Biomedical subjects

John D Brannan

Publications and source records attributed to John D Brannan.

11 recordsLinked to original sources

PubMed2005

The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline.

BACKGROUND: Inhaled mannitol is a new bronchial provocation test (BPT) developed to improve portability and standardisation of osmotic challenge testing. Osmotic challenge tests have an advantage over the traditional methods of measuring airway hyperresponsiveness using methacholine as they demonstrate higher specificity to identify asthma and thus the need for treatment with inhaled corticosteroids (ICS). The safety and the efficacy of mannitol (M) as a BPT to measure airway hyperresponsiveness were compared to hypertonic (4.5%) saline (HS) in people both with and without signs and symptoms of asthma. METHODS: A phase III, multi-centre, open label, operator-blinded, crossover design, randomised trial, with follow-up. Asthmatics and non-asthmatics (6-83 yr) were recruited and 592 subjects completed the study. Mannitol was delivered using a low resistance dry powder inhaler and HS was delivered using an ultrasonic nebuliser. The FEV1 was measured 60 seconds after each dose of mannitol (5,10,20,40,80,160,160,160 mg) and after each exposure to HS (0.5,1.0,2.0,4.0,8.0 minutes). A 15% fall in FEV1 defined a positive test. Adverse events were monitored and diaries kept for 7 days following the tests. RESULTS: Mean pre-test FEV1 (mean +/- SD) was 95.5 +/- 14% predicted. 296 were positive to mannitol (M+) and 322 positive to HS (HS+). A post study physician conducted clinical assessment identified 82.3% asthmatic (44% classified mild) and 17.7% non-asthmatic. Of those M+, 70.1% were taking ICS and of those mannitol negative (M-), 81.1 % were taking ICS. The % fall in FEV1 for mannitol in asthmatics was 21.0% +/- 5.7 and for the non-asthmatics, 5.5% +/- 4.8. The median PD15 M was 148 mg and PD15 HS 6.2 ml. The sensitivity of M to identify HS+ was 80.7% and the specificity 86.7%. The sensitivity of M compared with the clinical assessment was 59.8% and specificity 95.2% and increased to 88.7% and 95.0% respectively when the M- subjects taking ICS were excluded. Cough was common during testing. There were no serious adverse events. The diarised events were similar for mannitol and HS, the most common being headache (17.2%M, 19%HS), pharyngolaryngeal pain (5.1%M, 3%HS), nausea (4.3%M, 3%HS), and cough (2.2%M, 2.4%HS). CONCLUSION: The efficacy and safety of mannitol was demonstrated in non-asthmatic and clinically diagnosed asthmatic adults and children.

Administration, Inhalation↗

PubMed2005

Dissociation in the effect of nedocromil on mannitol-induced cough or bronchoconstriction in asthmatic subjects.

OBJECTIVE: Inhaled mannitol induces both bronchoconstriction and cough. Nedocromil sodium greatly attenuates mannitol-induced bronchoconstriction. Knowledge about the effect of nedocromil on mannitol-provoked cough might, therefore, clarify the mechanisms of this response. METHODOLOGY: Inhalation challenges with mannitol powder were performed after inhalation of 8 mg of nedocromil or its placebo in 24 subjects with asthma. The study was double-blind, randomised, and placebo-controlled. The mannitol-provoked coughs were manually recorded and the mannitol-induced bronchoconstriction was measured with a spirometer. RESULTS: The cumulative dose of mannitol that provoked at least two coughs tended to be higher on the nedocromil day than on the placebo day (34 (22--53) mg vs 26 (18--37) mg, P=0.051). The cumulative number of coughs per dose of mannitol was slightly, but significantly, lower on the nedocromil than on the placebo day (4.2 (2.8--6.3) coughs/100 mg vs 6.1 (4.0--9.4) coughs/100 mg, P=0.037). However, when analysed on a constant-dose basis, nedocromil provided no protection for coughing (-1% protection), whereas the protection for bronchoconstriction was clear (55% protection). CONCLUSIONS: Nedocromil strongly attenuates mannitol-induced bronchoconstriction but has a negligible effect on mannitol-provoked cough. Therefore, these responses seem to have different pathways in asthma. Recording of both provoked coughs and induced bronchoconstriction during mannitol challenge may provide supplementary information about a patient's disease.

