| 1. 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:
1. 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.
|
| 2. 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:
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.
|
| 3. 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.
|
| 4. 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.
|
| 5. 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 (PD20
or PC20 histamine or methacholine). Although the greatest
reduction in PD20 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 (PD20 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.
|
| 6. 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:
1. 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.
|
| 7. 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:
1. Barnes PJ et al.: Efficacy of
inhaled corticosteroids in asthma. J Allergy Clin Immunol 1998; 102:
531-538.
|
| 8. 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.
|
| 9. 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.
|
| 10. 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.
|
| 11. 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:
Pulmicort Respules
Paediatric asthma
|
| 12. 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.
Once daily Pulmicort
|
| 13. 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).
NebuChamber
Nebuhaler
Turbuhaler
Pulmicort Respules
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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