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Thorax 1984;39:1-7 Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from

Editorial Therapeutic aerosols 2- available by the inhaled route

Inhalation treatment can be said to have stood the umes have been written about them and their test of time, since records can be traced back several administration.3 Reiterating most of this would be thousand years. In ancient Greece, Hippocrates like taking "coals to Newcastle" for the readers of employed the inhalation of vapours distilled in a pot, Thorax and therefore only selected aspects will be the lid of which was pierced by a reed;' sulphur and mentioned. arsenic were said to have been used. The patient The naturally occurring catecholamine adrenaline breathing these hot vapours needed protection with was the earliest of these drugs to be given by inhala- moistened sponges to avoid scalding. The popularity tion,4 followed by isoprenaline (isopropylnoradren- of these inhalation procedures has waxed and aline) in about 1960. Since adrenaline, however, waned, as Miller' writes-at times they have been stimulates both a and ,3 receptors in the heart and over praised and unwisely used, and at other times periphery and isoprenaline stimulates 8,/ and (2 unreasonably condemned and virtually abandoned. receptors, both drugs may give rise to undesirable The latter phrase still applies to some extent today. cardiovascular side effects such as tachycardia or Until the middle of the present century, inhalation arrhythmias. Adrenaline, whether given by treatment with volatile aromatic substances with a or by inhalation, is now little used in Britain. It is, mild irritant action such as menthol, thymol, and however, still given by injection for acute in eucalyptus and smokes derived from burning vari- young patients and it is still available on prescription copyright. ous types of plant leaf, notably Atropa belladonna for use in an MDI or in a hand held "squeeze bulb" and Datura strammonium, was quite commonly inhaler in a mixture that also contains atropine recommended for disorders of the upper and lower methonitrate and papaverine hydrochloride (Bro- airways. Several present day pharmaceuticals used von). Furthermore, MDIs containing adrenaline are for respiratory treatment have been derived from freely available over the counter in the United http://thorax.bmj.com/ ancient remedies2-for example, khellin was the States. predecessor of cromoglycate, while burning Datura Chemical manipulation of the side chains of the strammonium leaves form the basis of the asthma adrenaline and isoprenaline molecules has led to the cigarette, which is still available from herbalists. development of sympathomimetic drugs possessing These substances have been largely replaced by a more selective action on respiratory f2 receptors. the range of modern pharmaceuticals available for , terbutaline, and fenoterol are the best inhalation either from a metered dose inhaler known of these compounds, but at least 14 related (MDI), dry inhaler, or nebuliser or for the drugs have been described.5 While cardiovascular nose by . Although the MDI is the most side effects are much reduced, skeletal muscle tre- on September 25, 2021 by guest. Protected popular method of administering mor and cramps are occasionally noted, even with and aerosols, the nebuliser has the the small doses taken by inhalation. One potential great merit of flexibility-virtually any drawback of treatment with f8 agonists is a fall in or can be nebulised. Most drugs are arterial oxygen tension owing to a transient worsen- inhaled for topical treatment of the upper and lower ing of ventilation:perfusion ratios.6 This is seen par- , but some may also be given as ticularly in severe acute asthma, where hypoxaemia aerosols for their systemic effect. may already be substantial. The potential effect on the heart of increasing hypoxaemia must be consi- Beta agonists dered. Supplemental oxygen treatment should, however, readily relieve this hypoxaemia.' Although Beta agonists are undoubtedly the most common early experience with isoprenaline suggested that /8 type of drug given by inhalation from an MDI. Vol- agonists might be inherently short acting, the selec- tive f2 agonists have been shown to be active for up Address for reprint requests: Dr SW Clarke, Department of to seven hours.8 Thoracic Medicine, Royal Free Hospital, London NW3 2QG. In Britain /8 agonists given by inhalation are the Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from 2 standard first line of treatment in asthma and butamol from an MDI is usually 200 gg, of which chronic obstructive airways disease, in which they about 10% or 20 ,mg will be deposited within the may be used on demand for relief of symptoms as bronchial tree'8'9 and stimulate ,8 receptors. By con- they arise or as regular maintenance treatment to trast, the nebulised dose is usually 5 mg in 1 ml avert symptoms. Their preventive effect is particu- (diluted with, say, 3 ml of saline). Of this 5 mg, 10% larly well seen in the suppression of exercise induced or 500 ,ug will reach the lungs,2' 25 times