Br. J. clin. Pharmac. (1992), 33, 439-444
Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes T. ENGEL, B. SCHARLING, B. SKOVSTED & J. H. HEINIG Allergy Unit TTA 7511, National University Hospital, Tagensvej 20, DK-2200 Copenhagen, Denmark
1 The efficacy of a metered dose inhaler (MDI) is highly dependent on the mode of inhalation. The relatively high built-in resistance in the Turbohaler® (TBH), a new dry powder inhaler device for inhalation of terbutaline sulphate and budesonide, reduces the flow during inhalation. We compared five different modes of inhalation using the terbutaline TBH in 10 stable asthmatic subjects, who were tested on 5 consecutive days. 2 Measurement of 10 different parameters of pulmonary function indicated that the full bronchodilatory effect of an inhaled dose was already achieved at 5 min after the inhalation. Inspiratory flows through the TBH varying from 34 to 88 1 min- 1 resulted in comparable bronchodilation, and a previous exhalation to residual volume proved of no value. However, if, prior to inhalation, an exhalation through the device was performed, a substantially reduced effect was seen. 3 Reducing the inspiratory flow to approximately 34 1 min-1 produced slightly reduced side effects and lower plasma terbutaline concentrations.
Keywords
terbutaline
asthma
inhalers
Introduction For many years ,32-adrenoceptor agonists have been one of the primary treatments of asthma, most commonly administered through chlorofluorocarbon (CFC) (Freon®)-driven metered dose inhalers (MDIs). In some asthmatics a significant decrease in ventilatory capacity develops after inhalation from MDIs (Ahmad, 1983; Engel et al., 1991; Sterling & Batten, 1969; Yarbrough et al., 1985). Thus, the manner in which the drug is delivered may influence the clinical outcome. The search for alternative ways of delivering metered doses to the lungs has therefore received a high priority. Currently, various dry powder MDIs are available. These inhalers solve the problem of bronchoconstriction seen with pressurized MDIs, since they do not contain CFC-gases and surfactants. Furthermore, they are breathactuated and the problem of coordination between actuation and inhalation is avoided. A major determinant of the efficacy of a dry powder inhaler is the flow through the inhaler during inhalation (Groth & Dirksen, 1983; Jaegfeldt et al., 1987; Newman et al., 1989; Pedersen & Steffensen, 1986; Pedersen et al., 1990; Richards et al., 1988). The terbutaline Turbohaler® (TBH), (Turbuhaler® in most European countries) supplies up to 200 doses of drug without reloading and is easy to handle and small in size (Wetterlin, 1988). An essential
component of the TBH is the removable mouthpiece, which has a relatively high built-in airflow resistance because of a narrow insert with spiral channels for deaggregation of the drug powder. When inhalation is performed through the TBH, maximum inspiratory flow is reduced to about 25% (Engel et al., 1990). However, practically all adults with airways obstruction are able to achieve inspiratory flows through the TBH of 30 1 min-1 or more (Engel et al., 1990), as are children above 6 years, even during acute wheezing (Pedersen et al., 1990). Below the age of 6 years an increasing proportion of children are unable to ?roduce inspiratory flows through the TBH of 301 min- or more (Pedersen et al., 1990). Inhalation of terbutaline from the TBH has been shown to produce an effect comparable with that of a pressurized MDI, when inhalation is performed through the TBH with an inspiratory flow of approximately 60 1 min-1 (Johnsen & Weeke, 1988; Persson et al., 1988). In children, a similar degree of bronchodilatation was observed when the inhaled flow through the TBH was 31 and 60 1 min-1, but reduced bronchodilatation occurred at rates below 31 1 min-' (Pedersen et al.,
1990). The aim of the present study was to assess the influence
Correspondence: Dr T. Engel, Allergy Unit T1A 7511, National University Hospital, Tagensvej 20, DK-2200 Copenhagen, Denmark
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of inhaled flow and volume through the TBH on pulmonary function, plasma terbutaline concentrations and side effects in stable adult asthmatics. T40:
Methods -
60
A:-
Design
B:
C: D:
80
The investigation was performed as an open, randomized, cross-over, cumulative dose-response study. All subjects attended the allergy clinic at 08.00 h on 5 consecutive days. On each day terbutaline (Bricanyl®) was inhaled from a TBH using different inhalation techniques (Table 1). On each study day the subjects abstained from caffeinecontaining beverages and inhaled 32-adrenoceptor agonists for at least 8 h prior to attending the clinic. Tobacco smoking was not allowed for at least 2 h before attending the clinic (four subjects were smokers). During an initial 30 min period, an intravenous cannula was inserted into a cubital vein. A baseline blood sample was drawn and baseline pulmonary function, BP and heart rate were measured. Inhalations of terbutaline were then performed every 30 min (Table 1). The same inhalation technique was used during the entire study day. Five and 20 min after each terbutaline inhalation, the pulmonary function measurements were repeated. Immediately prior to the next inhalation, a blood sample was drawn for assay of plasma terbutaline, and heart rate and blood pressure were measured. The study was approved by the local ethics committee and by the National Board of Health and Welfare. All subjects participated after having been given verbal and written information.
Subjects Eleven subjects who had been suffering from chronic bronchial asthma for a mean period of 13 years (range 4-20 years) were studied. All had been using inhaled 032-adrenoceptor agonists as their only asthma therapy during the previous 3 months. Furthermore, all subjects had demonstrated at least a 15% increase in forced exporatory volume in 1 s (FEV1) after inhalation of a P2-adrenoceptor agonist within the previous 6 months. One subject was excluded because, having participated in the study for 2 days, she claimed to be unable to attend the clinic for the remaining 3 days. The remaining 10 subjects completed the study (two females, eight males, mean age 25 years (range 19-40 years)). Baseline FEVy averaged 72.6% of predicted (ranging from 70.8-73.6% Table 1 Dose of terbutaline sulphate inhaled from the TBH on each of the 5 study days and the resulting cumulative dose during the day. (* a 0.25 mg TBH is not commercially available)
Dose number 1 2 3 4 5
Time (h)
08.30 09.00 09.30 10.00 10.30
Dose inhaled 0.25 mg* 0.25 mg* 0.50 mg 1.00 mg 2.00 mg
Cumulative dose (mg) 0.25 0.50 1.00 2.00 4.00
E:-
100
Figure 1 Schematic presentation of flows and volumes during inhalation from TBH on each of the 5 study days (A-E). The inhalation technique on day E was similar to that on day A, but was preceded by a slow exhalation from FRC to RV through the TBH prior to inhalation. on individual study days, and ranged from 48.0% (the lowest value recorded) to 88.4% (the highest value in any individual subject)).
