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Andolast, a Novel Calcium-activated Potassium-channel Opener, Inhibits AMP and Exercise Induced Bronchoconstriction in Asthma
Abstracts S307
J ALLERGY CLIN IMMUNOL VOLUME 119, NUMBER 1
Andolast, a Novel Calcium-activated Potassium-channel Opener, Inhibits AMP and Exercise Induced Bronchoconstriction in Asthma S. H. Arshad1, M. D’Amato2, L. Rovati2, S. T. Holgate1; 1University of Southampton, Southampton, UNITED KINGDOM, 2Rotta Research Laboratorium/Rottapharm, Monza, ITALY. RATIONALE: Both, inflammatory and neurogenic mechanisms are involved in mediating bronchoconstriction in asthma. Andolast, a novel tetrazolyl-benzamido derivative, belonging to a new class of calcium activated, potassium (K1) channel openers, was studied to evaluate its bronchoprotective properties. METHODS: A randomised, double blind, 2 treatment, 2 period cross-over study was undertaken in 12 adults with atopic asthma to assess the efficacy and safety of a 7 days treatment course with andolast 8 mg three times a day, administered as dry powder inhaler. These subjects have demonstrated responsiveness to exercise and adenosine monophosphate (AMP) challenge at baseline. The magnitude of the protecting effect of andolast on AMP and exercise induced bronchoconstriction was evaluated on separate occasions after at least 5 days of treatment and with a least 2 days of interval in between the tests according to a randomized sequence. RESULTS: There was more than 5 fold increase in PC20FEV1 to AMP challenge following treatment with andolast compared to placebo, indicating protection against AMP induced bronchoconstriction. The treatment effect was highly significant [5.44, 95% CI (2.26, 13.09); p 5 0.002]. For exercise challenge, the area under the curve for FEV1 fall between 0 and 30 minutes (AUC0-30) post-exercise was significantly less for andolast compared to placebo [-160.88 (-306.69, -15.07); p 5 0.034], indicating a suppression of exercise induced bronchoprovocation. Treatment or test sequence had no effects on any of the outcome measures. No adverse events were attributable to andolast. CONCLUSIONS: Andolast prevented bronchoconstriction induced by AMP and exercise challenges and thus holds promise as a novel therapeutic agent for asthma. Funding: Rotta Research Laboratorium/Rottapharm
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Differential Contribution Of Cysteinyl Leukotriene Receptor Type 1 Gene In Patients With Aspirin Hypersensitivity S. Kim1, E. Yang1, J. Choi2, H. Lee1, C. Suh1, D. Nahm1, H. Park1; 1Ajou University School of Medicine, Suwon, REPUBLIC OF KOREA, 2Bundang Jesaeng general Hospital, Seongnam, REPUBLIC OF KOREA. RATIONALE: Recent studies have found pathogenesis of aspirin hypersensitivity including aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/ angioedema (AICU) may be associated with a persistent production of cysteinyl leukotruenes (CysLTs), but still remains to be further clarified. CysLTs are synthesized by leukotriene C4 synthase (LTC4S) and exerts its functional effect via CysLT receptor type 1 (CysLTR1). METHODS: To investigate the role of genetic polymorphism of CysLTR1 and LTC4S in aspirin hypersensitivity, three single nucleotide polymorphisms including -634C>T for CysLTR1 gene and -444A>C for LTC4S gene were genotyped by primer extension method in 156 AIA patients and 105 AICU patients. mRNA expression levels of CysLTR1 and LTC4S genes were examined after aspirin provocation test. RESULTS: Significant associations of CysLTR1-634C>T polymorphism with AIA was noted compared to AICU within female subjects (p 5 0.01); frequency of rare genotype of CysLTR1-634C>T polymorphism was significantly higher in AIA compared with AICU. However, no significant associations were found between LTC4S promoter polymorphism with any phenotype of aspirin hypersensitivity. CysLTR1 mRNA level significantly increased after aspirin provocation in AIA patients (p 5 0.013), while no significant changes were noted in AICU patients. CONCLUSION: These results suggested that CysLTR1 -634C>T polymorphism can be a genetic marker differentiating AIA and AICU among the patients with aspirin hypersensitivity. This study was supported by a grant of the Korea Health 21 R&D project. Ministry of Health & Welfare, R.O.K. (03-PJ10-PG13-GD01-0002).
