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Systemic Bioavailability and Potency of High-Dose Inhaled Corticosteroids
Systemic Bioavailability and Potency of High-Dose Inhaled Corticosteroids* A Comparison of Four Inhaler Devices and Three Drugs in Healthy Adult Volunteers Deborah Wales, MD; Herminder Makker, MD; John Kane, BSc; Patrick McDowell, MD; and B. Ronan O’Driscoll, MD
Objectives: To compare the systemic bioavailability (assessed by cortisol suppression) of highdose budesonide when given by four inhaler devices and orally. Also studied are the relative systemic potencies of three inhaled steroids (budesonide, fluticasone propionate, and beclomethasone dipropionate) when given by metered-dose inhaler (MDI) with a large volume spacer. Design: Double-blind, crossover, placebo-controlled trial. Participants: Sixteen healthy, steroid-naive adult volunteers. Methods: On separate occasions, each subjects took 4 mg of budesonide through the following devices: MDI alone, MDI with 750-mL spacer, dry-powder inhaler and nebulizer; 4 mg of budesonide was also taken orally to assess the effects of GI absorption. For the drug comparison, each subject took 4 mg of budesonide, fluticasone, and beclomethasone, and 2 mg of budesonide and fluticasone by MDI and spacer. Results: Greatest percent suppression (95% confidence interval) of 9:00 AM cortisol with budesonide was observed with MDI alone (73% [57 to 90]) and turbohaler (72% [58 to 86]) compared with MDI spacer (42% [22 to 64]) and oral administration (14% [16- to 234]). Nebulized budesonide produced an insignificant rise in 9:00 AM cortisol level. The most suppressive drug (given by MDI spacer) was fluticasone at 4 mg (86% [82 to 91]) and at 2 mg (72% [59 to 85]). The least suppressive drug was budesonide at 4 mg (43% [22 to 64]) and at 2 mg (25% [3 to 47]). The effects of 4 mg of beclomethasone were intermediate (66% [49 to 82%]). Conclusions: The choice of delivery device for administration of budesonide can lead to important differences in systemic bioavailability. Fluticasone has greater systemic potency than budesonide or beclomethasone when given at microgram equivalent dosage. The systemic potency ratio of fluticasone propionate to budesonide in normal human volunteers in the present study is similar to the therapeutic potency ratio of the drug in asthmatic patients (approximately 2:1). (CHEST 1999; 115:1278 –1284) Key words: adrenal suppression; beclomethasone dipropionate; bioavailability; budesonide; fluticasone propionate; inhaled corticosteroids Abbreviations: HPA 5 hypothalamic-pituitary-adrenal; MDI 5 metered-dose inhaler
steroids are used extensively in the manI nhaled agement of asthma. Sometimes high doses
($ 1,500 mg/d) are necessary to control symptoms. Systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis can occur at these high doses; however, there are few reports of clinically important systemic effects from these drugs.1
*From Hope Hospital, Salford, UK. Manuscript received June 16, 1998; revision accepted November 24, 1998. Correspondence to: D. Wales, MD, Specialist Registrar, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. 1278
The therapeutic goal should be to optimize asthma control but to minimize potential systemic side effects. It is known that the choice of inhaler device can influence lung deposition (and systemic bioavailability) of inhaled corticosteroids, but the relative effects of various inhaler devices, spacer devices, nebulizers, and dry powder devices are poorly understood.2 In this study, two experiments were performed. The first experiment was to compare the relative effectiveness of several delivery techniques using a single steroid as a marker. Budesonide was taken via four different inhaler devices (metered-dose inhaler Clinical Investigations
[MDI] alone, MDI and large volume spacer, dry powder device, and nebulizer) and the systemic bioavailability was determined by measuring suppression of 9:00 am plasma cortisol level. The second experiment was to compare the relative potency of three inhaled steroids when given by MDI and spacer. Fluticasone, beclomethasone dipropionate, and budesonide were taken by large volume spacer, the preferred delivery system for high-dose steroids3 and suppression of 9:00 am plasma cortisol level was measured. Systemic bioavailability is largely determined by lung deposition and absorption.2 Previous studies of this nature have yielded conflicting results because low or moderate doses of inhaled steroids were administered producing only modest falls in morning cortisol levels with a high “signal to noise” ratio. For this reason, we used very high doses of inhaled steroid (4 mg) to ensure that any difference between drugs and devices would be demonstrated clearly. Materials and Methods Subjects Sixteen healthy, nonsmoking volunteers aged 25 to 42 years completed the study (12 were men). All were steroid naive and taking no other medication. Each subject gave written informed consent, and the study was approved by the Salford Local Research Ethics Committee. Protocol This was a double-blind, crossover, placebo-controlled trial. For the first experiment, subjects took 4 mg of budesonide through four inhaler systems and orally (to assess the effects of GI absorption). Each subject received, in random order, seven double-blind treatments of which two (randomly chosen) were placebo: (1) MDI without spacer device (20 inhalations from Pulmicort 200-mg inhaler; Astra Pharmaceuticals; Kings Langley, UK); (2) MDI and 750-mL spacer (20 inhalations of Pulmicort 200-mg inhaler using Nebuhaler 750-mL spacer; Astra Pharmaceuticals); (3) dry powder inhaler (10 inhalations of Pulmicort 400-mg Turbohaler; Astra Pharmaceuticals); (4) nebulized budesonide (four Pulmicort Respules, each containing 1 mg budesonide in 2 mL; Astra Pharmaceuticals); the solution was nebulized using a jet stream nebulizer (System 22; Medic-Aid; West Sussex, UK); (5) budesonide was taken orally (subjects swallowed the contents of four Pulmicort Respules); (6) placebo MDI inhaler, 20 actuations; and (7) placebo MDI inhaler, 10 actuations. All drugs were taken at 11:00 pm, and 9:00 am plasma cortisol levels were measured the following day. In the second experiment, the effects of the three commonly prescribed inhaled corticosteroids were compared. Each subject took the following in random order: (1) 4 mg of fluticasone (16 inhalations of Flixotide 250-mg inhaler; Allen and Hanbury’s; Stockley Park, UK) by MDI and spacer; (2) 4 mg of beclomethasone dipropionate (16 inhalations of Becloforte 250-mg inhaler; Allen and Hanbury’s) by MDI and spacer; (3) 2 mg of fluticasone (8 inhalations of Flixotide 250-mg inhaler; Allen and Hanbury’s)