Inhalation techniques used with the TBH Inhalation techniques were varied in random order according to a latin square design on each of the 5 consecutive study days (A-E) (Figure 1). A: Each inhalation was performed using the maximal inspiratory flow producible by the subjects from near residual volume (RV) to total lung capacity (TLC). This represented the 'standard' inhalation technique. B: Each inhalation was performed using the maximal inspiratory flow producible by the subjects, but inhalation was only performed from functional residual capacity (FRC) to TLC. This technique assessed the importance of volume during inhalation. C: Each inhalation was performed using the maximal inspiratory flow rate during the first half second of the inhalation and thereafter the rate was reduced to approximately 30 1 min- 1. Inhalation was performed from RV to TLC satisfying both the need for a high flow through the TBH in order to deaggregate the particles, and a low flow in order to produce a good intrapulmonary distribution of drug. D: Each inhalation was performed using a flow rate of approx. 301 min-' during the entire inhalation from RV to TLC. This technique simulated low inspiratory flows in non-cooperative subjects or during acute wheezing. E: Each inhalation was performed as described in (A), but was preceded by a slow exhalation from FRC to RV through the TBH. This technique simulated incorrect use of the device. All inhalations from the TBH were monitored with regard to flow and volume. The TBH was placed in a specially designed adapter and connected in series to a pneumotachograph with the integrator modified to record inspiratory measurements (Vitalograph Compact®, Vitalograph Ltd, Buckingham, U.K.) reported in ambient temperature and pressure (ATP). A breathholding pause of approximately 10 s (10.68 s ± 0.82 s, mean ± s.d.) followed each inhalation. Repeated -
inhalations omitting reloading of the TBH inhaler
in
Effects of inhaled terbutaline order to ensure complete release of each dose were not permitted, i.e. only a single inhalation was performed per terbutaline dose. On each study day, 30 min after inhalation of the last dose of terbutaline, the subjects reported any occurrence of palpitations, tremor, headache, tiredness, or other discomfort graded in a standard manner from 0 = none to 3 = severe.
Pulmonary function measurements All pulmonary function measurements were made in an 830 1 constant volume whole-body box (Jaeger Master Lab System®, Erich Jaeger GmbH & Co. KG, Wurzberg, F.R.G.). Body plethysmography was performed during panting (approximately 1 Hz), and always preceded the flow/volume measurement. At least five consecutive measurements of FRC and total airway resistance (Rtot) were made, results varying by more than ± 10% being discarded. This was followed by at least two technically correct flow/volume measurements with a variance of FEV1 not exceeding 5%. The highest results were reported, maximum expiratory flow at 50% of vital capacity (MEF5o) and mean transit time (MIT) values were noted from the curve with the highest FEV1 value.
Terbutaline released from the TBH On each study day, the subjects performed five inhalations during the initial 30 min period, using the designated inhalation technique, from the TBH through a Marquest MQ-303 viral filter (Respirgard II). By a combination of electrostatic and mechanical mechanisms, this filter retains virtually all particles of 1 ,um or larger (Marquest Medical Products, Colorado, U.S.A.). Therefore, essentially all of the particles released from the devices were collected on the filter. The amount of terbutaline on each filter was measured in a blinded fashion at AB DRACO, Lund, Sweden.
Measurement ofplasma terbutaline Within 4 min of sampling, blood was spun at 200 g for 10 min and separated. Plasma was stored at -20° C until assay for terbutaline. The plasma samples were analysed in a blinded fashion at bco Medical Services BW, Breda, The Netherlands. The plasma concentrations of terbutaline were determined by a gas chromatography chemical ionization mass spectrometry method according to Leferink et al. (1982, 1984). The lower limit of quantitation was 1 nmol 1-1.
Statistical analysis All comparisons of continuous data, e.g. pulmonary function, amount of terbutaline released from the TBH (Marquest MQ-303 viral filter), plasma terbutaline, blood pressure and heart rate were made using Student's t-test, paired or unpaired as appropriate. Comparisons of categorical variables (i.e. side effects) were made using the Wilcoxon-Pratt paired rank sum test for intrasubject comparisons, and the Mann-Whitney rank sum test for inter-subject comparisons. Because of the large number of comparisons the level of significance was set to 0.01 in order to reduce the risk of type I errors. Integral values of the effect parameters were calculated by summing the values obtained after inhalation of each dose of terbutaline.
Results Mean (± s.d.) values of inhaled peak flows and volumes through the TBH achieved with each inhalation technique (A-E) are shown in Table 2. No statistically significant differences were found with regard to peak inspiratory flow (PIF) when comparing days A, B, C, and E, and regarding inhaled volume on days A, C, D, and E (Figure 1). Inhalation techniques (A-C) resulted in deposits on the filter of 80 to 85% of the nominal dose. On study day .D, a significantly lower amount of terbutaline was found on the filter, and an even lower amount was found on study day E (Table 2). Except for study day E, the amount of terbutaline found on the filter was highly reproducible.
Pulmonary function There were no statistically significant differences in baseline values of FEV1 (Figure 2), Rt.,, specific airway conductance (SGaw) (Figure 3), MEF50 (Figure 4), vital capacity, nonforced (VC), RV, TLC, FRC, and MTT on the study days. The baseline value for PEF was significantly lower on day E than on the other study days (P < 0.01, paired t-test). All five inhalation techniques resulted in a highly significant bronchodilatation. Inhalation of 0.25 mg of terbutaline from the TBH caused a significant increase in FEV1 with techniques (A-D) (all P < 0.002, paired t-test). However, inhalation after a previous slow exhalation through the TBH (inhalation technique E) resulted in only a slight increase in FEV1 after the first
Table 2 Inhaled peak flows and volumes on each of the five study days (AE), amount of terbutaline collected on filter (after five doses of 0.5 mg), and percentage of the nominal terbutaline sulphate released by each of the five inhalation techniques (mean ± s.d.)
