Albuterol
DESCRIPTION:
The active component of VENTOLIN Inhalation Aerosol is albuterol, USP, racemic
((alpha)1-((TERT-butylamino)methyl)-4-hydroxy-M- xylene-(alpha),(alpha)'-diol)
and a relatively selective beta2-adrenergic bronchodilator.
Albuterol is the official generic name in the United States. The World Health
Organization recommended name for the drug is salbutamol. The molecular weight
of albuterol is 239.3, and the empirical formula is C13H21NO3. Albuterol is a
white to off-white crystalline solid. It is soluble in ethanol, sparingly
soluble in water, and very soluble in chloroform.
VENTOLIN Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral
inhalation. It contains a microcrystalline (95%(=)10 Mu-m) suspension of
albuterol in propellants (trichloromonofluoromethane and
dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg of
albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each 6.8-g
canister provides 80 inhalations and each 17-g canister provides 200
inhalations.
ACTIONS/CLINICAL PHARMACOLOGY:
In vitro studies and in vivo pharmacologic studies have demonstrated that
albuterol has a preferential effect on beta2-adrenergic receptors compared with
isoproterenol. While it is recognized that beta2-adrenergic receptors are the
predominant receptors in bronchial smooth muscle, data indicate that there is a
population of beta2-receptors in the human heart existing in a concentration
between 10% and 50%. The precise function of these receptors has not been
established.
The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol,
are at least in part attributable to stimulation through beta- adrenergic
receptors of intracellular adenyl cyclase, the enzyme that catalyzes the
conversion of adenosine triphosphate (ATP) to cyclic- 3',5'-adenosine
monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with
relaxation of bronchial smooth muscle and inhibition of release of mediators of
immediate hypersensitivity from cells, especially from mast cells.
Albuterol has been shown in most controlled clinical trials to have more effect
on the respiratory tract, in the form of bronchial smooth muscle relaxation,
than isoproterenol at comparable doses while producing fewer cardiovascular
effects. Controlled clinical studies and other clinical experience have shown
that inhaled albuterol, like other beta- adrenergic agonist drugs, can produce a
significant cardiovascular effect in some patients, as measured by pulse rate,
blood pressure, symptoms, and/or electrocardiographic changes.
Albuterol is longer acting than isoproterenol in most patients by any route of
administration because it is not a substrate for the cellular uptake processes
for catecholamines nor for catechol-O-methyl transferase.
The effects of rising doses of albuterol and isoproterenol aerosols were studied
in volunteers and asthmatic patients. Results in normal volunteers indicated
that albuterol is one half to one quarter as active as isoproterenol in
producing increases in heart rate. In asthmatic patients similar cardiovascular
differentiation between the two drugs was also seen.
PRECLINICAL:
Intravenous studies in rats with albuterol sulfate have demonstrated that
albuterol crosses the blood-brain barrier and reaches brain concentrations
amounting to approximately 5.0% of the plasma concentrations. In structures
outside the brain barrier (pineal and pituitary glands), albuterol
concentrations were found to be 100 times those in the whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated
the occurrence of cardiac arrhythmias and sudden death (with histologic evidence
of myocardial necrosis) when beta-agonists and methylxanthines are administered
concurrently. The clinical significance of these findings is unknown.
PHARMACOKINETICS:
Because of its gradual absorption from the bronchi, systemic levels of albuterol
are low after inhalation of recommended doses. Studies undertaken with four
subjects administered tritiated albuterol resulted in maximum plasma
concentrations occurring within 2 to 4 hours. Due to the sensitivity of the
assay method, the metabolic rate and half-life of elimination of albuterol in
plasma could not be determined. However, urinary excretion provided data
indicating that albuterol has an elimination half-life of 3.8 hours.
Approximately 72% of the inhaled dose is excreted within 24 hours in the urine,
and consists of 28% as unchanged drug and 44% as metabolite.
