Original Paper Respiration 1992;59:97-101
Respiratory Physiopathology Department, Civil Hospital of Udine, Italy
Key Words Hyperresponsiveness Mcthacholine challenge Asthma Sodium cromoglycate Nedocromil sodium Beclomethasone dipropionate
Long-Term Treatment with Sodium Cromoglycate, Nedocromil Sodium and Beclomethasone Dipropionate Reduces Bronchial Hyperresponsiveness in Asthmatic Subjects
Abstract 165 patients (106 males, 59 females) entered an open group comparative study of a 12-week test treatment on bronchial hyperresponsiveness (BHR) deter mined by mcthacholine challenge. Patients were randomly allocated to receive nedocromil sodium (4 mg q.i.d.), sodium cromoglycate (10 pg q.i.d.) and beclo methasone dipropionatc (500 pg t.i.d.). At the end of the study, an 2.25-fold in crease of the PD3,FEV|Was noted in all the treated patients. No significant dif ference was noted among the treatments.
Introduction Asthma is a chronic disease of the airways character ized by bronchial hyperresponsiveness (BHR), which can be defined as an increase in the ease and degree of airway narrowing in response to stimuli that affect normal sub jects little or in no way [1-31. There is incomplete knowledge on the mechanism of BHR but, up to now, it is widely accepted that triggering factors (specific antigens, viral infections and occupa tional agents) on the airways increase or allow the mainte nance of the asthmatic-like symptomatology [4-6]. The pathogenesis probably depends on a complex interaction of many cell types and their chemical mediators [7],
Received:
February 28. I«wi Accepted after revision: December 4.1991
In order to prevent the increase in BHR caused by spe cific antigens, noxious agents, SO: and toluene diisocya nate, a certain variety of drugs, e.g. corticosteroids, so dium cromoglycate (DNCG) and nedocromil sodium (NS), have been used [8-11]. Inhaled corticosteroids, DNCG and NS are known to reduce BHR [12-14], At the 7th ‘Socictas Europea Pneumologica’ Meeting in Amsterdam, our group presented a double-blind, pla cebo-controlled study where a longterm (12-week) treat ment with NS reduced BHR in atopic and nonatopic asth matic patients [15], All this evidence seems to indicate that only a long term reduction in the inflammation is able to reduce BHR.
Umberto Orcficc, Ml) Servizio di Fisiopatologia Kcspiratoriu O.C. Udine Udine (Italy)
©1992S. Karger AG. Basel 0025-7931/92/0592-0097 $ 2.75/0
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 7/16/2017 2:50:45 AM
Umberto Orefice Pierluigi Struzzo Roberto Dorigo Antonio Peratoner
Table 1. Patient characteristics
Variable
DNCG
NS
Control
BDP
Patients, n Mean age, years Range Sex, malc/fcmale Mean weight, kg Range Mean height, cm Range Mean duration of asthma, years' Range Atopic patients, n Nonatopic patients, n First challenge data range Last challenge data range Medication during the study Inhaled bronchodilator Oral steroid Ipratropium bromide FEV. Baseline At 4 weeks At 8 weeks At 12 weeks
39 33.8 23-50 25/14 69.2 55-84 171.1 162-184 16.8 (33) 8-30 11 28 8.2.88-9.9.88 2.5.88-11.12.88
42 35.6 20-52 22/20 70.1 52-85 170.9 156-181 17.0 (40) 10-30 13 29 1.2.88-30.9.88 25.4.88-25.11.88
44 33.2 20-50 30/14 73.3 54-88 173.4 160-185 14.0 (41) 7-30 13 31 25.1.88-26.11.88 21.4.88-19.12.88
40 35.6 23-48 29/11 70.7 57-87 171.3 155-179 14.8 (39) 8-28 10 30 25.1.88-23.9.88 21.4.88-16.12.88
39 18 1
42 21 0
44 24 9
40 0 0
2,223 ±753 2.117 ± 815 2,365 ±623 2,398 ±706
2,315 ±822 2.392 ±689 2,417 ±905 2.461 ±722
2,315 ±837 2,422 ±903 2,281 ±888 2,306 ±897
2,191 ±703 2,221 ±754 2,312±817 2,399 ± 705
1 Sample size is given in parentheses.
Methods Treatment
Subjects
! i 0
4
8
CUN.
CUN.
CLIN.
CUN.
CUN.
PFR
PFR
PFR
PFR
PFR
BHR
BHR
BHR
BHR
i -2
Baseline 1
i 12 Weeks
Fig. 1. Plan of the study. CLIN = Physical examination; PFR = functional evaluation.
