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The short-term bronchodilator effects of fenoterol and ipratropium in asthma
The short-term bronchodilator effects of fenoterol and ipratropium in asthma Richard Vancouver,
K. Elwood, B.C.,
M.B., M.R.C.P.,*
and Raja T. Abboud,
M.D., F.R.C.P.(C)
Canada
We studied the bronchodilator effects of inhaled,fenoterol, a relatively selective beta-2 adrenergic agent, and ipratropium an anticholinergic drug, singly and in combination in IO patients with asthma. The period of observation was 6 hr after aerosol administration. The six drug regimens used were fenoterol 100 t.Lg,fenoterol 200 Fg, fenoterol 50 pg combined with 20 t.Lg of ipratropium, fenoterol 100 t.Lg combined with 40 pg of ipratropium, 40 kg of ipratropium, and placebo. Measurements consisted of spirometry with determination of forced expiratory volume in one second (FEV,), maximal expiratory jlow at 50% of vital capacity (VsO), specific airway conductance, lung volumes, and heart rate. Bronchodilation with regimens containing fenoterol was rapid, with 7570 of the maximum response achieved by 5 min, while the peak effect of ipratropium was delayed for I to 2 hr. Fenoterol 100 pg produced approximately half the degree of improvement in FEV, and V,, compared with 200 p,g of fenoterol. The addition of 40 pg of ipratropium to 100 Fg of fenoterol resulted in bronchodilation equivalent to 200 pg fenoterol and was associated with a more prolonged effect than fenoterol 100 pg. Tremor was observed in two subjects inhaling fenoterol200 pg but was not observed with any other regimen. It is concluded that the combination of inhaled ipratropium and fenoterol is an effective bronchodilator in asthma, achieving efficacy similar to that of fenoterol alone but with,fewer side effects. (J ALLERGY CLIN IMMUNOL 69:467, 1982.)
The principal aim in the treatment of asthma is the relief of airflow obstruction, the main component of which is bronchospasm. The contribution of autonomic influences to bronchomotor tone in asthma has not been well defined, but both abnormalities in beta-adrenergic receptors’ and increased cholinergic activity23 3 have been postulated. It has been suggested that brocilial adrenoceptors are themselves abnormal in asthma, being partially blocked or inadequate in number. l On the other hand, increased vagal activity in asthmatics may result from a lower-than-normal threshold for stimulation of irri-
tant receptors, leading to excessive activity of vagal efferents producing exaggerated tone.2B3 This efferent activity is cholinergically mediated and therefore available for blockade with anticholinergic drugs such as atropine4, 5 or the recently developed atropine derivative, ipratropium bromide (Sch 1000),6-8 which can be administered in aerosol form and does not have the undesirable side effects of atropine. Because both autonomic abnormalities may play a role in asthma concurrently, the use of combined beta agonists and anticholinergic drugs as bronchodilators might prove superior to either alone. To evaluate this possibility, we evaluated in 10 asthmatic subjects the
From the Respiratory Division, Department of Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, B.C. Supported by a grant from Boehringer Ingeiheim and by the British Columbia Lung Association. Received for publication Sept. 28, 198 1. Accepted for publication Feb. 16, 1982. Reprint requests to: Dr. R. T. Abboud, Respiratory Division, Department of Medicine, Vancouver General Hospital, Vancouver, B.C., Canada V5Z lM9. *Fellow of the British Columbia Lung Association.
Abbreviations used FEV,: Forced expiratory volume in one second FVC: Forced vital capacity V,,: Maximal expiratory flow at 50% of FVC FRC: Functional residual capacity SG,,: Specific airway conductance TLC: Total lung capacity RV: Residual volume MEFV: Maximum expiratory flow volume
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1982 The
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TABLE
and
J. ALLERGY CLIN. IMMUNOL. MAY 1982
Abboud
I. Characteristics
and
Subject No.
Age (vr)
Height
1 2 3 4 5 6 7 8 9 10
28 37 27 61 21 49 40 28 54 30
163 176 168 156 170 172 180 150 160 182
34.1 16.9
167.7 10.4
Mean SD *Data
baseline
(cm)
lung
Sex
function
data
Duration asthma
F F M F M M M F F M
of (yr)
of the
10 asthmatic
subjects
FEV, &I*
% Increase in FEV, with 200 pg fenoterol
16 8 25 11 18 14 10 3 18 4
2.32 2.22 1.74 1.29 2.31 1.73 2.34 1.43 1.58 2.54
(73) (66) (44) (55) (47) (50) (69) (55) (63) (58)
12.7 6.8
1.95 (58.0) 0.44 (9.6)
V50 (Llsec)”
26 46 38 31 28 55 39 39 29 45
2.02 1.12 0.94 0.57 2.05 1.11 1.33 1.17 1.28 1.17
(42) (23) (16) (15) (40) (21) (23) (26) (32) (19)
37.6 9.3
1.27 (25.7) 0.45 (9.4)
in parentheses expressed as percent of predicted value.
short-term bronchodilator effects of inhaled fenoterol, a relatively selective beta-2 agonist, given in combination with ipratropium and compared them with the bronchodilator effects of either drug given alone.