CLINICAL TRIALS:
In controlled clinical trials involving adults with asthma, the onset of
improvement in pulmonary function was within 15 minutes, as determined by both
MMEF (maximum midexpiratory flow rate) and FEV1 (forced expiratory volume in 1
second). MMEF measurements also showed that near maximum improvement in
pulmonary function generally occurs within 60 to 90 minutes following two
inhalations of albuterol and that clinically significant improvement generally
continues for 3 to 4 hours in most patients. Some patients showed a therapeutic
response (defined by maintaining FEV1 values 15% or more above baseline) that
was still apparent at 6 hours. Continued effectiveness of albuterol was
demonstrated over a 13-week period in these same trials.
In controlled clinical trials involving children 4 to 12 years of age, FEV1
measurements showed that maximum improvement in pulmonary function occurs within
30 to 60 minutes. The onset of clinically significant ((>/=)15%) improvement in
FEV1 was observed as soon as 5 minutes following 180 mcg of albuterol in 18 of
30 (60%) children in a controlled dose-ranging study. Clinically significant
improvement in FEV1 continued in the majority of patients for 2 hours and in 33%
to 47% for 4 hours among 56 patients receiving inhalation aerosol in one
pediatric study. In a second study among 48 patients receiving inhalation
aerosol, clinically significant improvement continued in the majority for up to
1 hour and in 23% to 40% for 4 hours. In addition, at least 50% of the patients
in both studies achieved an improvement in FEF25%-75% (forced expiratory flow
rate between 25% and 75% of the forced vital capacity) of at least 20% for 2 to
5 hours. Continued effectiveness of albuterol was demonstrated over the 12-week
study period.
In other clinical studies in adults and children, two inhalations of VENTOLIN
Inhalation Aerosol taken approximately 15 minutes before exercise prevented
exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within
80% of baseline values in the majority of patients. One study in adults also
evaluated the duration of the prophylactic effect to repeated exercise
challenges, which was evident at 4 hours in the majority of patients and at 6
hours in approximately one third of the patients.
INDICATIONS AND USAGE:
VENTOLIN Inhalation Aerosol is indicated for the prevention and relief of
bronchospasm in patients 4 years of age and older with reversible obstructive
airway disease and for the prevention of exercise-induced bronchospasm in
patients 4 years of age and older.
VENTOLIN Inhalation Aerosol can be used with or without concomitant steroid
therapy.
CONTRAINDICATIONS:
VENTOLIN Inhalation Aerosol is contraindicated in patients with a history of
hypersensitivity to albuterol or any of its components.
WARNINGS:
PARADOXICAL BRONCHOSPASM: VENTOLIN Inhalation Aerosol can produce paradoxical
bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs,
VENTOLIN Inhalation Aerosol should be discontinued immediately and alternative
therapy instituted. It should be recognized that paradoxical bronchospasm, when
associated with inhaled formulations, frequently occurs with the first use of a
new canister or vial.
CARDIOVASCULAR EFFECTS: VENTOLIN Inhalation Aerosol, like all other beta-
adrenergic agonists, can produce a clinically significant cardiovascular effect
in some patients as measured by pulse rate, blood pressure, and/or symptoms.
Although such effects are uncommon after administration of VENTOLIN Inhalation
Aerosol at recommended doses, if they occur, the drug may need to be
discontinued. In addition, beta-agonists have been reported to produce
electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation
of the QTc interval, and ST segment depression. The clinical significance of
these findings is unknown. Therefore, VENTOLIN Inhalation Aerosol, like all
sympathomimetic amines, should be used with caution in patients with
cardiovascular disorders, especially coronary insufficiency, cardiac
arrhythmias, and hypertension.
DETERIORATION OF ASTHMA: Asthma may deteriorate acutely over a period of hours
or chronically over several days or longer. If the patient needs more doses of
VENTOLIN Inhalation Aerosol than usual, this may be a marker of destabilization
of asthma and requires reevaluation of the patient and treatment regimen, giving
special consideration to the possible need for anti- inflammatory treatment,
e.g., corticosteroids.
