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Inhaled adenosine receptor agonists induce bronchoconstriction and inflammation in asthma and are used as bronchial challenge agents for the diagnosis of asthma and in respiratory drug development. Recently developed dry powder aerosols of adenosine have several advantages over nebulised adenosine 5'-monophosphate (AMP) as bronchial challenge agents. However, reverse translation of this bronchial challenge technique to pre-clinical drug development is limited by the difficulty of administering powder aerosols to animals. The aim of the current study was to develop methods for delivering powder aerosols of adenosine receptor agonists to sensitised guinea pigs (as a model of allergic asthma) and evaluate their effect as challenge agents for the measurement of airway responsiveness. The PreciseInhale system delivered micronised AMP and adenosine powders, with mass median aerodynamic diameters of 1.81 and 3.21 mu m and deposition fractions of 31 and 48% in the lungs, respectively. Bronchoconstrictor responses in passively sensitised, anaesthetised, spontaneously breathing guinea pigs were compared to responses to nebulised and intravenously administered AMP and adenosine. AMP- and adenosine-induced bronchoconstriction following all routes of administration with the magnitude of response ranking intravenous > dry powder > nebulisation, probably reflecting differences in exposure to the adenosine agonists delivered by the different routes. In conclusion, the PreciseInhale system delivered AMP and adenosine dry powder aerosols accurately into the lungs, suggesting this method can be used to investigate drug effects on airway responsiveness.

Background: Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to more smoking-induced small airways disease. Thus targeting small airways may be important in treating asthmatic (ex-) smokers. We hypothesized that extrafine particle ICS improve small airways function more than non-extrafine particle ICS in asthmatic (ex-) smokers. Methods: We performed an open-label, randomized, three-way cross-over study comparing extrafine beclomethasone (HFA-QVAR) to non-extrafine beclomethasone (HFA-Clenil) and fluticasone (HFA-Flixotide) in 22 smokers and 21 ex-smokers with asthma (>= 5 packyears).Results: Improvement from baseline in PD20 adenosine after using QVAR, Clenil or Flixotide was 1.04 +/- 1.71, 1.09 +/- 2.12 and 0.94 +/- 1.97 doubling doses, mean +/- standard deviation (SD), respectively. The change from baseline in R-5-R-20 at PD20 adenosine after using QVAR, Clenil or Flixotide was -0.02 +/- 0.27, 0.02 +/- 0.21, and -0.02 +/- 0.31 kPa sL(-1), mean +/- SD, respectively. The change in PD20 adenosine and R5R20 at PD20 adenosine were neither statistically significant different between QVAR and Clenil (p = 0.86 and p = 0.82) nor between QVAR and Flixotide (p = 0.50 and p = 0.96).Conclusion: Similar effectiveness in improving small airways function was found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers. (C) 2017 Elsevier Ltd. All rights reserved.

Background Bronchial provocation is often used to confirm asthma. Dyspnea sensation, however, associates poorly with the evoked drop in FEV1. Provocation tests only use the large airways parameter FEV1, although dyspnea is associated with both large- and small airways dysfunction. Aim of this study was to explore if adenosine 5′-monophosphate (AMP) and adenosine evoke an equal dyspnea sensation and if dyspnea associates better with large or small airways dysfunction. Methods We targeted large airways with AMP and small airways with dry powder adenosine in 59 asthmatic (ex)-smokers with ≥5 packyears, 14 ± 7 days apart. All subjects performed spirometry, impulse oscillometry (IOS), and Borg dyspnea score. In 36 subjects multiple breath nitrogen washout (MBNW) was additionally performed. We analyzed the association of the change (Δ) in Borg score with the change in large and small airways parameters, using univariate and multivariate linear regression analyses. MBNW was analyzed separately. Results Provocation with AMP and adenosine evoked similar levels of dyspnea. ΔFEV1 was not significantly associated with ΔBorg after either AMP or adenosine provocation, in both univariate and multivariate analyses. In multivariate linear regression, a decrease in FEF25–75 during adenosine provocation was independently associated with an increase in Borg. In the multivariate analyses for AMP provocation, no significant associations were found between ΔBorg and any large or small airways parameters. Conclusion AMP and adenosine induce equally severe dyspnea sensations. Our results suggest that dyspnea induced with dry powder adenosine is related to small airways involvement, while neither large nor small airways dysfunction was associated with AMP-induced dyspnea. Trail registration NCT01741285 at www.clinicaltrials.gov, first registered Dec 4th, 2012. Electronic supplementary material The online version of this article (10.1186/s12890-019-0783-0) contains supplementary material, which is available to authorized users.