Terbutaline
Day A B C D E
PIF (1 min-1) 83.9 ± 15.1 77.9 ± 9.1 80.1 ± 12.6 33.8 ± 5.6 88.1 ± 13.0
sulphate IV (1)
3.75 ± 2.07 ± 3.88 ± 3.79 ± 3.58 ±
0.87 0.28 0.88 0.89 1.06
441
released (mg5 doses) 2.15 ± 0.35 2.02 ± 0.17 2.08 ± 0.23 1.44 ± 0.33 1.19 ± 1.03
% terbutaline sulphate 86.0 ± 14.0 80.8 ± 6.8 83.2 ± 9.2 57.6 ± 13.2 47.6 ± 41.2
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T. Engel et al. A: 0---
4.0F
B: o_.. 0-**C: D: E:
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cance with respect to the measurement of SGaw after inhalation of 0.25 mg of terbutaline (P = 0.01, paired ttest). No differences were found at any time between the degree of bronchodilatation obtained at 5 and 20 min (all P > 0.01, paired t-test). When all measurements from the 5 study days were grouped, FEV1 measured at 20 min averaged 0.01 1 (0.3%) higher than the 5 min value. The 5 min value was higher in 86 cases, the 20 min value in 119 cases, and the difference was within ± 0.01 1 in 44 cases. Results for the remaining measurements of pulmonary function (SGaw (Figure 3), PEF, MEF50 (Figure 4), Rt.t, VC, RV, and FRC) were similar to those obtained for FEV1.
a
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3.0
0.25
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1
2
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Terbutaline (mg) Figure 2 Cumulative dose-response relationships in FEV1 following inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
Plasma terbutaline concentrations Low concentrations of terbutaline were observed in the baseline blood sample on each of the four last study
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'when data for days (A-C) were compared. On study day D, slightly lower concentrations of plasma terbutaline _were found as compared with days (A-C) (AUC: P < 0.01, paired t-test). On study day E,
even
lower
plasma
terbutaline concentrations were found as compared with the other 4 study days (AUC: P < 0.01, paired t-test)
0.25
0.5
1
4
2
Terbutaline (mg) Figuire 3 Cumulative dose-response relationships in SGaw folloiwing inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
(Figure 5).
Although the different inhalation techniques resulted in slightly different degrees of bronchodilatation, and inhalation technique E in particular caused significantly less bronchodilatation than the other modes of inhalation, no significant differences between the five inhalation techniques could be demonstrated when bronchodilatation was related to plasma terbutaline concentrations
achieved after each dose (Figure 6). -A: *4.0 -
Side effects
-
B:*-
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An initial decrease in heart rate was found following inhalation of the first doses of terbutaline (Figure 7). An increase in heart rate following the last dose of terbutaline
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Figure 4 Cumulative dose-response relationships in MEF50 following inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
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doses, and a poor effect compared with the other four inhalation techniques (all P < 0.01, paired t-test) (Figures 2, 3, 4). The slow inhalation technique (technique D) tended to cause slightly less bronchodilatation compared with inhalation techniques (A-C) (Figures 2, 3, 4). However, this difference only reached statistical signifi-
0
0.25
0.5
1
2
4
Terbutaline (mg)
Figure 5 Plasma concentrations of terbutaline following inhalation of increasing (cumulative) doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
Effects of inhaled terbutaline A: B:
4.0 _
No subjects dropped out of the study because of side effects. Headache and tiredness were reported infrequently independent of study day (Figure 8); palpitations and tremor, however, were frequently reported on study days A, B, and C, less frequently on study day D and infrequently on study day E.
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Plasma terbutaline (nmol 1-') Figure 6 Bronchodilatation (FEV1) following inhalation of different doses of terbutaline from the TBH in relation to concomitant plasma terbutaline concentration in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
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Terbutaline (mg) Figure 7 Changes in heart rate following inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
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ABCDE ABCDE Palpitations Tremor
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Headache Figure 8 Side effects (symptom scores) from inhaling
cumulative 4 mg dose of terbutaline in 10 adult asthmatics. AE: Inhalation techniques (A-E) (see Figure 1 for further explanation).
was seen
with inhalation techniques A, B, and C, and
to a minor extent with inhalation techniques D and E
(Figure 7). No significant differences were found between the 5 study days, or as a result of inhalation of increasing doses of terbutaline with regard to systolic or diastolic BP.
Using the terbutaline TBH, no statistically significant differences were found when each of the four technically correct modes of inhalation (i.e. techniques (A-D)) were compared with regard to both large and small airways function. There was a trend for the slow inhalation mode (technique 'D') to cause slightly less bronchodilatation as compared with the other three modes of inhalation. The use of this mode, however, was accompanied by a reduction in side effects, slightly lower plasma terbutaline concentrations, and less deposition of terbutaline on the filters. Although in vitro data have suggested that lowering the inspiratory flow through the TBH from 60 to 28 1 min -1 results in a reduction of up to 50% in the number of particles smaller than 5 ,um (Jaegfeldt et al., 1987), the results of the present investigation indicate that this has little clinical relevance. Furthermore, most adults and children above the age of 5 years are capable of producing inhaled flows through the TBH of 30 1 min-' or more (Engel et al., 1990; Pedersen et al., 1990), indicating that they will obtain a satisfactory clinical effect. In children, a similar degree of bronchodilatation has been demonstrated when inhaled flow varies between 31 and 60 1 min-1 (Pedersen et al., 1990). In adults, bronchodilatation is similar when inhaled flows varies between 30 and 60 1 min-1, as evaluated from FEV1, although small airways function was less easily restored with the slower rate of inhalation (Dolovich et al., 1988). Using the budesonide TBH, the change in FEV1 was independent of inhaled flows (Engel et al., 1989). However, dependence on inhaled flow was demonstrated with respect to bronchial hyperresponsiveness to inhaled histamine (Engel et al., 1989). High inhaled flows result in reduced intrapulmonary deposition (Pavia et al., 1977) and thus reduced bronchodilatation (Dolovich et al., 1981; Newman et al., 1980, 1981). With the terbutaline TBH, increasing flow during inhalation results in higher yields of terbutaline from the device, as demonstrated in the present study (Table 2), and a better deaggregation of the drug particles (Jaegfeldt et al., 1987). The reduced intrapulmonary deposition from high inhaled flows may therefore be offset by better deaggregation with higher flows through the TBH. Furthermore, the mouthpiece of the TBH makes it impossible to produce inhaled flows greater than about 100 1 min-' (Engel et al., 1990). When an exhalation through the TBH is performed prior to inhalation, part of the dose is blown away. The remaining terbutaline agglomerates, and deaggregation during inhalation is compromised. In accordance with these considerations, inhalation after a previous exhalation through the TBH resulted in poor bronchodilatation. Also very low concentrations of plasma terbutaline and
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fewer side effects were observed. The actual degree of bronchodilatation achieved was, however, still directly related to the amount of terbutaline being released from the TBH, and to the concurrent plasma terbutaline concentration (Figure 6). Since the present study did not include a placebo control day, it is not possible to judge, as compared with placebo, to what extent inhalation after a previous exhalation through the TBH will result in bronchodilatation. Apart from being barely sensitive to inhaled flow, the bronchodilatation properties of the terbutaline TBH have also been shown to be independent of whether inhalation was performed from RV or FRC, whether or not the head was tilted backwards during inhalation, and whether a 10 s breath-holding pause followed the inhala-
tion in children (Hansen & Pedersen, 1989). In conclusion, the results of the present study have demonstrated that when inhalation is performed using the TBH, a similar degree of bronchodilatation is achieved irrespective of whether the inhalation is performed from FRC or RV, and regardless of the inspiratory flow, as long as the peak inspiratory flow is 34 1 min-1 or higher. A slow exhalation through the TBH prior to inhalation results in significantly reduced bronchodilatation. The authors thank Mrs Anne Larsen for skilful secretarial assistance, and AB DRACO, Sweden, for supplying the study material. The study was supported by a grant from AB DRACO.
