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Prolonged Effect of Inhaled Glycopyrrolate in Asthma
Prolonged Effect of Inhaled Glycopyrrolate in Asthma* Frederic B. Walke~ ~ M.D.;t Donald L. Kaise~ Dr:P.H.;t Mary Beth Kowal, R.N., M.S.N.;+ and Paul M. Suratt, M.D., EC.C.P.t
Glycopyrrolate, a quarternary ammonium anticholinergic compound is a potentially useful bronchodilator. To determine the efficacy, optimal dose, and duration of action of inhaled glycopyrrolate, we gave the drug to II asthmatic patients. Each subject received placebo or glycopyrrolate (100, 100, 600, or 1,!OO ,..,1> by inhalation in a double-blind, randomized, crossover design. Measurements included
FEV., FVC, heart rate, and blood pressure before administration of the drug and periodicaUy for 12 bourse For eight hours following all doses of glycopyrrolate, both FEV. and FVC (both as percent of predicted) were significantly greater for drug than for placebo. Glycopyrrolate may be a useful long-acting drug for the treatment of asthma.
The anticholinergic drug atropine produces bron-
Subjects were studied on five separate occasions, threeto 18 days apart. All studies began between 7:30 AM and 10:00 AM. Spirometry was done twice prior to drug administration to obtain baseline values and to ensure thatFEV1 values for each subject were between 30 and 80 percent of predicted values on the day of the study. If a subjects FEV1 values did not fall within the required range, or if the subject had symptoms of a respiratory tract infection, the tests were rescheduled. At the beginning of each study day, either placebo or glycopyrrolate was administered as two consecutive metered inhalations from an aerosol-generating cannister. On any given study day, a subject received either placebo or 100 ..,g, 200 ..,g, 600 ..,gor 1,200 ..,gof drug in a random order so that each subject over the course of the study received placebo and all doses of glycopyrrolate. The above doses of glycopyrrolate were chosen because a previous study of normal subjects showed a progressive increase in airway conductance in response to glycopyrrolate doses ranging from 100 to 1,600 ..,g.4 After drug administration, spirometry was performed at 30 minutes, hourly through eight hours, and again at ten and 12 hours. Pulse and blood pressure were recorded, and patients were questioned about drug side effects at each interval. An ECG wasobtained before and after each study session and rhythm strips were done two, foUI; six, and 12 hours after drug administration. Neither patient nor the investigator knewwhat the patient received on each day until the entire study was completed. Spirometry results were expressed as change in percent predicted values as shown in the following formula: post-treatment value - pre-treatment value 100 chan ~= x predicted value The pretreatment value was the mean of the two baseline values for the study day. The percent predicted. measure was chosen to limit the effects of age, height, and weight differences on the results and to avoid the potential bias in percentage of change from baseline measures. e Predicted values were calculated according to Morris et al." The FEV. and FVC were analyzed for differences among glycopyrrolate doses and placebo using analysis of variance (ANOVA) in a General Unear Model (GLM) format. In addition to dose, factors included in the model were FEV1 or FVC baseline on each respective study day and subject number (to adjust for repeated measures). Differences among specific doses were examined using dose specific least square means and pooled standard error.'
chodilation in patients with asthma; however, systemic side effects limit its clinical usefulness. 1 Quaternary ammonium anticholinergic compounds, such as glycopyrrolate, have fewer side effects than atropine and may be more clinically useful. 1-3 Previous research suggests glycopyrrolate is an effective bronchodilator in normal subjects and in patients with asthma induced by exercise and cold air. 4.5 However, the effectiveness of glycopyrrolate in subjects with other forms of asthma has not been evaluated. We studied the effectiveness, optimal dose, and duration of action of glycopyrrolate in patients with nonexercise-induced asthma. METHODS
Patients with clinical asthma were recruited from the practices of the authors and from the community by advertisement Study subjects had mild to moderate obstructive airway disease as defined by a screening FEV1 between 30 and 80 percent of predicted. Reversibility was documented by 15percent or greater improvement in FEV1 after two inhalations of isoproterenol. Subjects were excluded if they had emphysema, bronchiectasis, cystic fibrosis, heart failure, or ifthey were receiving oral corticosteroid therapy. No patients with chronic bronchitis were included. No patients were receiving cromolyn sodium. Long-acting theophylline preparations were stopped 24 hours before and other bronchodilators 12 hours before screening spirometry and before each study day. The study was approved by the institutional committee on human research and informed consent was obtained from each subject. A water seal survey spirometer was used to measure FEV1 and FVC. Values were calculated with a microprocessor. The highest values from three forced expirations were used for comparisons. *From the Department of Internal Medicine, Division of General Medicine Division of Pulmonary Diseases, University of Virginia Medical Center, Charlottesville. tThis study was supported by a grant from the A.H. Robins Company. t Associate Professor of Medicine iNurse Practitioner. Manuscript received May 5; revision accepted July 1. Reprint requem: Dr. Walket; Box 494, University of Virginia Medical Center, Charlotteaoille 22908
ana
RESULTS
Eleven subjects enrolled in the study, seven men CHEST I 91 I 1 I JANUARY. 1987
41
Table I-Patient DacriptiOn Prestudy Medications
Patient No.