165 asthmatic adults gave their informed consent to participate in the study. There were 106 males and 59 females, with a mean age of 34.6 years (range 20-52). The mean duration of asthma was 15.6 years (range 7-30). 47 patients were classified as atopic and 98 as nonatopic. All patients had a baseline FEV, of at least 75% of the pre dicted value. 31 patients had dust mites sensitization, 10 grass pollen and 6 had multiple sensitizations. Table 1summarizes the subjects’ characteristics and their division into subgroups. Patients were randomly allocated to DNCG, NS or BDP treatment. One group acted as controls. All groups were similar in the number of subjects, mean age, sex, asthma duration and atopy (table 1). Design
98
After a baseline period (2 weeks), metered dose inhalers were supplied. All patients were asked to inhale 2 puffs q.i.d. for 12 weeks. NS was administered at a daily dose of 16 mg, DNCG 40 pg/day and BDP 1,500 mg/day. Patients were submitted to a physical examination at baseline and every 4 weeks up to the 12th week. Figure 1 shows the plan of the study. Besides physical examination, a functional evaluation was also performed with a dry spirometer (Morgan M2) with a flow-volume curve study (O H IO Spirometer 840 with a x/y recorder). Patients
Orefice/Struzzo/Dorigo/Peratoner
Long-Term Treatment with DNCG, NS and BDP Reduces BHR
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 7/16/2017 2:50:45 AM
The aim of our study is to evaluate whether a prolonged treatment with anti-inflammatory drugs is able to reduce BHR in asthmatic subjects. To that end, we assessed the effect of 12 weeks of treat ment with three different anti-inflammatory drugs: NS, DNCG and beclomcthasone dipropionate (BDP), on air way responsiveness to inhaled methacholine in chronic asthmatic patients.
Symptom Score Diary cards were completed daily by the patients during the study. Symptoms were recorded on a scale, ranging from none (O) to severe (4) for symptoms during the night and during the day (cough, morn ing tightness, and morning, evening and night asthma). Medication Before entering the study, no patient was treated with oral or in haled corticosteroids. During the study, only inhaled (),-agonists or ipratropium bromide were allowed and, if a worsening of the symp tomatology was noted, an oral corticosteroid (7 mg of prednisone/ equivalent) was permitted. Antihistamines and ketotifen were not al lowed. No one received a specific immunotherapy. Chromone doses are the most commonly suggested while 1,500 mg of BDP is the dose that very likely has an anti-inflammatory effect on the airways [17]. Statistical Analysis The PD,0FEV, has been estimated by linear interpolation using the dose of methacholine causing a fall in FEV, of 20% or more and data prior to this for each methacholine challenge. To avoid param eter dispersion. PD^FEV, values were analyzed on a log 10 basis. Data were analyzed using one-way ANOVA followed by the StudcntNcwman-Keuls multiple range test, when the treatment contrast was significant Mann-Whitncy U test was used to analyze the data scores related to each group of patients.
Results Patient characteristics are summarized in table 1. 39, 42,44 and 40 are the numbers of patients who entered the DNCG, NS, BDP and control groups, respectively. The study started on the 25th January, 1988, and ended on the 19th December, 1988. Table 2 shows the number of patients who used an inhaled bronchodilator, with the dose of inhaled bronchodilator being fixed during the study in the control group. An evident decrease in oral steroid consumption was noted by week 8 in the DNCG group (from 18 at baseline to 2) and in the NS group (from 21 to 1) compared with the control group (from 24 down to 13). The reduction in the oral steroid consumption in the control group can be ex plained by a more accurate |)2-consumption and the assur ance of periodic functional and physical examinations. The deep knowledge of their illness and the strong rnoti-
Table 2. Patients using inhaled bronchodilators after the base line visit and reduction in the inhaled bronchodilator dose during the study
Treatment group
DNCG NS BDP Controls
Patients, n bronchodilator
reduced dose
%
39 42 40 44
13 21 26 5
33.3 50.0 65.0 11.3
Controls vs. DNCG: p 0.05, controls vs. NS: p 0.01, controls vs. BDP: p 0.005; DNCG vs. BDP: p 0.05; NS vs. DNCG and BDP: NS.
Table 3. Reductions in the oral steroid dose during the study
Patients, n BDP Daily dose1 3 mg deflazacort 5 mg deflazacort 9 mg deflazacort Use of oral steroids1 Reduced steroids. but did not stop Stopped steroids At 4 weeks At 8 weeks
DNCG
NS
Controls
-
8 9 1 18
6 10 5 21
8 14 2 24
-
2
1
3
9 7
12 8
2 9
-
-
After baseline visit.
