Clare P. Perry

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

BackgroundInhaled 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.MethodsA 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.ResultsMean 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).ConclusionThe efficacy and safety of mannitol was demonstrated in non-asthmatic and clinically diagnosed asthmatic adults and children.

The occurrence of refractoriness and mast cell mediator release following mannitol-induced bronchoconstriction

For several hours after exercise-induced bronchoconstriction, there is diminished responsiveness to repeated challenge. The mechanism causing this refractoriness is unclear. Inhalation of dry powder mannitol is a new bronchial provocation test that has been suggested as a surrogate for an exercise challenge. Refractoriness to repeated mannitol challenge has however not been established. Our objective was to investigate if repeated challenge with mannitol is associated with refractoriness and diminished release of mast cell mediators of bronchoconstriction. Sixteen subjects with asthma underwent repeated inhalation of mannitol 90 min apart. Lung function was assessed by forced expiratory volume in 1 s (FEV₁). The urinary excretion (ng/mmol creatinine) of the mediators 9α,11β-prostaglandin (PG) F₂ and leukotriene (LT) E₄ were measured. The group mean fall in FEV₁ after the second challenge was 48.5 ± 5.8% of the first (P < 0.001). The protection afforded by the initial challenge, however, varied considerably between subjects (range 88-0%). Furthermore, the urinary excretion of the two mediators was increased after both challenges. The average excretion of mediators after the challenges was significantly higher for the six most refractory subjects. This was observed both for LTE₄ (95.6 ± 5.2 vs. 58.0 ± 2.4 for the 6 least refractory) (P < 0.001) and for 9α,11β-PGF₂ (137.6 ± 6.7 vs. 50.1 ± 1.1 for the 6 least refractory) (P = 0.002). As occurs with exercise-induced bronchoconstriction, repeated inhalation of mannitol induced refractoriness. We propose that refractoriness is due to tachyphylaxis at the level of the airway smooth muscle responsiveness to mediators of bronchoconstriction rather than due to fatigue of their release from mast cells.

Sodium Cromoglycate Alone and in Combination With Montelukast on the Airway Response to Mannitol in Asthmatic Subjects

Background. Mannitol, inhaled as a dry powder, is used for bronchial provocation to identify bronchial hyperresponsiveness. Bronchoconstriction is associated with an increase in urinary excretion of the metabolites of prostaglandin D2 and leukotriene E4. Sodium cromoglycate provides about 60% protection against the fall in forced expiratory volume in one second (FEV1) provoked by inhaled mannitol and appears to do so by inhibiting the release of prostaglandin D2 but not leukotriene E4.The leukotriene receptor antagonist montelukast does not alter sensitivity to mannitol, as measured by the provoking dose to cause a 15% fall in FEV1 to mannitol, but it significantly enhances recovery from the bronchoconstriction provoked by mannitol. Objective. The authors proposed that the combination of these two drugs would be superior to sodium cromoglycate alone and result in greater protection from the bronchoconstriction provoked by mannitol. Methods. The % fall in FEV1 from baseline and the area under the 30-min FEV1 time curve and time to recover to 95% baseline FEV1 were used to express protection from 40 mg sodium cromoglycate alone, and in combination with 10 mg montelukast, in subjects with asthma. Mannitol was inhaled in the dose that caused a 20% fall in FEV1 on the screening day. The prechallenge medications were randomised on the 3 treatment days and were (1) placebo sodium cromoglycate and placebo montelukast; (2) sodium cromoglycate and placebo montelukast; and (3) sodium cromoglycate and montelukast. Results. The protection by sodium cromoglycate alone on the % fall in FEV1 was 64.4% ± 21.0% versus 65.8% ± 62.8% (p = NS) on the combination. The protection on the area under the 30-min FEV1 time curve for sodium cromoglycate was 81.8% ± 14.0% (p <.04) and 89.3% ± 9.8% for the combination (p <.001) compared with placebo. Recovery to 95% baseline FEV1 by 5/10 min occurred in 58%/66% of subjects on sodium cromoglycate and 66%/83% on the combination compared with 0%/0% on placebo. Conclusion. The addition of montelukast to sodium cromoglycate provided only a small additional benefit against the airway response to mannitol.

