Imran Aziz - Independent Researcher (original) (raw)
Papers by Imran Aziz
Journal of Allergy and Clinical Immunology, 1998
Objective: We have previously found that  2 -adrenoceptor downregulation and bronchodilator dese... more Objective: We have previously found that  2 -adrenoceptor downregulation and bronchodilator desensitization to albuterol occurred at 36 hours after stopping regular treatment with twice daily salmeterol. In this study we have evaluated these same effects with formoterol given once or twice daily on a regular basis. Methods: In a randomized, placebo-controlled, double-blind, double-dummy crossover study, 16 subjects with mild-tomoderate stable asthma (mean [SD] age, 32.5 [15.3] years; mean [SD] FEV 1 , 73.2 [12.1] percent predicted) receiving regular inhaled corticosteroid therapy received 1 week of treatment with formoterol dry powder (24 g twice daily [8 AM/8 PM]), formoterol (24 g once daily [8 PM]), or identical placebo. Lymphocyte  2 -adrenoceptor parameters and a dose-response curve to inhaled albuterol (200 to 1600 g) were evaluated at 36 hours after the last dose of each treatment period. Results: There were no significant differences in the mean values for albuterol dose-response effects among the three treatment regimens. Comparison of maximal bronchodilator responses between treatments (mean and SEM as change from baseline) revealed no significant differences between treatments for FEV 1 (0.47 L [0.06 L] for placebo vs 0.48 L [0.07 L] for 24 g once daily formoterol vs 0.51 L [0.08 L] for 24 g twice daily formoterol) or for forced expiratory flow, mid-expiratory phase (FEF 25-75 ) (0.80 L/sec [0.12 L/sec] for placebo vs 0.80 L/sec [0.16 L/sec] for 24 g once daily formoterol vs 0.89 L/sec [0.
In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol
Journal of Allergy and Clinical Immunology, 1999
It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the re... more It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the relaxant effect of albuterol in carbachol-contracted human bronchi. The primary aim of this study was to evaluate whether there is a potential in vivo interaction between long- and short-acting beta2-agonists in the presence of increased airway tone induced by methacholine. In addition, a post hoc analysis was made to evaluate the effects of beta2-adrenoceptor polymorphisms. Sixteen asthmatic subjects (mean age [+/-SD], 39 [13] years; FEV1, 81% [17%] of predicted value), all taking inhaled corticosteroids and having methacholine PD20 values of less than 500 micrograms, were randomized in double-blind, double-dummy, cross-over fashion to receive single doses of inhaled placebo, inhaled formoterol 12 micrograms, or inhaled salmeterol 50 micrograms followed 12 hours later by a single dose of inhaled albuterol 400 micrograms (low dose) or 1600 micrograms (high dose). Methacholine challenges were performed on each of 6 separate occasions 1 hour after albuterol. There was a greater numerical difference in geometric mean PD20 values between low- and high-dose albuterol after placebo dosing (671 micrograms vs 1080 micrograms, a 1.61-fold difference; P <.05) compared with low- and high-dose albuterol after formoterol dosing (660 micrograms vs 799 micrograms, a 1. 21-fold difference; P =.4), or after salmeterol dosing (568 micrograms vs 847 micrograms, a 1.49-fold difference; P =.055). PD20 values with high-dose albuterol in combination with formoterol or salmeterol were numerically lower than those found with high-dose albuterol in combination with placebo, but they were not significantly different. There was a significant difference between PD20 values with low-dose albuterol after dosing with formoterol (PD20 = 660 micrograms, a 1. 6-fold difference; P <.05) or with salmeterol (PD20 = 568 micrograms, a 1.9-fold difference; P <.05) compared with PD20 with high-dose albuterol after placebo dosing (PD20 = 1080 micrograms). Post hoc polymorphism analysis for pooled pretreatment with formoterol and salmeterol (excluding placebo pretreatment) showed significantly (P <.05) lower PD20 values with homozygous glycine-16 compared with heterozygous glycine/arginine-16 and significantly (P <.05) lower PD20 values with homozygous glutamate-27 compared with either heterozygous glutamate/glutamine-27 or homozygous glutamine-27. Compared with placebo, both salmeterol and formoterol caused a significant degree of antagonism of albuterol-induced bronchorelaxation in methacholine-contracted bronchi in vivo. This interaction could be caused by prolonged occupancy of airway beta2-adrenoceptors by long-acting beta2-agonists or by early tachyphylaxis 12 hours after a single-dose exposure. The degree of albuterol protection was also related to beta2-adrenoceptor polymorphism.