Adolescent↗

PubMed2004

Coughing during mannitol challenge is associated with asthma.

STUDY OBJECTIVES: To define whether coughing during mannitol challenge is a nonspecific side effect of this challenge or is associated with asthma. DESIGN: A prospective study. SETTING: University hospital. PARTICIPANTS: Thirty-seven steroid-naive, asthmatic subjects and 10 healthy subjects. MEASUREMENTS: The participants completed a symptom questionnaire, recorded peak expiratory flows (PEFs), and underwent spirometry, skin tests, and bronchial provocations with mannitol, histamine, and cold air. Seventeen of the asthmatic subjects were treated with budesonide, 800 micro g per day, and the measurements were repeated after 3 and 6 months of treatment. Coughs were recorded during the mannitol challenges, and the cough sensitivity was expressed as the cumulative number of coughs divided by the cumulative dose of mannitol. RESULTS: The asthmatic subjects coughed more during the mannitol challenge than the healthy subjects (8.3 coughs per 100 mg [95% confidence interval (CI), 6.2 to 11.0] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001). Even those asthmatic subjects who did not develop bronchoconstriction after the maximal cumulative dose of mannitol (635 mg) coughed significantly more than the healthy subjects (53 coughs [95% CI, 34 to 72] vs 12 coughs [95% CI, 4 to 21]; p = 0.003). Budesonide treatment decreased the cough sensitivity (p = 0.023), which was significantly associated with improvements in overall symptom frequency, cough frequency, diurnal PEF variation, FEV(1), and bronchial hyperresponsiveness. CONCLUSIONS: Coughing during mannitol challenge is associated with asthma and occurs independently of bronchoconstriction. It can be used to study the mechanisms of asthmatic cough. Furthermore, the measurement of the mannitol-provoked coughing may be useful both in the diagnosis of asthma as well as in the assessment of the effects of an anti-inflammatory therapy on this common disorder.

Adult↗

PubMed2004

Long-acting beta 2-adrenoceptor agonists and exercise-induced asthma: lessons to guide us in the future.

The safety and efficacy of long-acting beta(2)-adrenoceptor agonists (LABAs) taken intermittently for the prevention of exercise-induced asthma (EIA) in children is well established. However, the safety and efficacy of LABAs taken twice daily, either alone or in combination with inhaled corticosteroids, for the prevention of EIA is not as clear because of issues of tolerance (defined as being less responsive to the influence of LABAs). There have been many observations on short-acting beta(2)-adrenoceptor agonists (SABAs) and EIA that should have alerted us to the potential for tolerance and desensitization to occur with LABAs. For example, we expected that the use of LABAs for EIA would overcome the problem of the short duration of protection of SABAs, and to some extent they have. The protective period of a LABA is two to three times longer in duration than that of a SABA. However, when a LABA is taken daily it is apparent that the duration of its protective effect is reduced and there is a risk of EIA occurring well within the 12-hour administration schedules. Furthermore, daily use of LABAs attenuates the bronchodilator effect of SABAs, an effect that is greater the more severe the bronchoconstriction. This 'tolerance' increases both the time and the amount of therapy that is needed to recover from bronchoconstriction, and thus, could potentially impact on the success of rescue therapy should severe EIA occur. The daily use of LABAs also increases the sensitivity of the bronchial smooth muscle to contractile agents. This increase in sensitivity is almost equivalent to the extent to which inhaled corticosteroids reduce sensitivity to the same contractile agents. The increased sensitivity to contractile agents may occur either by a reduction in the inhibitory effect of beta(2)-adrenoceptor agonists on release of mediators from mast cells or by a direct effect on the bronchial smooth muscle. These unwanted effects of LABAs are not necessarily reduced by concomitant treatment with inhaled corticosteroids. As the number of children being treated with LABAs increases, it is predicted that problems with breakthrough EIA will also increase. We need to know the percentage of children taking a LABA daily who are requiring either extra doses of a beta(2)-adrenoceptor agonist to prevent (or reverse) EIA or other provocative stimuli. If this percentage is significant then we may need to reconsider the position of LABAs in the treatment of children with asthma who regularly perform strenuous physical activity.

