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Double-blind study of ipratropium bromide, a new anticholinergic bronchodilator
Double-blind study of ipratropium bromide, a new anticholinergic bronchodilator Paul Chervinsky,
M.D. New Bedford,
Mass.
The efficacy and acceptability of ipratropium given by metered-dose inhaler were evaluated in two double-blind crossover tests against placebo, one preceding and one following a 2-wk period of continual open-label ipratropium treatment. Ten patients with chronic bronchitis and 10 with bronchial asthma participated. Ipratropium produced increases in FEV, of more than 15% within 5 min of inhalation, and this effect was maintained for 4 to 5 hr. Statistically sign@cant mean increases over the FEV, baseline values were recorded after ipratropium treatment in both the initial and the jinal crossover tests. There were no adverse reactions to any of the placebo or ipratropium test doses or to the ipratropium treatment. Serial electrocardiograms, laboratory tests, blood pressure, and pulse rate showed no change from the baseline. Sputum volume and dry-weight determinations in the patients with bronchitis before and after the Il-day treatment revealed no changes.
In recent years the therapy of reversible obstructive airways disease has been advanced primarily by the introduction of longer-acting and more selective beta adrenergic agonists and by the use of more effective dosages of xanthine derivatives.’ Use of the latter type of drug can give rise to cardiovascular and central nervous system stimulation, which frequently limits the usefulness of these agents. It has long been known that parasympathetic cholinergic mechanisms are of critical importance in the bronchomotor responses and that in asthmatic patients bronchoconstriction may be inhibited by blocking the postganglionic parasympathetic efferent pathways with atropine. Atropine has been used to treat asthma in the past. However, the fear that it would cause drying of secretions and the side effects of systemic administration have restricted its application. A new anticholinergic agent, Atrovent (ipratropium bromide),* has recently been introduced which when inhaled in very small doses relieves bronchoconstriction without causing undesirable systemic effects. Chemically, the compound is the
Presented at the Thirty-second Annual Meeting of the American Academy of Allergy, San Juan, Puerto Rico, March 6-10, 1976. Received for publication March 3 1, 1976. Accepted for publication June 22, 1976. Reprint requests to: Paul Chervinsky, M.D., Allergy Associates, Inc., 190 Hawthorn St., New Bedford, Mass. 02740. *Supplies of Atrovent for this study were made available by Boehringer Ingelheim Ltd., Elmsford, N. Y. Vol.
59, No.
1, pp.
22-30
bromomethylate of N-isopropyl-nortropine tropate. Its structure is shown in Fig. 1. Pharmacologically, ipratropium bromide differs from atropine in that it exerts no central effects and may be characterized as a peripheral anticholinergic.* The purpose of this study was to determine the bronchodilator efficacy and patient acceptability of ipratropium bromide. Patients were continuously treated with this agent for a 2-wk period, and double-blind crossover tests against placebo were carried out at the beginning and the end of the treatment period. PATIENTS AND METHODS For this study, 22 patients with chronic obstructive pulmonary disease involving a reversible bronchospastic component were selected. They comprised 11 men and women ranging in age from 18 to 67 yr. Ten of the patients had bronchial asthma, which was moderately severe in 6 cases and severe in 5. Two women with chronic bronchitis were lost to follow-up during the course of the study so that data from only 20 patients was available for evaluation. Absence of hypersensitivity to atropine or its derivatives and of significant cardiac, renal, hepatic, or metabolic disease was a prerequisite for admission to the study. Besides being challenged with isoproterenol aerosol prior to the study to prove that they responded to inhaled bronchodilators, the patients were given a complete physical examination after a complete history of each had been obtained, and a standard battery of laboratory tests, including SMA- 12, hematocrit, hemoglobin, white blood cell and differential counts, and urinalysis, were performed. Examinations were repeated at the end of the treatment period. Concomitant medication during the study was held to a
lpratropium
VOLUME 59 NUMBER 1
minimum. Ten of the patients were allowed to continue steroid medication during the study at the same minimal dose levels used prior to the study. No other inhaled bronchodilators could be used during the study, but oral bronchodilators could be taken if needed. The 2-wk treatment schedule called for two inhalations of 20 pg (or 40 pg) of ipratropium bromide 4 times a day from a metered-dose inhaler (an additional two whiffs were permitted during the night should the patient be awakened by an acute attack). The double-blind crossover tests against placebo were performed in the early morning on days 0 and 1 and days 14 and 15, on which single test doses of either ipratropium bromide (40 pg) or placebo (two inhalations) were administered to patients randomly assigned to two groups that received either ipratropium bromide or placebo on the first test day and the other preparation on the second. No other anticholinergic medication was allowed for at least 24 hr prior to the first test day and for the duration of the study. To assess the drug’s efficacy, pulmonary function tests were performed on each test day before the treatment to secure baseline values and at the following intervals after administration of the single doses: 5. 15, and 30 min and 1, 2, 3, 4, 5, and 6 hr. The following values were determined: forced expiratory volume in 1 set (FEV,), forced vital capacity (FVC), forced midexpiratory flow (FEF2S(k.75’ir), and peak expiratory flow rate (PEFR). For technical reasons, statistical analysis had to be confined to the FEV, data. Data from all 20 patients were comand F&~-75, bined since there was no statistically significant heterogeneity in the characteristics of the patients with bronchial asthma and those with chronic bronchitis, respectively. Further, no statistically significant difference was found in the error mean squares of these two diagnostic groups. Blood pressure and pulse rate were measured along with pulmonary function at each test interval as well as before administration of test doses. An electrocardiogram (ECG) was recorded before the treatment and at the conclusion of the 6-hr study each day. Rhythm strips were taken at each test interval. The overall clinical impression of the effectiveness of the treatment based on the patient’s symptoms and general condition was recorded after each test dose, and a global evaluation of response was also made after 1 and 2 wk of continuous ipratropium treatment. In addition, the patients themselves were asked at the conclusion of the 2-wk treatment to compare the results with those produced by inhaled bronchodilators they had used in the past. In an effort to assess the possible effect of ipratropium inhalation on sputum volume and weight, a 24-hr collection of sputum was made in the chronic bronchitis patients before administration of the drug (day 0) and again on day 14. The statistical analysis of the results was based on the methods described by Wallenstein3 using differences from baseline values, for a two-period repeated-measurements changeover study design. If a statistically significant (p < 0.05) period effect, i.e., group/treatment interaction, was found, the first-period data were subjected to a two-way analysis of variance for re-
CH, -
bromide
CH -CH,
/ I CH,N-CH
23 +Br-
CH3 \
HC-O-C-CH-
CH,-CHFIG. 1. Structural
formula
for ipratropium
bromide.
peated measurements on one factor. This methodology is derived from Winer.4 Dunn’s multiple comparison among mean? was used to compare ipratropium bromide treatment with placebo treatment. Finally, Dunnett’s test6 was used to compare the means at the various measurement times with the baseline means for each treatment.
