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Home , Antileukotriene, Pranlukast

Annals of Clinical & Laboratory Science, vol. 34, no. 4, 2004 379

Brief Review: Advances in Therapy with Drugs

Graziano Riccioni,1 Carmine Di Ilio,1 Pio Conti,2 Theoharis C. Theoharides,3 Nicolantonio D’Orazio1 1 Department of Biomedical Sciences, University G. D’Annunzio, Chieti, Italy. 2 Department of Oncology and Neuroscience, University G. D’Annunzio, Chieti, Italy. 3 Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts, USA.

Abstract. Evidence from clinical trials and experience derived from managing patients with justify a broader role for (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, , , , and ) in several diseases in which play a pathogenic role. These include paranasal sinus disease, allergic fungal sinusitis, migraine, chronic urticaria, atopic dermatitis, chronic obstructive pulmonary disease, allergic conjunctivitis, mastocytosis, , 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 antagonists, sinusitis, migraine, urticaria, atopic dermatitis, chronic obstructive pulmonary disease, allergic conjunctivitis, mastocytosis, idiopathic pulmonary fibrosis, interstitial cystitis, irritable bowel syndrome

Introduction Two general approaches have been used successfully to regulate LTs actions: LTs synthesis The leukotrienes (LTs) are lipoxygenase products inhibition and LTs receptor antagonism. The LTs derived from (AA) metabolism that synthesis inhibitors block key steps in the can be grouped into 2 classes based on the presence biosynthetic pathway (ie, 5-LO or 5-LO activating or absence of a thioether-linked peptide. The protein) to inhibit production of both Cys-LTs and cysteinyl-LTs (Cys-LTs) contain a thioether linkage: LTB4, whereas the LT receptor antagonists (LTRAs) glutathione in LTC4, cysteinyl-glycine in LTD4, and selectively block the Cys-LT1 receptor on target cells. cysteine in LTE4. In contrast, LTB4, a dihydroxy derivative, is devoid of a thioether-linked peptide. Leukotriene Modifier Drugs These mediators are produced via the 5-lypoxy- genase (5-LO) pathway of AA by a variety of cells in Members of both types of LT blockers have been response to allergic or other cellular stimuli that approved for use in the USA, Europe, and other cause cell activation [1,2]. nations (eg, Japan). The US Food and Drug Administration approved zileuton, a 5-LO inhibitor, in 1996, and two LTs blockers, zafirlukast and Address correspondence to Graziano Riccioni, M.D., via S. Moffa 61, CP 188, 71016 San Severo (FG), Italy; tel 39 333 montelukast, in 1996 and 1998 respectively; pran- 636 6661; fax 39 882 371 735; e-mail: [email protected]. lukast was approved in Japan in 1995.

0091-7370/04/0400-0379. $2.25. © 2004 by the Association of Clinical Scientists, Inc.

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The efficacy of montelukast, zafirlukast, pran- headache (12.9% vs 11.7%), infections (3.5% vs lukast, and zileuton on bronchial asthma has been 3.4%), nausea (3.1% vs 2.0%), and diarrhea (2.8% established in numerous randomized, controlled, vs 2.1%). Other common adverse effects (eg, multicenter clinical trials. LTs modifiers reduce pharyngitis, rhinitis, flush syndrome, and increased asthma symptoms, short-acting β2-agonist (SABA) cough) occurred at incidences identical to or lower use, and asthma exacerbations, and improve all than placebo [6,9-12]. indexes of pulmonary function, as measured by the increases in forced expiratory flow at one sec (FEV1), Pranlukast. Pranlukast is an orally administered Cys- peak expiratory flow (PEF), quality of life (QoL), LTRA that is indicated for prophylactic treatment and indices of bronchial (blood of chronic bronchial asthma in pediatric and adult , inflammatory cells in the bronchial patients. In clinical trials, pranlukast was well mucosa, , substance P, tolerated with an adverse event profile similar to that neurokinin A, cationic protein, and of the placebo. Gastrointestinal events and hepatic serum myeloperoxidase)[3,4]. function abnormalities were the most common reported adverse effects, but were not significantly Leukotriene Drugs different from other LTRAs [6,13-18].