Administration, Inhalation↗

PubMed2003

Sensitivity and validity of three bronchial provocation tests to demonstrate the effect of inhaled corticosteroids in asthma.

STUDY OBJECTIVES: To compare the sensitivity and validity of mannitol, histamine, and cold air challenges to demonstrate the effect of inhaled corticosteroids (ICS) in asthma. DESIGN: A prospective study. PARTICIPANTS: Seventeen patients with recently diagnosed, steroid-naive asthma who fulfilled the diagnostic criteria of Finnish Social Insurance Institution and were hyperresponsive to both mannitol and histamine. INTERVENTIONS: The following procedures were carried out at baseline and after 3 months and 6 months of treatment with inhaled budesonide, 800 microg/d: symptom assessment with a questionnaire, ambulatory peak expiratory flow (PEF) measurements twice daily for 2 weeks, and bronchial challenges with mannitol, histamine, and cold air. RESULTS: Budesonide decreased the sum symptom score, daily use of bronchodilating drugs, and diurnal PEF variation, but did not change FEV(1) percentage of predicted significantly. In addition, budesonide significantly decreased mannitol (p = 0.005) and histamine (p = 0.002) response dose ratios. The magnitude of the budesonide-induced change in responsiveness to these two challenges did not differ significantly. The effect of budesonide on cold air responsiveness did not reach statistical significance (p = 0.064). Change in mannitol responsiveness correlated significantly with the changes in sum symptom score and in FEV(1). Change in cold air responsiveness correlated with the changes in sum symptom score and in diurnal PEF variation. Change in histamine responsiveness correlated only with change in FEV(1). CONCLUSIONS: Mannitol challenge is both a sensitive and valid test to demonstrate the effects of ICS in asthma. Histamine challenge is equally sensitive for this purpose, but its validity may be lower than that of mannitol challenge. Cold air challenge seems to be a valid test to demonstrate the effects of ICS, but its sensitivity may be lower than that of mannitol and histamine challenges.

Administration, Inhalation↗

PubMed2003

Responsiveness to three bronchial provocation tests in patients with asthma.

STUDY OBJECTIVES: To compare a new bronchial provocation test, the mannitol challenge, with cold air and histamine challenges to demonstrate airway hyperresponsiveness (AHR) in patients with difficult-to-diagnose asthma. DESIGN: A prospective study. PARTICIPANTS: Thirty-seven consecutive patients with recently diagnosed, steroid-naive, mild, or atypical asthma fulfilling the diagnostic criteria of Finnish Social Insurance Institution, and 10 healthy control subjects. INTERVENTIONS: Each subject completed a symptom questionnaire and underwent spirometry, diffusion capacity measurement, skin-prick tests, and bronchial provocations with mannitol, histamine, and cold air. The severity of asthma was classified according to the Global Initiative for Asthma (GINA). RESULTS: Fifty-one percent of the asthmatic patients responded to mannitol (> or =15% fall in FEV(1)), 24% to cold air (> or =9% fall in FEV(1)), and 81% or 49% to histamine (provocative dose causing a 15% fall in FEV(1) [PD(15)] < 1.0 mg or < 0.4 mg, respectively). None of the healthy control subjects responded. The GINA classification was not associated with responsiveness to any of the challenges. CONCLUSIONS: Mannitol is more sensitive than cold air in demonstrating AHR in patients with mild or atypical asthma. Histamine was more sensitive than both mannitol and cold air if 1.0 mg was used as a cut-off value for histamine PD(15). However, if the cut-off value for histamine PD(15) is lowered to 0.4 mg, which represents a specific diagnosis of asthma according to previous studies, the sensitivity values of mannitol and histamine challenges are comparable.

