A Comparison of Oral Procaterol and Albuterol in Reversible

Airflow Obstruction'?

THOMAS L. PETTY, MILAN L. BRANDON, WILLIAM W. BUSSE, PAUL CHERVINSKY,

WILLIAM SCHOENWETER, ALAIN BEAUPRE, LOUIS P. BOULET, and JORGE MAZZA

Introduction
P rocaterol is a long-acting, 132-selective
agonist (1,2) developed in Japan (3) and
marketed in several countries. It is an ef-
fective bronchodilator by oral adminis-
tration (4-7) and by inhalation (8). Struc-
turally, procaterol is unique with a car-
bostyril rather than a catecholamine
nucleus. This structure may render pro-
caterol less susceptible to enzymatic
degradation, as is suggested in its long
duration of action (5, 7, 9, 10).
In a previous 6-month, multicenter
study (11), patients with mild to moder-
ate reversible bronchospastic disease who
received oral procaterol (0.05 or 0.10mg
twicedaily) consistently showedmore im-
provement in spirometry measurements
than did those who received the widely
SUMMARY The efficacy and safety of orally administered procaterol hydrochloride, a potent ~2­
adrenergic bronchodilator, was compared with that of albuterol in an eight-center, double-blind study
conducted in 223 patients with mild to moderate, reversible bronchial airway obstruction. After a
1-wk placebo washout period, patients were administered either procaterol 0.05 mg twice daily for
2 wk followed by 0.10mg twice daily for 10 wk or albuterol 2 mg three times a day for 2 wk followed
by 4 mg three times a day for 10wk. Spirometry determinations 1.5h postdose showed consistently
greater percent improvements from predose in FVC, FEV" and FEF25 - 75 with procaterol than with
=
albuterol at Weeks 1,2,4,8, and 12. 1i'eatment differences were statistically significant (a 0.05)
after 2 wk, 2 months, and 3 months of treatment. Bronchodllatation was evident 0.5 h after dosing
and peaked at 1.5to 3 h postdose for both treatments. The duration of action (i.e., time until spirome-
try determinations were lower than those at 0.5 h postdose) was at least 5 h after procaterol but
only 3 h after albuterol. There was no evidence of tolerance with continued procaterol treatment,
whereas a diminished duration of response to albuterol was observed with long-term treatment.
Tremorwas reported statistically more frequently In patients receiving procaterol than in those receiv-
ing albuterol (a = 0.05); the frequencies of other adverse events were similar for the two groups.
No statistically significant treatment differences were noted for asthma symptoms, global evalua-
tions, ECGresults, vital signs, or clinical laboratory measurements. Under the dose regimen select-
ed for this stUdy, oral procaterol (0.1 mg twice daily) was found to have a rapid onset of action and
a duration and magnitude of bronchodilatation superior to that of oral albuterol (4 mg three times
a day). AM REV RESPIR DIS 1988; 138:1504-1509