by MDI and spacer; and (4) 2 mg of budesonide (10 inhalations of Pulmicort 200-mg inhaler using Nebuhaler 750-mL spacer; Astra Pharmaceuticals) by MDI and spacer. The results of the inhalation of 4 mg of budesonide through MDI and spacer and the two placebo inhalations from the first experiment were utilized in the second experiment. High doses of drugs were used to magnify the differences between them. Two milligrams of fluticasone and budesonide was used to assess the effects of doses that might be used in clinical practice and to study the dose-response relationship. Drugs were taken in random order at least 7 days apart. All subjects were instructed in the correct usage of the devices and their techniques were checked. Single deep inhalations from the device were followed by 10 s of breath-holding with a minimum interval of 30 s before the next dose. To minimize deposition on the spacer, only one puff of drug was delivered into the spacer at one time. Each spacer was primed with 20 puffs of drug prior to every drug administration in order to prevent drug adhering to the wall of the spacer due to the electrostatic attraction that occurs in new plastic spacer devices. Spacer devices were washed with water after use and allowed to dry naturally. A bank of three Nebuhaler devices and three Volumatic devices were used to deliver all treatments. All six devices were subjected to a similar amount of usage and washing during the course of the study. The aerosol canister and plastic actuators were masked to blind the treatment to the subjects and investigators. All aerosol containers had their labels removed and replaced with a code letter, and all MDI treatments were taken through the white “placebo” actuator supplied by the manufacturer of each drug. The chief investigator kept a record of all treatments and codes. Nebulized and oral budesonide were administered in an open manner as no suitable placebo was available. A single nebulizer was used throughout the study. Measurements Ten milliliters of venous blood was drawn between 8:30 and 9:30 am on the morning following each treatment. If a subject attended later than 9:30 am, the test was repeated 1 week later. Cortisol levels were measured using an in-house radioimmunoassay using cortisol antiserum from the Scottish Antibody Production Unit and a 125I cortisol derivative as label. Separation of the antibody bound and free fractions was accomplished with second antibody-coated cellulose. Standards were prepared in hormone-free human serum. The reference range for cortisol using this assay is 250 to 650 nmol/L at 9:00 am. Statistical Analysis For each treatment, we report the percentage change from the mean of two placebo measurements with 95% confidence intervals using software (Prism 2 Software; Graph Pad Software; San Diego, CA). Wilcoxon matched pairs signed rank test was used. The percent fall in plasma cortisol level for the least suppressive treatment (budesonide via MDI spacer) was also compared with all other treatments using Wilcoxon matched pairs signed rank test.
Results Effects of 4 mg of Budesonide Administered by Different Methods The greatest average percentage suppression of cortisol levels was seen with the MDI alone, producCHEST / 115 / 5 / MAY, 1999
1279
Figure 1. 9:00 am cortisol levels following the administration of 4 mg of budensonide by five different devices and two placebo devices. P1, P2 5 placebos; NEB 5 nebulizer; NH 5 nebuhaler; TH 5 Turbohaler.
ing a 73% fall (vs placebo, p 5 0.0002), and with the Turbohaler, which produced a 72% fall (vs placebo, p 5 0.0005) (Fig 1 and Table 1). The addition of a 750-mL volume spacer to the MDI reduced plasma cortisol suppression to 42% (vs placebo, p 5 0.0001). Oral budesonide produced a modest 14% fall in 9 am cortisol level (vs placebo, p 5 0.04). Nebulized budesonide caused no suppression of cortisol but a nonsignificant rise of 8%. (The assay system was checked for cross-reactivity with budesonide nebulizer solution at several concentrations but no such cross-reactivity was found.) Effects of Budesonide, Fluticasone, and Beclomethasone Dipropionate on 9:00 AM Cortisol Suppression Of the three drugs compared, fluticasone given by MDI and spacer produced the greatest average percentage suppression, 4 mg producing an 86% fall (vs placebo, p 5 0.0005) and 2 mg producing a 72%
fall (vs placebo, p 5 0.0005) (Fig 2 and Table 2). The least suppressive drug was budesonide. Four milligrams of budesonide produced a 43% fall (vs placebo, p 5 0.0001) and 2 mg produced a 25% fall (vs placebo, p 5 0.03). Beclomethasone fell between the two in potency producing a 66% fall after a 4-mg dose (vs placebo, p 5 0.0008). Discussion Inhaled corticosteroids in low and medium doses are safe with regard to systemic side effects; to our knowledge, there are no reported cases of clinically relevant adrenal suppression within the licensed dose range.1 However, when higher doses are employed to control asthma symptoms, adrenal suppression becomes a possibility.4 We used a model system of a single high dose of inhaled corticosteroid in normal volunteers. It is unlikely that any physician would prescribe a 4-mg dose of inhaled corticoste-
Table 1—Effects of 4 mg of Budesonide Administered by Five Different Methods* Device Placebo 1 Placebo 2 Bud, 4 mg Bud, 4 mg Bud, 4 mg Bud, 4 mg Bud, 4 mg
nebulized oral MDI 1 spacer Turbohaler MDI (no spacer)
Mean Cortisol (SD)
% Change
95% CI
p Value vs Placebo†
p Value vs Bud 4 mg via Spacer†
647 (379) 656 (387) 687 (463) 558 (393) 328 (271) 204 (290) 187 (244)
18 214 242 272 273
213, 128 234, 16 222, 264 258, 286 257, 290
0.45 0.18 0.0001 0.0005 0.0002
0.003 0.04 0.03 0.02
*Bud 5 budesonide; CI 5 confidence interval. †p values refer to Wilcoxon signed rank test. 1280
Clinical Investigations
Figure 2. 9:00 am serum cortisol levels with 4 mg and 2 mg of budesonide (BUD) and fluticasone (FLU) and two placebo devices. BDP 5 beclomethasone; P1, P2 5 placebos.