more than asthma.9 Inhaled treatment with /8 agonists alone the lung dose achieved with the MDI. Nevertheless, may control mild asthma. Combined with cromo- if the effect of dose is taken into account by the glycate they will control symptoms in most patients construction of dose response curves it is found that with extrinsic asthma and combined with inhaled the curves achieved with MDI and nebuliser are in most patients with intrinsic almost identical.22 A lung dose of only 30 ,ug asthma. Given in sufficient dosage an inhaled, fenoterol delivered by nebuliser has been shown to agonist may control attacks of severe acute asthma. cause maximal bronchodilatation in a group of Sometimes this is given in conjunction with par- asthmatics with FEV,s ranging from 27% to 78% of enteral /3 agonists or methyl xanthines and usually the normal predicted value.23 Arguably an increase treatment is supplemented by systemic cortico- in the dose from a nebuliser might be beneficial if steroids. Nebulised salbutamol has been particularly the degree of bronchoconstriction is severe and the successful in the treatment of children in hospital number of ,3 receptors to be stimulated is increased. with severe acute asthmatic attacks,'0 but its Fears that the large doses of 8 agonist convention- domiciliary use in such cases needs to be carefully ally given by nebuliser may be harmful are probably supervised and help must be sought early if there is a unfounded, although whether these doses are usu- poor response." ally required is another matter and needs further Beta agonists have the useful merit of increasing investigation. the rate of mucociliary clearance, which is known to be abnormally slow in many patients with obstruc- Other

tive airways disease.'2 Studies of the effect on clear- copyright. ance of aerosolised 83 agonists, however, have not ANTICHOLINERGIC DRUGS reached unanimous conclusions. Improvement of Anticholinergic drugs act by blocking the muscarinic clearance has been demonstrated after the adminis- action of acetylcholine. Atropine is an effective tration of adrenaline and isoprenaline," sal- bronchodilator and has been used for many years butamol,'4 and orciprenaline,'9 although the doses but it has the undesirable side effect of drying airway http://thorax.bmj.com/ used were larger than those usually required for secretions. It may also precipitate glaucoma and in bronchodilatation. In clinical practice patients often men it may induce urinary retention. The synthetic remark on improved expectoration after inhaling anticholinergic agent appears these drugs, though bronchodilatation alone may to be free from these side effects in the doses nor- improve coughing efficiency. mally delivered.24 It is an effective bronchodilator at One feature of treatment with ,3 agonists which is a dose one tenth of that required to inhibit saliva insufficiently appreciated is the wide variation in the production and one fiftieth of that causing tachycar- dose administered by the various routes. It should dia.3 It has a slightly slower onset of action than the be noted that the small dose of drug reaching the ,8 agonists but its duration of action is similar. Ipra- on September 25, 2021 by guest. Protected lungs and activating /8 receptors is responsible for tropium bromide delivered by nebuliser has been most of the bronchodilator effect'6 and the cardio- used successfully to control acute asthma,25 though vascular side effects.'" Absorption of drug into the here it is unlikely to supplant the ,8 agonists. In some systemic circulation via the lung may also play a bronchitic patients with airways obstruction ipra- part.'8 Most of the dose from an MDI is deposited in tropium may give dramatic relief, but occasionally the oropharynx.'9 Some of this may be absorbed paradoxical bronchoconstriction is noted.26 When through the buccal mucosa,20 though most is swal- ipratropium is given in conjunction with a ,8 agonist lowed and converted to an inactive metabolite dur- additional bronchodilatation may be achieved,27 ing its passage through the wall of the intestine or although the extent of this varies from patient to the liver.'8 About 75% (and in the case of iso- patient.28 It has been suggested that ipratropium and prenaline 90%) of the oral dose is converted, so that the ,B agonists may act preferentially on different the required oral dose is typically greater than the parts of the bronchial tree, but the evidence has inhaled dose by a factor of 10. With the nebuliser been conflicting. Some studies have shown that anti- most of the non-inhaled drug is retained within the cholinergic agents act on large conducting airways device itself.2' and / agonists on small airways;2930 others suggest To give an example, the inhaled dose of sal- that ipratropium is equally effective in both large 3 Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from and small airways,31 32 and yet others that ,8 agonists as a solution, which may be particularly useful for act chiefly on large airways.33 The final answer is treating asthmatic children as they may have awaited. difficulty using the spinhaler or MDI.

