermatitis, COPD, allergic conjunctivitis, mastocytosis, bronchiolitis, irritable bowel syndrome, idiopathic pulmonary fibrosis, and interstitial cystitis. The recognition of the importance of LTs in the pathogenesis of these diseases has led to the development of new applications of LTRAs. Controlled clinical trials with the currently used LTs blockers are needed to establish the effectiveness of these drugs for these various indications, especially since the LTRAs are generally safe and well tolerated, with adverse effect profiles similar to that of placebo. Another approach may be to inhibit the release of LTs from activated mast cells with select flavonoids [106–107]. Potential formulations combine the flavonoids with other natural substances with anti-allergic and anti-inflammatory activities [108–109].
References
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  D. Bouros and K. M. Antoniou Current and future therapeutic approaches in idiopathic pulmonary fibrosis Eur. Respir. J., October 1, 2005; 26(4): 693 - 703. [Abstract] [Full Text] [PDF]
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