Treatment with Pulmicort - general aspects
What do we mean by anti-inflammatory properties of Pulmicort?
What is the effect on asthma symptoms when starting treatment with Pulmicort?
What is the effect on airway function (morning PEF) when starting treatment with Pulmicort?
How rapidly is effect on symptoms and airway function demonstrable with Pulmicort?
What is the effect of Pulmicort on bronchial hyperresponsiveness?
Does treatment with Pulmicort protect against maximal airway narrowing?
What type of cells is affected with Pulmicort?
Does Pulmicort exhibit anti-oedema effects?
Is treatment with Pulmicort as effective as treatment with oral corticosteroids?
Does treatment with Pulmicort up-regulate airway smooth muscle ß2-receptors?
Is there a dose-response relationship for Pulmicort Turbuhaler?
What dosing regimen should be used with Pulmicort?
How is Pulmicort delivered to the airways?
What do we mean by anti-inflammatory properties of Pulmicort?
Bronchial biopsies, bronchoalveolar lavage or induced sputum obtained from patients with untreated asthma demonstrate shedding of the airway epithelium and an infiltration of eosinophils, mast cells and lymphocytes of the T helper cell phenotype in the bronchial mucosa.
Treatment with Pulmicort has been shown to restore the airway mucosa and significantly reduce the numbers of these inflammatory cells. An anti-inflammatory property of inhaled corticosteroids can be defined as the disappearance of inflammatory cells from the airway mucosa together with normalisation of the damaged airway epithelium.
Airway inflammation in a patient with mild asthma before and after treatment with Pulmicort
In the first biopsy (taken 9 months after first diagnosis, and before the patient had received any steroid treatment) there is an intense inflammatory reaction in the lamina propria and the airway epithelium (E) is severely damaged. By comparison, after three months of treatment with budesonide the picture is similar to that seen in normal airways, with an intact epithelium and no significant inflammatory cells).
Reference:
Laitinen LA et al.: A comparative study of the effects of an inhaled corticosteroid, budesonide, and a ß2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992; 90: 32-42.
What is the effect on asthma symptoms when starting treatment with Pulmicort?
Cough and chest tightness are asthma symptoms considered to be related to airway inflammation. Cough is often associated with an increased bronchial responsiveness (BHR = bronchial hyperresponsiveness). These symptoms are rapidly reduced when starting treatment with Pulmicort.
Reduction in asthma symptoms during treatment with Pulmicort
Symptoms were assessed by patient questionnaire (maximum score = 6). By symptomatic criteria these patients had mild asthma on admission to the study, but had airway hyperresponsiveness associated with this. By 12 months, symptoms were reduced to near-zero in the group treated with budesonide, but not in the group receiving placebo and salbutamol as needed).
Reference:
Juniper EF et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in non-steroid dependent asthmatics. Am Rev Respir Dis 1990; 142: 832-836.
What is the effect on airway function (morning PEF) when starting treatment with Pulmicort?
In patients not previously treated with inhaled corticosteroids airway function measured as peak expiratory flow rates (PEF) improve significantly (1), often within just a few days (2). The degree of improvement depends on the duration of asthma symptoms when starting treatment but is most pronounced in patients with a short duration of asthma symptoms (3).
Rapid onset of bronchodilation when starting treatment with Pulmicort
Onset of action of budesonide Turbuhaler expressed as mean change from baseline in daily morning peak expiratory flow (PEF, L/min) during the first 2 weeks on study medication. All patients treated analysis.
References:
1. Miyamoto T et al.: A double-blind, placebo-controlled dose-response study with budesonide Turbuhaler in Japanese asthma patients. Respirology 2000; 5: 247-256.
2. Kemp J, Wanderer AA, Ramsdell J, Southern DL, Weiss S, Aaronson D, Grossman J. Rapid onset of control with budesonide Turbuhaler in patients with mild- to-moderate asthma. Annals of Allergy, Asthma, & Immunology 1999; 82(5): 463-71
3. Selroos et al.: Effect of early vs. late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234.
How rapidly is effect on symptoms and airway function demonstrable with Pulmicort?
The effects of Pulmicort in asthma have different time frames. Asthma symptoms are significantly reduced already during the first treatment days (1). A significant improvement in airway function is usually demonstrable after one week of treatment, often the first time when lung function has been measured after starting treatment. However, if measured every day, significant effects may be observed already one or two days after starting treatment (2).
Treatment with inhaled corticosteroids in asthma patients is conceptually long-term treatment. Few studies have investigated the acute effects. Nevertheless, inhalation of single-doses of Pulmicort has been found to improve airway function in asthmatics in a dose dependent fashion (3). A significant improvement measured as peak expiratory flow (PEF) was observed one hour after administration of 400 µg and 1600 µg via pMDI and two hours after administration of 100 µg (3). Similarly, in a placebo-controlled study in 30 patients with stable asthma, administration of Pulmicort 1600 µg via pMDI with large volume spacer produced an increase in FEV1 within one hour and reached a level of statistical significance within 3-4 hours (4).