vation to improve can also be good reasons, even though oral steroid consumption, is still very high in this group (table 3). Individual PD 2 0 values arc shown in table 4 and ana lyzed in table 5. No statistically significant difference among the treatments was noted at baseline when PD20 was analyzed on a log 10 basis. Statistically significant dif ferences in the change from baseline to week 4, 8 and 12 (p
Respiratory Physiopathology Department, Civil Hospital of Udine, Italy
Key Words Hyperresponsiveness Mcthacholine challenge Asthma Sodium cromoglycate Nedocromil sodium Beclomethasone dipropionate
Long-Term Treatment with Sodium Cromoglycate, Nedocromil Sodium and Beclomethasone Dipropionate Reduces Bronchial Hyperresponsiveness in Asthmatic Subjects
Abstract 165 patients (106 males, 59 females) entered an open group comparative study of a 12-week test treatment on bronchial hyperresponsiveness (BHR) deter mined by mcthacholine challenge. Patients were randomly allocated to receive nedocromil sodium (4 mg q.i.d.), sodium cromoglycate (10 pg q.i.d.) and beclo methasone dipropionatc (500 pg t.i.d.). At the end of the study, an 2.25-fold in crease of the PD3,FEV|Was noted in all the treated patients. No significant dif ference was noted among the treatments.
Introduction Asthma is a chronic disease of the airways character ized by bronchial hyperresponsiveness (BHR), which can be defined as an increase in the ease and degree of airway narrowing in response to stimuli that affect normal sub jects little or in no way [1-31. There is incomplete knowledge on the mechanism of BHR but, up to now, it is widely accepted that triggering factors (specific antigens, viral infections and occupa tional agents) on the airways increase or allow the mainte nance of the asthmatic-like symptomatology [4-6]. The pathogenesis probably depends on a complex interaction of many cell types and their chemical mediators [7],
Received:
February 28. I«wi Accepted after revision: December 4.1991
In order to prevent the increase in BHR caused by spe cific antigens, noxious agents, SO: and toluene diisocya nate, a certain variety of drugs, e.g. corticosteroids, so dium cromoglycate (DNCG) and nedocromil sodium (NS), have been used [8-11]. Inhaled corticosteroids, DNCG and NS are known to reduce BHR [12-14], At the 7th ‘Socictas Europea Pneumologica’ Meeting in Amsterdam, our group presented a double-blind, pla cebo-controlled study where a longterm (12-week) treat ment with NS reduced BHR in atopic and nonatopic asth matic patients [15], All this evidence seems to indicate that only a long term reduction in the inflammation is able to reduce BHR.
Umberto Orcficc, Ml) Servizio di Fisiopatologia Kcspiratoriu O.C. Udine Udine (Italy)
©1992S. Karger AG. Basel 0025-7931/92/0592-0097 $ 2.75/0
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 7/16/2017 2:50:45 AM
Umberto Orefice Pierluigi Struzzo Roberto Dorigo Antonio Peratoner
Table 1. Patient characteristics
Variable
DNCG
NS
Control
BDP
Patients, n Mean age, years Range Sex, malc/fcmale Mean weight, kg Range Mean height, cm Range Mean duration of asthma, years' Range Atopic patients, n Nonatopic patients, n First challenge data range Last challenge data range Medication during the study Inhaled bronchodilator Oral steroid Ipratropium bromide FEV. Baseline At 4 weeks At 8 weeks At 12 weeks
39 33.8 23-50 25/14 69.2 55-84 171.1 162-184 16.8 (33) 8-30 11 28 8.2.88-9.9.88 2.5.88-11.12.88
42 35.6 20-52 22/20 70.1 52-85 170.9 156-181 17.0 (40) 10-30 13 29 1.2.88-30.9.88 25.4.88-25.11.88
44 33.2 20-50 30/14 73.3 54-88 173.4 160-185 14.0 (41) 7-30 13 31 25.1.88-26.11.88 21.4.88-19.12.88
40 35.6 23-48 29/11 70.7 57-87 171.3 155-179 14.8 (39) 8-28 10 30 25.1.88-23.9.88 21.4.88-16.12.88
39 18 1
42 21 0
44 24 9
40 0 0
2,223 ±753 2.117 ± 815 2,365 ±623 2,398 ±706
2,315 ±822 2.392 ±689 2,417 ±905 2.461 ±722
2,315 ±837 2,422 ±903 2,281 ±888 2,306 ±897
2,191 ±703 2,221 ±754 2,312±817 2,399 ± 705
1 Sample size is given in parentheses.
Methods Treatment
Subjects
! i 0
4
8
CUN.
CUN.
CLIN.
CUN.
CUN.
PFR
PFR
PFR
PFR
PFR
BHR
BHR
BHR
BHR
i -2
Baseline 1
i 12 Weeks
Fig. 1. Plan of the study. CLIN = Physical examination; PFR = functional evaluation.
