Repurposing drugs as inhaled therapies in asthma.

For the first 40 years of the 20th century treatment for asthma occurred in response to an asthma attack. The treatments were given by injection or orally and included the adrenergic agonists adrenalin/epinephrine and ephedrine and a phosphodiesterase inhibitor theophylline. Epinephrine became available as an aerosol in 1930.

Mechanisms and Biomarkers of Exercise-Induced Bronchoconstriction.

Exercise is a common trigger of bronchoconstriction. In recent years, there has been increased understanding of the pathophysiology of exercise-induced bronchoconstriction. Although evaporative water loss and thermal changes have been recognized stimuli for exercise-induced bronchoconstriction, accumulating evidence points toward a pivotal role for the airway epithelium in orchestrating the inflammatory response linked to exercise-induced bronchoconstriction.

Repurposing excipients as active inhalation agents: The mannitol story.

The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required.

'Indirect' challenges from science to clinical practice.

Indirect challenges act to provoke bronchoconstriction by causing the release of endogenous mediators and are used to identify airway hyper-responsiveness. This paper reviews the historical development of challenges, with exercise, eucapnic voluntary hyperpnoea (EVH) of dry air, wet hypertonic saline, and with dry powder mannitol, that preceded their use in clinical practice. The first challenge developed for clinical use was exercise.

Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects.

Exercise-induced bronchoconstriction displays refractoriness manifested as a decreased response to repeated exercise challenge within hours. The refractoriness may be attenuated by inhibition of the biosynthesis of prostaglandins (PG). The aim of the study was to determine which PGs and other lipid mediators are excreted during the refractory period.

Air quality and temperature effects on exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) is exaggerated constriction of the airways usually soon after cessation of exercise. This is most often a response to airway dehydration in the presence of airway inflammation in a person with a responsive bronchial smooth muscle. Severity is related to water content of inspired air and level of ventilation achieved and sustained.

An Apparatus to Deliver Mannitol Powder for Bronchial Provocation in Children Under Six Years Old.

Background: Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here.

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.

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.

A World Allergy Organization international survey on physical activity as a treatment option for asthma and allergies.

Background: Physical exercise has been shown to improve asthma symptoms, QoL, exercise capacity, bronchial hyperresponsiveness and lung function and is recommended as a supplementary treatment to pharmacotherapy for asthma. Clinicians are well placed to promote physically active lifestyles, but their role and practice towards promoting physically active lifestyles among patients has not been fully investigated. This study was designed to investigate the knowledge, propensity, attitude and practices of clinicians towards the promotion of physical activity among patients with asthma and allergies.

Urinary CC16 after challenge with dry air hyperpnoea and mannitol in recreational summer athletes.

Airway epithelial injury is regarded as a key contributing factor to the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. The concentration of the pneumoprotein club cell (Clara cell) CC16 in urine has been found to be a non-invasive marker for hyperpnoea-induced airway epithelial perturbation. Exercise-hyperpnoea induces mechanical, thermal and osmotic stress to the airways.

Assessment of EIB: What you need to know to optimize test results.

Respiratory symptoms and asthma control questionnaires are poor predictors of the presence or severity of exercise-induced bronchoconstriction (EIB), and objective measurement is recommended. To optimize the chance of a positive test result, there are several factors to consider when exercising patients for EIB, including the ventilation achieved and sustained during exercise, water content of the inspired air, and the natural variability of the response. The high rate of negative exercise test results has led to the development of surrogates to identify EIB in laboratory or office settings, including eucapnic voluntary hyperpnea of dry air and inhalation of hyperosmolar aerosols.

Refractoriness to exercise challenge: a review of the mechanisms old and new.

This article discusses the available literature on refractoriness in exercise-induced bronchoconstriction, namely, a decrease in airway responsiveness with repeated exercise challenges. The mechanisms of this naturally occurring protective feature is unknown. Reviewing previous studies together with findings in more recent studies, the authors propose desensitization of the G protein-coupled cysteinyl leukotriene receptor1 as the mechanism of refractoriness and that this desensitization occurs as a result of interplay between leukotrienes and prostaglandins.

Pathogenesis of exercise-induced bronchoconstriction.

This article presents the various potential mechanisms responsible for the development of exercise-induced bronchoconstriction (EIB). Although the etiology of EIB is multifactorial, and the physiologic processes involved may vary between individuals (especially between those with and without asthma), drying of the small airways with an associated inflammatory response seems prerequisite for EIB. Dysregulated repair processes following exercise-induced airway epithelial injury may also serve as basis for EIB development/progression.

The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia.

Inhalation of antibiotics and mucolytics is the most important combination of inhaled drugs for chronic obstructive lung diseases and has become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using a Calu-3 air-interface cell model.

An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction.

Background: Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma.

Methods: To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB.

Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis.

Background: Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks.

Methods: Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1≥50% predicted and ≥1 L participated in a randomized, placebo-controlled, double-blind study.

Respiratory health of elite athletes - preventing airway injury: a critical review.

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes.

Assessment and prevention of exercise-induced bronchoconstriction.

The assessment of exercise-induced bronchoconstriction (EIB) in athletes requires the measurement of forced expiratory volume in 1 s (FEV(1)) before and after vigorous exercise or a surrogate of exercise such as eucapnic voluntary hyperpnoea (EVH) of dry air or mannitol dry powder. Exercise testing in a laboratory has a low sensitivity to identify EIB, and exercise testing in the field can be a challenge in itself particularly in cold weather athletes. The EVH test requires the subject to ventilate dry air containing ∼5% CO(2) for 6 min through a low-resistance circuit at a rate higher than that usually achieved on maximum exercise.