The time course of the effects of Pulmicort Turbuhaler 200 µg, 800 µg and 1600 µg on lung function and inflammatory markers such as blood eosinophil numbers and serum ECP (eosinophil cationic protein) were compared in a study involving 24 asthma patients who had not previously received treatment with corticosteroids (5). Significant improvements in lung function were seen with all doses within five to six hours, but only the highest dose produced a significant improvement in inflammatory markers.
Rapid onset of action with Pulmicort
Increase in PEF after administration of Pulmicort 100 µg, 400 µg and 1600 µg via pMDI, and oral prednisolone 40 mg, in 12 patients with chronic asthma (Ellul-Micallef and Johansson, 1983). The effect of Pulmicort became apparent within 1 to 2 hours. Patients also received a single dose of oral budesonide 1600 µg for comparison.
References:
1. Juniper EF et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in non-steroid dependent asthmatics. Am Rev Respir Dis 1990; 142: 832-836.
2. Kemp J, Wanderer AA, Ramsdell J, Southern DL, Weiss S, Aaronson D, Grossman J. Rapid onset of control with budesonide Turbuhaler in patients with mild- to-moderate asthma. Annals of Allergy, Asthma, & Immunology 1999; 82(5): 463-71.
3. Ellul-Micallef R and Johansson S-Å. Acute dose-response studies in bronchial asthma with a new corticosteroid, budesonide. Br J Clin Pharmacol 1983; 15: 419-422.
4. Engel T et al. Single-dose inhaled budesonide in subjects with chronic asthma. Allergy 1991; 46: 547-553.
5. Le Merre C et al. Effect on lung function and inflammatory markers of single doses of inhaled budesonide in asthmatics. Am J Respir Crit Care Med 1997; 155: A352.
What is the effect of Pulmicort on bronchial hyperresponsiveness?
Treatment with Pulmicort will reduce the degree of non-specific bronchial hyperresponsiveness measured as the provocative dose or concentration of histamine or methacholine causing a 20% fall in FEV1 (PD 20 or PC 20 histamine or methacholine). Although the greatest reduction in PD 20 is seen during the first treatment month a gradual further reduction will be seen over several months (1).
Another study investigated the time course of the effects of Pulmicort 800 µg twice daily via pMDI with large volume spacer on bronchial hyperresponsiveness in 40 asthmatic patients. The first dose of Pulmicort produced a significant increase in FEV1 but also an improvement in bronchial hyperresponsiveness (PD 20 histamine), which was apparent six hours after administration (2).
In a further study 41 patients with stable asthma discontinued treatment with inhaled corticosteroids for four days, after which 26 patients with sputum eosinophilia were randomised to receive a single dose of Pulmicort Turbuhaler 2400 µg, or placebo, on two occasions approximately seven days apart. At six hours after dosing Pulmicort treatment was associated with a significant reduction in sputum eosinophils and a significant improvement in bronchial hyperresponsiveness (3).
Change in PC20 during treatment with Pulmicort
Patients (16 in each group) received either budesonide, 400 µg/day in divided twice daily dosage from pMDI plus spacer, or placebo. Both groups also received inhaled salbutamol as needed for symptomatic relief. The greatest improvement in the group treated with budesonide occurred over the first 3 months, but further progressive improvement continued throughout the year. The long-term changes seen in the group treated with budesonide are a sensitive indicator of improvement in airway inflammation.
References:
1. Juniper EF et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in non-steroid dependent asthmatics. Am Rev Respir Dis 1990; 142: 832-836.
2. Vathenen AS et al. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am Rev Respir Dis 1991; 143: 1317-1321.
3. Gibson PG et al. Acute anti-inflammatory effects of inhaled budesonide in asthma. A randomized controlled trial. Am J Respir Crit Care Med 2001; 163: 32-36.
Does treatment with Pulmicort protect against maximal airway narrowing?
Allergen exposure in an asthmatic patient sensitive to that specific allergen may cause a severe (maximal) airway narrowing. Such a severe acute attack of asthma may be fatal. In a double-blind crossover study asthmatic patients were treated with Pulmicort 400 µg daily or placebo (4 weeks) and the effects were evaluated by methacholine challenge tests.
Treatment with Pulmicort resulted in a shift of the methacholine dose-response curve to the right meaning improved bronchial responsiveness. But in addition the study showed that further airway narrowing did not occur when the highest doses of methacholine were administered. Patients achieved a plateau for methacholine. This means that the patients were protected against maximal airway narrowing.
This effect appears to be an important property of Pulmicort.
