REVIEW ARTICLE

Drugs 1999; 58 Suppl. 4: 35-41 0012-6667/99/0004-0035/$03.50/0 © Adis International Limited. All rights reserved.

Once-Daily Inhaled Corticosteroids in Children with Asthma Dry Powder Inhalers Christian Möller Department of Pediatrics, Umeå University, Umeå, Sweden

Abstract

The cornerstone of pharmacological management of asthma in childhood is inhaled corticosteroids. These drugs are intended for long term treatment and, consequently, compliance is a major issue. Once-daily administration of maintenance medication would simplify treatment and it is likely that it would lead to better compliance. Moreover, the excellent safety profile of inhaled corticosteroid treatment tailored to disease severity may, theoretically, be further improved with once-daily administration. Studies comparing inhaled corticosteroids given once or twice daily to patients with asthma indicate that unstable asthma is best treated with at least 2 daily doses. On the other hand, it has been demonstrated that, if the asthma is stabilised, most children can be treated with inhaled corticosteroids once daily without loss of efficacy. Thus, the data suggest that newly diagnosed asthma, or asthma after deterioration, should first be reliably controlled with inhaled corticosteroids divided into at least 2 daily doses. Once-daily maintenance treatment should then be tried with the aim of improving compliance and quality of life. A dry powder inhalation device is probably the best choice for children from the age of 5 years.

The aim of this paper is to review the possibility of giving corticosteroids once daily to children with asthma. Asthma is a chronic airway disease associated with inflammation of the intrapulmonary airways.[1-4] No available measure can give an immediate and definite cure, rather, efforts focus on providing continuous anti-inflammatory treatment. If possible, trigger factors such as allergens and irritants should be eliminated. Some cases of allergic asthma, especially in children, can be treated with immunotherapy in combination with other measures.[5] However, the cornerstone of

anti-inflammatory treatment of asthma is pharmacotherapy. Several anti-asthma drugs are claimed to have anti-inflammatory properties, e.g. the cromones, leukotriene antagonists and long-acting β 2-agonists.[6,7] Although all these treatment options are used in the treatment of asthma in children, corticosteroids are far more effective.[1-4,8,9] Because of their superior efficacy and low frequency of adverse effects, inhaled corticosteroids are preferred as maintenance therapy. Early institution of inhaled corticosteroids in children with asthma reduces the risk of later reduced lung capacity.[10,11]

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1. Compliance Issues in Children and Adolescents Compliance with inhaled corticosteroids in children may be difficult, as treatment, in most cases, is long term (i.e. years). The aim of treatment is elimination of symptoms using the lowest possible dosage. Thus, a well treated child should not have any residual symptoms of asthma. Once this level of control has been achieved, it is possible that some children may feel that the daily inhalations are no longer necessary. Teenagers, especially, want to feel healthy and fit in with their peers; they do not wish to be reminded of their disease by daily medication. It is not unnatural for them to miss some doses. Parental nagging may worsen the situation. Therefore, in both younger and older children, it is best to provide treatment that interferes with daily life as little as possible. There is evidence from studies in adults that compliance with medications taken once or twice daily is better than with medications taken more frequently.[12-14] Furthermore, once-daily treatment is easier to comply with than twice-daily treatment.[13,15] In summary, the main reason for attempting to give inhaled corticosteroids once daily to children is the simplicity of the medication regimen, which may lead to better quality of life and better compliance. Younger children may not understand intellectually why they need daily treatment when they are doing well and older children have emotional objections to maintenance medication. However, a simplified regimen should not compromise treatment efficacy or cause enhanced adverse effects. 2. Effect of Frequency of Administration on Adverse Effects and Efficacy There are other reasons, albeit theoretical, for giving inhaled corticosteroids once daily. In adult asthmatics receiving oral prednisolone once or twice daily, once-daily corticosteroid results in less adrenal suppression than the twicedaily regimen without loss of clinical efficacy.[16] Morning doses of inhaled corticosteroids spare the © Adis International Limited. All rights reserved.

