Download Effect of Propranolol on Elevated Arterial Blood Pressure

Effect of Propranolol on Elevated Arterial
Blood Pressure
By DAVI W. RICHARDSON, M.D., JACK FREUND, M.D., ARTHUR S. GEAR, M.D.,
H.
PAGE MAUCK, JR., M.D.,
AND
LESTER W. PRESTON, B.S.
SUMMARY
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Nineteen patients with moderately severe arterial hypertension received propranolol
(120 mg daily), or chlorthalidone (100 mg daily), both medications together, and
placebos in a double-blind crossover trial. Each treatment was given for 5 weeks;
blood pressure was measured at weekly intervals. Propranolol alone reduced arterial
pressure by 9/8 mm Hg, a statistically insignificant change. Use of chlorthalidone
alone was accompanied by an average reduction in arterial blood pressure of 23/9
mm Hg. Both drugs together lowered blood pressure by 33/15 mm Hg. Heart
rate was lower in regimens including propranolol; body weight and serum potassium
and chloride concentration were lower and blood urea nitrogen and serum creatinine
were higher in regimens containing chlorthalidone. Propranolol, in the dose given, is a
less effective hypotensive drug than is chlorthalidone.
Additional Indexing Words:
Chlorthalidone
Hypertension
Potassium supplementation
Weight
PRONETHALOL, an effective beta-adrenergic blocking agent, was observed to reduce arterial blood pressure in hypertensive
patients being treated for angina pectoris.1
Subsequently Prichard and Gillam2 3 compared propranolol, another beta-adrenergic
blocking drug, 120 to 640 mg/day, with previously administered methyldopa in 12 hypertensive patients and reported lower blood
pressure during use of propranolol. Since in
previous clinical trials2-6 the hypotensive effect
of propranolol was not compared with that of
placebo, we have evaluated the hypotensive
efficacy of propranolol in comparison with
Beta-adrenergic blockade
Blood chemistry
Heart rate
tient knew which therapy was being administered. We have compared propranolol, 120
mg/day, placebo, chlorthalidone, 100 mg/
day, and the combination of propranolol and
chlorthalidone as hypotensive agents in 19
hypertensive patients. The order of administration of drugs was randomized and unknown
to patient or physician. Propranolol, 120 mg/
day, had only moderate hypotensive effect.
Methods
Twenty-two patients entered the study. One
refused to return after the first week, one died
2 weeks before completion of the fourth period,
and one was stopped before entering the fourth
period which would have included chlorthalidone
and potassium, a combination withdrawn by its
manufacturer because of toxicity. Thus 19 patients, 5 male and 14 female, completed the entire study. The patients' ages ranged from 35
to 69 years. T.C., a 44-year-old Negro man, had
chronic nephritis manifest by persistent proteinuria, microscopic hematuria, cylinduria, and azotemia without pyuria or bacteriuria. G.W., a
57-year-old Negro woman, had probable hyperparathyroidism, with intermittent hypercalcemia,
a renal stone, and recurrent duodenal ulcer. She
that of inert tablets and a standard diuretic
in trials in which neither physician nor paFrom Departments of Medicine and Biometry,
Medical College of Virginia, Richmond, Virginia.
Work was supported by grants from the Virginia
Heart Association and from Ayerst Laboratories and
Geigy Pharmaceuticals.
Presented at the Fortieth Scientific Sessions of the
American Heart Association, San Francisco, California, October 21, 1967.
534
Circulation, Volume XXXVII, April 1968
PROPRANOLOL AND ELEVATED BLOOD PRESSURE
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did not have azotemia or infected urine. In the
remainder, no cause for hypertension could be
demonstrated despite multiple urinalyses, determination of urinary catecholamine excretion, intravenous pyelography, radioactive renography,
multiple determinations of serum sodium, potassium, chloride and bicarbonate concentrations,
and complete historical and physical examination. None of the patients had hemorrhagic or exudative retinopathy, congestive heart failure,
edema, asthma, or gout. Six had chemical diabetes mellitus; none received insulin. Each patient had been followed in the hypertension clinic
for months, and each had previously received
antihypertensive drugs. Each had diastolic blood
pressure averaging 88 mm Hg or more during
five weekly visits while receiving placebo tablets, save for one patient whose blood pressure
averaged 143/80 mm Hg prior to randomization
and 150/85 during the randomization placebo
period. All patients carried on their usual work
without restriction of diet or exercise.