RESULTS FEV1. On analysis, the FEVl data recorded at the different
intervals
after administration
in the initial
crossover test, i.e., on days 0 and 1, were found to lack consistency or, in statistical terms, to reflect a significant treatment/time interaction; the same was not true of the FEV, responses in the final test (days 14 and 15). The mean changes in FEV, from the mean baseline values for the 20 patients are presented for the initial and the final crossover tests in Tables I and II, and the corresponding mean percent changes are shown graphically in Figs. 2 and 3. The increases in FEV, obtained after ipratropium bromide administration in the initial test period were significantly (p < 0.05) greater than those obtained after placebo administration at 1 and 2 hr. They also substantially surpassed the palcebo responses at all other test intervals, and the grand mean increase for all the intervals after administration also exceeded the mean change after placebo to a statistically significant degree (p < 0.05). In the final crossover test, too, the grand mean FEV, increase after active drug administration exceeded the response to placebo to a highly significant degree (p < 0.01). In both the initial and the final test, mean FEV, increases following ipratropium inhalation rose above the clinically meaningful level of + 15% for at least 4 hr after administration. This level was never reached by the patients given placebo, who in fact showed mean decreases in FEV, at several test intervals. FEFmm . Geometric mean changes from geometric mean baseline values at the beginning and the end of the study are shown in Figs. 4 and 5. Statistically significant increases over baseline were recorded with ipratropium bromide in the initial test at seven measurement intervals but at only one interval with placebo.
24 Chervinsky
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
IIIII 0
5
15
30
60
I
I
I
I
120
160
240
300
MmtesafterTest
FIG.
2. Mean
ipratropium
percent
changes
bromide
therapy
in FEV,
relative
to baseline
in 20 patients (double-blind
I. Mean changes (from baseline) in FEV, (ml) at beginning of study (days 0 and 1) in 20 patients
TABLE
Time
lpratropium bromide* (40 IrId
Placebo*
Baseline
1,342.5
1,344.2
5 min 15 min 30 min 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr Grand
+251.5 +230.0 +258.8 +351.2 +388.1 +333.2 +268.6 +229.2 + 169.8 +276.3
-6.8 +32.0 -5.5 +44.5 +87.0 + 176.2 + 153.4 +93.6 +30.7 +67.2
Diierence between ipratropium bromide vs placebo
-1.7 +264.3 + 198.0 +264.3 +306.7t +301.1t + 157.0 +115.2 +135.6 +139.1 +209. It
mean
(over time)
I 360
Dose
values
at the
beginning
of 2 wk
of continuous
crossover test against placebo). TABLE II. Mean changes (from baseline) in FEV, (ml) at end of study (days 14 and 15) in 20 patients
Time
Baseline 5 min 15 min 30 min 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr Grand mean (over time)
lpratropium bromide* (40 CL91
1,364.0 +211.0 +216.0 +294.8 +277.2 +319.8 f253.2 +283.2 +143.6 +68.5 +229.7
Placebo*
1,333.5 -41.2 -34.8 -59.8 +6.8 +21.5 +42.8 -7.9 +2.1 -39.6 -12.9
Difference between ipratropium bromide vs placebo
+30.5 +258.2 +250.8 +354.61 +270.4 +398.3 +210.4 +291.1 +141.5 +108.1 +242.6$
*The 95% confidence limits for the mean changes at the individual intervals were 269.9 ml. tStatistically significant, p < 0.05.
*The 95% confidence limits for the mean changes at the individual intervals were 298.5 ml. tStatistically significant, p < 0.05. SStatistically highly significant, p < 0.01.
In the final test the FEF25~75s responses to placebo were consistently negative, whereas the differences between the mean values obtained after ipratropium treatment and the baseline values were statistically significant at most intervals. The overall mean increases after ipratropium bromide were significantly greater (p < 0.02) than the increase after placebo.
The small sample size of 20 patients and an intrinsically wide range of individual variability among these patients may have been responsible for failure to detect statistically significant differences in FEFzsS.751, between the active drug and placebo at the various intervals in the two crossover tests. FVC. The mean changes from the mean baseline values obtained in the 20 patients on days 0 and 1 and
lpratropium
VOLUME 59 NUMBER 1
lpratropium
_-
I
I
I
I
I
I
0
5
15
30
60
FIG. 3. Mean bromide
percent changes in FEV, relative therapy in 20 patients (double-blind
”
18
”
16
1
I
2
I
I
I
1
240
300
360
values at the end of 2 wk of continuous test against placebo).