Montelukast. Montelukast is an orally bioavailable Zileuton. Zileuton is the only marketed drug with a Cys-LTRA that is usually administered once daily. specific effect on Cys-LTs synthesis via inhibition of This drug has been approved for long-term the 5-LO . It is administered orally 4 times treatment of asthma in adults (10 mg/day) and daily and is approved for treatment of asthma in children age 2 to 14 yr (using lower dosages, patients 12 yr and older. It is metabolized by the depending on the age of the child). Therapeutic cytochrome P450 isoenzymes and may, therefore, concentrations do not inhibit cytochrome P450 interact with other drugs metabolized by these isoenzymes. The most common adverse effects , such as and warfarin. The use observed in adults at the 10 mg daily dosage were of zileuton is hampered by the dosing regimen and comparable to placebo, and included headache the requirement that liver enzymes be monitored. (18.4% vs 18.1%), abdominal pain (2.9% vs 2.5%), The adverse event profile in controlled clinical trials and cough (2.7% vs 2.4%). Elevations in liver was generally similar to LTRAs. The most common enzymes occurred at a frequency that was generally adverse effects compared to placebo included comparable with placebo. The most common headache (24.6% vs 24.0%), dyspepsia (8.2% vs adverse effects that occurred in children at an 2.9%), unspecified pain (7.8% vs 5.3%), nausea incidence of 2% were slightly (but not significantly) (5.5% vs 3.7%), abdominal pain (4.6% vs 2.4%), higher than placebo. These included diarrhea, laryn- and asthenia (3.8% vs 2.4%). Unlike the LTRAs, gitis, pharyngitis, nausea, otitis, sinusitis, and viral therapy with zileuton is associated with infections. The adverse event profile did not change hepatotoxicity, and liver function enzymes should with prolonged montelukast treatment [5-8]. be monitored during treatment. Elevations of liver function tests may progress, remain unchanged, or Zafirlukast. Zafirlukast is a Cys-LTRA that is resolve during continued treatment. At a dosage of approved for the treatment of asthma in children 600 mg, 4 times daily, zileuton carries a pregnancy age 7 yr or older. It is administered orally twice daily category C classification because of abnormalities and is metabolized by the liver; hepatic cytochrome noted in rabbit and rat fetuses [6,19-25]. P450 is inhibited by therapeutic concentrations. Therefore, there is a risk of drug interactions, and Recent Clinical Applications transient elevations of liver enzymes have been reported. The most common adverse effects that Paranasal sinus disease. LTs are inflammatory were comparable in incidence to placebo included mediators that have an important role in paranasal

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sinus disease (PSD) and the formation of nasal lactic . Inhibition of mast cells release polyps (NP). Cys-LTs are overproduced in asthmatic of anti-LT and other vasoactive molecules may be subjects with chronic hyperplastic rhinosinusistis such an approach [47,48]. (CHR) and NP [26]. In view of the fact that these agents lead to symptoms in asthmatics patients, the Chronic urticaria. Chronic urticaria (CU) is one of use of LTRAs, particularly montelukast and the most common and, in its chronic course, zafirlukast, seems appropriate [27,28]. A number excruciating dermato-allergic diseases. Athough the of studies have indicated their role in inhibiting nasal pathogenesis of CU is not fully understood, recent symptoms in asthmatic patients. In addition, it has studies have identified several important triggering been suggested that many aspirin-intolerant asthma factors. The dermal mast cells and their mediators patients have NP and that treatment with the LTRAs play a central role in CU, which is a cutaneous results in improvement and resolution of the NP autoimmune disorder mediated by autoantibodies [29-32]. The LTRAs might be good alternatives to to the high affinity IgE receptor on mast cells, with the long-term administration of oral steroids, in view consequent production of various chemokines, of their systemic anti-inflammatory effects and cytokines, and LTs [49-52]. LTRAs might be acceptable safety profiles [33-37]. effective for the treatment of CU [53,54]. Several studies documented that combined therapy with Allergic fungal sinusitis. Allergic fungal sinusitis montelukast and zafirlukast produced significantly (AFS) is a non-invasive form of highly recurrent, greater improvement than placebo or cetirizine chronic, allergic, hypertrophic rhinosinusitis that can monotherapy [55-57]. be distinguished clinically, histopatologically, and prognostically from the other forms of chronic Atopic dermatitis. Atopic dermatitis (AD) is a fungal rhinosinusitis. There are characteristic chronic, relapsing, eczematous disorder of the skin presenting symptoms, physical examination that occurs in persons of all ages, but is more findings, and laboratory tests (eg, elevated total common in children. AD is associated with other serum IgE and positive inhalant skin tests). atopic diseases such as allergic rhinoconjuntivitis and Treatment involves sinus surgery, topical and bronchial asthma. Nearly 80% of children with AD systemic , , and LTRAs eventually develop or asthma. AD [38-40]. Ongoing studies are elucidating the is classified as mixed (ie, cases associated with pathophysiological relationships and treatment respiratory ) or pure, with intrinsic and options for AFS and other forms of CHR [41,42]. extrinsic variants. In the extrinsic type, interleukin- 4 (IL-4) is secreted by T-cells isolated from Migraine. Migraine (M) is a paroxysmal disorder spontaneous lesions and skin-derived T-lymphocytes characterized by recurrent attacks of headache, with express more IL-13. There is evidence for enhanced or without associated visual and gastrointestinal LTs production in the pathogenesis of AD [58,59]. disturbances. M can be classified in two main groups: It has been suggested that LTRAs may be more common and classic. There is evidence that confirms successful for the treatment of the extrinsic subgroup the important roles of AA, prostaglandins, and LTs of AD. In small clinical trials and case studies, in the pathogenesis of M, based on measurements montelukast was found to be a safe and effective of this substances in biological fluids during and after alternative to steroid-sparing therapy in the the attack [43-45]. Non-steroidal anti-inflammatory management of patients with AD [59-62]. The same agents (NSAIDs) have been widely used for treating was true in pediatric patients treated with chewable M. A 2-mo,open-label study evaluated montelukast montelukast day (5 mg/day for 24 wk) [63]. There (10 or 20 mg/day) for prophylaxis of M and showed are also supportive case reports [64]. its potential as an effective, well-tolerated, prophylactic agent [46]. The pathogenesis of M is Chronic obstructive pulmonary disease. LTs are not well understood and there is need for prophy- involved in airway inflammation and mucus hyper-

