Eur J Clin Pharmacol (1991) 40:41%418 003169709100101R © Springer-Verlag 1991
Inhaled procaterol versus salbutamol in bronchial asthma K. Liippo 1, M. Silvasti 2, and H. Tukiainen s 1 Department of Diseases of the Chest, Turku University Central Hospital, Turku, a Medical Department, Orion Pharmaceutica, Kuopio and s Department of Pulmonary Diseases, Kuopio University Central Hospital, Siilinj~irvi, Finland Received: February 19,1990/Accepted in revised form: September 24,1990
Summary. Procaterol is a new, potent, long-acting beta-2adrenergic bronchodilator. T h e m a g n i t u d e and duration of the i m m e d i a t e b r o n c h o d i l a t a t i o n p r o d u c e d by inhaled procaterol aerosol have b e e n c o m p a r e d with those produced by inhaled salbutamol aerosol in 20 asthmatic patients. Patients inhaled two puffs of procaterol (20 gg) or two puffs of salbutamol (200 gg) and PEF, F V C and FEV1 were m e a s u r e d after 5, 15, 30, 60, 120 and 180 min. T h e changes in m e a n PEF, FEV1 and F V C values were greater a f t e r p r o c a t e r o l t h a n s a l b u t a m o l , but the difference in b r o n c h o d i l a t a t i o n was not significant. T h e response to rimiterol after 180rain was greater in the salbutamol group. T h e increases in heart rate and systolic b l o o d pressure were slightly higher after procaterol. E l e v e n patients r e p o r t e d adverse effects; 5 after procaterol, 3 after salbutamol, and 3 after b o t h drugs. Thus, p r o c a t e r o l was a p o t e n t b r o n c h o d i l a t o r w h e n inhaled as a single dose of 20 ~tg, but it did not a p p e a r to be an ultra long-acting preparation. Key words: Procaterol, salbutamol, bronchial asthma; side effects, bronchodilation, effect duration
Procaterol is a p o t e n t new beta-2-adrenergic bronchodilator, which has b e e n f o u n d to be m o r e beta-2-selective and long-acting on oral administration than previous sympathomimetics, e.g. salbutamol [Crowe et al. 1985, Petty et al. 1988], F e w studies of its effect in aerosol f r o m have b e e n r e p o r t e d [Dahl et al. 1985, B a r o n t i et al. 1987]. T h e objective of the present trial was to c o m p a r e the magnitude and duration of the immediate b r o n c h o d i l a t a t i o n p r o d u c e d by inhaled procaterol and salbutamol in patients with bronchial asthma.
Materials and methods Twenty patients, 12 males and 8 females, with stable bronchial asthma, were selected for the study. They were allowed to use conventional anti-asthmatic medication. The mean age of the patients was 44 y (range 18-77 y) and the mean duration of asthmatic symptoms was 2.8 y (range 0,1-9 y). Asthma was graded according to the preceding 12-month history as mild [1] if bronchodilators were needed occa-
sionally, moderate [2] if the in use was regular, severe [3] if there had been up to three courses ofcorticosteroids or hospital admissions, and very severe [4] if there had been more of the latter. The mean severity score of asthma was 1.7 (0.2). Four of the patients took oral and 6 look regular inhalation corticosteroid therapy. Seven were on theophylline tablets and 10 patients had no regular medication. The predicted mean FEV1 in the patients was 69%. Before procaterol medication FEV1 was 2.63 1 (SEM 0.20) and before salbutamol it was 2.60 (0.21) 1. FVC was 3.93 (0.25) 1before both treatment periods.
Study design The study was carried out as an open randomized crossover design, consisting of two different 3-hour treatment periods in random order, in which procaterol or salbutamol was given on consecutive days. The patient inhaled two puffs of procaterol (procaterol hydrochloride 10 gg/dose, Otsuka Pharmaceutical, Japan) or two puffs of salbutamoI (100gg/dose, Glaxo Pharmaceuticals, England) one minute apart under the supervision of a nurse, at 08.00 h. The measurements of peak expiratory flow (PEF) with a Wright Peak Flow meter, and forced vital capacity (FVC) and forced expiratory volume in i s (FEVz) with a Vitalograph spirometer, were performed 5, 15, 30, 60, 120 and 180 rain after the last inhalation of the study drug. At the same time heart rate (HR) and blood pressure (BP) were measured and possible side-effects were recorded. At 180 min three puffs of rimiterol aerosol (200 gg/dose, Riker Laboratories, England) were inhaled to measure the remaining bronchial obstruction, and 5 min after the last inhalation the same parameters were recorded as during the 3-hour treatment period.