MATERIALS
AND METHODS
Ten patients with asthma, as defined by the criteria of the American Thoracic Society,g were studied. Subjects were selected who did not have histories of chronic bronchitis and who showed a greater than 20% increase in FEV, after inhalation of 200 pg of fenoterol by aerosol. Informed consent was obtained from all patients. The characteristics of the patients and their lung function data are shown in Table I. Subjects ranged from 2 1 to 6 1 yr of age; only one (subject 6) was a current smoker, two (subjects 7 and 10) were exsmokers, and the remainder were nonsmokers. At the time of study, the patients’ asthmatic conditions were stable and controlled with various regimens consisting of combinations of inhaled beta-2 adrenergic drugs, oral theophylline, and inhaled beclomethasone; none of the patients was receiving anticholinergic medication. The FEV, at the time of selection for study is shown in Table I, which also indicates the percent increase in FEV, after inhalation of 200 pg of fenoterol. Each subject was studied on 6 different days, at least 3 days apart, to determine the effect of six different regimens as follows: 100 lg fenoterol, 200 pg fenoterol, 50 I*g fenoterol plus 20 pg ipratropium, 100 pg fenoterol plus 40 pg ipratropium, placebo, and 40 pg ipratropium. Each aerosol regimen was delivered in an identical manner by a series of six immediately consecutive inhalations from a set of six coded metered dose inhalers; each inhaler puff delivered 50 pg of fenoterol, 20 pg of ipratropium, or placebo, depending on the particular set of six inhalers used. Subjects inhaled maximally from resting lung volume, held their breath for 5 set, exhaled to resting lung volume, and immediately repeated the procedure for the subsequent inhalers; the six inhalations were completed in approximately 1
min. The first five regimens, i.e., fenoterol alone and in combination with ipratropium, and placebo, were given in a double-blind randomized manner. The sixth regimen of ipratropium was given in a single-blind manner. Patients were instructed to abstain from bronchodilator drugs for at least 12 hr prior to the study. Patients reported to the laboratory at 8:00 A.M. and baseline measurements of FEV, were performed; if these differed by more than 20% from previous baseline values, the study on that day was postponed and the patient was restudied on another occasion. Spirometry was performed with an Ohio 842 rolling seal spirometer, along with measurement of FEV, and FVC and determination of MEFV curves; at least two comparable tracings were obtained, and the best effort was used. The MEFV curves were recorded on a rapid response X-Y recorder (Hewlett Packard 7045 A), and v,,, was determined from the best curve. FRC, airway resistance, and thoracic gas volume were measured in a constant volume body plethysmograph (W. E. Collins Inc.), according to the techniques of DuBois et al.,‘O using an Electronics for Medicine DR-8 recorder. At least four measurements were made and the mean value was used for calculation. Airway resistance was converted to its reciprocal conductance, which was divided by thoracic gas volume to obtain SG,,. TLC was calculated by adding FRC and inspiratory capacity. RV was obtained by subtracting FVC from TLC. Table I shows the values of vso, FVC, TLC, FRC, RV, and SG,, obtained prior to drug administration on the initial day. Predicted values for FEV, were obtained from Morris et al.,” for Qso from Chemiack and Raber,” and for lung volumes from Goldman and Becklake.13 Heart rate by radial pulse palpation and spirometric values were determined before and at 5, 10,20,30, and 60 min after drug administration and hourly thereafter for 6 hr; plethysmography was done at all time intervals except at 5 min. For each parameter determined, the percent change at the different time intervals after aerosol inhalation was calculated with reference to the measurement obtained prior to inhalation. Mean values plus or minus standard e~ors were
VOLUME
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Fenoterol
and
ipratropium
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NUMBER 5
(see
SG., 0.073 0.055 13.045 0.069 ~0.100 0.046 10.085 0.082 10.096 0.059
3.30 4.59 3.52 2.18 3.50 4.42 5.47 3.03 2.60 4.37
0.071 0.020
(92)
TLC (LP
FRC uJ*
:i!;
x: cm H,O)-1
2.55 5.30 4.59 3.46 3.93 4.70 7.04 2.10 3.33 6.57
(92) (155) (136) (140) (125) (133) (176) (95) (125) (160)
3.69(93.5)
4.36
(133.7)
1.01 (12.4)
1.62 (26.6)
(110) (78) (82) (85) (105)
(110) (103) (89)
(81)
computed for the group as a whole. For statisticalanalysis, a log transformation was made of the calculated values of percent change from baseline. Analysis of variance was applied at each time point, with both drug and patient effect
considered in the analysis; a p value less than 0.05 was considered statistically significant. Whenever a statistically significant drug effect was noted, Duncan’s multiple range test’? was used to determine which regimens were significantly different.
RESULTS The mean percent change in FEV, for the 10 subjects is shown for each regimen in Fig. 1. The onset of action of any regimen containing fenoterol was rapid, achieving statistical significance compared with placebo by 5 min, at which time approximately 75% of the eventual peak bronchodilation occurred. In contrast, bronchodilation with ipratropium alone was more gradual, not reaching statistical significance until 20 min and having a maximum effect between 60 and 120 min. The maximal bronchodilator effect resulted from the inhalation of 200 pg of fenoterol alone and from the combination of 40 pg of ipra&opium to half that dose of fenoterol (100 pg). The addition of ipratropium to fenoterol 100 @g also had the effect of prolonging the duration of action when compared with 100 pg of fenoterol alone, resulting in a mean of 15% improvement even at 5 hr. The 100 pg fenoterol dose produced approximately half the degree of improvement of fenoterol 200 pg, as expected. The peak bronchodilator effect of fenoterol 100 pg wa.s approximately equivalent to 40 pg ipratropium given alone; however, 40 pg of ipratropium had a significant bronchodilator effect at 4 hr, while fenoterol 100 pg had no such significant effect.
5.45 8.15 7.22 5.34 6.12 8.61
(109) (135)
E 2.15 3.56 3.70 3.16 2.62 4.19 5.75 1.27 2.80 5.24
(151) (178) (224) (204) (165) (202) (265) (113) (175) (252)
7.14(124.2)
3.44
(192.9)
2.21 (16.4)
1.36 (46.3)
(116) (127) (107) (138)
11.22 (158) 4.30 5.40 9.61
(106)
(118) (128)
The total bronchodilator effect of each regimen over the 6 hr observation period was examined by integrating the areas under the curve for each patient and then calculating the mean percent change averaged over the 6 hr. The mean bronchodilation achieved over 6 hr by the six treatment regimens and expressed as percent change in FEV, are shown in Table II; the greatest improvement (about 26%) resulted from fenoterol 200 pg and from the high-dose combination of fenoterol and ipratropium. In general the findings obtained with measurements of flow rates from MEFV curves were similar to the FEV, data. Results of percent change in $‘,, are shown in Fig. 2. All drug regimens containing fenoterol showed significant improvement in ‘?,, at 5 to 60 min, while 40 p.; of ipratropium did not show a statistically significant effect until 60 min. The average bronchodilator effects over the 6 hr period, obtained by integrating the areas under the curves, are shown in Table II. Fenoterol 200 pg had a greater effect than fenoterol 100 ,ug or ipratropium alone but was not significantly different from the combinations of fenoterol and ipratropium. Changes in specific airway conductance expressed as percent improvement over the initial value are shown in Fig. 3. The results in general are similar to those obtained with FEV, and \jsO; however, the peak improvement in SG,, with ipratropium tended to be less than that of fenoterol 100 pg, although these two regimens had equal peak effects on both 7j5,, and FEV,. The average percent improvement over the 6 hr period, determined by integrating the area under the curve, was not significantly different between any of the drug regimens (Table II); mean increases in SG,, ranged from 62% to 84%.
