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Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease
Acute Bronchodilating Effects of Ipratropium Bromide and Theophylline in Chronic Obstructive Pulmonary Disease EUGENE
R.
BLEECKER,
M.D.,
AND
E. JAMES BRITT,M.D.,
Ba/timore, May/and
The bronchodilator effects of a single dose of ipratropium bromide aerosol (36 lug) and short-acting theophylline tablets (dose titrated to produce serum levels of lo-20 pg/mL) were compared in a double-blind, placebo-controlled crossover study in 21 patients with stable, chronic obstructive pulmonary disease. Mean peak forced expiratory volume in 1 second (FEVr) increases over baseline and the proportion of patients attaining at least a 15% increase in the FEVl (responders) were 31% and 90%, respectively, for ipratropium and 17% and 50%, respectively, for theophylline. The average FEVl increases during the 6-hour observation period were 18% for ipratropium and 8% for theophylline. The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline. While side effects were rare, those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems. These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction.
From the Division of Pulmonary and Critical Care Medicine, University of Mary land School of Medlclne, and Francis Scott Key Medical Center, Baltimore, Maryland. This research was funded by a grant from Boehrlnger lngelheim Pharmaceuticals, Inc., Ridgefield, Connecticut. Requests fo; reprints should be addressed to Eugene R. Bleecker, M.D., Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, MSTF Room 800, 10 South Pine Street, Baltimore, Maryland 21201.
4A-24s
October 21, 1991
The American Journal of Medicine
urrently, in the United States more than 20 million people have clinical evidence of chronic obstructive pulmonary disease (COPD). Established COPD, often considered irreversible, produces significant morbidity and is the fifth most frequent cause of death in the United States [l]. These figures may underestimate the true incidence of this disease, since COPD develops gradually and insidiously over many years. Patients with early chronic airflow obstruction are usually asymptomatic, and the presence of airflow obstruction is not diagnosed clinically unless pulmonary function is measured. This is evident from initial results from an NIH-sponsored clinical trial, the Lung Health Study. In this study nearly 6,000 asymptomatic subjects with mild to moderate airflow obstruction were recruited by screening cigarette smokers who did not have clinical symptoms or a prior history of respiratory disease [2]. Theophylline (or aminophylline) is one of the most commonly used bronchodilators for the treatment of chronic airflow obstruction in the United States. Controlled studies have shown that it can reduce dyspnea in ambulatory patients with irreversible airways obstruction, thereby possibly improving respiratory muscle function and stimulating hypoxic ventilatory drive potential [3,4]. However, the potential toxicity of theophylline has received recent attention, and use of this drug often requires careful monitoring of serum theophylline levels. Further restrictions on its use occur in some patients because of frequent side effects involving the cardiovascular, central nervous, and gastrointestinal systems [5-81. These side effects occur more frequently in the elderly with preexisting cardiovascular disease. Ipratropium bromide is a synthetic quaternary ammonium congener of atropine that is administered directly to the airways by inhalation. Since it is only minimally absorbed, it produces few side effects when compared to absorbable anticholinergic agents such as atropine. Ipratropium bromide has no effect on mucociliary clearance, bladder function, or intraocular tension [9]. Previous studies have shown that ipratropium is more effective in chronic bronchitis and emphysema than inhaled p-
C
Volume 91 (SIUPPI 4A)
OBSTRUCTIVE
sympathomimetic bronchodilators. It has been shown to produce a greater magnitude and duration of bronchodilator effect in patients with COPD [lo141. This double-blind, placebo-controlled, crossover study was designed to compare the acute bronchodilator effects of a single dose of inhaled ipratropium bromide with short-acting theophylline tablets in adult patients with stable, moderate to severe COPD. Comparisons were made of the magnitude and duration of the bronchodilator effects, the percentage of patients responding to treatment, and the incidence of adverse reactions.