Sex
Age
Theophylline
Beta-Agonist
X
X X X X X X X X X X X
1 18 M 220M 322M 4 23 F 5 25 M 6 27 F 7 31 M 8 31 M 9 47 M 10 48 F 11 68 F MeaIlS 32.7 SD 14.7
X X
X
X
X X
Prestudy FEV*
Inhaled Steroid
3.31 (75) 3.09 (67) 3.50 (SO) 2.56 (69) 3.45 (76) 1.42 (54) 2.93 (67) 2.08 (48) 2.56 (66) 1.00 (45) 1.61 (61) 2.50 (64.4) 0.82 (10.8)
X
X X
~
*Numben in parentheses are percent predicted.
and four women (Table 1). All gave a clinical history of asthma for at least five years (mean 26.5 years, SD 15.2). Mean age was 32.7 years (SD 14.7), and mean baseline FEVl was 64.4 percent ofpredicted (SD 10.8 percent). Three subjects reported hay fever or pollen
gl ycopyrrolate ---placebo
• •
1200 lAg
.1
-.0
• • •• -.1
LLI
LL
.1
• •
~r -+_+-..r'+-+-+-+----I-----
I
800JA,G
.0
~ i_ --I- -
I
-.0
• • • -.1
200
.1
• •
100".g
+ _+- +- +-- +- +- -- -I--- --I
• •
lAg
~r-+-+-~'+-+-+-+----I-----
.0
u
> LL
.0
~i_-~-+-+-+--+--+-+----I-----I
I
-.1
•
r-+-+-..r'+-+-+-+----I-----
o
-.1
I
•
I
•
•
•
•
"
•
HOURS
•
.1
II
.1
FIGURE 1. Mean percentage of change over time in FEV1 as percent predicted in patients receiving a single inhaled dose of placebo 'or glycopyrrolate. Vertical bars are ± SEM. Means are adjusted by analysis of variance (see ten). Responses to glycopyrrolate are statistically different from placebo &om one half through eight hours after drug administration (P<. (5).
&0
- gIycopyrrolate ---placebo
• • • -.1
t--+-+-..r'+-+-+-+----I-----I
I
.... >
allergy, five had drug allergies, and four reported no allergic history. The two subjects with the lowest pre-study FEVl level did not complete all 12hours of the protocol on all study days. One subject stopped three hours after receiving placebo and four hours after glycopyrrOlate doses of600 and 1,200 JLg. The second subject stopped four hours after receiving placebo and seven hours
I
•
I
•
•
•
•
,
I
•
.8
••
.1
HOURS FIGURE 2. Mean percentage of change over time in FVC as percent predicted in patients receiving a single inhaled dose of placebo or glycopyrrolate. Vertical bars are ± SEM. MeaIlS are adjusted by analysis of variance (see text). Responses to glycopyrrolate are statistically different &om placebo &om one half through eight hours after drug administration (P<. (5). Inhaled GIycopynoIate In Asttvna ('ItWker ei aI)
Table 2-Sitk Effecta Observed After GlycopflfT01ate Patient
Side Effect
Dose (...g)
Duration (hr)
A B C
Headache Dry mouth Dry mouth Dry inouth Blurred vision Lightheaded Blurred vision
1200 1200 200 1200 200 600 600
1.5 12 12 12 4 6 4
D
after receiving 200 IJ.g of glycopyrrolate. These two subjects completed the entire protocol for all other glycopyrrolate doses. All available observations from these patients were included in the statistical analysis. All doses of glycopyrrolate produced significant improvement in FEVl and FVC from one-half hour through eight hours after treatment (p
In this study, inhaled glycopyrrolate improved airway obstruction in patients with nonexercise-induced asthma. Mean improvements in percent predicted FEVl and FVC were significantly better than placebo from one half hour through eight hours after drug treatment. The drug was well tolerated by patients at all doses tested; only minimal anticholinergic side effects were reported. Glycopyrrolate is similar to ipratropium bromide, another quaternary ammonium compound with anticholinergic properties. Both compounds produce bronchodilation with minimal anticholinergic side effects; however, the duration of action of glyeopyrrolate appears to be longer than that shown with ipratropium." The safety of glycopyrrolate has been established by extensive clinical use orally to control gastric acidity," parenterally as an antisialogogue," and as an antimuscarinic during reversal of neuromuscular blockade. n The eight-hour duration of action of glycopyrrolate is unusual among inhaled bronchodilators. Most inhaled beta. agonists have only a four to six hour duration of action. Although not statistically significant, all doses of glycopyrrolate tested led to greater improvement in FEV1 and FVC than placebo through 12 hours. The lack of statistical significance at ten and 12 hours may be because the study, limited by multiple comparisons and small sample size, did not have the statistical