METHYL XANTHINES Corticosteroids Given orally, the methyl xanthines, of which theophylline and aminophylline (and caffeine) are Inhaled corticosteroids are highly effective in con- the best known, have been the first line treatment trolling asthma and can achieve this without induc- for asthma in the United States for many years, ing systemic side effects. The drugs used (beclo- although they may soon be superseded by inhaled ,8 methasone dipropionate, betamethasone valerate, agonists. of methyl xanthines triamcinolone acetonide, and budesonide) exert a requires careful adjustment of the dose to exploit a topical effect in the lungs but are inactivated when "therapeutic window" represented by plasma con- absorbed from the gut. The doses required are tiny centrations of from 10 to 20 p.g/ml if the optimum (400-800 ,ug daily), plasma levels are low, and effect is to be obtained without producing unaccept- therefore systemic side effects (including adrenal able side effects ranging from headache, nausea, and suppression) are minimal.40 Many patients taking abdominal discomfort to fatal fits.34 The inhaled oral corticosteroids below the dose level of 10 mg route offers the prospect of symptomatic control prednisolone daily to control their asthma are able with low blood concentrations and minimal risk to switch entirely to the much smaller dose of of side effects. It is possible to produce useful inhaled corticosteroids. bronchodilatation but the methyl xanthines are Recently an MDI containing a high dose of much less effective than ,3 agonists administered by beclomethasone dipropionate has been introduced aerosol.35 Furthermore, they have an unpleasant (Becloforte). It contains 250 yg a dose, five times bitter taste,36 although conceivably this could be more than the standard preparation (Becotide). This disguised by the addition of flavouring agents. formulation improves control in patients with more severe asthma and may permit treatment with oral Sodium cromoglycate steroids to be reduced or stopped in up to two thirds copyright. of patients who are inadequately controlled on con- Sodium cromoglycate is a very powerful prophylac- ventional doses of beclomethasone.4' There is little tic drug for asthma3' and an example of one which is evidence of abnormal adrenal function in patients effective only by the inhaled route, since gastro- taking up to 1500 ,ug of high dose beclomethasone intestinal absorption is poor. It prevents the daily, but above this level adrenal suppression is http://thorax.bmj.com/ degranulation of mast cells and hence the release of observed in some patients.42 It has been suggested chemical mediators in the airway walls. In normal that high dose treatment with inhaled steroids may subjects, moreover, cromoglycate has the ability to achieve satisfactory control when given only twice modify the airway response to respiratory heat daily, and this appears to be so in those with stable loss,38 which is relevant to its particular effect in asthma. In unstable asthma, however, there is a case exercise induced asthma. Further, this drug may for taking doses four times daily for otherwise a have minor bronchodilator effects.38a Undoubtedly prohibitive number of puffs may be required.43 it has revolutionised the management of extrinsic Oropharyngeal candidiasis is a recognised side asthma and particularly exercise induced asthma, effect of treatment with inhaled steroids; the inci- on September 25, 2021 by guest. Protected and may also be effective in late onset asthma. dence varies widely (0-91 %) in different study The well known Spinhaler, developed in the late populations," probably depending on the criteria 1960s, for delivery of cromoglycate in powder form, used to define the condition. In a recent study clini- represented a novel approach to the administration cally confirmed candidiasis was present in 9% of of drugs by inhalation, although it had been pre- patients on low dose beclomethasone and 12% on ceded by another dry powder device, the Aerohaler, the high dose-an insignificant difference.4' These in 1949.39 Recently cromoglycate has been formu- figures increased to 13-5% and 17% respectively lated for administration by an MDI. Curiously, the when patients with local symptoms who did not have standard 2 mg dose of sodium cromoglycate from an clinically confirmed candidiasis were included. The MDI (two puffs) has roughly the same effect as 20 incidence of this complication may be related