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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We addressed the question of whether the prolonged local retention of the glucocorticoid (GC) budesonide (BUD) within airway tissue, due to reversible fatty acid esterification, is associated with
protracted topical anti-inflammatory activity and improved airway
selectivity, when compared with fluticasone propionate (FP). BUD
or FP at 25 nmol/kg was administered intratracheally or subcutaneously to adrenalectomized rats, followed by lipopolysaccharide (LPS) intratracheal instillation. The trachea and main bronchi were
lavaged 6 h after LPS, and tumor necrosis factor-alpha (TNF-
) concentration and cell number in the lavage fluid were measured. Instilled 1 h before LPS, both GCs reduced TNF- by 70% (p < 0.05) and mononuclear cells by 55% (p < 0.01), with no reduction
in neutrophils. Instilled 6 h before LPS, a significant reduction of
TNF- (59%, p < 0.02) and mononuclear cells (47%, p < 0.05) was
achieved only with BUD. After subcutaneous administration, no
significant effects were observed. BUD did not exert higher systemic activity than FP, measured as plasma corticosterone suppression. In conclusion, BUD exerted a more prolonged topical
anti-inflammatory activity, and a higher airway selectivity than FP,
possibly because of its reversible fatty acid esterification within
airway tissue. This may contribute to the high efficacy and safety
of BUD in asthma, even with once-daily inhalation.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In asthma therapy today, glucocorticoids (GCs) are mainly administered by inhalation in order to achieve a high local concentration at the target, the airway mucosa-submucosa, and to minimize the risk of adverse systemic effects by reducing the dose requirement. High airway concentrations, a high receptor affinity, and an extensive subsequent first-pass metabolism in liver and gut together explain the therapeutic activity and airway selectivity of inhaled GCs (1).
Budesonide (BUD) and fluticasone propionate (FP) are inhaled GCs used in asthma therapy. It has been suggested that FP, by virtue of its higher lipophilicity, would be better retained than BUD in the airway-lung tissue. This, together with the higher receptor affinity of FP, was proposed to result in a longer duration of local anti-inflammatory action of FP compared with less lipophilic GCs such as BUD (2). However, regarding functional duration, there is a series of studies reporting that BUD given once daily in mild-moderate asthma is as effective as the same total dose of BUD (3) or FP (8) given twice daily.
Recently, we have shown in a kinetic study (9) that BUD is retained in rat large airway tissue for a longer time than FP, although FP is 6 to 8 times more lipophilic than BUD. This is most likely explained by the fact that, in the airway tissue BUD, but not FP, forms long-chain fatty acid C-21 esters which are 500 to 10,000 times more lipophilic than BUD itself (9, 10). This esterification process is reversible; BUD esters are gradually hydrolyzed, and intact BUD is slowly regained, becoming available to the receptor (9).
In the present functional study, in a rat model similar to that used in the kinetic study (9), we addressed the question of whether the prolonged retention of BUD in large airway tissue is associated with a protracted topical anti-inflammatory activity, and improved airway selectivity, when compared with FP. A longer effect of BUD, compared with FP, was recently shown after pulse incubation of transfected Rat 1 cells, where the same type of reversible conjugation of BUD occurs (11).
In the present study, the reduction of tumor necrosis factor- (TNF-) production, within the topically treated large
airway area, was used as a measure of the topical anti-inflammatory activity of BUD and FP. TNF- is regarded as one of
the initiators of inflammatory mechanisms mediating acute
and chronic inflammation. TNF- contributes to the pathophysiology of inflammatory airway diseases such as asthma
(12, 13). We have previously shown (14) that in adrenalectomized (ADX) rats, intratracheal lipopolysaccharide (LPS) induces a clear biphasic release of TNF- into the airways, peaking at 2 and 6 h after LPS. In sham-operated rats, LPS induced
the same initial TNF- peak at 2 h, whereas the 6-h peak was
nearly absent, probably suppressed by a rise of endogenous
corticosterone peaking at 4 h (14). In contrast to the TNF-
response, there were no major differences between sham-
operated and ADX rats in the LPS-induced cellular response,
only its slight prolongation in ADX rats. In the present study,
the susceptibility of the 2-h and 6-h TNF- peaks to inhibition
by exogenous GCs, administered either locally in the airways
or systemically, was investigated in ADX rats. On the basis of
these results, the magnitude of the 6-h TNF- peak was chosen as the most GC-sensitive variable for studying the topical
efficacy and selectivity (in combination with plasma corticosterone suppression) of BUD and FP administered into the airways of ADX rats. As a secondary variable, the cellular response was also monitored.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Design
BUD or FP was instilled intratracheally in a 100-µl volume into ADX
rats 1 to 16 h before intratracheal instillation of 100 µg LPS (in a 50-µl
volume). Control rats received 0.9% saline instead of steroid, followed by LPS. Instillation was performed under enflurane anaesthesia (Efrane, Abbot, Italy) delivered via vaporizer together with N2O/
O2. At 2 or 6 h after LPS, the trachea and main bronchi were lavaged
ex vivo with phosphate-buffered saline (PBS) and the concentration
of TNF- in supernatants of the lavage fluid was determined by
ELISA (Cytoscreen rat TNF- kit; BioSource International, Camarillo, CA). Cells in resuspended lavage pellets were counted and identified using cytospin preparations. To study topical airway selectivity,
BUD or FP was also administered subcutaneously to ADX rats as
well as being instilled intratracheally into normal rats. Suppression of
plasma corticosterone in normal rats was used as a measure of systemic activity. Plasma corticosterone was measured by radioimmunoassay (RIA) (Rat corticosterone kit [ 125I]RIA assay system; Amersham Int., Amersham, UK). Lavage and plasma samples were assayed
in duplicate.
