WO2002055057A2

WO2002055057A2 - Treatment of asthma and other lung conditions

Info

Publication number: WO2002055057A2
Application number: PCT/IE2002/000003
Authority: WO
Inventors: Conor Burke; Leonard W. Poulter
Original assignee: Corcoran, Noel, M.
Priority date: 2001-01-12
Filing date: 2002-01-11
Publication date: 2002-07-18
Also published as: AU2002219473A1; WO2002055057A3

Abstract

An improved treatment for patients with diseases caused by inflammation of the airways is disclosed. The treatment may be administered both in the emergency room or whilst in transit and comprises a pharmaceutical, for the treatment of such patients, which is safe, cheap, easy to administer and which maximally humidifies the airways or bronchi of the lungs. Also disclosed is an improved method of monitoring asthma status in asthmatics and for treatment of acute asthma attacks. A portable device is disclosed, that can be carried by people suffering from diseases of the respiratory system, for the treatment or prevention of respiratory distress. A device for delivering humidified to a human subject is disclosed. The device comprises a water reservoir (11), a means for forming humidified air (15) from the water in the reservoir, a heating means (12) for either heating the humidified air or the water in the reservoir, to between 15 and 100 °C, and a mouthpiece adapted to deliver the humidified air to the subject (16).

Description

Treatment of Asthma and Other Lung Conditions

The present invention relates to the treatment of diseases caused by airways inflammation; in particular asthma and Chronic Obstructive Pulmonary Disease; to methods of monitoring respiratory status in patients with such diseases; to devices for monitoring respiratory status and to devices for the prevention of and the treatment of acute respiratory distress. In particular, the invention relates to methods and devices for use in acute asthma attacks. The invention also relates to improved methods of and devices for air-conditioning in, for example, aircraft and buildings.

The diseases which can be treated or monitored by the invention include asthma, bronchitis, cigarette lung (bronchitis and emphysema), emphysema, cystic fibrosis, bronchiolitis and bronchiectasis.

Field of the Invention

Asthma is a disease characterised by intermittent airways obstruction. In western countries it affects 15% of the paediatric population and 7Vι% of the adult population. It is caused by inflammation of the human airways and is associated with allergic reactions. Conventional treatment is by bronchodilators and anti-inflammatory drugs such as corticosteroids. Recent emphasis on the treatment of well asthmatics (i.e. those not in acute attacks) concentrates on the use of corticosteroids to prevent asthmatic attacks. Corticosteroids are also used as preventatives in other groups of patients with obstructive lung diseases such as those mentioned above, together with bronchodilators, oxygen and in the case of cystic fibrosis patients together with antibiotics.

In recent years we have come to an understanding that air conditioning systems in buildings and on aircraft cause problems for certain people. For example on long haul flights, the air conditioning systems in the aircraft alter the temperature and humidity of the air. If the air conditioning does not work properly, inappropriate temperatures and levels of humidity develop which dry the airways of the passengers. We know that under exertion asthmatics have acute asthmatic attacks when the airways are dried. This drying of the airways on aircraft passengers thus could lead to uncomfortable breathing or actual asthmatic attacks. Humidifying the air in an aircraft has traditionally been done by carrying large volumes of water on the plane, but this has the disadvantage of increased fuel costs for the airlines. There has been a trend to use recirculating air, but this has the disadvantage of spreading diseases such as TB and respiratory viruses. Thus a device which could be used on aircraft to humidify the airways of people who develop or are likely to develop respiratory problems on board the aircraft would be an advantage. Alternatively people suffering from asthma or other diseases of airways inflammation could carry a portable device to humidify their airways for use on aircraft.

Similarly, problems have arisen in what is known as "Sick Building Syndrome" and again a device for use in air conditioned buildings by people known to have asthma or related airways diseases would be an advantage.

Airway dehydration triggers bronchoconstriction in exercise, in virtually all patients with active asthma (1-5). Furthermore, eucapnic voluntary hyperventilation using dry air is similar to exercise and methacholine challenge in provoking bronchoconstriction in asthmatic subjects (6-9). More recently, epidemiological studies have demonstrated a high prevalence of asthma in Nordic skiers, who habitually inhale cold, dry air (10-11).

