Abstract
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 μm 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.
Highlights
Airway hyperresponsiveness (AHR) is present in most patients with asthma and in many patients with chronicDrug Deliv. and Transl
The aim of this study was to develop improved methods to deliver adenosine receptor agonist powder aerosols to sensitised guinea pigs to measure airway responsiveness. In this feasibility/proof-ofconcept study, we have investigated whether administration of dry powder aerosols of adenosine agonists can be used to induce airway obstruction in a pre-clinical model of allergic asthma
The current paper describes the novel anaesthetic regime, evaluates the use of the PreciseInhale system for delivering adenosine receptor agonist powders to sensitised guinea pigs and compares the resultant bronchial obstruction with that produced by nebulisation and intravenous delivery of the same agents
Summary
Airway hyperresponsiveness (AHR) is present in most patients with asthma and in many patients with chronicDrug Deliv. and Transl. Delivery of adenosine as a dry powder aerosol overcomes the issues identified above [11, 12], and bronchial challenge in subjects with asthma has demonstrated that adenosine and AMP appear to induce airway obstruction in a similar manner [13]. Based on these findings, we reasoned that if dry powder adenosine is useful clinically as an inducer of airway obstruction, this should be reverse translated into pre-clinical models to provide more relevant test systems for studying asthma pathophysiology and to aid in the development of novel drug treatments for affecting AHR
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