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1.
Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways.
Brown, RH, Reynolds, C, Brooker, A, Talalay, P, Fahey, JW
Respiratory research. 2015;(1):106
Abstract
BACKGROUND It is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients. METHODS Forty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption. RESULTS Sulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane. Moreover, in individuals in whom the FEV1 response to MCh challenge decreased after sulforaphane administration, i.e., sulforaphane was protective, the activities of Nrf2-regulated antioxidant and anti-inflammatory genes decreased. In contrast, individuals in whom sulforaphane treatment enhanced the FEV1 response to MCh, had increased expression of the activities of these genes. High resolution CT scans disclosed that in asthmatics sulforaphane treatment resulted in a significant reduction in specific airway resistance and also increased small airway luminal area and airway trapping modestly but significantly. CONCLUSION These findings suggest the potential value of blocking the bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as sulforaphane.
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2.
Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing.
Brannan, JD, Gulliksson, M, Anderson, SD, Chew, N, Seale, JP, Kumlin, M
The European respiratory journal. 2006;(5):944-50
Abstract
Mannitol inhalation increases urinary excretion of 9alpha,11beta-prostaglandin F2 (a metabolite of prostaglandin D2 and marker of mast cell activation) and leukotriene E4. The present study tested the hypothesis that beta2-adrenoreceptor agonists and disodium cromoglycate (SCG) protect against mannitol-induced bronchoconstriction by inhibition of mast cell mediator release. Fourteen asthmatic subjects inhaled mannitol (mean dose 252+/-213 mg) in order to induce a fall in forced expiratory volume in one second (FEV1) of > or = 25%. The same dose was given 15 min after inhalation of formoterol fumarate (24 microg), SCG (40 mg) or placebo. Pre- and post-challenge urine samples were analysed by enzyme immunoassay for 9alpha,11beta-prostaglandin F2 and leukotriene E4. The maximum fall in FEV1 of 32+/-10% on placebo was reduced by 95% following formoterol and 63% following SCG. Following placebo, there was an increase in median urinary 9alpha,11beta-prostaglandin F2 concentration from 61 to 92 ng.mmol creatinine(-1), but no significant increase in 9alpha,11beta-prostaglandin F2 concentration in the presence of either formoterol (69 versus 67 ng.mmol creatinine(-1)) or SCG (66 versus 60 ng.mmol creatinine(-1)). The increase in urinary leukotriene E4 following placebo (from 19 to 31 ng.mmol creatinine(-1)) was unaffected by the drugs. These results support the hypothesis that the drug effect on airway response to mannitol is due to inhibition of mast cell prostaglandin D2 release.
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3.
Prolonged effect of montelukast in asthmatic children with exercise-induced bronchoconstriction.
Kim, JH, Lee, SY, Kim, HB, Kim, BS, Shim, JY, Hong, TJ, Hong, SJ
Pediatric pulmonology. 2005;(2):162-6
Abstract
Accumulating evidence shows that cysteinyl leukotrienes are the most important mediators in exercise-induced bronchoconstriction (EIB). In contrast to several studies in adults, there are few long-term studies of leukotriene receptor antagonists (LTRAs) in children with EIB. The aim of this study was to assess the prolonged clinical and bronchoprotective effects of montelukast in asthmatic children with EIB. We randomly assigned 64 asthmatic children with EIB. Forty subjects received montelukast (5 mg/day), and 24 subjects received placebo once daily for 8 weeks. Exercise challenge was performed before and after 8 weeks of treatment. Of the 40 patients in the montelukast group, 28 patients crossed over after 8 weeks. The response was measured as asthma symptom score, maximum percent fall in forced expiratory volume in 1 sec (FEV(1)) from pre-exercise baseline, and time to recovery of FEV(1) to within 10% of pre-exercise baseline (time to recovery). Following 8 weeks of treatment with montelukast, the montelukast group compared with placebo showed significant improvements in all endpoints, including asthma symptom score, maximum percent fall in FEV(1) after exercise, and time to recovery. In the cross-over group, even 8 weeks after stopping montelukast treatment, all endpoints were significantly and persistently improved. These results indicate that montelukast provides clinical protection from airway hyperresponsiveness in asthmatic children with EIB, and suggest that LTRAs may be useful for the long-term management of asthmatic children with EIB.
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4.
Inhibitory effect of a leukotriene receptor antagonist (montelukast) on neurokinin A-induced bronchoconstriction.