470
Elwood
and Abboud
J. ALLERGY CLIN. IMMUNOL. MAY 1992
FEY 1
I 150
c-4
FlOO
s - 4 -4 * - *
F200 FSO + s20 FitlO + 540
SGAY
e_ p
w -- 1
FlOO F200
w-
00 + 520
s 4 e-4
FlOO + 540 P
. - 4
540
\
-10
0
1 IO
1 20
30
1 60
1
1 120
1
1
1
180 TIME INTERVAL( MINUTES1
1 240
1
1 X0
1
I 360
FIG. 1. Mean percent change in FEV, in the 10 asthmatic subjects with the different drug regimens. Note that the maximal response to ipratropium was delayed compared with regimens containing fenoterol. F700, Fenoterol 100 pg; F200, fenoterol 200 pg; F50 + S20, fenoterol 50 pg plus 20 pg ipratropium, FIUO + WI, fenoterol 100 pg plus 40 pg ipratropium, P, placebo; S40, 40 pg ipratropium.
-301 0
1 IO
1 20
1 30
1 60
'
120
1 180
1 240
1
1 3CO
1
k 36
TIME INTERVAL( MINUTES1
FIG. 3. Mean percent change in SGW in the 10 asthmatic subjects. Note that the peak effect of 40 pg of ipratropium was less than that with 100 pg of fenoterol, while their peak effects on FEV, and i/,, were similar. See Fig. 1 legend for abbreviations.
averaged over the 6 hr period (Table II). Of interest was the finding that fenoterol 200 pg did not have a significant effect on FRC. RV was statistically significantly reduced by all drug regimens for up to 60 min after aerosol inhalation; the greatest decrease was observed with the high-dose combination regimen (Table II). The changes in TLC were minimal and variable (Table II). There were no significant changes in heart rate and none of the patients complained of palpitations or headache. Two patients had mild and transient tremor with the high dose of fenoterol, but no other side effects were noted. 0
IO
20
30
60
120
I80
240
300
360
TIME INTERVAL( MINUTES)
FIG. 2. Mean percent change in \i,, in the subjects. See Fig. 1 legend for abbreviations.
10 asthmatic
With all drug regimens there was a trend for an increase in FVC (Fig. 4, A, Table II). The changes in FRC and RV are shown in Fig. 4, B and C. Statistically significant decreases in FRC at 10 min were obtained with only two regimens, fenoterol 100 pg and the combination of fenoterol 100 pg with ipratropium; the greatest decrease in FRC was obtained with the latter regimen, which resulted in a statistically significant decrease of 9.9% + 2.6%, when
DISCUSSION Our findings verify previously reported studies on the effectiveness of the anticholinergic aerosol, ipratropium, used alone15 and in combination with betaadrenergic aerosols16 in asthma. We found that the combination of 100 pg of fenoterol with 40 pg of ipratropium produced bronchodilation equivalent to fenoterol alone in a dose of 200 pg; in addition, the combination may have a more prolonged action as suggested by a greater effect on FEV, and SG,, at 4 and 5 hr. It should be noted that the recommended dose of fenoterol for clinical use is 200 to 400 pg but maximal effect is achieved with 200 pg.“, I* The onset of action of any regimen containing fenoterol was rapid, with 75% of the eventual bronchodilation
VOLUME 69 NUMBEF: 5
TABLE
II. Mean
Fenoterol
effect of the different FEV,
--
Fenoterol 100 pg Fenoterol 200 pg Fenoterol 50 pg + ipratropium
20
12.1 -t 3.2 25.4 + b.O+ 20.4 i 3.21
drug
irso
23.5 + 6.1 51.4 c 10.31 41.8 t 5.31
regimens
on lung function
62.6 + 13.0t 68.1 c 14.4i 68.4 + 14.21.
in the 10 asthmatic
FVC
SGaw
f
ipratropium
471
patients*
FRC
RV
-4.7 2 2.6 0.3 k 2.8 -0.2 r 5.0
-5.6 k 3.0 0.4 2 5.4 -7.8 t 5.2
4.4t
-9.9
+ 2.bt
-9.2
+- 5.8-i- -1.8
2 1.5
5.3
-0.5
5 4.0
-7.1
-+ 5.2
5 2.0
3.1 2 2.4 9.1
and
4.0
9.1 t 2.2
TLC
-0.9 2 1.4 3.3 k 0.7 -0.4 t 2.4
ccg
Fenoterol 100 26.2 -+ 8.8-t 48.8 ? 15.9? 84.0 i 22.11- 10.0 lr pg t ipratropium 40 p,g Ipratropium .40 20.1 c 6.bt 34.8 ? 9.8t 61.9 L 12.91 8.5 t Pg Placebo 1.4 * 3.4 3.5 k 6.4 9.7 * 9.3 -0.5 t -*Mean % change c SE determined by integrating the area under the curve over I-Statistically significantly different f&n pl&ebo, p < 0.05. achieved by 5 min. Ipratropium, on the other hand, was slower in reaching its peak effect, which occurred
between 60 and 120 min and tended to have a more prolonged bronchodilator effect than fenoterol alone. Combination of the two drugs allowed a rapid onset of action, while prolonging the duration of bronchodilation, and achieved what appears to be an additive effect. An interesting finding was that the smaller dose of the combination of fenoterol(50 pg) and ipratropium (20 pg) produced greater bronchodilation than would be expected by adding half the effect of 100 pg of fenoterol alone to half the effect of 40 pg of ipratropium alone, as shown by comparison of areas under the curve for FEV, and vs,,. This finding may be evidence for synergism at lower doses, but because we did not determine the effects of the smaller doses alone, we acould not assess this possibility. Evidence suggestive of synergistic effect has been reported by other investigators. I93 2o The alternative explanation was that the maximal effects of ipratropium may occur at doses lower than 40 pg, as has been shown by Gross.13 The site of action of these bronchodilator drugs has been studied by other investigators.21* 22 McFadden et al.*’ have shown that ipratropium will effectively block exercise-induced bronchospasm if the site of airflow limitation is in large airways as demonstrated by flow volume curves obtained with helium. In normal subjects, a&opine predominantly dilates large airways in contrast to beta-adrenergic drugs, which have a predominant effect on small airways.22 In this study we determined SG,, as well as flow from MEFV curves to try to differentiate the predominant bronchodilator effect, since changes in SG,, are more likely to reflect changes in large airways than is vso.
2.2
2.1 k 4.0
7.2 k 4.4
-0.8
2.6 ‘- 2.7
the 6 hr observation period.