3
25
bromide
120 180 Minutes after Test Dose
to baseline crossover
bromide
4
5
ipratropium
6
Hours
FIG. 4. Geometric of continuous
mean ipratropium
changes of FEF2ss-75% (Llmin) from bromide therapy in 20 patients
days 14 and 15, respectively, are presented graphically in Figs. 6 and 7. Here the superior response to ipratropium bromide when compared with placebo becomes particularly evident in the final test results since a fairly large placebo response was obtained in the initial test, before continuous treatment with the parasympatholytic drug had been initiated. PEFR. Mean percent changes obtained in the initial and final tests after ipratropium bromide and placebo are presented in Figs. 8 and 9. It is seen that in the initial test, mean increases in the peak expiratory flow rate exceeded 15% at all intervals up to 5 hr, reaching a peak of nearly 34% at 2 hr, while increases after
geometric (double-blind
mean
baseline crossover
at the beginning of 2 wk test against placebo).
placebo reached a mean peak of only 8.4%. Again, after 2 wk of continuous ipratropium treatment, the placebo responses fell off sharply, whereas response to ipratropium remained at approximately the same level as observed in the initial test. Global responses. To evaluate the individual patients’ global responses, numerical ratings were used to indicate that the response was either excellent (5), good (4), or fair (3); that there was no change in the patient’s condition (2); or that it was worse (1). The mean value of the ratings assigned to the results produced by ipratropium bromide in the initial test was 4 as compared with 2.5 for placebo. The mean response
26
Chervinsky
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
2 E
24 22
>
20
‘: k
18
2 z
16 14 12
z
10
3 ? E
6
5
2
E .o f
E & c.7
8 4
O -2 -4 -6 -8 -10
2
1
3
4
5
6
Hours
FIG. 5. Geometric mean continuous ipratropium
changes bromide
of FEFzs%-7s~ (Llmin) therapy in 20 patients
from geometric (double-blind
mean baseline at the end of 2 wk of crossover test against placebo).
2800
2700
^ 5
2600
2500
2400
2300
0
FIG. 6. Mean values patients (double-blind
of FVC (ml) crossover
5
15
30
60
ii0 Minutes
180 after Test Dose
at the beginning of 2 wk of continuous test against placebo).
to ipratropium bromide in the final crossover test was rated 3.6 as compared with 2.4 for placebo. In both cases the difference between the active drug and placebo was highly significant (p < 0.01). We further rated the patients’ global responses after 7 and 14 days of continuous ipratropium bromide therapy. The mean ratings were 3.4 and 3.5, respectively (Tables III and IV). The patients’ own expressed preferences at the end of this 2-wk treatment were inconclusive: while 8 patients found ipratropium bromide better than previ-
240
300
ipratropium
360
bromide
therapy
in 20
ously used bronchodilator aerosols, 3 found the effects to be the same, 8 others preferred inhaled bronchodilators used before the study, and 1 had no preference. Sputum study. Sputum data obtained on days 0 and 15 of the study from 8 patients with chronic bronchitis revealed no statistically significant differences in the mean values for volume and dry weight (no data were available from the other 2 patients with chronic bronchitis) (Table V). Blood pressure. Both ipratropium bromide and
lpratropium
VOLUME 59 NUMBER 1
I
. lpratropium
bromide
27
bromide
2500
I
2400
‘\
,’ \ 2300
\
J
\
’
\
\
Y \ -1--
A’/
240
300
.
2200 e 0
5
15
30
60
120 Mm&s
FIG. 7. Mean (double-blind
Placebo
*-N ---W-l--*-
180
360
after Test Dose
values of FVC (ml) at the end of 2 wk of continuous crossover test against placebo).
ipratropium
bromide
therapy
in 20 patients
80 ,
E .5
70
$ .n
E 2 =.c E
6o
2
40
E ;
30
5 g
20
50
:: ,g ”
10
zF+
0
L
-10
1 1
3
2
4
5
6
Hour?
FIG. 8. Mean bromide
therapy
changes of PEFR in 20 patients
(Llmin) from (double-blind
baseline crossover
placebo decreased the mean systolic blood pressure, whereas no consistent pattern emerged from diastolic blood pressure readings. No substantial difference in the magnitude of the changes after ipratropium bromide and placebo, respectively, is apparent. Pulse rate. Table VI shows the mean changes from baseline pulse rates at the various intervals in the
at the beginning of 2 wk test against placebo).
of continuous
ipratropium
initial and final crossover tests. Once again, all the mean changes were negative after both ipratropium bromide and placebo, and no significant difference was apparent between the two preparations in the magnitude of the changes recorded after inhalation. ECG changes. No significant ECG changes were noted except in 1 patient, a 23-year-old woman with
28
Chervinsky
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
60 .-2
a,
70
% a
E 6o 2 :
50
E J‘
40
u ;
30
5
m 20 b
5 0
10
g
0
f -10 1
3
2
4
5
6
Hours FIG. 9. Mean changes therapy in 20 patients
of PEFR (Llmin) from baseline at the end of 2 wk of continuous (double-blind crossover test against placebo).
TABLE III. Global medical evaluation* end of study (days 14 and 15)
of patients’
responses
to treatment
ipratropium
at beginning
bromide
(days 0 and 1) and
Treatment?
No. of patients
Days 0 and I Bronchial asthma patients Chronic bronchitis patients Combined data (both diagnostic groups) Days 14 and IS Bronchial asthma patients Chronic bronchitis patients Combined data (both diagnostic groups)
lpratropium bromide (40 CL(J)
Placebo (0 Ml)
Difference
p value
10
4.2
2.1
2.1
0.02
10
3.8
2.9
0.9
0.10
20
4.0
2.5
1.5
co.01
10
3.5
2.5
1.0
0.18
IO
3.6
2.4
1.2
0.01
20
3.6
2.4
1.2
*The patient’sresponsewasscoredas follows:excellent= 5; good = 4; fair = 3; no change= 2; worse= 1. tValues aremeansof the raw scores. bronchial asthma, who showed a normal ECG before the start of the study but exhibited generalized nonspecific T wave changes after the initial test dose of ipratropium bromide. No such changes were seen in the ECG taken at the end of the final crossover test. Adverse reactions. No adverse reactions of any
kind were observed or reported on any of the test days or duing the 2-wk treatment period. Physical examination and laboratory data. Physical examinations performed at the end of the 2-wk period disclosed no particularly remarkable changes. Laboratory data secured at the end of the treatment
lpratropium
VOLUME 59 NUMBER 1
TABLE
IV.
Global
medical
evaluation*
of response
to ipratropium
bromide
treatment
during
bromide
29
the Z-wk study
period Mean No. of patients
Bronchial asthma patients Chronic bronchitis patients Combined data (both diagnostic group)
scores
Day 7
Day 15
Mean of difference
p value
2.9 4.0 3.4
3.5 3.6 3.5
-0.6 +0.4 -0.1
0.19 0.17 0.72
IO IO 20
*The patient’sresponseto continuingtreatmentwasscoredas follows:excellent= 5; good = 4; fair = 3; no change= 2: worse= I. TABLE V. Sputum data collected from patients with chronic bronchitis* at beginning (day 0) and end (day 14) of study Mean
Variable
Volume (ml’) Dry weight (%)
Day 0 23.5 1.9
TABLE
baseline patients*
Pulse (bpm): mean differences at various intervals after test doses
VI.