Crimi, N, Pagano, C, Palermo, F, Mastruzzo, C, Prosperini, G, Pistorio, MP, Vancheri, C
The Journal of allergy and clinical immunology. 2003;(4):833-9
Abstract
BACKGROUND Tachykinins are potent contractors of human airways producing a dose-related bronchoconstriction when administered by means of inhalation to asthmatic subjects. OBJECTIVE The aim of this study was to examine the effective role played by leukotrienes (LTs) in neurokinin A (NKA)-induced bronchoconstriction in asthmatic patients. METHODS To address this question, we investigated the protective effect of a selective cysteinyl LT receptor antagonist, montelukast, against inhaled NKA and determined LTE(4) excretion in the urine. RESULTS Inhaled NKA in the absence of any drug treatment produced a concentration-related bronchospasm with a geometric mean provocative concentration required to produce a 15% decrease in FEV(1) from the postsaline baseline value (PC(15)) value of 290.9 microg/mL (+SE, 407.1 microg/mL; -SE, 207.84 microg/mL). Montelukast pretreatment significantly increased (P <.01) the PC(15) NKA value (708.8 microg/mL; +SE, 890.47 microg/mL; -SE, 564.15 microg/mL) in comparison with placebo (394.4 microg/mL; +SE, 491.88 microg/mL; -SE, 248.16 microg/mL) and produced a shift of the NKA concentration-response curve to the right in all the subjects studied. When compared with placebo, montelukast did not have a significant protective effect against methacholine challenge; the geometric mean PC(15) values obtained were 0.87 and 0.96 mg/mL with placebo and montelukast, respectively. Although we have not observed any increase in urinary LTE(4) excretion after NKA inhalation, we have shown that pretreatment of asthmatic subjects with montelukast elicits a significant protection against NKA-induced bronchoconstriction. CONCLUSION In asthmatic subjects NKA-induced bronchoconstriction is indirectly caused by the release of LTs, and this mechanism could explain some of the antiasthmatic and anti-inflammatory effects of LT antagonists.
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5.
Exercise-induced bronchoconstriction in children: montelukast attenuates the immediate-phase and late-phase responses.
Melo, RE, Solé, D, Naspitz, CK
The Journal of allergy and clinical immunology. 2003;(2):301-7
Abstract
BACKGROUND Montelukast, a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. We and others have shown that there is a late-phase response 3 to 8 hours after exercise in a subset of asthmatic patients. OBJECTIVE We sought to evaluate the protective effect of montelukast on immediate-phase and late-phase responses after exercise challenges. METHODS Twenty-two atopic asthmatic children aged 7 to 16 years with reproducible exercise-induced bronchoconstriction (minimum of 15% decrease of FEV(1) from baseline) were enrolled in this placebo-controlled crossover study. Exercise challenges were performed while breathing cold dry air, and FEV(1) measurements were taken up to 480 minutes after exercise. Patients underwent exercise challenges on a screening day and 1 week after placebo treatment. Subsequently, after a week with no treatment, pulmonary function was assessed after breathing dry cold air (control day). Finally, an exercise challenge was carried out after a week of treatment with montelukast. RESULTS Reproducible late-phase reactions occurred in 5 of 22 patients, which correlated with the extent of the immediate response (P <.05). After 1 week of treatment with montelukast, a significant decrease of immediate responses was observed. Montelukast treatment compared with placebo was associated with a lower mean maximum decrease of FEV(1) (mean +/- SEM: 17.3% +/- 2.4% and 35.1% +/- 2.6%, respectively), decrease of the area above the curve (267.8% +/- 42.7%/min and 868.0% +/- 103.8%/min, respectively), and shorter time for recovery (6.9 +/- 1.1 minutes and 30.9 +/- 4.0 minutes, respectively; P <.05). Treatment with montelukast also abolished late-phase responses. CONCLUSION Once daily treatment with oral montelukast attenuated the immediate-phase response and abolished the late-phase response induced by means of exercise challenge in asthmatic children.
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6.
Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma.
Rorke, S, Jennison, S, Jeffs, JA, Sampson, AP, Arshad, H, Holgate, ST
Thorax. 2002;(4):323-7
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Abstract
BACKGROUND Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast. METHODS In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge. RESULTS Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo. CONCLUSIONS Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.
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Effects of montelukast on physical performance and exercise economy in adult asthmatics with exercise-induced bronchoconstriction.
Steinshamn, S, Sandsund, M, Sue-Chu, M, Bjermer, L
Scandinavian journal of medicine & science in sports. 2002;(4):211-7
Abstract
Leukotriene antagonists are effective in the treatment of exercise-induced bronchoconstriction. Montelukast is a specific cysteinyl-leukotriene receptor1 antagonist without known effects on the pulmonary vessels, which in theory should be advantageous with respect to gas exchange. In addition to lung function, we investigated the effects of montelukast on parameters of gas exchange and physical performance in 16 asthmatics with exercise-induced bronchoconstriction in a double-blind cross-over placebo-controlled study. Subjects were tested at an ambient temperature of -15 degrees C with a tread mill exercise protocol consisting of consecutive workloads of 80% V'O(2max) (6 min), rest (4 min), 60% V'O(2max) (6 min) and step increments of exercise until exhaustion. Montelukast reduced the maximum post-exercise fall in FEV1 (P < 0.01), improved the running time to exhaustion in 11 of 16 test subjects (one unchanged) (P = 0.03), and reduced the Borg score at exhaustion (P = 0.03) and the breathing frequency after 3 min at 60% V'O(2max) (P = 0.03). V'(O2), V'CO(2), minute ventilation, ventilatory equivalents, respiratory exchange ratio, heart rate and oxygen pulse were not significantly different after montelukast and placebo. We conclude that montelukast has a beneficial effect on physical performance in most adults with exercise-induced asthma without any observed effect on gas-exchange parameters.