PATIENTSAND METHODS Study Design Twenty-nine patients aged 35-79 were recruited to the study. Patients with moderate to severe COPD whose forced expiratory volume in 1 second (FEVJ, in the absence of treatment, was less than 65% of the predicted normal value were selected. Patients who had a history of asthma, atopy, or peripheral eosinophilia, or a family history of asthma or hay fever, were excluded, as were patients who had evidence of other significant systemic diseases. Inhaled P-adrenergic drugs were withheld for 10 hours immediately before laboratory testing on each study day. Long-acting theophylline preparations were withheld for 36 hours before the start of testing, and short-acting preparations for 24 hours. Oral p agonists and cromolyn sodium were not permitted during the study.The protocol for this study was approved by the institutional review board of the Francis Scott Key Medical Center. All patients were fully informed of the nature of the study and gave their written consent to participate. Each subject received each of the following treatments: short-acting tablets of theophylline to produce serum theophylline levels of lo-20 pg/mL, plus two puffs from a placebo inhaler; two puffs (total of 36 pg) of ipratropium bromide from a metered dose inhaler, plus placebo tablets; and two puffs from a placebo inhaler, plus placebo tablets. Individual theophylline doses were titrated to produce serum theophylline levels between 10 and 20 ,ug/mL 2 hours after dosing. A double-blind crossover design was employed, and all treatments occurred at approximately the same time of day within a 28-day period of time. On each of the blinded test days, spirometry was performed at baseline and at 30 minutes and 1,2,3, 4, 5, and 6 hours after administration of the study drugs. Testing on the subsequent days was postponed if the baseline FEVl differed by more than 10% from the baseline value on the first test day.
AIRWAYS DlSEASEiBLEECKER
and BRlll
Serum concentrations of theophylline were verified in blood samples taken at 2 hours. Pulse was recorded and side effects elicited at each observation period. General linear model analysis of variance was used to compare the treatment groups and the results of spirometry.
RESULTS The preliminary results of this study are as follows. Of the 29 patients recruited to the study, eight patients were excluded from the analysis of efficacy (but included in the safety evaluation) either because they failed to report for the required number of visits (five patients) or because of subtherapeutic serum theophylline levels (three patients) in the theophylline arm of the study. Thus, in the theophylline arm of the study, the three patients with theophylline levels of 7, 8, and 9 pg/mL were excluded from analysis. On the test day on which theophylline was administered, the average serum theophylline levels 2 hours after dosing were approximately 13 PgimL, and ranged from lo-19 pg/mL. For the 21 subjects included in the data analysis, the mean age was 57.6 years. Their baseline FEV, was 1.07 t 0.08 L (mean 2 SEM), FEVi percentage predicted was 41.2 ? 2.7%, and FEViiforced vital capacity (FVC) ratio was 50.4 t 0.13%. In terms of the primary criteria applied to comparison of the treatments, ipratropium proved considerably more effective than theophylline. The differences in the peak FEVl values obtained after treatment were significant (31% after ipratropium and 18% after theophylline, p cO.01) (Figure 1). The mean increase in FEVi for the 6 hours after drug administration was 8% for theophylline and 18% after ipratropium (Figure 2). The FVC responses to ipratropium also exceeded the responses to theophylline. The mean duration of effect for FEVi was 3.8 hours after ipratropium and 2.4 hours after theophylline. The mean duration of effect for FVC differed only slightly between ipratropium and theophylline. Of the patients who responded to ipratropium, 90% showed an increase of FEVi of at least 15%, compared with only 50% of the patients treated with theophylline alone. Adverse experiences were infrequent; they occurred in 13% (3 of 24) of those who received ipratropium and 15% (4 of 26) of those who received theophylline. One of 25 patients also had an adverse experience after placebo treatment. The most frequent reaction was tachycardia, which was recorded in two patients after theophylline. Among the patients who experienced tachycardia, peak
October 21, 1991
The American Journal of Medicine
Volume 91 (suppl 4A)
4A-25s
OBSTRUCTIVE
AIRWAYS DISEASE / BLEECKER and BRlll
COMMENTS
Mean Y!ISEM I
Peak % Change from Baseline FEV,
10
0 Li
I
Theophylline
Ipratropium II
igure 1. The peak increase from baseline FEVl with ipratropium was significantly greater than with theophylline (p
*Or 35 30 25 20 15 10 -
5-
placebo
Theophylline
Ipratropium
L-
Figure 2. Average effect of ipratropium and theophylline on percentage change in FEV1.This figure depicts the average improvement in FEVi over the &hour period of evaluation. The median duration of >15% improvement in FEV, was 5 hours for ipratropium.