However, comparison of SG,, and \;rso did not help in differentiating the predominant site of action of these drugs. Contrary to what we expected, ipratropium had a lower peak effect on SG,, than fenoterol 100 pg, although their peak effects on FEV, and !?,, were equivalent. Although all our subjects were selected to have a significant bronchodilator effect with fenoterol as indicated by FEVI, two of them showed less than 10% improvement in FEV, with ipratropium. This finding indicates that bronchodilator response to fenoterol in asthmatic subjects may not necessarily indicate responsiveness to anticholinergic aerosols. Therefore, before advocating the use of ipratropium in a particular patient, it would be advisable to check its bronchodilator effect with a period of observation of at least 1 hr before concluding that it has no effect. However, since our asthmatic subjects were preselected to have a greater than 20% bronchodilator response to fenoterol, we could not evaluate the possibility that some other asthmatic subjects may respond poorly to fenoterol while showing a significant bronchodilator effect with ipratropium. With regard to the effects on lung volumes, it was interesting to note that fenoterol 100 pg or combinations of fenoterol 100 pg with ipratropium resulted in a greater decrease in FRC than that with fenoterol 200 pg. Since inhalation of beta-2 agonists in large doses has been shown to result in a decrease in lung elastic recoil,*” a possible explanation is that the larger dose of fenoterol had a greater effect on decreasing lung elastic recoil, which could counteract the decrease in FRC that would be expected with bronchodilation and lead to the finding of a greater decrease in FRC with 100 pg of fenoterol than with 200 ,ug. Two of our subjects experienced mild tremor at the
472,
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and
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J. ALLERGY CLIN. IMMUNOL. MAY 1982
modes of action may be of benefit in the management of patients with asthma, allowing comparable efficacy with fewer side effects.
A-WC
We thank Dr. Michael Schulzer for his advice on the statisticalanalysesand Ms. Anna Hejja for her expert computer programming and for performing the statistical analyses.
REFERENCES
C-RV
1
10
FIG. 4. Mean (C) in the abbreviations.
20
30
1
60 120 180 TIME INTtA\rAL ( MINUTES)
1
240
1
I
300
percent changes in FVC (A) FRC (B), and 10 asthmatic subjects. See Fig. 1 legend
3fi
RV for
higher dose of fenoterol (200 pg), but they tolerated the combination of 100 pg of fenoterol and 40 pg of ipratropium without side effects. This finding suggests that similar bronchodilation might be achieved without side effects by using combination therapy such as 100 pg of fenoterol with 40 ,pg of ipratropium, or even the lower dose combination of 50 pg of fenoterol and 20 pg of ipratropium. In conclusion, ipratropium and fenoterol are effective inhaled bronchodilators in asthma when given either alone or in combination. The addition of 40 pg of ipratropium to 100 pg of fenoterol produced bronchodilation equivalent in extent but without side effects when compared with fenoterol 200 pg. Even lower doses in combination produced greater-thananticipated effects, suggesting possible synergism. The combination of these two drugs with different
1. Szentivanyi A: The p-adrenergic theory of atopic abnormality in bronchial asthma. J ALLERGY 42~203, 1968. 2. Gold WM: The role of the parasympathetic nervous system in airways disease. Postgrad Med J Sl(Supp1. 7):53, 1975. 3. Nadel JA: Neurophysiological aspects of asthma, in Austen KF, Lichtenstein LM, editors: Asthma, physiology, immunopharmacology and treatment, 2nd International Symposium. New York, 1973, Academic Press, Inc., pp. 29-38. 4. Simonsson BG, Skoogh B, Ekstrom-Jodal B: Exercised induced airways constriction. Thorax 27: 169, 1972. 5. Yu DYC, Galant SP, Gold WM: Inhibition of antigen-induced bronchoconstriction by atropine in asthmatic patients. J Appl Physiol 32~823, 1972. 6. Poppius H, Salorine Y, Viljanen AA: Inhalation of a new anticholinergic drug, Sch 1000, in asthma and chronic bronchitis: effect on airways resistance, thoracic gas volume, blood gases and exercise-induced asthma. Bull Physiopathol Respir 8:643, 1972. 7. Chan-Yeung M: The effect of Sch 1000 and disodium cromoglycate on exercise induced asthma. Chest 71:320, 1977. 8. Ruffin RE, Cockcroft DW, Hargreave FE: A comparison of the protective effect of fenoterol and Sch 1000 on allergen-induced asthma. J ALLERGY CLIN IMMUNOL 61:42, 1978. 9. American Thoracic Society, Committee on Diagnostic Standards for Non-tuberculous Respiratory Diseases: Definitions and classification of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis 85:762, 1962. 10. Dubois AB, Botelho SY, Comroe JH: A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J Clin Invest 35:327, 1956. 11. Morris JF, Koski A, Johnson LC: Spirometric standards for healthy non-smoking adults. Am Rev Respir Dis 103~57, 1971. 12. Chemiack RM, Raber MB: Normal standards for ventilatory function using an automated wedge spirometer. Am Rev Respir Dis 106~38, 1973. 13. Goldman MH, Becklake MR: Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberculosis 79~457, 1959. 14. Steel RGD, Tot-tie JH: Principles and procedures of statistics. New York, 1960, McGraw-Hill Book Co., Inc., pp. 107-109. 15. Gross J: Sch 1000: a new anticholinergic bronchodilator. Am Rev Respir Dis 112:823, 1975. 16. Lightbody IM, Ingram CG, Legge JS, Johnston RN: Ipratropium bromide, salbutamol and prednisone in bronchial asthma and chronic bronchitis. Chest 72: 18 1, 1978. 17. Tweel HK: Th 1165a, a new bronchodilator; a clinical comparative evaluation with metaproterenol. Ann Allergy 29: 142, 1971. 18. Wettengel R, Fabel H: Placebo comparison with berotec me-
VOLUME 69 NUMBER 5
tcred dose aerosol at incremental doses. Int J Clin Pharmacol Ther Toxic01 4(Suppl.):96, 1971. 19. Gutersohn J, Joosh H, Herzog H: Effects on airway resistance of SCH 1000 MD1 or Fenoterol MD1 and the combined administration of threshold doses of both compounds. Post Grad Med J 5: 113, 1975. (Abst.) 20. Offermeyer G: Synergistic effect of SCH 1000 and P-adrenergics on isolated orgars. Postgrad Med J 51(Suppl. 7): 117, 1975.
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21. McFadden ER, Ingram RH, Hynes RL, Wellman JJ: Predominant site of flow limitation and mechanisms of post-exertional asthma. J Appl Physiol 42:746, 1977. 22. Hensley MJ, O’Cain CF, McFadden ER, Ingram RH: Distribution of bronchodilation in normal subjects: beta agonist versus a&opine. J Appl Physiol 45:778, 1978. 23. Detroyer A, Yernault JC, Rodenstein D: Influence of beta-2 agonist aerosols on pressure-volume characteristics of the lungs. Am Rev Respir Dis 45:987, 197X.