Concomitant inhaled corticosteroid resensitises cardiac β2-adrenoceptors in the presence of long-acting β2-agonist therapy
European Journal of Clinical Pharmacology, 1998
Objective: The aim of the present study was to evaluate the effects of concomitant inhaled cortic... more Objective: The aim of the present study was to evaluate the effects of concomitant inhaled corticosteroid therapy on the sensitivity of cardiac β2-adrenoceptors in patients receiving regular long-acting β2-agonists. Methods: Twelve healthy subjects (6 female), mean age 29 years, were randomised in a double-blind cross-over study to receive either inhaled placebo or inhaled budesonide 1.2 mg twice daily, each for 7 days, with a minimum of 7 days washout period between the two treatments. Patients also received concomitant treatment with inhaled eformoterol 24 μg twice daily during each of the 2 treatment periods. The patients attended the laboratory during both treatment periods at 0730 hours, when a dose-response curve for systemic β2-adrenoceptor responses to inhaled salbutamol (0.8–3.2 mg) was constructed before and after completing 7 days of each treatment. Early morning (0800 hours) plasma cortisol was also evaluated as a marker of systemic glucocorticoid activity. Results: There was a significant fall in 0800 hours plasma cortisol induced by budesonide comparing pre- and post- values (407 vs 322 nmol · l−1, but not with placebo. There were no differences in the response to salbutamol prior to treatment when comparing eformoterol with placebo versus eformoterol with budesonide. Comparing before and after within-treatment heart rate response, there was a significant reduction in peak salbutamol response with eformoterol and placebo, which was partially reversed by eformoterol and budesonide. For between-treatment comparisons after eformoterol treatment, the heart rate was significantly higher in the presence of budesonide in comparison with placebo for peak salbutamol response (change from baseline), i.e. 24.2 vs 34.7 beats · min−1. There was, however, no significant difference in the peak delta potassium response to salbutamol after eformoterol treatment when comparing budesonide with placebo (−0.39 vs −0.48 mmol · l−1). Conclusion: Concomitant therapy with inhaled budesonide resensitised the cardiac β2-adrenoceptor response to salbutamol in subjects who were receiving regular twice-daily eformoterol. This may be of clinical relevance in terms of the propensity for systemic β2-mediated adverse effects with repeated puffs of salbutamol, which might conceivably occur in the setting of acute asthma.
2Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy
Clinical Science, 1999
... Correspondence: Professor BJ Lipworth. ... Patients were randomized into a parallel group, do... more ... Correspondence: Professor BJ Lipworth. ... Patients were randomized into a parallel group, double-blind, double dummy design to receive treatment for 2 weeks with each of the following: (a) formoterol, 12 µg in the morning; (b) formoterol, 6 µg in the morning and at bed-time; (c ...
European Respiratory Journal, 1998
American Journal of Medicine, 2000
PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-... more PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta2-adrenoceptor polymorphism, which predisposes them to agonist-induced down-regulation and desensitization of the beta2-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta2-agonist (inhaled formoterol, 12 μg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype.SUBJECTS AND METHODS: We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine that produced a 20% decline in forced expiratory volume in 1 second [FEV1]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose of each treatment.RESULTS: Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9-fold) for formoterol. As compared with placebo, zafirlukast caused a significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant (P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo.CONCLUSIONS: Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta2-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.
