A study of the mechanism of the antiasthmatic action of inhaled budesonide

doi:10.1016/0091-6749(90)90071-B

Journal of Allergy and Clinical Immunology

Volume 85, Issue 5, May 1990, Pages 872-880

https://doi.org/10.1016/0091-6749(90)90071-B Get rights and content

Abstract

Inhaled antiasthmatic steroids have been assumed and yet never proved to exert their antiasthmatic effect by topical action in the airways. We tested the hypothesis that the efficacy of inhaled budesonide (BUD) might be due instead to its systemic activity after absorption. We compared inhaled and oral BUD with doses selected to ensure higher peak plasma levels and a greater area under the plasma concentration curve with the oral treatment. After pretreatment with beclomethasone to maximize asthma control, 47 adults with asthma were randomized to receive 0.4 mg of inhaled BUD per day (n = 16) or 1.4 mg of oral BUD per day (n = 15), or placebo (n = 16) in double-blind fashion and then followed weekly until asthma relapsed or for 8 weeks if no relapse occurred. “Relapse” was defined as a drop in the mean peak expiratory flow rate >2 SEM below the mean during the baseline week before switching to the test drugs. The time to relapse was the primary outcome variable. Time to relapse was longer with inhaled than with oral BUD (medians, 22 versus 7.9 days; p = 0.003) or placebo (medians, 22 versus 9 days; p = 0.004). Oral BUD and placebo did not differ (p = 0.41). The morning serum cortisol levels remained normal during all three treatments. Thus, at conventional dosage the antiasthmatic effect of inhaled BUD may be fully explained by a local intrapulmonary action.

References (39)

MD Chaplin et al.
Correlation of flunisolide plasma levels to eosinopenic response in humans
J Allergy Clin Immunol
(1980)
HA Orgel et al.
Clinical, rhinomanometric, and cytologic evaluation of seasonal allergic rhinitis treated with beclomethasone dipropionate as acqueous nasal spray or pressurized aerosol
J Allergy Clin Immunol
(1986)
PW Welsh et al.
Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy
CE Reed et al.
Effects of topical nasal treatment on asthma symptoms
J Allergy Clin Immunol
(1988)
M Andersson et al.
Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids
J Allergy Clin Immunol
(1987)
JH Toogood
Steroids in asthma
Lancet
(1979)
H Morrow Brown et al.
Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma
Br Med J
(1972)
HA Orgel et al.
Flunisolide aerosol in treatment of steroid-dependent asthma in children
Ann Allergy
(1983)
RN Brodgen et al.
Beclomethasone dipropionate: a reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis
Drugs
(1984)
E Adelroth et al.
High-dose inhaled budesonide in the treatment of severe steroid-dependent asthmatics
Allergy
(1985)

SP Clissold et al.

Budesonide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis

Drugs

(1984)

DM Harris

Clinical pharmacology of beclomethasone dipropionate

MD Chaplin et al.

Flunisolide metabolism and dynamics of a metabolite

Clin Pharmacol Ther

(1980)

R Brattsand et al.

The lung disposition of budesonide in guinea pig and rat

Eur J Respir Dis

(1982)

A Ryrfeldt et al.

Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid

Eur J Respir Dis

(1982)

S Pedersen et al.

Pharmacokinetics of budesonide in children with asthma

Eur J Clin Pharmacol

(1987)

S-A Johansson et al.

Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man

Eur J Respir Dis

(1982)

R Brattsand et al.

Route of administration and rapid inactivation as determinants of the lung-specific actions of glucocorticosteroids

JM Henriksen et al.

Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing, and asthma

Am Rev Respir Dis

(1984)

Cited by (48)