Despite these observations which suggest that airway dehydration may be mechanistically important in triggering bronchoconstriction, we are not aware of any investigations of airway dehydration in patients with naturally occurring asthma exacerbations in the emergency room. This study describes the establishment of a novel dry air tachypnoea challenge, to directly test the relationship between airway dehydration and bronchoconstriction.

The present inventors have shown for the first time that there is a relationship between dehydration of the expired air, and bronchoconstriction in acute asthmatic subjects presenting to the emergency department. The implication for this in the acute asthma setting, is that asthmatics are worsening the bronchoconstriction with their tachypnoeic response, by drying their airways. This can be abolished by humidifying the inspired air, thus breaking this vicious cycle. Thus, humidified air should be considered a simple, safe adjuvant to standard emergency room treatment of acute asthmatic subjects. Humidified air, as a treatment for asthma, has never been suggested in the medical literature.

Object of the Inventions

It is therefore an object of the present invention to improve the treatment of patients with diseases caused by airways inflammation, both in the emergency room, whilst travelling and at home. In particular it is an object of the present invention to provide a novel pharmaceutical for the treatment of such patients. It is a further object to provide a pharmaceutical which is safe, cheap, easy to administer and which maximally humidifies the airways or bronchi of the lungs. It is also an object to provide improved methods of monitoring asthma status in asthmatics, and to provide devices for monitoring asthma status and for treatment of acute asthma attacks. It is a particular object to provide a portable device for the treatment or prevention of respiratory distress which can be carried by people suffering from airways diseases.

It is a further object of the invention to prevent or reverse the effects of an asthmatic stimulus to a cell. Many compounds are released by dehydrated epithelial cells and it is an object to prevent their release or to reverse the effects of an asthmatic stimulus to a cell. Many compounds are released by dehydrated epithelial cells and it is an object to prevent their release or to reverse the effects of hypoosmality.

Currently, in Great Britain, respiratory disease annually costs the Exchequer £2 billion, including lost working hours, of which £680 million is spent on drugs. The worldwide drugs market for asthma and related conditions is £20 billion and is expected to reach £40 billion in the next ten years. It is therefore an object of the invention to provide asthma and obstructive lung disease treatments which are less costly, are more effective (thus resulting in fewer lost working hours), which have reduced side effects in patients and which reduce the problem of drug resistance. Clearly being able to use less drug means reduced drug costs, reduced side effects and less drug resistance.

Summary of the Invention

According to the present invention there is provided use of humidified air in the preparation of a medicament for the treatment of asthma and related lung conditions. Preferably, the humidified air is selected from an aerosol of water, water vapour or a mixture of the two. Suitably the aerosol of water comprises droplets with a size in the range 0.1 to 30 microns in diameter, preferably 5 to 10 microns in diameter. Preferably the humidified air is maintained at a temperature in the range 15°C to 100°C, preferably 20°C to 60°C , more preferably 35 °C to 39 °C, most preferably 37 °C. Suitably the humidified air is fully saturated with water.

The weight (i.e. size) of the particle determines where it is deposited. Particles in the size range 1 to 30 microns in diameter are selectively deposited in the airways of the lung rather than in the mouth or in the alveloli; the airways being the site of the airways inflammation disease process.

The invention also provides a pharmaceutical composition comprising humidified air. The humidified air is preferably fully saturated with water. The humidified air is preferably selected from water vapour, an aerosol of water or a mixture of the two. Preferably the aerosol of water comprises droplets in the size range 0.1 to 30 microns, preferably 5 to 10 microns in diameter. The humidified air is preferably maintained at a temperature in the range 15°C to 100°C , preferably 20°C to 60°C , more preferably 35°C to 39°C , most preferably 37°C. The pharmaceutical composition may further comprise one or more drugs selected from bronchodilators, anti-inflammatory drugs, decongestants, immune-modulators, antibiotics, cytokines or liposomes.