hypothalamic-pituitary-adrenal (HPA) axis.[17,18] Experience with children taking oral corticosteroids indicates that the risk of systemic adverse effects diminishes if the medication is given as few times during the day as possible.[19] Moreover, there are studies with oral corticosteroids showing that the dose should be given in the morning in order to reduce adverse effects.[20] Whether these observations can be extrapolated to inhaled corticosteroids is not clear. Serious adverse effects associated with prolonged treatment with corticosteroids, such as reduced growth velocity, HPA axis impairment and osteoporosis, are too seldom seen to be properly studied in randomised, prospective investigations of children on low to moderate dosages of inhaled corticosteroids. High dosages of once-daily inhaled corticosteroids have not yet been tried in children with severe asthma. Thus, we do not know if once-daily administration of inhaled corticosteroids reduces the risk of adverse effects, or if it is best to give a once-daily dose in the morning. However, a short term study of inhaled budesonide 800μg daily in children indicated that a single morning dose had a sparing effect on growth and collagen turnover compared with twice daily administration.[21] In clinical trials, medication is often controlled, patients are seen frequently, and those not taking the drugs according to the protocol are regarded as dropouts. Compliance in studies is probably far better than in clinical practice. Administration of any medicine more than twice daily is difficult for patients, and may lead to reduced compliance.[12] These reservations should be kept in mind when considering the several studies that have found that administering inhaled corticosteroids 4 times daily gives better asthma control than twice daily administration.[18,22-25] This difference in efficacy between 4 times daily and twice daily was not found in other studies.[26-34] As might be expected, at least in long term studies, compliance with administration 4 times daily was lower than with less frequent regimens.[25,26] It has been suggested that the different outcomes of the various studies could result from the Drugs 1999; 58 Suppl. 4

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circadian rhythm of asthma[35] and its relationship to the time of therapy with inhaled corticosteroids.[36] In one study, it was found that systemic corticosteroids are more effective in asthma if given at 1500h compared with any other time of the day.[35] In another study comparing inhaled corticosteroids 4 times daily with the same total dose given at 1500h only, the once-daily regimen resulted in better efficacy.[36] In most of the studies comparing treatment twice daily with 4 times daily, the exact times of administration were not specified. One study compared inhaled corticosteroids once daily at 1700h with once daily at 2200h or twice daily without finding any differences.[37] A more plausible explanation for the contradictory results of the studies is the inclusion criteria, which differ between studies. It appears that patients with non-stable asthma respond better if the daily dosage of inhaled corticosteroids is divided into 4 daily doses,[18,22-25] whereas patients with stable asthma who need maintenance treatment with inhaled corticosteroids do just as well with 2 daily doses.[27-28] Despite the studies indicating that inhaled corticosteroids should be divided into 4 daily doses, the usual regimen is twice daily, mainly for reasons of compliance. In adults, administration once daily has been compared with twice or 3 times daily with equivocal results.[38-47] However, the studies do indicate that patients with stable asthma, i.e. with the most mild symptoms, do just as well on once-daily as on twice-daily treatment.[37,39,41,42,45,46] Most of these studies of once-daily administration have been performed in adults and have used budesonide. In the majority of these studies, it appeared that once-daily administration of budesonide is as effective as twice-daily administration.[41,42,45,46] However, this does not appear to be the case for beclomethasone dipropionate,[38,40] flunisolide[44] or fluticasone propionate.[47] It is probable that different groups of patients have been studied and that the results are not directly comparable; conversely, it is possible that there is a genuine difference between the different inhaled © Adis International Limited. All rights reserved.