prescribed bronchodilator terbutaline

(2.5 mg three times daily).
Albuterol is another widelyused, oral-
ly active, (3-agonist bronchodilator. centers) trial conducted within the period of pulmonary function tests (PFT). Long-acting
Studies in vitro (1, 2) and in vivo (6) have 1 yr. Patients with mild-to-moderate, revers- theophylline preparations could be used ex-
indicated that procaterol is more potent ible bronchial airway obstruction wereselect- cept during the 12h prior to PFT. According
ed for the study. This disorder was defined to protocol, use of oral p-agonists was not
and has a longer duration of action than as a baseline FEV 1 40 to 800/0 of predicted allowed during the study.
does albuterol. In a single-dose study in normal or a FEF 25-75 lessthan 60% of predict- Clinical assessments were made at screen-
patients with bronchial asthma, the du- ed normal, and a 15% improvement overbase- ing, before and after the first dose of active
ration and magnitude of bronchodilata- line in FEV 1 or a 25% improvement in medication, and after I, 2, 4, 8, and 12 wk
tion with 4 mg of albuterol was found FEF25 - 7 5 after inhalation of 150 ug isoprote- of double-blind treatment.
equivalent to that produced by 0.05 and renol from a metered-dose inhaler. The physician investigator evaluated the
0.10mg of procaterol. The present study After a l-wk, single-blind period during severity of distress experienced by the patient
compared the safety and efficacy of oral which all patients receivedtwo placebo tablets during the week preceding each visit for each
procaterol (0.10 mg) given twice daily three times a day, patients were randomly as-
with oral albuterol (4 mg) given three signed to one of two treatment groups:
procaterol 0.05 mg twice a day for 2 wk fol-
times a day in patients with reversible, lowed by 0.1 mg twice a day for 10 wk, or (Received in original form May 22, 1987 and in
chronic, stable, mild-to-moderate airflow albuterol2 mg three times a day for 2 wk fol- revised form June 7, 1988)
obstruction. This was a 3-month paral- lowed by 4 mg three times a day for 10 wk.
From the Webb-Waring Lung Institute, Den-
1
lel study. The dosages of albuterol used Patients received two tablets of study drug ver, Colorado; the Allergy Medical Group, San Die-
werewithin the recommended range (12). three times a day throughout the study. Dos- go, California; the University Hospital Allergy Clin-
Furthermore, the starting doses of age was reduced if adverse events occurred. ic, Madison, Wisconsin; Allergy Associates, New
procaterol and albuterol used in this Patients requiring daily oral corticosteroids Bedford, Massachusetts; the Nicollet Park Medi-
study were identical to those used in a wereexcluded from the study. However, short cal Center, Minneapolis, Minnesota; the Hospital
Maisonneuve-rosemont and the Hospital Laval,
previous study performed in Japan in (5- to 7-day) courses of oral corticosteroids Quebec, Quebec; and the University of Western On-
which the two drugs were found to be could be used to manage exacerbations of
tario, London, Ontario, Canada.
comparable in efficacy and safety (4). bronchospasm; a stable-dose treatment of in- 2 Supported by Parke-Davis Pharmaceutical Re-
haled corticosteroids was also allowed. Beta- search Division of Warner-Lambert.
agonist aerosols and short-acting oral theoph- 3 Requests for reprints should be addressed to
Methods ylline preparations could be used as needed Thomas L. Petty, M.D., Webb-Waring Lung Insti-
This was a cooperative, multicenter (eight during the study except during the 8 h before tute, 4200 East Ninth Avenue, Denver, CO 80262.

