Review of the Unique Properties of

Edward J. O’Connell, MD
Department of Pediatrics, AlleugylImmunology Mayo Clinic, Rochestel;Minnesota

ABSTRACT

Background: The aim of inhaled corticosteroid (ICS) therapy for asthma is to

attain high therapeutic activity in the airways while keeping the risk of systemic
adverse effects relatively low. However, the physicochemical and pharmacokinetic
properties of various ICSs affect this ratio, thereby influencing their ability to ful-
fill the requirements of an ideal agent.
Objective: This article reviews the physical and pharmacokinetic properties of
budesonide, outlining how they, safety data, and use of different inhalation de-
vices enable budesonide to meet many of the clinical requirements of an ideal ICS
for the treatment of asthma.
Results: ICS efficacy is influenced by lipophilicity lung deposition, and reten-
tion in airway tissue, whereas the rate of elimination determines systemic activ-
ity Budesonide is retained in the airways to a greater extent than other ICSs
because of an esterification process that increases its lipophilicity The prolonged
retention of budesonide in the airways may contribute to its efficacy when ad-
ministered QD. In addition to a pressurized metered-dose inhaler, budesonide is
available as a dry-powder inhaler and in nebulized form, which can be used by
asthma patients aged 26 months.
Conclusions: When combined with delivery devices suitable for a spectrum of
patient groups, the physical and pharmacokinetic properties of budesonide lend
it many of the characteristics of an ideal ICS, including favorable efficacy and tol-
erability profiles. (Clin Thev: 2003;25[Suppl C]:C42-C60) Copyright 0 2003 Ex-
cerpta Medica, Inc.
Key words: budesonide, airway selectivity, efficacy, safety

Acceptedjor publication July 3, 2003.

Printed in the USA. Reproduction in whole or part is not permitted. 0149.2918103/$19.00

C42 CopyrIght@ 2003 Excerpta Mednlnc.

 E.J. O’Connell

INTRODUCTION
Asthma is a chronic inflammatory disorder of the airways, affecting -5% of adults
and -10% of children wor1dwide.l It remains a serious global health problem
despite the introduction of effective new treatments. Since the discovery of the
extensive inflammatory basis of the disease, inhaled corticosteroids (ICSs) have
played a central role in the management of asthma. It is now widely accepted that
they are effective in controlling inflammation and improving lung function and
asthma symptoms. As a result, ICSs are recommended as first-line therapy for all
patients with persistent asthma.2-5
Over the past decade, our understanding of the molecular mechanisms involved
in the control of inflammation has improved considerably Glucocorticosteroids
mediate their effects through cytoplasmic glucocorticoid (GC) receptors that are
present on most cells, although to varying extents.6 After glucocorticosteroids bind
to the GC receptors, the glucocorticosteroid-GC receptor complex alters the tran-
scription of a wide range of inflammatory mediators, thereby reducing inflamma-
tion.7 Because GC receptors are present throughout the body, the aim of ICS ther-
apy is to achieve high local therapeutic activity in the airways while keeping the
risk of systemic adverse effects relatively low. The airway selectivity of ICSs is de-
termined by their physicochemical and pharmacokinetic properties, as well as by
the drug formulation and the delivery device.’ Desirable features of an ICS include
a high affinity and potency for GC receptors, and prolonged lung retention com-
bined with low oral bioavailability, rapid clearance, and systemic elimination.g In
addition, an ICS should be clinically effective at low doses, suitable for patients of
all ages and for all asthma severities when used with the appropriate delivery
device, and have a favorable safety profile (ie, a good therapeutic margin with
minimal systemic effects), particularly during long-term therapy
The successful use of beclomethasone, a first-generation ICS, was initially re-
ported in 1972.1° However, this ICS was not specifically developed for adminis-
tration by inhalation. ‘r The search for a corticosteroid with an improved ratio of
topical-to-systemic activity led to the development of budesonide. l2
The current article reviews the physical and pharmacokinetic properties of
budesonide, outlining how these factors, the available safety data, and the use of
different inhalation devices enable budesonide to meet many of the clinical re-
quirements of an ideal KS for the treatment of asthma.