Funding: Korea Health 21 R &D project. Ministry of Health & Welfare, R.O.K. (03-PJ10-PG13-GD01-0002).
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Modulation Of Cysteinyl Leukotriene (CysLT) Production And Responsiveness By Corticosteroids (CCS) J. A. Negri, L. Borish, J. W. Steinke; University Of Virginia Health Systems, Charlottesville, VA. RATIONALE: CCS are not thought to influence the secretion of CysLTs that occurs acutely during allergic reactions and similarly do not modulate bronchospastic responses following inhalation challenges with CysLTs. We hypothesized that CCS might inhibit metabolic pathways responsible for CysLT production and would thereby diminish the release of CysLTs in allergic diseases. Similarly, we hypothesized that CCS would modulate basal or cytokine-dependent expression of the CysLT receptors (CysLT1R and CysLT2R). METHODS: We investigated influences of fluticasone (10-9 and 10-7 M) on basal and IL-4-stimulated expression of mRNA transcripts for 5-lipoxygenase (5-LO), leukotriene C4 synthase (LTC4S), CysLT1R and CysLT2R within T lymphocytes, monocytes, and eosinophils enriched from healthy donors by quantitative RT-PCR. Effects on protein expression were subsequently evaluated by Western hybridization. RESULTS: Circulating immune cells express low levels of LTC4S and 5LO mRNA and expression was not influenced by CCS. In T lymphocytes, IL-4 induced LTC4S transcript expression (6.2-fold), which was prevented by fluticasone. While not altering basal or IL-4-stimulated CysLT1 receptor expression, fluticasone significantly inhibited IL-4-induced CysLT2R transcript production in all cell types tested. The ability of fluticasone to inhibit IL-4-induced expression of CysLT2R mRNA was confirmed at the protein level. CONCLUSIONS: While not blocking the acute release of CysLTs, CCS may diminish the capacity of cells to synthesize these compounds and thereby modulate their production. CCS did not alter CysLT1R expression, consistent with their lack of influence on bronchospasm that is mediated through the CysLT1R. Decreases in CysLT2R expression by CCS could modulate the profibrotic and remodeling effects mediated by these receptors. Funding: GlaxoSmithKline
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J ALLERGY CLIN IMMUNOL VOLUME 119, NUMBER 1
Andolast, a Novel Calcium-activated Potassium-channel Opener, Inhibits AMP and Exercise Induced Bronchoconstriction in Asthma S. H. Arshad1, M. D’Amato2, L. Rovati2, S. T. Holgate1; 1University of Southampton, Southampton, UNITED KINGDOM, 2Rotta Research Laboratorium/Rottapharm, Monza, ITALY. RATIONALE: Both, inflammatory and neurogenic mechanisms are involved in mediating bronchoconstriction in asthma. Andolast, a novel tetrazolyl-benzamido derivative, belonging to a new class of calcium activated, potassium (K1) channel openers, was studied to evaluate its bronchoprotective properties. METHODS: A randomised, double blind, 2 treatment, 2 period cross-over study was undertaken in 12 adults with atopic asthma to assess the efficacy and safety of a 7 days treatment course with andolast 8 mg three times a day, administered as dry powder inhaler. These subjects have demonstrated responsiveness to exercise and adenosine monophosphate (AMP) challenge at baseline. The magnitude of the protecting effect of andolast on AMP and exercise induced bronchoconstriction was evaluated on separate occasions after at least 5 days of treatment and with a least 2 days of interval in between the tests according to a randomized sequence. RESULTS: There was more than 5 fold increase in PC20FEV1 to AMP challenge following treatment with andolast compared to placebo, indicating protection against AMP induced bronchoconstriction. The treatment effect was highly significant [5.44, 95% CI (2.26, 13.09); p 5 0.002]. For exercise challenge, the area under the curve for FEV1 fall between 0 and 30 minutes (AUC0-30) post-exercise was significantly less for andolast compared to placebo [-160.88 (-306.69, -15.07); p 5 0.034], indicating a suppression of exercise induced bronchoprovocation. Treatment or test sequence had no effects on any of the outcome measures. No adverse events were attributable to andolast. CONCLUSIONS: Andolast prevented bronchoconstriction induced by AMP and exercise challenges and thus holds promise as a novel therapeutic agent for asthma. Funding: Rotta Research Laboratorium/Rottapharm