heart rates ranged from 104 to 108 beats per minute after theophylline. The time to onset of tachycardia averaged 4.3 hours after theophylline. In the majority of the patients affected, the tachycardia persisted for 1 hour. After theophylline, two patients experienced nausea and one patient complained of mild dizziness. The adverse experiences reported after ipratropium treatment included fatigue lasting 3 hours in one patient and 5 hours in a second patient, and a headache persisting for 4 hours in a third patient. 4A-26s
October 21, 1991
The American Journal of Medicine
Theophylline is a major component of bronchodilator therapy in patients with chronic obstructive airway disease. Interestingly, ipratropium bromide given by metered dose inhaler has been known for more than a decade to improve pulmonary function in patients with COPD [15]. Two studies that directly compared ipratropium bromide with theophylline were performed in patients with almost exclusively the diagnosis of asthma [16,17]. Both were double-blind crossover studies: one evaluated single doses [17], whereas the other involved an 8-week treatment schedule with each of the two drugs [16]. The controlled-release theophylline used in the COPD study proved more effective in improving. lung function than ipratropium; in the single-dose study, ipratropium and theophylline produced equal maximal bronchodilation. In both trials, combined treatment with the two drugs was found to produce additive therapeutic effects. The use of subjects with a clinical diagnosis of asthma is important since ipratropium has been shown to be less effective in asthmatics than in patients with chronic bronchitis and airflow obstruction [9]. This single-dose study demonstrates the capability of theophylline and ipratropium in patients with COPD. Administration of theophylline produced an 8% improvement in FEV1, while inhaled ipratropium produced an average 18% improvement in FEVi during the 6-hour period after administration. In addition, the peak bronchodilator effect of ipratropium was significantly greater than after theophylline. With increasing concern about toxicity, especially in the older age groups, use of theophylline as single-agent therapy would seem to provide limited therapeutic benefit. Since ipratropium was the more potent single agent, this study supports the use of aerosolized ipratropium rather than theophylline in the treatment of chronic airflow obstruction when only one of these agents is used for therapy. In other studies, where ipratropium has been compared to therapy with inhaled p adrenergics [18], the anticholinergic agent has been shown to be a more effective bronchodilator in patients with obstructive lung disease secondary to bronchitis and emphysema [lO,ll]. Because ipratropium is very poorly absorbed, the risk of toxicity is minimal in these patients who are often elderly and have coexisting cardiovascular disease. Thus, inhaled ipratropium is an important therapeutic agent for the management of patients with chronic airflow obstruction. REFERENCES 1. NCHS. Vital Statistics of the United States, 1986, vol II. Hyattsville, Maryland: US Department of Health and Human Serwces, Public Health Service, 1988: 5.
Volume 91 (suppl 4A)
OBSTRUCTIVE 2. Anthonisen NJ, Lung health study. Am Rev Resprr DIS 1989; 140: 871-2. 3. Murciano D, Auclair M-H, Parrente R, Aubrer M. A randomized controlled trial of theophylline in patients with severe chronic obstrucbve pulmonary drsease. N Engl J Med 1989; 320: 1521-5. 4. Mahler DA, Matthay RA, Snyder PE, Wells CK, Loke J. Sustarned-release theophylline reduces dyspnea in nonreversible obstructive airway disease. Am Rev Respir DIS 1985; 131: 22-5. 5. Marks MD. Theophylline: primary or tertiary drug? A brief review. Ann Allergy 1987; 59: x5-7. 6. Rossrng TH. Methylxanthrnes in 1989. Ann Intern Med 1989; 110: 502-4. 7. Lam A, Newhouse MT. Management of asthma and chronic airflow Ikmitation. Are methylxanthlnes obsolete? Chest 1990; 98: 44-52. 8. Newhouse MT. Is theophyllrne obsolete? Chest 1990; 98: 1-2. 9. Gross NJ. lpratropium bromrde. N Engl J Med 1988; 319: 486-94. 10. Tashkin DP, Ashutosh K, Bleecker ER, et al. Comparison of the anticholinergrc bronchodilator rpratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A go-day multicenter study. Am J Med 1986; 81 (Suppl 5A): 59-68. 11. Braun SR, McKenzie WN, Copeland C, Knight L, Ellersieck M. A comparison of the effect of rpratropium and albuterol rn the treatment of chronic obstructive airway disease. Arch Intern Med 1989; 149: 544-7.