Such a pharmaceutical could allow the targeting of drugs in a focused therapy. It also has the advantage that freons are not necessary, as they are in many conventional nebulizers; there being moves in certain countries to ban the use of freons in nebulizers, on health and environmental grounds.

In a further aspect the invention relates to a method for treating acute respiratory distress comprising administering to the patient humidified air at a saturation level of at least 75%, more preferably at least 90% most preferably 100%. Preferably, the humidified air comprises an aerosol of water particles having a size in the range 0.1 to 30 microns in diameter, preferably 5 to 10 microns in diameter. Suitably, the humidified air is maintained at a temperature in the range 15 °C to 100°C, preferably 20°C to 60°C more preferably 35°C to 39°C, most preferably 37°C.

In a still further aspect the invention provides a device for monitoring the relative humidity of expired air of a human subject comprising a collection means for collecting exhaled air from the subject , a means for measuring the humidity of the exhaled air and a means for displaying the humidity level of the exhaled air.

Preferably, the collection means is adapted to collect the first 150mls of air exhaled by the subject, more preferably the device is adapted to discard the first 50mls of exhaled air and to collect the next lOOmls of air exhaled by the subject. Suitably the collection means is provided with an in-line turbine to measure the flow-through of air and to activate shut-off valves to trap a defined volume of the exhaled air.

At normal resting breathing the total exhalation is about 500 mis. Generally speaking the first 50 mis of exhaled air in a 70kg male is mouth volume, the next 100 mis air is airways air (which is the site of the asthma disease process) and the final 350 mis is alveolar air (the alveoli not being involved in asthma). The object of the invention is to trap and analyse that airways air. In a particular embodiment the device is adapted to measure the humidity of the air immediately it exits the mouth, or more preferably whilst still in the mouth. This is preferable because the humidity of the exhaled air will approximate to room conditions in a matter of seconds after exhalation. The invention also provides a device for delivering humidified air to a human subject comprising a water reservoir, a means for forming humidified air from the water in the reservoir, a heating means for either heating the humidified air or the water in the reservoir to between 15 and 100°C and a mouthpiece adapted to deliver the humidified air to the subject. Preferably, the device is adapted to deliver fully saturated air at 15 to 100 °C.

Preferably the mouthpiece is provided with a non-return valve so that the subject can breath in humidified air and then exhale without interference to the flow or composition of the humidified air.

Suitably the means to heat the humidified air or the water in the reservoir comprises a powerpack and a heating element.

In one embodiment heated water from the water reservoir is fed by capillary action to a means to generate an aerosol. Suitably the aerosol is fed to a breathing chamber for subsequent delivery to a mouthpiece.

The means to generate the aerosol may be selected from a jet nebulizer, an ultrasonic nebulizer or a vibrating disc nebulizer.

Brief Description of the Drawings

The invention will now be described in greater detail with reference to the accompanying drawings in which:-

Figure 1:

Mean (SEM) respiratory rate (panel A), tidal volume and peak flow (panel B), and relative humidity (panel C). measured in 10 asthmatic subjects presenting to the emergency room with acute bronchoconstriction (open bars), and 10 control subjects presenting to the emergency room for nonrespiratory causes (filled bars). Figure 2.

Following a dry air tachypnoea challenge in 19 asthmatic subjects, and 10 control subjects in the laboratory, the mean maximum drop in FEN_X was calculated. Nine of the asthmatic subjects responded to the challenge (>10% drop in FEVj), while 10 of the asthmatic subjects demonstrated a similar FEVj response to the control group. R: responder asthmatic subjects, NR: nonresponder asthmatic subjects, and C: control subjects.

Figure 3: Panel A: Mean (SEM) FEN_! changes over time following a dry air tachypnoea challenge in asthmatic responders (filled squares), asthmatic nonresponders (open triangles), and control subjects (filled triangles).

Panel B: Mean (SEM) relative humidity % changes over time following a dry air tachypnoea challenge in asthmatic responders (filled squares), asthmatic nonresponders (open triangles), and control subjects (filled triangles).