Each patient was seen at weekly intervals for
30 weeks. At each visit the patient was weighed
and arterial pressure was recorded by one of
two nurses who made all measurements through-
535
out the study. Patients lay for 10 minutes in a
quiet room, after which blood pressure was measured three times in the supine position and
three times in the standing position. Heart rate
was recorded with the patients supine. Pills remaining in the bottles issued the previous week
were counted in an attempt to ensure that medication was taken properly, and the patient was
reminded how to take the medications. At 3week intervals, blood was drawn for hemoglobin
concentration, white cell count, autoanalyzer estimation of urea nitrogen and of serum concentrations of creatinine, sodium, potassium, chloride, bicarbonate, bilirubin, alkaline phosphatase
and glutamic-oxalacetic transaminase. At the
first five weekly visits, each patient received
sufficient medicaments for him to take one dummy capsule of chlorthalidone twice daily and one
dummy tablet of propranolol three times daily
in the ensuing week. Thereafter, each received
treatment for 5 weeks with each of the four
possible combinations: (1) both medications
dummy; (2) both active (propranolol, 40 mg
for use thrice daily, and chlorthalidone, 50
mg for use twice daily); (3) active chlorthalidone, 50 mg for use twice a day and dummy pro-
Table 1
Pressures
Arterial
in
Position
Between the Initial Placebo Period (Single-Blind) and
Comparison of
Lying
the Treatment Placebo Period* (Randomized; Double-Blind)
Patient
D.C.
J.H.
L.G.
M.T.
G.W.
P.A.
T.C.
S.M.
P.T.
E.P.
C.H.
C.B.
L.S.
P.H.
A.R.
M.C.
L.W.
E.A.
C.A.
Age
(yr)
Sex
Race
F
40
M
49
F
40
F
35
F
49
M
55
Average for period
45
M
F
52
F
43
F
50
Average for period
F
44
F
67
M
54
F
69
F
37
F
55
Average for period
F
49
F
45
M
46
Average for period
Overall averages
*Period = 5 weeks.
Circulation, Volume XXXVII, April 1968
N
N
Treatment
placebo period
N
N
N
N
First
First
First
First
First
First
N
N
N
N
Second
Second
Second
Second
N
N
N
Third
Third
Third
Third
Third
Third
N
N
N
Fourth
Fourth
Fourth
N
N
w
Systolic (mm Hg)
Initial
Treatment
Diastolic (mm Hg)
Initial
Treatment
88.8
142.8
229.5
159.4
154.9
210.7
169.6
148.8
216.0
164.1
153.5
99.7
220.8
182.3
120.3
107.3
101.2
126.2
114.0
(177.8)
(180.9)
(105.5)
(110.0)
206.0
168.0
164.3
144.0
191.1
167.2
161.2
148.2
121.9
102.4
115.0
98.9
97.5
104.3
(170.6)
(166.9)
(104.3)
(103.9)
133.0
131.9
150.4
188.0
193.8
160.8
88.1
80.4
112.6
113.7
113.7
110.0
87.8
84.2
121.3
114.0
112.3
108.3
(162.8)
(103.1)
(104.7)
199.2
137.7
198.1
94.8
94.3
136.9
96.0
99.2
129.0
(178.3)
(172.3)
(108.7)
(105.0)
(108.1)
(106.7)
143.0
187.6
196.5
152.7
165.0
(163.0)
184.3
131.1
215.9
(177.1)
(171.5)
152.2
119.9
97.2
96.5
96.3
93.0
125.7
99.9
RICHARDSON ET AL.