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Effect of ozagrel hydrochloride, a thromboxane synthetase inhibitor, on alcoholic beverage-induced bronchoconstriction in asthmatic patients.
Myou, S, Fujimura, M, Nishi, K, Kita, T, Kurashima, K, Tachibana, H, Ishiura, Y, Nakao, S
Prostaglandins, leukotrienes, and essential fatty acids. 2002;(4):397-401
Abstract
Acetaldehyde is thought to be a main factor of alcohol-induced asthma. The thromboxane (TX) synthetase inhibitor, ozagrel hydrochloride, inhibits acetaldehyde-induced bronchoconstriction in asthmatic patients. The present study evaluated the involvement of TXA(2) on alcoholic beverage-induced bronchoconstriction. Four patients with alcohol-induced asthma received ozagrel (400 mg for 4 days) or placebo using a single-blind, randomized, cross-over design. On two separate study days, each subject drank the same brand and volume of alcoholic beverage (beer or Japanese sake) and bronchoconstriction was assessed as the change in peak expiratory flow (PEF). The effect of ozagrel on the aerosolized challenge of acetaldehyde was investigated in the same subjects. Although aerosolized acetaldehyde-induced bronchoconstriction was significantly prevented by ozagrel, there were no differences in the time course of the decrease in PEF or the maximum fall in PEF after alcohol intake between placebo and ozagrel. We conclude that TXA(2) is not involved in alcoholic beverage-induced bronchoconstriction.
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Regional expiratory flow limitation studied with Technegas in asthma.
Pellegrino, R, Biggi, A, Papaleo, A, Camuzzini, G, Rodarte, JR, Brusasco, V
Journal of applied physiology (Bethesda, Md. : 1985). 2001;(5):2190-8
Abstract
Regional expiratory flow limitation (EFL) may occur during tidal breathing without being detected by measurements of flow at the mouth. We tested this hypothesis by using Technegas to reveal sites of EFL. A first study (study 1) was undertaken to determine whether deposition of Technegas during tidal breathing reveals the occurrence of regional EFL in induced bronchoconstriction. Time-activity curves of Technegas inhaled during 12 tidal breaths were measured in four asthmatic subjects at control conditions and after exposure to inhaled methacholine at a dose sufficient to abolish expiratory flow reserve near functional residual capacity. A second study (study 2) was conducted in seven asthmatic subjects at control and after three increasing doses of methacholine to compare the pattern of Technegas deposition in the lung with the occurrence of EFL. The latter was assessed at the mouth by comparing tidal with forced expiratory flow or with the flow generated on application of a negative pressure. Study 1 documented enhanced and spotty deposition of Technegas in the central lung regions with increasing radioactivity during tidal expiration. This is consistent with increased impaction of Technegas on the airway wall downstream from the flow-limiting segment. Study 2 showed that both methods based on analysis of flow at the mouth failed to detect EFL at the time spotty deposition of Technegas occurred. We conclude that regional EFL occurs asynchronously across the lung and that methods based on mouth flow measurements are insensitive to it.
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Fog-induced respiratory responses are attenuated by nedocromil sodium in humans.
Lavorini, F, Fontana, GA, Pantaleo, T, Camiciottoli, G, Castellani, W, Maluccio, NM, Pistolesi, M
American journal of respiratory and critical care medicine. 2001;(5):1117-20
Abstract
Fog inhalation induces cough and bronchoconstriction in patients with asthma, but only cough in normal subjects; whether it also influences the pattern of breathing is unclear. Nedocromil sodium (NCS) inhibits the cough response to inhalation of several pharmacological agents but its effects on fog-induced cough and changes in the pattern of breathing are unknown. We evaluated the effects of no drug, placebo, and 4- and 8-mg NCS administration on the cough threshold and changes in the pattern of breathing during fog inhalation in 14 healthy subjects. Measurements of tidal volume (VT), duration of inspiratory and expiratory times (TI and TE, respectively), total duration of the respiratory cycle (TT), mean inspiratory flow (VT/TI), duty cycle (TI/TT), respiratory frequency (f, 60/TT), and inspiratory minute ventilation (V I) were obtained by inductive plethysmography. Median cough threshold values were unaffected by placebo, but were increased (p < 0.01) by both NCS doses. In no-drug and placebo trials, inhalation of the threshold fog concentration caused increases in both VT/TI and V I (p always < 0.05) due to selective increases (p < 0.01) in VT. These changes were markedly attenuated by both NCS doses administration. Thus, fog induces coughing and increases in VT, VT/ TI, and V I in healthy subjects; NCS possesses antitussive effects and attenuates fog-induced changes in the pattern of breathing, possibly through inhibition of rapidly adapting "irritant" receptors.