A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol
Journal of Allergy and Clinical Immunology, 1999
Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for... more Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for bronchoprotective effects. It is not known whether a high dose of short-acting beta2 -agonist could overcome this subsensitivity. The objective of this study was to investigate the acute effects of a high dose of inhaled albuterol on methacholine-induced bronchoconstriction in patients receiving regular treatment with salmeterol or formoterol. Ten stable asthmatic subjects (mean age, 34 years; FEV1, 77% of predicted value), all taking inhaled corticosteroids (methacholine PD20 < 500 microg), were recruited into a randomized, single-blind, crossover study. After an initial 1-week run-in period, subjects underwent 3 separate treatment periods each of 9 days (separated by a washout of at least 5 days) comprising inhaled placebo twice daily, inhaled salmeterol dry powder 50 microg twice daily, or inhaled formoterol dry powder 12 microg twice daily. Methacholine challenge was performed 1 hour after the first dose and after 7 days of treatment. After 9 days of treatment, a third methacholine challenge was performed 1 hour after inhalation of a single 1600 microg dose of albuterol dry powder. There was significant (P <.001) improvement in geometric mean PD20 after the first dose of active treatment as compared with placebo (78 microg) versus salmeterol (266 microg, a 3.4-fold difference [95% CI 1.9 to 6.1]) and versus formoterol (318 microg, a 4.1-fold difference [95% CI 2.3 to 7.3]). This bronchoprotection diminished with regular treatment, although it remained significant (P <.01) compared with placebo (68 microg) versus salmeterol (144 microg, a 2.1-fold difference [95% CI 1.2 to 3.8]) and versus formoterol (230 microg, 3.4-fold difference [95% CI 1.9 to 6.2]). After 9 days, the protection afforded by a single dose of albuterol after placebo pretreatment (889 microg) was significantly (P =.005) higher in comparison with albuterol protection after salmeterol pretreatment (338 microg, a 2.7-fold difference [95% CI 1.1 to 6.8]) and after formoterol pretreatment (247 microg, a 3.6-fold difference [95% 1.4 to 9.1]). Thus in stable asthmatic subjects receiving regular salmeterol or formoterol, bronchoprotective subsensitivity was not overcome by administering a high dose of albuterol. Further studies are required to evaluate the clinical relevance of this pharmacologic phenomenon when albuterol is used in acute asthma.
Comparative trough effects of formoterol and salmeterol on lymphocyte β2-adrenoceptor – regulation and bronchodilatation
European Journal of Clinical Pharmacology, 1999
Objectives: The primary aim of the present study was to evaluate comparative trough effects of fo... more Objectives: The primary aim of the present study was to evaluate comparative trough effects of formoterol and salmeterol on β2-adrenoceptor regulation and bronchodilator response after regular twice-daily treatment, with a secondary aim to evaluate any possible association with β2-adrenoceptor polymorphism. Methods: Sixteen asthmatic subjects, with mean (SD) age 33(9) years, all taking inhaled corticosteroids and with a forced expiratory volume in 1 s (FEV1) of 81(12)% predicted were recruited to take part in a randomised single-blind, three-way cross-over study. The subjects received three treatments each for 1 week, with 1-week washout periods in between: (1) formoterol dry powder, 12 μg twice daily, (2) salmeterol dry powder, 50 μg twice daily, or (3) placebo, twice daily. Spirometry and lymphocyte β2-adrenoceptor parameters were measured before the first dose and 12 h after the last dose of each treatment, as well as domiciliary peak flow during each treatment. Results: There were no differences in β2-adrenoceptor density (Bmax) between the three treatments prior to the first dose; whereas, after the last dose, Bmax was lower with both active treatments than with placebo, but was significant for salmeterol only – a 1.2-fold geometric mean fold difference (95% CI 1- to 1.4-fold), P = 0.04. Compared with placebo, there were n = 9 of 16 subjects with salmeterol and n = 6 of 16 with formoterol who had a greater than 15% fall in Bmax. Post-hoc trend analysis of polymorphism showed that the propensity for downregulation appeared to be related to the occurrence of an allelic substitution of glycine at codon 16 – 8 of 13 for salmeterol versus 5 of 13 for formoterol with a greater than 15% fall compared with placebo. There were no significant differences between salmeterol and formoterol in terms of mean or individual values for downregulation. There was evidence of persistent bronchodilator activity with both active treatments compared with placebo; this was significant for forced expiratory flow rate between 25% and 75% of vital capacity (FEF25–75) – the mean difference versus salmeterol was 0.39 l/s (95% CI 0.06–0.70), P = 0.02, and versus formoterol was 0.35 l/s (95% CI 0.16–0.53), P = 0.001. These effects were mirrored by significant improvements in morning peak flow rate compared with placebo – mean difference versus salmeterol was 24 l/min (95% CI 7–42), P = 0.01, and versus formoterol was 36 l/min (95% CI 25–48), P < 0.0001. Conclusion: There were no differences between regular treatment with formoterol and salmeterol in their effects on lymphocyte β2-adrenoceptor regulation at the end of a 12-h dosing interval, with both drugs exhibiting a residual degree of bronchodilator activity at the same time point. Further studies to evaluate receptor regulation and bronchodilator response are required in susceptible patients who have the homozygous glycine-16 polymorphism.
