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RESPIRATORY MEDICINE (1998) 92, 354-357

A comparison of bronchodilating effects of and oxitropium bromide in stable chronic obstructive pulmonary disease

M. CAZZOLA*, M. G. MATERA+, F. DI PERNA”, F. CALDERARO, C. CALIFANO* AND A. VINCIGUERRA*

*Division of Pneumology and Allergology and Respiratory Clinical Pharmacology Unit, A. Cardarelli Hospital, Naples, Italy ‘institute of Pharmacology and Toxicology, Medical School, Second Neapolitan University, Naples, Italy

Anti- agents are generally regarded as the therapy of first choice in the treatment of stable chronic obstructive pulmonary disease (COPD), considering that they may be more effective than in inhaled &agonist. However, results of the authors’ recent studies conflict to some extent with this suggestion because they demonstrate that this is true only for short acting &agonists but not for long-acting P,-agonists. Oxitropium bromide is an anti-cholinergic drug that has been shown to produce a similar degree of bronchodilation to that obtained with , but with a longer-lasting effect. In the present study, the time course of inhaled oxitropium bromide bronchodilation in comparison to that of inhaled salmeterol in a group of patients with partially reversible COPD was evaluated. Twelve male patients with moderate to severe COPD participated in the study. The study had a single-bind, cross-over, randomized design. The bronchodilator activity of 5Opg salmeterol hydroxynaphthoate, 200 and 400 pg oxitropium bromide and placebo, which were all inhaled from a metered-dose inhaler, was investigated on several non-consecutive days. The highest FVC and FEV,, obtained from one or the other of the reproducible curves, were kept for analysis. Measurements were performed at the following times: immediately before inhalation of treatment, and at 15, 30, 60, 120, 180, 240, 300, 360, 480, 600 and 720 min after inhalation of the individual treatment. Salmeterol tended to have a delayed time to peak effect, but had a longer duration of effect than oxitropium. The response to salmeterol exceeded the response to 200 ,ug oxitropium for 12 h, but its responseswere significantly (PcO.05) greater than those to 2OOpg oxitropium from 10 to 12 h. From 3 to 12 h, salmeterol also surpassed 4OOpg oxitropium but differences were not significant (PcO.05). The mean FEV, area under the curve was significantly (PcO.05) larger after salmeterol when compared to 2OOpg oxitropium bromide, but there was no significant difference (P

RESPIR. MED. (1998) 92, 354-357

Introduction seenwith an inhaled &agonist (2). However, results of the present authors’ study (3) conflict with this suggestion Recent guidelines from the American Thoracic Society (1) to some extent because they demonstrate that this is true suggest the inhaled administration of an anti-cholinergic only for short-acting &agonists, and not for long-acting agent as first-line therapy in stable chronic obstructive &-agonists. The authors have recently shown that the onset pulmonary disease (COPD), considering that in most of bronchodilation after 40,~g ipratropium bromide is patients who have COPD, inhaled quaternary anti- slower than that after 2OOpg . Moreover, ipra- cholinergic drugs offer greater bronchodilation than that tropium bromide produces a longer-lasting bronchodilation than salbutamol. In contrast, 50,~~gsalmeterol, a long- Received 15 January 1997 and accepted in revised form 27 acting &agonist, is as effective as ipratropium bromide October 1997. in terms of the degree of bronchodilation, and has a Correspondence should be addressed to: M. Cazola, Via de1 Parco longer duration of action (12 h) than anti-cholinergic Margherita 24, 80121 Napoli, Italy. agents (6 h).

0954.6111/98/020354+04 $12.00/O 0 1998 W. B.SAUNDERS COMPANYLTD SALMETEROL AND ~XITR~PIUM IN STABLE C~PD 355

TABLE 1. Anthropometric data and pulmonary function of patients

Age Height Weight FEV, FEV, FVC FVC Patient Sex (years) (cm) (kg) (1) (% predicted) (1) (% predicted)

1 M 53 173 75 1.21 35 1.80 42 2 M 57 165 71 1.58 54 2.18 59 3 M 69 156 54 0.45 19 1.03 35 6 M 50 163 92 0.98 32 1.42 38 7 M 74 161 65 0.49 21 0.81 27 8 M 58 167 71 0.45 15 0.78 21 9 M 59 167 83 0.59 20 0.86 23 10 M 57 157 65 0.35 13 0.58 18 11 M 49 161 53 0.78 26 1.41 39 12 M 69 164 63 1.18 46 1.64 50