Protocols
In the first series of experiments, rats were instilled intratracheally
with BUD or FP at 25 or 12.5 nmol/kg body weight (or saline) followed
1 h later by instillation of LPS. Lavage was collected 6 h after LPS to
study steroid effect on the late TNF- peak. In the second series, BUD
at 100 nmol/kg body weight was instilled 1 to 5 h before LPS, and lavage collected 2 h after LPS to study the early TNF- peak.
A dose of 25 nmol/kg body weight was chosen for the time- response study. BUD, FP, or saline was instilled intratracheally or injected subcutaneously (in the back) 6 h before LPS instillation. Lavage was collected 6 h after LPS. A shorter (1 h before LPS) and a longer (12 h before LPS) pretreatment time with intratracheal BUD and FP were also studied.
The systemic effects of the 12.5, 25, and 100 nmol/kg body weight doses of BUD and FP were studied in normal rats by measurements of plasma corticosterone. Blood plasma was collected 3 h after intratracheal instillation or subcutaneous administration of BUD or FP, i.e., when steroid-induced suppression of plasma corticosterone is most evident. During the last hour before exsanguination, rats were subjected to cold stress to strongly stimulate the hypothalamic-pituitary-adrenal axis.
Materials
BUD and FP (Astra Draco AB, Lund, Sweden) were prepared in sterile 0. 9% saline, sonicated on ice for 2 min on the day of experiment,
and vigorously shaken before application. In the series where plasma
corticosterone was measured, 20% polyethylene glycol 660 hydroxystearate (Solutol HS 15; BASF, Ludvigshafen, Germany) in water
(0.1% ethanol) was used as a vehicle for both FP and BUD. LPS (B E-coli 026: B6) from Difco Laboratories (Detroit, MI) was dissolved in
sterile 0.9% saline and stored in aliquots at 
25° C. Aliquots were diluted to final concentration just before intratracheal instillation.
Animals
Male Sprague-Dawley rats were supplied by Möllegaard Breeding Centre Ltd. (Skensved, Denmark). Rats were housed 6 per standard wire-topped cage in rooms with a 12 h artificial light:12 h dark cycle, at 20 to 22° C and 50 to 60% humidity, with food and water freely available. Rats were adrenalectomized or were sham-operated under enflurane anaesthesia (Efrane, Abbot, Italy) 7 d before experiments. ADX rats were maintained with 0.9% saline in the drinking water. On the day of experiment, the rats weighed 240 to 280 g. The experimental protocol was approved by the Malmö/Lund ethics committee on animal experiments.
Tracheobronchial Lavage
Tracheobronchial lavage was performed according to a technique
modified from Erjefält and Persson (15). Briefly, after heart puncture
of the anesthetized rat (performed after intraperitoneal injection of
1.5 ml sodium pentobarbital 60 mg/ml; Apoteksbolaget, Umeå, Sweden), the trachea and lungs were taken out in toto (the larynx was tied
off before excision). After a brief rinse in ice-cold saline, the lungs
with trachea were placed on a Petri dish kept on ice. Each lobar bronchus was tied off at the lung surface, and a small incision was made in
the trachea directly under the larynx. A plastic tube (PE-50) was introduced through a small incision in the left bronchus and secured
with a ligature. A volume of 175 µl PBS buffer at room temperature
was gently infused via a plastic tube into the left bronchus, and the
trachea and main stem bronchi were carefully lavaged 5 times. Lavage
fluid was centrifuged at 4° C for 10 min at 1,000 g, and the supernatant collected and stored at 70° C.