USE OF ANTI-INFLAMMATORY AGENTS: The use of beta- adrenergic agonist
bronchodilators alone may not be adequate to control asthma in many patients.
Early consideration should be given to adding anti-inflammatory agents, e.g.,
corticosteroids.
IMMEDIATE HYPERSENSITIVITY REACTIONS: Immediate hypersensitivity reactions may
occur after administration of albuterol inhalation aerosol, as demonstrated by
rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and
oropharyngeal edema.
The contents of VENTOLIN Inhalation Aerosol are under pressure. Do not puncture.
Do not use or store near heat or open flame. Exposure to temperatures above 120
deg F may cause bursting. Never throw container into fire or incinerator. Keep
out of reach of children.
PRECAUTIONS:
GENERAL: Albuterol, as with all sympathomimetic amines, should be used with
caution in patients with cardiovascular disorders, especially coronary
insufficiency, cardiac arrhythmias, and hypertension; in patients with
convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who
are unusually responsive to sympathomimetic amines. Clinically significant
changes in systolic and diastolic blood pressure have been seen in individual
patients and could be expected to occur in some patients after use of any beta-
adrenergic bronchodilator.
Large doses of intravenous albuterol have been reported to aggravate preexisting
diabetes mellitus and ketoacidosis. As with other beta- agonists, albuterol may
produce significant hypokalemia in some patients, possibly through intracellular
shunting, which has the potential to produce adverse cardiovascular effects. The
decrease is usually transient, not requiring supplementation.
Although there have been no reports concerning the use of VENTOLIN Inhalation
Aerosol during labor and delivery, it has been reported that high doses of
albuterol administered intravenously inhibit uterine contractions. Although this
effect is extremely unlikely as a consequence of aerosol use, it should be kept
in mind.
INFORMATION FOR PATIENTS: The action of VENTOLIN Inhalation Aerosol may last up
to 6 hours or longer. VENTOLIN Inhalation Aerosol should not be used more
frequently than recommended. Do not increase the dose or frequency of VENTOLIN
Inhalation Aerosol without consulting your physician. If you find that treatment
with VENTOLIN Inhalation Aerosol becomes less effective for symptomatic relief,
your symptoms become worse, and/or you need to use the product more frequently
than usual, you should seek medical attention immediately. While you are using
VENTOLIN Inhalation Aerosol, other inhaled drugs and asthma medications should
be taken only as directed by your physician. Common adverse effects include
palpitations, chest pain, rapid heart rate, and tremor or nervousness. If you
are pregnant or nursing, contact your physician about use of VENTOLIN Inhalation
Aerosol. Effective and safe use of VENTOLIN Inhalation Aerosol includes an
understanding of the way that it should be administered.
In general, the technique for administering VENTOLIN Inhalation Aerosol to
children is similar to that for adults, since children's smaller ventilatory
exchange capacity automatically provides proportionally smaller aerosol intake.
Children should use VENTOLIN Inhalation Aerosol under adult supervision, as
instructed by the patient's physician.
See illustrated Patient's Instructions for Use section of the full prescribing
information.
DRUG INTERACTIONS: Other short-acting sympathomimetic aerosol bronchodilators
should not be used concomitantly with albuterol. If additional adrenergic drugs
are to be administered by any route, they should be used with caution to avoid
deleterious cardiovascular effects.
MONOAMINE OXIDASE INHIBITORS OR TRICYCLIC ANTIDEPRESSANTS: Albuterol should be
administered with extreme caution to patients being treated with monoamine
oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of
discontinuation of such agents, because the action of albuterol on the vascular
system may be potentiated.
