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Comparison Between a New Once-Daily, Bronchodilating Drug, Bambuterol, and Terbutaline Sustained-Release, Twice Daily

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Eur Resplr J 1988, 1, 223- 226 Comparison between a new once-daily, bronchodilating drug, bambuterol, and terbutaline sustained-release, twice daily G. Persson*, Y. Gnosspelius**, S. Anehus•• Comparison between a new once-daily , bronchodilating drug, bambutero/, *Department of Internal Medicine, Division of and terburaline sustained-release. twice daily. G. Persson, Y. Gnosspelius. Allergy, University Hospital of Lund. Lu nd, S. Anehus. Sweden. ABSTRACT: Bambuterol is a prodrug, from which terbutaline is slowly **Department of Clinical Research, AB Draco generated. The objectives of the study were to evaluate whether bambuterol, (subsidiary of AB Astra), Lund, Sweden. given once dnily, can control symptoms in asthmatic patients and to compare Correspondence: G. Persson, M.D., Depart­ the bronchodilatmg effect and the side effects with those of terbutaline ment of Internal Medicine, Division of Allergy, sustained-release (SR) tablets given twice daily. Twenty-five out-patients with University Hospital of Lund, S-221 85 LUND, bronchial asthma were treated during two consecutive 14-day periods with Sweden. either 30 mg bambutcrol tabl ets once el·cry el'cning or 2 x 5 mg terbutaline S R tablets morning and evening. The study had a double-blind, cross-over and Keywords: Asthma; bambuterol; prodrug; tcr· randomized design. The mean evening peak expiratory flow rate (PJ.:t<R) (i.e. 24 butaline. h after intake of bambuterol and 1.2 h nfter intake of tcrbutallne SR) was significantly (p < 0.001) higbf!r during bambuterol than du.ring terbutalinc Received: December 15, 1986; accepted after revision: October 17, 1987. treatment (432 ''·f 415//min). The need for ~- adrcnoceptor agonist aerosol in the daytime was significantly (p < 0.05) lower during treatment with bambuterol once daily (0.70 puffs) than with terbutaline SR h.i.d. (1.04 puffs). The type and intensity of the side effects were the same during both treatments. Eur Respir J . 1988, I. 223- 226. Bambuterol is a new bronchodilator prodrug in the The aim of the present study was to evaluate form of bisdimethy!-carbamate of terbutaline (I]. The whether bambuterol is suitable for once daily admin­ terbutaline part of this prodrug is protected from istration in asthmatic patients, with regard to the being metabolized during absorption and during the duration of its bronchodilating effect and its side first-pass through the liver. This means that bambu­ effects, compared to terbutaline SR treatment twice terol can act as an inner depot from which terbutaline daily. is slowJy generated. Human pharmacological and clinical studies have shown that bambuterol provides Patients and methods safe and reliable generation of terbutaline (2, 3). Sustained-release (SR) terbutaline (administered Twenty-five outpatients (eleven males and fourteen twice daily) has a good bronchodilating effect [4, 5}. females) with bronchial asthma participated in the The bronchodilation obtained is. comparable to that study. AU patients received written and verbal of oral sustained-release preparations of theophylline information and gave their informed consent to [6]. participation. The study was approved by the local Tn the first clinical studies, bambuterol was admin­ Ethics Committee at the University of Lund. istered twice daily [2, 3}. When compared to terbutal­ The study consisted of two consecutive treatment ine SR, the generated terbutaline plasma concentra­ periods, each lasting for fourteen days: bambuterol tion curve and bronchodilation showed a more tablets 30 mg once every evening and terbutaline SR prolonged profile after bambuterol (2]. A good 10 mg (two 5 mg tablets) b.i.d. The treatments were correlation was found between the plasma concentra­ given by using a randomized, double-blind, cross­ tion of terbutaline and the bronchodilating effect. over design with a double-dummy technique. Each Bambuterol given once daily to healthy volunteers patient's medication was provided in blister-packs, in produced a plasma profile of generated terbutaline order to obtain maximal patient compliance. from bambuterol with a peak/trough ratio of I .9 The patients were between 18 and 60 yr old (mean compared to a ratio of 2.4 for terbutaline SR given 40.6 yr) with a mean weight of72.3 kg (range 54 to 95 twice daily (Nyberg et at. , personal communication). kg). The mean d uration of asthma was 21 yr (range These results indicate that bambuterol administered J-45 yr) a nd the mean basal forced expiratory volume only once daily may have a good bronchodilating in o ne second (FEY 1) 2. 