1504
PROCATEROL AND ALBUTEROL IN REVERSIBLE AIRFLOW OBSTRUCTION 1505

of fivesymptoms (wheezing,dyspnea, cough, TABLE 1

sputum production, and nocturnal sleepqual- PATIENT CHARACTERISTICS
ity) and rated them on a five-point scale of
Mean Values
none, mild, moderate, severe,and very severe.
The frequency of acute exacerbations that re- Procaterol Albuterol
quired medical attention was also recorded. Characteristic (n = 112) tn = 111)
At the end of Week 12, both the physician Age, yr 34.4 (14.5)' 38.0 (14.2)*
and the patient assessed the patient's global Weight,lbs 157.5 (34.0)' 160.3 (34.6)*
clinical improvement relative to the start of Height, inches 66.0 (3.6)' 66.1 (4.0)*
the study. A five-point scale of worse, no Sex
change, improved, much improved, and very Male 60 (53.6%) 51 (45.9%)
much improved was used. Female 52 (46.4%) 60 (54.1%)
Effect was quantified by standard volume- Baseline FVC, L 3.2 3.3
time expiratory spirograms with analysis of Baseline FEV1 , LIs 2.2 2.3
FVC, FEV I, and forced expiratory flow be- Baseline FEF2s- 7s, LIs 1.6 1.7
tween 25 and 750/0 of the FVC (FEF 2s- 7s) . • Standard deviation.
Spirograms were obtained at screening, and
before and at 1.5h after oral dosing at Weeks
1,2, and 8, and additionally at 0.5.3,5, and
8 h postdose on Day 1 and Weeks 4 and 12. patients in the procaterol treatment group 2 wk of double-blind treatment. The dos-
The ISO volume method of calculating (n=32) than in the albuterol group age was decreased from 0.10 mg twice a
FEF 2s- 7s after bronchodilatation (13) was used (n=24) reported concurrent use of oral day to 0.05 mg twice a day for five pa-
in some of the clinics; non-ISO volume forced steroids because of exacerbation of asth- tients who reported adverse events with
expiratory flows were used in others. Despite ma during the study. However, all pa- procaterol administration. Twoof the five
these differences, FEF 2s- 7s results were com- later returned to the O.lO-mg dosage.
tients who received oral steroids within
bined in this analysis. All other PFT proce-
dures were performed in accordance with 7 days of a PFT were excluded from anal- None of these patients was excluded from
those of the Snowbird Epidemiology Stan- yses on the basis of that particular test. efficacy or safety analyses.
dardization Project (14). The best of three Short-term courses of nonspecific adren- Sixteen (7.2070) of the 223 patients
forced expiratory efforts, defined as the ergic bronchodilators (epinephrine and withdrew from the study before complet-
highest combination ofFVC and FEV 1 , was ephedrine) wereused as required for acute ing the 3-month, double-blind treatment
selected. bronchospastic episodes. These patients period. In the procaterol treatment
A 12-leadelectrocardiogram plus a 30-slead were not excluded as this was not expect- group, seven patients withdrew because
II rhythm strip were recorded at screening. ed to affect study results. of adverse events, two because of lack
At the time of the first dose of active medica- Patients assigned to the albuterol treat- of efficacy, two because of patient prefer-
tion and after 4 and 12 wk of treatment, a ment group receivedthree tablets of study ence, and one because of administrative
30-s lead II rhythm strip was recorded pre-
dose and just before the 1.5-h postdose PFT. drug a day. The dose was increased from reasons. In the albuterol treatment group,
Laboratory tests were performed at screen- 2 mg three times a day after the second one patient withdrew because of lack of
ing and after 4 and 12wk of treatment. Heart week of the double-blind phase, with the efficacy, one because of administrative
rate and sitting blood pressure were recorded exception of one patient whose dose was reasons, one because of concurrent ill-
at each clinic visit. Any side effects or addi- increased to 4 mg three times a day on ness, and pne was lost to follow-up.
tional diagnoses were recorded at each clinic Day 8. Patients assigned to the procater-
visit. 01 treatment group received two tablets Evaluation of Asthma Symptoms
of procaterol and one identical placebo For each patient, the asthma symptom
Results tablet each day. Three patients had their ratings at the last visit were compared
Patient Characteristics, Treatment, procaterol dosage increased to 0.10 mg with those at the first screening visit to
and Disposition twice a day after 1 wk instead of after determine whether the patient had im-
A total of 223 patients were randomized
to treatment; 112 received procaterol and
111 received albuterol. The demographic TABLE 2
and pulmonary characteristics of the two
SUMMARY OF CONCURRENT ANTIASTHMA, STEROID, AND
treatment groups were similar, as shown
ANTIHISTAMINE USE
in table 1.
Concurrent antiasthma, steroid, and Procaterol Albuterol Total
(n = 112) (n = 111) (n = 223)
antihistamine medications used during
the three-month study are given in table Medication Type (n) (%) (n) (%) (n) (%)
2. The procaterol and albuterol treatment Cromolyn 3 2.7 5 4.5 6 3.6
groups were similar in percent of patients Bronchodilators 109 97.3 107 96.4 216 96.9
using various medications. Specifically, Theophylline 82 73.2 81 73.0 163 73.1
the use of theophylline was similar in the (3-agonists, oral 3 2.7 0 0.0 3 1.3
(3-agonists, aerosols 103 92.0 102 91.9 205 91.9
two treatment groups. Despite the pro-
Nonspecific adrenergic 14 12.5 15 13.5 29 13.0
tocol requirements, three patients in the ACTH 5 4.5 5 4.5 10 4.5
procaterol treatment group used oral 13- Corticosteroids 59 52.7 59 53.2 118 52.9
agonists other than procaterol during the Oral 32 28.6 24 21.6 56 25.1
study (two during the placebo baseline Inhaled 47 42.0 47 42.3 94 42.2
Antihistamines 23 20.5 20 18.0 43 19.3
period and one on Days 8 and 9). More
1506 PETTY, BRANDON, BUSSE, CHERVINSKY, SCHOENWETER, BEAUPRE, BOULET, AND MAZZA