Protection against maximal airway narrowing during treatment with Pulmicort 
Sixteen atopic patients with mild asthma received either budesonide Turbuhaler 800 µg/day or placebo for 4 weeks and complete dose-response curves to methacholine were obtained at different time points. After 4 weeks mean maximal fall in FEV1 had decreased from 41.6 to 33.7% (p = 0.0004) in the budesonide treated patients, and the changes between placebo and budesonide were also statistically significant (p = 0.03).
Reference:
Bel E et al: The effect of inhaled corticosteroids on the maximal degree of airway narrowing to methacholine in asthmatic subjects. Am Rev Respir Dis 1991; 143: 109-113.
What type of cells is affected with Pulmicort?
Treatment with Pulmicort will reduce the numbers of eosinophils, mast cells and lymphocytes.
In addition Pulmicort will affect the secretion and production of cytokines from macrophages and lymphocytes, reduce plasma leakage between endothelial cells, reduce mucus secretion, and up-regulate the number of ß2-adrenoceptors.
Effects of corticosteroids on inflammatory airway cells in asthma
Reference:
Barnes PJ et al.: Efficacy of inhaled corticosteroids in asthma. J Allergy Clin Immunol 1998; 102: 531-538.
Does Pulmicort exhibit anti-oedema effects?
Experimental preclinical studies as well as studies in man involving the nasal mucosa have demonstrated clear anti-oedema effects of budesonide (Pulmicort) (1). This is a reaction considered to be part of the anti-inflammatory action of Pulmicort.
A clinical correlate of anti-oedema effects of Pulmicort is the effect demonstrated in children with croup. A meta-analysis clearly showed that treatment with Pulmicort is effective (2).
Antiinflammatory mechanisms of corticosteroids include effects on airway microcirculation
Through several mechanisms, GCS influence most processes and cells involved in the inflammatory response in airway mucosa. For example, GCS inhibit activation of T-cells, reduce mast cell number, and reduce the recruitment, mediator release and survival time of eosinophils. Effects on plasma leakage cause the anti-oedema activity from vessels as well as through the epithelium.
References:
1. Persson CGA. Airway microcirculation, epithelium, and glucocorticoids. In.: Schleimer RP, Busse WW, O´Byrne PM (eds), Inhaled glucocorticoids in asthma. Mechanisms and clinical actions. Marcel Dekker, New York 1997, pp167-201.
2. Ausejo et al. The effectiveness of glucocorticoids in treating croup: a meta-analysis. Br Med J 1999; 319: 595-600.
Is treatment with Pulmicort as effective as treatment with oral corticosteroids?
After oral dosing of systemic glucocorticosteroids it is difficult to obtain sufficiently high local concentrations of glucocorticosteroids on the airway mucosa (1). For hydrocortisone a correlation of about 1:1 was found between plasma levels and lung epithelial lining fluid (ELF) concentrations after i.v. administration (2). Two studies have been reported on the lung uptake of prednisolone and methylprednisolone in rabbits (3-4). ELF/plasma ratios of 3.6 for methylprednisolone (3) and 1.7 for prednisolone (4) were found.
In contrast, inhalation of drug will result in a high topical drug concentration (1). Budesonide concentrations in lung biopsies and plasma after inhalation via a pMDI with large volume spacer were shown to differ by a factor of about 9 (5).
Clinical studies have shown that in asthma maintenance treatment the efficacy of inhaled Pulmicort can be superior to even high doses of oral corticosteroids, e.g. prednisolone (6,7).
Efficacy of Pulmicort compared with oral corticosteroids 
In this relatively complex study, both prednisone and budesonide showed a dose-response relationship. The potency ratio of budesonide to prednisone for the desired effect was 25:1. Systemic effects were significantly lower with each dose of budesonide than with the dose of prednisone that achieved a similar effect on relapses.
References:
1. Edsbäcker S, Szefler SJ. Glucocorticoid pharmacokinetics. Principles and clinical applications. In: Inhaled glucocorticoids in asthma (Eds. Schleimer RP, Busse WW, O´Byrne PM), Marcel Dekker, New York 1997; 381-445.
2. Braude AC, Rebuck AS. Pulmonary disposition of cortisol. Ann Intern Med 1982; 97: 59-60.
3. Greos LS et al. Methylprednisolone achieves greater concentrations in the lung than prednisolone. Am Rev Respir Dis 1991; 144: 586-592.
4. Vichyanond P et al. Penetration of corticosteroids into lung: evidence for a difference between methylprednisolone and prednisolone. J Allergy Clin Immunol 1989; 84: 867-873.
5. van den Bosch JMM et al. Relationship between lung tissue and blood plasma concentrations of inhaled budesonide. Biopharm Drug Dispos 1993; 14: 455-459.