BETA-BLOCKERS: Beta-adrenergic receptor blocking agents not only block the
pulmonary effect of beta-agonists, such as VENTOLIN Inhalation Aerosol, but may
produce severe bronchospasm in asthmatic patients. Therefore, patients with
asthma should not normally be treated with beta- blockers. However, under
certain circumstances, e.g., as prophylaxis after myocardial infarction, there
may be no acceptable alternatives to the use of beta-adrenergic blocking agents
in patients with asthma. In this setting, cardioselective beta-blockers should
be considered, although they should be administered with caution.
DIURETICS: The ECG changes and/or hypokalemia that may result from the
administration of nonpotassium-sparing diuretics (such as loop or thiazide
diuretics) can be acutely worsened by beta-agonists, especially when the
recommended dose of the beta-agonist is exceeded. Although the clinical
significance of these effects is not known, caution is advised in the
coadministration of beta-agonists with nonpotassium-sparing diuretics.
DIGOXIN: Mean decreases of 16% to 22% in serum digoxin levels were demonstrated
after single- dose intravenous and oral administration of albuterol,
respectively, to normal volunteers who had received digoxin for 10 days. The
clinical significance of these findings for patients with obstructive airway
disease who are receiving albuterol and digoxin on a chronic basis is unclear.
Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels
in patients who are currently receiving digoxin and albuterol.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: In a 2-year study in
Sprague-Dawley rats, albuterol sulfate caused a significant dose-related
increase in the incidence of benign leiomyomas of the mesovarium at dietary
doses of 2.0, 10, and 50 mg/kg (approximately 15, 70, and 340 times,
respectively, the maximum recommended daily inhalation dose for adults on a
mg/m(squared) basis, or, approximately 6, 30, and 160 times, respectively, the
maximum recommended daily inhalation dose for children on a mg/m(squared)basis).
In another study this effect was blocked by the coadministration of propranolol,
a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice,
albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to
500 mg/kg (approximately 1700 times the maximum recommended daily inhalation
dose for adults on a mg/m(squared) basis, or, approximately 800 times the
maximum recommended daily inhalation dose for children on a mg/m(squared)basis).
In a 22-month study in the Golden hamster, albuterol sulfate showed no evidence
of tumorigenicity at dietary doses up to 50 mg/kg (approximately 225 times the
maximum recommended daily inhalation dose for adults on a mg/m(squared)basis,
or, approximately 110 times the maximum recommended daily inhalation dose for
children on a mg/m(squared)basis).
Albuterol sulfate was not mutagenic in the Ames test with or without metabolic
activation using tester strains S. TYPHIMURIUM TA1537, TA1538, and TA98 or E.
COLI WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S.
CEREVISIAE S9 nor any mitotic gene conversion in yeast strain S. CEREVISIAE JD1
with or without metabolic activation. Fluctuation assays in S. TYPHIMURIUM TA98
and E. COLI WP2, both with metabolic activation, were negative. Albuterol
sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1
strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg.
Reproduction studies in rats demonstrated no evidence of impaired fertility at
oral doses up to 50 mg/kg (approximately 340 times the maximum recommended daily
inhalation dose for adults on amg/m(squared) basis).
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category C. Albuterol sulfate has been
shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses
of 0.025, 0.25, and 2.5 mg/kg (approximately 2/25, 1.0, and 8.0 times,
respectively, the maximum recommended daily inhalation dose for adults on a
mg/m(squared) basis), showed cleft palate formation in 5 of 111 (4.5%) fetuses
at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5mg/kg. The drug did not
induce cleft palate formation at the lowest dose, 0.025 mg/kg. Cleft palate also
occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of
isoproterenol (positive control) sc (approximately 8 times the maximum
recommended daily inhalation dose for adults on a mg/m(squared) basis).
A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19
fetuses (37%) fetuses when albuterol sulfate was administered orally at a 50
mg/kg dose (approximately 680 times the maximum recommended daily inhalation
dose for adults on a mg/m(squared) basis).