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Differential Contribution Of Cysteinyl Leukotriene Receptor Type 1 Gene In Patients With Aspirin Hypersensitivity S. Kim1, E. Yang1, J. Choi2, H. Lee1, C. Suh1, D. Nahm1, H. Park1; 1Ajou University School of Medicine, Suwon, REPUBLIC OF KOREA, 2Bundang Jesaeng general Hospital, Seongnam, REPUBLIC OF KOREA. RATIONALE: Recent studies have found pathogenesis of aspirin hypersensitivity including aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/ angioedema (AICU) may be associated with a persistent production of cysteinyl leukotruenes (CysLTs), but still remains to be further clarified. CysLTs are synthesized by leukotriene C4 synthase (LTC4S) and exerts its functional effect via CysLT receptor type 1 (CysLTR1). METHODS: To investigate the role of genetic polymorphism of CysLTR1 and LTC4S in aspirin hypersensitivity, three single nucleotide polymorphisms including -634C>T for CysLTR1 gene and -444A>C for LTC4S gene were genotyped by primer extension method in 156 AIA patients and 105 AICU patients. mRNA expression levels of CysLTR1 and LTC4S genes were examined after aspirin provocation test. RESULTS: Significant associations of CysLTR1-634C>T polymorphism with AIA was noted compared to AICU within female subjects (p 5 0.01); frequency of rare genotype of CysLTR1-634C>T polymorphism was significantly higher in AIA compared with AICU. However, no significant associations were found between LTC4S promoter polymorphism with any phenotype of aspirin hypersensitivity. CysLTR1 mRNA level significantly increased after aspirin provocation in AIA patients (p 5 0.013), while no significant changes were noted in AICU patients. CONCLUSION: These results suggested that CysLTR1 -634C>T polymorphism can be a genetic marker differentiating AIA and AICU among the patients with aspirin hypersensitivity. This study was supported by a grant of the Korea Health 21 R&D project. Ministry of Health & Welfare, R.O.K. (03-PJ10-PG13-GD01-0002).
Funding: Korea Health 21 R &D project. Ministry of Health & Welfare, R.O.K. (03-PJ10-PG13-GD01-0002).
1200
Modulation Of Cysteinyl Leukotriene (CysLT) Production And Responsiveness By Corticosteroids (CCS) J. A. Negri, L. Borish, J. W. Steinke; University Of Virginia Health Systems, Charlottesville, VA. RATIONALE: CCS are not thought to influence the secretion of CysLTs that occurs acutely during allergic reactions and similarly do not modulate bronchospastic responses following inhalation challenges with CysLTs. We hypothesized that CCS might inhibit metabolic pathways responsible for CysLT production and would thereby diminish the release of CysLTs in allergic diseases. Similarly, we hypothesized that CCS would modulate basal or cytokine-dependent expression of the CysLT receptors (CysLT1R and CysLT2R). METHODS: We investigated influences of fluticasone (10-9 and 10-7 M) on basal and IL-4-stimulated expression of mRNA transcripts for 5-lipoxygenase (5-LO), leukotriene C4 synthase (LTC4S), CysLT1R and CysLT2R within T lymphocytes, monocytes, and eosinophils enriched from healthy donors by quantitative RT-PCR. Effects on protein expression were subsequently evaluated by Western hybridization. RESULTS: Circulating immune cells express low levels of LTC4S and 5LO mRNA and expression was not influenced by CCS. In T lymphocytes, IL-4 induced LTC4S transcript expression (6.2-fold), which was prevented by fluticasone. While not altering basal or IL-4-stimulated CysLT1 receptor expression, fluticasone significantly inhibited IL-4-induced CysLT2R transcript production in all cell types tested. The ability of fluticasone to inhibit IL-4-induced expression of CysLT2R mRNA was confirmed at the protein level. CONCLUSIONS: While not blocking the acute release of CysLTs, CCS may diminish the capacity of cells to synthesize these compounds and thereby modulate their production. CCS did not alter CysLT1R expression, consistent with their lack of influence on bronchospasm that is mediated through the CysLT1R. Decreases in CysLT2R expression by CCS could modulate the profibrotic and remodeling effects mediated by these receptors. Funding: GlaxoSmithKline
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