Cell Analysis
Cells in the lavage pellet were resuspended in 100 µl sterile cell culture media (RPMI 1640 with 10% fetal calf serum, both from Gibco BRL, Paisley, Scotland, UK). The total number of cells in the pellets was counted in a Bürker chamber. Differential counting (on 400 cells) was done on cytospin slides (5 × 104 cells per slide) after standard May-Grünwald-Giemsa staining (Sigma Diagnostics, St. Louis, MO). Neutrophils, eosinophils, mononuclear cell fraction (including monocytes/macrophages and mast cells), and lymphocytes were counted.
Data Analysis
The results are presented as arithmetic mean values with SEM. TNF-
concentration values in lavage fluid refer to the 2-fold diluted samples. Statistical comparisons were performed with a t test for independent samples preceded by analysis of variance (ANOVA), and calculated for pooled variance and degrees of freedom obtained from
ANOVA. Differences were considered significant at p < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF- Release
Intratracheal instillation of LPS induced a biphasic TNF- release in the airways of ADX rats, peaking at 2 h and 6 h, and reaching average levels of 250 to 350 pg/ml for both peaks (not shown here, see reference 14). BUD at 100 nmol/kg body
weight reduced the first TNF- peak by at most 30% (Figure
1) when administered 2 h (p < 0.05) or 3 h (p < 0.01) before
LPS (but not at 1 h or 4 to 5 h). In contrast, the same BUD
dose, instilled 1 h before LPS, inhibited the second peak by
96% (p < 0.01), decreasing TNF- concentrations to below or
just above the lower detection limit of the assay (15.6 pg/ml).
The inhibition of the second TNF- peak by BUD was dose-dependent: 25 and 12.5 nmol/kg body weight doses reduced
the second TNF- peak by 73% (p < 0.05) and 47% (p < 0.05), respectively (Figure 2). FP instilled 1 h before LPS reduced the second TNF- peak to the same extent as BUD: by
70% (p < 0.05) at 25 nmol/kg body weight (Figure 3A) and by
48% (p < 0.05) at 12.5 nmol/kg body weight (not shown).
BUD and FP, instilled at 25 nmol/kg body weight suppressed
the second TNF- peak in ADX rats to approximately 100 pg/
ml, that is, to the concentration observed in sham-operated
LPS-challenged rats (14).
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When BUD and FP at 25 nmol/kg body weight were instilled 6 h before LPS (Figure 3B), BUD still reduced the
TNF- second peak by 59% (p < 0.02), whereas the 26% reduction achieved by FP was not statistically significant (p < 0.3). Neither steroid was effective when instilled 12 h before
LPS (not shown).
Cell Response
Both BUD and FP, instilled intratracheally 1 h before LPS, significantly decreased the number of mononuclear cells in lavage fluid, collected 6 h after LPS instillation, compared with the LPS-treated controls. BUD decreased mononuclear cells by 55% at 25 nmol/kg body weight (p < 0.01; Figure 4A) and by 58% at 12.5 nmol/kg body weight (p < 0.001; not shown). FP decreased mononuclear cells in a dose-dependent manner; at 25 nmol/kg body weight by 57% (p < 0.01; Figure 4A) and at 12.5 nmol/kg body weight by 34% (p < 0.02; not shown).
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When BUD and FP at 25 nmol/kg body weight were instilled 6 h before LPS, BUD decreased the number of mononuclear cells by 47% (p < 0.05) whereas the 33% decrease brought about by FP was not statistically significant (p < 0.2). In contrast to mononuclear cells, the number of neutrophils was not significantly decreased, when either BUD or FP was instilled 1 h or 6 h before LPS (not shown).
Airway Selectivity
In contrast to intratracheal instillation, subcutaneous administration of BUD at 25 nmol/kg body weight 6 h before LPS had no significant effect on TNF- concentration or the number of mononuclear cells in the airways 6 h after LPS. The difference between the effects achieved with BUD after intratracheal
and subcutaneous administration was statistically significant
(Figures 5A and 6A). Under the same conditions, FP did not
significantly reduce concentrations of TNF- or mononuclear
cells when administered by either the intratracheal or the subcutaneous route (Figures 5B and 6B).