Initial
values
Day 23.1 2.4
14
Mean of differences
pvalue
-0.4 +0.03
0.73 0.20
*Althoughtherewere 10 patientsin this group,datawereavailable from only 8 of them. period also reflected no significant changes that could in any way be related to the bronchodilator administered . DISCUSSION The parasympathetic nervous system exerts its influence on the airways through both nervous reflex and biochemical mechanisms. The relative importance of these clinically in patients with asthma has not yet been elucidated. Vagally mediated reflex bronchoconstriction has been shown to be caused by many diverse physical and irritant agents, including histamine, infection, dust, and chemicals. These responses are abolished by vagal blockade.’ The biochemical mechanisms are involved in the homeostatic autonomic counterbalancing control of the smooth muscles of the bronchi, maintaining them in the state of patency required for adequate air conduction. The sympathetic system, through norepinephrine activation of adenyl cyclase, increases the intracellular concentration of adenosine monophosphate (cyclic 3’5’-AMP), causing bronchodilation. Conversely, the parasympathetic system, through acetylcholine activation of guanyl cyclase, increases the intracellular concentration of guanosine monophosphate (cyclic GMP), causing bronchoconstriction.* Desired adjustments can be made by shifting the balance, either raising the level of one or lowering the level of the
test
Ipratropium bromide (40 w9)
Mean 92.5 baseline (bpm) Time after administration -3.6 5 min 15 min -5.3 30 min -4.1 I hr 2 hr 3 hr
-5.3 -5.6
-11.1
4 hr 5 hr 6 hr
-7.6 -6.8 -4.9
Final
Placebo
Ipratropium bromide (40 P9)
91.8
91.1
-1.2 -4.6 -6.3 -5.9 -5.9 -0.2 -6.5 -6.9 -5.3
-3.0 -4.5 -5.9 -8.2 -5.7 -8.4 -8.4 -7.0 -2.8
from in 20
testt
Placebo 95.2
-4.8 -5.2 -7.6 -9.0 -7.6 -9.6 -8.0 -6.4 -7.8
*Differencesfrom baselineare basedon
the combined data from the two test days, i.e., days 0 and 1 at the beginning (initial test) and days 14 and 15 at the end of the study (final test). tAfter 2 wk of continuous treatment with ipratropium bromide.
other of the two opposing agents. In clinical practice to date, major efforts to achieve bronchodilation have been aimed at increasing the concentration of cyclic AMP, either by speeding its rate of synthesis using beta-2 stimulants or by the administration of xanthines, which slow its distruction. Atropine is the classic parasympatholytic agent that inhibits the action of acetylcholine and so allows the existing AMP in the cell to produce bronchodilation. However, the therapeutic usefulness of atropine is limited by undesirable side effects such as hesitancy in urination, blurring of vision, and dry mouth, which have recently been reported.s Ipratropium bromide administered by a metereddose inhaler appears to lack the deleterious effects
30
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
Chervinsky
attributed to atropine while retaining its beneficial properties. In this study, no adverse side effects followed the use of ipratropium bromide, and no changes were noted physically or on serial ECGs. Analysis of sputum data from the group with asthmatic bronchitis revealed no statistically significant changes in either volume or percent of dry weight from the beginning of the study through the end of the 2-wk period. In addition, the bronchodilator responses were longer lasting than those obtained in our prior studies with isoproterenol, persisting for a 4-hr period. The fact that a peak effect was not reached until after 30 min in some cases probably explains why this group of patients did not prefer ipratropium bromide to previously used bronchodilator aerosols. It could indicate that ipratropium bromide should be given on a routine prophylactic basis rather than just for acute episodes. Since there is no stimulation of the alpha or beta adrenergic systems, the unpleasant cardiac and nervous side effects often seen with the beta stimulants were not evident. Beta-blocking drugs such as propranolol may cause acute bronchoconstriction in asthmatics. However, this bronchoconstrictive effect can be prevented by atropine. lo Therefore ipratropium may be the therapeutic agent of choice in those patients with asthma who have cardiac disease which necessitates propranolol therapy.
Ipratropium bromide is a new addition to the pharmacologic armamentarium for the treatment of bronchospastic conditions. Being an effective bronchodilator free of side effects, it may well assume a major role in long-term maintenance therapy of reversible obstructive airway disease. REFERENCES 1. Chervinsky, P., and Chervinsky, G.: Metaproterenol tablets: Their duration of effect by comparison with ephedrine, Curr. Ther. Res. 17~507, 1975. 2. Ulmer, W. T.: Inhalation therapy with atropine derivatives, Med. Klin. 66:326, 1971. 3. Wallenstein, S.: The two-period repeated measurements change-over design with application to bioavailability trails. Paper presented at American Statistical Association Annual Meeting, New York, December, 1973. 4. Winer, B. J.: Statistical principles in experimental design, ed. 2, New York, 197 1, McGraw-Hill Book Co. 5. Dunn, P. J.: Multiple comparisons among means, J. Am. Stat. Assoc. 56:52, 1961. 6. Dunnett, C. W.: New tables for multiple comparisons with a control, Biometrics 20:482, 1964. nervous system I. Gold, W. M.: The role of the parasympathetic in airways disease, Postgrad. Med. J. 51:53, 1975. autonomic mechanisms in asthma, J. 8. Reed, C. E.: Abnormal ALLERGY CLIN.~MMUNOL. 53:34, 1974. 9. Klock, L. E., Miller, T. D., Morris, A. H., et al.: A comparative study of atropine sulfate and isoproterenol hydrochloride in chronic bronchitis, Am. Rev. Respir. Dis. 112:371, 1975. 10. Grieco, M. H., and Pierson, R. N.: Mechanism of bronchoconstriction due to beta-adrenergic blockade, J. ALLERGY CLIN.IMMUN~L. &143, 1971.