K. Elwood, B.C.,
M.B., M.R.C.P.,*
and Raja T. Abboud,
M.D., F.R.C.P.(C)
Canada
We studied the bronchodilator effects of inhaled,fenoterol, a relatively selective beta-2 adrenergic agent, and ipratropium an anticholinergic drug, singly and in combination in IO patients with asthma. The period of observation was 6 hr after aerosol administration. The six drug regimens used were fenoterol 100 t.Lg,fenoterol 200 Fg, fenoterol 50 pg combined with 20 t.Lg of ipratropium, fenoterol 100 t.Lg combined with 40 pg of ipratropium, 40 kg of ipratropium, and placebo. Measurements consisted of spirometry with determination of forced expiratory volume in one second (FEV,), maximal expiratory jlow at 50% of vital capacity (VsO), specific airway conductance, lung volumes, and heart rate. Bronchodilation with regimens containing fenoterol was rapid, with 7570 of the maximum response achieved by 5 min, while the peak effect of ipratropium was delayed for I to 2 hr. Fenoterol 100 pg produced approximately half the degree of improvement in FEV, and V,, compared with 200 p,g of fenoterol. The addition of 40 pg of ipratropium to 100 Fg of fenoterol resulted in bronchodilation equivalent to 200 pg fenoterol and was associated with a more prolonged effect than fenoterol 100 pg. Tremor was observed in two subjects inhaling fenoterol200 pg but was not observed with any other regimen. It is concluded that the combination of inhaled ipratropium and fenoterol is an effective bronchodilator in asthma, achieving efficacy similar to that of fenoterol alone but with,fewer side effects. (J ALLERGY CLIN IMMUNOL 69:467, 1982.)
The principal aim in the treatment of asthma is the relief of airflow obstruction, the main component of which is bronchospasm. The contribution of autonomic influences to bronchomotor tone in asthma has not been well defined, but both abnormalities in beta-adrenergic receptors’ and increased cholinergic activity23 3 have been postulated. It has been suggested that brocilial adrenoceptors are themselves abnormal in asthma, being partially blocked or inadequate in number. l On the other hand, increased vagal activity in asthmatics may result from a lower-than-normal threshold for stimulation of irri-
tant receptors, leading to excessive activity of vagal efferents producing exaggerated tone.2B3 This efferent activity is cholinergically mediated and therefore available for blockade with anticholinergic drugs such as atropine4, 5 or the recently developed atropine derivative, ipratropium bromide (Sch 1000),6-8 which can be administered in aerosol form and does not have the undesirable side effects of atropine. Because both autonomic abnormalities may play a role in asthma concurrently, the use of combined beta agonists and anticholinergic drugs as bronchodilators might prove superior to either alone. To evaluate this possibility, we evaluated in 10 asthmatic subjects the
From the Respiratory Division, Department of Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, B.C. Supported by a grant from Boehringer Ingeiheim and by the British Columbia Lung Association. Received for publication Sept. 28, 198 1. Accepted for publication Feb. 16, 1982. Reprint requests to: Dr. R. T. Abboud, Respiratory Division, Department of Medicine, Vancouver General Hospital, Vancouver, B.C., Canada V5Z lM9. *Fellow of the British Columbia Lung Association.
Abbreviations used FEV,: Forced expiratory volume in one second FVC: Forced vital capacity V,,: Maximal expiratory flow at 50% of FVC FRC: Functional residual capacity SG,,: Specific airway conductance TLC: Total lung capacity RV: Residual volume MEFV: Maximum expiratory flow volume
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1982 The
C. V. Mosby
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Vol.
69, No.
5, pp. 467-473
468
Elwood
TABLE
and
J. ALLERGY CLIN. IMMUNOL. MAY 1982
Abboud
I. Characteristics
and
Subject No.
Age (vr)
Height
1 2 3 4 5 6 7 8 9 10
28 37 27 61 21 49 40 28 54 30
163 176 168 156 170 172 180 150 160 182
34.1 16.9
167.7 10.4
Mean SD *Data
baseline
(cm)
lung
Sex
function
data
Duration asthma
F F M F M M M F F M
of (yr)
of the
10 asthmatic
subjects
FEV, &I*
% Increase in FEV, with 200 pg fenoterol
16 8 25 11 18 14 10 3 18 4
2.32 2.22 1.74 1.29 2.31 1.73 2.34 1.43 1.58 2.54
(73) (66) (44) (55) (47) (50) (69) (55) (63) (58)
12.7 6.8
1.95 (58.0) 0.44 (9.6)
V50 (Llsec)”
26 46 38 31 28 55 39 39 29 45
2.02 1.12 0.94 0.57 2.05 1.11 1.33 1.17 1.28 1.17
(42) (23) (16) (15) (40) (21) (23) (26) (32) (19)
37.6 9.3
1.27 (25.7) 0.45 (9.4)
in parentheses expressed as percent of predicted value.
short-term bronchodilator effects of inhaled fenoterol, a relatively selective beta-2 agonist, given in combination with ipratropium and compared them with the bronchodilator effects of either drug given alone.