to the mg of powder in each spincap, which emphasises the number of puffs taken rather than the total dose of relative inefficiency of dry powder inhalation, even steroid inhaled. The candidiasis usually resolves though a broadly similar percentage of the dose is either spontaneously or with appropriate treatment, likely to reach the lungs from the two devices.'8 and only occasionally does it prove necessary to stop Cromoglycate is also available for use in nebulisers the steroid. In patients who are immunocomprom- Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from 4 ised for any reason further action may be necessary. saline should be used if the inhaled volume is The frequency of candidiasis is reduced by the use of more than a few millilitres. a spacer device with the MDI,45 reflecting the reduc- Saline aerosol is bland and may well improve tion in oropharyngeal deposition achieved by such mucociliary clearance, particularly in a hypertonic means.46 concentration (7-1 %), when it facilitates expectora- The other local complication is dysphonia, the tion.49 It may liquefy sputum by enhancing chloride incidence of which also varies widely (O-55%).44 A (and water) flux across the bronchial mucosa.50 typical bilateral adductor vocal cord deformity with Mucolytic aerosols are also widely used. bowing of the cords on phonation has been N-acetylcysteine (Airbron) is the best known in Bri- described, which probably represents a local steroid tain and 2 mercaptoethane sulphonate (Mistabron) myopathy; it is reversible within a few weeks of in Europe.5' Mistabron appeared to enhance stopping treatment with inhaled steroids.44 mucociliary clearance in patients with chronic bron- chitis,52 although the results did not quite reach Combination inhalers statistical significance-a feature of so many studies of mucolytics. In patients with cystic fibrosis, how- Inhalers containing two or more drugs have been ever, inhaled Mistabron significantly improved used for some time with varying degrees of accepta- respiratory function, although there was no change bility. Brovon and Intal Co (cromoglycate and iso- in cough frequency, sputum volume, or the fre- prenaline) are examples. These have been criticised quency of antibiotic prescriptions compared with the because the required dose of one of the compounds pretreatment period.53 might lead to an excessive intake of the other. Thus the flexibility of using, say, a 18 agonist for relief of Antihistamines wheeze and cromoglycate for prevention is lost. Recently further combinations have appeared-for Antihistamines have rarely been given as aerosols example, fenoterol plus ipratropium (Duovent) and since they are said to have no effect in asthma. salbutamol plus beclomethasone (Ventide). They Recently, however, two inhaled H, receptor copyright. may improve compliance when patients are in a antagonists (clemastine and chlorpheniramine) have stable state but at the expense of therapeutic flexibil- been shown to have a bronchodilator effect in ity and with the risk of misconceptions-though this asthmatic children54 and clemastine aerosol can pre- is not to deny their usefulness. vent exercise induced asthma.55 Inhalation may

permit a greater quantity of drug to reach the lungs http://thorax.bmj.com/ Water, saline, and mucolytic aerosols than is possible after oral administration without giv- ing rise to undesirable side effects, notably seda- Tenacious bronchial secretions may accumulate in tion,56 and antihistamine aerosols should perhaps be chronic bronchitis, bronchiectasis, cystic fibrosis, reconsidered. and asthma. Traditionally, aerosols have been used in an attempt to liquefy these secretions and help Antibiotics sputum clearance, either by mucociliary action or coughing. The value of antibiotic aerosols in respiratory tract Water has been inhaled for many years, exem- has been questioned in the past and they on September 25, 2021 by guest. Protected plified by the steam aerosol and vapour produced have been thought to have little advantage over sys- from a boiling kettle for treating childhood croup. temic treatment.57 Higher drug concentrations in the Early studies showed that the inhalation of water sputum, however, may be attained with inhalation aerosol does liquefy and clear secretions.47 It may than with oral treatment. A combination of two also be an irritant, however, and cause broncho- nebulised antibiotic (carbenicillin and gen- constriction in asthmatics.48 