power to detect a small but clinically significant effect. The loss of statistical significance after eight hours may reflect the loss of data from the two patients who also were unable to tolerate placebo beyond three and four hours, respectively. Of note, both subjects benefited from drug therapy; one subject completed the entire 12 hours on three drug treatment days and the other on two drug treatment days. Patients varied in their responses to glycopyrrolate. Clinical parameters, including response to isoproterenol, did not predict which patients were likely to respond. In clinical practice, it may be useful to give patients glycopyrrolate and monitor their change in FEVl or FVC to identify patients especially likely to benefit from therapy. This study was unable to show a difference among the various doses of glycopyrrolate tested, Doses even smaller than 100 IJ.g may be effective. Glycopyrrolate offers promise as an effective drug to treat patients with asthma. It may be useful in asthmatic patients who require a long-acting bronchodilator; including patients with early morning exacerbations of asthma interfering with sleep. It may also help patients who have unacceptable adrenergic side effects from betas agonist agents or patients who do not respond adequately to beta, agonist treatment. 12 Additional studies should include trials directly comparing glycopyrrolate to beta, agonists and trials of glycopyrrolate in conjunction with beta, agonists. ACKNOWLEDGMENTS: The authors thank Ms. Shirley Bryant and Ms. Nancy Knott who together prepared the manuscript. REFERENCES
1 Rebuck AS, Chapman KR, Braude AC, Anticholinergic therapy of asthma. Chest 1982; 82:55-57 2 Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129:856-70 3 Robertson C, Levison H. Bronchodilators in asthma. Chest 1985; 87:64-68 4 Gal T], Suratt PM, Lu JY Glycopyrrolate and atropine inhalation: comparative effects on normal airway function. Am Rev Respir Dis 1984; 129:871-73 5 Johnson BE, Suratt PM, Gal TJ, Wtlhoit SC. Effect of inhaled glycopyrrolate and atropine in asthma. Chest 1984; 85:325-28 6 Eliasson 0, DeGraff AC. The use of criteria fOr reversibility and obstruction to define patient groups for bronchodilator trials. Am Rev Respir Dis 1985; 132:858-64 7 Morris JF, Koski A, Johnson tc, Spirometric standards for healthy non-smoking adults. Am Rev Respir Dis 1971; 103:57-67 8 Kleinbaum D, Kupper L. Applied regression analysis and other multivariate methods. North Scituate, Mass: Duxbury Press, 1978 9 Sun DCH. Comparative study of the effectof glyeopyrrolate and propantheline on basalgastric secretion. Ann NY Acad Sci 1962; 99:153-57 10 Wyant GM, Kao E. Glycopyrrolate methylbromide: effect on salivary secretion. Can Anaesth Soc J 1974; 21:230-41 11 Rammamurthy S, Shaker MH, Wmnie AE Glycopyrrolate as a substitute for atropine in neostigmine reversal of muscle relaxant drugs. Can Anaesth Soc J 1972; 19:399-411 12 Chemiack RM. Comprehensive approach to asthma. Chest 1985; 87:94-97 CHEST I 91 I 1 I JANUARY, 1987
51
Glycopyrrolate, a quarternary ammonium anticholinergic compound is a potentially useful bronchodilator. To determine the efficacy, optimal dose, and duration of action of inhaled glycopyrrolate, we gave the drug to II asthmatic patients. Each subject received placebo or glycopyrrolate (100, 100, 600, or 1,!OO ,..,1> by inhalation in a double-blind, randomized, crossover design. Measurements included
FEV., FVC, heart rate, and blood pressure before administration of the drug and periodicaUy for 12 bourse For eight hours following all doses of glycopyrrolate, both FEV. and FVC (both as percent of predicted) were significantly greater for drug than for placebo. Glycopyrrolate may be a useful long-acting drug for the treatment of asthma.