536
Table 2
Arterial Blood Pressure-Lying Position
Treatment
First week
Second week
Third week
Fourth week
Fifth week
Systolic pressure
170.08
172.57
172.95
172.00
162.35
162.08
165.84
162.82
146.42
147.10
141.05
144.37
148.56
142.05
143.05
139.80
138.46
138.73
Diastolic pressure
105.18
106.68
108.37
Dummy*
164.82
Propranololt
Chlorthalidonet
Propranolol plus
153.83
chlorthalidone§
Dummy
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Propranolol
Chlorthalidone
Propranolol plus
chlorthalidone
99.17
97.20
95.45
98.18
92.78
97.05
94.37
96.91
106.70
98.67
97.74
92.28
94.18
91.02
90.63
92.11
103.40
Means not connected by vertical lines are significantly different (P < 0.05).
*1 inert tablet resembling propranolol three times daily plus 1 inert tablet resembling
chlorthalidone twice daily.
tPropranolol, 40 mg, three times daily plus 1 dummy chlorthalidone tablet twice daily.
*Chlorthalidone, 50 mg, and KC1, 0.5 g, twice daily plus 1 dummy propranolol tablet three
times daily.
§Propranolol, 40 mg, three times daily plus chlorthalidone, 50 mg, twice daily.
Table 3
Average Arterial Blood Pressure-Standing Position
Treatment
First week
Second week
Third week
Systolic pressure
165.40
170.50
Dummy*
162.25
Propranololt
153.77
161.55
Chlorthalidonet
142.47
Propranolol plus
chlorthalidone§
136.31
Dummy
113.87
Propranolol
Fourth week
Fifth week
168.25
170.56
160.75
159.30
158.14
143.22
137.05
138.72
142.63
140.13
135.43
133.37
132.95
114.05
117.25
117.42
116.49
107.95
109.72
106.37
107.72
108.28
Chlorthalidone
105.07
105.37
103.40
104.19
103.93
Propranolol plus
101.70
102.46
99.62
98.65
98.32
Diastolic
pressure
chlorthalidone
Means not connected by vertical lines are significantly different (P < 0.05).
*1 inert tablet resembling propranolol three times daily plus 1 inert tablet resembling
chlorthalidone twice daily.
tPropranolol, 40 mg, three times daily plus 1 dummy chlorthalidone tablet twice daily.
*Chlorthalidone, 50 mg, and KC1, 0.5 g, twice daily plus 1 dummy propranolol tablet three
times daily.
§Propranolol, 40 mg, three times daily plus chlorthalidone, 50 mg, twice daily.
Circulation, Volume XXXVII, April 1968
PROPRANOLOL AND ELEVATED BLOOD PRESSURE
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pranolol; and (4) dummy chlorthalidone and active propranolol, 40 mg for use thrice daily. The
order of administration was randomized and
unknown to patient and observers. During the
period when chlorthalidone was given without
propranolol, potassium chloride, 500 mg, was
added to each chlorthalidone capsule in order
to observe the effect of potassium supplementation on serum potassium concentration. Blood
pressure during that period in the double-blind
crossover in which the patient received both
dummies was used as the control pressure,
against which drug effects were compared. Analysis of variance for a randomized block design7
(that is, each patient was considered as a complete block) was performed separately for each
treatment period and each variable. Subsequently, Duncan's multiple-range test8 was used to
determine the statistical significance of the observed response differences among all treatment
Results
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Effects on Arterial Pressure
The effect on blood pressure of the patients'
habituation to the examination was observed
by comparing the average pressure during
the initial 5-week pre-randomization period
of placebo administration with the average
pressure during the "treatment" 5-week period in the double-blind trial in which the
patient received placebos. Table 1 shows the
data for each patient. In none of the four
placebo periods during the double-blind comparison was the group average pressure significantly different from the average pressure
during the pre-randomization period. It is
thus reasonable to assume that the changes
in blood pressure observed during administration of active drugs are the result of the
_
drugs, rather than lapse of time or habituation to the experimental procedure.