References Ahmad, D. (1983). Effects of aerosol propellants on airways function. In Metered dose inhalers, ed. Epstein, S. W., pp. 22-26. Astra Pharmaceuticals, Canada. Dolovich, M. B., Ruffin, R. E., Roberts, R. & Newhouse, M. T. (1981). Optimal delivery of aerosols from metered dose inhalers. Chest, 80 (Suppl.), 911-915. Dolovich, M. B., Vanzieleghem, M., Hidinger, K-G. & Newhouse, M. T. (1988). Influence of inspiratory flow rate (VI) on the response to terbutaline (T) inhaled via the Turbuhaler (TH). [abstract]. NER Allergy Proc., 9, 380. Engel, T., Heinig, J. H., Madsen, F. & Nikander, K. (1990). Peak inspiratory flow and inspiratory vital capacity of patients with asthma measured with and without a new drypowder inhaler device (Turbuhaler). Eur. resp. J., 3, 1037-1041. Engel, T., Heinig, J. H., Malling, H-J., Scharling, B., Nikander, K. & Madsen, F. (1989). Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or via Turbuhaler. Allergy, 44, 220-225. Engel, T., Skovsted, B., Scharling, B. & Heinig, J. H. (1991). Bronchoconstriction in adult asthmatics induced by pressurized metered dose inhalers [abstract]. Schweiz. med. Wschr., 121 (suppl. 40/I), 28. Groth, S. & Dirksen, H. (1983). Optimal inhalation procedure for the fenoterol powder inhaler. Eur. J. resp. Dis., 64 (Suppl. 130), 17-24. Hansen, 0. R. & Pedersen, S. (1989). Optimal inhalation technique with terbutaline Turbuhaler. Eur. resp. J., 2, 637-639. Jaegfeldt, H., Andersson J. A. R. & Wetterlin K. I. L. (1987). Particle size distribution from different modifications of Turbuhaler. In Proceedings of an international workshop on a new inhaler, eds Newman, S. P., Moren, F. & Crompton, G. K., pp. 90-99. London: Medicom. Johnsen, C. R. & Weeke, E. R. (1988). Turbuhaler: a new device for dry powder terbutaline inhalation. Allergy, 43, 392-395. Leferink, J. G., Baillie, T. A. & Lindberg, C. (1984). Quantitative analysis of terbutaline by gas chromatography-mass spectrometry. Eur. J. resp. Dis., 65 (Suppl. 134), 25-32. Leferink, J. G., Dankers, J. & Maes, R. A. A. (1982). A timesaving method for determination of 2 sympathomimetics terbutaline, salbutamol and feneterol. J. Chromatogr., 229,
217-221. Newman, S. P., Moren, F., Trofast, E., Talaee, N. & Clarke, S. W. (1989). Deposition and clinical efficacy of terbutaline sulphate from Turbuhaler, a new multi-dose powder inhaler. Eur. resp. J., 2, 247-252. Newman, S. P.. Pavia, D. & Clarke, S. W. (1980). Simple instructions for using pressurized aerosol bronchodilators. J. Roy. Soc. Med., 73, 776-779. Newman, S. P., Pavia, D. & Clarke, S. W. (1981). Improving the bronchial deposition of pressurized aerosols. Chest, 80 (Suppl.), 909-911. Pavia, D., Thomson, M. L., Clarke, S. W. & Shannon, H. S. (1977). Effect of lung function and mode of inhalation on penetration of aerosol into the human lung. Thorax, 32, 194-197. Pedersen, S. & Steffensen, G. (1986). Fenoterol powder inhaler technique in children: influence of inspiratory flow rate and breath holding. Eur. J. resp. Dis., 68, 207-214. Pedersen, S., Hansen, 0. R. & Fuglsang, G. (1990). Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch. Dis. Child, 65, 308-319. Persson, G., Gruvstad, E. & Stoahl, E. (1988). A new multiple dose powder inhaler, (Turbuhaler), compared with a pressurized inhaler in a study of terbutaline in asthmatics. Eur. resp. J., 1, 681-684. Richards, R., Simpson, S. F., Renwick, A. G. & Holgate, S. T. (1988). Inhalation rate of sodium cromoglycate determines plasma pharmacokinetics and protection against AMP-induced bronchoconstriction in asthma. Eur. resp. J., 1, 896-901. Sterling, G. M. & Batten, J. C. (1969). Effects of aerosol propellants and surfactants on airway resistance. Thorax, 24, 228-231. Wetterlin, K. I. L. (1988). Turbuhaler: a new powder inhaler for administration of drugs to the airways. Pharmac. Res., 5, 506-508. Yarbrough, J., Lyndon, R. N., Mansfield, E. & Ting, S. (1985). Metered dose inhaler induced bronchospasm in asthmatic patients. Ann. Allergy, 55, 25-27.