TABLE 3 TABLE 4

NUMBER AND PERCENT OF PATIENTS PERCENT OF PATIENTS SHOWING A CLINICAL RESPONSE 1.5 HOURS POSTDOSE*
SHOWING IMPROVEMENT IN
Dosage Times
ASTHMA SYMPTOMS

Albuterol MeasuremenUGroup Initial Dose Two Weeks Two Months Three Months
Procaterol
(n = 112) (n = 109) FEV
Procaterol 40.2t 38.7t 3S.7t 4S.9t
Symptom (n) (%) (n) (%)
Albuterol 25.0 25.5 19.4 2S.7
Wheezing 40 35.7 40 36.7 FEV j
Dyspnea 32 28.6 44 4004 SO.7t SOAt 55.1t S5.3t
Procaterol
Cough 28 25.0 39 35.8 38.0 2S.8 32.0 35.2
Albuterol
Sputum production 31 27.7 38 34.9
Sleeplessness 33 29.5 25 22.9 FEF25- 75
Procaterol 58.0 S2.3t S4.3t 67.3t
Albuterol 47.S 44.3 44.7 40.9
At least one pulmonary function test
proved. The results are shown in table 3. Procaterol 73.2t 73.St 74.5t 78.6t
Albuterol 54.S 55.7 50.5 50.5
The two treatments were similar in the
number and percent of patients showing • An increase of 15% or more in FVC and FEV, or of 25% or more in FEF25 - 75 •
improvement in wheezing. Although a t Significantly different from albuterol («<11 = 0.05. Mantel-Haenszel chi-square analysis).

higher percent of patients showed im-

provement in sleeplessness in the pro-
caterol group than in the albuteroIgroup
and improvement in the other symptoms
was more frequent among patients in the
albuterol group than among those in the
procaterol group, a chi-square analysis
using a two-tailed Fisher's exact test
showed no statistically significant differ-
ences between the two treatment groups
(a = 0.05) for any of the five symptoms.
In global evaluations by physician or
patient, the percent of patients showing
improvement was similar (approximate-
ly 65070 to 68070) for the procaterol and
albuterol groups. Thus, there were no
statistical differences between treatment
groups in global evaluation (Mantel-
Haenszel chi-square analysis) (15).
According to protocol, PFT was per-
formed at scheduled times regardless of
exacerbations of asthma. Unfortunate-
ly, the severity of asthma exacerbations
was not recorded. Thirty-three (29.5070)
patients in the procaterol treatment group
reported 44 exacerbations of asthma. In
the albuterol group, 22 (20.2070) patients
reported 35 exacerbations of asthma.
There was no statistically significant
difference between treatment groups in
this respect (chi-square analysis). Asth-
ma exacerbations were most frequently
treated with steroids in both the procater-
01 (67070) and the albuterol (640/0) treat-
ment groups.
cific visit for one or more of the follow- comparable at predose for all PFT at
ing reasons: using a long-acting theoph- each observation.
ylline preparation within 12 h of PFT The percentage of patients showing a
(n= 1), oral daily steroids within 7 days clinical response in any single PFT (in-
of PFT (n= 11), intramuscular dose of creases of 15% or more in FVC and FEV 1
steroids just prior to visit (n = 1),lessthan or of 25 % or more in FEF 2S-75) and over-
8 h since last dose (n = 1), and not using all (a response in at least one test) at 1.5
drug for more than 5 consecutive days h postdose (time of peak effect) is given
(withdrawals) (n = 3). in table 4. The difference between the two
There was very little change in predose groups was statistically significant
mean spirometry values throughout the (Mantel-Haenszel chi-square analysis)
study from those obtained on Day 1 (da- (15) after the initial dose (except for
ta not shown). An analysis of variance FEF2s - 7s) and after 2 wk, 2 months, and
was performed on all predose measure- 3 months, with procaterol showing a
ments at all visits using center, treatment, greater response rate.
and treatment by center interaction in the The mean percent improvement (i,e.,
model (16, 17). No statistically signifi- mean percent change from predose tak-
cant differences between centers or treat- en from the actual mean change from
ment groups werenoted at any of the time predose) in PFT 1.5 h postdose at each
periods or for any of the parameters even visit is shown in table 5. The mean per-
though methodologies differed between cent improvement from predose to 1.5 h
centers. Therefore, treatment groups were postdose was greater with procaterol than
TABLE 5
MEAN PERCENT IMPROVEMENT IN PULMONARY FUNCTION
MEASUREMENTS 1.5 HOURS POSTDOSE*
Dosage Times
Three
Initial Dose Two Weeks Two Months Months
Measurement/Group (n) (%) (n) (%) (n) (%) (n) (%)