M.D. New Bedford,
Mass.
The efficacy and acceptability of ipratropium given by metered-dose inhaler were evaluated in two double-blind crossover tests against placebo, one preceding and one following a 2-wk period of continual open-label ipratropium treatment. Ten patients with chronic bronchitis and 10 with bronchial asthma participated. Ipratropium produced increases in FEV, of more than 15% within 5 min of inhalation, and this effect was maintained for 4 to 5 hr. Statistically sign@cant mean increases over the FEV, baseline values were recorded after ipratropium treatment in both the initial and the jinal crossover tests. There were no adverse reactions to any of the placebo or ipratropium test doses or to the ipratropium treatment. Serial electrocardiograms, laboratory tests, blood pressure, and pulse rate showed no change from the baseline. Sputum volume and dry-weight determinations in the patients with bronchitis before and after the Il-day treatment revealed no changes.
In recent years the therapy of reversible obstructive airways disease has been advanced primarily by the introduction of longer-acting and more selective beta adrenergic agonists and by the use of more effective dosages of xanthine derivatives.’ Use of the latter type of drug can give rise to cardiovascular and central nervous system stimulation, which frequently limits the usefulness of these agents. It has long been known that parasympathetic cholinergic mechanisms are of critical importance in the bronchomotor responses and that in asthmatic patients bronchoconstriction may be inhibited by blocking the postganglionic parasympathetic efferent pathways with atropine. Atropine has been used to treat asthma in the past. However, the fear that it would cause drying of secretions and the side effects of systemic administration have restricted its application. A new anticholinergic agent, Atrovent (ipratropium bromide),* has recently been introduced which when inhaled in very small doses relieves bronchoconstriction without causing undesirable systemic effects. Chemically, the compound is the
Presented at the Thirty-second Annual Meeting of the American Academy of Allergy, San Juan, Puerto Rico, March 6-10, 1976. Received for publication March 3 1, 1976. Accepted for publication June 22, 1976. Reprint requests to: Paul Chervinsky, M.D., Allergy Associates, Inc., 190 Hawthorn St., New Bedford, Mass. 02740. *Supplies of Atrovent for this study were made available by Boehringer Ingelheim Ltd., Elmsford, N. Y. Vol.
59, No.
1, pp.
22-30
bromomethylate of N-isopropyl-nortropine tropate. Its structure is shown in Fig. 1. Pharmacologically, ipratropium bromide differs from atropine in that it exerts no central effects and may be characterized as a peripheral anticholinergic.* The purpose of this study was to determine the bronchodilator efficacy and patient acceptability of ipratropium bromide. Patients were continuously treated with this agent for a 2-wk period, and double-blind crossover tests against placebo were carried out at the beginning and the end of the treatment period. PATIENTS AND METHODS For this study, 22 patients with chronic obstructive pulmonary disease involving a reversible bronchospastic component were selected. They comprised 11 men and women ranging in age from 18 to 67 yr. Ten of the patients had bronchial asthma, which was moderately severe in 6 cases and severe in 5. Two women with chronic bronchitis were lost to follow-up during the course of the study so that data from only 20 patients was available for evaluation. Absence of hypersensitivity to atropine or its derivatives and of significant cardiac, renal, hepatic, or metabolic disease was a prerequisite for admission to the study. Besides being challenged with isoproterenol aerosol prior to the study to prove that they responded to inhaled bronchodilators, the patients were given a complete physical examination after a complete history of each had been obtained, and a standard battery of laboratory tests, including SMA- 12, hematocrit, hemoglobin, white blood cell and differential counts, and urinalysis, were performed. Examinations were repeated at the end of the treatment period. Concomitant medication during the study was held to a
lpratropium
VOLUME 59 NUMBER 1
minimum. Ten of the patients were allowed to continue steroid medication during the study at the same minimal dose levels used prior to the study. No other inhaled bronchodilators could be used during the study, but oral bronchodilators could be taken if needed. The 2-wk treatment schedule called for two inhalations of 20 pg (or 40 pg) of ipratropium bromide 4 times a day from a metered-dose inhaler (an additional two whiffs were permitted during the night should the patient be awakened by an acute attack). The double-blind crossover tests against placebo were performed in the early morning on days 0 and 1 and days 14 and 15, on which single test doses of either ipratropium bromide (40 pg) or placebo (two inhalations) were administered to patients randomly assigned to two groups that received either ipratropium bromide or placebo on the first test day and the other preparation on the second. No other anticholinergic medication was allowed for at least 24 hr prior to the first test day and for the duration of the study. To assess the drug’s efficacy, pulmonary function tests were performed on each test day before the treatment to secure baseline values and at the following intervals after administration of the single doses: 5. 15, and 30 min and 1, 2, 3, 4, 5, and 6 hr. The following values were determined: forced expiratory volume in 1 set (FEV,), forced vital capacity (FVC), forced midexpiratory flow (FEF2S(k.75’ir), and peak expiratory flow rate (PEFR). For technical reasons, statistical analysis had to be confined to the FEV, data. Data from all 20 patients were comand F&~-75, bined since there was no statistically significant heterogeneity in the characteristics of the patients with bronchial asthma and those with chronic bronchitis, respectively. Further, no statistically significant difference was found in the error mean squares of these two diagnostic groups. Blood pressure and pulse rate were measured along with pulmonary function at each test interval as well as before administration of test doses. An electrocardiogram (ECG) was recorded before the treatment and at the conclusion of the 6-hr study each day. Rhythm strips were taken at each test interval. The overall clinical impression of the effectiveness of the treatment based on the patient’s symptoms and general condition was recorded after each test dose, and a global evaluation of response was also made after 1 and 2 wk of continuous ipratropium treatment. In addition, the patients themselves were asked at the conclusion of the 2-wk treatment to compare the results with those produced by inhaled bronchodilators they had used in the past. In an effort to assess the possible effect of ipratropium inhalation on sputum volume and weight, a 24-hr collection of sputum was made in the chronic bronchitis patients before administration of the drug (day 0) and again on day 14. The statistical analysis of the results was based on the methods described by Wallenstein3 using differences from baseline values, for a two-period repeated-measurements changeover study design. If a statistically significant (p < 0.05) period effect, i.e., group/treatment interaction, was found, the first-period data were subjected to a two-way analysis of variance for re-
CH, -
bromide
CH -CH,
/ I CH,N-CH
23 +Br-
CH3 \
HC-O-C-CH-
CH,-CHFIG. 1. Structural
formula
for ipratropium
bromide.
peated measurements on one factor. This methodology is derived from Winer.4 Dunn’s multiple comparison among mean? was used to compare ipratropium bromide treatment with placebo treatment. Finally, Dunnett’s test6 was used to compare the means at the various measurement times with the baseline means for each treatment.