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corticosteroids and that only budesonide is suitable for once-daily treatment. There is evidence that budesonide is retained in the tissue for longer than other corticosteroids and thus exerts a more prolonged anti-inflammatory effect.[48-52] The case for once-daily treatment in children is even stronger than in adults. Simplicity, probably leading to better compliance, is the main reason for attempting once-daily administration of inhaled corticosteroids in this population. Moreover, the risk of delaying growth in small children is reduced. The following sections consider the special features of delivering inhaled corticosteroids to children, and then review the clinical trials of oncedaily administration of these agents in children. 3. Delivery Issues with Inhaled Corticosteroids in Children Delivering inhaled corticosteroids to small children is difficult, as they do not have the physical coordination to properly use a pressurised metered dose inhaler (pMDI), nor are they able to use a dry powder inhaler proficiently under the age of 4 years, despite training.[53] Nebulisers using a suspension of budesonide are effective, even in infants,[54,55] but studies of other nebulised corticosteroids, e.g. beclomethasone dipropionate and fluticasone propionate, have shown little effect.[56-58] In children aged 3 to 6 years, systemic availability of budesonide is about half that seen with nebulised budesonide in adults,[59] and treatment with nebulisers is time consuming. Instead, a pMDI with a spacer is often used in small children. Children aged from 4 to 5 years are able to use dry powder devices,[60] and children aged from 7 to 10 years can be trained to use a pMDI properly. In some parts of the world, e.g. in Nordic countries, dry powder devices are preferred in older children as well. One reason for this is that propellants and lubricants are avoided. Another reason is that budesonide dry powder via Turbuhaler® gives a higher proportion of lung deposition than the aerosol[61] and is at least as effective.[62,63] Drugs 1999; 58 Suppl. 4

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A new device for inhalation of corticosteroids as dry powder, Accuhaler®/Diskus®, differs from Turbuhaler® in that it instantly provides verification of the dose taken to the patient.[64] With Turbuhaler®, on the other hand, the amount of drug substance delivered is so small, the patient often does not ‘feel’ the dose being delivered. While the Accuhaler®/ Diskus® inhaler provides a more consistent dose over varying age groups and inspiratory flows than the Turbuhaler®, it does so at the expense of a low fine particle mass and a high proportion of coarse particles from the Accuhaler®/ Diskus® compared with the Turbuhaler®.[65] Lung deposition in children aged from 6 years is probably better with the Turbuhaler® than with the Accuhaler/Diskus®.[66,67] In younger children, dry powder inhalers are not reliable in all circumstances, and careful and repeated tuition is required if such devices are to be used in children aged 5 years or younger.[68,53] Despite this, a dry powder device is probably the best choice for children from the age of 5 years because of simplicity of administration and the advantages of allowing lower doses to be used. In children, comparisons of once-daily with twice-daily administration have only been performed with budesonide dry powder and only in patients with mild to moderate asthma. When comparing these studies of inhaled corticosteroids administered once or twice daily, it should be kept in mind that, with the same nominal dose, lung deposition is better with the dry powder inhaler Turbuhaler® than with other devices. 4. Clinical Trials of Once-Daily Inhaled Corticosteroids in Children The first investigation was open and involved switching patients on budesonide from twice-daily to once-daily administration. No deterioration in symptom score or peak flow was observed during the 4-week study period.[69] Another study included 167 asthmatic children aged 5 to 12 years from 37 centres. All children were receiving inhaled β2-agonists and their asthma was not well controlled, i.e. they had © Adis International Limited. All rights reserved.

asthma symptoms and peak flow values less than 90% of predicted, on 0 to 200 μg/day of inhaled corticosteroids. They were randomised in a doubleblind manner to budesonide dry powder, either 200μg in the morning and evening or 400μg in the evening for 8 weeks. Morning and evening peak flow values as well as symptoms and bronchodilator usage were recorded. Both groups of children improved significantly compared with run-in without any significant differences between the groups, with one exception: the children receiving 400μg once daily in the evening had a better evening peak flow after 8 weeks.[70] In a trial that included only corticosteroid-naive children, Jónasson and co-workers studied 163 children with asthma and near normal lung function.[71] The children were randomised in a doubleblind manner into 4 groups: budesonide dry powder 100μg or 200μg once daily in the morning, or 100μg twice daily, or placebo. Treatment was for 12 weeks. The primary efficacy variable was the fall in forced expiratory volume in 1 second after an exercise test. All active treatment groups showed better results than the placebo group, and there were no significant differences between the active treatments. However, in a methacholine bronchial provocation test, only the group of children receiving 100μg twice daily improved compared with the placebo group. It should be noted that the study duration was too short to accurately assess maximal effect on bronchial hyperresponsiveness.[72] The authors concluded that low doses of inhaled budesonide, given once or twice daily, provided protection against exerciseinduced bronchoconstriction in children with mild asthma and near normal lung function. Our own study included 206 children aged 5 to 15 years with asthma for at least 6 months.[73] The children needed budesonide (dry powder) 200 to 400 μg/day to keep them free from symptoms. During a 2-week run-in period they were maintained on their previous dose of budesonide, i.e. 100 to 200μg twice daily. If their asthma was stable during this period, they were randomised to receive the same daily dose in either 2 daily doses (morning Drugs 1999; 58 Suppl. 4