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secretion, characteristically present in asthma and Treatment of ocular allergy should begin with chronic obstructive pulmonary disease (COPD) conservative measures including avoidance, [65]. Many studies have demonstrated selective environmental control, ocular irrigation, and cold increases of exhaled LTB4 and PGE2 in patients with compresses [72]. Pharmacotherapy of AC consists COPD who may be relatively resistant to inhaled of several classes of drugs: antihistamines, therapy [66]. In a randomized, stabilizers, NSAIDs, topical steroids, and, in cases double-blind, crossover, and placebo-controlled of AK, cyclosporine [71]. Many studies have study of 23 patients with severe CODP, a single oral evaluated the signs and symptoms of coexisting dose of 40 mg of zafirlukast demonstrated signif- vernal keratoconjunctivitis in asthmatic patients icant or antibronchoconstrictor treated with oral montelukast. There were significant effects compared to placebo [67], even in patients and persistent reductions of ocular signs and who are smokers [68]. symptoms in asthmatic patients with vernal A preliminary double-blind, randomized, keratoconjunctivitis who were treated for 15 days placebo-controlled trial evaluated the effects of with montelukast. This points to a need for double- zileuton (500 mg twice/day), or placebo, on sputum blind, placebo-controlled trials to evaluate the LTB4 and myeloperoxidase (a marker of sputum potential of this new treatment in patients with neutrophil number and activation) concentrations vernal keratoconjuctivitis [74,75]. in 17 patients with COPD and chronic bronchitis. This study suggested that the leukotriene synthesis Mastocytosis. Systemic mastocytosis (SM) is a rare, inhibitor produced modest reductions in some often misdiagnosed, condition characterized by the measures of neutrophilic bronchial inflammation in accumulation, abnormal proliferation, and activ- patients with COPD [69]. A retrospective study ation of mast cells in various tissues. SM has been documented that administration of montelukast (10 treated with various inhibitors of mast-cell mg/day) to 20 patients with moderate to severe mediators, including corticosteroids, antihistamines, COPD produced significant improvement in and interferon [76,77]. A trial in young patients shortness of breath, sputum production, wheezing, with SM showed that treatment with montelukast and nocturnal symptoms, as well as significant (0.25 mg/kg body wt) resulted in improvement of reductions in use of oral and inhaled corticosteroids, their symptoms and skin lesions [78]. inhaled , and supplemental oxygen. There were also significant reductions in the number Bronchiolitis. Many published studies have of visits to the emergency department, number of documented increased LTE4 levels in patients with hospitalizations, and duration of hospitalizations for infectious diseases due to respiratory syncytial virus acute exacerbations of COPD [70]. (RSV), such as bronchitis, pneumonia, and bronch- iolitis, suggesting that LTs may be involved. Cys- Allergic conjunctivitis. Allergic conjuctivitis (AC) LTs, in fact, are released during RSV infection and is the most frequent form of ocular allergy in patients may contribute to the inflammatory state [79]. In a who consult ophthalmologists and allergists [71,72]. 36-mo, double-blind trial, 130 infants (median age The severity of the disease ranges from mild itching 9 mo) who were hospitalized with acute RSV and redness, as seen in seasonal AC, to the serious, bronchiolitis were randomized into 2 parallel- vision-threatening forms of ocular allergy that affect comparison groups of 5-mg montelukast chewable the cornea, such as atopic keratoconjunctivitis (AK). tablets or matching placebo given for 28 days starting The pathogenesis of AC involves a complex within 7 days after the onset of symptoms. Infants mechanism that centers around IgE-mediated mast in the montelukast group were free of symptoms on cell degranulation and release of multiple performed 22% of the days and nights, which was significantly and newly formed inflammatory mediators. The lower than the placebo group, and there were signif- diagnosis of AC is usually a clinical one that is made icant reductions in daytime coughing and clinical on a thorough history and careful examination [73]. exacerbations compared to the placebo [80-84].