Oxitropium bromide is another anti-cholinergic drug. It placebo, which were all inhaled from a metered-dose has been shown to produce a similar degree of broncho- inhaler and holding chamber (AeroChamber) with mouth- dilation to that obtained with ipratropium bromide, but piece, was investigated on several non-consecutive days. with a longer-lasting effect (4). The duration of action The four treatments were: (i) oxitropium bromide (2OOpg, would suggest that a twice daily regimen might be suitable 100pug per inhalation) plus placebo (two inhalations); (ii) for some individuals. However, a direct comparison of oxitropium bromide (200 pug) plus oxitropium bromide the profile of the bronchodilatory effects of oxitropium (2OOpg); (iii) salmeterol (5Opg, 25 pugper inhalation) plus bromide and salmeterol over a 12-h study period in a placebo; and (iv) placebo plus placebo. No oral broncho- controlled laboratory environment in patients with COPD dilators were permitted for 1 week before or during the is still lacking. study, whereas inhaled short-acting bronchodilator drug Therefore, the time course of inhaled oxitropium bro- and inhaled long-acting bronchodilator agent were not mide bronchodilation in comparison to that of inhaled permitted for at least 12 or 24 h prior to each test, respect- salmeterol in a group of patients with stable COPD was ively. Consumption of cola drinks, coffee or tea, and evaluated in the present study. smoking in the hours before and during the investigation were also avoided. Spirometric testing was performed according to the pro- Patients and Methods cedures described in the American Thoracic Society’s 1987 update (5). Three acceptable forced expiratory manoeuvres Twelve male patients with moderate to severeCOPD, but in were performed in order to obtain two reproducible results a stable phase of disease, participated in the study after for FVC and FEV,. The highest FVC and FEV,, obtained giving their informed consent. All fulfilled the criteria from one or the other of the reproducible curves, were kept proposed by the American Thoracic Society (5): i.e. >40 for analysis. Measurements were performed at the follow- years of age; current or former smokers (> 10 pack-years) ing times: immediately before inhalation of treatment, and without a history of asthmatic attacks; reporting either at 15, 30, 60, 120, 180, 240, 300, 360,480, 600 and 720 min chronic cough with or without sputum production or after inhalation of the individual treatment. The pulse rate dyspnoea when walking quietly on level ground, or both; and blood pressure were also measured after at least 5 min had had no change in symptom severity or treatment in the of rest prior to each spirometric measurement, and 12-lead preceding 4 weeks; had shown no signs of a respiratory electrocardiogram was taken prior to the inhalation of tract infection in the month preceding or during the trial; every treatment and after 3, 6 and 12 h. Patients were asked were not taking oral or inhaled corticosteroids for at least to note any side-effects at each time period. 3 months; and had a FEV, <65X1 of predicted normal and The functional indices’ increases from baseline after a FVC ~70% after had been withheld for salmeterol, oxitropium bromide and placebo were assessed. 24 h. Patients with a history of , allergic rhinitis The change in FEV, was chosen as the primary outcome or atopy, or with a total blood eosinophil count over variable to demonstrate bronchodilation (6). As an expres- 400 mm- 3 were excluded. Table 1 outlines the baseline sion of the total effect of each treatment, the areas under the characteristics of the population studied. FEV, responseetime curves (AUC) from baseline to 12 h The study, which was carried out according to the rules were determined for each patient using the trapezoidal rule. of the declaration of Helsinki, was performed using a Comparisons of baseline characteristics among the four single-blind, balanced, cross-over, randomized design. The groups were performed by ANOVA analysis and Fisher’s bronchodilator activity of 200 and 4OOpg oxitropium exact test. Analysis of spirometric data and those of pulse bromide (Boehringer Ingelheim, Florence, Italy), 50 pug rate and blood pressure were performed using the Student’s salmeterol hydroxynaphthoate (Glaxo, Verona, Italy) and t-test for paired variables. The time-averaged changes in the M. CAZZOLA ET AL

(a) 1.300 =FT T T e gb 1.800 2 d 1. B 1.650 s 2 l.... 2 1.500

n.9nc-l_.___ 1.350 0 60 120180240300360420480540600660720 0 60 120180240300360420480540600660720 Time (min) Time (min) FIG. 1. Mean ( f SE) absolute changes (1) in (a) FEV, and (b) FVC from baseline at different times after inhalation of salmeterol 50 lug (A), oxitropium 200 pug( q ), oxitropium 400 pg (0) or placebo (0).