18 I (range 0.75- 3.95 !). The effect. mean increase in FEV1 was 44% (19-147%) 15 min 224 G. PERSSON, Y. GNOSSPELJUS, S. ANEHUS after the last inhalations of terbutaline (Bricanyl<Bl) 450 P£:FR HORNING n•lS aerosol or salbutamol (Ventoline®) aerosol (I+ 5 L/min. puffs, with an interval of 15 min). Patients receiving 110 inhaled or oral corticosteroids were allowed to 130 bambute~:ol continue this treatment, provided that the dosage was 30 1119 x I 120 kept constant during the study. Theophyllines, anti­ · terbut411ne SR cholinergics and other ~-adrenoceptor agonists were 10 1119 • 2 110 ···. ..... · discontinued, but rimiterol (Pulmadil®) aerosol was ._... · permitted, if needed, but not later than four hours 400 before each PEFR recording. 390 The PEFR was recorded (highest of three values) 380 .__.._.._.__.__...._...._...._...._;_...._;_;_J-.j on the morning and evening before drug intake, using 0 I 2 3 1 5 6 7 8 9 10 II 12 13 14 a Wright mini-Peak Flow Meter. The patients also DAYS recorded their asthma symptoms throughout the day and night (breathlessness, cough, wheezing), the number of times they woke during the night because 150 PEFR £V£:NING of asthma, the use of rimiterol aerosol and the side L/Din. effects (tremor, palpitations, headache and uneasi­ ness) during the day and night. Asthma symptoms 440 and side effects were scored using a six-graded scale: 430 0 =no symptoms; I =slight; 2 =slight to moderate; bambut.erol 30 109 X I 3 =moderate; 4 =moderately severe; 5 =severe symp­ 120 . .. ........ ···,····.• . ••• .~· 0 • • •• ••• toms. ··. ... ...... ·· ., ....: .... terbutaline SR HO At the end of the study, the patients were asked in 10 tDq ¥ 2 which of the two periods they experienced the fewest ·.. :" asthmatic symptoms and the fewest side effects and 400 which of the two periods they preferred. 3 90 .__.._.__.__.__".._ .._...._...._1.-1.-.1-.1-.&-.J The statisticaJ evaluations were based on the last 0 I 2 3 4 5 6 7 B 9 10 II 12 13 14 ten days in each 14-day period. A steady state had DAYS then been obtained and the risk of any carry-over Fig. I. Day-to-day variations in the morning PEFR (upper panel) effect was considered to be eliminated. The student's and the evening PEFR (lower panel) during 14 days of treatment paired t-test was used to compare the PEFR and the with bambuterol once daily or sustained-release terbutaline twice daily. Statistical calculations were made on days 5- 14. number of rirniterol puffs in the two periods. The Wilcoxon signed rank test was used in the evaluation of the subjective grading of asthmatic symptoms, the tendency towards fewer asthma symptoms during side effects, the number of times the patients awoke, treatment with bambuterol. Five patients reported and the patient's preference for one of the prepar­ sleep disturbances due to asthma during the bambu­ ations. In this study, the power of the statistical terol period and seven during treatment with terbutal­ evaluation was 80%, using the paired two-tailed t-test ine SR (table I). and a p-value of less than 0.05 to reveal a true Very few patients experienced any side effects and difference of at least 10% in the mean PEFR between those who did scored them as mild-to-moderate (table treatments. 1). There was no difference between the two treatment periods. Fifteen, out of 25 patients, preferred the period Results with bambuterol and only one patient failed to The mean morning PEFR ( ± SEM) was almost the distinguish between the two periods (table 2). same during the two treatments (bambuterol: 425 23 //min; terbutaline: 415 22 1/min), but the ± ± Discussion mean evening PEFR was significantly higher (p<O.OOI) during bambuterol (432±23 //min) than The results in healthy volunteers indicated that during terbutaline SR treatment (415 ± 23 //min). The bambuterol should be suitable for once-daily admin­ day-to-day variations in the morning and evening istration. One objective of the present study was to PEFR during the two periods are shown in figure I. evaluate this in patients with bronchial asthma. The The need for a P-adrenoceptor agonist aerosol was next was to find out at what time of day bambuterol small during both treatments (table I). However, in should be administered. To achieve an effective the daytime the number of puffs was significantly protection against early morning wheezing, which is (p < 0.05) lower when bambuterol was used. very troublesome for many asthmatic patients, bam­ The patients scored their asthma symptoms as buterol should be administered in the evening. mild-to-moderate during both treatment periods The reference drug used in this study was terbutal­ (table 1). No statistically significant difference was ine SR. This P-agonist was chosen because of the long found between the treatments, but there was a duration of its effect and its twice-daily dosage BAMBUTEROL IN BRONCHIAL ASTHMA 225 Table 1. -Asthma symptom score, sleep disturbances, side effect score and number of B-aerosol puffs during the last ten days in each period (mean values, n=25) DAY NIGHT bambuterol terbutalinc SR bambutcrol tcrbulaline SR 30 mgxl 10 mgx2 30 mgxl 10 mgx2 Asthma symptoms* 0.24 (13) 0.36 (13) 0.11 (9) 0.16 (10) No.
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