INHERENT PROPERTIES OF ICSs

To optimize the topical-to-systemic ratio of ICSs, research has focused on their
structure-activity relationship. It was found that lipophilic substitution at the 16a
and 17a positions on the corticosteroid nucleus increases airway selectivity. l1 In
the case of budesonide, lipophilic acetal groups at the 16a and 1701 positions en-
hance glucocorticosteroid receptor binding, prolong airway retention, and increase

c43
CLINICAL THERAPEUTICS”

systemic metabolism. Some ICSs (ie, fluticasone propionate) contain halogen

groups i3,14; the absence of halogen atoms on the corticosteroid nucleus contributes
to the optimal topical-to-systemic activity ratio of budesonide (Figure 111).r5

Physical Properties
The physical properties of ICSs affect their airway selectivity Although it is im-
portant for an ICS to have a high receptor-binding affinity, topical efficacy is also
influenced by lipophilicity lung deposition, and retention in airway tissue.
Second-generation ICSs have a wide range of lipophilicities (Table I).16-21 High
lipophilicity is an advantageous property associated with a high receptor affinity,22
but it also reduces water solubility and increases the likelihood of mucociliary clear-
ance. Moreover, there is a strong correlation between lipophilicity and the volume of
distribution of an ICS2* Highly lipophilic compounds are readily partitioned into
peripheral tissue, resulting in a large volume of distribution and leading to excessive
systemic distribution and retention. Both fluticasone propionate2r and mometasone
furoate16 have larger volumes of distribution than budesonide (Table I).18J9
After inhalation, ICSs enter the circulation by direct absorption from the lungs
and by oropharyngeal deposition leading to the gastrointestinal tract. The oral
bioavailability of a second-generation ICS is low-6% to 11% for budesonide23
and 4% for both fluticasone propionate24 and mometasone furoate.16 Therefore,
the main systemic source of an ICS with a high first-pass metabolism in the liver
is absorption from the lungs. 25 Lung deposition of the ICS and its related systemic
effects depend on the formulation and the inhaler device. For corticosteroids with
low oral bioavailability an inhaler that deposits a high proportion of the drug in
the lungs may produce greater adverse systemic effects; however, in clinical prac-
tice, this risk of systemic effects can be reduced with lower doses.22 Budesonide is
retained in the lungs to a greater extent than with other ICSs due to a unique es-
terification process described in the next section. This process increases the airway
selectivity of budesonide.

CH,OH

I::-:
HO, O-. zH
. . 0’ ’ -C,H,

/ /
0

Figure I _ Structure of budesonide. Reproduced with permission of Marcel Dekker from

Brattsand and Axelsson.” In: Schleimer et al, eds. Inhaled Glucocorticoids in
Asthma: Mechanisms and Clinical Actions. I99735 l-379.

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Table I. Physical and pharmacokinetic properties of inhaled corticosteroids (ICSs). Potency measures are given relative to
budesonide.‘“2’

First-Pass Relative Relative

Inactivation, % Elimination Volume of Lipophilicity, Receptor Topical Blanching
KS Halogenated Delivered Dose Half-Life, h Distribution, L log I<’ Binding Affinity Potency

Budesonide No 89 2.3 180 3.7 I I

BDPIBMP No NA <2/NA NA 4.814.3 0.41 I. I 0.510.4

Fluticasone propionate Yes >99 14.4 859 4.5 2.3 I

Mometasone furoate Yes >99 4.5 332 NA NA NA

BDP = beciomethasone dipropionate; BMP = beclomethasone monopropionate (metaboli-te of BDP); NA = not available.
CLINICAL THERAPEUTIC?

Budesonide Pharmacokinetics
The pharmacokinetic properties of budesonide have been extensively investi-
gated and are well characterized. The rate of elimination of ICSs is important
in determining their systemic activity and is expressed as the elimination half-
life, derived from the systemic clearance and the volume of distribution.26 Bu-
desonide has a shorter terminal half-life20 than fluticasone propionate’r and
mometasone furoate16 (Table I). Thus, systemic accumulation of budesonide
is more easily avoided, which is of particular importance during long-term
treatment.