roid, but this ultrahigh dose allowed us to make a comparison of drugs and devices that would be very difficult to make with low doses of inhaled steroids due to the high “signal to noise” ratio. A possible weakness of our study is that we have used such high (unlicensed) doses of inhaled corticosteroids in normal volunteers. It is likely that the lung deposition, pharmacokinetics, and pharmacodynamics of the inhaled drugs would be different if low doses of inhaled steroids were given to asthmatic subjects with narrow, inflamed airways and mucus plugs. However, although the absolute effect might be different in asthmatic subjects, there is no reason to believe that the relative effects of the drugs and devices would be significantly different in asthmatic subjects compared with normal control subjects. For example, the study of Agertoft and Pederson5 suggested that the budesonide Turbohaler had twice the therapeutic potency of budesonide given by
MDI spacer device to asthmatic children, and the authors suggested that the Turbohaler device may deliver twice as much steroid to the lungs. This is consistent with the approximate 2:1 systemic potency ratio for these devices in the present study. Furthermore, the relative systemic potency of fluticasone to budesonide in the present study (slightly . 2:1 potency at equal microgram doses) is similar to the reported therapeutic potency of these agents when given in repeated doses to asthmatic subjects.6 Our systemic potency ratio (fluticasone to budesonide . 2:1) is almost identical to that of Clark and Lipworth7 who studied the dose response curves for cortisol suppression when twice-daily doses of budesonide and fluticasone were given to asthmatic subjects for 4 days. We believe, therefore, that the relative potency of drugs and devices that we found in normal volunteers who received single high doses of steroids is very similar to the relative potency of
Table 2—Effects of Budesonide, Beclomethasone, and Fluticasone Given by Large Volume Spacer* Device
Mean Cortisol (SD)
% Change
95% CI
p Value vs Placebo†
p Value vs Bud 4 mg via Spacer†
Placebo, mean Bud, 2 mg Bud, 4 mg BDP, 4 mg FP, 2 mg FP, 4 mg
652 (375) 424 (275) 328 (271) 215 (175) 189 (268) 93 (118)
25 43 66 72 86
23, 247 222, 264 249, 282 259, 285 282, 291
0.03 0.0001 0.0008 0.0005 0.0005
0.32 0.049 0.013 0.002
*BDP 5 beclomethasone dipropionate; FP 5 fluticasone; other abbreviations are expanded in Table 1. †p values refer to Wilcoxon signed rank test. CHEST / 115 / 5 / MAY, 1999
1281
the same drugs and devices when inhaled steroids are given to asthmatic subjects in repeated doses. However, the absolute effects are probably different, as healthy subjects with normal airways receive higher doses to the lungs than asthmatic subjects. This has been shown for inhaled salbutamol (1.5:1 ratio for lung deposition in normal subjects vs asthmatic subjects)8 and for inhaled fenoterol (2:1 ratio for plasma fenoterol level).9 No similar information is available for inhaled steroids, but the 72% suppression of plasma cortisol in normal volunteers by 2 mg of fluticasone (by MDI spacer) in the present study compared with 58% suppression in the study of Tan and Lipworth10 (using MDI alone) in patients with mild asthma and would imply a ratio of at least 1.2:1 for normal subjects compared with asthmatic patients. In the present study, we first looked at the effects of different delivery devices on serum cortisol levels when a single high dose of budesonide was administered. We found that systemic bioavailability was significantly influenced by the choice of delivery system. Most of the bioavailability of inhaled corticosteroids is through absorption in the lung.2 This has been shown in previous studies by Pederson et al11 who assessed the effects of mouth rinsing with activated charcoal and Selroos and Halme12 who employed mouth rinsing with water and showed a reduction in systemic effects (due to GI absorption) of only 15 to 20%. In our study, high-dose oral budesonide produced a modest 14% suppression of 9:00 am cortisol level, in keeping with the results of the above studies. By comparison, high-dose inhaled budesonide caused up to 73% suppression of plasma cortisol in the present study, confirming that the systemic effect is mostly due to pulmonary, not GI, absorption. However, we cannot exclude the possibility that the GI absorption of the preparation that we used (Pulmicort Respules) may be different from that of the MDI preparation. The elevated mean cortisol level for the group (652 nmol/L) reflects the inclusion of three subjects taking the combined oral contraceptive pill, which may increase levels of steroid binding proteins and therefore elevate cortisol levels. These subjects had cortisol levels of 1,470, 1,327, and 1,310 nmol/L with little variation between the values on the two placebo days. Their cortisol levels suppressed in a similar manner to the other subjects. The remaining 13 subjects had a mean serum cortisol level of 486 nmol/L. The data were reanalyzed for the 13 subjects who were not taking oral contraception, and the results were unaffected. Devices that provide high lung deposition will be more effective in controlling asthma but more likely to cause systemic side effects such as adrenal sup1282
pression. The two devices in our study that produced the most suppression of 9:00 am cortisol levels were MDI alone and Turbohaler dry powder device. Four milligrams of budesonide given by MDI alone produced a 73% fall in 9:00 am cortisol level, and this was reduced to 43% by the addition of a large volume spacer. Conflicting evidence is available on the effect of spacer devices on systemic bioavailability. Toogood et al13 reported a nonsignificant increase in suppression of the HPA axis by the addition of a spacer to an MDI, whereas other authors found the opposite effect.14 –16 In the present study, less adrenal suppression was seen when inhaled budesonide was given through a large volume spacer. Normal subjects with good inhaler technique and absence of bronchospasm may achieve optimal delivery to the lung using MDI alone. Asthmatic subjects with poor inhaler technique and bronchospasm, however, may obtain better lung deposition using a spacer (and possibly greater systemic side effects). The incorrect use of a spacer device may leave more of the activated dose within the spacer and less available for systemic absorption through the lung. An inadequately primed spacer with high static electricity, multiple actuations, and a delay between actuation and inhalation all reduce drug delivery to the lung. Washing and polishing a spacer device may also affect its performance. These caveats may explain the conflicting data produced by previous studies, most of which were conducted before the optimal method of use of large volume spacers had been established. In the present study, all precautions were taken to ensure maximum drug delivery to the lung from the large volume spacer, and the impressive cortisol suppression caused by fluticasone and beclomethasone (given by large volume spacer) confirm that this objective was achieved. Our study is in agreement with most of the previous studies in showing that the large volume spacer device reduces the systemic absorption of inhaled steroids. This is an unexpected result, as one would expect the spacer device to increase lung deposition (the main source of systemic absorption) while reducing GI deposition, which is a less important source of systemic absorption.2 There are few studies comparing the clinical benefit of inhaled steroids given by MDI spacer compared with MDI alone. If the increased deposition that was shown in laboratory studies could be confirmed in clinical practice, the therapeutic index of inhaled steroids would be enhanced by the use of a large volume spacer (increased benefit with decreased systemic effect). Nebulized budesonide produced no fall in 9:00 am plasma cortisol level. It is likely that this is due to Clinical Investigations