6. Toogood JH. Efficiency of inhaled versus oral steroid treatment of chronic asthma. N Engl Reg Allergy Proc 1987; 8: 98-103.
7. Busse WW. A comparison of inhaled versus oral corticosteroids as maintenance therapy in asthma. In.: Schleimer RP, Busse WW, O´Byrne PM (eds), Inhaled glucocorticoids in asthma. Mechanisms and clinical actions. Marcel Dekker, New York 1997, pp481-492.
Does treatment with Pulmicort up-regulate airway smooth muscle ß2 -receptors?
Chronic treatment with short-acting ß2-agonists will down-regulate the ß2-receptors. Administration of Pulmicort will result in up-regulation of the ß-receptors which is of importance for maintained bronchodilation with ß2-agonists.
References:
1. Roth M, et al. Interaction between glucocorticoids and ß2-agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002;360:1293-9.
2. Aziz I, Lipworth BJ. A bolus of inhaled budesonide rapidly reverses airway sub sensitivity and ß2-adrenoceptor down-regulation after regular inhaled formoterol. Chest 1999; 115(3): 623-8.
Is there a dose-response relationship for Pulmicort Turbuhaler?
Several clinical dose-response studies have shown a statistically significant dose-response relationship. However, the dose-response curve is rather flat, which means that it has been hard to find statistically significant differences between doubling doses. A four times higher dose has been required for demonstrating a difference between doses (1,2)
Based on results of dose-response studies different maintenance doses of Pulmicort for the treatment of asthma can be recommended. Patients with mild persistent asthma are usually well controlled on 100 µg to 400 µg Pulmicort daily, patients with moderate severe asthma on 400 µg to 800 µg daily, and patients with severe persistent asthma on 800 µg to 1600 µg daily. It should be noticed, however, that patients requiring daily doses of Pulmicort above 800 µg usually are better controlled on a combination of an inhaled corticosteroid and an inhaled long-acting ß2-agonist (3).
Dose-response with Pulmicort Turbuhaler in patients not previously treated with inhaled corticosteroids 
Three doses of Pulmicort Turbuhaler were given for 6 weeks to 267 adult Japanese patients (mean age 51 years) with mild-to-moderate asthma, in this double-blind, placebo-controlled, randomized, parallel group study (2). Compared with placebo all improvements in the budesonide groups were statistically significant and a significant dose-response was demonstrated (P< 0.001). The difference between the 200 and 800 µg doses was also statisticallly significant.
References:
1. Busse WW et al.: Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol 1998; 101: 457-463.
2. Miyamoto T et al.: A double-blind, placebo-controlled dose-response study with budesonide Turbuhaler in Japanese asthma patients. Respirology 2000; 5: 247-256.
3. GINA guidelines
Read more about dose response:
What dosing regimen should be used with Pulmicort?
Twice daily dosing of Pulmicort has been most widely applied. However, patients with well-controlled asthma can use Pulmicort once daily - a dose that can be used from the start of treatment by patients with mild persistent asthma (1). Pulmicort was the first inhaled corticosteroid approved for once-daily treatment.
Patients with deteriorating asthma can be better controlled on more frequent dosing, e.g. four times daily, compared to less frequent dosing (2).
When patients deteriorate a doubling of the inhaled steroid dose may not be sufficient. The use of a four times higher dose has been recommended (3).
References:
1. O´Byrne PM (ed). Once-daily corticosteroid therapy in asthma: improving compliance with budesonide - A seminar-in-print. Drugs 1999; 58 (suppl 4): 1-53.
2. Malo JL et al. Four-times-a-day dosing frequency is better than twice-a-day regimen in subjects requiring high-dose inhaled steroid, budesonide, to control moderate to severe asthma. Am Rev Respir Dis 1989; 140: 624-628.
3. Keeley D. Higher dose inhaled corticosteroids in childhood asthma - What we do doesn’t work and what we don’t do does. Br Med J 2001; 322: 504-5.
How is Pulmicort delivered to the airways?
Pulmicort can be administered by using a nebuliser (budesonide suspension for nebulisation; Pulmicort Respules®). This is an ideal delivery system for children under 2 years of age.
Pulmicort is also available as a pressurized metered dose inhaler (Pulmicort pMDI), which can be attached to a spacer, preferably to NebuChamber. This is the preferred delivery system for children aged 2-5 years.
The most widely used delivery system is the inspiratory flow driven dry powder inhaler, Turbuhaler®, which delivers twice as much drug to the airways compared with a pMDI, allowing half of the dose to be used (1,2).
References:
1. Thorsson L, Edsbäcker S, Conradson TL. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered dose inhaler (pMDI). Eur Respir J 1994; 7: 1839-1844.
2. Agertoft L, Pedersen S. Importance of the inhalation device on the effect of budesonide . Arch Dis Child 1993;69:130-3.
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