Mannitol test results in asthmatic adults receiving inhaled corticosteroids

To the Editor: Bronchial hyperresponsiveness (BHR) is measured by using provocation agents that act either directly on specific receptors to cause contraction of airway smooth muscle and airway narrowing (eg, methacholine) or indirectly via the release of mast cell mediators (eg, exercise and mannitol). The methacholine challenge test (MCT), particularly using the tidal volume method, is highly sensitive, although not highly specific, for identifying the BHR of asthma. Indirect tests while highly specific for the diagnosis of asthma are usually considered less sensitive than MCT to identify BHR. The sensitivity of indirect tests to identify BHR is reduced during treatment with inhaled corticosteroids (ICS). The inhibition of exercise-induced bronchoconstriction by ICS is a good example of this. A recent study reported BHR to MCT in asthmatic subjects receiving ICS. The provoking concentration of methacholine to induce a 20% fall in FEV1 at 8 mg/mL (PC20) had an overall sensitivity of 77% todetectBHRand a sensitivity of 69% inwhite subjects. The authors concluded that the utility of theMCT to rule out a diagnosis of asthma depends on the racial and atopic status. Others have suggested that there were potentially false-negative tests because the dosimeter method involving deep inhalation was used and the subjects may not have had current symptoms. We report the sensitivity of an indirect test to identify BHR, using inhaled mannitol, administered by a controlled deep inhalation in asthmatic subjects currently taking ICS. We analyzed the subjects in the original phase 3 trial used in the evaluation of the mannitol test for registration as a test for BHR. The population included asthmatic patients, required to be symptomatic at study entry, and nonasthmatic subjects with no clinical diagnosis of asthma. At the end of the study, a clinical diagnosis of asthma was also made by a respiratory physician with no

Inspiratory Flows and Volumes in Subjects with Cystic Fibrosis Using a New Dry Powder Inhaler Device

Introduction: Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF). Efficient drug administration via DPIs depends on the device resistance and adequate (≥ 45L/min) inspiratory flows and volumes generated by individuals. Dry-powder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if CF patients’ inspiratory flows and volumes are adequate to use the RS01 DPI device. Materials and Methodology: An open, non-interventional study; enrolled 25 CF subjects, aged ≥ 6 years with FEV1 ≥ 30 to < 90‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer. Results: The mean inspiratory volume (IV) of CF subjects was 1.83L ± 0.97. Their achieved mean ± SD peak inspiratory flow (PIF) was 75.5 ± 27.2L/min. Twenty-three subjects (92%) achieved PIF of > 45L/min with the inhaler device; eighteen of those subjects (78%) had a baseline FEV1 of > 1L. Conclusion: Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in CF patients.

Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device.

Introduction: Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF) or non-CF bronchiectasis. Efficient drug administration via DPIs depends on the device resistance and adequate (≥45L/min) inspiratory flows and volumes generated by individuals. Drypowder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if non-CF bronchiectasis patients’ inspiratory flows and volumes are adequate to use the RS01 DPI device. Materials and Methodology: An open, non-interventional study; enrolled 17 subjects with non-CF bronchiectasis, 18 to 80 years, with baseline FEV1 ≥1.0L and ≥50‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer. Results: The mean inspiratory volume (IV) of non-CF bronchiectasis subjects was 2.08 ± 0.5L and achieved a mean PIF of 78.6 ± 11.2L/min with the inhaler device. Conclusion: Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in non-CF bronchiectasis patients.

Inhaled Mannitol in the Diagnosis and the Management of Asthma

The need for a diagnostic test for asthma was established when it was realized that asthma symptoms could not be relied upon to predict the presence, or not, of airway hyper-responsiveness and inflammation, the hallmarks of asthma. A need to identify asthmatic patients who were overtreated or undert