Panel C: Mean (SEM) FEN_X changes over time following a dry air tachypnoea challenge in asthmatic responders (filled squares), and in the same responder subjects following a humidified air tachypnoea challenge (open circles).

Figure 4:

Shows a device for monitoring exhaled air.

Figure 5:

Shows a device for delivering humidified air to a patient.

Detailed Description of the Invention Materials and Methods:

1 Accident and Emergency room studies: (a) Subjects: 10 acutely ill, consecutive asthmatic subjects (5 Male), mean (CI) age 29.2 years (18.2- 39.6), and 10 nonasthmatic control subjects attending the emergency room at the same time, with non cardio-respiratory symptoms (6 Male), age 32.1 years (27.8-36.4), were recruited into this study. Patients with bronchitis, emphysema, or other known lung diseases were excluded, and all had normal chest radiographs. All subjects gave informed consent, and the local hospital ethics committee approved the study, (b) Procedures: Respiratory rate was counted manually, and peak flow readings were measured using a standard portable vitalograph. The first 150mls of an expired breath, to reflect predominantly anatomical dead space air, was trapped in a polyethylene container, and relative humidity measured using an air probe hygrometer (Hygromer, Rotronic, Switzerland). Tidal volume, and oxygen saturations were measured in all subjects, by a CO₂SMO+ respiratory profile monitor (Novametrics Medical Systems Inc. - see below). All measurements were made immediately on the subjects arrival in the emergency room, and before administration of any treatment. 2 Laboratory studies: (a) Subjects: Nineteen asthmatic subjects (9 Male), mean (CI) age 26.9 years (20.8-33.1) with mild asthma (as defined by the American Thoracic Society), and ten non-asthmatic control subjects (4 Male), age 24.7 years (23.1 - 26.2), participated in this study. All subjects had a baseline FEVj greater than 70% predicted. Of the nineteen asthmatic subjects. thirteen were controlled on maintenance low dose inhaled corticosteroid therapy, while the remaining six were controlled by inhaled, short acting Beta-agonist therapy alone. Subjects did not take any medication for 12 hours prior to the session, and none had a respiratory infection or asthma exacerbation in the 6-week period prior to the study. (B) Procedures:. - All subjects underwent a bronchial provocation protocol using nebulised buffered isotonic histamine phosphate (Medicare Ltd. Ireland), as previously described (12). Two weeks later, and immediately prior to the tachypnoea challenge, baseline spirometry was performed, using a computerised Gould 2400 system. The best of 3 valid VEV₁ measurements was considered as the baseline value. There were 2 study days; each separated by at least 48 hours. On the first study day, each subject, wearing a nose clip, breathed dry air at room temperature, through a mouthpiece attached to the subject connection of a Y-shaped circuit, for 10 minutes. The Y-shaped circuit had inspiratory and expiratory limbs, and a subject connection with a dead space of 15mls. The circuit had demand-flow, non-rebreathing performance characteristics. Dry air was fed into the system from a medical compressed air cylinder. The subject connection was fitted with a differential pressure pneumotachograph, and a solid state mainstream infrared CO₂ sensor. The respiratory rate, end-tidal CO₂, and tidal volume, were monitored continuously, and recorded at 30-second intervals by a CO₂SMO+ respiratory profile monitor (Novametrics Medical Systems Inc.). Subjects breathed at 50% of their calculated resting normal tidal volume, in order to produce tachypnoea, and were coached to maintain a respiratory rate which maintained end-tidal CO₂ within normal limits (38-42 mmHg). No supplemental CO₂ was added to the circuit. On the second study day, subjects breathed in a similar pattern as that described above, but the inspired air was fully humidified at 37°C (Fisher and Paykel Healthcare Ltd). After each challenge, subjects recovered breathing ambient laboratory conditions, and FEN_! was measured immediately, and after 5, 10, 20 and 30 minutes. Exhaled air humidity measurements were made immediately before, and immediately after the 10-minute tachypnoea challenges, as described above. Analyses of Data:

Where data was shown to be normally distributed, group mean values were compared by using Student's t-test and considered significantly different if the p-value was less than 0.05. Values are expressed as means and CI, unless otherwise stated. Differences between groups were assessed by one way AΝONA analysis. Calculations of geometric mean values of the provocative dose causing a 20% fall in FEN_j (PD20) were performed on log-transformed raw data. Tachypnoea-induced bronchoconstriction was determined as the maximal percentage change in FEN_X from baseline. The statistical calculations were controlled by the use^~of a validated statistical software package for personal computers (Graph Pad Prism Inc., San Diego).

Results:

Accident and Emergency room studies:

The asthmatic group were more tachypnoeic (Fig. la), mean (CI) respiratory rate 27.9 (25.3-30.5) than the control group, 12.6 (10.5-14.7) (p<0.0001). There was also a significant difference in tidal volume (p=0.0043), and peak flow measurements (p<0.0001), between the asthmatic and control groups (Fig. lb). No difference in oxygen saturations was observed between the asthmatic group, 96.7% (95.4-98), and the control group 97.8% (97.3-98.2) (ρ=0.08). Based on the relative humidity of the first 150mls of exhaled air measurements (Fig. lc), the expired air in the asthmatic group, 78.2% (76.3-80.1) was significantly dryer than the control group, 86.3% (84.5-88.1) (p<0.0001).

Laboratory studies:

Nineteen stable asthmatic subjects, and 10 non-asthmatic controls, were subjected to a dry air tachypnoea challenge (see methods). Nine of the 19 asthmatic subjects, but none of the control subjects, responded with a >10% drop in FEN_α values from baseline following this challenge (Fig. 2). The mean maximum drop in FEV was 12.1% in the asthmatic responder group, versus 4.5% in the asthmatic non-responder group (p<0.0001). There was no significant change in FENj from baseline in the control group, with a mean maximum change of 1.8% (Fig.2). During the tachypnoea challenges, there was no difference in tidal volume (p=0.27), respiratory rate (p=0.25), and End-tidal CO₂ (EtCO₂) levels (p=0.18), recorded between the groups (Table 1), and no difference in minute volume recorded between responders, nonresponders, and control subjects (p=0.88) (Table 1). Comparison between the responder and nonresponder asthmatic subjects, revealed an immediate difference in FEV after the dry air tachypnoea challenge (p=0.0074), which was maximal 5 minutes post challenge (p=0.0004), and remained significant up to 20 minutes (p=0.0069), but was no longer significant at 30 minutes post challenge (p=0.1163) (Fig. 3a). The responders had significantly greater bronchial hyperreactivity to inhaled histamine, mean (CI) 0.7 mg/ml (0.1-1.3), versus nonresponders, 3.7 mg/ml (1.6-5.9) (p=0.009), and GIΝA (Global Initiative for Asthma) symptom scores; responders 1.9 (1.4-2.3), versus nonresponders 1.2 (0.9-1.5) (p=0.03). The dry air tachypnoea challenge caused a similar reduction in the humidity of the exhaled air from baseline values, in all groups (Fig. 3b). To investigate whether the drying of the airways during the tachypnoea challenge was responsible for the drop in FENj in the responder group, 8 of the 9 responders were subjected to a humidified air tachypnoea challenge. The ninth subject was excluded due to β-agonist use on the morning of the challenge. This experiment revealed that humidifying the air used during the tachypnoea manoeuvre, abolished the drop in FEN_! at all times over the 30 minute post-challenge period (Fig. 3c). When the air used during the tachypnoea challenge was humidified, no drop in humidity from baseline values was observed in the exhaled air immediately after the tachypnoea manoeuvre (data not shown). Together, these results show that while the dry air tachypnoea manoeuvre consistently results in reduced humidity of exhaled air, this is only associated with reduced FEN₂ in those asthmatic subjects with more severe symptoms and bronchial hyperreactivity.