European Respiratory Journal, 2005
Chronic cough is a common and distressing symptom. A novel algorithm has been developed for the m... more Chronic cough is a common and distressing symptom. A novel algorithm has been developed for the management of chronic cough, in which an assessment of clinical probability of disease determines the need to proceed to investigation.
European Respiratory Journal, 2002
Evaluation of impulse oscillation system: comparison with forced oscillation technique and body p... more Evaluation of impulse oscillation system: comparison with forced oscillation technique and body plethysmography. J. Hellinckx, M. Cauberghs, K. De Boeck, M. Demedts. #ERS Journals Ltd 2001.
Sex-related Differences in Cough Reflex Sensitivity in Patients with Chronic Cough
Among patients attending specialist cough clinics there is an excess of females, but the reason f... more Among patients attending specialist cough clinics there is an excess of females, but the reason for this sex difference is unknown. We tested the hypothesis that the sensitivity of the cough reflex is greater in female compared with male patients with chronic cough. Inhalation cough challenges with capsaicin and citric acid were performed in a large group of patients with chronic cough. The concentrations of tussive agent causing two (C2) and five (C5) coughs were calculated. Measurements of capsaicin cough reflex sensitivity (median [interquartile range]) were significantly lower for female patients compared with male patients (C2: 1.9 [0.5 to 5.5] versus 5.3 [2.2 to 11.5] micro M, p = 0.0026; C5: 8.6 [2.2 to 34.0] versus 51.2 [7.2 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 100] micro M, p = 0.0007). Similarly for citric acid challenge, values were significantly lower for female compared with male patients (C2: 53.5 [17.3 to 145.4] versus 118.1 [41.4 to 381.7] mM, p = 0.0064; C5: 300.0 [97.1 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 1,000] versus 830.4 [300.0 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 1,000] mM, p = 0.032). There were significant correlations between capsaicin and citric acid C2 values (r(s) = 0.54, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and C5 values (r(s) = 0.57, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). These findings indicate a sex difference in cough sensitivity in patients with chronic cough, as previously reported in healthy volunteers. This may explain the female preponderance in cough clinics.
European Respiratory Journal, 2001
Respiratory Medicine, 2002
available online at http://www.idealibrary.com on FIG 3. Chest radiograph (a) and the HRCTof the ... more available online at http://www.idealibrary.com on FIG 3. Chest radiograph (a) and the HRCTof the thorax (b) in the second patient at presentation.
Letter
European Respiratory Journal, 2001
Pulmonary Pharmacology & Therapeutics, 2002
Whilst nebulisers are commonly used in the treatment of cystic fibrosis (CF), nebulised aerosol l... more Whilst nebulisers are commonly used in the treatment of cystic fibrosis (CF), nebulised aerosol lung deposition in individual patients is not routinely assessed in clinical practice. The present study was designed to evaluate whether a comparative measurement of aerosol lung deposition from nebulisers using a widely available scintigraphic method could be employed to assist the selection of the best system for individual patients. Lung deposition of the radiolabelled aerosol from the Pari LC Plus (Pari Medical Ltd) nebuliser and the HaloLite Adaptive Aerosol Delivery (AAD 1 ) system (Profile Therapeutics Ltd) was measured using planar scintigraphy in 10 healthy volunteers and 6 CF patients. The HaloLite AAD 1 delivered on average 2.1 times (P 0.003) as much aerosol to the lungs compared with Pari LC Plus. Only two subjects had higher lung deposition from Pari LC Plus than HaloLite AAD 1 system. There was marked inter-individual variation in the deposition pattern in CF patients. The aerosol deposition from HaloLite AAD 1 had higher central distribution than that obtained with the Pari LC Plus. The overall intersubject variability of the delivered dose was 56% with Pari LC Plus and 24% with HaloLite AAD 1 (P50.05). The measurement of aerosol deposition from nebulisers can be performed using a simple and widely available methodology, and may improve nebuliser selection in CF patients.