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils. Electronic supplementary material The online version of this article (10.1186/s12931-018-0961-2) contains supplementary material, which is available to authorized users.

Background: Bronchial provocation is often used to confirm asthma. Dyspnea sensation correlates poorly with the provocative dose that causes the FEV1 to drop ≥20% (PD20). Aim: To explore if dyspnea sensation associates better with small airways then large airways function. Methods: We induced dyspnea with dry powder adenosine and nebulized adenosine 5’‑monophosphate (AMP), targeting the small and large airways, respectively, 14±7 days apart. We obtained spirometry, impulse oscillometry (IOS), and Borg score in all subjects, but multiple breath nitrogen washout (MBNW) was only limited available. Subjects were asthmatic (ex‑)smokers with ≥5 packyears. We analyzed the correlation between the change (Δ) in large and small airways parameters to ΔBorg in univariate and multivariate linear regression analysis. MBNW was analyzed separately. Results: We included 61 subjects of which 36 performed MBNW. Provocation with adenosine and AMP evoked similar levels of dyspnea. The large airways parameter, ΔFEV1 was not significantly correlated with ΔBorg after either adenosine or AMP provocation, in both univariate and multivariate analyses. Multivariate linear regression models for ΔBorg included for adenosine: gender, smoking status, ΔFEV1, ΔFEF25-75, ΔR20, ΔR5‑R20, and ΔScond and for AMP: gender, smoking status, ΔFEV1, ΔFEF25-75, ΔR20, ΔX5, and ΔLCI5%. ΔFEF25-75 during adenosine provocation was independently associated with ΔBorg, but for ΔBorg during AMP provocation no significant associations were found. Conclusion: Our results suggest that dyspnea sensation induced with dry powder adenosine is related to small airways involvement, while neither large nor airways small airways dysfunction was associated with AMP induced dyspnea.

Inhaled airway challenges provoke bronchoconstriction in susceptible subjects and are a pivotal tool in the diagnosis and monitoring of obstructive lung diseases, both in the clinic and in the development of new respiratory medicines. This article reviews the main challenge agents that are in use today (methacholine, mannitol, adenosine, allergens, endotoxin) and emphasises the importance of controlling how these agents are administered. There is a danger that the optimal value of these challenge agents may not be realised due to suboptimal inhaled delivery; thus considerations for effective and reproducible challenge delivery are provided. This article seeks to increase awareness of the importance of precise delivery of inhaled agents used to challenge the airways for diagnosis and research, and is intended as a stepping stone towards much-needed standardisation and harmonisation in the administration of inhaled airway challenge agents.

Background: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. Objective: We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. Design: In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min(-1)) and once with a high flow rate (60 l min(-1)). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV1 reflects the large airways, and FEF25-75%, R5-R20 and X5 reflect the small airways. Results: The four adenosine tests were not significantly different with respect to the threshold values of FEV1 (p = 0.12), FEF25-75% (p = 0.37), R5-R20 (p = 0.60) or X5 (p = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. Conclusions: In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.