Clearly a device which an asthmatic can use to monitor the level of dehydration of expired air would be of great benefit to asthmatics. Such a device is shown in Figure 4. The device comprises a mouth piece (1) into which the human subject blows. The mouthpiece (1) is connected to a flow through chamber (2). The flow-through chamber (2) is provided with an inline turbine (3) which measures the flow of air and activates a valve assembly (4) to trap a defined 100 mis of air. The defined 100 mis of air is trapped in a collection means (5). This chamber or collection means (5) is provided with a humidity monitor (6) which records the humidity and displays it on a display (7). The flow-through chamber (2) is provided with an exhaust (8) to vent air other than the defined 100 mis which is exhaled by the patient.

A device for delivering humidified air to acute asthmatic patients is described in Figure 5. The device comprises a water reservoir (11) which is provided with a heating element (12). The water reservoir (11) is in communication with a breathing chamber (13). A capillary tube (14) connects the water in the water reservoir (11) with the breathing chamber (13) and moves water by capillary action from the reservoir (11) into the breathing chamber (13). The capillary tube (14) feeds the water to a oscillating washer or mesh (15) having a plurality of apertures. The oscillation of the mesh (15) generates an aerosol of water particles. The breathing chamber (13) is in communication with a mouth piece (16) for delivery of the aerosol to the mouth of a human subject. The mouth piece (16) is provided with a suitable non-return valve (17) and an exit port (18) which allow exhaled air to exit the device. This allows humidified air to be breathed in and air to be exhaled normally. The device is also provided with a power pack (17) to power the heating element (12) and the oscillating washer or mesh (15). Clearly the aerosol can be generated in a number of ways. Conventional jet nebulizers blow a jet of air through the liquid to produce an aerosol. In ultrasonic nebulizers the ultrasonic vibration of a disk creates the aerosol. Alternatively the 5 aerosol can be generated by a dome-shaped metal plate with a plurality of holes, the plate being connected to an oscillator. When water is placed in contact with the moving plate, micro pumping action pours the liquid through the holes creating a fine particle aerosol.

10 Discussion:

The data demonstrates dehydration of expired air in patients with acute asthma in the emergency room. We analysed the first 150 mis of the expirate to reflect "airway" air (i.e. air mainly originating from the bronchi and bronchioles, the site of

15 asthma) rather than "alveolar" air. Under normal circumstances, the human airway becomes progressively drier as inspiration proceeds because inspired air is drier than peri-bronchial fluid. The inspired air is progressively humidified along the airways, and alveolar air is fully saturated with water vapour (13-15). During expiration, the airway water loss is replenished as the fully saturated alveolar air moves proximally through the

20 airways (16-18). Thus the initial expirate, comprising anatomical deadspace air, which has not had the benefit of alveolar humidification, is drier than the rest of the expired "alveolar" air (19). Our data is consistent with other reports (19) in showing dehydration of the initial expirate, which was present in the control, as well as the asthma subjects. However we further demonstrate significantly greater dehydration of

25 expired air in the asthma subjects, than in the control subjects. We are not aware of any similar data in respect of naturally occurring asthma exacerbations.

- *>

The bronchoconstrictor impact of fluid loss from the airway has been recognised for many years. Exercise-induced bronchoconstriction, a feature of 70-80% of

30 asthmatics, (20) is triggered by drying of the bronchial epithelium, due to airway water loss from the tracheobronchial tree, during the conditioning of large volumes of air (1-

5). Eucapnic voluntary hyperventilation manoeuvres, designed to simulate exercise induced bronchoconstriction in the laboratory, demonstrate that airway fluid loss has a similar bronchoconstrictor effect to histamine (6-9). Other workers demonstrate the release of histamine, a potent broncho-constrictor, and other proinflamatory bronchoconstrictor mediators, including cysteinyl-leukotrienes, (21) from mast cells and other airway cells under hyper-osmolar conditions (22-24). Furthermore, clinicians ^■ have long recommended swimming as the exercise least troublesome to asthmatic patients because of the humidity of the inspired air, a phenomenon which is supported by comparative studies of diverse sporting activities (25-27). These considerations underline the broncho-constrictor potential of airway dehydration.