Journal of Allergy and Clinical Immunology, 1998
Objective: We have previously found that  2 -adrenoceptor downregulation and bronchodilator dese... more Objective: We have previously found that  2 -adrenoceptor downregulation and bronchodilator desensitization to albuterol occurred at 36 hours after stopping regular treatment with twice daily salmeterol. In this study we have evaluated these same effects with formoterol given once or twice daily on a regular basis. Methods: In a randomized, placebo-controlled, double-blind, double-dummy crossover study, 16 subjects with mild-tomoderate stable asthma (mean [SD] age, 32.5 [15.3] years; mean [SD] FEV 1 , 73.2 [12.1] percent predicted) receiving regular inhaled corticosteroid therapy received 1 week of treatment with formoterol dry powder (24 g twice daily [8 AM/8 PM]), formoterol (24 g once daily [8 PM]), or identical placebo. Lymphocyte  2 -adrenoceptor parameters and a dose-response curve to inhaled albuterol (200 to 1600 g) were evaluated at 36 hours after the last dose of each treatment period. Results: There were no significant differences in the mean values for albuterol dose-response effects among the three treatment regimens. Comparison of maximal bronchodilator responses between treatments (mean and SEM as change from baseline) revealed no significant differences between treatments for FEV 1 (0.47 L [0.06 L] for placebo vs 0.48 L [0.07 L] for 24 g once daily formoterol vs 0.51 L [0.08 L] for 24 g twice daily formoterol) or for forced expiratory flow, mid-expiratory phase (FEF 25-75 ) (0.80 L/sec [0.12 L/sec] for placebo vs 0.80 L/sec [0.16 L/sec] for 24 g once daily formoterol vs 0.89 L/sec [0.
In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol
Journal of Allergy and Clinical Immunology, 1999
It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the re... more It has been shown in vitro that prior treatment with salmeterol and formoterol antagonizes the relaxant effect of albuterol in carbachol-contracted human bronchi. The primary aim of this study was to evaluate whether there is a potential in vivo interaction between long- and short-acting beta2-agonists in the presence of increased airway tone induced by methacholine. In addition, a post hoc analysis was made to evaluate the effects of beta2-adrenoceptor polymorphisms. Sixteen asthmatic subjects (mean age [+/-SD], 39 [13] years; FEV1, 81% [17%] of predicted value), all taking inhaled corticosteroids and having methacholine PD20 values of less than 500 micrograms, were randomized in double-blind, double-dummy, cross-over fashion to receive single doses of inhaled placebo, inhaled formoterol 12 micrograms, or inhaled salmeterol 50 micrograms followed 12 hours later by a single dose of inhaled albuterol 400 micrograms (low dose) or 1600 micrograms (high dose). Methacholine challenges were performed on each of 6 separate occasions 1 hour after albuterol. There was a greater numerical difference in geometric mean PD20 values between low- and high-dose albuterol after placebo dosing (671 micrograms vs 1080 micrograms, a 1.61-fold difference; P <.05) compared with low- and high-dose albuterol after formoterol dosing (660 micrograms vs 799 micrograms, a 1. 21-fold difference; P =.4), or after salmeterol dosing (568 micrograms vs 847 micrograms, a 1.49-fold difference; P =.055). PD20 values with high-dose albuterol in combination with formoterol or salmeterol were numerically lower than those found with high-dose albuterol in combination with placebo, but they were not significantly different. There was a significant difference between PD20 values with low-dose albuterol after dosing with formoterol (PD20 = 660 micrograms, a 1. 6-fold difference; P <.05) or with salmeterol (PD20 = 568 micrograms, a 1.9-fold difference; P <.05) compared with PD20 with high-dose albuterol after placebo dosing (PD20 = 1080 micrograms). Post hoc polymorphism analysis for pooled pretreatment with formoterol and salmeterol (excluding placebo pretreatment) showed significantly (P <.05) lower PD20 values with homozygous glycine-16 compared with heterozygous glycine/arginine-16 and significantly (P <.05) lower PD20 values with homozygous glutamate-27 compared with either heterozygous glutamate/glutamine-27 or homozygous glutamine-27. Compared with placebo, both salmeterol and formoterol caused a significant degree of antagonism of albuterol-induced bronchorelaxation in methacholine-contracted bronchi in vivo. This interaction could be caused by prolonged occupancy of airway beta2-adrenoceptors by long-acting beta2-agonists or by early tachyphylaxis 12 hours after a single-dose exposure. The degree of albuterol protection was also related to beta2-adrenoceptor polymorphism.