Background: Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to smoking-induced small airways disease. Aim: Targeting the small airways may be important in treating asthmatic smokers and ex-smokers. We hypothesized that extrafine particle ICS improves small airways function more than non-extrafine particle ICS in these patients. Methods: We performed a two-center, open-label, randomized, three-way cross-over study comparing two-week extrafine beclomethasone (HFA-QVAR 200 µg b.i.d.) to non-extrafine beclomethasone (HFA-Clenil 400 µg b.i.d.) and fluticasone (HFA-Flixotide 250 µg b.i.d.) in 22 smokers and 21 ex-smokers with asthma (≥5 packyears). Primary outcomes were the provocative dose of adenosine inducing a 20% fall in FEV1 (PD20) and peripheral airway resistance measured with impulse oscillometry (R5-R20) at PD20. Results: Improvement from baseline in the PD20 adenosine after using QVAR, Clenil or Flixotide was 1.04±1.71, 1.09±2.12 and 0.94±1.97 doubling doses mean ± standard deviation (SD), respectively. The change from baseline in R5-R20 at PD20 adenosine after using QVAR, Clenil or Flixotide was 0.02±0.27, 0.02±0.21, and -0.02±0.31 kPa·sL−1 mean ± SD, respectively. For the change in PD20 adenosine and R5-R20 at PD20 adenosine, the differences between QVAR and Clenil (p=0.86 and p=0.82) or between QVAR and Flixotide (p=0.50 and p=0.96) were not statistically significant. Conclusion: Similar results were found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers. Both were equally effective in improving airway hyperresponsiveness.

Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.

Adenosine is an indirect stimulus to assess bronchial hyperresponsiveness (BHR(2)) in asthma. Bronchial challenge tests are usually performed with nebulised solutions of adenosine 5'-monophosphate (AMP(3)). The nebulised AMP test has several disadvantages, like long administration times and a restrictive maximum concentration that does not result in BHR in all patients. In this study, we investigated the applicability of dry powder adenosine for assessment of BHR in comparison to nebulised AMP. Dry powder adenosine was prepared in doubling doses (0.01-80 mg) derived from the nebulised AMP test with addition of two higher doses. Five asthmatic subjects performed two bronchial challenge tests, one with nebulised AMP following the 2-min tidal breathing method; the second with dry powder adenosine administered with an investigational inhaler and single slow inhalations (inspiratory flow rate 30-40 L/min). All subjects reached a 20% fall in FEV₁(4) with the new adenosine test (PD20(5)) compared to four subjects with the AMP test (PC₂₀(6)). Dry powder adenosine was well tolerated by all subjects and better appreciated than nebulised AMP. In conclusion, this new bronchial challenge test appears to be a safe and convenient alternative to the nebulised AMP test to assess BHR in asthmatic subjects.

Dry powder administration of adenosine by use of an effective inhaler may be an interesting alternative to nebulisation of adenosine 5 '-monophosphate in bronchial challenge testing, because of a shorter administration time and more consistent delivered fine particle dose over the entire dose range. In this study, we tested various powder formulations and classifier based dispersion principles and investigated the in vitro performance of the most promising formulation/classifier combination in a new test inhaler system. Spray-dried formulations of either pure adenosine (100%) or adenosine and lactose as diluent (1% and 10% adenosine) were prepared to cover the entire expected dose range for adenosine (0.01-20 mg). All three powders, in all 12 suggested doses, dispersed well with the newly developed test inhaler with a multiple air jet classifier disperser, into aerosols with an average volume median diameter of 3.1 mu m (3.0-3.3 mu m). For eleven out of 12 dose steps, the fine particle fractions

Introduction: Pulmonary vaccination could be a promising alternative to vaccination by injection. Administration of a vaccine to the lungs does not require the use of needles, which reduces the number of trained healthcare workers needed, the risk of needle-stick injuries and needle waste. Besides a systemic immune response, pulmonary vaccination may also induce a mucosal immune response. Such a local response may increase the effectiveness of vaccination against airborne pathogens. Although this route of administration has been studied for decades, no pulmonary vaccine is commercially available yet, due to various challenges mostly intrinsic to pulmonary drug delivery and vaccine formulation. Areas covered: This review discusses the inhalation devices and formulation strategies that may be suitable for the pulmonary administration of vaccines. In addition, critical parameters are addressed, such as the target population, to help assessing whether pulmonary administration of a specific vaccine may be feas...