(Received 6 August 1991, accepted 25 October 1991)
Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes T. ENGEL, B. SCHARLING, B. SKOVSTED & J. H. HEINIG Allergy Unit TTA 7511, National University Hospital, Tagensvej 20, DK-2200 Copenhagen, Denmark
1 The efficacy of a metered dose inhaler (MDI) is highly dependent on the mode of inhalation. The relatively high built-in resistance in the Turbohaler® (TBH), a new dry powder inhaler device for inhalation of terbutaline sulphate and budesonide, reduces the flow during inhalation. We compared five different modes of inhalation using the terbutaline TBH in 10 stable asthmatic subjects, who were tested on 5 consecutive days. 2 Measurement of 10 different parameters of pulmonary function indicated that the full bronchodilatory effect of an inhaled dose was already achieved at 5 min after the inhalation. Inspiratory flows through the TBH varying from 34 to 88 1 min- 1 resulted in comparable bronchodilation, and a previous exhalation to residual volume proved of no value. However, if, prior to inhalation, an exhalation through the device was performed, a substantially reduced effect was seen. 3 Reducing the inspiratory flow to approximately 34 1 min-1 produced slightly reduced side effects and lower plasma terbutaline concentrations.
Keywords
terbutaline
asthma
inhalers
Introduction For many years ,32-adrenoceptor agonists have been one of the primary treatments of asthma, most commonly administered through chlorofluorocarbon (CFC) (Freon®)-driven metered dose inhalers (MDIs). In some asthmatics a significant decrease in ventilatory capacity develops after inhalation from MDIs (Ahmad, 1983; Engel et al., 1991; Sterling & Batten, 1969; Yarbrough et al., 1985). Thus, the manner in which the drug is delivered may influence the clinical outcome. The search for alternative ways of delivering metered doses to the lungs has therefore received a high priority. Currently, various dry powder MDIs are available. These inhalers solve the problem of bronchoconstriction seen with pressurized MDIs, since they do not contain CFC-gases and surfactants. Furthermore, they are breathactuated and the problem of coordination between actuation and inhalation is avoided. A major determinant of the efficacy of a dry powder inhaler is the flow through the inhaler during inhalation (Groth & Dirksen, 1983; Jaegfeldt et al., 1987; Newman et al., 1989; Pedersen & Steffensen, 1986; Pedersen et al., 1990; Richards et al., 1988). The terbutaline Turbohaler® (TBH), (Turbuhaler® in most European countries) supplies up to 200 doses of drug without reloading and is easy to handle and small in size (Wetterlin, 1988). An essential
component of the TBH is the removable mouthpiece, which has a relatively high built-in airflow resistance because of a narrow insert with spiral channels for deaggregation of the drug powder. When inhalation is performed through the TBH, maximum inspiratory flow is reduced to about 25% (Engel et al., 1990). However, practically all adults with airways obstruction are able to achieve inspiratory flows through the TBH of 30 1 min-1 or more (Engel et al., 1990), as are children above 6 years, even during acute wheezing (Pedersen et al., 1990). Below the age of 6 years an increasing proportion of children are unable to ?roduce inspiratory flows through the TBH of 301 min- or more (Pedersen et al., 1990). Inhalation of terbutaline from the TBH has been shown to produce an effect comparable with that of a pressurized MDI, when inhalation is performed through the TBH with an inspiratory flow of approximately 60 1 min-1 (Johnsen & Weeke, 1988; Persson et al., 1988). In children, a similar degree of bronchodilatation was observed when the inhaled flow through the TBH was 31 and 60 1 min-1, but reduced bronchodilatation occurred at rates below 31 1 min-' (Pedersen et al.,
1990). The aim of the present study was to assess the influence
Correspondence: Dr T. Engel, Allergy Unit T1A 7511, National University Hospital, Tagensvej 20, DK-2200 Copenhagen, Denmark
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of inhaled flow and volume through the TBH on pulmonary function, plasma terbutaline concentrations and side effects in stable adult asthmatics. T40:
Methods -
60
A:-
Design
B:
C: D:
80
The investigation was performed as an open, randomized, cross-over, cumulative dose-response study. All subjects attended the allergy clinic at 08.00 h on 5 consecutive days. On each day terbutaline (Bricanyl®) was inhaled from a TBH using different inhalation techniques (Table 1). On each study day the subjects abstained from caffeinecontaining beverages and inhaled 32-adrenoceptor agonists for at least 8 h prior to attending the clinic. Tobacco smoking was not allowed for at least 2 h before attending the clinic (four subjects were smokers). During an initial 30 min period, an intravenous cannula was inserted into a cubital vein. A baseline blood sample was drawn and baseline pulmonary function, BP and heart rate were measured. Inhalations of terbutaline were then performed every 30 min (Table 1). The same inhalation technique was used during the entire study day. Five and 20 min after each terbutaline inhalation, the pulmonary function measurements were repeated. Immediately prior to the next inhalation, a blood sample was drawn for assay of plasma terbutaline, and heart rate and blood pressure were measured. The study was approved by the local ethics committee and by the National Board of Health and Welfare. All subjects participated after having been given verbal and written information.
Subjects Eleven subjects who had been suffering from chronic bronchial asthma for a mean period of 13 years (range 4-20 years) were studied. All had been using inhaled 032-adrenoceptor agonists as their only asthma therapy during the previous 3 months. Furthermore, all subjects had demonstrated at least a 15% increase in forced exporatory volume in 1 s (FEV1) after inhalation of a P2-adrenoceptor agonist within the previous 6 months. One subject was excluded because, having participated in the study for 2 days, she claimed to be unable to attend the clinic for the remaining 3 days. The remaining 10 subjects completed the study (two females, eight males, mean age 25 years (range 19-40 years)). Baseline FEVy averaged 72.6% of predicted (ranging from 70.8-73.6% Table 1 Dose of terbutaline sulphate inhaled from the TBH on each of the 5 study days and the resulting cumulative dose during the day. (* a 0.25 mg TBH is not commercially available)
Dose number 1 2 3 4 5
Time (h)
08.30 09.00 09.30 10.00 10.30
Dose inhaled 0.25 mg* 0.25 mg* 0.50 mg 1.00 mg 2.00 mg
Cumulative dose (mg) 0.25 0.50 1.00 2.00 4.00
E:-
100
Figure 1 Schematic presentation of flows and volumes during inhalation from TBH on each of the 5 study days (A-E). The inhalation technique on day E was similar to that on day A, but was preceded by a slow exhalation from FRC to RV through the TBH prior to inhalation. on individual study days, and ranged from 48.0% (the lowest value recorded) to 88.4% (the highest value in any individual subject)).