165 asthmatic adults gave their informed consent to participate in the study. There were 106 males and 59 females, with a mean age of 34.6 years (range 20-52). The mean duration of asthma was 15.6 years (range 7-30). 47 patients were classified as atopic and 98 as nonatopic. All patients had a baseline FEV, of at least 75% of the pre dicted value. 31 patients had dust mites sensitization, 10 grass pollen and 6 had multiple sensitizations. Table 1summarizes the subjects’ characteristics and their division into subgroups. Patients were randomly allocated to DNCG, NS or BDP treatment. One group acted as controls. All groups were similar in the number of subjects, mean age, sex, asthma duration and atopy (table 1). Design
98
After a baseline period (2 weeks), metered dose inhalers were supplied. All patients were asked to inhale 2 puffs q.i.d. for 12 weeks. NS was administered at a daily dose of 16 mg, DNCG 40 pg/day and BDP 1,500 mg/day. Patients were submitted to a physical examination at baseline and every 4 weeks up to the 12th week. Figure 1 shows the plan of the study. Besides physical examination, a functional evaluation was also performed with a dry spirometer (Morgan M2) with a flow-volume curve study (O H IO Spirometer 840 with a x/y recorder). Patients
Orefice/Struzzo/Dorigo/Peratoner
Long-Term Treatment with DNCG, NS and BDP Reduces BHR
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 7/16/2017 2:50:45 AM
The aim of our study is to evaluate whether a prolonged treatment with anti-inflammatory drugs is able to reduce BHR in asthmatic subjects. To that end, we assessed the effect of 12 weeks of treat ment with three different anti-inflammatory drugs: NS, DNCG and beclomcthasone dipropionate (BDP), on air way responsiveness to inhaled methacholine in chronic asthmatic patients.
Symptom Score Diary cards were completed daily by the patients during the study. Symptoms were recorded on a scale, ranging from none (O) to severe (4) for symptoms during the night and during the day (cough, morn ing tightness, and morning, evening and night asthma). Medication Before entering the study, no patient was treated with oral or in haled corticosteroids. During the study, only inhaled (),-agonists or ipratropium bromide were allowed and, if a worsening of the symp tomatology was noted, an oral corticosteroid (7 mg of prednisone/ equivalent) was permitted. Antihistamines and ketotifen were not al lowed. No one received a specific immunotherapy. Chromone doses are the most commonly suggested while 1,500 mg of BDP is the dose that very likely has an anti-inflammatory effect on the airways [17]. Statistical Analysis The PD,0FEV, has been estimated by linear interpolation using the dose of methacholine causing a fall in FEV, of 20% or more and data prior to this for each methacholine challenge. To avoid param eter dispersion. PD^FEV, values were analyzed on a log 10 basis. Data were analyzed using one-way ANOVA followed by the StudcntNcwman-Keuls multiple range test, when the treatment contrast was significant Mann-Whitncy U test was used to analyze the data scores related to each group of patients.
Results Patient characteristics are summarized in table 1. 39, 42,44 and 40 are the numbers of patients who entered the DNCG, NS, BDP and control groups, respectively. The study started on the 25th January, 1988, and ended on the 19th December, 1988. Table 2 shows the number of patients who used an inhaled bronchodilator, with the dose of inhaled bronchodilator being fixed during the study in the control group. An evident decrease in oral steroid consumption was noted by week 8 in the DNCG group (from 18 at baseline to 2) and in the NS group (from 21 to 1) compared with the control group (from 24 down to 13). The reduction in the oral steroid consumption in the control group can be ex plained by a more accurate |)2-consumption and the assur ance of periodic functional and physical examinations. The deep knowledge of their illness and the strong rnoti-
Table 2. Patients using inhaled bronchodilators after the base line visit and reduction in the inhaled bronchodilator dose during the study
Treatment group
DNCG NS BDP Controls
Patients, n bronchodilator
reduced dose
%
39 42 40 44
13 21 26 5
33.3 50.0 65.0 11.3
Controls vs. DNCG: p 0.05, controls vs. NS: p 0.01, controls vs. BDP: p 0.005; DNCG vs. BDP: p 0.05; NS vs. DNCG and BDP: NS.
Table 3. Reductions in the oral steroid dose during the study
Patients, n BDP Daily dose1 3 mg deflazacort 5 mg deflazacort 9 mg deflazacort Use of oral steroids1 Reduced steroids. but did not stop Stopped steroids At 4 weeks At 8 weeks
DNCG
NS
Controls
-
8 9 1 18
6 10 5 21
8 14 2 24
-
2
1
3
9 7
12 8
2 9
-
-
After baseline visit.
vation to improve can also be good reasons, even though oral steroid consumption, is still very high in this group (table 3). Individual PD 2 0 values arc shown in table 4 and ana lyzed in table 5. No statistically significant difference among the treatments was noted at baseline when PD20 was analyzed on a log 10 basis. Statistically significant dif ferences in the change from baseline to week 4, 8 and 12 (p