Introduction Many children with CF are treated with inhaled antibiotics, mostly by nebulisation, although first generation capsule-based dry powder inhalers (DPIs) with antibiotics are now available. Such inhalers generally require inhaled volumes ≥1 L and high flow rates (≥60 L/min) to deliver the entire dose. Aim To determine whether children with CF are able to perform the inspiratory manoeuvres needed to operate a capsule-based DPI effectively and how their inhalations are affected by the inhaler resistance and their disease. Methods We recorded inspiratory flow manoeuvres of children with and without CF ( n =35 and n =103 respectively, 4-14 years old) through a test inhaler with variable airflow resistance and calculated total inhaled volume (V) and peak inspiratory flow rate (PIF). Results Minimal V (0.5 L) and PIF values (20 L/min) of children with CF and healthy controls were the same, but the age-related increases of both parameters were slightly higher for the healthy controls ( p p =0.08 respectively; see Figure). Resistance in the range 0.31-0.45 kPa 0.5 .L.min -1 (medium to high) affected PIF but not total inhaled volume. Conclusions Our findings indicate that inhaled volumes and PIFs of the youngest children (with and without CF) are too low to operate currently marketed antibiotic DPIs effectively. By implication, the development of DPIs specifically for children is highly desired.

Historically, the inhaled route has been used for the delivery of locally-acting drugs for the treatment of respiratory conditions, such as asthma, COPD, and airway infections. Targeted delivery of substances to the lungs has some key advantages over systemic administration, including a more rapid onset of action, an increased therapeutic effect, and, depending on the agent inhaled, reduced systemic side effects since the required local concentration in the lungs can be obtained with a lower dose. Fortunately, when designed properly, inhaled drug delivery devices can be very effective and safe for getting active agents directly to their site of action.

Age appropriateness is a major concern of pulmonary delivery devices, in particular of dry powder inhalers (DPIs), since their performance strongly depends on the inspiratory flow manoeuvre of the patient. Previous research on the use of DPIs by children focused mostly on specific DPIs or single inspiratory parameters. In this study, we investigated the requirements for a paediatric DPI more broadly using an instrumented test inhaler. Our primary aim was to assess the impact of airflow resistance on children's inspiratory flow profiles. Additionally, we investigated children's preferences for airflow resistance and mouthpiece design and how these relate to what may be most suitable for them. We tested 98 children (aged 4.7-12.6 years), of whom 91 were able to perform one or more correct inhalations through the test inhaler. We recorded flow profiles at five airflow resistances ranging from 0.025 to 0.055 kPa(0.5).min.L-1 and computed various inspiratory flow parameters from these recordings. A sinuscope was used to observe any obstructions in the oral cavity during inhalation. 256 flow profiles were included for analysis. We found that both airflow resistance and the children's characteristics affect the inspiratory parameters. Our data suggest that a medium-high resistance is both suitable for and well appreciated by children aged 5-12 years. High incidences (up to 90%) of obstructions were found, which may restrict the use of DPIs by children. However, an oblong mouthpiece that was preferred the most appeared to positively affect the passageway through the oral cavity. To accommodate children from the age of 5 years onwards, a DPI should deliver a sufficiently high fine particle dose within an inhaled volume of 0.5 L and at a peak inspiratory flow rate of 25-40 L.min(-1). We recommend taking these requirements into account for future paediatric inhaler development.

Fine excipient particles or 'fines' have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of 'fine lactose fines' (FLF, X50= 1.95 mm) with a similar size and shape as micronised budesonide were studied and compared to those of 'coarse lactose fines' (CLF, X50= 3.94 mm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions. © 2014 Grasmeijer et al.