May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide?
2022, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
This explanation is seemingly supported by clinical trials with higher and sustained systemic ICS administration to mimic the plasma level curve reached by inhalation (same total area under the time-plasma level curve). Such studies are available for BUD and FP, both showing lost efficacy without direct airway deposition [133,134]. This outcome may be relevant for FP, showing low plasma levels when inhaled (cf Fig. 3).
The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile.
In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon.
Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as “maintenance plus reliever therapy” (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles.
We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as “anti-inflammatory reliever”.
The pulmonary route as a way to drug repositioning in COVID-19 therapy
2021, Journal of Drug Delivery Science and Technology
Citation Excerpt :
The review published by Anderson brings several examples of drugs that were administered by oral or intravenous route and became available as inhaled in order to reduce side-effects, dose, and allow a prophylactic treatment [54]. A classic example was budesonide, where the oral and aerosol formulations were compared and only the inhaled form showed antiasthmatic effect, proving that its local action in the airways was better than systemic activity after absorption [55]. The repurpose of iloprost (Ilomedin®) was also interesting.
The outbreak of the disease caused by the new coronavirus (COVID-19) has been affecting society's routine and its patterns of interaction worldwide, in addition to the impact on the global economy. To date, there is still no clinically effective treatment for this comorbidity, and drug repositioning might be a good strategy considering the established clinical safety profile. In this context, since COVID-19 affects the respiratory tract, a promising approach would be the pulmonary drug delivery.
Identify repurposing drug candidates for the treatment of COVID-19 based on the data of ongoing clinical trials and in silico studies and also assess their potential to be applied in formulations for pulmonary administration.
A integrative literature review was conducted between June and July 2020, by extracting the results from Clinical Trials, PubMed, Web of Science and Science Direct databases.
By crossing the results obtained from diverse sources, 21 common drugs were found, from which only 4 drugs presented studies of pulmonary release formulations, demonstrating the need for greater investment and incentive in this field.
Even though the lung is a target that facilitates viral infection and replication, formulations for pulmonary delivery of suitable drugs are still lacking for COVID-19 treatment. However, it is indisputable that the pandemic constitutes a concrete demand, with a profound impact on public health, and that, with the appropriate investments, it will give the pharmaceutical industry an opportunity to reinforce the pulmonary delivery field.
Repurposing drugs as inhaled therapies in asthma
2018, Advanced Drug Delivery Reviews
Citation Excerpt :
A new steroid, budesonide, was patented in 1973 and became available commercially in 1981 [77] and investigated in children [77–79] and adults [80] during the mid- 1980s. The oral and aerosol formulations of budesonide were compared and the inhaled form only was found to be efficacious [81]. The budesonide was developed for delivery as a dry powder from a breath actuated device known as the Turbuhaler [82].
For the first 40 years of the 20th century treatment for asthma occurred in response to an asthma attack. The treatments were given by injection or orally and included the adrenergic agonists adrenalin/epinephrine and ephedrine and a phosphodiesterase inhibitor theophylline. Epinephrine became available as an aerosol in 1930. After 1945, isoprenaline, a non-selective beta agonist, became available for oral use but it was most widely used by inhalation. Isoprenaline was short-acting with unwanted cardiac effects. More selective beta agonists, with a longer duration of action and fewer side-effects became available, including orciprenaline in 1967, salbutamol in 1969 and terbutaline in 1970. The inhaled steroid beclomethasone was available by 1972 and budesonide by 1982. Spirometry alone and in response to exercise was used to assess efficacy and duration of action of these drugs for the acute benefits of beta₂ agonists and the chronic benefits of corticosteroids. Early studies comparing oral and aerosol beta₂ agonists found equivalence in bronchodilator effect but the aerosol treatment was superior in preventing exercise-induced bronchoconstriction. Inhaled drugs are now widely used including the long-acting beta₂ agonists, salmeterol and formoterol, and the corticosteroids, fluticasone, ciclesonide, mometasone and triamcinolone, that act locally and have low systemic bio-availability. Repurposing drugs as inhaled therapies permitted direct delivery of low doses of drug to the site of action reducing the incidence of unwanted side-effects and permitting the prophylactic treatment of asthma.
Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?
2008, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
The pulmonary available drug will ultimately become absorbed into the systemic circulation, where it may exert systemic (side) effects. For inhaled asthma and COPD medication, the lung is the target and clear relationships between the dose reaching and absorbed by the lungs and its clinical effect has been established for β2-agonists [16] and inhaled steroids [17–20]. It has also been possible to document a difference in clinical effects for different inhalers of the same drug [16–18], suggesting the obvious: differences in lung deposition for different inhalers will translate into differences in local therapeutic effect.
The role of airway clearance in inhaled drug therapy is complex. Disease-induced bronchoconstriction results in a central drug-deposition pattern where mucociliary clearance is most efficient. When drug-induced bronchodilation is achieved, deposition and uptake becomes more peripheral, and because there is less mucociliary clearance in the periphery, this will lead to an unintentional increase in lung exposure and enhance the risk of systemic side effects. In addition, mucociliary clearance is pathologically reduced in both asthma and chronic obstructive pulmonary disease. Among inhaled corticosteroids, rate of dissolution and lung uptake differs considerably. For the slowly dissolving, lipophilic steroids, the contribution of mucociliary clearance to these findings appears significant, and variability in lung and systemic exposure resulting from variable mucociliary function appears to be amplified. In addition, dose optimisation of non-stable asthma becomes more complex. The present review highlights the impact of mucociliary clearance on inhaled corticosteroid disposition and identifies critical areas where more research is needed.
Budesonide inhalation suspension: A nebulized corticosteroid for persistent asthma
2002, Journal of Allergy and Clinical Immunology
Guidelines for managing asthma in pediatric patients published by the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics recommend the use of inhaled corticosteroids for the management of persistent asthma in infants and young children. When these guidelines were published, pressurized metered-dose inhalers and dry-powder inhalers were the only delivery devices available for inhaled corticosteroids in the United States. These devices can be difficult for young children to use correctly. Furthermore, no inhaled corticosteroid was approved in the United States for the treatment of children younger than 4 years. Budesonide inhalation suspension (Pulmicort Respules; AstraZeneca LP, Wilmington, Del) was developed to meet the medication delivery needs of infants and young children with persistent asthma. Pulmicort Respules is the first inhaled corticosteroid approved for administration by means of a nebulizer and the only inhaled corticosteroid approved in the United States for infants as young as 12 months. Budesonide has been studied extensively worldwide. In the United States the tolerability and efficacy of budesonide inhalation suspension were confirmed in 3 placebo-controlled multicenter trials. These studies demonstrated that both once- and twice-daily dosing of budesonide inhalation suspension (0.25-1 mg) improved pulmonary function and ameliorated asthma symptoms in infants and young children with persistent asthma. Budesonide inhalation suspension was well tolerated, and the incidences of reported adverse events were similar among patients in the budesonide, placebo, and conventional asthma therapy groups. This article reviews the results of these studies, as well as the pharmacokinetics, pharmacodynamics, and clinical use of budesonide inhalation suspension. (J Allergy Clin Immunol 2002;109:730-42.)
Methods used to assess pulmonary deposition and absorption of drugs
2001, Drug Discovery Today
The assessment of pulmonary drug absorption and deposition is becoming increasingly important in drug development. Absorption information can be used to maximize pulmonary selectivity, to screen drug candidates and to help evaluate the bioequivalence of generic inhalation products. Several methods are available to investigate pulmonary drug absorption and deposition, ranging from in vitro experiments to in vivo pharmacokinetic and pharmacodynamic analyses. In combination, these methods can indicate the fate of an inhaled drug.