&sterification
As mentioned previously, budesonide is retained in airway tissue to a greater
extent than other ICSs. After entering a cell in the airways, inhaled budesonide
primarily binds to the GC receptor. Following dissociation of protein molecules
that hold the receptor in an inactive state, the GC-receptor complex translocates
to the nucleus7 This complex acts as a transcription factor for upregulating anti-
inflammatory mediators and downregulating proinflammatory mediators. In ad-
dition, the GC-receptor complex directly interacts with the transcription factors,
activator protein 1, and nuclear factor KB, blocking gene transcription at the level
of DNA binding and counteracting the effects of proinflammatory cytokines.6
This mechanism is believed to be extremely important in the anti-inflammatory
action of ICSS.~~
Excess (unbound) budesonide forms esters with long-chain fatty acids, pro-
ducing a depot of highly lipophilic inactive budesonide within the ce11.27 Intra-
cellular lipases then hydrolyze the ester conjugates, releasing the less lipophilic
free budesonide into the ce11.27a28These processes, respectively called esterifica-
tion and de-esterification, are reversible and concentration dependent, and have
been demonstrated in human lung tissue. 29,30 Furthermore, they are specific for
the airways27,31 and are probably unique to budesonide because they are depen-
dent on the ICS structure.32 Esterification increases the retention time of budes-
onide locally (Figure 2) and is associated with a greater prolongation of the anti-
inflammatory effect compared with that of fluticasone propionate.27%33 The slow,
continuous release of free budesonide into the airways supports its suitability for
QD administration. 27,33 The prolonged, selective airway retention and short
plasma half-life of budesonide, as well as its esterification and low uptake in sys-
temic tissues, increase its airway selectivity.

PHYSICAL AND PHARMACOKINETIC EFFECTS

ON CLINICAL EFFICACY OF BUDESONIDE
Logically, an ideal ICS must demonstrate a dose-response effect and should be
clinically effective at low doses, In large, placebo-controlled studies34,35 of treatment

C46
 E.J.O’Connell

20 2h 6h 24 h
min
Time After Instillation

Figure 2. Greater retention of budesonide (BUD) versus fluticasone propionate (FP) in

the trachea and main bronchi after intratracheal instillation of radiolabeled
drug in rats. Mean tissue radioactivity is expressed as picomoles of glucocortico-
steroid equivalents per gram of tissue related to I nmol of administered glu-
cocorticosteroid. Bars indicate 95% Cl. Tissue radioactivity at 24 hours as a
percentage of that at 20 min is indicated for each drug. Reprinted with per-
mission of the American Society for Pharmacology and Experimental Thera-
peutics from Miller-Larsson et al, 27 Drug Metab Dispos. I998;26:623-630.

administered via dry-powder inhaler (DPI),* the clinical efficacy of budesonide

demonstrated a dose-response effect at 100 to 400 pg BID in adult patients with
mild to moderate persistent asthma (Figure 3A) and at 100 to 800 pg BID in
adults with moderate to severe persistent disease. In a 12-week, double-blind,
randomized study in 473 adults with moderate to severe persistent asthma,35
budesonide administered via DPI (100, 200, 400, and 800 pg BID) improved
lung function at low doses. All doses of budesonide significantly improved
the mean change in morning peak expiratory flow compared with placebo
(P < 0.001). Budesonide via DPI has similarly demonstrated a dose-response
effect (100-400 pg BID) in children and adolescents aged 6 to 18 years with mod-
erate to severe persistent asthma (Figure 3B; statistical significance not provided).36

‘Trademark: Pulmicort Turbuhaler@ (AstraZeneca Pharmaceuticals LP, Wilmington, Delaware).

c47
CLINICALTHERAPEUTICS@

Budesonide
+ iOO&BID
+c 2OOpg BID
CI- 4OOpg BID
+- 800/.1gBlD
A 1- Placebo

-0.4 1 I I I I I 1
0 o-2 2-4 4-6 6-a B-10 IO-12

Weeks

I I I 1 I I
0 o-2 2-I 4-6 6-8 B-IO IO-12

Weeks

Figure 3. Dose-response effect of budesonide showing the change in peak expiratory

flow (PEF) from baseline (A) in adult patients with moderate persistent
asthma35 (all doses significantly improved mean change vs placebo [P < O.OOl])
and (B) in children and adolescent patients with moderate to severe asthma.36
Reprinted with permission of Elsevier from Busse et al,35jAllergy C/in Immunol.
1998; IO I :457-463, and Shapiro et al,36j Pediotr. 1998; I32:976-982.