The anticholinergic drug atropine produces bron-
Subjects were studied on five separate occasions, threeto 18 days apart. All studies began between 7:30 AM and 10:00 AM. Spirometry was done twice prior to drug administration to obtain baseline values and to ensure thatFEV1 values for each subject were between 30 and 80 percent of predicted values on the day of the study. If a subjects FEV1 values did not fall within the required range, or if the subject had symptoms of a respiratory tract infection, the tests were rescheduled. At the beginning of each study day, either placebo or glycopyrrolate was administered as two consecutive metered inhalations from an aerosol-generating cannister. On any given study day, a subject received either placebo or 100 ..,g, 200 ..,g, 600 ..,gor 1,200 ..,gof drug in a random order so that each subject over the course of the study received placebo and all doses of glycopyrrolate. The above doses of glycopyrrolate were chosen because a previous study of normal subjects showed a progressive increase in airway conductance in response to glycopyrrolate doses ranging from 100 to 1,600 ..,g.4 After drug administration, spirometry was performed at 30 minutes, hourly through eight hours, and again at ten and 12 hours. Pulse and blood pressure were recorded, and patients were questioned about drug side effects at each interval. An ECG wasobtained before and after each study session and rhythm strips were done two, foUI; six, and 12 hours after drug administration. Neither patient nor the investigator knewwhat the patient received on each day until the entire study was completed. Spirometry results were expressed as change in percent predicted values as shown in the following formula: post-treatment value - pre-treatment value 100 chan ~= x predicted value The pretreatment value was the mean of the two baseline values for the study day. The percent predicted. measure was chosen to limit the effects of age, height, and weight differences on the results and to avoid the potential bias in percentage of change from baseline measures. e Predicted values were calculated according to Morris et al." The FEV. and FVC were analyzed for differences among glycopyrrolate doses and placebo using analysis of variance (ANOVA) in a General Unear Model (GLM) format. In addition to dose, factors included in the model were FEV1 or FVC baseline on each respective study day and subject number (to adjust for repeated measures). Differences among specific doses were examined using dose specific least square means and pooled standard error.'
chodilation in patients with asthma; however, systemic side effects limit its clinical usefulness. 1 Quaternary ammonium anticholinergic compounds, such as glycopyrrolate, have fewer side effects than atropine and may be more clinically useful. 1-3 Previous research suggests glycopyrrolate is an effective bronchodilator in normal subjects and in patients with asthma induced by exercise and cold air. 4.5 However, the effectiveness of glycopyrrolate in subjects with other forms of asthma has not been evaluated. We studied the effectiveness, optimal dose, and duration of action of glycopyrrolate in patients with nonexercise-induced asthma. METHODS
Patients with clinical asthma were recruited from the practices of the authors and from the community by advertisement Study subjects had mild to moderate obstructive airway disease as defined by a screening FEV1 between 30 and 80 percent of predicted. Reversibility was documented by 15percent or greater improvement in FEV1 after two inhalations of isoproterenol. Subjects were excluded if they had emphysema, bronchiectasis, cystic fibrosis, heart failure, or ifthey were receiving oral corticosteroid therapy. No patients with chronic bronchitis were included. No patients were receiving cromolyn sodium. Long-acting theophylline preparations were stopped 24 hours before and other bronchodilators 12 hours before screening spirometry and before each study day. The study was approved by the institutional committee on human research and informed consent was obtained from each subject. A water seal survey spirometer was used to measure FEV1 and FVC. Values were calculated with a microprocessor. The highest values from three forced expirations were used for comparisons. *From the Department of Internal Medicine, Division of General Medicine Division of Pulmonary Diseases, University of Virginia Medical Center, Charlottesville. tThis study was supported by a grant from the A.H. Robins Company. t Associate Professor of Medicine iNurse Practitioner. Manuscript received May 5; revision accepted July 1. Reprint requem: Dr. Walket; Box 494, University of Virginia Medical Center, Charlotteaoille 22908
ana
RESULTS
Eleven subjects enrolled in the study, seven men CHEST I 91 I 1 I JANUARY. 1987
41
Table I-Patient DacriptiOn Prestudy Medications
Patient No.