FVC
Pulmonary Function Tests Procaterol 112 13.3 lOS 17.4t 98 13.7* 98 17.1t
Two patients had FEV 1 and FEF25-75 Albuterol 108 10.7 lOS 11.0 103 10.3 105 904
results predose on Day 1 not within the FEV,
ranges specified for entry into the study. Procaterol 112 19.7* lOS 2S.5t 98 zz.at 98 28.0t
These two patients remained in the study Albuterol 108 15.3 lOS 17.0 103 14.7 105 13.S
and received albuterol, but their test FEF25 - 75
results were excluded from all efficacy Procaterol 112 37.3 lOS 51.1t 98 56.9t 98 53.7t
Albuterol 105 28.0 lOS 29.7 103 29.8 105 27.6
analyses. Fifteen additional patients were
excluded from PFT summaries at a spe- Significantly different from albuterol, 'p < 0.05. t p < 0.01; P values on F test on two-way ANOVA.
PROCATEROL AND ALBUTEROL IN REVERSIBLE AIRFLOW OBSTRUCTION 1507

with albuterol for all three PFT (FVC t AFTER INITIAL DOSE .------, PROCATfROl
FEV 1 , and FEF2 S - 1 S ) . Analysis of vari-
ance showed a statistically significant
30 e------. ALBUTEROL
difference (a = 0.05) between the two
treatment groups after 2 wk, 2 months,
and 3 months of treatment. In general
0/0 20
CHANGE ;;~.--------._--

.'. '
improvement in pulmonary function af-
ter the first 0.05-mg dose of procaterol 10
was less on Day 1than at later times dur-
ing the study, as expected from the low-
er initial dosage. This was not observed o
with albuterol, however. Pulmonary -5 I
L L----4...---'-_L...--...L.-_--I...-_----I_
I _....L...-_----J-_ _" " - - _ " : " "I

function tests performed at 3t 5 t and 8 0.5 1.5 3.0 5.0 8.0

h postdose generally showed greater im-
HOURS
provement for the procaterol group than
for the albuterol group, with a statisti- .------1 PROCATfROL
cally significant difference in favor of 30 .-----~ ALBUTEROL
the procaterol group in many cases.
Statisticallysignificant interactions be-
tween treatment and study center (two- 0/0 20
way analysis of variance) were found on- CHANGE ,.,-A--------., ....
" .... ... .....
ly for the differences between the pre- ...... ,~
dose and 1.5-h postdose FVC and FEV t
10
............... _-----
measurements at the 3-month observa- --- ----... _- ....
tion. Four centers showed a greater mean o
change from predose to postdose for the -5 LL-----'-_L-....L---........I-_ _'I - _ - - L . . -_ _'
I - - - _ ~_ _~ _ ~

albuterol treatment group than for the 0.5 1.5 3.0 5.0 8.0
procaterol treatment group. Results HOURS
from all other centers were similar to the AFT£R THREE MONTHS
overall results, with greater mean .------1 PROCATEROl
changes in the procaterol than in the al- 30 * * .------ ALBUTEROL
buterol treatment groups.
The mean percent change of FEV t
from predose values through 8 h post- 0/0 20
dose after the initial dose, 1 month, and CHANGE ,,;
,.",. .. -------., .....
~ ...............
3 months of treatment is shown in fig- 10 " ...... ......
ure 1. A response was apparent at 0.5 h, ................... --
and peak response occurred 1.5 to 3 h
postdose for both procaterol and al- o ....................................................................... : ~~~~.~.::.":".':".'to_.4"~:.:~
buterol. The duration of bronchodilat- - 5 u.__ --'--~----'----l
I
,
_ _..L........._---'------'----:::"-::-----'-_..I....-_=-'