C48
 E.J. O’Connell

QD Versus MD Administration of Budesonide

Budesonide provides effective asthma control in most patients with stable
asthma when administered BID.37 However, evidence suggests that compliance
with treatment improves as the dosing frequency decreases38; thus, QD adminis-
tration of asthma therapy may lead to improved control. The efficacy of QD ad-
ministration with budesonide via DPI has been investigated both in adults39-42
and children.43-45 The results of these studies suggest that QD budesonide effec-
tively controls mild to moderate persistent asthma. Nebulized QD budesonide is
also effective in infants46,47 and is approved in the United States for use in chil-
dren aged 212 months with mild or moderate persistent asthma.
The effectiveness of QD budesonide is thought to be linked to the esterification
process. 32 Therefore, a QD treatment that produces continuous anti-inflammatory
effects may have positive implications for increased patient compliance and bet-
ter treatment outcomes in asthma therapy

Quality of Life
In addition to its adverse effect on lung function, asthma has a marked impact
on the health-related quality of life (HRQL) of patients. The effect of budesonide
on patients’ HRQL has been investigated in several studies.42,48-50
The long-term effects of ICSs on HRQL were examined for the first time in the
Formoterol and Corticosteroids Establishing Therapy study.48 During the run-in
period, there were significant improvements in HRQL, as assessed by Asthma
Quality of Life Questionnaire (AQLQ) scores, in all patients who received budes-
onide via DPI 800 pg BID (P < 0.001).
The effect of maintenance treatment with budesonide via DPI was investigated
in 309 adult patients with mild to moderate stable asthma in a placebo-controlled
study 42 Patients were randomized to receive budesonide 200 or 400 pg once
daily for 6 weeks. The dose of budesonide was then reduced to 200 pg for an ad-
ditional 12 weeks in patients who had received the 400~pg dose, and was left un-
changed in those who had received the 200~pg dose. Statistically significant and
clinically relevant improvements in overall AQLQ score and in all domains were
observed with the budesonide treatment groups at 6 and 18 weeks compared
with the placebo group.49

DELIVERY OF BUDESONIDE TO THE AIRWAYS

Various inhalation devices are available to deliver corticosteroids to the lungs.
The principal systems are pressurized metered-dose inhalers (pMDIs), DPIs, and
nebulizers. Because pMDIs require coordination between actuation and inhalation,
they may be difficult for children to use correctly However, using a pMD1 in com-
bination with a spacer can eliminate the need for such coordination. DPIs or neb-
ulizers may be easier to manipulate in this patient group. In some DPIs, the pow-

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CLINICAL THERAPEUTICS@

der is contained in a compartment, small capsule, or disk. The pMDI and DPI
may be inappropriate for very young children because they need to hold their
breath for 10 seconds after inhalation. ICSs are recommended for the manage-
ment of persistent asthma in infants and young children3 However, some ICSs
cannot be used to treat young children and infants with asthma because suitable
delivery devices are not available.
Budesonide can be delivered via DPI, pMDI with spacer, or nebulizer as an
inhalation suspension,” and it can be used by asthma patients of all ages. Budes-
onide is the first ICS to be approved for administration with a nebulizer; this for-
mulation was developed in response to the specific delivery needs of infants and
young children. 51 As mentioned previously, budesonide is the only ICS approved
in the United States for use in children aged 212 months; it is also licensed for
use in children aged 18 years when administered as an inhalation suspension.
Nebulizers produce a water-based aerosol of the drug that is administered to the
patient via mouthpiece or face mask. Although budesonide is more water soluble
than some other ICSs, it is mainly in suspension in the aerosol rather than
in the solution. Because beclomethasone dipropionate and fluticasone propi-
onate are -100 times less soluble than budesonide, they are less suitable for
nebulization.47,52
In clinical trials,46,47a53-56b u d esonide inhalation suspension has been shown to
be an effective treatment in infants aged 26 months and in young children with
mild to severe persistent asthma. Furthermore, budesonide inhalation suspension
is effective in the treatment of children with acute asthma.56x57 In a study of chil-
dren aged 5 to 16 years randomized to treatment with budesonide inhalation sus-
pension or oral prednisolone, 58 change in forced expiratory volume in 1 second
from baseline after 24 hours was significantly improved only in the budesonide
group (P < O.Ol>, and the budesonide group had a greater improvement in
breathlessness compared with the oral prednisolone group (P < 0.05). In another
study, 57 children aged 2 to 12 years were treated with 3 doses of nebulized budes-
onide and salbutamol at 30-minute intervals or a single dose of oral prednisolone
followed by 3 doses of nebulized salbutamol. The budesonide/salbutamol group
had greater improvements in respiratory rate, pulmonary index, and respiratory
distress scores compared with the prednisolonekalbutamol group (all P < O.Ol>,
and significantly more patients in the budesonidekalbutamol group were fit for
discharge within 2 hours of treatment compared with the prednisolonekalbutamol
group (P < 0.001). Currently, the recommended course of action to resolve acute
exacerbations is to use rapid-acting inhaled beta,-agonists with the addition of
oral GCs if there is an inadequate response to beta,-agonists.59 Therefore, the use
of budesonide inhalation suspension may reduce the need for oral corticosteroid