the inefficiency of nebulized delivery systems compared with MDIs and spacer devices. Wilson and Lipworth17 had a similar result (no suppression of cortisol) using a different nebulizer system (Ventstream; Medic-Aid). However, it has been demonstrated recently that budesonide given by a novel nebulizer (Pari Inhaler Boy; Pari; Starnberg, Germany), which activates only during inspiration, will achieve similar clinical effects (and cortisol suppression) to the same dose of budesonide given by MDI spacer.18 This implies that nebulized budesonide given by conventional nebulizers is likely to be less efficient than the same dose of budesonide given by MDI spacer. In the second part of our study, we used a single high dose of each of three commonly prescribed inhaled corticosteroids in the United Kingdom to evaluate differences between the drugs in their effects on the HPA axis. Although a number of authors have suggested that fluticasone may have less effect than budesonide on morning cortisol levels when given at therapeutic equivalent doses, these studies were undertaken to study the comparative efficacy of the drugs; cortisol studies were a secondary end point and were not always complete.6,19 Furthermore, these studies involved spacer devices in an unspecified proportion of cases, which makes direct comparison of the drugs more difficult. A further problem with such studies is that most of the patients were already taking medium to high doses of inhaled steroids prior to inclusion in the studies and the mean baseline cortisol level was , 300 nmol/L, whereas all 32 baseline (placebo) measurements in the present study were . 300 nmol/L, confirming that the patients of Barnes et al6 and Ayres et al18 already had mild suppression of their cortisol level before entering the studies. In contrast, most studies that were designed to compare the systemic potency of fluticasone, budesonide, and beclomethasone (in normal volunteers and asthmatic subjects) have found that fluticasone is more potent when given at microgram equivalent doses.7,20 –22 Clark and Lipworth7 showed that twice-daily dosing of fluticasone in asthmatic subjects for 4 days produced suppression of both overnight urinary free cortisol and 8:00 am cortisol. This was evident for dosages ranging from 250 to 1,000 mg bid. Fluticasone was more than twice as potent as budesonide at all dose levels in these asthmatic subjects, a finding that was replicated in the present study using normal volunteers. Kellerman et al23 showed the systemic effects of fluticasone (1,000 mg bid when given to 118 asthmatic patients for 29 days) was only slightly less than that of 10 mg of prednisolone qd. The high degree of systemic bioavailability of fluticasone would be predicted from its known high affinity for
the steroid receptor. In addition, the drug/receptor complex has a longer half-life than that of the other steroids. Our study suggests that fluticasone has at least 2:1 potency with reference to systemic side effects, a ratio similar to its known 2:1 therapeutic potency compared with beclomethasone and budesonide.6,19 These findings suggest a similar therapeutic index for fluticasone and budesonide (similar clinical benefit and similar systemic effects at equipotent doses). It is likely that beclomethasone has a lower therapeutic index (due to greater oral bioavailability and active metabolites), and it is recommended that budesonide or fluticasone should be used if very high doses of inhaled steroid are required.24 In conclusion, the present study shows that ultrahigh doses of inhaled corticosteroids produce a substantial fall in serum cortisol level, allowing useful comparisons to be made between the effects of different inhaler devices and different drugs. We found that the choice of inhaler device can influence the degree of systemic bioavailability of inhaled steroids, and we found that the systemic potency ratio of fluticasone propionate to budesonide is at least 2:1 in normal human volunteers, a level similar to that reported in asthmatic subjects for therapeutic and systemic effects. References 1 Geddes DM. Inhaled corticosteroids: benefits and risks. Thorax 1992; 47:404 – 407 2 Lipworth BJ. New perspectives on inhaled drug delivery and systemic bioactivity. Thorax 1995; 50:105–110 3 The British Guidelines on Asthma Management. Thorax 1997; 52(suppl 1):S1–S20 4 Todd G, Dunlop K, McNaboe J, et al. Growth and adrenal suppression in asthmatic children treated with high dose fluticasone propionate. Lancet 1996; 348:27–29 5 Agertoft L, Pederson S. Importance of the inhalation device on the effect of budesonide. Arch Dis Child 1993; 69:130 – 133 6 Barnes NC, Marone G, Maria GU, et al. A comparison of fluticasone propionate, 1 mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma. Eur Respir J 1993; 6:877– 884 7 Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997; 52:55–58 8 Melchlor R, Biddescombe MF, Mak VHF, et al. Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction. Thorax 1993; 48:506 –511 9 Lipworth BJ, Newnham DM, Clarke RA, et al. Comparison of the relative airways and systems potencies of inhaled fenoterol and salbutamol in asthmatic patients. Thorax 1995; 50:54 – 61 10 Tan KS, Grove A, Cargill RI, et al. Effects of inhaled fluticasone propionate and oral prednisolone on lymphocyte beta 2-adrenoceptor function in asthmatic patients. Chest 1996; 109:343–347 11 Pederson S, Steffersen G, Ohlsson SV. The influence of orally CHEST / 115 / 5 / MAY, 1999
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12 13 14 15
16 17 18