ing action was at least 5 h for procaterol 0.5 1.5 3.0 5.0
on Day 1 and this was maintained HOURS
through 3 months of treatment. In con- Fig. 1. Mean percent change of FE~ from predose values during 8 h postdose with procaterol (solid lines) and
trast, the duration of action of albuterol albuterol (dashed lines). Asterisks indicate p < 0.05; analysis of variance comparing groups.
appeared to decrease over the three-
month trial. Throughout the study 36 t

to 40070 of the patients who received TABLE 6

procaterol maintained clinically signifi- MOST FREQUENTLY REPORTED ADVERSE EVENTS·
cant improvement in at least one PFT Procaterol Albuterol
measurement for 8 h after procaterol
administration. Adverse
Number of Reports Patients Number of Reports Patients
------

Experience Mild Moderate Severe (N) (%) Mild Moderate Severe (N) (%)
Adverse Events
Tremor" 54 25 13 63 56.3 14 7 1 18 16.2
The most frequently reported adverse Palpitation 3 3 2 7 6.3 4 1 0 3 2.7
events are listed in table 6. Tremor oc- Headache 1 1 1 3 2.7 2 5 0 5 4.5
curred more frequently in patients receiv- Nervousness 3 0 1 3 2.7 3 2 0 3 2.7
ing procaterol (56.3070) than in those Tachycardia 2 2 1 4 3.6 1 0 0 1 0.9
Myalgia 1 0 2 3 2.7 1 1 0 2 1.8
receiving albuterol (16.2070). This differ- Insomnia 1 1 1 3 2.7 0 1 0 1 0.9
ence was statistically significant by chi- Dyspepsia 0 1 1 2 1.8 1 0 0 1 0.9
square analysis (p < 0.05). There wereno Dizziness 0 1 1 2 1.8 1 0 0 1 0.9
statistically significant differences be- Coughing 2 0 1 3 2.7 0 0 0 0 0.0
tween treatment groups in the incidence • Reported by three or more patients.
of other adverse events. t Severity of one occurence of tremor was not specified.
1508
In 49 of the 63 procaterol-treated pa-
tients who reported tremor, the tremor
occurred at the lower dosage, usually dur-
ing the first week of the study. Of the
93 reports of tremor in this group, 79
(850/0) were mild or moderate in severity.
Five of these patients withdrew from the
study and five additional patients re-
quired a reduction in dosage. Of the 18
albuterol-treated patients who reported
22 instances of tremor, 16were receiving
the lower dosage. None of these patients
withdrew from the study.
Information regarding time to tremor
after drug administration was available
for 34 patients in the procaterol group
and nine in the albuterol group. After
procaterol, tremor began less than 1 h
postdose in four (120/0) of the patients,
between 1 and 2 h postdose in 29 (85%)
of the patients, and more than 2 h post-
dose in one (30/0) patient. All nine of the
patients in the albuterol group who
reported tremor experienced this adverse
event beginning 1 to 2 h postdose, Data
available on first reports of tremor indi-
cated that it generally subsided within
4 h of onset. Tremor subsided within 14
days of onset in more than 500/0 of pa-
tients reporting this symptom.
Two additional patients in the pro-
caterol treatment group withdrew from
the study because of adverse events: one
because of rash and one because of
insomnia.
Electrocardiograms
Electrocardiograms were taken predose
and at 1.5 h postdose on Day 1, and after
4 and 12wk of treatment. Thirteen (120/0)
patients in the procaterol group and 10
(9%) in the albuterol group had one or
more electrocardiogram abnormalities at
one or more times during the double-
blind portion of the study, but not at
screening. The abnormalities were simi-
lar in type in both treatment groups. The
most frequent of these was sinus tachy-
cardia, which occurred in 10 patients
receiving procaterol and seven receiving
albuterol. Sinus tachycardia was mild in
most cases, with heart rates above 110
beats/min noted for only two patients in
each treatment group. Two of these four
patients also had elevated heart rates pre-
dose on Day 1. Three patients in each
treatment group experienced premature
ventricular contractions, and premature
atrial contractions occurred in one pa-
tient receiving procaterol and two pa-
tients receiving albuterol. One patient in
the procaterol group showed sinus ar-
rhythmia, a shortened Q-T interval, and
