Antiinflammatory therapies for cystic fibrosis: past, present, and future.

Johnson CE.

School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York 14260, USA. prescott buffalo.edu

Inflammation is a major component of the vicious cycle characterizing cystic fibrosis pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Antiinflammatory drugs for cystic fibrosis lung disease appear to have beneficial effects on disease parameters. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possesses antiinflammatory properties. Inhaled corticosteroids, colchicine, methotrexate, montelukast, pentoxifylline, nutritional supplements, and protease replacement have not had a significant impact on the disease. Therapy with oral corticosteroids, ibuprofen, and fish oil is limited by adverse effects. Azithromycin appears to be safe and effective, and is thus the most promising antiinflammatory therapy available for patients with cystic fibrosis. Pharmacologic therapy with antiinflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred.

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The role of leukotrienes in allergic rhinitis.

Henderson WR Jr.

Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0642, USA. petersm umich.edu

OBJECTIVE: To review the role of cysteinyl leukotrienes (cysLTs) in allergic rhinitis and the scientific rationale for therapy with leukotriene receptor antagonists (LTRAs). DATA SOURCES: Relevant basic science and clinical articles were identified by a search of the PubMed database for articles published from 1984 to 2004 using the following keywords: allergic rhinitis; nose; immune response; allergen challenge; leukotrienes C, D, and E; cysteinyl leukotriene; cysteinyl leukotriene receptor; cytokine; leukocyte; montelukast; zafirlukast; and pranlukast. STUDY SELECTION: The authors' expert opinion was used to select studies for inclusion in this review. RESULTS: CysLTs are synthesized via 5-lipoxygenase metabolism of arachidonic acid by mast cells and basophils during the early-phase response to antigen and by eosinophils and macrophages during the late phase. The cysLT levels in nasal secretions are elevated after short-term allergen instillation and in allergy season in patients with allergic rhinitis. These lipid mediators act locally and systemically by interacting with receptors, particularly the cysLT1 receptor, on target cells. Evidence derived from topical application of cysLTs in the nose and from the effects of LTRAs indicates that cysLTs contribute to nasal mucous secretion, congestion, and inflammation. CysLTs promote allergic inflammation by enhancing immune responses and the production, adhesion, migration, and survival of inflammatory cells such as eosinophils. They also increase the generation of an array of other proinflammatory mediators, such as cytokines, which in turn increase the production of and receptors for cysLTs. Clinical trials have demonstrated that LTRAs have significant but modest efficacy as single agents but additive efficacy when used with other classes of agents. CONCLUSIONS: CysLTs fulfill the criteria for relevant mediators of allergic rhinitis via their diverse effects on immune, inflammatory, and local structural components of disease. By blocking the cysLT1 receptor responsible for most of these effects, LTRAs represent a useful approach to treatment of this important and prevalent disorder.

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An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma.

Scadding GK.

Royal National Throat, Nose and Ear Hospital, London, UK.

BACKGROUND: Nasal polyposis occurs frequently in patients with intrinsic asthma, especially in those who are aspirin sensitive. It can be difficult to treat effectively, even with surgery and regular topical intranasal corticosteroids many patients are still symptomatic. OBJECTIVE: To investigate the response to montelukast, a leukotriene D4 receptor antagonist, as an add-on therapy to topical and inhaled corticosteroids in patients, both aspirin sensitive (AS) and aspirin tolerant (AT), with nasal polyposis and asthma. METHODS: Nasal polyposis symptoms were assessed by visual analogue scales; nasal polyps were assessed by nasendoscopy and via the measurement of nasal volumes by acoustic rhinometry. The nasal airway was assessed by nasal inspiratory peakflow (NIPF). Asthma was monitored using symptom scores and peak expiratory flow measurements. Aspirin sensitivity was assessed by history together with intranasal lysine aspirin challenge. Upper and lower airway nitric oxide measurements were made before and during treatment. RESULTS: Clinical subjective improvement in nasal polyposis occurred in 64% AT (P < 0.01), patients and 50% AS patients (P > 0.05); asthma improvement in 87% AT and 61% AS patients (P < 0.05 for both). Objective changes in peak flow occurred only in AT patients (P < 0.05). Acoustic rhinometry, nasal inspiratory peak flow and nitric oxide levels did not change significantly in any group, however, correlations were seen between nitric oxide levels and polyp scores and between nitric oxide levels and acoustic rhinometry changes. Improvement on montelukast therapy was not associated with any of the following variables: age, sex, skin prick test positivity, disease duration or aspirin sensitivity. (P > 0.05 for all). CONCLUSION: The findings are consistent with a subgroup of nasal polyps/asthma patients in whom leukotriene receptor antagonists are effective. This is not related to aspirin sensitivity. Further placebo-controlled studies need to be undertaken.

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Effect of montelukast on nuclear factor kappaB activation and proinflammatory molecules.

Furukawa S.

Department of Pediatrics, Yamaguchi University School of Medicine, Yamaguchi, Japan.

BACKGROUND: Montelukast is known as a cysteinyl leukotriene 1 receptor antagonist. However, the action of montelukast in terms of nuclear factor KB (NF-kappaB) activation and the production of proinflammatory molecules is unknown. OBJECTIVE: To demonstrate the potential anti-inflammatory effect of montelukast. METHODS: We examined whether montelukast inhibits the activation of NF-kappaB, a transcription factor that regulates the expression of proinflammatory molecules. The inhibitory effects of montelukast on tumor necrosis factor kappa (TNF-kappa)--induced NF-kappaB activation on THP-1 cells, a human monocytic leukemia cell line, were evaluated by flow cytometry, and those on lipopolysaccharide-induced interleukin 1beta (IL-1beta), IL-6, TNF-alpha, and monocyte chemoattractant protein 1 (MCP-1) production in peripheral blood mononuclear cells were evaluated by enzyme-linked immunosorbent assay. RESULTS: Flow cytometry demonstrated that montelukast inhibited NF-kappaB activation in THP-1 cells in a dose-related manner. Furthermore, 10(-5)M montelukast significantly inhibited lipopolysaccharide-induced IL-6, TNF-alpha, and MCP-1 production in the peripheral blood mononuclear cells of controls and patients with asthma. Lipopolysaccharide-induced IL-1beta production was not inhibited by montelukast. CONCLUSIONS: These findings suggest that high doses of montelukast modulate the production of IL-6, TNF-alpha, and MCP-1 through the inhibition of NF-kappaB activation. However, the anti-inflammatory effect of montelukast at therapeutic doses in patients with asthma needs to be further investigated.

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Effects of montelukast in patients with persistent asthma using inhaled corticosteroids plus additional second-line therapy.

Lee DK.

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