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After intratracheal instillation of 25 nmol/kg body weight, there was no difference between BUD and FP when comparing the magnitude of plasma corticosterone suppression, although suppression by BUD was not statistically significant owing to the slightly greater variation between data (Figure 7A). On the other hand, FP suppressed plasma corticosterone to a higher degree than BUD at both 12.5 and 100 nmol/kg body weight (Figure 7A). In contrast to intratracheal instillation, both GCs suppressed plasma corticosterone to the same degree after subcutaneous administration at all doses tested, although suppression by BUD at 12.5 nmol/kg body weight was not statistically significant (Figure 7B). Moreover, FP suppressed plasma corticosterone to the same extent after intratracheal as after subcutaneous administration. In contrast, intratracheal BUD suppressed plasma corticosterone to a lower degree than subcutaneous BUD both at 12.5 and 100 nmol/kg body weight, whereas there was no difference at 25 nmol/kg body weight.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Duration of Anti-inflammatory Activity
We have previously shown that the bimodal pattern of local
TNF- release in the LPS challenged rat airways is probably
dependent on the concentration of circulating endogenous
GC, as the second TNF- peak (but not the first one) is
strongly potentiated by adrenalectomy (14). In the present
study, we show that the second TNF- peak in ADX rats is
also much more susceptible than the early peak to inhibition
by intratracheally applied exogenous GCs. The biphasic TNF-
release in the airways resembles temporally the dual inflammatory reaction seen after bronchial challenge with allergen.
The immediate allergic response is probably due to the release
of preformed and newly synthesized mediators from mast cells
stimulated by IgE antibodies. In humans, the immediate response is more resistant to exogenous GCs than the late one (16) and this has been attributed to an insensitivity of lung mast cells to steroids (17). This is consistent with the concept that mast cells may have contributed largely to the first TNF- peak in this rat model, whereas the second peak may originate from monocytes-macrophages or bronchial epithelial cells (14).
In the present study, BUD and FP at 25 nmol/kg body
weight instilled intratracheally 1 h before LPS (7 h before the
measurement of TNF-), both inhibited the second TNF-
peak by approximately 70%. However, when BUD or FP was
instilled 6 h before LPS (12 h before the measurement of
TNF-), a significant reduction of TNF- persisted only for
BUD. The same temporal difference between BUD and FP
was observed in the reduction of mononuclear cell numbers. Thus, BUD exerted a more prolonged anti-inflammatory activity than FP, despite the fact that BUD is less lipophilic, the
receptor affinity for BUD is half that of FP (18, 19), and the in
vitro half-life of the BUD-receptor complex formed is said to
be only about half that of FP (5 to 6 h versus 10 h; 18, 20).
The temporal difference in the topical activity of BUD and
FP in the airways observed in this study cannot be explained by a difference in initial bioavailability, because BUD and FP
were equally effective when administered 1 h before LPS,
showing that they were both topically bioavailable in the aqueous solution applied. Furthermore, equal plasma corticosterone suppression by topical and systemic FP shows that topical
FP was bioavailable to the same extent as systemic FP. The
prolonged anti-inflammatory activity of BUD cannot be explained by its greater systemic activity because, in contrast to
intratracheal BUD, subcutaneous BUD did not significantly
reduce either the late TNF- peak or the number of mononuclear cells, and BUD at 25 nmol/kg body weight did not suppress plasma corticosterone to the higher extent than FP at the
same dose. Moreover, FP suppressed plasma corticosterone
equally after intratracheal and subcutaneous administration,
whereas the suppression by BUD was generally lower after intratracheal than after subcutaneous administration.
The pharmacodynamics of inhaled GCs are determined by a variety of pharmacokinetic parameters (1, 21). In a theoretical model, a slow pulmonary absorption rate was shown to be the most important pharmacokinetic characteristic for optimal pulmonary targeting (22). The residence time in airway and lung tissue after inhalation determines the duration of GC availability and hence the duration of topical GC activity. We have recently shown that although the initial airway-lung concentrations of BUD and FP are equally high after topical administration, BUD is retained for a longer time than FP in the rat large airway tissue (9). This difference is probably related to the intracellular formation of very lipophilic BUD fatty acid esters at carbon-21 (9, 10) whereas no such esters are formed by FP. It has been confirmed both in vitro and in vivo that reversible BUD esterification occurs also in human bronchial and lung tissue (10, 23, 24).