PETTY, BRANDON, BUSSE, CHERVINSKY, SCHOENWETER, BEAUPRE, BOULET, AND MAZZA
early repolarization, which were not con-
sidered clinically significant by the in-
vestigator.
Vital Signs
There were slight increases in systolic
blood pressure and heart rate and slight
decreases in diastolic blood pressure post-
dose in both treatment groups. These
changes were minimal and of no clinical
significance. Beta-agonists are known to
cause a slight decrease in diastolic blood
pressure.
Clinical Laboratory Determinations
There were isolated deviations from the
normal ranges for glucose, lactic de-
hydrogenase, and uric acid that were not
drug-attributable. One patient receiving
procaterol had minimal decreases in he-
moglobin, hematocrit, and red blood
cells for which drug association could not
be ruled out. Otherwise, no clinically sig-
nificant hematologic changes or hepatic
or renal function abnormalities were
found in either treatment group. Serum
glucose, cholesterol, and calcium deter-
minations also showed no clinically sig-
nificant variations throughout the study.
Discussion
Oral procaterol administered twice daily
was shown to be an effective and well-
tolerated B-agonist bronchodilator for
the treatment of mild to moderate revers-
ible airflow obstruction. At the doses
studied, procaterol produced consistently
greater improvements in FVC, FEV l , and
FEF25-75 than did albuterol; similarly, the
percent of patients with a clinical re-
sponse was greater in the procaterol than
in the albuterol treatment groups. The
bronchodilating efficacy of procaterol
did not diminish with chronic adminis-
trations. The duration of effect of al-
buterol, however, diminished over the 3-
month trial. Tremor, although generally
well tolerated, occurred statistically more
often after procaterol treatment than af-
ter albuterol treatment. There were no
signs of drug-attributable changes in re-
nal or hepatic function.
Minor variations in dosing occurred
for which patients were not excluded
from efficacy analyses. In addition, al-
though the protocol stated otherwise,
three patients who received other orall3-
agonists during the study (two during the
placebo baseline period and one on Days
8 and 9) were included in efficacy analy-
ses. The judgment calls on these protocol
variations can be debated; however, the
small numbers involved should preclude
their having a marked influence on the
results.
Tolerance to procaterol did not develop
during the course of this 3-month study.
Thus, a greater than 20% mean increase
from baseline in FEV l was maintained
1.5 through 5 h postdose after 3 months
of procaterol administration, and the ef-
fect 8 h postdose did not appear to
change during the study. In contrast, the
albuterol treatment group showed a
steady decrease in effect 5 h postdose
from the initial dose through 3 months
of treatment, and was essentially with-
out effect at 8 h postdose.
Tremor, the most frequently reported
adverse event, occurred more frequently
in the procaterol group than in the al-
buterol group. However, only five pro-
caterol patients withdrew because of
tremor, and tolerance to this side effect
appeared to develop. This profile of side
effects of procaterol treatment has been
reported previously (7).
The doses of procaterol and albuterol
chosen for this study were based on previ-
ous single-dose (6) and multiple-dose (4)
studies in which the two were essentially
equivalent. In retrospect, it appears that
the efficacy of 4 mg three times a day
of albuterol was not equivalent to that
of 0.10 mg twice a day of procaterol. If
a higher dose of alb uteroI had been used,
not only would the efficacy data have
been more comparable, but the safety
profile of the two compounds would
probably have been more alike. Regard-
less, this study did demonstrate the
potency of procaterol compared with that
of albuterol. Furthermore, that the ef-
fectiveness of procaterol was maintained
in terms of peak effect and duration of
action throughout 3 months of treatment
is indisputable.
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