Statistical analysis Arithmetic means with SD and SEM were calculated for all the variables measured. The statistical significance of differences between the results for the two treatments was tested by the paired t-test. The level of significance was P < 0.05. Data analysis showed that the statistical power of the study was about 70% calculated from the main lung function parameters.
Results N o significant differences in p r e t r e a t m e n t P E E FEV1 or F V C were shown b e t w e e n the two t r e a t m e n t days. T h e changes in m e a n PEF, FEV1 and the F V C after procaterol
418
K. Liippo et al.: Procaterol vs salbutamo]
100
j
80 ¸ f-
60LILU D-
40
i
0 5
I
15
•
Procaterol
0
Salbutamol
Fig. 1. Change in peak expiratory flow (PEF) after inhalation of procatero120 gg or salbutamo1200 gg (mean with SEM)
3'0 Time(min)
Table 1. Change in peak expiratory flow (PEF), forced expiratory volume in one second (FEV~) and forced vital capacity (FVC) after inhalation of 600 ~tg rimitero1180 min after procaterol 20 gg or salbutamo1200 gg
Procaterol Mean SD SEM Salbutamol Mean SD SEM
PEF (1/min)
FEVt (1)
FVC (1)
9.6 12.9 2.9
0.07 0.10 0.02
0.13 0.27 0.06
18.3 28.9 6.5
0.20* 0.22 0.05
0.22 0.30 0.07
* P < 0.05 vs procaterol
were somewhat greater than after salbutamol, but the difference was not statistically significant. The maximum change in PEF after procaterol was 88.5 1.min -1 at 60min, and after salbutamol it was 70.0 1.min -1 at 30 min. At 180 min the change in mean PEF was 221. min 1higher after procaterol than salbutatool. The changes in PEF values are shown in Fig. 1. No significant difference in FEV1 or FVC was identified between the two medications. The response of all spirometric variables to rimiterol after 180 min is shown in Table 1. All the changes were greater after salbutamol and the mean increase in FEV1 was significantly greater (P < 0.05). During both treatment days increases in H R and BP were noted. The mean heart rates of the patients on procaterol and on salbutamol before treatment were 78 (13) and 74 (10), respectively (P < 0.05). The heart rate was higher at all times after procaterol, but the change after salbutamol was significantly higher at 5 minutes (P < 0.05). Although the increase in blood pressure was slight after both treatments the level of systolic pressure at 60 min was a little higher after procaterol than after salbutamol: 124 m m Hg vs 120 m m Hg (P < 0.05). No significant difference was detected between the diastolic blood pressure levels. The number of patients reporting adverse ef-
1130
fects was 11 (55%), 5 after procaterol, 3 after salbutamol and 3 after both medications.
Discussion Procaterol has been shown here to be an active drug when inhaled as a single dose of 20 gg. It induced a slightly better bronchodilator response than 200 ~tg inhaled salbutamol. However, procaterol also produced more tremor than salbutamol and heart rate and blood pressure were higher after procaterol. The findings indicate that the doses employed in this study were not quite equivalent. The bronchodilator profile of procaterol suggest that procaterol is more long-acting than salbutamol, but the present follow-up period was too short to draw a firmer conclusion, and the observed differences were not statistically significant. It is apparent however, that inhaled procaterol is a potent bronchodilator, although it is not an ultra longacting preparation.
Acknowledgements. We thank Professor E. Tala for critical review of the manuscript, and Mrs. S. Mett~ilfi for her technical assistance.