AIRWAYS DISEASEIBLEECKER
and BRITT
12. Ashutosh K, Lang S: Comparison between long-term treatment of chronic bronchrtic airway obstruction with ipratropium bromrde and metaproterenol. Ann Allergy 1984; 53: 401-6. 13. Lees AW, Allan GW, Smith J. Nebulized ipratropium bromide and salbutamol in chronic bronchrtis. Br J Clin Pratt 1980; 34: 340-2. 14. Jenkrns CR; Chow CM, Fisher BL, Marlin GE. lpratropium bromide and fenoterol by aerosolized solution. Br J Clin Pharmacol 1982; 14: 113-5. 15. Jenne JW, Sever JR, Druz WS, Solano JV, Cohen SM, Sharp JT. The effect of maintenance theophylline therapy on long work in severe chronic obstructive pulmonary drsease while standing and walking. Am Rev Respir Dis 1984; 130: 600-5. 16. Sahay JN, Chatterjee SS, Summerfield PJF. A comparatrve trial of ipratropium bromide (Atrovent), controlled release theophylline (Phyllocontin), and a combination of these in patients wrth reversible airflow obstruction. 198-202.
Br J Clin Pratt 1986; 40:
17. Kreisman H, Cohen C, Ghezzo E, Vickerson F, Frank H, Wolkove N. Combined therapy with ipratropium and theophyllrne rn asthma. Ann Allergy 1984; 52: 90-3. 18. Bezel R, Brandli 0, Braun P, et a/. Die Kombinatron von Anticholinergika, Beta2 Sympathomimetika und Theophyllin in der Behandlung der chronischen obstruktiven Lungenkrankheit. Schweiz Rundsch Med Prax 1987; 76: 632-6.
October 21, 1991
The American Journal of Medicine
Volume 91 (suppl 4A)
4A-275
R.
BLEECKER,
M.D.,
AND
E. JAMES BRITT,M.D.,
Ba/timore, May/and
The bronchodilator effects of a single dose of ipratropium bromide aerosol (36 lug) and short-acting theophylline tablets (dose titrated to produce serum levels of lo-20 pg/mL) were compared in a double-blind, placebo-controlled crossover study in 21 patients with stable, chronic obstructive pulmonary disease. Mean peak forced expiratory volume in 1 second (FEVr) increases over baseline and the proportion of patients attaining at least a 15% increase in the FEVl (responders) were 31% and 90%, respectively, for ipratropium and 17% and 50%, respectively, for theophylline. The average FEVl increases during the 6-hour observation period were 18% for ipratropium and 8% for theophylline. The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline. While side effects were rare, those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems. These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction.
From the Division of Pulmonary and Critical Care Medicine, University of Mary land School of Medlclne, and Francis Scott Key Medical Center, Baltimore, Maryland. This research was funded by a grant from Boehrlnger lngelheim Pharmaceuticals, Inc., Ridgefield, Connecticut. Requests fo; reprints should be addressed to Eugene R. Bleecker, M.D., Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, MSTF Room 800, 10 South Pine Street, Baltimore, Maryland 21201.