The vogue for inhaling tamicin) was found recently to be effective in treat- medicinal waters with an increased mineral content ing respiratory infections in patients with cystic at some European spas is not supported by any fibrosis.58 Other types of aerosolised antibiotics may objective evidence of its efficacy. Fortunately, only a prove clinically useful, particularly where an antibio- tiny amount (about 10%) of the nebulised water will tic may be harmful if present systemically. enter the lungs and it is probably harmless. This is Unfavourable past reports of antibiotic aerosols are not to deny that a water aerosol may be a useful likely to have been due in part to incorrect nebulisa- means of humidifying the inspired air. Here a word tion resulting in inadequate drug concentrations in of caution is needed. With some ultrasor.ic nebulis- the lung periphery. Antibiotic solutions are more ers the volume of inhaled water might be such as to viscous than water or saline and are more difficult to cause pulmonary oedema. Isotonic fluid such as nebulise. Further work on antibiotic aerosols is 5 Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from required to characterise the particle size and the bronchodilators (and other drugs) needs to be better aerosol output required to achieve effective con- defined. centrations in the lung. propellants used in MDIs can cause palpitations if they are inhaled in sufficient Potential problems of the inhaled route quantity,68 but this should occur only if they are used excessively over a very short period.69 Extremely The advantages of aerosols have been propounded large doses of oral salbutamol can be given with but what of their disadvantages? It has been sug- apparent safety, at least in normal subjects.'0 Pres- gested that therapeutic aerosols might not be able to surised inhalers are thus thought to be safe if used in reach the appropriate receptor sites in the lung in the recommended manner,7' and given the tiny drug the face of severe airways obstruction or mucus dose administered this would appear to be reason- hypersecretion. In practice bronchodilator aerosols able. Fears were expressed in the mid 1970s that the seem able to improve lung function as reflected by use of chlorofluorocarbon propellants might damage tests of both large and small airways in most cases,59 the in the earth's atmosphere that pro- suggesting adequate aerosol distribution. In the tects against ultraviolet radiation.72 Subsequently treatment of a severe acute asthmatic attack, how- these propellants have been banned in many coun- ever, treatment with subcutaneous adrenaline or /2 tries except for medical use. MDIs are unlikely to agonist may be required since nebulised broncho- contribute significantly to environmental problems dilators may be effective only after the patient has compared with the unrestricted use of consumer actually begun to expectorate sputum.60 products such as hair sprays and fly killers. There seem to be few long term side effects associated with the regular intake of aerosolised Inhaled drugs for systemic treatment bronchodilators, cromoglycate, or corticosteroids. Contrary to popular opinion, there is no addictive Some drugs are rapidly absorbed virtually effect of regular bronchodilator treatment and, unchanged through the mucosa of the upper airways oddly enough, although tolerance or tachyphylaxis into the systemic circulation. Others if soluble may to / agonists can occur in normal subjects this is not be absorbed from the lower airways and alveoli. copyright. generally seen in asthmatic patients with conven- Glyceryl trinitrate and ergotamine, for example, are tional doses.6' both prepared as MDIs and sprayed into the buccal The safety of inhaled bronchodilators has been cavity for rapid absorption and control of angina and the subject of much debate. The use of metered dose migraine respectively. As an example of absorption isoprenaline aerosols was linked statistically to the from the lower airways and alveoli, the use of hepa- http://thorax.bmj.com/ epidemic of deaths from asthma in the late 1960s,62 rin by inhalation has been proposed for systemic in which 3500 patients were said to have died. This anticoagulation.73 epidemic is now thought to have been caused Absorption through the nasal mucosa is also poss- primarily by an overreliance on the use of ible. Nebulised insulin is rapidly absorbed via the isoprenaline MDIs and a failure of patients to seek