Disease relevance of ONO-RS 411

• Churg-Strauss syndrome after corticosteroid withdrawal in an asthmatic patient treated with pranlukast [1].
• We investigated the contribution of peptide leukotrienes to LPS-induced acute lung injury using a potent antagonist, ONO-1078 (ONO) [2].
• To examine the relative role of cysteinyl leukotrienes in immediate airway obstruction in human subjects with asthma after allergen challenge, we investigated the effect of ONO-1078, a potent receptor antagonist of cysteinyl leukotrienes, on the response [3].
• Because of its anti-inflammatory effects, ONO-1078 should be useful in the treatment of bronchial asthma [4].
• Pranlukast improves not only hypersensitivity to analgesic, but also bronchial hyperresponsiveness in aspirin-intolerant asthma [5].

High impact information on ONO-RS 411

• The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma [6].
• In particular, the cysteinyl-leukotriene analogues SKF 104,353, ONO-1078, and BAYu9773 were strong inhibitors (IC50 values: 0.13, 3. 7, and 7.6 microM, respectively) [7].
• Pranlukast treatment for 2 weeks decreased mean sputum eosinophil count from 0.15 x 10(6)/g (5.3% of cells) before treatment to 0.02 x 10(6)/g (0.7% of cells) after treatment (p < 0.05), whereas placebo did not [8].
• CONCLUSION: Pretreatment with pranlukast attenuated allergen-induced airway responses and the decrease in circulating myeloid dendritic cells, demonstrating a novel role of cysteinyl leukotrienes in dendritic cell trafficking [9].
• In a randomized, double-blind crossover study, we examined the effects of 2 weeks of treatment with pranlukast 300 mg twice a day or placebo on allergen-induced changes in airway eosinophil number and bone marrow eosinophil progenitors in 15 subjects with mild asthma [8].

Chemical compound and disease context of ONO-RS 411

• We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine in 32 adult patients with mild or moderate bronchial asthma; those who were in stable clinical condition were allocated to this study [10].
• Lung inflammation, cytokine profiles, LT production, and viral RNA in lung tissues were compared in 5 groups of 8 mice each: controls, D farinae allergen sensitized, D farinae sensitized and RSV infected, D farinae sensitized and RSV infected with dexamethasone, and D farinae sensitized and RSV infected with pranlukast, an LTRA [11].
• The leukotriene receptor antagonist pranlukast (SB 205312, ONO-1078) has demonstrated clinical activity as an antiasthma drug in traditional challenge models, including exercise-induced asthma and inhaled bronchoprovocations with sulpyrine (an aspirin analogue), antigen, methacholine, leukotriene C4, and leukotriene D4 [12].
• Twenty-two patients with moderate to severe bronchial asthma receiving an inhaled corticosteroid (beclomethasone dipropionate) were treated with pranlukast (225 mg b.i.d.) for 4 weeks, and their peak expiratory flow (PEF) and asthmatic symptoms were monitored during the treatment period [13].
• These results suggest that LTC4 may play a role in the pathogenesis of delayed cerebral vasospasm, directly or indirectly, and ONO-1078 may have a therapeutic effect on the prevention of the development of delayed cerebral vasospasm [14].

Biological context of ONO-RS 411

• Provocation of bronchoconstriction was completely inhibited in subjects whose plasma ONO-1078 levels were more than 0.5 microgram/ml [15].
• We conclude that (1) ONO-1078 attenuates LPS-induced acute lung injury; and (2) this effect appears mainly a result of its potent antagonistic actions against peptide leukotrienes and also, in part, the suppression of neutrophil chemotaxis [2].
• Mean morning home PEFR increased by 10.8 to 18.61/min (95% CI 0.2 to 29.3 l/min) in patients treated with pranlukast compared with a slight deterioration in those given placebo [16].
• We conclude that LTC(4) S genotype is predictive of the clinical response to a cysLT(1) antagonist, pranlukast, in Japanese patients with moderate asthma [17].
• We examined the interaction between the clinical response to a cysLT(1) antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C(4) synthase (LTC(4) S) gene in Japanese patients with moderate asthma [17].