4A-24s
October 21, 1991
The American Journal of Medicine
urrently, in the United States more than 20 million people have clinical evidence of chronic obstructive pulmonary disease (COPD). Established COPD, often considered irreversible, produces significant morbidity and is the fifth most frequent cause of death in the United States [l]. These figures may underestimate the true incidence of this disease, since COPD develops gradually and insidiously over many years. Patients with early chronic airflow obstruction are usually asymptomatic, and the presence of airflow obstruction is not diagnosed clinically unless pulmonary function is measured. This is evident from initial results from an NIH-sponsored clinical trial, the Lung Health Study. In this study nearly 6,000 asymptomatic subjects with mild to moderate airflow obstruction were recruited by screening cigarette smokers who did not have clinical symptoms or a prior history of respiratory disease [2]. Theophylline (or aminophylline) is one of the most commonly used bronchodilators for the treatment of chronic airflow obstruction in the United States. Controlled studies have shown that it can reduce dyspnea in ambulatory patients with irreversible airways obstruction, thereby possibly improving respiratory muscle function and stimulating hypoxic ventilatory drive potential [3,4]. However, the potential toxicity of theophylline has received recent attention, and use of this drug often requires careful monitoring of serum theophylline levels. Further restrictions on its use occur in some patients because of frequent side effects involving the cardiovascular, central nervous, and gastrointestinal systems [5-81. These side effects occur more frequently in the elderly with preexisting cardiovascular disease. Ipratropium bromide is a synthetic quaternary ammonium congener of atropine that is administered directly to the airways by inhalation. Since it is only minimally absorbed, it produces few side effects when compared to absorbable anticholinergic agents such as atropine. Ipratropium bromide has no effect on mucociliary clearance, bladder function, or intraocular tension [9]. Previous studies have shown that ipratropium is more effective in chronic bronchitis and emphysema than inhaled p-
C
Volume 91 (SIUPPI 4A)
OBSTRUCTIVE
sympathomimetic bronchodilators. It has been shown to produce a greater magnitude and duration of bronchodilator effect in patients with COPD [lo141. This double-blind, placebo-controlled, crossover study was designed to compare the acute bronchodilator effects of a single dose of inhaled ipratropium bromide with short-acting theophylline tablets in adult patients with stable, moderate to severe COPD. Comparisons were made of the magnitude and duration of the bronchodilator effects, the percentage of patients responding to treatment, and the incidence of adverse reactions.
PATIENTSAND METHODS Study Design Twenty-nine patients aged 35-79 were recruited to the study. Patients with moderate to severe COPD whose forced expiratory volume in 1 second (FEVJ, in the absence of treatment, was less than 65% of the predicted normal value were selected. Patients who had a history of asthma, atopy, or peripheral eosinophilia, or a family history of asthma or hay fever, were excluded, as were patients who had evidence of other significant systemic diseases. Inhaled P-adrenergic drugs were withheld for 10 hours immediately before laboratory testing on each study day. Long-acting theophylline preparations were withheld for 36 hours before the start of testing, and short-acting preparations for 24 hours. Oral p agonists and cromolyn sodium were not permitted during the study.The protocol for this study was approved by the institutional review board of the Francis Scott Key Medical Center. All patients were fully informed of the nature of the study and gave their written consent to participate. Each subject received each of the following treatments: short-acting tablets of theophylline to produce serum theophylline levels of lo-20 pg/mL, plus two puffs from a placebo inhaler; two puffs (total of 36 pg) of ipratropium bromide from a metered dose inhaler, plus placebo tablets; and two puffs from a placebo inhaler, plus placebo tablets. Individual theophylline doses were titrated to produce serum theophylline levels between 10 and 20 ,ug/mL 2 hours after dosing. A double-blind crossover design was employed, and all treatments occurred at approximately the same time of day within a 28-day period of time. On each of the blinded test days, spirometry was performed at baseline and at 30 minutes and 1,2,3, 4, 5, and 6 hours after administration of the study drugs. Testing on the subsequent days was postponed if the baseline FEVl differed by more than 10% from the baseline value on the first test day.
AIRWAYS DlSEASEiBLEECKER
and BRlll
Serum concentrations of theophylline were verified in blood samples taken at 2 hours. Pulse was recorded and side effects elicited at each observation period. General linear model analysis of variance was used to compare the treatment groups and the results of spirometry.