Sex
Age
Theophylline
Beta-Agonist
X
X X X X X X X X X X X
1 18 M 220M 322M 4 23 F 5 25 M 6 27 F 7 31 M 8 31 M 9 47 M 10 48 F 11 68 F MeaIlS 32.7 SD 14.7
X X
X
X
X X
Prestudy FEV*
Inhaled Steroid
3.31 (75) 3.09 (67) 3.50 (SO) 2.56 (69) 3.45 (76) 1.42 (54) 2.93 (67) 2.08 (48) 2.56 (66) 1.00 (45) 1.61 (61) 2.50 (64.4) 0.82 (10.8)
X
X X
~
*Numben in parentheses are percent predicted.
and four women (Table 1). All gave a clinical history of asthma for at least five years (mean 26.5 years, SD 15.2). Mean age was 32.7 years (SD 14.7), and mean baseline FEVl was 64.4 percent ofpredicted (SD 10.8 percent). Three subjects reported hay fever or pollen
gl ycopyrrolate ---placebo
• •
1200 lAg
.1
-.0
• • •• -.1
LLI
LL
.1
• •
~r -+_+-..r'+-+-+-+----I-----
I
800JA,G
.0
~ i_ --I- -
I
-.0
• • • -.1
200
.1
• •
100".g
+ _+- +- +-- +- +- -- -I--- --I
• •
lAg
~r-+-+-~'+-+-+-+----I-----
.0
u
> LL
.0
~i_-~-+-+-+--+--+-+----I-----I
I
-.1
•
r-+-+-..r'+-+-+-+----I-----
o
-.1
I
•
I
•
•
•
•
"
•
HOURS
•
.1
II
.1
FIGURE 1. Mean percentage of change over time in FEV1 as percent predicted in patients receiving a single inhaled dose of placebo 'or glycopyrrolate. Vertical bars are ± SEM. Means are adjusted by analysis of variance (see ten). Responses to glycopyrrolate are statistically different from placebo &om one half through eight hours after drug administration (P<. (5).
&0
- gIycopyrrolate ---placebo
• • • -.1
t--+-+-..r'+-+-+-+----I-----I
I
.... >
allergy, five had drug allergies, and four reported no allergic history. The two subjects with the lowest pre-study FEVl level did not complete all 12hours of the protocol on all study days. One subject stopped three hours after receiving placebo and four hours after glycopyrrOlate doses of600 and 1,200 JLg. The second subject stopped four hours after receiving placebo and seven hours
I
•
I
•
•
•
•
,
I
•
.8
••
.1
HOURS FIGURE 2. Mean percentage of change over time in FVC as percent predicted in patients receiving a single inhaled dose of placebo or glycopyrrolate. Vertical bars are ± SEM. MeaIlS are adjusted by analysis of variance (see text). Responses to glycopyrrolate are statistically different &om placebo &om one half through eight hours after drug administration (P<. (5). Inhaled GIycopynoIate In Asttvna ('ItWker ei aI)
Table 2-Sitk Effecta Observed After GlycopflfT01ate Patient
Side Effect
Dose (...g)
Duration (hr)
A B C
Headache Dry mouth Dry mouth Dry inouth Blurred vision Lightheaded Blurred vision
1200 1200 200 1200 200 600 600
1.5 12 12 12 4 6 4
D
after receiving 200 IJ.g of glycopyrrolate. These two subjects completed the entire protocol for all other glycopyrrolate doses. All available observations from these patients were included in the statistical analysis. All doses of glycopyrrolate produced significant improvement in FEVl and FVC from one-half hour through eight hours after treatment (p
In this study, inhaled glycopyrrolate improved airway obstruction in patients with nonexercise-induced asthma. Mean improvements in percent predicted FEVl and FVC were significantly better than placebo from one half hour through eight hours after drug treatment. The drug was well tolerated by patients at all doses tested; only minimal anticholinergic side effects were reported. Glycopyrrolate is similar to ipratropium bromide, another quaternary ammonium compound with anticholinergic properties. Both compounds produce bronchodilation with minimal anticholinergic side effects; however, the duration of action of glyeopyrrolate appears to be longer than that shown with ipratropium." The safety of glycopyrrolate has been established by extensive clinical use orally to control