The blood pressure associated with each
regimen is summarized in tables 2 and 3 and
figure 1. Propranolol, 40 mg three times a
day, reduced blood pressures with the patient
in the lying down position by 9 and 8 mm
Hg, systolic and diastolic, as compared with
placebo. Statistically significant reduction in
diastolic pressure attributable to propranolol
occurred only in 2 of the 5 weeks. There
was no evidence of greater hypotensive effect
in the fifth than in the first week of propranolol administration. Chlorthalidone alone, 50
mg twice a day, reduced pressure an average
pairs.
All patients were interviewed at each visit, after blood pressure and pulse had been recorded.
No special effort was made to have a particular
physician interview a particular patient throughout the study; in fact, each patient was seen by
all four physicians at some time. Physicians were
instructed to ask at each visit about anv discomfort or change in daily habit; about sleepiness,
diarrhea, shortness of breath, swelling, and dizziness; and to record all symptoms. At the end of
the study, all recorded symptoms were tabulated
by study period without knowledge of which
drug was received in any period. They were then
retabulated by drug regimen.
537
120
Dummy
x--x Propronolol
A-A Chlorthalidone
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100
X.
-
*
_ __o_
-
X.
90
IE
3
2
WEEKS OF TREATMENT
1
4
5
Figure 1
Arterial pressure, recorded in the supine position, on
each regimen. Each point is the average for 19 patients. The four regimens were placebo, propranolol,
120 mg daily, chlorthalidone, 100 mg daily, and propranolol plus chlorthalidone (P&C).
RICHARDSON ET AL.
538
20
0
10
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* - Lying
o - Standing
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Propronolol
40mg/ tid
Chlortholidone
50mg / bid
Propronolol
Chlortholidone
Figure 2
The changes in systolic arterial pressure observed in individual patients during active drug
regimens. The horizontal line at zero represents each patient's pressure during the second
through fifth weeks of placebo medication in the double-blind trial. Each point represents the
change in blood pressure observed in one patient during the second through the fifth week on the
indicated regimen, and is the mean of 12 measurements, three each week. Closed circles show
changes in supine and open circles changes in standing blood pressure.
of 23/9 mm Hg as compared with the placebo.
Propranolol and chlorthalidone together reduced pressure an average of 33/15 mm Hg
below that observed during administration
of the placebo. Blood pressure was not significantly lower during administration of pro-
pranolol and chlorthalidone together than with
chlorthalidone alone. The effects of drug regimens on blood pressure in the standing position were similar to those observed in the
supine position (tables 2 and 3). Figures 2 and
3 show the changes of systolic and diastolic
Circulation, Volume XXXVII, April 1968
PROPRANOLOL AND ELEVATED BLOOD PRESSURE
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o -
Standing
(-40
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Propronolol
40mg/tid
Chlorthalidone
50mg /bid
Propronolol
Chlortholidone
Figure 3
Changes in diastolic arterial pressure observed
regimens. See legend for figure 2.
in individual patients during active drug
Table 4
Heart Rate in Treatment Period
First week
HR
Drug
C
D
79.2
76.8
C + P 71.3
P
65.0
Second week
HR
Drug
Third week
Fourth week
Drug
HR
Fifth week
HR
Drug
C
83.9
(Incomplete
C
84.1
C
77.8
D
75.1
data not
D
76.4
D
77.4
C+P 68.6
analyzed)
C + P 66.2
C+P
68.2
P
67.6
P
65.8
P
64.1
Means not connected by the same vertical line are significantly different (P < 0.05)Duncan's multiple range test.
Abbreviations: HR = heart rate; D = dummy; P = propranolol; C = chlorthalidone; and
C + P = chlorthalidone plus propranolol.
individual patients associated with
each active drug regimen.
pressure in
Heart Rate, Weight, and Blood Chemistry
The heart rate was consistently lower in
the two regimens which included propranolol
Circulation, Volume XXXVII, April 1968
(table 4). Sinus rhythm was present in all
subjects throughout the study.
In each week of the treatment period, there
was a significant (P <0.05) difference among
the body weights (table 5). For all treatment
weeks the weights during the two chlorthali-
RICHARDSON ET AL.