RESULTS The preliminary results of this study are as follows. Of the 29 patients recruited to the study, eight patients were excluded from the analysis of efficacy (but included in the safety evaluation) either because they failed to report for the required number of visits (five patients) or because of subtherapeutic serum theophylline levels (three patients) in the theophylline arm of the study. Thus, in the theophylline arm of the study, the three patients with theophylline levels of 7, 8, and 9 pg/mL were excluded from analysis. On the test day on which theophylline was administered, the average serum theophylline levels 2 hours after dosing were approximately 13 PgimL, and ranged from lo-19 pg/mL. For the 21 subjects included in the data analysis, the mean age was 57.6 years. Their baseline FEV, was 1.07 t 0.08 L (mean 2 SEM), FEVi percentage predicted was 41.2 ? 2.7%, and FEViiforced vital capacity (FVC) ratio was 50.4 t 0.13%. In terms of the primary criteria applied to comparison of the treatments, ipratropium proved considerably more effective than theophylline. The differences in the peak FEVl values obtained after treatment were significant (31% after ipratropium and 18% after theophylline, p cO.01) (Figure 1). The mean increase in FEVi for the 6 hours after drug administration was 8% for theophylline and 18% after ipratropium (Figure 2). The FVC responses to ipratropium also exceeded the responses to theophylline. The mean duration of effect for FEVi was 3.8 hours after ipratropium and 2.4 hours after theophylline. The mean duration of effect for FVC differed only slightly between ipratropium and theophylline. Of the patients who responded to ipratropium, 90% showed an increase of FEVi of at least 15%, compared with only 50% of the patients treated with theophylline alone. Adverse experiences were infrequent; they occurred in 13% (3 of 24) of those who received ipratropium and 15% (4 of 26) of those who received theophylline. One of 25 patients also had an adverse experience after placebo treatment. The most frequent reaction was tachycardia, which was recorded in two patients after theophylline. Among the patients who experienced tachycardia, peak
October 21, 1991
The American Journal of Medicine
Volume 91 (suppl 4A)
4A-25s
OBSTRUCTIVE
AIRWAYS DISEASE / BLEECKER and BRlll
COMMENTS
Mean Y!ISEM I
Peak % Change from Baseline FEV,
10
0 Li
I
Theophylline
Ipratropium II
igure 1. The peak increase from baseline FEVl with ipratropium was significantly greater than with theophylline (p
*Or 35 30 25 20 15 10 -
5-
placebo
Theophylline
Ipratropium
L-
Figure 2. Average effect of ipratropium and theophylline on percentage change in FEV1.This figure depicts the average improvement in FEVi over the &hour period of evaluation. The median duration of >15% improvement in FEV, was 5 hours for ipratropium.
heart rates ranged from 104 to 108 beats per minute after theophylline. The time to onset of tachycardia averaged 4.3 hours after theophylline. In the majority of the patients affected, the tachycardia persisted for 1 hour. After theophylline, two patients experienced nausea and one patient complained of mild dizziness. The adverse experiences reported after ipratropium treatment included fatigue lasting 3 hours in one patient and 5 hours in a second patient, and a headache persisting for 4 hours in a third patient. 4A-26s
October 21, 1991
The American Journal of Medicine
Theophylline is a major component of bronchodilator therapy in patients with chronic obstructive airway disease. Interestingly, ipratropium bromide given by metered dose inhaler has been known for more than a decade to improve pulmonary function in patients with COPD [15]. Two studies that directly compared ipratropium bromide with theophylline were performed in patients with almost exclusively the diagnosis of asthma [16,17]. Both were double-blind crossover studies: one evaluated single doses [17], whereas the other involved an 8-week treatment schedule with each of the two drugs [16]. The controlled-release theophylline used in the COPD study proved more effective in improving. lung function than ipratropium; in the single-dose study, ipratropium and theophylline produced equal maximal bronchodilation. In both trials, combined treatment with the two drugs was found to produce additive therapeutic effects. The use of subjects with a clinical diagnosis of asthma is important since ipratropium has been shown to be less effective in asthmatics than in patients with chronic bronchitis and airflow obstruction [9]. This single-dose study demonstrates the capability of theophylline and ipratropium in patients with COPD. Administration of theophylline produced an 8% improvement in FEV1, while inhaled ipratropium produced an average 18% improvement in FEVi during the 6-hour period after administration. In addition, the peak bronchodilator effect of ipratropium was significantly greater than after theophylline. With increasing concern about toxicity, especially in the older age groups, use of theophylline as single-agent therapy would seem to provide limited therapeutic benefit. Since ipratropium was the more potent single agent, this study supports the use of aerosolized ipratropium rather than theophylline in the treatment of chronic airflow obstruction when only one of these agents is used for therapy. In other studies, where ipratropium has been compared to therapy with inhaled p adrenergics [18], the anticholinergic agent has been shown to be a more effective bronchodilator in patients with obstructive lung disease secondary to bronchitis and emphysema [lO,ll]. Because ipratropium is very poorly absorbed, the risk of toxicity is minimal in these patients who are often elderly and have coexisting cardiovascular disease. Thus, inhaled ipratropium is an important therapeutic agent for the management of patients with chronic airflow obstruction. REFERENCES 1. NCHS. Vital Statistics of the United States, 1986, vol II. Hyattsville, Maryland: US Department of Health and Human Serwces, Public Health Service, 1988: 5.