Adult↗

PubMed2003

Methods for "indirect" challenge tests including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols.

Bronchial provocation tests that use stimuli that act indirectly to cause airway narrowing have a high specificity for identifying people with active asthma who have the potential to respond to treatment with antiinflammatory drugs. The first test to be developed was exercise and it was used to assess the efficacy of drugs such as sodium cromoglycate. Eucapnic voluntary hyperpnea was developed later, as a surrogate test for exercise. Hypertonic aerosols were introduced to mimic the dehydrating effects of evaporative water loss that occurs during hyperpnea. A wet aerosol of 4.5% saline or a dry powder formulation of mannitol is used. At present the indirect challenge tests are becoming increasingly recognised as appropriate for monitoring treatment with inhaled steroids. Indirect tests identify those with potential for exercise-induced bronchoconstriction, an important problem for some occupations, such as the defence forces, fire fighters and the police force and for some athletic activities. The advantage in using an indirect challenges, over a direct challenge with a single pharmacological agonist, is that a positive response indicates that inflammatory cells and their mediators (prostaglandins, leukotrienes and histamine) are present in the airways in sufficient numbers and concentration to indicate that asthma is active at the time of testing. The corollary to this is that a negative test in a known asthmatic indicates good control or mild disease. Another advantage is that healthy subjects do not have significant airway narrowing to indirect challenge tests. The protocols used for challenge with indirectly acting stimuli are presented in detail.

Adult↗

PubMed2002

Bronchial provocation tests: the rationale for using inhaled mannitol as a test for airway hyperresponsiveness.

The use of histamine and methacholine is well established for identifying airway hyperresponsiveness (AHR) but the AHR to these agents is not specific for asthma diagnosis. Further, these agents do not identify or exclude exercise-induced asthma (EIA) so they are inappropriate for some occupational and sporting assessments. Measurement of AHR by pharmacological agents has other limitations in that a positive response does not necessarily identify a person who will respond to inhaled steroids and responses do not differentiate between doses of steroids. As most asthmatics remain hyperresponsive to these agents after treatment they have not been useful for guiding steroid dose reduction. Bronchial provocation tests (BPTs) with physical stimuli such as exercise, eucapnic voluntary hyperpnea and hypertonic saline have provided useful information on presence and severity of asthma and EIA. These tests however, can be time consuming and require more resources compared with the pharmacological tests. To simplify testing, a challenge has been developed that uses a dry powder of mannitol administered from a simple hand-held device. The mannitol is given in increasing doses from capsules containing from 5 mg to 40 mg. Mannitol responsiveness identifies people with EIA and those who will respond to inhaled steroids. Mannitol responsiveness is reduced following treatment with inhaled steroids, and some subjects become unresponsive within 6 to 8 weeks. Responsiveness to mannitol can be used to predict risk of exacerbation during back titration of steroids. Should this BPT become more readily available it would be the first to provide a common operating standard for use in the laboratory, office, or field.

Asthma↗

PubMed2002

Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects.