Inhalation techniques used with the TBH Inhalation techniques were varied in random order according to a latin square design on each of the 5 consecutive study days (A-E) (Figure 1). A: Each inhalation was performed using the maximal inspiratory flow producible by the subjects from near residual volume (RV) to total lung capacity (TLC). This represented the 'standard' inhalation technique. B: Each inhalation was performed using the maximal inspiratory flow producible by the subjects, but inhalation was only performed from functional residual capacity (FRC) to TLC. This technique assessed the importance of volume during inhalation. C: Each inhalation was performed using the maximal inspiratory flow rate during the first half second of the inhalation and thereafter the rate was reduced to approximately 30 1 min- 1. Inhalation was performed from RV to TLC satisfying both the need for a high flow through the TBH in order to deaggregate the particles, and a low flow in order to produce a good intrapulmonary distribution of drug. D: Each inhalation was performed using a flow rate of approx. 301 min-' during the entire inhalation from RV to TLC. This technique simulated low inspiratory flows in non-cooperative subjects or during acute wheezing. E: Each inhalation was performed as described in (A), but was preceded by a slow exhalation from FRC to RV through the TBH. This technique simulated incorrect use of the device. All inhalations from the TBH were monitored with regard to flow and volume. The TBH was placed in a specially designed adapter and connected in series to a pneumotachograph with the integrator modified to record inspiratory measurements (Vitalograph Compact®, Vitalograph Ltd, Buckingham, U.K.) reported in ambient temperature and pressure (ATP). A breathholding pause of approximately 10 s (10.68 s ± 0.82 s, mean ± s.d.) followed each inhalation. Repeated -
inhalations omitting reloading of the TBH inhaler
in
Effects of inhaled terbutaline order to ensure complete release of each dose were not permitted, i.e. only a single inhalation was performed per terbutaline dose. On each study day, 30 min after inhalation of the last dose of terbutaline, the subjects reported any occurrence of palpitations, tremor, headache, tiredness, or other discomfort graded in a standard manner from 0 = none to 3 = severe.
Pulmonary function measurements All pulmonary function measurements were made in an 830 1 constant volume whole-body box (Jaeger Master Lab System®, Erich Jaeger GmbH & Co. KG, Wurzberg, F.R.G.). Body plethysmography was performed during panting (approximately 1 Hz), and always preceded the flow/volume measurement. At least five consecutive measurements of FRC and total airway resistance (Rtot) were made, results varying by more than ± 10% being discarded. This was followed by at least two technically correct flow/volume measurements with a variance of FEV1 not exceeding 5%. The highest results were reported, maximum expiratory flow at 50% of vital capacity (MEF5o) and mean transit time (MIT) values were noted from the curve with the highest FEV1 value.
Terbutaline released from the TBH On each study day, the subjects performed five inhalations during the initial 30 min period, using the designated inhalation technique, from the TBH through a Marquest MQ-303 viral filter (Respirgard II). By a combination of electrostatic and mechanical mechanisms, this filter retains virtually all particles of 1 ,um or larger (Marquest Medical Products, Colorado, U.S.A.). Therefore, essentially all of the particles released from the devices were collected on the filter. The amount of terbutaline on each filter was measured in a blinded fashion at AB DRACO, Lund, Sweden.
Measurement ofplasma terbutaline Within 4 min of sampling, blood was spun at 200 g for 10 min and separated. Plasma was stored at -20° C until assay for terbutaline. The plasma samples were analysed in a blinded fashion at bco Medical Services BW, Breda, The Netherlands. The plasma concentrations of terbutaline were determined by a gas chromatography chemical ionization mass spectrometry method according to Leferink et al. (1982, 1984). The lower limit of quantitation was 1 nmol 1-1.
Statistical analysis All comparisons of continuous data, e.g. pulmonary function, amount of terbutaline released from the TBH (Marquest MQ-303 viral filter), plasma terbutaline, blood pressure and heart rate were made using Student's t-test, paired or unpaired as appropriate. Comparisons of categorical variables (i.e. side effects) were made using the Wilcoxon-Pratt paired rank sum test for intrasubject comparisons, and the Mann-Whitney rank sum test for inter-subject comparisons. Because of the large number of comparisons the level of significance was set to 0.01 in order to reduce the risk of type I errors. Integral values of the effect parameters were calculated by summing the values obtained after inhalation of each dose of terbutaline.
Results Mean (± s.d.) values of inhaled peak flows and volumes through the TBH achieved with each inhalation technique (A-E) are shown in Table 2. No statistically significant differences were found with regard to peak inspiratory flow (PIF) when comparing days A, B, C, and E, and regarding inhaled volume on days A, C, D, and E (Figure 1). Inhalation techniques (A-C) resulted in deposits on the filter of 80 to 85% of the nominal dose. On study day .D, a significantly lower amount of terbutaline was found on the filter, and an even lower amount was found on study day E (Table 2). Except for study day E, the amount of terbutaline found on the filter was highly reproducible.
Pulmonary function There were no statistically significant differences in baseline values of FEV1 (Figure 2), Rt.,, specific airway conductance (SGaw) (Figure 3), MEF50 (Figure 4), vital capacity, nonforced (VC), RV, TLC, FRC, and MTT on the study days. The baseline value for PEF was significantly lower on day E than on the other study days (P < 0.01, paired t-test). All five inhalation techniques resulted in a highly significant bronchodilatation. Inhalation of 0.25 mg of terbutaline from the TBH caused a significant increase in FEV1 with techniques (A-D) (all P < 0.002, paired t-test). However, inhalation after a previous slow exhalation through the TBH (inhalation technique E) resulted in only a slight increase in FEV1 after the first
Table 2 Inhaled peak flows and volumes on each of the five study days (AE), amount of terbutaline collected on filter (after five doses of 0.5 mg), and percentage of the nominal terbutaline sulphate released by each of the five inhalation techniques (mean ± s.d.)