Concomitant inhaled corticosteroid resensitises cardiac β2-adrenoceptors in the presence of long-acting β2-agonist therapy
European Journal of Clinical Pharmacology, 1998
Objective: The aim of the present study was to evaluate the effects of concomitant inhaled cortic... more Objective: The aim of the present study was to evaluate the effects of concomitant inhaled corticosteroid therapy on the sensitivity of cardiac β2-adrenoceptors in patients receiving regular long-acting β2-agonists. Methods: Twelve healthy subjects (6 female), mean age 29 years, were randomised in a double-blind cross-over study to receive either inhaled placebo or inhaled budesonide 1.2 mg twice daily, each for 7 days, with a minimum of 7 days washout period between the two treatments. Patients also received concomitant treatment with inhaled eformoterol 24 μg twice daily during each of the 2 treatment periods. The patients attended the laboratory during both treatment periods at 0730 hours, when a dose-response curve for systemic β2-adrenoceptor responses to inhaled salbutamol (0.8–3.2 mg) was constructed before and after completing 7 days of each treatment. Early morning (0800 hours) plasma cortisol was also evaluated as a marker of systemic glucocorticoid activity. Results: There was a significant fall in 0800 hours plasma cortisol induced by budesonide comparing pre- and post- values (407 vs 322 nmol · l−1, but not with placebo. There were no differences in the response to salbutamol prior to treatment when comparing eformoterol with placebo versus eformoterol with budesonide. Comparing before and after within-treatment heart rate response, there was a significant reduction in peak salbutamol response with eformoterol and placebo, which was partially reversed by eformoterol and budesonide. For between-treatment comparisons after eformoterol treatment, the heart rate was significantly higher in the presence of budesonide in comparison with placebo for peak salbutamol response (change from baseline), i.e. 24.2 vs 34.7 beats · min−1. There was, however, no significant difference in the peak delta potassium response to salbutamol after eformoterol treatment when comparing budesonide with placebo (−0.39 vs −0.48 mmol · l−1). Conclusion: Concomitant therapy with inhaled budesonide resensitised the cardiac β2-adrenoceptor response to salbutamol in subjects who were receiving regular twice-daily eformoterol. This may be of clinical relevance in terms of the propensity for systemic β2-mediated adverse effects with repeated puffs of salbutamol, which might conceivably occur in the setting of acute asthma.
2Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy
Clinical Science, 1999
... Correspondence: Professor BJ Lipworth. ... Patients were randomized into a parallel group, do... more ... Correspondence: Professor BJ Lipworth. ... Patients were randomized into a parallel group, double-blind, double dummy design to receive treatment for 2 weeks with each of the following: (a) formoterol, 12 µg in the morning; (b) formoterol, 6 µg in the morning and at bed-time; (c ...
European Respiratory Journal, 1998
American Journal of Medicine, 2000
PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-... more PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta2-adrenoceptor polymorphism, which predisposes them to agonist-induced down-regulation and desensitization of the beta2-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta2-agonist (inhaled formoterol, 12 μg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype.SUBJECTS AND METHODS: We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine that produced a 20% decline in forced expiratory volume in 1 second [FEV1]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose of each treatment.RESULTS: Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9-fold) for formoterol. As compared with placebo, zafirlukast caused a significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant (P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo.CONCLUSIONS: Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta2-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.