RESULTS FEV1. On analysis, the FEVl data recorded at the different
intervals
after administration
in the initial
crossover test, i.e., on days 0 and 1, were found to lack consistency or, in statistical terms, to reflect a significant treatment/time interaction; the same was not true of the FEV, responses in the final test (days 14 and 15). The mean changes in FEV, from the mean baseline values for the 20 patients are presented for the initial and the final crossover tests in Tables I and II, and the corresponding mean percent changes are shown graphically in Figs. 2 and 3. The increases in FEV, obtained after ipratropium bromide administration in the initial test period were significantly (p < 0.05) greater than those obtained after placebo administration at 1 and 2 hr. They also substantially surpassed the palcebo responses at all other test intervals, and the grand mean increase for all the intervals after administration also exceeded the mean change after placebo to a statistically significant degree (p < 0.05). In the final crossover test, too, the grand mean FEV, increase after active drug administration exceeded the response to placebo to a highly significant degree (p < 0.01). In both the initial and the final test, mean FEV, increases following ipratropium inhalation rose above the clinically meaningful level of + 15% for at least 4 hr after administration. This level was never reached by the patients given placebo, who in fact showed mean decreases in FEV, at several test intervals. FEFmm . Geometric mean changes from geometric mean baseline values at the beginning and the end of the study are shown in Figs. 4 and 5. Statistically significant increases over baseline were recorded with ipratropium bromide in the initial test at seven measurement intervals but at only one interval with placebo.
24 Chervinsky
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
IIIII 0
5
15
30
60
I
I
I
I
120
160
240
300
MmtesafterTest
FIG.
2. Mean
ipratropium
percent
changes
bromide
therapy
in FEV,
relative
to baseline
in 20 patients (double-blind
I. Mean changes (from baseline) in FEV, (ml) at beginning of study (days 0 and 1) in 20 patients
TABLE
Time
lpratropium bromide* (40 IrId
Placebo*
Baseline
1,342.5
1,344.2
5 min 15 min 30 min 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr Grand
+251.5 +230.0 +258.8 +351.2 +388.1 +333.2 +268.6 +229.2 + 169.8 +276.3
-6.8 +32.0 -5.5 +44.5 +87.0 + 176.2 + 153.4 +93.6 +30.7 +67.2
Diierence between ipratropium bromide vs placebo
-1.7 +264.3 + 198.0 +264.3 +306.7t +301.1t + 157.0 +115.2 +135.6 +139.1 +209. It
mean
(over time)
I 360
Dose
values
at the
beginning
of 2 wk
of continuous
crossover test against placebo). TABLE II. Mean changes (from baseline) in FEV, (ml) at end of study (days 14 and 15) in 20 patients
Time
Baseline 5 min 15 min 30 min 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr Grand mean (over time)
lpratropium bromide* (40 CL91
1,364.0 +211.0 +216.0 +294.8 +277.2 +319.8 f253.2 +283.2 +143.6 +68.5 +229.7
Placebo*
1,333.5 -41.2 -34.8 -59.8 +6.8 +21.5 +42.8 -7.9 +2.1 -39.6 -12.9
Difference between ipratropium bromide vs placebo
+30.5 +258.2 +250.8 +354.61 +270.4 +398.3 +210.4 +291.1 +141.5 +108.1 +242.6$
*The 95% confidence limits for the mean changes at the individual intervals were 269.9 ml. tStatistically significant, p < 0.05.
*The 95% confidence limits for the mean changes at the individual intervals were 298.5 ml. tStatistically significant, p < 0.05. SStatistically highly significant, p < 0.01.
In the final test the FEF25~75s responses to placebo were consistently negative, whereas the differences between the mean values obtained after ipratropium treatment and the baseline values were statistically significant at most intervals. The overall mean increases after ipratropium bromide were significantly greater (p < 0.02) than the increase after placebo.
The small sample size of 20 patients and an intrinsically wide range of individual variability among these patients may have been responsible for failure to detect statistically significant differences in FEFzsS.751, between the active drug and placebo at the various intervals in the two crossover tests. FVC. The mean changes from the mean baseline values obtained in the 20 patients on days 0 and 1 and
lpratropium
VOLUME 59 NUMBER 1
lpratropium
_-
I
I
I
I
I
I
0
5
15
30
60
FIG. 3. Mean bromide
percent changes in FEV, relative therapy in 20 patients (double-blind
”
18
”
16
1
I
2
I
I
I
1
240
300
360
values at the end of 2 wk of continuous test against placebo).
3
25
bromide
120 180 Minutes after Test Dose
to baseline crossover
bromide
4
5
ipratropium
6
Hours
FIG. 4. Geometric of continuous
mean ipratropium
changes of FEF2ss-75% (Llmin) from bromide therapy in 20 patients
days 14 and 15, respectively, are presented graphically in Figs. 6 and 7. Here the superior response to ipratropium bromide when compared with placebo becomes particularly evident in the final test results since a fairly large placebo response was obtained in the initial test, before continuous treatment with the parasympatholytic drug had been initiated. PEFR. Mean percent changes obtained in the initial and final tests after ipratropium bromide and placebo are presented in Figs. 8 and 9. It is seen that in the initial test, mean increases in the peak expiratory flow rate exceeded 15% at all intervals up to 5 hr, reaching a peak of nearly 34% at 2 hr, while increases after
geometric (double-blind
mean
baseline crossover
at the beginning of 2 wk test against placebo).