There are no adequate and well-controlled studies in pregnant women. Albuterol
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
During worldwide marketing experience, various congenital anomalies, including
cleft palate and limb defects, have been rarely reported in the offspring of
patients being treated with albuterol. Some of the mothers were taking multiple
medications during their pregnancies. No consistent pattern of defects can be
discerned, and a relationship between albuterol use and congenital anomalies has
not been established.
USE IN LABOR AND DELIVERY: Because of the potential for beta-agonist
interference with uterine contractility, use of VENTOLIN Inhalation Aerosol for
relief of bronchospasm during labor should be restricted to those patients in
whom the benefits clearly outweigh the risk.
TOCOLYSIS: Albuterol has not been approved for the management of preterm labor.
The benefit:risk ratio when albuterol is administered for tocolysis has not been
established. Serious adverse reactions, including maternal pulmonary edema, have
been reported during or following treatment of premature labor with beta2-
agonists, including albuterol.
NURSING MOTHERS: It is not known whether this drug is excreted in human milk.
Because of the potential for tumorigenicity shown for albuterol in some animal
studies, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
PEDIATRIC USE: Safety and effectiveness in children below 4 years of age have
not been established.
DRUG INTERACTIONS:
Other short-acting sympathomimetic aerosol bronchodilators should not be used
concomitantly with albuterol. If additional adrenergic drugs are to be
administered by any route, they should be used with caution to avoid deleterious
cardiovascular effects.
MONOAMINE OXIDASE INHIBITORS OR TRICYCLIC ANTIDEPRESSANTS: Albuterol should be
administered with extreme caution to patients being treated with monoamine
oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of
discontinuation of such agents, because the action of albuterol on the vascular
system may be potentiated.
BETA-BLOCKERS: Beta-adrenergic receptor blocking agents not only block the
pulmonary effect of beta-agonists, such as VENTOLIN Inhalation Aerosol, but may
produce severe bronchospasm in asthmatic patients. Therefore, patients with
asthma should not normally be treated with beta- blockers. However, under
certain circumstances, e.g., as prophylaxis after myocardial infarction, there
may be no acceptable alternatives to the use of beta-adrenergic blocking agents
in patients with asthma. In this setting, cardioselective beta-blockers should
be considered, although they should be administered with caution.
DIURETICS: The ECG changes and/or hypokalemia that may result from the
administration of nonpotassium-sparing diuretics (such as loop or thiazide
diuretics) can be acutely worsened by beta-agonists, especially when the
recommended dose of the beta-agonist is exceeded. Although the clinical
significance of these effects is not known, caution is advised in the
coadministration of beta-agonists with nonpotassium-sparing diuretics.
DIGOXIN: Mean decreases of 16% to 22% in serum digoxin levels were demonstrated
after single- dose intravenous and oral administration of albuterol,
respectively, to normal volunteers who had received digoxin for 10 days. The
clinical significance of these findings for patients with obstructive airway
disease who are receiving albuterol and digoxin on a chronic basis is unclear.
Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels
in patients who are currently receiving digoxin and albuterol.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The adverse reactions to albuterol are similar in nature to reactions to other
sympathomimetic agents, although the incidence of certain cardiovascular effects
is lower with albuterol.
PERCENT INCIDENCE OF ADVERSE REACTIONS IN PATIENTS
(>/=)12 YEARS OF AGE IN A 13-WEEK CLINICAL TRIAL*
Percent Incidence
Reaction Albuterol Isoproterenol
Tremor <15% <15%
Nausea <15% <15%
Tachycardia 10% 10%
Palpitations <10% <15%
Nervousness <10% <15%
Increased blood
pressure <5% <5%
Dizziness <5% <5%
Heartburn <5% <5%
* A 13-week double-blind study compared albuterol and isoproterenol inhalation
aerosols in 147 asthmatic patients.