nose in dogs, particularly when dissolved in a rela- medical advice when their asthma worsened, rather tively acid medium; and it has been suggested that than by a direct toxic effect of the inhalers them- this would be a simple and painless method of long selves.63 This topic is discussed in a recent edi- term treatment in diabetes.74 Nicotine given either torial.64 as a liquid spray or as snuff has been used as a substi- on September 25, 2021 by guest. Protected A similar increase in deaths from asthma has tute for smoking. The use of a nicotine MDI has also occurred in New Zealand since 1976,65 though an been suggested as a means of enabling smokers to increased incidence of asthma has been noted at the obtain nicotine75 without having to inhale more same time. The suggestion that the increase may harmful components of tobacco smoke, though have resulted from the combination of high dose /3 whether this would replace cigarettes is dubious. agonists and theophylline66 seems unlikely. Over- These examples stimulate us to consider how other reliance on nebulised bronchodilators, leading to drugs could be inhaled for their systemic effect, delay in seeking expert advice when the patient s offering the potential advantages of a simple route asthma may be deteriorating disastrously,67 is more of administration and rapid onset of action. plausible. The problem is not the nebulised Aerosol treatment has undoubtedly come a long bronchodilator aerosol itself but rather poor educa- way in the past two decades. The waxing and waning tion of patients about the limitations of aerosol of popularity referred to by Miller' almost certainly treatment and the threshold for seeking medical reflected the lack of understanding of the principles help if the bronchodilator fails to bring relief. As of aerosol treatment. The recent surge of interest mentioned earlier, the optimum dose for nebulised has been generated by the application of scientific Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from 6 method to the physical, pharmacological, and clini- 19 Newman SP, Pavia D, Mor6n F, Sheahan NF, Clarke with their use. Some of the SW. Deposition of pressurised aerosols in the human cal problems associated respiratory tract. Thorax 1981;36:52-5. problems have now been solved and aerosol treat- 20 Rodenstein D, Stanescu DC. Mouth spraying versus ment is on a much firmer scientific basis. inhalation of fenoterol aerosol in healthy subjects and STEWART W CLARKE asthmatic patients. Br J Dis Chest 1982;76:365-73. STEPHEN P NEWMAN 21 Lewis RA, Fleming JS, Balachandran W, Tattersfield Department of Thoracic Medicine AE. Particle size distribution and deposition from a jet nebuliser: influence of humidity and temperature. Royal Free Hospital Clin Sci 1981;62:5P (abstract). London 22 Cushley MJ, Lewis RA, Tattersfield AE. Comparison of three techniques of inhalation on the airway response to terbutaline. Thorax 1983;38:908-13. References 23 Ruffin RE, Kenworthy MC, Newhouse MT. Response of asthmatic patients to fenoterol inhalation: a method of Miller WF. Aerosol therapy in acute and chronic quantifying the airway bronchodilator dose. Clin respiratory disease. Arch Intern Med 1973;131:148- Pharmacol Ther 1978;23:338-45. 55. 24 Ruffin RE, Newhouse MT. Ipratropium bromide (SCH 2 Ziment 1. Respiratory and therapeutics. 1000) monohydrate aerosol: bronchodilator effect of Philadelphia: WB Saunders, 1978:1-7 three dose levels in asthmatics. Lung 1978;155:141- Paterson JW, Woolcock AJ, Shenfield GM. Bron- 6. chodilator drugs. Am Rev Respir Dis 25 Ward MJ, Fentem PH, Roderick-Smith WH, Davies D. 1979;120: 1149-88. lpratropium bromide in acute asthma. Br Med J 4 Barger G, Dale HH. Chemical structure and 1981 ;282:598-600. sympathomimetic action of amines. J Physiol 26 Patel KR, Tullet WM. Bronchoconstriction in response 1910;41: 19-59. to ipratropium bromide. Br Med J 1983;286: 1318. 5 Leifer KN, Wittig HJ. The beta-2 sympathomimetic 27 Lightbody IM, Ingram CG, Legge JS, Johnston RN. aerosols in the treatment of asthma. Ann Allergy Ipratropium bromide, salbutamol and prednisolone in 1975;35:69-80. bronchial asthma and chronic bronchitis. Br J Dis 6 Paterson JW, Shenfield GM. Bronchodilators. Thorax Chest 1978;72:181-6. and Tuberculosis Association Rev 1974;4:25-74. 28 Ullah MI, Newman GB, Saunders KB. Influence of age copyright. 7 Woolcock AJ. Inhaled drugs in the prevention of on response to ipratropium and salbutamol in asthma. asthma. Am Rev Respir Dis 1977;115: 191-4. Thorax 1981;36:523-30. 