A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol
Journal of Allergy and Clinical Immunology, 1999
Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for... more Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for bronchoprotective effects. It is not known whether a high dose of short-acting beta2 -agonist could overcome this subsensitivity. The objective of this study was to investigate the acute effects of a high dose of inhaled albuterol on methacholine-induced bronchoconstriction in patients receiving regular treatment with salmeterol or formoterol. Ten stable asthmatic subjects (mean age, 34 years; FEV1, 77% of predicted value), all taking inhaled corticosteroids (methacholine PD20 < 500 microg), were recruited into a randomized, single-blind, crossover study. After an initial 1-week run-in period, subjects underwent 3 separate treatment periods each of 9 days (separated by a washout of at least 5 days) comprising inhaled placebo twice daily, inhaled salmeterol dry powder 50 microg twice daily, or inhaled formoterol dry powder 12 microg twice daily. Methacholine challenge was performed 1 hour after the first dose and after 7 days of treatment. After 9 days of treatment, a third methacholine challenge was performed 1 hour after inhalation of a single 1600 microg dose of albuterol dry powder. There was significant (P <.001) improvement in geometric mean PD20 after the first dose of active treatment as compared with placebo (78 microg) versus salmeterol (266 microg, a 3.4-fold difference [95% CI 1.9 to 6.1]) and versus formoterol (318 microg, a 4.1-fold difference [95% CI 2.3 to 7.3]). This bronchoprotection diminished with regular treatment, although it remained significant (P <.01) compared with placebo (68 microg) versus salmeterol (144 microg, a 2.1-fold difference [95% CI 1.2 to 3.8]) and versus formoterol (230 microg, 3.4-fold difference [95% CI 1.9 to 6.2]). After 9 days, the protection afforded by a single dose of albuterol after placebo pretreatment (889 microg) was significantly (P =.005) higher in comparison with albuterol protection after salmeterol pretreatment (338 microg, a 2.7-fold difference [95% CI 1.1 to 6.8]) and after formoterol pretreatment (247 microg, a 3.6-fold difference [95% 1.4 to 9.1]). Thus in stable asthmatic subjects receiving regular salmeterol or formoterol, bronchoprotective subsensitivity was not overcome by administering a high dose of albuterol. Further studies are required to evaluate the clinical relevance of this pharmacologic phenomenon when albuterol is used in acute asthma.
Comparative trough effects of formoterol and salmeterol on lymphocyte β2-adrenoceptor – regulation and bronchodilatation
European Journal of Clinical Pharmacology, 1999
Objectives: The primary aim of the present study was to evaluate comparative trough effects of fo... more Objectives: The primary aim of the present study was to evaluate comparative trough effects of formoterol and salmeterol on β2-adrenoceptor regulation and bronchodilator response after regular twice-daily treatment, with a secondary aim to evaluate any possible association with β2-adrenoceptor polymorphism. Methods: Sixteen asthmatic subjects, with mean (SD) age 33(9) years, all taking inhaled corticosteroids and with a forced expiratory volume in 1 s (FEV1) of 81(12)% predicted were recruited to take part in a randomised single-blind, three-way cross-over study. The subjects received three treatments each for 1 week, with 1-week washout periods in between: (1) formoterol dry powder, 12 μg twice daily, (2) salmeterol dry powder, 50 μg twice daily, or (3) placebo, twice daily. Spirometry and lymphocyte β2-adrenoceptor parameters were measured before the first dose and 12 h after the last dose of each treatment, as well as domiciliary peak flow during each treatment. Results: There were no differences in β2-adrenoceptor density (Bmax) between the three treatments prior to the first dose; whereas, after the last dose, Bmax was lower with both active treatments than with placebo, but was significant for salmeterol only – a 1.2-fold geometric mean fold difference (95% CI 1- to 1.4-fold), P = 0.04. Compared with placebo, there were n = 9 of 16 subjects with salmeterol and n = 6 of 16 with formoterol who had a greater than 15% fall in Bmax. Post-hoc trend analysis of polymorphism showed that the propensity for downregulation appeared to be related to the occurrence of an allelic substitution of glycine at codon 16 – 8 of 13 for salmeterol versus 5 of 13 for formoterol with a greater than 15% fall compared with placebo. There were no significant differences between salmeterol and formoterol in terms of mean or individual values for downregulation. There was evidence of persistent bronchodilator activity with both active treatments compared with placebo; this was significant for forced expiratory flow rate between 25% and 75% of vital capacity (FEF25–75) – the mean difference versus salmeterol was 0.39 l/s (95% CI 0.06–0.70), P = 0.02, and versus formoterol was 0.35 l/s (95% CI 0.16–0.53), P = 0.001. These effects were mirrored by significant improvements in morning peak flow rate compared with placebo – mean difference versus salmeterol was 24 l/min (95% CI 7–42), P = 0.01, and versus formoterol was 36 l/min (95% CI 25–48), P < 0.0001. Conclusion: There were no differences between regular treatment with formoterol and salmeterol in their effects on lymphocyte β2-adrenoceptor regulation at the end of a 12-h dosing interval, with both drugs exhibiting a residual degree of bronchodilator activity at the same time point. Further studies to evaluate receptor regulation and bronchodilator response are required in susceptible patients who have the homozygous glycine-16 polymorphism.