MATERIALS
AND METHODS
Ten patients with asthma, as defined by the criteria of the American Thoracic Society,g were studied. Subjects were selected who did not have histories of chronic bronchitis and who showed a greater than 20% increase in FEV, after inhalation of 200 pg of fenoterol by aerosol. Informed consent was obtained from all patients. The characteristics of the patients and their lung function data are shown in Table I. Subjects ranged from 2 1 to 6 1 yr of age; only one (subject 6) was a current smoker, two (subjects 7 and 10) were exsmokers, and the remainder were nonsmokers. At the time of study, the patients’ asthmatic conditions were stable and controlled with various regimens consisting of combinations of inhaled beta-2 adrenergic drugs, oral theophylline, and inhaled beclomethasone; none of the patients was receiving anticholinergic medication. The FEV, at the time of selection for study is shown in Table I, which also indicates the percent increase in FEV, after inhalation of 200 pg of fenoterol. Each subject was studied on 6 different days, at least 3 days apart, to determine the effect of six different regimens as follows: 100 lg fenoterol, 200 pg fenoterol, 50 I*g fenoterol plus 20 pg ipratropium, 100 pg fenoterol plus 40 pg ipratropium, placebo, and 40 pg ipratropium. Each aerosol regimen was delivered in an identical manner by a series of six immediately consecutive inhalations from a set of six coded metered dose inhalers; each inhaler puff delivered 50 pg of fenoterol, 20 pg of ipratropium, or placebo, depending on the particular set of six inhalers used. Subjects inhaled maximally from resting lung volume, held their breath for 5 set, exhaled to resting lung volume, and immediately repeated the procedure for the subsequent inhalers; the six inhalations were completed in approximately 1
min. The first five regimens, i.e., fenoterol alone and in combination with ipratropium, and placebo, were given in a double-blind randomized manner. The sixth regimen of ipratropium was given in a single-blind manner. Patients were instructed to abstain from bronchodilator drugs for at least 12 hr prior to the study. Patients reported to the laboratory at 8:00 A.M. and baseline measurements of FEV, were performed; if these differed by more than 20% from previous baseline values, the study on that day was postponed and the patient was restudied on another occasion. Spirometry was performed with an Ohio 842 rolling seal spirometer, along with measurement of FEV, and FVC and determination of MEFV curves; at least two comparable tracings were obtained, and the best effort was used. The MEFV curves were recorded on a rapid response X-Y recorder (Hewlett Packard 7045 A), and v,,, was determined from the best curve. FRC, airway resistance, and thoracic gas volume were measured in a constant volume body plethysmograph (W. E. Collins Inc.), according to the techniques of DuBois et al.,‘O using an Electronics for Medicine DR-8 recorder. At least four measurements were made and the mean value was used for calculation. Airway resistance was converted to its reciprocal conductance, which was divided by thoracic gas volume to obtain SG,,. TLC was calculated by adding FRC and inspiratory capacity. RV was obtained by subtracting FVC from TLC. Table I shows the values of vso, FVC, TLC, FRC, RV, and SG,, obtained prior to drug administration on the initial day. Predicted values for FEV, were obtained from Morris et al.,” for Qso from Chemiack and Raber,” and for lung volumes from Goldman and Becklake.13 Heart rate by radial pulse palpation and spirometric values were determined before and at 5, 10,20,30, and 60 min after drug administration and hourly thereafter for 6 hr; plethysmography was done at all time intervals except at 5 min. For each parameter determined, the percent change at the different time intervals after aerosol inhalation was calculated with reference to the measurement obtained prior to inhalation. Mean values plus or minus standard e~ors were
VOLUME
69
Fenoterol
and
ipratropium
469
NUMBER 5
(see
SG., 0.073 0.055 13.045 0.069 ~0.100 0.046 10.085 0.082 10.096 0.059
3.30 4.59 3.52 2.18 3.50 4.42 5.47 3.03 2.60 4.37
0.071 0.020
(92)
TLC (LP
FRC uJ*
:i!;
x: cm H,O)-1
2.55 5.30 4.59 3.46 3.93 4.70 7.04 2.10 3.33 6.57
(92) (155) (136) (140) (125) (133) (176) (95) (125) (160)
3.69(93.5)
4.36
(133.7)
1.01 (12.4)
1.62 (26.6)
(110) (78) (82) (85) (105)
(110) (103) (89)
(81)
computed for the group as a whole. For statisticalanalysis, a log transformation was made of the calculated values of percent change from baseline. Analysis of variance was applied at each time point, with both drug and patient effect
considered in the analysis; a p value less than 0.05 was considered statistically significant. Whenever a statistically significant drug effect was noted, Duncan’s multiple range test’? was used to determine which regimens were significantly different.
RESULTS The mean percent change in FEV, for the 10 subjects is shown for each regimen in Fig. 1. The onset of action of any regimen containing fenoterol was rapid, achieving statistical significance compared with placebo by 5 min, at which time approximately 75% of the eventual peak bronchodilation occurred. In contrast, bronchodilation with ipratropium alone was more gradual, not reaching statistical significance until 20 min and having a maximum effect between 60 and 120 min. The maximal bronchodilator effect resulted from the inhalation of 200 pg of fenoterol alone and from the combination of 40 pg of ipra&opium to half that dose of fenoterol (100 pg). The addition of ipratropium to fenoterol 100 @g also had the effect of prolonging the duration of action when compared with 100 pg of fenoterol alone, resulting in a mean of 15% improvement even at 5 hr. The 100 pg fenoterol dose produced approximately half the degree of improvement of fenoterol 200 pg, as expected. The peak bronchodilator effect of fenoterol 100 pg wa.s approximately equivalent to 40 pg ipratropium given alone; however, 40 pg of ipratropium had a significant bronchodilator effect at 4 hr, while fenoterol 100 pg had no such significant effect.
5.45 8.15 7.22 5.34 6.12 8.61
(109) (135)
E 2.15 3.56 3.70 3.16 2.62 4.19 5.75 1.27 2.80 5.24
(151) (178) (224) (204) (165) (202) (265) (113) (175) (252)
7.14(124.2)
3.44
(192.9)
2.21 (16.4)
1.36 (46.3)
(116) (127) (107) (138)
11.22 (158) 4.30 5.40 9.61
(106)
(118) (128)
The total bronchodilator effect of each regimen over the 6 hr observation period was examined by integrating the areas under the curve for each patient and then calculating the mean percent change averaged over the 6 hr. The mean bronchodilation achieved over 6 hr by the six treatment regimens and expressed as percent change in FEV, are shown in Table II; the greatest improvement (about 26%) resulted from fenoterol 200 pg and from the high-dose combination of fenoterol and ipratropium. In general the findings obtained with measurements of flow rates from MEFV curves were similar to the FEV, data. Results of percent change in $‘,, are shown in Fig. 2. All drug regimens containing fenoterol showed significant improvement in ‘?,, at 5 to 60 min, while 40 p.; of ipratropium did not show a statistically significant effect until 60 min. The average bronchodilator effects over the 6 hr period, obtained by integrating the areas under the curves, are shown in Table II. Fenoterol 200 pg had a greater effect than fenoterol 100 ,ug or ipratropium alone but was not significantly different from the combinations of fenoterol and ipratropium. Changes in specific airway conductance expressed as percent improvement over the initial value are shown in Fig. 3. The results in general are similar to those obtained with FEV, and \jsO; however, the peak improvement in SG,, with ipratropium tended to be less than that of fenoterol 100 pg, although these two regimens had equal peak effects on both 7j5,, and FEV,. The average percent improvement over the 6 hr period, determined by integrating the area under the curve, was not significantly different between any of the drug regimens (Table II); mean increases in SG,, ranged from 62% to 84%.