The data demonstrates an increased respiratory rate, and increased minute volume in the asthma patients in the emergency room. This respiratory pattern is the most likely explanation for the dryer exhaled air in the asthma group. The drier expirate of our asthmatic patients is not related to administration of oxygen, or any other therapy, as all our measurements were made prior to treatment. The well preserved oxygen saturation of all our patients, permitted the necessary measurements of respiratory rate, tidal volume, peak flow, and expiratory humidity, before treatment, without any risk to patients (see Methods). Since the control measurements were also made on patients in the emergency room at the same time, any factors such as anxiety relating to attendance in the emergency room do not explain the observed differences a novel in humidity between asthmatic and control subjects.

This study describes a dry air tachypnoea challenge in the laboratory, which caused dehydration of the expired air in all of the asthmatic and control subjects. The results show that dry air tachypnoea could result in bronchoconstriction in asthmatic subjects. Interestingly this phenomenon was most obvious in those patients with more severe bronchial hyperreactivity and higher GINA scores. Furthermore, when the tachypnoea challenge was repeated using humidified air, the bronchoconstriction effect was abolished. It therefore appears that airway dehydration, and not the tachypnoea manoeuvre per se, caused the observed drop in FEN_! following this challenge. Although we recognise that the decrease in FEN_X following the tachypnoea challenge was relatively modest, our asthma group had mild stable disease which was well controlled on treatment. Furthermore, while hypocapnia is a known bronchoconstrictor (28-30), by maintaining end-tidal CO₂ within normal limits without the confounding factor of CO₂ rebreathing in our subjects, we have effectively ruled out hypocapnia as contributing to the observed bronchoconstriction.

This laboratory data, and other reports (1-5), establish that airway dehydration alone can cause bronchoconstriction. Given the relationship between baseline bronchial hyperreactivity and responsiveness to dry air tachypnoea, it is possible that airway dehydration could provoke greater bronchoconstriction in patients with greater bronchial hyperreactivity and more severe asthma. Thus, airway dehydration, initially caused by the tachypnoea and increased minute ventilation associated with acute asthma, could precipitate a vicious cycle, resulting in further bronchoconstriction, more severe asthma, and greater airway dehydration.

Humidification of the inspired air-oxygen mixture is not currently recommended in the guidelines for the treatment of acute asthma. Many patients receive some form of humidification such as bubble-through humidification of added oxygen at room temperature. This has limited effect on the overall humidity of the inspired mixture. For example, 40% oxygen in air, is made up of approximately three parts air to one part oxygen; therefore humidification of the oxygen alone, and only to room temperature, is of limited effect on the overall humidity of the inspired mixture. Full effective humidification, would require humidification of all inspired air and oxygen at 37°C. In summary, significant airway dehydration in acute asthma has been demonstrated. In addition, the laboratory results demonstrate the bronchoconstrictor potential of airway dehydration in clinically stable asthmatic subjects.

_ The words "comprises/comprising" and the words "having/including" when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. Table 1: Clinical Parameters recorded during tachypnoea challenges, in laboratory studies.

Tidal Volume Respiratory rate End-tidal CO2

(mis) (bpm) (πunHg)

Responders to dry air tachypnoea challenge

Mean (SEM) 245(19) 45(1) 37(1)

Nonresponders to dry air tachypnoea challenge

Mean (SEM) 248(15) 43(2) 38(1)

Humidified' air tachypnoea challenge

Mean (SEM) 283(17) 48(1) 38(1)

Nonasthmatic Control Group

Mean (SEM) 236(16) 46(1) 40(1)

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Claims

1. Use of humidified air in the preparation of a medicament for the treatment of asthma and related lung conditions.

2. Use as claimed in claim 1 wherein the humidified air is selected from an aerosol of water, water vapour or a mixture of the two.

3. Use as claimed in claim 2 wherein the aerosol of water comprises droplets with a size in the range 0.1 to 30 microns in diameter, preferably 5 to 10 microns in diameter.