“Trademark: Pulmcort Respules@ (AstraZeneca).

c50
 E.J. O’Connell

therapy in pediatric patients with acute asthma, but more evidence is required to
assess the use of ICSs in this setting.
As discussed previously, the formulation of the drug and the type of inhaler
device influence lung deposition and the therapeutic ratio of the ICS. A strong
correlation between clinical efficacy and lung deposition has been demon-
strated.(jO Lung deposition of budesonide is twice as high when administered via
DPI versus pMDI 20; this increase in lung deposition is associated with a 2-fold
increase in the bronchodilatory effect. 61 Moreover, there is less variability in
lung deposition within subjects (coefficient of variation, 32.9% vs 64.7%, re-
spectively) and between subjects (coefficient of variation, 28.4% vs 61.8%,
respectively) with DPI compared with a pMD1 in healthy volunteers62; similar
results have been found in patients with asthma (Table II).63 There is a good cor-
relation between in vitro fine-particle dose (aerodynamic diameter <5 pm) and in
vivo lung deposition. 20,64Budesonide via DPI produces a higher proportion of fine
particles than other devices,64 and may lead to more effective lung deposition.
Because the flow of inspired air is responsible for the generation and deliv-
ery of the aerosol with a DPI, any impairment of airflow may limit efficacy. Drug
delivery through DPIs is also affected by the intrinsic resistance of the inhaler.65
Budesonide via DPI has a relatively high intrinsic resistan.ce (1.00 cm H,O”’
min-l vs 0.03 cm H,01’2 min-l for typical inspiratory airway resistance); there-
fore, impaired airflow has little effect on inspiratory flow,65 Most patients-
even children aged 3 to 10 years or those with acute asthma-can generate
sufficient inspiratory flow for effective therapy (>30 Urnin) with the DPI.66-68

Table II. In vivo analysis of variability in budesonide lung deposition in healthy volunteers
and patients with asthma using dry-powder inhaler (DPI)* and a pressurized
metered-dose inhaler (pMDI). 62,63 Reprinted with permission of Elsevier from
Borgstrijm et al,63 lntj Pharm. 2000; I93:227-230.

Variability, CV%

Comparison DPI pMDl

Healthy volunteers
Within subjects 32.9 64.7
Between subjects 28.4 61.8
Patients
Within patients 39.3 39. I
Between patients 8.2 61.2

CV = coefficient of variation.
“Trademark Pulmicort Turbuhaler@ (AstraZeneca Pharmaceuticals LF: Wilmington, Delaware)

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CLINICAL THERAPEUTICS@

SAFETY PROFILE OF BUDESONIDE

More than 580 clinical trials involving >38,000 patients and healthy volunteers-
as well as >lO billion treatment days in clinical use-have confirmed that budes-
onide is well tolerated in patients of all ages with differing asthma severities (Pe-
riodic Safety Update Report, AstraZeneca Pharmaceuticals LP, Wilmington,
Delaware, October 2001).