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^☆: Supported by grants from AB Draco, Lund, Sweden, and the Department of Medicine, Victoria Hospital, London, Canada.

^∗: From the Department of Medicine, Victoria Hospital, London, Canada.

^∗∗: From the Department of Clinical Research, Clinical Pharmacology, AB Draco, Lund, Sweden.

^∗∗∗: Stat-lab. Department of Statistical and Actuarial Sciences, University of Western Ontario, London, Canada

^∗∗∗∗: Department of Clin- ical Research, Clinical Pharmacology, AB Draco

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Original articleA study of the mechanism of the antiasthmatic action of inhaled budesonide☆

Abstract

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma

Br Med J

Flunisolide aerosol in treatment of steroid-dependent asthma in children

Ann Allergy

Beclomethasone dipropionate: a reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis

Drugs

High-dose inhaled budesonide in the treatment of severe steroid-dependent asthmatics

Allergy

Budesonide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis

Drugs

Clinical pharmacology of beclomethasone dipropionate

Flunisolide metabolism and dynamics of a metabolite

Clin Pharmacol Ther

The lung disposition of budesonide in guinea pig and rat

Eur J Respir Dis

Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid

Eur J Respir Dis

Pharmacokinetics of budesonide in children with asthma

Eur J Clin Pharmacol

Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man

Eur J Respir Dis

Route of administration and rapid inactivation as determinants of the lung-specific actions of glucocorticosteroids

Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing, and asthma

Am Rev Respir Dis

Original article
A study of the mechanism of the antiasthmatic action of inhaled budesonide☆