References Baronti A, Lelli M, Manini G, Verdiani P (1987) Procaterol metered aerosol in patients with chronic obstructive pulmonary disease. Int J Clin Pharmacol Res 7:363-368 Crowe MJ, Counihan HE, O'Malley K (1985) A comparative study of a new selective beta-2-adrenoceptor agonist, procaterol and salbutamol in asthma. Br J Clin Pharmaco119: 787-791 Dahl R, Harving H, Henriksen K, Ronne K, Scholer P (1985) Procaterol and terbutaline in bronchial asthma. Allergy 40:501-505 Petty TL, Brandon ML, Busse WW, Chervinsky R Schoenweter W, Beaupre A, Boulet LR Mazza J (1988) A comparison of oral procaterol and albuterol in reversible airflow obstruction. Am Rev Respir Dis 138:1504-1509 K. Liippo, M. D. Department of Diseases of The Chest Turku University Central Hospital Paimio Hospital SF-21540 Preitilfi Finland
Inhaled procaterol versus salbutamol in bronchial asthma K. Liippo 1, M. Silvasti 2, and H. Tukiainen s 1 Department of Diseases of the Chest, Turku University Central Hospital, Turku, a Medical Department, Orion Pharmaceutica, Kuopio and s Department of Pulmonary Diseases, Kuopio University Central Hospital, Siilinj~irvi, Finland Received: February 19,1990/Accepted in revised form: September 24,1990
Summary. Procaterol is a new, potent, long-acting beta-2adrenergic bronchodilator. T h e m a g n i t u d e and duration of the i m m e d i a t e b r o n c h o d i l a t a t i o n p r o d u c e d by inhaled procaterol aerosol have b e e n c o m p a r e d with those produced by inhaled salbutamol aerosol in 20 asthmatic patients. Patients inhaled two puffs of procaterol (20 gg) or two puffs of salbutamol (200 gg) and PEF, F V C and FEV1 were m e a s u r e d after 5, 15, 30, 60, 120 and 180 min. T h e changes in m e a n PEF, FEV1 and F V C values were greater a f t e r p r o c a t e r o l t h a n s a l b u t a m o l , but the difference in b r o n c h o d i l a t a t i o n was not significant. T h e response to rimiterol after 180rain was greater in the salbutamol group. T h e increases in heart rate and systolic b l o o d pressure were slightly higher after procaterol. E l e v e n patients r e p o r t e d adverse effects; 5 after procaterol, 3 after salbutamol, and 3 after b o t h drugs. Thus, p r o c a t e r o l was a p o t e n t b r o n c h o d i l a t o r w h e n inhaled as a single dose of 20 ~tg, but it did not a p p e a r to be an ultra long-acting preparation. Key words: Procaterol, salbutamol, bronchial asthma; side effects, bronchodilation, effect duration
Procaterol is a p o t e n t new beta-2-adrenergic bronchodilator, which has b e e n f o u n d to be m o r e beta-2-selective and long-acting on oral administration than previous sympathomimetics, e.g. salbutamol [Crowe et al. 1985, Petty et al. 1988], F e w studies of its effect in aerosol f r o m have b e e n r e p o r t e d [Dahl et al. 1985, B a r o n t i et al. 1987]. T h e objective of the present trial was to c o m p a r e the magnitude and duration of the immediate b r o n c h o d i l a t a t i o n p r o d u c e d by inhaled procaterol and salbutamol in patients with bronchial asthma.
Materials and methods Twenty patients, 12 males and 8 females, with stable bronchial asthma, were selected for the study. They were allowed to use conventional anti-asthmatic medication. The mean age of the patients was 44 y (range 18-77 y) and the mean duration of asthmatic symptoms was 2.8 y (range 0,1-9 y). Asthma was graded according to the preceding 12-month history as mild [1] if bronchodilators were needed occa-
sionally, moderate [2] if the in use was regular, severe [3] if there had been up to three courses ofcorticosteroids or hospital admissions, and very severe [4] if there had been more of the latter. The mean severity score of asthma was 1.7 (0.2). Four of the patients took oral and 6 look regular inhalation corticosteroid therapy. Seven were on theophylline tablets and 10 patients had no regular medication. The predicted mean FEV1 in the patients was 69%. Before procaterol medication FEV1 was 2.63 1 (SEM 0.20) and before salbutamol it was 2.60 (0.21) 1. FVC was 3.93 (0.25) 1before both treatment periods.
Study design The study was carried out as an open randomized crossover design, consisting of two different 3-hour treatment periods in random order, in which procaterol or salbutamol was given on consecutive days. The patient inhaled two puffs of procaterol (procaterol hydrochloride 10 gg/dose, Otsuka Pharmaceutical, Japan) or two puffs of salbutamoI (100gg/dose, Glaxo Pharmaceuticals, England) one minute apart under the supervision of a nurse, at 08.00 h. The measurements of peak expiratory flow (PEF) with a Wright Peak Flow meter, and forced vital capacity (FVC) and forced expiratory volume in i s (FEVz) with a Vitalograph spirometer, were performed 5, 15, 30, 60, 120 and 180 rain after the last inhalation of the study drug. At the same time heart rate (HR) and blood pressure (BP) were measured and possible side-effects were recorded. At 180 min three puffs of rimiterol aerosol (200 gg/dose, Riker Laboratories, England) were inhaled to measure the remaining bronchial obstruction, and 5 min after the last inhalation the same parameters were recorded as during the 3-hour treatment period.