540
Table 5
Weight (lb) in Treatment Period
First week
Drug Weight
Second week
Drug Weight
Fort
wee
Fourth week
Drug Weight
Third week
Drug Weight
Fitwe
Fifth week
Drug Weight
P
167.4
P
167.8
P
166.6
P
166.8
P
166.6
D
165.7
D
165.4
D
166.0
D
165.4
D
165.8
C
163.0
C+P 163.8
C
162.8
C + P 162.8
C+P 163.7
C + P 163.2
162.4
C
C
C+P 164.9
162.3
C
163.2
Means not connected by the same vertical line are significantly different (P < 0.05)
Duncan's multiple range test.
Abbreviations: D = dummy; P - propranolol: C -- chlorthalidone; and C + P - chlorthalidone plus propranolol.
Table 6
Clinical Laboratory Data: Fifth Week of Each Treatment Period
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Chloride
Chloride
(mEq/L)
Blood urea nitrogen
Blood urea nitrogen
(mg/100 ml)
25.2
C+P
C
P
D
24.0
20.0
18.4
P
D
C
C+P
C+P
1.56
C
P
1.52
1.38
1.35
C+P
C
D
P
Sodium
(mEq / L)
D
p
C
C+P
C+P
(mg/100 ml)
103.3
103.2
99.8
99.5
C+P
P
C
0.107
0.094
0.060
D
0.058
26.4
26.3
25.5
25.4
Bilirubin, total
(mg! 100 ml)
C+P
P
C
143.8
143.0
142.8
142.0
C+P
C
D
P
21.3
20.6
19.0
18.4
Alkaline phosphatase
(Bessey-Lowry units)
4.31
4.28
3.90
3.891
P
C
C+ P
D
1.69
1.47
1.42
1.29
0.334
0.321
0.310
0.270
D
White cell count
(cell / mm3)
SGOT
(Karmen units)
Potassium
(mEq / L)
p
D
C
Bilirubin, direct
Carbon dioxide
(mM/L)
Creatinine
(mg/100 ml)
D
Biliruhin, direct
P
D
C
C+P
6952i
6511
6327
6280
Hemoglobin
(gl 100 ml)
C
D
C+P
P
13.62
13.39
13.34
12.98
Means not connected by the same vertical line are significantly differenct (P < 0.05)Duncan's multiple range test.
Abbreviations: D - dummy; P - propranolol; C - chlorthalidone; and C + P - chlorthalidone plus propranolol.
done regimens were slightly less, but the
statistical significance of these differences
was more definitive in the earlier weeks.
Blood chemical and hematological analyses are shown in table 6. During the administration of the two chlorthalidone regimens,
concentration of blood urea nitrogen and
serum creatinine were higher; those for se-
rum potassium and chloride were lower. There
was no difference between the serum potassium levels for the chlorthalidone regimen
and for the combined chlorthalidone and propranolol regimen; in the former regimen, 0.5 g
of potassium chloride was incorporated into
each capsule of chlorthalidone.
No significant differences among the four
Circulation, Volume XXXVII, April 19(38
PROPRANOLOL AND ELEVATED BLOOD PRESSURE
541
Table 7
Possible Side Effects
Placebo
Pt. t
No. *
Symptom
Headache
Dizziness
Dyspnea
Cough and
wheezing
Fatigue
Sleepiness
Nausea
Propranolol
Pt.
No.
6
6
11
4
1
6
3
1
5
2
1
1
3
0
4
3
3
0
1
4
0
3
2
3
2
2
2
0
Chlorthalidone
and KC1
Pt.
No.
Propranolol
and
chlorthalidone
Pt.
No.
2
9
2
2
6
1
2
7
9
1
1
3
5
3
6
3
2
5
7
5
6
7
3
4
5
3
1
1
*No. = Number of times symptom was recorded.
tPt.
-
Number of patients who developed this symptom.
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regimens were noted with respect to blood
hemoglobin, white cell count, serum carbon
dioxide content, bilirubin concentration, nor
serum glutamic-oxalacetic transaminase and
alkaline phosphatase.