Terbutaline
Day A B C D E
PIF (1 min-1) 83.9 ± 15.1 77.9 ± 9.1 80.1 ± 12.6 33.8 ± 5.6 88.1 ± 13.0
sulphate IV (1)
3.75 ± 2.07 ± 3.88 ± 3.79 ± 3.58 ±
0.87 0.28 0.88 0.89 1.06
441
released (mg5 doses) 2.15 ± 0.35 2.02 ± 0.17 2.08 ± 0.23 1.44 ± 0.33 1.19 ± 1.03
% terbutaline sulphate 86.0 ± 14.0 80.8 ± 6.8 83.2 ± 9.2 57.6 ± 13.2 47.6 ± 41.2
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T. Engel et al. A: 0---
4.0F
B: o_.. 0-**C: D: E:
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cance with respect to the measurement of SGaw after inhalation of 0.25 mg of terbutaline (P = 0.01, paired ttest). No differences were found at any time between the degree of bronchodilatation obtained at 5 and 20 min (all P > 0.01, paired t-test). When all measurements from the 5 study days were grouped, FEV1 measured at 20 min averaged 0.01 1 (0.3%) higher than the 5 min value. The 5 min value was higher in 86 cases, the 20 min value in 119 cases, and the difference was within ± 0.01 1 in 44 cases. Results for the remaining measurements of pulmonary function (SGaw (Figure 3), PEF, MEF50 (Figure 4), Rt.t, VC, RV, and FRC) were similar to those obtained for FEV1.
a
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3.5 F
3.0
0.25
0
0.5
1
2
4
Terbutaline (mg) Figure 2 Cumulative dose-response relationships in FEV1 following inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
Plasma terbutaline concentrations Low concentrations of terbutaline were observed in the baseline blood sample on each of the four last study
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tion occurred following inhalation of each dose of terbutaline (Figure 5). No statistically significant differ-
-e-/.'
in
plasma terbutaline concentrations
were
found
'when data for days (A-C) were compared. On study day D, slightly lower concentrations of plasma terbutaline _were found as compared with days (A-C) (AUC: P < 0.01, paired t-test). On study day E,
even
lower
plasma
terbutaline concentrations were found as compared with the other 4 study days (AUC: P < 0.01, paired t-test)
0.25
0.5
1
4
2
Terbutaline (mg) Figuire 3 Cumulative dose-response relationships in SGaw folloiwing inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
(Figure 5).
Although the different inhalation techniques resulted in slightly different degrees of bronchodilatation, and inhalation technique E in particular caused significantly less bronchodilatation than the other modes of inhalation, no significant differences between the five inhalation techniques could be demonstrated when bronchodilatation was related to plasma terbutaline concentrations
achieved after each dose (Figure 6). -A: *4.0 -
Side effects
-
B:*-
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An initial decrease in heart rate was found following inhalation of the first doses of terbutaline (Figure 7). An increase in heart rate following the last dose of terbutaline
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Figure 4 Cumulative dose-response relationships in MEF50 following inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
D: E:
0)
C
10 0)
E
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doses, and a poor effect compared with the other four inhalation techniques (all P < 0.01, paired t-test) (Figures 2, 3, 4). The slow inhalation technique (technique D) tended to cause slightly less bronchodilatation compared with inhalation techniques (A-C) (Figures 2, 3, 4). However, this difference only reached statistical signifi-
0
0.25
0.5
1
2
4
Terbutaline (mg)
Figure 5 Plasma concentrations of terbutaline following inhalation of increasing (cumulative) doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
Effects of inhaled terbutaline A: B:
4.0 _
No subjects dropped out of the study because of side effects. Headache and tiredness were reported infrequently independent of study day (Figure 8); palpitations and tremor, however, were frequently reported on study days A, B, and C, less frequently on study day D and infrequently on study day E.
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Discussion .R (1tN I
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Plasma terbutaline (nmol 1-') Figure 6 Bronchodilatation (FEV1) following inhalation of different doses of terbutaline from the TBH in relation to concomitant plasma terbutaline concentration in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
A: *--B: * -.-* C:*.0
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80.0
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Terbutaline (mg) Figure 7 Changes in heart rate following inhalation of increasing doses of terbutaline from the TBH in 10 adult asthmatics. A-E: Inhalation techniques on days A-E (see Figure 1 for further explanation).
3r
o
2
0 0.
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ABCDE ABCDE Palpitations Tremor
III
II
ABCDE
I
E
ABCDE Tiredness
Headache Figure 8 Side effects (symptom scores) from inhaling
cumulative 4 mg dose of terbutaline in 10 adult asthmatics. AE: Inhalation techniques (A-E) (see Figure 1 for further explanation).
was seen
with inhalation techniques A, B, and C, and
to a minor extent with inhalation techniques D and E
(Figure 7). No significant differences were found between the 5 study days, or as a result of inhalation of increasing doses of terbutaline with regard to systolic or diastolic BP.
Using the terbutaline TBH, no statistically significant differences were found when each of the four technically correct modes of inhalation (i.e. techniques (A-D)) were compared with regard to both large and small airways function. There was a trend for the slow inhalation mode (technique 'D') to cause slightly less bronchodilatation as compared with the other three modes of inhalation. The use of this mode, however, was accompanied by a reduction in side effects, slightly lower plasma terbutaline concentrations, and less deposition of terbutaline on the filters. Although in vitro data have suggested that lowering the inspiratory flow through the TBH from 60 to 28 1 min -1 results in a reduction of up to 50% in the number of particles smaller than 5 ,um (Jaegfeldt et al., 1987), the results of the present investigation indicate that this has little clinical relevance. Furthermore, most adults and children above the age of 5 years are capable of producing inhaled flows through the TBH of 30 1 min-' or more (Engel et al., 1990; Pedersen et al., 1990), indicating that they will obtain a satisfactory clinical effect. In children, a similar degree of bronchodilatation has been demonstrated when inhaled flow varies between 31 and 60 1 min-1 (Pedersen et al., 1990). In adults, bronchodilatation is similar when inhaled flows varies between 30 and 60 1 min-1, as evaluated from FEV1, although small airways function was less easily restored with the slower rate of inhalation (Dolovich et al., 1988). Using the budesonide TBH, the change in FEV1 was independent of inhaled flows (Engel et al., 1989). However, dependence on inhaled flow was demonstrated with respect to bronchial hyperresponsiveness to inhaled histamine (Engel et al., 1989). High inhaled flows result in reduced intrapulmonary deposition (Pavia et al., 1977) and thus reduced bronchodilatation (Dolovich et al., 1981; Newman et al., 1980, 1981). With the terbutaline TBH, increasing flow during inhalation results in higher yields of terbutaline from the device, as demonstrated in the present study (Table 2), and a better deaggregation of the drug particles (Jaegfeldt et al., 1987). The reduced intrapulmonary deposition from high inhaled flows may therefore be offset by better deaggregation with higher flows through the TBH. Furthermore, the mouthpiece of the TBH makes it impossible to produce inhaled flows greater than about 100 1 min-' (Engel et al., 1990). When an exhalation through the TBH is performed prior to inhalation, part of the dose is blown away. The remaining terbutaline agglomerates, and deaggregation during inhalation is compromised. In accordance with these considerations, inhalation after a previous exhalation through the TBH resulted in poor bronchodilatation. Also very low concentrations of plasma terbutaline and
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T. Engel et al.