PERCENT INCIDENCE OF ADVERSE REACTIONS
IN CHILDREN 4 TO 11 YEARS OF AGE IN A 12-WEEK TRIAL*
Reaction Percent Incidence
Central nervous system
Headache 3%
Nervousness 1%
Lightheadedness <1%
Tremor <1%
Agitation 1%
Nightmares 1%
Hyperactivity 1%
Aggressive behavior 1%
Gastrointestinal
Nausea and/or vomiting 6%
Stomachache 3%
Diarrhea 1%
Oropharyngeal
Throat irritation 6%
Discoloration of teeth 1%
Respiratory
Epistaxis 3%
Cough 2%
Musculoskeletal
Muscle cramp 1%
* A 12-week double-blind trial in 104 patients aged 4 to 11 years.
Rare cases of urticaria, angioedema, rash, bronchospasm, hoarseness, and
oropharyngeal edema have been reported after the use of inhaled albuterol.
In addition, albuterol, like other sympathomimetic agents, can cause adverse
reactions such as hypertension, angina, vertigo, central nervous system
stimulation, sleeplessness, and unusual taste.
OVERDOSAGE:
The expected symptoms with overdosage are those of excessive beta-adrenergic
stimulation and/or occurrence or exaggeration of any of the symptoms listed
under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension,
tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache,
tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and
sleeplessness. Hypokalemia may also occur.
As with all sympathomimetic aerosol medications, cardiac arrest and even death
may be associated with abuse of VENTOLIN Inhalation Aerosol. Treatment consists
of discontinuation of VENTOLIN Inhalation Aerosol together with appropriate
symptomatic therapy. The judicious use of a cardioselective beta-receptor
blocker may be considered, bearing in mind that such medication can produce
bronchospasm. There is insufficient evidence to determine if dialysis is
beneficial for overdosage of VENTOLIN Inhalation Aerosol.
The oral median lethal dose of albuterol sulfate in mice is greater than 2000
mg/kg (approximately 6800 times the maximum recommended daily inhalation dose
for adults on a mg/m(squared) basis, or, approximately 3200 times the maximum
recommended daily inhalation dose for children on a mg/m(squared) basis). In
mature rats, the sc median lethal dose of albuterol sulfate is approximately 450
mg/kg (approximately 3000 times the maximum recommended daily inhalation dose
for adults on a mg/m(squared) basis, or, approximately 1400 times the maximum
recommended daily inhalation dose for children on a mg/m(squared) basis). In
small young rats, the sc median lethal dose is approximately 2000 mg/kg
(approximately 14,000 times the maximum recommended daily inhalation dose for
adults on amg/m(squared) basis, or, approximately 6400 times the maximum
recommended daily inhalation dose for children on a mg/m(squared) basis). The
inhalation median lethal dose has not been determined in animals.
DOSAGE AND ADMINISTRATION:
For treatment of acute episodes of bronchospasm or prevention of asthmatic
symptoms, the usual dosage for adults and children 4 years of age and older is
two inhalations repeated every 4 to 6 hours; in some patients, one inhalation
every 4 hours may be sufficient. More frequent administration or a larger number
of inhalations are not recommended. It is recommended to "test spray" VENTOLIN
Inhalation Aerosol into the air before using for the first time and in cases
where the aerosol has not been used for a prolonged period of time.
The use of VENTOLIN Inhalation Aerosol can be continued as medically indicated
to control recurring bouts of bronchospasm. During this time most patients gain
optimal benefit from regular use of the inhaler. Safe usage for periods
extending over several years has been documented.
If a previously effective dosage regimen fails to provide the usual response,
this may be a marker of destabilization of asthma and requires reevaluation of
the patient and the treatment regimen, giving special consideration to the
possible need for anti-inflammatory treatment, e.g., corticosteroids.
EXERCISE-INDUCED BRONCHOSPASM PREVENTION:
The usual dosage for adults and children 4 years and older is two inhalations 15
minutes before exercise.
For treatment, see above.
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