470
Elwood
and Abboud
J. ALLERGY CLIN. IMMUNOL. MAY 1992
FEY 1
I 150
c-4
FlOO
s - 4 -4 * - *
F200 FSO + s20 FitlO + 540
SGAY
e_ p
w -- 1
FlOO F200
w-
00 + 520
s 4 e-4
FlOO + 540 P
. - 4
540
\
-10
0
1 IO
1 20
30
1 60
1
1 120
1
1
1
180 TIME INTERVAL( MINUTES1
1 240
1
1 X0
1
I 360
FIG. 1. Mean percent change in FEV, in the 10 asthmatic subjects with the different drug regimens. Note that the maximal response to ipratropium was delayed compared with regimens containing fenoterol. F700, Fenoterol 100 pg; F200, fenoterol 200 pg; F50 + S20, fenoterol 50 pg plus 20 pg ipratropium, FIUO + WI, fenoterol 100 pg plus 40 pg ipratropium, P, placebo; S40, 40 pg ipratropium.
-301 0
1 IO
1 20
1 30
1 60
'
120
1 180
1 240
1
1 3CO
1
k 36
TIME INTERVAL( MINUTES1
FIG. 3. Mean percent change in SGW in the 10 asthmatic subjects. Note that the peak effect of 40 pg of ipratropium was less than that with 100 pg of fenoterol, while their peak effects on FEV, and i/,, were similar. See Fig. 1 legend for abbreviations.
averaged over the 6 hr period (Table II). Of interest was the finding that fenoterol 200 pg did not have a significant effect on FRC. RV was statistically significantly reduced by all drug regimens for up to 60 min after aerosol inhalation; the greatest decrease was observed with the high-dose combination regimen (Table II). The changes in TLC were minimal and variable (Table II). There were no significant changes in heart rate and none of the patients complained of palpitations or headache. Two patients had mild and transient tremor with the high dose of fenoterol, but no other side effects were noted. 0
IO
20
30
60
120
I80
240
300
360
TIME INTERVAL( MINUTES)
FIG. 2. Mean percent change in \i,, in the subjects. See Fig. 1 legend for abbreviations.
10 asthmatic
With all drug regimens there was a trend for an increase in FVC (Fig. 4, A, Table II). The changes in FRC and RV are shown in Fig. 4, B and C. Statistically significant decreases in FRC at 10 min were obtained with only two regimens, fenoterol 100 pg and the combination of fenoterol 100 pg with ipratropium; the greatest decrease in FRC was obtained with the latter regimen, which resulted in a statistically significant decrease of 9.9% + 2.6%, when
DISCUSSION Our findings verify previously reported studies on the effectiveness of the anticholinergic aerosol, ipratropium, used alone15 and in combination with betaadrenergic aerosols16 in asthma. We found that the combination of 100 pg of fenoterol with 40 pg of ipratropium produced bronchodilation equivalent to fenoterol alone in a dose of 200 pg; in addition, the combination may have a more prolonged action as suggested by a greater effect on FEV, and SG,, at 4 and 5 hr. It should be noted that the recommended dose of fenoterol for clinical use is 200 to 400 pg but maximal effect is achieved with 200 pg.“, I* The onset of action of any regimen containing fenoterol was rapid, with 75% of the eventual bronchodilation
VOLUME 69 NUMBEF: 5
TABLE
II. Mean
Fenoterol
effect of the different FEV,
--
Fenoterol 100 pg Fenoterol 200 pg Fenoterol 50 pg + ipratropium
20
12.1 -t 3.2 25.4 + b.O+ 20.4 i 3.21
drug
irso
23.5 + 6.1 51.4 c 10.31 41.8 t 5.31
regimens
on lung function
62.6 + 13.0t 68.1 c 14.4i 68.4 + 14.21.
in the 10 asthmatic
FVC
SGaw
f
ipratropium
471
patients*
FRC
RV
-4.7 2 2.6 0.3 k 2.8 -0.2 r 5.0
-5.6 k 3.0 0.4 2 5.4 -7.8 t 5.2
4.4t
-9.9
+ 2.bt
-9.2
+- 5.8-i- -1.8
2 1.5
5.3
-0.5
5 4.0
-7.1
-+ 5.2
5 2.0
3.1 2 2.4 9.1
and
4.0
9.1 t 2.2
TLC
-0.9 2 1.4 3.3 k 0.7 -0.4 t 2.4
ccg
Fenoterol 100 26.2 -+ 8.8-t 48.8 ? 15.9? 84.0 i 22.11- 10.0 lr pg t ipratropium 40 p,g Ipratropium .40 20.1 c 6.bt 34.8 ? 9.8t 61.9 L 12.91 8.5 t Pg Placebo 1.4 * 3.4 3.5 k 6.4 9.7 * 9.3 -0.5 t -*Mean % change c SE determined by integrating the area under the curve over I-Statistically significantly different f&n pl&ebo, p < 0.05. achieved by 5 min. Ipratropium, on the other hand, was slower in reaching its peak effect, which occurred
between 60 and 120 min and tended to have a more prolonged bronchodilator effect than fenoterol alone. Combination of the two drugs allowed a rapid onset of action, while prolonging the duration of bronchodilation, and achieved what appears to be an additive effect. An interesting finding was that the smaller dose of the combination of fenoterol(50 pg) and ipratropium (20 pg) produced greater bronchodilation than would be expected by adding half the effect of 100 pg of fenoterol alone to half the effect of 40 pg of ipratropium alone, as shown by comparison of areas under the curve for FEV, and vs,,. This finding may be evidence for synergism at lower doses, but because we did not determine the effects of the smaller doses alone, we acould not assess this possibility. Evidence suggestive of synergistic effect has been reported by other investigators. I93 2o The alternative explanation was that the maximal effects of ipratropium may occur at doses lower than 40 pg, as has been shown by Gross.13 The site of action of these bronchodilator drugs has been studied by other investigators.21* 22 McFadden et al.*’ have shown that ipratropium will effectively block exercise-induced bronchospasm if the site of airflow limitation is in large airways as demonstrated by flow volume curves obtained with helium. In normal subjects, a&opine predominantly dilates large airways in contrast to beta-adrenergic drugs, which have a predominant effect on small airways.22 In this study we determined SG,, as well as flow from MEFV curves to try to differentiate the predominant bronchodilator effect, since changes in SG,, are more likely to reflect changes in large airways than is vso.
2.2
2.1 k 4.0
7.2 k 4.4
-0.8
2.6 ‘- 2.7
the 6 hr observation period.