4. Use as claimed in any preceding claim wherein the humidified air is maintained at a temperature in the range 15 °C to 100°C, preferably 20°C to 60°C , more preferably 35 °C to 39 °C, most preferably 37 °C.

5. Use as claimed in any preceding claim wherein the humidified air is fully saturated with water.

6. A pharmaceutical composition comprising humidified air.

7. A pharmaceutical composition as claimed in claim 6 wherein the humidified air is fully saturated with water.

8. A pharmaceutical composition as claimed in claim 6 or 7 wherein the humidified air is selected from water vapour, an aerosol of water or a mixture of the two.

9. A pharmaceutical composition as claimed in claim 8 wherein the aerosol of water compresses droplets in the size range 0.1 to 30 microns, preferably 5 to 10 microns in diameter.

10. A pharmaceutical composition as claimed in any of claims 6 to 9 wherein the humidified air is maintained at a temperature in the range 15°C to 100°C , preferably 20°C to 60°C , more preferably 35°C to 39°C , most preferably 37°C.

11. A pharmaceutical composition as claimed in any of claims 6 to 10 further comprising one or more drugs selected from bronchodilators, anti-inflammatory drugs, decongestants, immune-modulators, antibiotics, cytokines or liposomes.

12. A method for treating acute respiratory distress comprising administering to the patient humidified air at a saturation level of at least 75%, more preferably at least 90% most preferably 100%.

13. A method as claimed in claim 12 wherein the humidified air comprises an aerosol of water particles having a size in the range 0.1 to 30 microns in diameter, preferably 5 to 10 microns in diameter.

14. A method as claimed in claim 12 or 13 wherein the humidified air is maintained at a temperature in the range 15°C to 100°C, preferably 20°C to 60°C more preferably 35°C to 39°C, most preferably 37°C.

15. A device for monitoring the relative humidity of expired air of a human subject comprising a collection means for collecting exhaled air from the subject , a means for measuring the humidity of the exhaled air and a means for displaying the humidity level of the exhaled air.

16. A device as claimed in claim 15 wherein the collection means is adapted to collect the first 150mls of air exhaled by the subject.

17. A device as claimed in claim 15 wherein the collection means is adapted to discard the first 50mls of exhaled air and to collect the next lOOmls of air exhaled by the subject.

18. A device as claimed in any of claims 15 to 17 wherein the collection means is provided with an in-line turbine to measure the flow-through of air and to activate shut- off valves to trap a defined volume of the exhaled air.

19. A device for delivering humidified air to a human subject comprising a water reservoir, a means for forming humidified air from the water in the reservoir, a heating means for either heating the humidified air or the water in the reservoir, to between 15 and 100°C, and a mouthpiece adapted to deliver the humidified air to the subject.

20. A device as claimed in claim 19 wherein the means for forming humidified air is a means for forming an aerosol.

21. A device as claimed in claim 19 or 20 wherein the mouthpiece is provided with a non-return valve.

22. A device as claimed in any of claims 19 to 21 wherein the means to heat the humidified air or the water in the reservoir comprises a powerpack and a heating element.

23. A device as claimed in any of claims 19 to 22 wherein heated water from the water reservoir is fed by capillary action to a means to generate an aerosol.

24. A device as claimed in any of claims 19 to 23 wherein the aerosol is fed to a breathing chamber for subsequent delivery to a mouthpiece.

25. A device as claimed in any of claims 19 to 24 wherein the means to generate the aerosol may be selected from a jet nebulizer, an ultrasonic nebulizer or a vibrating disc nebulizer.

26. Use of humidified air substantially as described herein with reference to the accompanying drawings.

27. A pharmaceutical composition air substantially as described herein with reference to the accompanying drawings.

28. A method for treating acute respiratory distress air substantially as described herein with reference to the accompanying drawings.

29. A device for monitoring relative humidity of expired air substantially as described herein with reference to the accompanying drawings.

30. A device for delivering humidified air substantially as described herein with reference to the accompanying drawings.

Tomkins & Co.