Local Adverse Effects

Local adverse effects (eg, cough, hoarseness, sore throat) may be associated
with ICS treatment. Because they are dose dependent, maximizing drug delivery
to the lungs and minimizing oropharyngeal deposition with delivery devices such
as the DPI could reduce these effects. The incidence of local adverse effects is
lower when budesonide is administered via DPI rather than via pMD1: one study
reported incidences of 5.8% versus 17%, respectively.69,70 Notably, among 90 pa-
tients using the budesonide DPI as their first ICS device, no cases of oropharyn-
geal candidiasis or hoarseness were reported after >2 years of use.‘O

Systemic Adverse Effects

Safety evaluations have revealed no evidence that administration of budesonide
at the recommended doses is associated with any clinically relevant systemic ad-
verse effects.
Short-term studies using sensitive markers of hypothalamic-pituitary-adrenal
(HPA) axis function have been used to assess the systemic potency of IC.SJ.~~-~~
However, the clinical relevance of such investigations is limited75; long-term stud-
ies that measure plasma cortisol concentrations after adrenocorticotrophic hormone
stimulation are now used more frequently 76,77Treatment with budesonide for 1 year
did not produce deteriorations in HPA axis function in adults78 or children.79
Although short-term studies have indicated that ICS can cause a transient re-
duction of growth rate in children with asthma,80s81 a long-term (>9 years),
prospective studys2 found no evidence that budesonide therapy (mean daily dose,
412 p.g> in children with asthma affected the children’s expected final adult
height. These data were supported by results from the Childhood Asthma Man-
agement Program Research Group study published in 200083 and are unique for
budesonide-no long-term data are available for the final adult height of patients
using other ICSs.
Studies with ICSs have shown conflicting results concerning their effects on
bone metabolism and fracture rate. 84-s8 However, administration of budesonide
(mean daily dose, 504 pg) for 3 to 6 years had no adverse effect on bone min-
eral density in children with chronic asthma,84 and 2 years of treatment with
budesonide via DPI had no significant effects on bone mineral density compared
with noncorticosteroid treatment in adults (0.1% vs 0.4% increase in lumbar

c52
 E.J. O’Connell

spine, 0.9% vs 0.4% reduction in neck of the femur).85 Data from the European
Respiratory Society study on chronic obstructive pulmonary disease86 further
support the findings that long-term treatment with budesonide has no statistically
significant effect on fracture risk. Recent retrospective reviews of data from trials
of asthma therapy *‘,** have concluded that there is no evidence for an increased
risk of loss of bone mineral density with ICS treatment.
Increased intraocular pressure and cataract formation are recognized adverse ef-
fects of oral corticosteroids. An analysis of pooled data from 4 prospective stud-
ies89 found no statistically significant increase in intraocular pressure in asthmatic
patients aged 6 to 70 years who were treated with budesonide (200-1600 pg/d)
for up to 20 weeks. Retrospective case-control and epidemiologic studies90-g2 have
suggested a link between use of ICSs and an increased risk of cataracts, although
this effect may be confined to patients receiving high average daily doses (>l mg
for >2 years) and/or older adults. g2 Studies of long-term treatment with budesonide
have found no evidence of any association with an increased risk of cataract
formation in adults (mean age, 53 years)86 or children.93
Recent data from Sweden in mothers using budesonide during pregnancyg4,95
suggested that there was no increase in the rate of congenital malformations or
other clinically relevant effects associated with pregnancy outcomes. These data
contributed to the US Food and Drug Administrations approval of budesonide as
the only KS with a category B pregnancy rating.96

CONCLUSIONS
When combined with delivery devices suitable for the spectrum of patient groups,
the physical and pharmacokinetic characteristics of budesonide lend it many of
the characteristics of an ideal ICS. These include favorable efficacy and tolerabil-
ity profiles and a high therapeutic index, which makes it acceptable for long-term
treatment; the availability of QD administration; effective treatment of asthma in
patients of all ages and asthma severities; and a positive impact on patients’ qual-
ity of life. Thus, based on current knowledge, it appears that budesonide has the
potential to be an ideal ICS.

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Address correspondence to: Edward J. O’Connell, MD, Department of

Pediatrics, Allergy/Immunology, Mayo Clinic, 200 First Street SW Rochester, MN
55905. E-mail: oconnell.edward@mayo.edu

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