deposited budesonide on the systemic availability of budesonide after inhalation from a turbohaler. Br J Clin Pharmacol 1993; 36:211–214 Selroos O, Halme M. Effect of a volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from an MDI and dry powder inhaler. Thorax 1991; 46:891– 894 Toogood JH, Baskerville J, Jennings B, et al. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984; 129:723–729 Prahl P, Jensen T. Decreased adreno-cortical suppression utilizing the nebuhaler for inhalation of steroid aerosols. Clin Allergy 1987; 17:393–398 Farrer M, Francis AJ, Pearce SJ. Morning serum cortisol concentrations after 2 mg of inhaled beclomethasone in normal subjects: effects of a 750-mL spacing device. Thorax 1990; 45:740 –742 Brown PH, Blundell G, Greening AP, et al. Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids? Thorax 1990; 45:736 –739 Wilson AM, Lipworth BJ. Systemic dose response relationships with oral and inhaled corticosteroids in asthmatics [abstract]. Thorax 1997; 52:A57 Bisguard H, Nikander K, Munch E. Comparative study of budesonide as a nebulized suspension vs pressurized
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19
20
21
22 23
24
meter-dose inhaler in adult asthmatics. Respir Med 1998; 92:44 – 49 Ayres JG, Bateman ED, Lundback B, et al. High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily or budesonide, 1.6 mg daily, in patients with chronic severe asthma: International Study Group. Eur Respir J 1995; 8:579 –586 Grahnen A, Eckernas SA, Brundin RM, et al. An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers. Br J Clin Pharmacol 1994; 38:521–525 Boe J, Bakke P, Rodolen T, et al. High-dose inhaled steroids in asthmatics: moderate efficacy gain and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Eur Respir J 1994; 7:2179 –2184 Brus RHP, Bodenheimer S. High dose inhaled steroids in asthmatic children. Lancet 1996; 348:820 – 821 Kellerman D, Stricker W, Howland W, et al. Effects of inhaled fluticasone propionate (FP) on the HPA axis of patients with asthma. Eur Respir J 1996; 9(suppl 23):162S Barnes P. Inhaled glucocorticoids: new developments relevant to updating the Asthma Management Guidelines. Respir Med 1996; 7:329 –334
Clinical Investigations
Objectives: To compare the systemic bioavailability (assessed by cortisol suppression) of highdose budesonide when given by four inhaler devices and orally. Also studied are the relative systemic potencies of three inhaled steroids (budesonide, fluticasone propionate, and beclomethasone dipropionate) when given by metered-dose inhaler (MDI) with a large volume spacer. Design: Double-blind, crossover, placebo-controlled trial. Participants: Sixteen healthy, steroid-naive adult volunteers. Methods: On separate occasions, each subjects took 4 mg of budesonide through the following devices: MDI alone, MDI with 750-mL spacer, dry-powder inhaler and nebulizer; 4 mg of budesonide was also taken orally to assess the effects of GI absorption. For the drug comparison, each subject took 4 mg of budesonide, fluticasone, and beclomethasone, and 2 mg of budesonide and fluticasone by MDI and spacer. Results: Greatest percent suppression (95% confidence interval) of 9:00 AM cortisol with budesonide was observed with MDI alone (73% [57 to 90]) and turbohaler (72% [58 to 86]) compared with MDI spacer (42% [22 to 64]) and oral administration (14% [16- to 234]). Nebulized budesonide produced an insignificant rise in 9:00 AM cortisol level. The most suppressive drug (given by MDI spacer) was fluticasone at 4 mg (86% [82 to 91]) and at 2 mg (72% [59 to 85]). The least suppressive drug was budesonide at 4 mg (43% [22 to 64]) and at 2 mg (25% [3 to 47]). The effects of 4 mg of beclomethasone were intermediate (66% [49 to 82%]). Conclusions: The choice of delivery device for administration of budesonide can lead to important differences in systemic bioavailability. Fluticasone has greater systemic potency than budesonide or beclomethasone when given at microgram equivalent dosage. The systemic potency ratio of fluticasone propionate to budesonide in normal human volunteers in the present study is similar to the therapeutic potency ratio of the drug in asthmatic patients (approximately 2:1). (CHEST 1999; 115:1278 –1284) Key words: adrenal suppression; beclomethasone dipropionate; bioavailability; budesonide; fluticasone propionate; inhaled corticosteroids Abbreviations: HPA 5 hypothalamic-pituitary-adrenal; MDI 5 metered-dose inhaler
steroids are used extensively in the manI nhaled agement of asthma. Sometimes high doses
($ 1,500 mg/d) are necessary to control symptoms. Systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis can occur at these high doses; however, there are few reports of clinically important systemic effects from these drugs.1
*From Hope Hospital, Salford, UK. Manuscript received June 16, 1998; revision accepted November 24, 1998. Correspondence to: D. Wales, MD, Specialist Registrar, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. 1278
The therapeutic goal should be to optimize asthma control but to minimize potential systemic side effects. It is known that the choice of inhaler device can influence lung deposition (and systemic bioavailability) of inhaled corticosteroids, but the relative effects of various inhaler devices, spacer devices, nebulizers, and dry powder devices are poorly understood.2 In this study, two experiments were performed. The first experiment was to compare the relative effectiveness of several delivery techniques using a single steroid as a marker. Budesonide was taken via four different inhaler devices (metered-dose inhaler Clinical Investigations
[MDI] alone, MDI and large volume spacer, dry powder device, and nebulizer) and the systemic bioavailability was determined by measuring suppression of 9:00 am plasma cortisol level. The second experiment was to compare the relative potency of three inhaled steroids when given by MDI and spacer. Fluticasone, beclomethasone dipropionate, and budesonide were taken by large volume spacer, the preferred delivery system for high-dose steroids3 and suppression of 9:00 am plasma cortisol level was measured. Systemic bioavailability is largely determined by lung deposition and absorption.2 Previous studies of this nature have yielded conflicting results because low or moderate doses of inhaled steroids were administered producing only modest falls in morning cortisol levels with a high “signal to noise” ratio. For this reason, we used very high doses of inhaled steroid (4 mg) to ensure that any difference between drugs and devices would be demonstrated clearly. Materials and Methods Subjects Sixteen healthy, nonsmoking volunteers aged 25 to 42 years completed the study (12 were men). All were steroid naive and taking no other medication. Each subject gave written informed consent, and the study was approved by the Salford Local Research Ethics Committee. Protocol This was a double-blind, crossover, placebo-controlled trial. For the first experiment, subjects took 4 mg of budesonide through four inhaler systems and orally (to assess the effects of GI absorption). Each subject received, in random order, seven double-blind treatments of which two (randomly chosen) were placebo: (1) MDI without spacer device (20 inhalations from Pulmicort 200-mg inhaler; Astra Pharmaceuticals; Kings Langley, UK); (2) MDI and 750-mL spacer (20 inhalations of Pulmicort 200-mg inhaler using Nebuhaler 750-mL spacer; Astra Pharmaceuticals); (3) dry powder inhaler (10 inhalations of Pulmicort 400-mg Turbohaler; Astra Pharmaceuticals); (4) nebulized budesonide (four Pulmicort Respules, each containing 1 mg budesonide in 2 mL; Astra Pharmaceuticals); the solution was nebulized using a jet stream nebulizer (System 22; Medic-Aid; West Sussex, UK); (5) budesonide was taken orally (subjects swallowed the contents of four Pulmicort Respules); (6) placebo MDI inhaler, 20 actuations; and (7) placebo MDI inhaler, 10 actuations. All drugs were taken at 11:00 pm, and 9:00 am plasma cortisol levels were measured the following day. In the second experiment, the effects of the three commonly prescribed inhaled corticosteroids were compared. Each subject took the following in random order: (1) 4 mg of fluticasone (16 inhalations of Flixotide 250-mg inhaler; Allen and Hanbury’s; Stockley Park, UK) by MDI and spacer; (2) 4 mg of beclomethasone dipropionate (16 inhalations of Becloforte 250-mg inhaler; Allen and Hanbury’s) by MDI and spacer; (3) 2 mg of fluticasone (8 inhalations of Flixotide 250-mg inhaler; Allen and Hanbury’s)