12 h after drug administration, between each treatment and All AUC 0m,2hs for active treatments were signifi- placebo, and between drugs were compared by means of cantly greater than for placebo (P>O.O5). The mean ( f SE) the distribution-free cross-over analysis (7). With respect to AK-,,,, for salmeterol (2.23 lh - i * 0.42) was signifi- the multiple testing of two lung function parameters, the cantly (P>O.O5) greater than for 2OOpg oxitropium bro- significance level of 0.05 was considered as relevant. mide (1.13 lh- i f 0.28), and that for 400,~g oxitropium bromide (1.72 lh - i * 0.37) was significantly (P>O.O5) greater than for 2OOpg oxitropium bromide. There was Results no significant difference (P>O.O5) between salmeterol and 400 pg oxitropium bromide AUC,-,,,s. All 12 patients completed the 4-day study. There were No significant changes in pulse rate, blood pressure, or no significant differences between the baseline spirometric electrocardiograms were found among the three groups as values of the four treatment groups (P>O.O5). compared with placebo group. The mean absolute changes in FEV, and FVC following No patient complained of adverse symptoms and did not the four treatment regimens are shown in Fig. 1. The mean notice any difference in the taste of the inhaler. individual peak bronchodilation, expressed as the maxi- mum increase in FEV, over baseline values, occurred 3 h after inhalation of salmeterol (range: 30-360 min), 2 h Discussion after inhalation of 200,~~goxitropium (range: 15480 min) and 2 h after inhalation of 4OOpg oxitropium (range: The growing realization in recent years that airways 15480 min). It must be highlighted that when individual obstruction in patients with COPD can be relieved signifi- subjects were considered, there was a heterogeneous cantly with the use of bronchodilators has changed the response to the various bronchodilator regimens. However, clinical approach to treating this disease. In light of the when the mean duration of drug action was evaluated by morbidity and mortality associated with COPD, there is comparing the response to placebo with those of the test adequate justification for physicians to use bronchodilators, drug, salmeterol produced a significant (BO.05) increase individualized to the patient and clinical situation. over placebo for 12 h, whereas the duration of broncho- In patients with stable COPD, the conventional dose of dilation after 200,~g oxitropium was somewhat shorter, anti-cholinergic drug, two puffs, usually produces more lasting for 5 and 8 h, respectively, and 4OOpg oxitropium bronchodilation than two puffs of P-agonist. The result is sustained the action over baseline for 10 h. Salmeterol probably a dose effect, i.e. two puffs of anti-cholinergic tended to have a delayed time to peak effect, but a longer agent support a greater fraction of the maximum effect than duration of effect than oxitropium. The response of sal- the conventional doses of P-agonists (8,9). Unfortunately, meter01 exceeded that of 200 pg oxitropium for 12 h but its very few studies have compared equi-effective doses of responses were significantly (P~0.05) greater than those anti-cholinergic agents and &-adrenoceptor agonists, which of 2OOpg oxitropium from 10 to 12 h. From 3 to 12 h, questions the validity of many of the studies published salmeterol also surpassed400 pg oxitropium but differences previously in the literature. Skorodin et al. (10) found doses were not significant (BO.05). Of the salmeterol group, nine of 100400,~~g oxitropium bromide were better than 15Opg patients had at least 8 h 15% improvement of FEV, over of isoproterenol. Firth et al. (11) showed that the effect of baseline, and six patients had at least 12 h; only three 2OOpg oxitropium bromide was less rapid than that of patients of the 2OOpg oxitropium group had at least 8 h of 400,~~gfenoterol, but its duration of action was greater than FEV, increase >15% over baseline and two had at least that of . Moreover, it has been demonstrated that 12 h; six patients showed at least a 15% improvement for when larger than usual doses of each agent are given to 8 h and three for 12 h following inhalation of 4OOpg COPD patients, anti- induce a similar or a oxitropium. Analysis of the FVC responses showed similar greater degree of bronchodilation than an adrenergic agent effects to FEV, by the four study treatments. (12). All these studies concluded that an anti-cholinergic SALMETEROLAND OXITROPIUM IN STABLE C~PD 357

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