Volume 91 (suppl 4A)
OBSTRUCTIVE 2. Anthonisen NJ, Lung health study. Am Rev Resprr DIS 1989; 140: 871-2. 3. Murciano D, Auclair M-H, Parrente R, Aubrer M. A randomized controlled trial of theophylline in patients with severe chronic obstrucbve pulmonary drsease. N Engl J Med 1989; 320: 1521-5. 4. Mahler DA, Matthay RA, Snyder PE, Wells CK, Loke J. Sustarned-release theophylline reduces dyspnea in nonreversible obstructive airway disease. Am Rev Respir DIS 1985; 131: 22-5. 5. Marks MD. Theophylline: primary or tertiary drug? A brief review. Ann Allergy 1987; 59: x5-7. 6. Rossrng TH. Methylxanthrnes in 1989. Ann Intern Med 1989; 110: 502-4. 7. Lam A, Newhouse MT. Management of asthma and chronic airflow Ikmitation. Are methylxanthlnes obsolete? Chest 1990; 98: 44-52. 8. Newhouse MT. Is theophyllrne obsolete? Chest 1990; 98: 1-2. 9. Gross NJ. lpratropium bromrde. N Engl J Med 1988; 319: 486-94. 10. Tashkin DP, Ashutosh K, Bleecker ER, et al. Comparison of the anticholinergrc bronchodilator rpratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A go-day multicenter study. Am J Med 1986; 81 (Suppl 5A): 59-68. 11. Braun SR, McKenzie WN, Copeland C, Knight L, Ellersieck M. A comparison of the effect of rpratropium and albuterol rn the treatment of chronic obstructive airway disease. Arch Intern Med 1989; 149: 544-7.
AIRWAYS DISEASEIBLEECKER
and BRITT
12. Ashutosh K, Lang S: Comparison between long-term treatment of chronic bronchrtic airway obstruction with ipratropium bromrde and metaproterenol. Ann Allergy 1984; 53: 401-6. 13. Lees AW, Allan GW, Smith J. Nebulized ipratropium bromide and salbutamol in chronic bronchrtis. Br J Clin Pratt 1980; 34: 340-2. 14. Jenkrns CR; Chow CM, Fisher BL, Marlin GE. lpratropium bromide and fenoterol by aerosolized solution. Br J Clin Pharmacol 1982; 14: 113-5. 15. Jenne JW, Sever JR, Druz WS, Solano JV, Cohen SM, Sharp JT. The effect of maintenance theophylline therapy on long work in severe chronic obstructive pulmonary drsease while standing and walking. Am Rev Respir Dis 1984; 130: 600-5. 16. Sahay JN, Chatterjee SS, Summerfield PJF. A comparatrve trial of ipratropium bromide (Atrovent), controlled release theophylline (Phyllocontin), and a combination of these in patients wrth reversible airflow obstruction. 198-202.
Br J Clin Pratt 1986; 40:
17. Kreisman H, Cohen C, Ghezzo E, Vickerson F, Frank H, Wolkove N. Combined therapy with ipratropium and theophyllrne rn asthma. Ann Allergy 1984; 52: 90-3. 18. Bezel R, Brandli 0, Braun P, et a/. Die Kombinatron von Anticholinergika, Beta2 Sympathomimetika und Theophyllin in der Behandlung der chronischen obstruktiven Lungenkrankheit. Schweiz Rundsch Med Prax 1987; 76: 632-6.
October 21, 1991
The American Journal of Medicine
Volume 91 (suppl 4A)
4A-275