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and evening) or as a single dose in the morning for 12 weeks. The primary efficacy variable was morning peak flow. The children treated twice daily showed higher peak flow values at the end of the study period, but the difference was close to the limits regarded as indicative of equivalence and was not regarded as clinically important. The conclusion was that once-daily administration of budesonide dry powder is as effective as twicedaily administration in children whose asthma is stabilised at corticosteroid dosages of 200 to 400 μg/day. All studies, whether in adults or children, indicating a similar efficacy of inhaled corticosteroids with once-daily and twice-daily administration in stable asthma have one methodological flaw. The patients were divided into groups treated with the same daily dosage either once or twice daily. In an ideal trial, groups with halved dosages of inhaled corticosteroids should also have been included. On the other hand, in studies showing better efficacy with twice-daily than with once-daily treatment, many of the patients included appeared to have non-stable asthma. All these studies have shown similar efficacy with once-daily and twice-daily treatment, whether given to corticosteroid-naive children or to children with stable asthma receiving low to moderate dosages of budesonide. However, some of the studies[71,73] were able to demonstrate a nonsignificant improvement in efficacy using twice-daily treatment compared with once-daily treatment. Conversely, in one of the previously mentioned investigations,[70] it was shown that, when the dosage of inhaled budesonide was increased in children with mild asthma symptoms, the effect of budesonide given as a single dose in the evening was better than when the same dosage was given twice daily. Nevertheless, the group receiving once-daily treatment had less improvement in clinical symptoms despite their greater improvement in peak flow values. There are no studies documenting once-daily administration in children requiring high dosages of inhaled corticosteroids. It is likely that the ma© Adis International Limited. All rights reserved.

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jority of these children would need treatment at least twice daily to gain the maximum effect, but that a subgroup could manage just as well on oncedaily treatment. 5. Conclusions On the basis of present knowledge, a practical recommendation is that children with asthma should first be stabilised on inhaled corticosteroids divided into at least 2 daily doses. When the inflammation is consistently controlled on the lowest possible total daily dosage, a change to oncedaily treatment should be attempted. A trial of once-daily administration is mandatory, as compliance with a treatment that will probably be continued for years improves if therapy is simplified. A dry powder inhaler device is probably the most suitable for children from the age of 5 years. Dry powder devices avoid the use of propellants and lubricants, and certain drug/device combinations (e.g. budesonide given by Turbuhaler®) provide a higher proportion of lung deposition, allowing the possibility of a lower dosage. References 1. International Consensus Report on Diagnosis and Management of Asthma. International Asthma Management Project. Allergy 1992; 47 Suppl. 13: 1-61 2. Anon. Asthma: a follow up statement from an international paediatric asthma consensus group. Arch Dis Child 1992; 67: 240-8 3. Global Initiative for Asthma. NHLBI/WHO Workshop report. NIH Publication 95-3659. Bethesda: National Heart, Lung and Blood Institute, National Institutes of Health, 1995 4. Dahl R, Bjermer L, editors. Nordic consensus report on asthma management. Respir Med 1999; 93 5. Bousquet J, Lockey RF, Malling H-J, editors. WHO Position Paper. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998; 53 Suppl. 44: 1-42 6. Nakamura Y, Hoshino M, Sim JJ, et al. Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax 1998; 53: 835-41 7. Palmqvist M, Balder B, Lowhagen O, et al. Late asthmatic reaction decreased after pretreatment with salbutamol and formoterol, a new long-acting beta 2-agonist. J Allergy Clin Immunol 1992; 89: 844-9 8. Barnes PJ. Efficacy of inhaled corticosteroids in asthma. J Allergy Clin Immunol 1998; 102: 531-8 9. Simons FE. Benefits and risks of inhaled glucocorticoids in children with persistent asthma. J Allergy Clin Immunol 1998; 102: S77-84