Side Effects
Table 7 presents the number of times a
symptom occurred during each regimen, and
the number of patients who experienced each
symptom. Headache occurred most frequently
during placebo administration and least frequently in regimens containing chlorthalidone.
Dizziness, on the other hand, occurred least
frequently during the placebo period, and
most frequently during administration of chlorthalidone. Dyspnea, cough, and wheezing occurred more frequently in regimens containing
propranolol, with or without chlorthalidone.
Fatigue occurred more often with regimens
containing chlorthalidone or propranolol than
with placebo. Other recorded symptoms, mentioned by only one or two patients each,
included nocturia, present in all four regimens;
angina pectoris, also present in all four regimens; urinary urgency, diarrhea, indigestion,
nocturnal leg cramps, and stuffy nose.
Discussion
Propranolol in a dose of 40 mg three times
daily caused an average blood pressure reduction of 9 mm Hg systohic and 8 mm Hg
diastolic. These changes are statistically insignificant. The modest effect of propranolol
is similar to that found by Waal,4 who obCirculation, Volume XXXVII, April 1968
served an average decrease in blood pressure
of 12/6 mm Hg when propranolol, 45 to 150
mg/day, was added to other antihypertensive
medication in 89 hypertensive patients. Similarly, Richards5 found an average decrease
in pressure of 11/12 mm Hg in nine patients
with elevated arterial pressure during administration of propranolol, 150 to 300 mg/day
for 8 to 15 weeks. Paterson and Dollery6
compared the effects of propranolol, 80 mg/
day, propranolol, 240 mg/day, and hydrochlorthiazide, 50 mg/day, on 11 hypertensive
patients who received each regimen for 6
weeks. Arterial pressure (lying) was 13/5 mm
Hg higher with propranolol, 240 mg/day, and
14/6 mm Hg higher with propranolol, 80 mg/
day, than with hydrochlorthiazide. Though
Prichard and Gillam3 have suggested that prolonged administration (4 weeks or more) of
propranolol produces greater reduction of arterial pressure than is seen in the first 3 weeks,
our results with those of Waal4 and of Paterson and Dollery6 show no greater hypotensive effect after 5 or 6 weeks of propranolol
than after 1 to 3 weeks.
Addition of potassium chloride, 0.5 g twice
a day, to chlorthalidone had no noticeable
effect on serum potassium concentration. Thus,
there seems little reason for administration
of capsules combining potassium, at least in
this dose, with chlorthalidone.
Analysis of side effects suggests that reduction in blood pressure lessened the prevalence of headache in this group of patients
542
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with mild to moderate hypertensive disease.
The greater frequency with which dyspnea
and wheezing occurred while patients were
taking propranolol is in keeping with known
effects of the drug, which blocks adrenergic
bronchodilation and, by reducing adrenergic
stimulation of the heart, favors cardiac decompensation. In no patient were symptoms severe enough to require alteration of medication. One patient died in the fourth week
period of the study, while taking propranolol
alone. She was a 52-year-old Negress with recurrent ventral hernia which had previously
been repaired surgically without prolonged
success. The hernia protruded one day, producing pain and vomiting for 2 hours, and
then reduced itself spontaneously. She stopped
taking propranolol that day. Two days later
the hernia protruded again, and she entered
the hospital with abdominal pain, vomiting,
and hypotension. The hernia could not be
reduced. Shock and puhnonary edema followed, and the patient died 36 hours later
with continued pulmonary edema. Permission
RICHARDSON ET AL.
for autopsy was not given. The contribution
of propranolol to her death is uncertain. Infusion of isoproterenol resulted in tachycardia
and reduction in arterial pressure, suggesting
that beta-adrenergic blockade was not present.
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Circulation, Volume XXXVII, Aprl 1968
Effect of Propranolol on Elevated Arterial Blood Pressure
DAVID W. RICHARDSON, JACK FREUND, ARTHUR S. GEAR, H. PAGE
MAUCK, JR. and LESTER W. PRESTON
Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017
Circulation. 1968;37:534-542
doi: 10.1161/01.CIR.37.4.534
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