BACKGROUND: In the adenosine 5'-monophosphate (AMP) bronchial challenge test, AMP is usually administered according to dosing protocols for methacholine. We investigated whether the 2-min tidal breathing challenge test for methacholine is applicable to AMP. Parameters known to affect nebulizer output were studied. Our aim was to determine whether control of additional parameters is needed for currently standardized protocols.METHODS: The study was performed with the Sidestream nebulizer from the APS Pro Aerosol Provocation System (CareFusion Respiratory). The effects of AMP concentration, jet pressure, and suction flow rate on nebulizer output rate and aerosol droplet size distribution were determined.RESULTS: The volume median diameter for water increased from 5.10 μm to 8.49 μm when the jet pressure was reduced to obtain the prescribed output rate of 0.13 mL/min. The output rate was increased when a suction flow rate was used to remove the aerosol. Increasing the AMP concentration resulted in smaller droplets and a lower output rate when a suction flow was applied.CONCLUSIONS: The effects of AMP concentration on nebulizer performance may result in changes in the administered dose and site of deposition of AMP at dose escalation. All of the investigated parameters influence nebulizer performance, hence the outcome of a bronchial challenge test. Therefore, these parameters should not only be specified in challenge testing, but be actively controlled as well.

Summary Background: In bronchial challenge testing lung deposition of the stimulus may be poorly controlled due to incorrect use of nebulisers. Furthermore, the need for freshly prepared solutions burdens personnel and budget. In this study we aim to develop a dry powder alternative with higher reproducibility, better stability and lower costs than the current nebulisation test. Methods: Different pharmacological stimuli in the solid state were characterised on physico-chemical properties to determine the optimal conditions for processing and storage and were tested on their potential for dry powder inhalation. Adenosine and methacholine were micronised and dispersed with the Twincer ™ dry powder inhaler (DPI). Laser diffraction technique was applied to measure particle size distributions in the aerosol clouds. Results: Adenosine allows processing under ambient conditions. It was mixed with a lactose carrier in various mass ratios to produce adhesive mixtures and nucleus agglomerates. With three formulations, almost the entire dose range could be delivered with the Twincer ™ DPI. However, the process of preparing nucleus agglomerates might not be suitable for upscaling. Currently, spherical pellets are investigated as a more robust alternative. Methacholine is very hygroscopic and should therefore not be exposed to a high relative humidity. The methacholine particles leaving the Twincer ™ had an appropriate particle size distribution for inhalation. However, inhaler retention was high and should be reduced by controlling processing and storage conditions. Conclusions: Dry powder adenosine and methacholine seem promising alternatives for nebulisation. Methacholine must be handled under dry conditions. The highest doses of adenosine require further fine tuning.

Children are an important target group for inhalation therapy, but little is known about their intellectual and inspiratory capacities to operate dry powder inhalers (DPIs). Most studies so far have focused either on a specific DPI, or on (single) inhala- tion parameters and how these are affected by airflow resistance, which leaves many questions for the development of new devices for the pediatric population unanswered. In this study, we investigated the applicability of DPIs in children by a more systematic approach by using a test inhaler with variable airflow resistance and exchangeable mouthpiece design. The test inhaler was instrumented to record inhalation curves and equipped with fiberglass optics (sinuscope) to study the passageway for the aerosol through the mouth cavity. We examined for 103 school children (aged 4-12 years) whether they were able to use the test inhaler according to the instructions given. Nearly all (91) were able to perform one or more correct inhalations. We computed PIFs, inhaled volumes, and inhalation times from in total 256 recordings, and tested relationships with height and airflow resistance upon significance. We also noted preferences for airflow resistance and mouthpiece design, and investigated how these variables affect the inhalation maneuver. Ultimately, we aim to use the data from this study not only for prescribing the most appropriate type of currently marketed DPI to children, but particularly to design a new DPI that performs well within the range of inspiratory capacities (PIF and inhaled volume) to be expected for children.