gastric acidity," parenterally as an antisialogogue," and as an antimuscarinic during reversal of neuromuscular blockade. n The eight-hour duration of action of glycopyrrolate is unusual among inhaled bronchodilators. Most inhaled beta. agonists have only a four to six hour duration of action. Although not statistically significant, all doses of glycopyrrolate tested led to greater improvement in FEV1 and FVC than placebo through 12 hours. The lack of statistical significance at ten and 12 hours may be because the study, limited by multiple comparisons and small sample size, did not have the statistical
power to detect a small but clinically significant effect. The loss of statistical significance after eight hours may reflect the loss of data from the two patients who also were unable to tolerate placebo beyond three and four hours, respectively. Of note, both subjects benefited from drug therapy; one subject completed the entire 12 hours on three drug treatment days and the other on two drug treatment days. Patients varied in their responses to glycopyrrolate. Clinical parameters, including response to isoproterenol, did not predict which patients were likely to respond. In clinical practice, it may be useful to give patients glycopyrrolate and monitor their change in FEVl or FVC to identify patients especially likely to benefit from therapy. This study was unable to show a difference among the various doses of glycopyrrolate tested, Doses even smaller than 100 IJ.g may be effective. Glycopyrrolate offers promise as an effective drug to treat patients with asthma. It may be useful in asthmatic patients who require a long-acting bronchodilator; including patients with early morning exacerbations of asthma interfering with sleep. It may also help patients who have unacceptable adrenergic side effects from betas agonist agents or patients who do not respond adequately to beta, agonist treatment. 12 Additional studies should include trials directly comparing glycopyrrolate to beta, agonists and trials of glycopyrrolate in conjunction with beta, agonists. ACKNOWLEDGMENTS: The authors thank Ms. Shirley Bryant and Ms. Nancy Knott who together prepared the manuscript. REFERENCES
1 Rebuck AS, Chapman KR, Braude AC, Anticholinergic therapy of asthma. Chest 1982; 82:55-57 2 Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129:856-70 3 Robertson C, Levison H. Bronchodilators in asthma. Chest 1985; 87:64-68 4 Gal T], Suratt PM, Lu JY Glycopyrrolate and atropine inhalation: comparative effects on normal airway function. Am Rev Respir Dis 1984; 129:871-73 5 Johnson BE, Suratt PM, Gal TJ, Wtlhoit SC. Effect of inhaled glycopyrrolate and atropine in asthma. Chest 1984; 85:325-28 6 Eliasson 0, DeGraff AC. The use of criteria fOr reversibility and obstruction to define patient groups for bronchodilator trials. Am Rev Respir Dis 1985; 132:858-64 7 Morris JF, Koski A, Johnson tc, Spirometric standards for healthy non-smoking adults. Am Rev Respir Dis 1971; 103:57-67 8 Kleinbaum D, Kupper L. Applied regression analysis and other multivariate methods. North Scituate, Mass: Duxbury Press, 1978 9 Sun DCH. Comparative study of the effectof glyeopyrrolate and propantheline on basalgastric secretion. Ann NY Acad Sci 1962; 99:153-57 10 Wyant GM, Kao E. Glycopyrrolate methylbromide: effect on salivary secretion. Can Anaesth Soc J 1974; 21:230-41 11 Rammamurthy S, Shaker MH, Wmnie AE Glycopyrrolate as a substitute for atropine in neostigmine reversal of muscle relaxant drugs. Can Anaesth Soc J 1972; 19:399-411 12 Chemiack RM. Comprehensive approach to asthma. Chest 1985; 87:94-97 CHEST I 91 I 1 I JANUARY, 1987
51