In contrast to our previous study in rat (9), no studies have been performed in humans comparing BUD and FP tissue concentrations directly measured in the lower airways and lung. Nevertheless, the results of separate studies where BUD or FP was investigated gave similar tissue concentrations for BUD as for FP (24). The BUD concentration in the peripheral lung was 8 pmol per gram tissue (4 pmol/g for BUD and 4 pmol/g BUD ester) at 4 h after inhalation via Turbuhaler (AstraZeneca R&D Lund, Lund, Sweden) (24) and on average 5.5 pmol/g at 1.5 to 4 h after inhalation of 1.6 mg via Nebuhaler (AstraZeneca R&D Lund) (25; in this study, esters were not measured). In the former study, concentrations of up to 36 pmol/g (19 pmol/g of BUD and 17 pmol/g of BUD ester) were found in central lung tissue. Similarly, concentrations of FP up to approximately 10 pmol/g in peripheral lung and 20 to 40 pmol/g in central parts of the lung were achieved at 3 to 4 h after inhalation of 1 mg FP via Volumatic (Glaxo Wellcome, Greenford, UK) (26). However, as mentioned by these investigators, the highest FP concentrations were obtained in two of three patients having viscous mucus in the airways and in the patient who had the lowest FEV1. Thus, the FP tissue concentration in central parts of the lungs may have been overestimated, because mucus plugs may have trapped undissolved FP crystals and hindered mucociliary clearance (26).
The pulmonary residence times of various inhaled steroids have been estimated indirectly from their plasma profiles, i.e., mean absorption time (MAT) and time of maximal plasma concentration (tmax). MAT and tmax calculated for BUD and FP indicated a faster absorpion and thus shorter residence time in the lungs for BUD than for FP (27). However, although MAT and tmax provide an estimate of overall rate of absorption (including rate of dissolution, mucosal uptake, and release into the systemic circulation from the lung and the gastrointestinal tract), and may provide a satisfactory estimate of pulmonary residence time (after correction for the orally absorbed portion swallowed after inhalation), they do not provide a specific estimate of residence time in the airways, and particularly not in the large airways. The greater vascularization, larger absorption surface, and lack of mucociliary transporter will make the alveoli and peripheral airways primary sites of systemic absorption of the drug deposited in the lungs. In the airways with functioning mucociliary clearance, undissolved particles will be partly cleared and eventually swallowed, because the half-life of crystal dissolution of very lipophilic GCs [e.g., more than 5 h for beclomethasone dipropionate, (20)] is comparable with the half-life of mucociliary clearance (4 h, cited from reference 22). Thus, as the rate of absorption may not specifically mirror the tissue residence time of GCs in the large airways, further studies are required where steroid concentrations are measured directly within the airway tissue at various times after inhalation. Recently, one such study was performed in the human nose, where it was shown that BUD and its esters were retained in the nasal mucosa in vivo to a greater extent and for a longer time than FP (28). Dose-corrected tissue levels of intact BUD in nasal mucosa were 3.5 and 13.7 times higher than of FP at 2 and 6 h, respectively, after administration of a single dose of BUD (Rhinocort Aqua [AstraZeneca R&D Lund] 256 µg) or FP (Flutide Nasal [GlaxoWellcome] 20 µg). The ratios between concentrations of total BUD (BUD + BUD ester) and FP were even higher, 5.6 and 20.1 at 2 and 6 h, respectively.
From the results of our previous animal study (9) extrapolated to inhalation by humans, as well as from the human studies cited previously (24), the conclusion can be drawn that
shortly after inhalation of clinically relevant GC doses (0.2 to 2 mg), a local GC concentration of approximately 10
8 to 107 M
is achieved in the airway tissue, and a concentration approximately 2 to 4 times lower in lung parenchyma. The receptor affinity constant (Kd) determined in vitro for GCs of the inhaled
type is reported to be of the order of 109 M (18). Thus,
shortly after inhalation, the local GC concentration in airway
and lung tissue exceeds by at least several-fold the level required for 50% receptor saturation. This implies that minor differences in receptor affinity between inhaled GCs are probably
of no initial functional significance, whereas the dwell-time of a
GC in the airway and lung tissue may be much more important for the duration of topical antiasthmatic efficacy. This is supported by the results of the present study, where BUD and FP
were equally efficacious when administered shortly before airway challenge, but only BUD, with its longer dwell time in large
airway tissue (9), retained its activity during the late inflammatory response, when administered 6 h before challenge.