OBJECTIVE: The aim of the study was to investigate whether treatment using inhaled corticosteroids decreases airway responsiveness to inhaled mannitol in asthmatic subjects. METHODOLOGY: Before treatment or a change in treatment with inhaled corticosteroids, 18 asthmatic subjects had measurements of lung function and airway sensitivity to mannitol taken and they completed a self-administered questionnaire on asthma symptoms. The procedure was repeated 6-9 weeks after taking 800-2400 microg/day of budesonide. RESULTS: There were significant reductions in airway sensitivity (provoking dose to induce a 15% fall in FEV1 (PD15)) and airway reactivity measured by the response dose ratio (RDR; final percentage fall FEV1/total dose of mannitol administered). The PD15 (Gmean (95%CI)) increased from 78 mg (51, 117) before treatment to 289 mg (202, 414) following treatment (P < 0.001). All subjects had a significant increase beyond the repeatability of 0.9 doubling doses with seven subjects becoming unresponsive. There was a 4.2 (3.4, 4.9)-fold improvement in the RDR with the value before the treatment period 0.18 (0.12, 0.28) decreasing to 0.04 (0.03, 0.08) following treatment (P < 0.001). These improvements were associated with significant improvements in lung function and symptom severity. CONCLUSION: Treatment with the inhaled corticosteroid budesonide caused a decrease in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms.

Administration, Inhalation↗

PubMedDate not supplied

Questionnaire responses that predict airway response to hypertonic saline.

BACKGROUND: Airway hyperresponsiveness to hypertonic saline (HS) is associated with airway inflammation. We investigated if responsiveness to HS was predicted by asthma symptoms in the last 3 months. OBJECTIVES: To investigate if responsiveness to HS can be estimated by questionnaire items investigating asthma symptoms of the last 3 months. METHODS: Six hundred and four patients with physician-diagnosed asthma being assessed for asthma severity were studied. Bronchial provocation with 4.5% saline was performed, and a questionnaire was administered. The response to 4.5% saline was reported as the provoking dose to cause a 15% fall in the forced expiratory volume in 1 s FEV(1) (PD(15)) and the response-dose ratio (RDR). RESULTS: Based on the GINA guidelines, asthma severity was intermittent in 497 patients, mild in 107 patients, moderate in 3 patients and severe in 1 patient. A PD(15) to 4.5% saline was recorded in 234 of the 604. Questions on self-recognition of asthma, dust as a trigger, food as a trigger, and frequency of bronchodilator use were significant predictors for a PD(15), and currently taking steroids decreased the likelihood of a positive response to 4.5% saline. Using a multiple-linear regression model, a difference in the RDR could be calculated between those who answered positively compared with the reference group, who answered negatively. This difference could be used as a guide for predicting abnormal reactivity. An increase in RDR in response to 4.5% saline, compared with the reference group, was demonstrated in the presence of self-recognition of asthma severity, dust and cats as a trigger or use of bronchodilator during sleep hours. CONCLUSIONS: Because of the high positive predictive value of HS for identifying patients with asthma it might be that the need for bronchodilator use at night not only predicts airway hyperresponsiveness to HS, it also could reflect the severity of asthma.

Adolescent↗

PubMedDate not supplied

Beta2-agonists and exercise-induced asthma.

Beta2-agonists taken immediately before exercise provide significant protection against exercise- induced asthma (EIA) in most patients. However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First, there is a significant minority (15-20%) of asthmatics whose EIA is not prevented by beta2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use, there is a decline in duration of the protective effect of long-acting beta2-agonists. Third, if breakthrough EIA occurs, recovery of lung function is slower in response to a beta2-agonist, and additional doses are often required to achieve pre-exercise values. If a person who takes a beta2-agonist daily experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of EIA. These problems likely result from desensitization of the beta2-receptor on the mast cell, which enhances mediator release, and on the bronchial smooth muscle, which enhances the bronchoconstrictor response and delays recovery from EIA. These effects are reversed within 72 h after cessation of a beta2-agonists. The important clinical question is: Are we actually compromising the beneficial effects of beta2-agonists on the prevention and recovery from EIA by prescribing them daily? Patients with EIA need to ensure that their doses of inhaled corticosteroid or other anti-inflammatory therapy are optimized so that, if necessary, a beta2-agonist can be used intermittently as prophylactic medication with greater confidence in the outcome.

Adrenergic beta-Agonists↗