placebo reached a mean peak of only 8.4%. Again, after 2 wk of continuous ipratropium treatment, the placebo responses fell off sharply, whereas response to ipratropium remained at approximately the same level as observed in the initial test. Global responses. To evaluate the individual patients’ global responses, numerical ratings were used to indicate that the response was either excellent (5), good (4), or fair (3); that there was no change in the patient’s condition (2); or that it was worse (1). The mean value of the ratings assigned to the results produced by ipratropium bromide in the initial test was 4 as compared with 2.5 for placebo. The mean response
26
Chervinsky
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
2 E
24 22
>
20
‘: k
18
2 z
16 14 12
z
10
3 ? E
6
5
2
E .o f
E & c.7
8 4
O -2 -4 -6 -8 -10
2
1
3
4
5
6
Hours
FIG. 5. Geometric mean continuous ipratropium
changes bromide
of FEFzs%-7s~ (Llmin) therapy in 20 patients
from geometric (double-blind
mean baseline at the end of 2 wk of crossover test against placebo).
2800
2700
^ 5
2600
2500
2400
2300
0
FIG. 6. Mean values patients (double-blind
of FVC (ml) crossover
5
15
30
60
ii0 Minutes
180 after Test Dose
at the beginning of 2 wk of continuous test against placebo).
to ipratropium bromide in the final crossover test was rated 3.6 as compared with 2.4 for placebo. In both cases the difference between the active drug and placebo was highly significant (p < 0.01). We further rated the patients’ global responses after 7 and 14 days of continuous ipratropium bromide therapy. The mean ratings were 3.4 and 3.5, respectively (Tables III and IV). The patients’ own expressed preferences at the end of this 2-wk treatment were inconclusive: while 8 patients found ipratropium bromide better than previ-
240
300
ipratropium
360
bromide
therapy
in 20
ously used bronchodilator aerosols, 3 found the effects to be the same, 8 others preferred inhaled bronchodilators used before the study, and 1 had no preference. Sputum study. Sputum data obtained on days 0 and 15 of the study from 8 patients with chronic bronchitis revealed no statistically significant differences in the mean values for volume and dry weight (no data were available from the other 2 patients with chronic bronchitis) (Table V). Blood pressure. Both ipratropium bromide and
lpratropium
VOLUME 59 NUMBER 1
I
. lpratropium
bromide
27
bromide
2500
I
2400
‘\
,’ \ 2300
\
J
\
’
\
\
Y \ -1--
A’/
240
300
.
2200 e 0
5
15
30
60
120 Mm&s
FIG. 7. Mean (double-blind
Placebo
*-N ---W-l--*-
180
360
after Test Dose
values of FVC (ml) at the end of 2 wk of continuous crossover test against placebo).
ipratropium
bromide
therapy
in 20 patients
80 ,
E .5
70
$ .n
E 2 =.c E
6o
2
40
E ;
30
5 g
20
50
:: ,g ”
10
zF+
0
L
-10
1 1
3
2
4
5
6
Hour?
FIG. 8. Mean bromide
therapy
changes of PEFR in 20 patients
(Llmin) from (double-blind
baseline crossover
placebo decreased the mean systolic blood pressure, whereas no consistent pattern emerged from diastolic blood pressure readings. No substantial difference in the magnitude of the changes after ipratropium bromide and placebo, respectively, is apparent. Pulse rate. Table VI shows the mean changes from baseline pulse rates at the various intervals in the
at the beginning of 2 wk test against placebo).
of continuous
ipratropium
initial and final crossover tests. Once again, all the mean changes were negative after both ipratropium bromide and placebo, and no significant difference was apparent between the two preparations in the magnitude of the changes recorded after inhalation. ECG changes. No significant ECG changes were noted except in 1 patient, a 23-year-old woman with
28
Chervinsky
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
60 .-2
a,
70
% a
E 6o 2 :
50
E J‘
40
u ;
30
5
m 20 b
5 0
10
g
0
f -10 1
3
2
4
5
6
Hours FIG. 9. Mean changes therapy in 20 patients
of PEFR (Llmin) from baseline at the end of 2 wk of continuous (double-blind crossover test against placebo).
TABLE III. Global medical evaluation* end of study (days 14 and 15)
of patients’
responses
to treatment
ipratropium
at beginning
bromide
(days 0 and 1) and
Treatment?
No. of patients
Days 0 and I Bronchial asthma patients Chronic bronchitis patients Combined data (both diagnostic groups) Days 14 and IS Bronchial asthma patients Chronic bronchitis patients Combined data (both diagnostic groups)
lpratropium bromide (40 CL(J)
Placebo (0 Ml)
Difference
p value
10
4.2
2.1
2.1
0.02
10
3.8
2.9
0.9
0.10
20
4.0
2.5
1.5
co.01
10
3.5
2.5
1.0
0.18
IO
3.6
2.4
1.2
0.01
20
3.6
2.4
1.2
*The patient’sresponsewasscoredas follows:excellent= 5; good = 4; fair = 3; no change= 2; worse= 1. tValues aremeansof the raw scores. bronchial asthma, who showed a normal ECG before the start of the study but exhibited generalized nonspecific T wave changes after the initial test dose of ipratropium bromide. No such changes were seen in the ECG taken at the end of the final crossover test. Adverse reactions. No adverse reactions of any
kind were observed or reported on any of the test days or duing the 2-wk treatment period. Physical examination and laboratory data. Physical examinations performed at the end of the 2-wk period disclosed no particularly remarkable changes. Laboratory data secured at the end of the treatment
lpratropium
VOLUME 59 NUMBER 1
TABLE
IV.
Global
medical
evaluation*
of response
to ipratropium
bromide
treatment
during
bromide
29
the Z-wk study
period Mean No. of patients
Bronchial asthma patients Chronic bronchitis patients Combined data (both diagnostic group)
scores
Day 7
Day 15
Mean of difference
p value
2.9 4.0 3.4
3.5 3.6 3.5
-0.6 +0.4 -0.1
0.19 0.17 0.72
IO IO 20
*The patient’sresponseto continuingtreatmentwasscoredas follows:excellent= 5; good = 4; fair = 3; no change= 2: worse= I. TABLE V. Sputum data collected from patients with chronic bronchitis* at beginning (day 0) and end (day 14) of study Mean
Variable
Volume (ml’) Dry weight (%)
Day 0 23.5 1.9
TABLE
baseline patients*
Pulse (bpm): mean differences at various intervals after test doses
VI.