European Respiratory Journal, 2005
Chronic cough is a common and distressing symptom. A novel algorithm has been developed for the m... more Chronic cough is a common and distressing symptom. A novel algorithm has been developed for the management of chronic cough, in which an assessment of clinical probability of disease determines the need to proceed to investigation.
European Respiratory Journal, 2002
Evaluation of impulse oscillation system: comparison with forced oscillation technique and body p... more Evaluation of impulse oscillation system: comparison with forced oscillation technique and body plethysmography. J. Hellinckx, M. Cauberghs, K. De Boeck, M. Demedts. #ERS Journals Ltd 2001.
Sex-related Differences in Cough Reflex Sensitivity in Patients with Chronic Cough
Among patients attending specialist cough clinics there is an excess of females, but the reason f... more Among patients attending specialist cough clinics there is an excess of females, but the reason for this sex difference is unknown. We tested the hypothesis that the sensitivity of the cough reflex is greater in female compared with male patients with chronic cough. Inhalation cough challenges with capsaicin and citric acid were performed in a large group of patients with chronic cough. The concentrations of tussive agent causing two (C2) and five (C5) coughs were calculated. Measurements of capsaicin cough reflex sensitivity (median [interquartile range]) were significantly lower for female patients compared with male patients (C2: 1.9 [0.5 to 5.5] versus 5.3 [2.2 to 11.5] micro M, p = 0.0026; C5: 8.6 [2.2 to 34.0] versus 51.2 [7.2 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 100] micro M, p = 0.0007). Similarly for citric acid challenge, values were significantly lower for female compared with male patients (C2: 53.5 [17.3 to 145.4] versus 118.1 [41.4 to 381.7] mM, p = 0.0064; C5: 300.0 [97.1 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 1,000] versus 830.4 [300.0 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 1,000] mM, p = 0.032). There were significant correlations between capsaicin and citric acid C2 values (r(s) = 0.54, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and C5 values (r(s) = 0.57, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). These findings indicate a sex difference in cough sensitivity in patients with chronic cough, as previously reported in healthy volunteers. This may explain the female preponderance in cough clinics.
European Respiratory Journal, 2001
Respiratory Medicine, 2002
available online at http://www.idealibrary.com on FIG 3. Chest radiograph (a) and the HRCTof the ... more available online at http://www.idealibrary.com on FIG 3. Chest radiograph (a) and the HRCTof the thorax (b) in the second patient at presentation.
Letter
European Respiratory Journal, 2001
Pulmonary Pharmacology & Therapeutics, 2002
Whilst nebulisers are commonly used in the treatment of cystic fibrosis (CF), nebulised aerosol l... more Whilst nebulisers are commonly used in the treatment of cystic fibrosis (CF), nebulised aerosol lung deposition in individual patients is not routinely assessed in clinical practice. The present study was designed to evaluate whether a comparative measurement of aerosol lung deposition from nebulisers using a widely available scintigraphic method could be employed to assist the selection of the best system for individual patients. Lung deposition of the radiolabelled aerosol from the Pari LC Plus (Pari Medical Ltd) nebuliser and the HaloLite Adaptive Aerosol Delivery (AAD 1 ) system (Profile Therapeutics Ltd) was measured using planar scintigraphy in 10 healthy volunteers and 6 CF patients. The HaloLite AAD 1 delivered on average 2.1 times (P 0.003) as much aerosol to the lungs compared with Pari LC Plus. Only two subjects had higher lung deposition from Pari LC Plus than HaloLite AAD 1 system. There was marked inter-individual variation in the deposition pattern in CF patients. The aerosol deposition from HaloLite AAD 1 had higher central distribution than that obtained with the Pari LC Plus. The overall intersubject variability of the delivered dose was 56% with Pari LC Plus and 24% with HaloLite AAD 1 (P50.05). The measurement of aerosol deposition from nebulisers can be performed using a simple and widely available methodology, and may improve nebuliser selection in CF patients.