by MDI and spacer; and (4) 2 mg of budesonide (10 inhalations of Pulmicort 200-mg inhaler using Nebuhaler 750-mL spacer; Astra Pharmaceuticals) by MDI and spacer. The results of the inhalation of 4 mg of budesonide through MDI and spacer and the two placebo inhalations from the first experiment were utilized in the second experiment. High doses of drugs were used to magnify the differences between them. Two milligrams of fluticasone and budesonide was used to assess the effects of doses that might be used in clinical practice and to study the dose-response relationship. Drugs were taken in random order at least 7 days apart. All subjects were instructed in the correct usage of the devices and their techniques were checked. Single deep inhalations from the device were followed by 10 s of breath-holding with a minimum interval of 30 s before the next dose. To minimize deposition on the spacer, only one puff of drug was delivered into the spacer at one time. Each spacer was primed with 20 puffs of drug prior to every drug administration in order to prevent drug adhering to the wall of the spacer due to the electrostatic attraction that occurs in new plastic spacer devices. Spacer devices were washed with water after use and allowed to dry naturally. A bank of three Nebuhaler devices and three Volumatic devices were used to deliver all treatments. All six devices were subjected to a similar amount of usage and washing during the course of the study. The aerosol canister and plastic actuators were masked to blind the treatment to the subjects and investigators. All aerosol containers had their labels removed and replaced with a code letter, and all MDI treatments were taken through the white “placebo” actuator supplied by the manufacturer of each drug. The chief investigator kept a record of all treatments and codes. Nebulized and oral budesonide were administered in an open manner as no suitable placebo was available. A single nebulizer was used throughout the study. Measurements Ten milliliters of venous blood was drawn between 8:30 and 9:30 am on the morning following each treatment. If a subject attended later than 9:30 am, the test was repeated 1 week later. Cortisol levels were measured using an in-house radioimmunoassay using cortisol antiserum from the Scottish Antibody Production Unit and a 125I cortisol derivative as label. Separation of the antibody bound and free fractions was accomplished with second antibody-coated cellulose. Standards were prepared in hormone-free human serum. The reference range for cortisol using this assay is 250 to 650 nmol/L at 9:00 am. Statistical Analysis For each treatment, we report the percentage change from the mean of two placebo measurements with 95% confidence intervals using software (Prism 2 Software; Graph Pad Software; San Diego, CA). Wilcoxon matched pairs signed rank test was used. The percent fall in plasma cortisol level for the least suppressive treatment (budesonide via MDI spacer) was also compared with all other treatments using Wilcoxon matched pairs signed rank test.
Results Effects of 4 mg of Budesonide Administered by Different Methods The greatest average percentage suppression of cortisol levels was seen with the MDI alone, producCHEST / 115 / 5 / MAY, 1999
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Figure 1. 9:00 am cortisol levels following the administration of 4 mg of budensonide by five different devices and two placebo devices. P1, P2 5 placebos; NEB 5 nebulizer; NH 5 nebuhaler; TH 5 Turbohaler.
ing a 73% fall (vs placebo, p 5 0.0002), and with the Turbohaler, which produced a 72% fall (vs placebo, p 5 0.0005) (Fig 1 and Table 1). The addition of a 750-mL volume spacer to the MDI reduced plasma cortisol suppression to 42% (vs placebo, p 5 0.0001). Oral budesonide produced a modest 14% fall in 9 am cortisol level (vs placebo, p 5 0.04). Nebulized budesonide caused no suppression of cortisol but a nonsignificant rise of 8%. (The assay system was checked for cross-reactivity with budesonide nebulizer solution at several concentrations but no such cross-reactivity was found.) Effects of Budesonide, Fluticasone, and Beclomethasone Dipropionate on 9:00 AM Cortisol Suppression Of the three drugs compared, fluticasone given by MDI and spacer produced the greatest average percentage suppression, 4 mg producing an 86% fall (vs placebo, p 5 0.0005) and 2 mg producing a 72%
fall (vs placebo, p 5 0.0005) (Fig 2 and Table 2). The least suppressive drug was budesonide. Four milligrams of budesonide produced a 43% fall (vs placebo, p 5 0.0001) and 2 mg produced a 25% fall (vs placebo, p 5 0.03). Beclomethasone fell between the two in potency producing a 66% fall after a 4-mg dose (vs placebo, p 5 0.0008). Discussion Inhaled corticosteroids in low and medium doses are safe with regard to systemic side effects; to our knowledge, there are no reported cases of clinically relevant adrenal suppression within the licensed dose range.1 However, when higher doses are employed to control asthma symptoms, adrenal suppression becomes a possibility.4 We used a model system of a single high dose of inhaled corticosteroid in normal volunteers. It is unlikely that any physician would prescribe a 4-mg dose of inhaled corticoste-
Table 1—Effects of 4 mg of Budesonide Administered by Five Different Methods* Device Placebo 1 Placebo 2 Bud, 4 mg Bud, 4 mg Bud, 4 mg Bud, 4 mg Bud, 4 mg
nebulized oral MDI 1 spacer Turbohaler MDI (no spacer)
Mean Cortisol (SD)
% Change
95% CI
p Value vs Placebo†
p Value vs Bud 4 mg via Spacer†
647 (379) 656 (387) 687 (463) 558 (393) 328 (271) 204 (290) 187 (244)
18 214 242 272 273
213, 128 234, 16 222, 264 258, 286 257, 290
0.45 0.18 0.0001 0.0005 0.0002
0.003 0.04 0.03 0.02
*Bud 5 budesonide; CI 5 confidence interval. †p values refer to Wilcoxon signed rank test. 1280
Clinical Investigations
Figure 2. 9:00 am serum cortisol levels with 4 mg and 2 mg of budesonide (BUD) and fluticasone (FLU) and two placebo devices. BDP 5 beclomethasone; P1, P2 5 placebos.