Drugs 1999; 58 Suppl. 4

40

10. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373-81 11. van Essen-Zandvliet EE, Dutch Chronic Nonspecific Lung Disease Study Group. Long-term intervention in childhood asthma: the Dutch study results. Mon Arch Chest Dis 1995; 50: 201-7 12. Hussar DA. Patient non-compliance. J Am Pharm Assoc 1975; 15: 183-201 13. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA 1989; 261: 3273-7 14. Mann M, Eliasson O, Patel K, et al. A comparison of effects of bid and qid dosing on compliance with inhaled flunisolide. Chest 1992; 101: 496-9 15. Matthew D, Hingson R. Improving patient compliance: a guide for physicians. Med Clin North Am 1971; 61: 879-89 16. McAllister WA, Hetzel M, Emery P, et al. Comparison of efficacy and adrenal suppression produced by alternate-day, daily and twice-daily prednisolone regimens for chronic asthma. Thorax 1983; 38: 230-1 17. Toogood J, Jennings B, Lefcoe N. Morning-dose beclomethasone aerosol (BA) is clinically effective and spares adrenal function. Ann R Coll Phys Surg (Can) 1980; 13: 110 18. Toogood JH, Baskerville JC, Jennings B,et al. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid budesonide. J Allergy Clin Immunol 1982; 70: 288-98 19. Byron MA, Jackson J, Ansell BM. Effect of different corticosteroid regimens on hypothalamic-pituitary-adrenal axis and growth in juvenile chronic arthritis. J R Soc Med 1983; 76: 452-7 20. Casaneuva FF, Burguera B, Tome MA. Depending on the time of administration, dexamethasone potentiates or blocks growth hormone release in man. Neuroendocrinology 1990; 51: 46-91 21. Heuck C, Wolthers OD, Kollerup G, et al. Adverse effects of inhaled budesonide (800μg) on growth and collagen tunover in children with asthma: a double-blind comparison of oncedaily versus twice-daily administration. J Pediatr 1998; 133: 608-12 22. Dahl R, Johansson SA. Clinical effect of b.i.d. and q.i.d. administration of inhaled budesonide, a double-blind controlled study. Eur J Respir Dis 1982; 63 Suppl. 122: 268-9 23. Toogood JH. Concentrated aerosol formulations in asthma. Lancet 1983; 2: 790-1 24. Malo JL, Ghezzo H, Trudeau C, et al. Duration of action of inhaled terbutaline at two different doses and of albuterol in protecting against bronchoconstriction induced by hyperventilation of dry cold air in asthmatic subjects. Am Rev Respir Dis 1989; 140: 817-21 25. Malo J-L, Cartier A, Ghezzo H, et al. Comparison of four-timesa-day and twice-a-day dosing regimens in subjects requiring 1200 micrograms or less of budesonide to control mild to moderate asthma. Respir Med 1995; 89: 537-43 26. Mecoy R, Laby B. Beclomethasone dipropionate in twice daily treatment of asthma. Aust Fam Physician 1980; 9: 721-8 27. Munch EP, Taudorf E, Weeke B. Dose frequency in the treatment of asthmatics with inhaled topical steroids. Eur J Respir Dis 1982; 63: 143 28. Nyholm E, Frame MH, Cayton RM. Therapeutic advantage of twice-daily over four-times-daily inhalation budesonide in the treatment of chronic asthma. Eur J Respir Dis 1984; 65: 339-45