However, comparison of SG,, and \;rso did not help in differentiating the predominant site of action of these drugs. Contrary to what we expected, ipratropium had a lower peak effect on SG,, than fenoterol 100 pg, although their peak effects on FEV, and !?,, were equivalent. Although all our subjects were selected to have a significant bronchodilator effect with fenoterol as indicated by FEVI, two of them showed less than 10% improvement in FEV, with ipratropium. This finding indicates that bronchodilator response to fenoterol in asthmatic subjects may not necessarily indicate responsiveness to anticholinergic aerosols. Therefore, before advocating the use of ipratropium in a particular patient, it would be advisable to check its bronchodilator effect with a period of observation of at least 1 hr before concluding that it has no effect. However, since our asthmatic subjects were preselected to have a greater than 20% bronchodilator response to fenoterol, we could not evaluate the possibility that some other asthmatic subjects may respond poorly to fenoterol while showing a significant bronchodilator effect with ipratropium. With regard to the effects on lung volumes, it was interesting to note that fenoterol 100 pg or combinations of fenoterol 100 pg with ipratropium resulted in a greater decrease in FRC than that with fenoterol 200 pg. Since inhalation of beta-2 agonists in large doses has been shown to result in a decrease in lung elastic recoil,*” a possible explanation is that the larger dose of fenoterol had a greater effect on decreasing lung elastic recoil, which could counteract the decrease in FRC that would be expected with bronchodilation and lead to the finding of a greater decrease in FRC with 100 pg of fenoterol than with 200 ,ug. Two of our subjects experienced mild tremor at the
472,
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and
Abboud
J. ALLERGY CLIN. IMMUNOL. MAY 1982
modes of action may be of benefit in the management of patients with asthma, allowing comparable efficacy with fewer side effects.
A-WC
We thank Dr. Michael Schulzer for his advice on the statisticalanalysesand Ms. Anna Hejja for her expert computer programming and for performing the statistical analyses.
REFERENCES
C-RV
1
10
FIG. 4. Mean (C) in the abbreviations.
20
30
1
60 120 180 TIME INTtA\rAL ( MINUTES)
1
240
1
I
300
percent changes in FVC (A) FRC (B), and 10 asthmatic subjects. See Fig. 1 legend
3fi
RV for
higher dose of fenoterol (200 pg), but they tolerated the combination of 100 pg of fenoterol and 40 pg of ipratropium without side effects. This finding suggests that similar bronchodilation might be achieved without side effects by using combination therapy such as 100 pg of fenoterol with 40 ,pg of ipratropium, or even the lower dose combination of 50 pg of fenoterol and 20 pg of ipratropium. In conclusion, ipratropium and fenoterol are effective inhaled bronchodilators in asthma when given either alone or in combination. The addition of 40 pg of ipratropium to 100 pg of fenoterol produced bronchodilation equivalent in extent but without side effects when compared with fenoterol 200 pg. Even lower doses in combination produced greater-thananticipated effects, suggesting possible synergism. The combination of these two drugs with different
1. Szentivanyi A: The p-adrenergic theory of atopic abnormality in bronchial asthma. J ALLERGY 42~203, 1968. 2. Gold WM: The role of the parasympathetic nervous system in airways disease. Postgrad Med J Sl(Supp1. 7):53, 1975. 3. Nadel JA: Neurophysiological aspects of asthma, in Austen KF, Lichtenstein LM, editors: Asthma, physiology, immunopharmacology and treatment, 2nd International Symposium. New York, 1973, Academic Press, Inc., pp. 29-38. 4. Simonsson BG, Skoogh B, Ekstrom-Jodal B: Exercised induced airways constriction. Thorax 27: 169, 1972. 5. Yu DYC, Galant SP, Gold WM: Inhibition of antigen-induced bronchoconstriction by atropine in asthmatic patients. J Appl Physiol 32~823, 1972. 6. Poppius H, Salorine Y, Viljanen AA: Inhalation of a new anticholinergic drug, Sch 1000, in asthma and chronic bronchitis: effect on airways resistance, thoracic gas volume, blood gases and exercise-induced asthma. Bull Physiopathol Respir 8:643, 1972. 7. Chan-Yeung M: The effect of Sch 1000 and disodium cromoglycate on exercise induced asthma. Chest 71:320, 1977. 8. Ruffin RE, Cockcroft DW, Hargreave FE: A comparison of the protective effect of fenoterol and Sch 1000 on allergen-induced asthma. J ALLERGY CLIN IMMUNOL 61:42, 1978. 9. American Thoracic Society, Committee on Diagnostic Standards for Non-tuberculous Respiratory Diseases: Definitions and classification of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis 85:762, 1962. 10. Dubois AB, Botelho SY, Comroe JH: A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J Clin Invest 35:327, 1956. 11. Morris JF, Koski A, Johnson LC: Spirometric standards for healthy non-smoking adults. Am Rev Respir Dis 103~57, 1971. 12. Chemiack RM, Raber MB: Normal standards for ventilatory function using an automated wedge spirometer. Am Rev Respir Dis 106~38, 1973. 13. Goldman MH, Becklake MR: Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberculosis 79~457, 1959. 14. Steel RGD, Tot-tie JH: Principles and procedures of statistics. New York, 1960, McGraw-Hill Book Co., Inc., pp. 107-109. 15. Gross J: Sch 1000: a new anticholinergic bronchodilator. Am Rev Respir Dis 112:823, 1975. 16. Lightbody IM, Ingram CG, Legge JS, Johnston RN: Ipratropium bromide, salbutamol and prednisone in bronchial asthma and chronic bronchitis. Chest 72: 18 1, 1978. 17. Tweel HK: Th 1165a, a new bronchodilator; a clinical comparative evaluation with metaproterenol. Ann Allergy 29: 142, 1971. 18. Wettengel R, Fabel H: Placebo comparison with berotec me-
VOLUME 69 NUMBER 5
tcred dose aerosol at incremental doses. Int J Clin Pharmacol Ther Toxic01 4(Suppl.):96, 1971. 19. Gutersohn J, Joosh H, Herzog H: Effects on airway resistance of SCH 1000 MD1 or Fenoterol MD1 and the combined administration of threshold doses of both compounds. Post Grad Med J 5: 113, 1975. (Abst.) 20. Offermeyer G: Synergistic effect of SCH 1000 and P-adrenergics on isolated orgars. Postgrad Med J 51(Suppl. 7): 117, 1975.
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and
ipratropium
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21. McFadden ER, Ingram RH, Hynes RL, Wellman JJ: Predominant site of flow limitation and mechanisms of post-exertional asthma. J Appl Physiol 42:746, 1977. 22. Hensley MJ, O’Cain CF, McFadden ER, Ingram RH: Distribution of bronchodilation in normal subjects: beta agonist versus a&opine. J Appl Physiol 45:778, 1978. 23. Detroyer A, Yernault JC, Rodenstein D: Influence of beta-2 agonist aerosols on pressure-volume characteristics of the lungs. Am Rev Respir Dis 45:987, 197X.