Anatomical context of ONO-RS 411

• In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased (p = 0.007 and p = 0.025, respectively), compared with no change in the ONO-1078 group [18].
• Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma [19].
• As pranlukast pretreatment did not affect plasma extravasation induced by mast cell degranulation, and depletion of platelets did not influence the pranlukast-inhibitable plasma extravasation induced by rhC5a injection, cys-LTs are most likely produced by transcellular biosynthesis involving PMNs and vascular wall cells [20].
• ONO-1078 antagonizes diarrhea-causing changes in ion transport and smooth muscle contraction induced by peptidoleukotrienes in rat and human colon in vitro [21].
• To do this we tested the effects of the selective and potent LTD(4) antagonist pranlukast on airway responses to ovalbumin (OVA) challenge of naive recipients of CD4(+) T cells isolated from the cervical lymph nodes of OVA-sensitized donor rats [22].

Associations of ONO-RS 411 with other chemical compounds

• The effect of an oral leukotriene antagonist, ONO-1078, on allergen-induced immediate bronchoconstriction in asthmatic subjects [3].
• METHODS: Four groups of BALB/c mice (control mice, Dermatophagoides farinae allergen-sensitized mice, pranlukast cysLT receptor antagonist-treated allergen-sensitized mice, and dexamethasone-treated allergen-sensitized mice) were examined [23].
• [(3)H]LTD(4) binding and LTD(4)-induced calcium mobilization in HEK-293 cells expressing the CysLT receptor were potently inhibited by the structurally distinct CysLTR antagonists pranlukast, montelukast, zafirlukast, and pobilukast; the rank order potency was pranlukast = zafirlukast > montelukast > pobilukast [24].
• RESULTS: A single dose of pranlukast produced a 10.6 fold increase in PC35sGaw (95% confidence interval (CI) 4.4 to 25.5; p < 0.001) for LTD4 at 3.5 hours after dosing compared with placebo [25].
• RESULTS: When the pranlukast and placebo treated groups were compared there were decreases in beta 2 agonist use, symptom score, and airway methacholine responsiveness after pranlukast but no increase in FEV1 was seen [19].

Gene context of ONO-RS 411

• Multidrug resistance-reversing agents, such as ONO-1078 and MK571, that directly interact and inhibit the transporting activity of MRP1 may be useful for treating ATL patients [26].
• These findings indicate that ONO-1078 suppresses the production of IL-4 (a cytokine that affects IgG antibody production), IL-5, and GM-CSF (cytokines that affect eosinophil activation) by peripheral blood mononuclear cells under stimulation with specific antigens in patients with bronchial asthma [4].
• RESULTS: Production of IL-4, IL-5, and GM-CSF by mononuclear cells under stimulation with mite antigen was markedly suppressed when they were exposed to ONO-1078 at a concentration of 10 microg/mL [4].
• Pranlukast inhibits NF-kappaB activation and MUC2 gene expression in cultured human epithelial cells [27].
• However, pranlukast did not inhibit MUC5AC gene transcription activity induced by lipoteichoic acid (LTA) in NCI-H292 cells [27].

Analytical, diagnostic and therapeutic context of ONO-RS 411

• METHODS: Ten atopic, nonsmoking patients with mild asthma and previously demonstrated early- and late-phase allergen-induced asthmatic responses participated in a double-blind, placebo-controlled, cross-over study, comparing treatment with either 450 mg pranlukast given twice daily or placebo for 5.5 days [28].
• In clinical trials, pranlukast was well tolerated in adult and paediatric patients with asthma, with an adverse event profile similar to that of placebo [29].
• Using fibreoptic bronchoscopy, bronchial biopsy specimens were obtained before and after treatment with either pranlukast (n = 10) or placebo (n = 7) [19].
• Pranlukast attenuated neurological deficits, reduced infarct volume and ameliorated neuron loss in the ischemic core 24 h after reperfusion; it reduced infarct volume, ameliorated neuron loss and inhibited astrocyte proliferation in the boundary zone 14 days after reperfusion [30].
• Flow cytometry demonstrated that pranlukast and MK-571 inhibit NF-kappa B activation in 1.3% DMSO-differentiated U-937 and Jurkat cells in a dose-related manner [31].

References