Asthma is an inflammatory disease of the airways causing them to be hyperresponsive to a wide range of stimuli. It is a common disease both in children and adults and most asthmatics suffer from allergies and from exercise-induced asthma (EIA). The stimulus for EIA is the loss of water by evaporation from the airway surface liquid (ASL) in the process of humidifying large volumes of air in a short time. Since the volume of the ASL is very small in the first 10 generations of airways, and the water is evaporated faster than it is replaced, a transient increase in osmolarity i.e. hyperosmolarity of the ASL is predicted to occur. This hyperosmolarity causes release of histamine, prostaglandins and leukotrienes from inflammatory cells situated on or near the airway surface. These bronchoconstricting substances cause hyperresponsive airway smooth muscle to contract and the airways to narrow i.e. an ‘attack’ of asthma. Identifying EIA is important as it can be prevented.

Fig. 1.

Testing for EIA however can be difficult requiring the subject to perform 6 to 8 minutes of vigorous exercise by running or cycling in a temperate environment. To overcome the requirement for exercise equipment we proposed that the cellular events associated with EIA could be reproduced in an asthmatic simply by inhaling a hyperosmolar aerosol. Mannitol (C₆ H₁₄ O₆ mol weight 182) is a naturally occurring sugar alcohol found in the sap of the manna tree and in many vegetables. It was decided that mannitol, a molecule generally regarded as safe and well known as an osmotic diuretic could be used to increase the osmolarity of the ASL. We developed a dry powder preparation of mannitol, suitable for inhalation and deposition in the lower airways in humans. The mannitol is delivered in increasing doses, by inhaling the powder from a capsule using an inhaler device. One minute after each dose of the mannitol the forced expiratory volume in one second (FEV₁) is measured following a maximum inspiration. The dose of mannitol is increased until a 15% reduction in FEV₁, a positive test result, occurs, or a cumulative dose of 635 mg has been inhaled. Those subjects with a positive mannitol test are also highly likely to have their asthma provoked by exercise. For these reasons the mannitol test is used for assessing those who wish to enter an occupation where a history of asthma may be contra indicated e.g. defence forces and underwater diving. The mannitol test, is a point of need and standardised test to identify ‘bronchial hyperresponsiveness’ A mannitol test kit was developed and is known as Aridol® or Osmohale®_. A positive test result is indicative of active inflammation of the airways that resolves over time in response to treatment with inhaled corticosteroids. Mannitol dry powder has also been used in clinical trials to enhance clearance of secretions in patients with muco-ciliary dysfunction e.g. cystic fibrosis or bronchiectasis (Bronchitol^®). The airways of these patients are dehydrated due to an imbalance between the load of mucus produced and the water available at the airway surface. Dehydrated mucus has abnormal physical properties that impair its clearance i.e. mucus is sticky and viscous. Mannitol, as an osmotic substance, given by inhalation, has the potential to bring water to the airway surface to rehydrate the mucus. The result is that the viscosity of the mucus is reduced leading to enhanced clearance of secretions both by ciliary action and by cough. In patients with cystic fibrosis, there is an increase in the FEV₁ following treatment with mannitol and for some patients a reduction in exacerbations. These patients are treated with beta agonists before taking the mannitol in order to prevent airway narrowing.

Sandra D Anderson
Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

Publication

Repurposing excipients as active inhalation agents: The mannitol story.
Anderson SD, Daviskas E, Brannan JD, Chan HK
Adv Drug Deliv Rev. 2018 Aug

Read offline:     

Related Articles:

	The allergies go marching on: the atopic march and… Atopic/allergic family of diseases affects >20% of the global population and encompasses allergic asthma, hay fever, food allergy, atopic dermatitis, and allergic rhinitis. Frequently, individuals with an allergic condition develop…
	Poverty may affect the developing brain through… Socioeconomic disadvantage, which is prevalent in the United States and worldwide, is consistently associated with lower academic achievement and higher risk for emotional and behavioral problems. Exposure to socioeconomic disadvantage…
	Sustainable solutions: Tamarind Seed Kernel powder… The majority of petroleum-based adhesives applied in the wood industry today, particularly formaldehyde-based adhesives. Their application trend is increasing due to their wide availability, superior bonding, durability, and resistance to…
	Chronic cough cured by proxy Chronic cough causes a severe burden on an individual’s quality of life. Habit cough is a chronic functional cough, meaning it has no physical basis. Habit cough is identified as…
	The complementary anti-inflammatory and anticancer… Inflammation is an important and extremely complex biological process involving a high number of mediators responsible for the activation of multiple cascades, providing a wide range of possible targets for…
	Could mometasone furoate be a viable glucocorticoid… Glucocorticoids are medications widely used to treat inflammation and allergies, and in contexts of immunosuppression such as after transplants. They are well-established and safe. The problem is that, when used…