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Irritable bowel syndrome. Irritable bowel syndrome uction of an antifibrotic cytokine, interferon-γ, and (IBS) is a functional intestinal motor disorder of the antiinflammatory/antifibrotic , clinically consisting of altered bowel habits, abdom- PGE2, suggesting that the 5-lipoxygenase pathway inal pain, and the absence of any detectable organic may influence the fibrotic response either directly pathologic process [85]. The most used definition via production of LTs or indirectly by modulating in epidemiological studies is represented by the the biosynthesis of other protective mediators revised ROME II criteria, where IBS is characterized [93,94]. Clinical trials are currently underway or in by abdominal discomfort or pain that cannot be the planning stages, and include drugs such as explained by structural or biochemical abnormal- interferon-γ1b, pirfenidone, acetylcysteine, etaner- ities and that has at least 2 of the following 3 features: cept (a tumor necrosis factor α-antagonist), bosentan (a) the pain is relieved by defecation; (b) the onset (an endothelin-1 receptor antagonist), and zileuton of symptoms is associated with altered frequency of [95,96]. Use of LTRAs may provide an alternative bowel movements (diarrhea or constipation); and treatment approach to modulating this pathway in (c) the onset of symptoms is associated with an IPF [96]. alteration in the form of the stool (loose, watery, or pellet-like) [85,86]. Beneficial effects of montelukast Interstitial cystitis. Interstitial cystitis (IC) is a have been observed in humans with IBS [87] and debilitating, chronic, bladder disease characterized in rats with experimental colitis [88]. Case reports by urinary urgency and frequency, with bladder and of asthmatic patients with IBS and nontropical sprue pelvic pain on bladder filling. The condition is easily documented improvement of symptoms (partic- confused with urinary tract infections that do not ularly diarrhea) after 1 wk of treatment with respond to antibiotic therapy. The diagnosis of IC montelukast (10 mg/day) [87]. In a published study, is difficult and should be based on the patient’s 20% of patients with IBS had an partial case of sprue. history, the physical examination, and cystoscopy. These patients may benefit from treatment with The pathophysiology of IC is multimodal [97] and LTRAs [89]. the most consistent pathological finding is a large number of activated bladder mast cells [98]. Idiopathic pulmonary fibrosis. Idiopathic Numerous pharmacologic treatments have addressed pulmonary fibrosis (IPF), also termed cryptogenic this condition with limited success [99], including fibrosing alveolitis, is a clinicopathological syndrome pentosan polysulfate, heparin, tricyclic anti- characterised by cough, exertional dyspnea, basilar depressants, intravesical dimethyl sulfoxide, and crackles, a restrictive defect on pulmonary function bacille Calmette-Guerin [100-102]. The presence tests, honeycombing on high-resolution, thin- of LTD4 receptors in human detrusor myocytes and section, computed tomography (CAT) scans, and increased urinary LTE4 in patients with IC and histological diagnosis of usual interstitial pneumonia detrusor mastocytosis implies a role for cysteinyl- on lung biopsy. The clinical course is indolent, but containing LTs as proinflammatory mediators in this inexorable. The molecular processes that underlie disease [103]. In 10 women with IC, who were the pulmonary fibrogenesis may provide targets for diagnosed according to the US National Institute therapeutic intervention [90,91]. Current of Diabetes and Digestive and Kidney Diseases therapeutic strategies are aimed at suppressing (NIDDKD) criteria, treatment with montelukast inflammation. Patients with IPF have increased lung (10 mg/day for 3 mo) resulted in significant LTB4 and LTC4 levels, suggesting constitutive mitigation of urinary frequency and pain [104]. activation of the 5-LO pathway in this disorder [92]. Mice deficient in 5-lipoxygenase have reduced Conclusions capacity to biosynthesize cys-LTs, reduced lung inflammation, and reduced lung fibrosis following Most of the long-term therapeutic experience with intratracheal administration of bleomycin [93]. In LTRAs comes from treating children with asthma 5-lipoxygenase-null mice there is increased prod- [105]. However, these agents may also be useful for

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