roid, but this ultrahigh dose allowed us to make a comparison of drugs and devices that would be very difficult to make with low doses of inhaled steroids due to the high “signal to noise” ratio. A possible weakness of our study is that we have used such high (unlicensed) doses of inhaled corticosteroids in normal volunteers. It is likely that the lung deposition, pharmacokinetics, and pharmacodynamics of the inhaled drugs would be different if low doses of inhaled steroids were given to asthmatic subjects with narrow, inflamed airways and mucus plugs. However, although the absolute effect might be different in asthmatic subjects, there is no reason to believe that the relative effects of the drugs and devices would be significantly different in asthmatic subjects compared with normal control subjects. For example, the study of Agertoft and Pederson5 suggested that the budesonide Turbohaler had twice the therapeutic potency of budesonide given by
MDI spacer device to asthmatic children, and the authors suggested that the Turbohaler device may deliver twice as much steroid to the lungs. This is consistent with the approximate 2:1 systemic potency ratio for these devices in the present study. Furthermore, the relative systemic potency of fluticasone to budesonide in the present study (slightly . 2:1 potency at equal microgram doses) is similar to the reported therapeutic potency of these agents when given in repeated doses to asthmatic subjects.6 Our systemic potency ratio (fluticasone to budesonide . 2:1) is almost identical to that of Clark and Lipworth7 who studied the dose response curves for cortisol suppression when twice-daily doses of budesonide and fluticasone were given to asthmatic subjects for 4 days. We believe, therefore, that the relative potency of drugs and devices that we found in normal volunteers who received single high doses of steroids is very similar to the relative potency of
Table 2—Effects of Budesonide, Beclomethasone, and Fluticasone Given by Large Volume Spacer* Device
Mean Cortisol (SD)
% Change
95% CI
p Value vs Placebo†
p Value vs Bud 4 mg via Spacer†
Placebo, mean Bud, 2 mg Bud, 4 mg BDP, 4 mg FP, 2 mg FP, 4 mg
652 (375) 424 (275) 328 (271) 215 (175) 189 (268) 93 (118)
25 43 66 72 86
23, 247 222, 264 249, 282 259, 285 282, 291
0.03 0.0001 0.0008 0.0005 0.0005
0.32 0.049 0.013 0.002
*BDP 5 beclomethasone dipropionate; FP 5 fluticasone; other abbreviations are expanded in Table 1. †p values refer to Wilcoxon signed rank test. CHEST / 115 / 5 / MAY, 1999
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the same drugs and devices when inhaled steroids are given to asthmatic subjects in repeated doses. However, the absolute effects are probably different, as healthy subjects with normal airways receive higher doses to the lungs than asthmatic subjects. This has been shown for inhaled salbutamol (1.5:1 ratio for lung deposition in normal subjects vs asthmatic subjects)8 and for inhaled fenoterol (2:1 ratio for plasma fenoterol level).9 No similar information is available for inhaled steroids, but the 72% suppression of plasma cortisol in normal volunteers by 2 mg of fluticasone (by MDI spacer) in the present study compared with 58% suppression in the study of Tan and Lipworth10 (using MDI alone) in patients with mild asthma and would imply a ratio of at least 1.2:1 for normal subjects compared with asthmatic patients. In the present study, we first looked at the effects of different delivery devices on serum cortisol levels when a single high dose of budesonide was administered. We found that systemic bioavailability was significantly influenced by the choice of delivery system. Most of the bioavailability of inhaled corticosteroids is through absorption in the lung.2 This has been shown in previous studies by Pederson et al11 who assessed the effects of mouth rinsing with activated charcoal and Selroos and Halme12 who employed mouth rinsing with water and showed a reduction in systemic effects (due to GI absorption) of only 15 to 20%. In our study, high-dose oral budesonide produced a modest 14% suppression of 9:00 am cortisol level, in keeping with the results of the above studies. By comparison, high-dose inhaled budesonide caused up to 73% suppression of plasma cortisol in the present study, confirming that the systemic effect is mostly due to pulmonary, not GI, absorption. However, we cannot exclude the possibility that the GI absorption of the preparation that we used (Pulmicort Respules) may be different from that of the MDI preparation. The elevated mean cortisol level for the group (652 nmol/L) reflects the inclusion of three subjects taking the combined oral contraceptive pill, which may increase levels of steroid binding proteins and therefore elevate cortisol levels. These subjects had cortisol levels of 1,470, 1,327, and 1,310 nmol/L with little variation between the values on the two placebo days. Their cortisol levels suppressed in a similar manner to the other subjects. The remaining 13 subjects had a mean serum cortisol level of 486 nmol/L. The data were reanalyzed for the 13 subjects who were not taking oral contraception, and the results were unaffected. Devices that provide high lung deposition will be more effective in controlling asthma but more likely to cause systemic side effects such as adrenal sup1282
pression. The two devices in our study that produced the most suppression of 9:00 am cortisol levels were MDI alone and Turbohaler dry powder device. Four milligrams of budesonide given by MDI alone produced a 73% fall in 9:00 am cortisol level, and this was reduced to 43% by the addition of a large volume spacer. Conflicting evidence is available on the effect of spacer devices on systemic bioavailability. Toogood et al13 reported a nonsignificant increase in suppression of the HPA axis by the addition of a spacer to an MDI, whereas other authors found the opposite effect.14 –16 In the present study, less adrenal suppression was seen when inhaled budesonide was given through a large volume spacer. Normal subjects with good inhaler technique and absence of bronchospasm may achieve optimal delivery to the lung using MDI alone. Asthmatic subjects with poor inhaler technique and bronchospasm, however, may obtain better lung deposition using a spacer (and possibly greater systemic side effects). The incorrect use of a spacer device may leave more of the activated dose within the spacer and less available for systemic absorption through the lung. An inadequately primed spacer with high static electricity, multiple actuations, and a delay between actuation and inhalation all reduce drug delivery to the lung. Washing and polishing a spacer device may also affect its performance. These caveats may explain the conflicting data produced by previous studies, most of which were conducted before the optimal method of use of large volume spacers had been established. In the present study, all precautions were taken to ensure maximum drug delivery to the lung from the large volume spacer, and the impressive cortisol suppression caused by fluticasone and beclomethasone (given by large volume spacer) confirm that this objective was achieved. Our study is in agreement with most of the previous studies in showing that the large volume spacer device reduces the systemic absorption of inhaled steroids. This is an unexpected result, as one would expect the spacer device to increase lung deposition (the main source of systemic absorption) while reducing GI deposition, which is a less important source of systemic absorption.2 There are few studies comparing the clinical benefit of inhaled steroids given by MDI spacer compared with MDI alone. If the increased deposition that was shown in laboratory studies could be confirmed in clinical practice, the therapeutic index of inhaled steroids would be enhanced by the use of a large volume spacer (increased benefit with decreased systemic effect). Nebulized budesonide produced no fall in 9:00 am plasma cortisol level. It is likely that this is due to Clinical Investigations