Initial
values
Day 23.1 2.4
14
Mean of differences
pvalue
-0.4 +0.03
0.73 0.20
*Althoughtherewere 10 patientsin this group,datawereavailable from only 8 of them. period also reflected no significant changes that could in any way be related to the bronchodilator administered . DISCUSSION The parasympathetic nervous system exerts its influence on the airways through both nervous reflex and biochemical mechanisms. The relative importance of these clinically in patients with asthma has not yet been elucidated. Vagally mediated reflex bronchoconstriction has been shown to be caused by many diverse physical and irritant agents, including histamine, infection, dust, and chemicals. These responses are abolished by vagal blockade.’ The biochemical mechanisms are involved in the homeostatic autonomic counterbalancing control of the smooth muscles of the bronchi, maintaining them in the state of patency required for adequate air conduction. The sympathetic system, through norepinephrine activation of adenyl cyclase, increases the intracellular concentration of adenosine monophosphate (cyclic 3’5’-AMP), causing bronchodilation. Conversely, the parasympathetic system, through acetylcholine activation of guanyl cyclase, increases the intracellular concentration of guanosine monophosphate (cyclic GMP), causing bronchoconstriction.* Desired adjustments can be made by shifting the balance, either raising the level of one or lowering the level of the
test
Ipratropium bromide (40 w9)
Mean 92.5 baseline (bpm) Time after administration -3.6 5 min 15 min -5.3 30 min -4.1 I hr 2 hr 3 hr
-5.3 -5.6
-11.1
4 hr 5 hr 6 hr
-7.6 -6.8 -4.9
Final
Placebo
Ipratropium bromide (40 P9)
91.8
91.1
-1.2 -4.6 -6.3 -5.9 -5.9 -0.2 -6.5 -6.9 -5.3
-3.0 -4.5 -5.9 -8.2 -5.7 -8.4 -8.4 -7.0 -2.8
from in 20
testt
Placebo 95.2
-4.8 -5.2 -7.6 -9.0 -7.6 -9.6 -8.0 -6.4 -7.8
*Differencesfrom baselineare basedon
the combined data from the two test days, i.e., days 0 and 1 at the beginning (initial test) and days 14 and 15 at the end of the study (final test). tAfter 2 wk of continuous treatment with ipratropium bromide.
other of the two opposing agents. In clinical practice to date, major efforts to achieve bronchodilation have been aimed at increasing the concentration of cyclic AMP, either by speeding its rate of synthesis using beta-2 stimulants or by the administration of xanthines, which slow its distruction. Atropine is the classic parasympatholytic agent that inhibits the action of acetylcholine and so allows the existing AMP in the cell to produce bronchodilation. However, the therapeutic usefulness of atropine is limited by undesirable side effects such as hesitancy in urination, blurring of vision, and dry mouth, which have recently been reported.s Ipratropium bromide administered by a metereddose inhaler appears to lack the deleterious effects
30
J. ALLERGY CLIN. IMMUNOL. JANUARY 1977
Chervinsky
attributed to atropine while retaining its beneficial properties. In this study, no adverse side effects followed the use of ipratropium bromide, and no changes were noted physically or on serial ECGs. Analysis of sputum data from the group with asthmatic bronchitis revealed no statistically significant changes in either volume or percent of dry weight from the beginning of the study through the end of the 2-wk period. In addition, the bronchodilator responses were longer lasting than those obtained in our prior studies with isoproterenol, persisting for a 4-hr period. The fact that a peak effect was not reached until after 30 min in some cases probably explains why this group of patients did not prefer ipratropium bromide to previously used bronchodilator aerosols. It could indicate that ipratropium bromide should be given on a routine prophylactic basis rather than just for acute episodes. Since there is no stimulation of the alpha or beta adrenergic systems, the unpleasant cardiac and nervous side effects often seen with the beta stimulants were not evident. Beta-blocking drugs such as propranolol may cause acute bronchoconstriction in asthmatics. However, this bronchoconstrictive effect can be prevented by atropine. lo Therefore ipratropium may be the therapeutic agent of choice in those patients with asthma who have cardiac disease which necessitates propranolol therapy.
Ipratropium bromide is a new addition to the pharmacologic armamentarium for the treatment of bronchospastic conditions. Being an effective bronchodilator free of side effects, it may well assume a major role in long-term maintenance therapy of reversible obstructive airway disease. REFERENCES 1. Chervinsky, P., and Chervinsky, G.: Metaproterenol tablets: Their duration of effect by comparison with ephedrine, Curr. Ther. Res. 17~507, 1975. 2. Ulmer, W. T.: Inhalation therapy with atropine derivatives, Med. Klin. 66:326, 1971. 3. Wallenstein, S.: The two-period repeated measurements change-over design with application to bioavailability trails. Paper presented at American Statistical Association Annual Meeting, New York, December, 1973. 4. Winer, B. J.: Statistical principles in experimental design, ed. 2, New York, 197 1, McGraw-Hill Book Co. 5. Dunn, P. J.: Multiple comparisons among means, J. Am. Stat. Assoc. 56:52, 1961. 6. Dunnett, C. W.: New tables for multiple comparisons with a control, Biometrics 20:482, 1964. nervous system I. Gold, W. M.: The role of the parasympathetic in airways disease, Postgrad. Med. J. 51:53, 1975. autonomic mechanisms in asthma, J. 8. Reed, C. E.: Abnormal ALLERGY CLIN.~MMUNOL. 53:34, 1974. 9. Klock, L. E., Miller, T. D., Morris, A. H., et al.: A comparative study of atropine sulfate and isoproterenol hydrochloride in chronic bronchitis, Am. Rev. Respir. Dis. 112:371, 1975. 10. Grieco, M. H., and Pierson, R. N.: Mechanism of bronchoconstriction due to beta-adrenergic blockade, J. ALLERGY CLIN.IMMUN~L. &143, 1971.