8 Sackner MA, Silva GT. Effects of terbutaline aerosol in 29 Ingram RH, Wellman JJ, McFadden ER, Mead J. Rela- reversible airway obstruction. Chest 1978;73:802-6. tive contributions of large and small airways to flow 9 Andersen SD, Seale JP, Rozea P, Bandler L, Theobald limitation in normal subjects and after atropine and G, Lindsay DA. Inhaled and oral salbutamol in exer- isoprenaline. J Clin Invest 1977;59:696-703. http://thorax.bmj.com/ cise induced asthma. Am Rev Respir Dis 30 Hensley MJ, O'Cain CF, McFadden ER, Ingram RH. 1976;114:493-7. Distribution of bronchodilatation in normal subjects: Edmunds AT, Godfrey S. Cardiovascular response dur- beta-agonist versus atropine. J Appl Physiol ing severe acute asthma and its treatment in children. 1978;45:778-82. Thorax 1981;36:534-40. 31 Douglas NJ, Sudlow MF, Flenley DC. Effect of an "Lillington AW, Campbell AN, Poulier RA. Safe drugs inhaled atropine-like agent on normal airway func- for childhood asthma? Lancet 1983;ii: 1032-3. tion. J Appl Physiol 1979;46:256-62. 2 Pavia D, Bateman JRM, Clarke SW. Deposition and 32 Partridge MR, Saunders KB. Site of action of ipra- clearance of inhaled particles. Bull Eur Physiopathol tropium bromide, and clinical and physiological Respir 1980;16:335-66. determinants of response in patients with asthma. on September 25, 2021 by guest. Protected 3 Foster WM, Bergofsky EH, Bohning DE, Lippmann M, Thorax 1981;36:530-3. Albert RE. Effect of adrenergic agents and their mode 33 Tashkin DP, Trevor E, Chopra SK, Taplin GV. Site of of action on mucociliary clearance in man. J Appl airway dilatation in asthma following inhaled versus Physiol 1976;41:146-52. subcutaneous terbutaline. Comparison of physiologic '4 Fazio F, Lafortuna D. Effects of inhaled salbutamol on tests with radionuclide lung images. Am J Med mucociliary clearance in patients with chronic bron- 1980;68: 14-26. chitis. Chest 1981;80, suppl:827-30. 34 Anonymous. Theophylline benefits and difficulties. Lan- ,s Yeates DB, Spektor DM, Leifkauf GD, Pitt BR. Effects cet 1983;ii:607-8. of drugs on mucociliary transport in the trachea and Is Bohadana AB, Peslin R, Teculescu D, Polu JM, Bel- bronchial airways. Chest 1981 ;80, suppl:870-3. leville F, Massin N. The bronchodilator action of 16 Ruffin RE, Montgomery JM, Newhouse MT. Site of theophylline aerosol in subjects with chronic airflow beta-adrenergic receptors in the respiratory tract. obstruction. Bull Eur Physiopathol Respir Chest 1978;74:256-60. 1980;16:13-24. 7 Collier JG, Dobbs RJ, Williams 1. Salbutamol aerosol 36 Cushley Mi, Holgate ST. Efficacy of inhaled methyl causes a tachycardia due to the inhaled rather than the xanthines as bronchodilators in asthma. Thorax swallowed fraction. Br J Clin Pharmacol 1983;38:223. 1980;9:273-4. 37 Altounyan REC. Review of clinical activity and mode of 18 Davies DS. Pharmacokinetics of inhaled substances. action of sodium cromoglycate. Clin Allergy 1980;10, Postgrad Med J 1975;51, suppl 7:69-75. suppl: 481-9. Thorax: first published as 10.1136/thx.39.1.1 on 1 January 1984. Downloaded from 7 38 Fanta CH, McFadden ER, Ingram RH. Effects of Hartley JPR, Nogrady SG. Effect of an inhaled antihis- cromolyn sodium on the response to respiratory heat tamine on exercise-induced asthma. Thorax loss in normal subjects. Am Rev Respir Dis 1980;35:675-9. 1981;123: 161-4. 56 Clarke CH, Nicholson AN. Performance studies with 38a Jones RM, Horn CR, Lee DV, Brennan SR. Broncho- antihistamines. Br J Clin Pharmacol 1978;6:31-5. dilator effects of disodium cromoglycate in exercise- 5 Williams MH. Steroid and antibiotic aerosols. Am Rev induced bronchoconstriction. Br J Dis Chest Respir Dis 1974;110:122-7. 1981 ;77: 362-9. 5 Hodson ME, Penketh ARL, Batten JC. Aerosol car- 39 Gorman WG, Hall GD. Inhalation aerosols. In: Swar- benicillin and gentamicin treatment of Pseudomonas brick J, ed. Current concepts in the pharmaceutical sci- aeruginosa in patients with cystic fibrosis. ences. Philadelphia: Lea and Febriger, 1973:97-148. Lancet 1981 ;ii: 1137-9. 4 Clark TJH. Safety of inhaled corticosteroids. Eur J 5 Clark TJH. Factors influencing the route of administra- Respir Dis 1982;63, suppl 122:235-42. tion of airway therapy. In: Sadoul P, Milic-Emili J, Smith MJ, Hodson ME. High dose beclomethasone Simonsson BG, Clark TJH, eds. Small airways in inhaler in the treatment of asthma. Lancet health and disease. 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