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29. Meltzer EO, Kemp JP, Welch MJ, et al. Effect of dosing schedule on efficacy of beclomethasone dipropionate aerosol in chronic asthma. Am Rev Respir Dis 1985; 131: 732-6 30. Boyd G, Abdallah S, Clark R. Twice or four times daily beclomethasone dipropionate in mild stable asthma? Clin Allergy 1985; 15: 383-9 31. So SY, Lam WK. Twice daily administration of beclomethasone dipropionate dry-powder in the management of chronic asthma. Asian Pac J Allergy Immunol 1986; 4: 129-32 32. Williams H, Jones ER, Silbert JR. Twice daily versus four times daily treatment with beclomethasone dipropionate in the control of mild childhood asthma. Thorax 1986; 41: 602-5 33. Smith MJ, Hodson ME. Twice daily beclomethasone dipropionate administered with a concentrated aerosol inhaler: efficacy and patient compliance. Thorax 1986; 41: 960-3 34. Tukiainen H, Vaara J, Terho E, et al. Comparison of twice-daily and four-times daily administration of beclomethasone dipropionate in patients with severe chronic bronchial asthma. Eur J Clin Pharmacol 1986; 30: 319-22 35. Reinberg A, Halberg F, Falliers CJ. Circadian timing of methylprednisolone effects in asthmatic boys. Chronobiologia 1974; 1: 333-47 36. Pincus DJ, Szefler SJ, Ackerson LM, et al. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol 1995; 95: 1172-8 37. Gagnon M, Cote J, Milot J, et al. Comparative safety and efficacy of single or twice daily administration of inhaled beclomethasone in moderate asthma. Chest 1994; 105: 1732-7 38. McGivern DV, Ward M, Macfarlane JT, et al. Failure of once daily inhaled corticosteroid treatment to control chronic asthma. Thorax 1984; 39: 933-4 39. Stiksa G, Glennow C. Once daily inhalation of budesonide in the treatment of chronic asthma: a clinical comparison. Ann Allergy 1985; 55: 49-51 40. Munch EP, Laursen LC, Dirksen A, et al. Dose frequency in the treatment of asthmatics with inhaled topical steroids. Comparison between a twice daily and a once daily dosing regimen. Eur J Respir Dis 1985; 67: 254-60 41. Jones AH, Langdon CG, Lee PS, et al. Pulmicort Turbuhaler once daily as initial prophylactic therapy for asthma. Respir Med 1994; 88: 293-9 42. Campbell LM, Gunn SD, Sweeney D, et al. Once daily budesonide: effective control of moderately severe asthma with 800 μg once daily inhaled via Turbuhaler when compared with 400 μg twice daily. Eur J Clin Res 1995; 7: 1-14 43. Weiner P, Weiner M, Azgad Y. Long-term clinical comparison of single versus twice daily administration of inhaled budesonide in moderate asthma. Thorax 1995; 50/12: 1270-3 44. ZuWallack RL, Rosen JP, Cohen L, et al. The effectiveness of once-daily dosing of inhaled flunisolide in maintaining asthma control. J Allergy Clin Immunol 1997; 99: 278-85 45. Chisholm SL, Dekker FW, Knuistingh Neven A, et al. Oncedaily budesonide in mild asthma. Respir Med 1998; 92: 421-5 46. Venables TL, Addlestone MB, Smithers AJ, et al. A comparison of the efficacy and patient acceptability of once daily budesonide via Turbuhaler and twice daily fluticasone propionate via Diskhaler at an equal daily dose of 400 mcg in adult asthmatics. Br J Clin Res 1996; 7: 15-32 47. Johansson L-O. A comparison of once-daily fluticasone propionate (FP) 200 μg and budesonide (bud) 400 μg and twicedaily of fluticasone propionate (FP) 100 μg [abstract]. Am J Resp Crit Care Med 1998; 157 (3 Pt 2): A404