BUD fatty acid esters are inactive (11), however they are gradually hydrolyzed by intracellular lipases and free BUD is released as shown in the rat trachea ex vivo (9). It is known that reversible fatty acid esterification serves as a reservoir for some endogenous steroids such as cholesterol and estrogens (29). Similarly, esterified BUD provides a local depot of latent, gradually regenerable, active BUD. It is logical that the gradual release of active BUD from its ester depot would prolong receptor saturation and thereby also anti-inflammatory activity. A prolonged retention and activity of BUD compared with FP was also shown after pulse treatment of the transfected Rat 1 cell line (rat fibroblasts), in which the same reversible esterification of BUD occurs (11). Moreover, in that cell system, it was recently demonstrated that partial blocking (80%) of BUD esterification by the inhibitor of acyl-CoA:cholesterol acyl transferase (ACAT), cyclandelate, shortened the duration of GC activity mediated by a 30-min pulse treatment with BUD (30). This provides direct evidence that the prolonged activity of BUD is a result of the formation of lipophilic esters.
Airway Selectivity
The extent of formation of BUD fatty acid esters in airway and
lung tissue seems to depend on BUD availability (9). In another
study (31), we have shown that 20 min after intratracheal administration of radioactive BUD, the fraction of esterified BUD
in trachea and lung was 
70%, with the ester preponderance persisting over 6 h, whereas after systemic (intramuscular) administration, when the radioactivity in lung and trachea was approximately 1 to 2 orders of magnitude lower, the fraction of esterified BUD was only 30 to 40%. Thus, the highest proportion
and concentration of BUD esters are achieved at the application site in the large airways, where deposition of the inhaled
substance is greater per surface area and the absorption rate is
probably slower than in the peripheral lung.
The capacity to synthesize and maintain the high concentrations of BUD esters is different in different tissues. In our previous study (9), BUD esters were not detectable in the plasma after acute topical intratracheal application of radioactive BUD. Because a large proportion of the systemic compartment is made up of striated muscles, we have investigated the balance between the intact and esterified BUD in that tissue (31). Even after local intramuscular injection around the soleus muscle, the maximum proportion of BUD esters in that muscle was only approximately 10%, as compared with more than 70% in airway and lung tissue after intratracheal instillation (31). Thus, the formation of a large airway-lung depot of esterified BUD depends on the combination of high local levels of BUD and high capacity of that tissue to synthesize BUD esters. In this way, BUD combines the very high lipophilicity of reversible BUD esters, formed preferentially at the application site in the airways and lung, with the moderate lipophilicity of the circulating, mainly intact BUD molecule. This contributes to the rather short terminal plasma half-life of BUD (32) and thus to a low total body burden. This mechanism may contribute to the high therapeutic ratio of BUD, and explain why in this rat study the extended anti-inflammatory activity of BUD at the large airway level was not coupled to potentiated corticosterone suppression, and why BUD exerted better topical selectivity for the large airways than FP.
Recently, in the theoretical pharmacokinetic-pharmacodynamic model, based on human experimental data (33), it has been shown that incorporation of a local ester depot of BUD may lead to both a prolonged duration of action and an increased airway-lung selectivity (especially on a once-daily inhalation regimen) compared with a model excluding an ester pool. This is in line with clinical knowledge that in mild-moderate asthma, BUD given once a day is as effective as the same total dose of BUD (3) or FP (8) given twice daily. BUD is currently the only inhaled GC approved for once-daily treatment of mild to moderate asthma.
Conclusions
In this animal model, topical BUD exerted a prolonged anti-inflammatory activity compared with FP. This was probably because of the prolonged retention of BUD in large airway tissue due to reversible intracellular fatty acid esterification. The prolonged anti-inflammatory activity was not coupled to raised systemic activity, indicating the high airway selectivity of topically applied BUD. As the same reversible BUD esterification occurs in human airway and nasal mucosa, this mechanism probably contributes to the high efficacy and high therapeutic ratio of BUD when administered as a once-daily inhalation in asthma and rhinitis.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Anna Miller-Larsson, AstraZeneca R&D Lund, Lund S-221 87, Sweden. E-mail: anna.miller-larsson{at}astrazeneca.com
(Received in original form June 19, 1998 and in revised form April 17, 2000).
Acknowledgments: The authors thank the personnel of the Animal Department of AstraDraco AB for performing the adrenalectomies and for excellent technical assistance during animal experiments. We are also grateful to Kevin Cheeseman, Staffan Edsbäcker, and Elisabet Wieslander for valuable comments on the manuscript.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Wieslander, E.,
E.-L. Delander,
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