Statistical analysis Arithmetic means with SD and SEM were calculated for all the variables measured. The statistical significance of differences between the results for the two treatments was tested by the paired t-test. The level of significance was P < 0.05. Data analysis showed that the statistical power of the study was about 70% calculated from the main lung function parameters.
Results N o significant differences in p r e t r e a t m e n t P E E FEV1 or F V C were shown b e t w e e n the two t r e a t m e n t days. T h e changes in m e a n PEF, FEV1 and the F V C after procaterol
418
K. Liippo et al.: Procaterol vs salbutamo]
100
j
80 ¸ f-
60LILU D-
40
i
0 5
I
15
•
Procaterol
0
Salbutamol
Fig. 1. Change in peak expiratory flow (PEF) after inhalation of procatero120 gg or salbutamo1200 gg (mean with SEM)
3'0 Time(min)
Table 1. Change in peak expiratory flow (PEF), forced expiratory volume in one second (FEV~) and forced vital capacity (FVC) after inhalation of 600 ~tg rimitero1180 min after procaterol 20 gg or salbutamo1200 gg
Procaterol Mean SD SEM Salbutamol Mean SD SEM
PEF (1/min)
FEVt (1)
FVC (1)
9.6 12.9 2.9
0.07 0.10 0.02
0.13 0.27 0.06
18.3 28.9 6.5
0.20* 0.22 0.05
0.22 0.30 0.07
* P < 0.05 vs procaterol
were somewhat greater than after salbutamol, but the difference was not statistically significant. The maximum change in PEF after procaterol was 88.5 1.min -1 at 60min, and after salbutamol it was 70.0 1.min -1 at 30 min. At 180 min the change in mean PEF was 221. min 1higher after procaterol than salbutatool. The changes in PEF values are shown in Fig. 1. No significant difference in FEV1 or FVC was identified between the two medications. The response of all spirometric variables to rimiterol after 180 min is shown in Table 1. All the changes were greater after salbutamol and the mean increase in FEV1 was significantly greater (P < 0.05). During both treatment days increases in H R and BP were noted. The mean heart rates of the patients on procaterol and on salbutamol before treatment were 78 (13) and 74 (10), respectively (P < 0.05). The heart rate was higher at all times after procaterol, but the change after salbutamol was significantly higher at 5 minutes (P < 0.05). Although the increase in blood pressure was slight after both treatments the level of systolic pressure at 60 min was a little higher after procaterol than after salbutamol: 124 m m Hg vs 120 m m Hg (P < 0.05). No significant difference was detected between the diastolic blood pressure levels. The number of patients reporting adverse ef-
1130
fects was 11 (55%), 5 after procaterol, 3 after salbutamol and 3 after both medications.
Discussion Procaterol has been shown here to be an active drug when inhaled as a single dose of 20 gg. It induced a slightly better bronchodilator response than 200 ~tg inhaled salbutamol. However, procaterol also produced more tremor than salbutamol and heart rate and blood pressure were higher after procaterol. The findings indicate that the doses employed in this study were not quite equivalent. The bronchodilator profile of procaterol suggest that procaterol is more long-acting than salbutamol, but the present follow-up period was too short to draw a firmer conclusion, and the observed differences were not statistically significant. It is apparent however, that inhaled procaterol is a potent bronchodilator, although it is not an ultra longacting preparation.
Acknowledgements. We thank Professor E. Tala for critical review of the manuscript, and Mrs. S. Mett~ilfi for her technical assistance.
References Baronti A, Lelli M, Manini G, Verdiani P (1987) Procaterol metered aerosol in patients with chronic obstructive pulmonary disease. Int J Clin Pharmacol Res 7:363-368 Crowe MJ, Counihan HE, O'Malley K (1985) A comparative study of a new selective beta-2-adrenoceptor agonist, procaterol and salbutamol in asthma. Br J Clin Pharmaco119: 787-791 Dahl R, Harving H, Henriksen K, Ronne K, Scholer P (1985) Procaterol and terbutaline in bronchial asthma. Allergy 40:501-505 Petty TL, Brandon ML, Busse WW, Chervinsky R Schoenweter W, Beaupre A, Boulet LR Mazza J (1988) A comparison of oral procaterol and albuterol in reversible airflow obstruction. Am Rev Respir Dis 138:1504-1509 K. Liippo, M. D. Department of Diseases of The Chest Turku University Central Hospital Paimio Hospital SF-21540 Preitilfi Finland