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48. Miller-Larsson A, Mattson H, Ohlsson D, et al. Prolonged release from the airways tissue of glucocorticoids BUD and fluticasone dipropionate as compared to beclomethasone dipropionate and hydrocortisone. Am J Respir Crit Care Med 1994; 149 (4 Pt 2): A466 49. Brattsand R, Miller-Larsson A, Wieslander E, et al. Reversible fatty acid conjugation of budesonide − a mechanism contributing to prolonged local retention and activity. Eur Respir J 1997; 10 Suppl. 25: 296S 50. Miller-Larsson A, Jansson P, Runström A, et al. Reversible fatty acid conjugation of budesonide results in a prolonged topical anti-inflammatory activity in airways as compared to fluticasone propionate. Am J Respir Crit Care Med 1997; 155 (4 Pt 2): A353 51. Miller-Larsson A, Hjertberg E, Mattson H, et al. Reversible fatty acid conjugation of budesonide results in a prolonged retention in airway tissue as compared to fluticasone propionate. Am J Respir Crit Care Med 1997; 155 (4 Pt 2): A353 52. Wieslander E, Delander EL, Järkelid L, et al. Reversible fatty acid conjugation of budesonide results in prolonged antiinflammatory activity as compared to fluticasone propionate. Am J Respir Crit Care Med 1997; 155 (4 Pt 2): A353 53. Agertoft L, Pedersen S. Importance of training for correct Turbuhaler use in preschool children. Acta Paediatr 1998; 87: 842-7 54. de Blic J, Delacourt C, Le Bourgeois M, et al. Efficacy of nebulized budesonide in treatment of severe infantile asthma: a double-blind study. J Allergy Clin Immunol 1996; 98: 14-20 55. Ilangovan P, Pedersen S, Godfrey S, et al. Treatment of severe steroid dependent preschool asthma with nebulised budesonide suspension. Arch Dis Child 1993; 68: 356-9 56. Bingham A, Manjra AL, Lee BW, et al. A comparison of the effect of nebulised fluticasone propionate 1mg twice daily with oral prednisolone in children aged 4-16 years with an acute exacerbation of asthma. Am J Respir Crit Care Med 1998; 157 (3): A404 57. Francis P, Geelhoed G, Harris MA, et al. Effect of nebulised fluticasone propionate 1mg twice daily compared with oral prednisolone in pre-school children aged 48 months or less with an acute exacerbation of asthma. Eur Respir J 1997; 10 Suppl. 25: 275S 58. Webb MS, Milner AD, Hiller EJ, et al. Nebulised beclomethasone dipropionate suspension. Arch Dis Child 1986; 61 (11): 1108-10 59. Agertoft L, Andersen A, Weibull E, et al. Systemic availability and pharmacokinetics of nebulised budesonide in preschool children. Arch Dis Child 1999; 80 (3): 241-7 60. Pedersen S, Hansen OR, Fuglsang G. Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch Dis Child 1990; 65: 308-19

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61. Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler (P-MDI). Eur Respir J 1994; 7: 1839-44 62. Agertoft L, Pedersen S. Importance of the inhalation device on the effect of budesonide. Arch Dis Child 1993; 69 (1): 130-3 63. Pauwels RA, Hargreave FE, Camus P, et al. A 1-year comparison of Turbuhaler vs pressurized metered-dose inhaler in asthmatic patients. Chest 1996; 110: 53-7 64. Schlaeppi M, Edwards K, Fuller RW, et al. Patient perception of the Diskus inhaler: a comparison with the Turbuhaler inhaler. Br J Clin Pract 1996; 50 (1): 14-9 65. Bisgaard H, Klug B, Sumby BS, et al. Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma. Eur Respir J 1998; 11 (5): 1111-5 66. Lipworth BJ, Clark DJ. Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices. Pulmon Pharmacol Ther 1997; 10 (4): 211-4 67. Wildhaber JH, Devadason SG, Wilson JM, et al. Lung deposition of budesonide from Turbuhaler in asthmatic children. Eur J Pediatr 1998; 157 (12): 1017-22 68. Bisgaard H, Pedersen S, Nikander K. Use of budesonide Turbuhaler in young children suspected of asthma. Eur Respir J 1994; 7: 740-2 69. McCarthy TP. The use of a once daily inhaled glucocorticosteroid (budesonide) in the management of childhood asthma. Br J Clin Res 1993; 4: 55-61 70. Campbell LM, Bodalia B, Gogbashian CA, PETITE Research Group, et al. Once-daily budesonide: 400 micrograms once daily is as effective as 200 micrograms twice daily in controlling childhood asthma. Int J Clin Practice 1998; 52: 213-9 71. Jónasson G, Carlsen KH, Blomqvist P. Clinical efficacy of lowdose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998; 12: 1099-104 72. van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Rev Respir Dis 1992; 146: 547-54 73. Möller C, Strömberg L, Oldaeus G, et al. Efficacy of once-daily versus twice-daily administration of budesonide via Turbuhaler in children with stable asthma. Pediatr Pulmonol. In press

Correspondence and reprints: Associate Professor Christian Möller, Department of Pediatrics, Umeå University, S-901 85 Umeå, Sweden. E-mail: [email protected]

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