the inefficiency of nebulized delivery systems compared with MDIs and spacer devices. Wilson and Lipworth17 had a similar result (no suppression of cortisol) using a different nebulizer system (Ventstream; Medic-Aid). However, it has been demonstrated recently that budesonide given by a novel nebulizer (Pari Inhaler Boy; Pari; Starnberg, Germany), which activates only during inspiration, will achieve similar clinical effects (and cortisol suppression) to the same dose of budesonide given by MDI spacer.18 This implies that nebulized budesonide given by conventional nebulizers is likely to be less efficient than the same dose of budesonide given by MDI spacer. In the second part of our study, we used a single high dose of each of three commonly prescribed inhaled corticosteroids in the United Kingdom to evaluate differences between the drugs in their effects on the HPA axis. Although a number of authors have suggested that fluticasone may have less effect than budesonide on morning cortisol levels when given at therapeutic equivalent doses, these studies were undertaken to study the comparative efficacy of the drugs; cortisol studies were a secondary end point and were not always complete.6,19 Furthermore, these studies involved spacer devices in an unspecified proportion of cases, which makes direct comparison of the drugs more difficult. A further problem with such studies is that most of the patients were already taking medium to high doses of inhaled steroids prior to inclusion in the studies and the mean baseline cortisol level was , 300 nmol/L, whereas all 32 baseline (placebo) measurements in the present study were . 300 nmol/L, confirming that the patients of Barnes et al6 and Ayres et al18 already had mild suppression of their cortisol level before entering the studies. In contrast, most studies that were designed to compare the systemic potency of fluticasone, budesonide, and beclomethasone (in normal volunteers and asthmatic subjects) have found that fluticasone is more potent when given at microgram equivalent doses.7,20 –22 Clark and Lipworth7 showed that twice-daily dosing of fluticasone in asthmatic subjects for 4 days produced suppression of both overnight urinary free cortisol and 8:00 am cortisol. This was evident for dosages ranging from 250 to 1,000 mg bid. Fluticasone was more than twice as potent as budesonide at all dose levels in these asthmatic subjects, a finding that was replicated in the present study using normal volunteers. Kellerman et al23 showed the systemic effects of fluticasone (1,000 mg bid when given to 118 asthmatic patients for 29 days) was only slightly less than that of 10 mg of prednisolone qd. The high degree of systemic bioavailability of fluticasone would be predicted from its known high affinity for
the steroid receptor. In addition, the drug/receptor complex has a longer half-life than that of the other steroids. Our study suggests that fluticasone has at least 2:1 potency with reference to systemic side effects, a ratio similar to its known 2:1 therapeutic potency compared with beclomethasone and budesonide.6,19 These findings suggest a similar therapeutic index for fluticasone and budesonide (similar clinical benefit and similar systemic effects at equipotent doses). It is likely that beclomethasone has a lower therapeutic index (due to greater oral bioavailability and active metabolites), and it is recommended that budesonide or fluticasone should be used if very high doses of inhaled steroid are required.24 In conclusion, the present study shows that ultrahigh doses of inhaled corticosteroids produce a substantial fall in serum cortisol level, allowing useful comparisons to be made between the effects of different inhaler devices and different drugs. We found that the choice of inhaler device can influence the degree of systemic bioavailability of inhaled steroids, and we found that the systemic potency ratio of fluticasone propionate to budesonide is at least 2:1 in normal human volunteers, a level similar to that reported in asthmatic subjects for therapeutic and systemic effects. References 1 Geddes DM. Inhaled corticosteroids: benefits and risks. Thorax 1992; 47:404 – 407 2 Lipworth BJ. New perspectives on inhaled drug delivery and systemic bioactivity. Thorax 1995; 50:105–110 3 The British Guidelines on Asthma Management. Thorax 1997; 52(suppl 1):S1–S20 4 Todd G, Dunlop K, McNaboe J, et al. Growth and adrenal suppression in asthmatic children treated with high dose fluticasone propionate. Lancet 1996; 348:27–29 5 Agertoft L, Pederson S. Importance of the inhalation device on the effect of budesonide. Arch Dis Child 1993; 69:130 – 133 6 Barnes NC, Marone G, Maria GU, et al. A comparison of fluticasone propionate, 1 mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma. Eur Respir J 1993; 6:877– 884 7 Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997; 52:55–58 8 Melchlor R, Biddescombe MF, Mak VHF, et al. Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction. Thorax 1993; 48:506 –511 9 Lipworth BJ, Newnham DM, Clarke RA, et al. Comparison of the relative airways and systems potencies of inhaled fenoterol and salbutamol in asthmatic patients. Thorax 1995; 50:54 – 61 10 Tan KS, Grove A, Cargill RI, et al. Effects of inhaled fluticasone propionate and oral prednisolone on lymphocyte beta 2-adrenoceptor function in asthmatic patients. Chest 1996; 109:343–347 11 Pederson S, Steffersen G, Ohlsson SV. The influence of orally CHEST / 115 / 5 / MAY, 1999
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deposited budesonide on the systemic availability of budesonide after inhalation from a turbohaler. Br J Clin Pharmacol 1993; 36:211–214 Selroos O, Halme M. Effect of a volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from an MDI and dry powder inhaler. Thorax 1991; 46:891– 894 Toogood JH, Baskerville J, Jennings B, et al. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 1984; 129:723–729 Prahl P, Jensen T. Decreased adreno-cortical suppression utilizing the nebuhaler for inhalation of steroid aerosols. Clin Allergy 1987; 17:393–398 Farrer M, Francis AJ, Pearce SJ. Morning serum cortisol concentrations after 2 mg of inhaled beclomethasone in normal subjects: effects of a 750-mL spacing device. Thorax 1990; 45:740 –742 Brown PH, Blundell G, Greening AP, et al. Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids? Thorax 1990; 45:736 –739 Wilson AM, Lipworth BJ. Systemic dose response relationships with oral and inhaled corticosteroids in asthmatics [abstract]. Thorax 1997; 52:A57 Bisguard H, Nikander K, Munch E. Comparative study of budesonide as a nebulized suspension vs pressurized
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meter-dose inhaler in adult asthmatics. Respir Med 1998; 92:44 – 49 Ayres JG, Bateman ED, Lundback B, et al. High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily or budesonide, 1.6 mg daily, in patients with chronic severe asthma: International Study Group. Eur Respir J 1995; 8:579 –586 Grahnen A, Eckernas SA, Brundin RM, et al. An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers. Br J Clin Pharmacol 1994; 38:521–525 Boe J, Bakke P, Rodolen T, et al. High-dose inhaled steroids in asthmatics: moderate efficacy gain and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Eur Respir J 1994; 7:2179 –2184 Brus RHP, Bodenheimer S. High dose inhaled steroids in asthmatic children. Lancet 1996; 348:820 – 821 Kellerman D, Stricker W, Howland W, et al. Effects of inhaled fluticasone propionate (FP) on the HPA axis of patients with asthma. Eur Respir J 1996; 9(suppl 23):162S Barnes P. Inhaled glucocorticoids: new developments relevant to updating the Asthma Management Guidelines. Respir Med 1996; 7:329 –334
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