fewer side effects were observed. The actual degree of bronchodilatation achieved was, however, still directly related to the amount of terbutaline being released from the TBH, and to the concurrent plasma terbutaline concentration (Figure 6). Since the present study did not include a placebo control day, it is not possible to judge, as compared with placebo, to what extent inhalation after a previous exhalation through the TBH will result in bronchodilatation. Apart from being barely sensitive to inhaled flow, the bronchodilatation properties of the terbutaline TBH have also been shown to be independent of whether inhalation was performed from RV or FRC, whether or not the head was tilted backwards during inhalation, and whether a 10 s breath-holding pause followed the inhala-
tion in children (Hansen & Pedersen, 1989). In conclusion, the results of the present study have demonstrated that when inhalation is performed using the TBH, a similar degree of bronchodilatation is achieved irrespective of whether the inhalation is performed from FRC or RV, and regardless of the inspiratory flow, as long as the peak inspiratory flow is 34 1 min-1 or higher. A slow exhalation through the TBH prior to inhalation results in significantly reduced bronchodilatation. The authors thank Mrs Anne Larsen for skilful secretarial assistance, and AB DRACO, Sweden, for supplying the study material. The study was supported by a grant from AB DRACO.
References Ahmad, D. (1983). Effects of aerosol propellants on airways function. In Metered dose inhalers, ed. Epstein, S. W., pp. 22-26. Astra Pharmaceuticals, Canada. Dolovich, M. B., Ruffin, R. E., Roberts, R. & Newhouse, M. T. (1981). Optimal delivery of aerosols from metered dose inhalers. Chest, 80 (Suppl.), 911-915. Dolovich, M. B., Vanzieleghem, M., Hidinger, K-G. & Newhouse, M. T. (1988). Influence of inspiratory flow rate (VI) on the response to terbutaline (T) inhaled via the Turbuhaler (TH). [abstract]. NER Allergy Proc., 9, 380. Engel, T., Heinig, J. H., Madsen, F. & Nikander, K. (1990). Peak inspiratory flow and inspiratory vital capacity of patients with asthma measured with and without a new drypowder inhaler device (Turbuhaler). Eur. resp. J., 3, 1037-1041. Engel, T., Heinig, J. H., Malling, H-J., Scharling, B., Nikander, K. & Madsen, F. (1989). Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or via Turbuhaler. Allergy, 44, 220-225. Engel, T., Skovsted, B., Scharling, B. & Heinig, J. H. (1991). Bronchoconstriction in adult asthmatics induced by pressurized metered dose inhalers [abstract]. Schweiz. med. Wschr., 121 (suppl. 40/I), 28. Groth, S. & Dirksen, H. (1983). Optimal inhalation procedure for the fenoterol powder inhaler. Eur. J. resp. Dis., 64 (Suppl. 130), 17-24. Hansen, 0. R. & Pedersen, S. (1989). Optimal inhalation technique with terbutaline Turbuhaler. Eur. resp. J., 2, 637-639. Jaegfeldt, H., Andersson J. A. R. & Wetterlin K. I. L. (1987). Particle size distribution from different modifications of Turbuhaler. In Proceedings of an international workshop on a new inhaler, eds Newman, S. P., Moren, F. & Crompton, G. K., pp. 90-99. London: Medicom. Johnsen, C. R. & Weeke, E. R. (1988). Turbuhaler: a new device for dry powder terbutaline inhalation. Allergy, 43, 392-395. Leferink, J. G., Baillie, T. A. & Lindberg, C. (1984). Quantitative analysis of terbutaline by gas chromatography-mass spectrometry. Eur. J. resp. Dis., 65 (Suppl. 134), 25-32. Leferink, J. G., Dankers, J. & Maes, R. A. A. (1982). A timesaving method for determination of 2 sympathomimetics terbutaline, salbutamol and feneterol. J. Chromatogr., 229,
217-221. Newman, S. P., Moren, F., Trofast, E., Talaee, N. & Clarke, S. W. (1989). Deposition and clinical efficacy of terbutaline sulphate from Turbuhaler, a new multi-dose powder inhaler. Eur. resp. J., 2, 247-252. Newman, S. P.. Pavia, D. & Clarke, S. W. (1980). Simple instructions for using pressurized aerosol bronchodilators. J. Roy. Soc. Med., 73, 776-779. Newman, S. P., Pavia, D. & Clarke, S. W. (1981). Improving the bronchial deposition of pressurized aerosols. Chest, 80 (Suppl.), 909-911. Pavia, D., Thomson, M. L., Clarke, S. W. & Shannon, H. S. (1977). Effect of lung function and mode of inhalation on penetration of aerosol into the human lung. Thorax, 32, 194-197. Pedersen, S. & Steffensen, G. (1986). Fenoterol powder inhaler technique in children: influence of inspiratory flow rate and breath holding. Eur. J. resp. Dis., 68, 207-214. Pedersen, S., Hansen, 0. R. & Fuglsang, G. (1990). Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch. Dis. Child, 65, 308-319. Persson, G., Gruvstad, E. & Stoahl, E. (1988). A new multiple dose powder inhaler, (Turbuhaler), compared with a pressurized inhaler in a study of terbutaline in asthmatics. Eur. resp. J., 1, 681-684. Richards, R., Simpson, S. F., Renwick, A. G. & Holgate, S. T. (1988). Inhalation rate of sodium cromoglycate determines plasma pharmacokinetics and protection against AMP-induced bronchoconstriction in asthma. Eur. resp. J., 1, 896-901. Sterling, G. M. & Batten, J. C. (1969). Effects of aerosol propellants and surfactants on airway resistance. Thorax, 24, 228-231. Wetterlin, K. I. L. (1988). Turbuhaler: a new powder inhaler for administration of drugs to the airways. Pharmac. Res., 5, 506-508. Yarbrough, J., Lyndon, R. N., Mansfield, E. & Ting, S. (1985). Metered dose inhaler induced bronchospasm in asthmatic patients. Ann. Allergy, 55, 25-27.
(Received 6 August 1991, accepted 25 October 1991)
