Effects of Inhaled Fluticasone Propionate and Oral Prednisolone on Lymphocyte β2-Adrenoceptor Function in Asthmatic Patients

doi:10.1378/chest.109.2.343

Chest

Volume 109, Issue 2, February 1996, Pages 343-347

https://doi.org/10.1378/chest.109.2.343 Get rights and content

The aim of the study was to evaluate the facilitatory effects of inhaled corticosteroid on in vitro parameters of lymphocyte β₂-adrenoceptor function in asthmatic patients. Serum cortisol level was also evaluated as a measure of systemic bioactivity. Ten (four female) asthmatic subjects were evaluated, mean (SEM) age was 28.6(2.0) years, and FEV₁ was 79.9%(8.7) predicted. Single doses of inhaled placebo (PL), fluticasone propionate, 1,000 µg (F1000), fluticasone propionate, 2,000 µg(F2000), or oral prednisolone, 50 mg(PRED), were given at 10 PM the previous night and measurements were made 10 h later. Values for β₂-receptor density (logBmax: fmol/10⁶cells) were significantly (p<0.05) greater than PL with PRED but not with inhaled fluticasone (as means and 95% confidence interval [CI] for difference vs PL): PL, 0.27; F1000, 0.30; F2000, 0.32; and PRED, 0.48 (95% CI vs PL, 0.075 to 0.341). Maximal cyclic adenosine monophosphate (cAMP) responses to isoproterenol hydrochloride (isoprenaline (Emax; pmol/10⁶cells) mirrored those for Bmax: PL, 4.00; F1000,4.68; F2000, 4.26; and PRED, 7.46 (95% CI vs PL, −0.01 to 6.91). Receptor affinity (Kd) was not significantly altered by any treatment. There was significant (p<0.05) suppression of serum cortisol (nmol/L) with F2000 and PRED compared with PL: PL, 307.9; F1000, 323.2; F2000, 130.1 (95% CI vs PL, 69.76 to 285.8) and PRED, 51.8 (95% CI vs PL, 144.11 to 368.01). Thus, high-dose inhaled fluticasone propionate did not have any facilitatory effects on lymphocyte β₂-adrenoceptor parameters as compared with oral prednisolone which upregulated β₂-receptor density and increased cAMP response. In contrast, high-dose inhaled fluticasone (2,000 µg) significantly suppressed serum cortisol. In conclusion, there would appear to be a dissociation in systemic sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte β₂-adrenoceptor regulation.

Section snippets

Patients

Ten (four female) asthmatic patients were studied, with a mean (SEM) age of 28.6 (2.0) years, FEV₁ of 3.4 L (0.3), 79.9% (8.7) predicted, and mean forced expiratory flow during the middle half of the FVC (FEF_25-75)) of 3.0 L (0.4), 66.5% (9.7) predicted. Hematologic and biochemical parameters were normal prior to inclusion. All gave written, informed consent before being randomized in a double-blind, placebo-controlled crossover study approved by Tayside Medical Ethics Committee. All except one

RESULTS

Lymphocyte β ₂-Adrenoceptors

Parameters of receptor density (Bmax) and maximal cAMP responses to isoproterenol (Emax) showed a significant (p<0.05) increase after oral prednisolone, but not after inhaled fluticasone, with the mean (SEM) values for logBmax (fmol/10⁶ cells) being as follows: PL, 0.27 (0.03); F1000,0.30 (0.03); F2000, 0.32 (0.03); and PRED, 0.48 (0.03) (95% CI, PRED vs PL, 0.075 to 0.341). The results for Emax (cAMP response, pmol/10⁶cells) mirrored those for Bmax: PL, 4.00 (0.83);

DISCUSSION

The results of this study indicate that high-dose inhaled fluticasone, in a dose sufficient to suppress serum cortisol, did not have any significant facilitatory effects on lymphocyte β₂-adrenoceptor parameters. This is in contrast to oral prednisolone that upregulated β₂-receptor density and increased cAMP responses. This would suggest a dissociation in systemic sensitivity between the effects of inhaled corticosteroid on adrenal suppression and lymphocyte β₂-adrenoceptor regulation. Inhaled

REFERENCES (25)

HoggerP et al.
Binding kinetics of fluticasone propionate to the human glucocorticoid receptor
Steroids
(1994)
HardingSM
The human pharmacology of fluticasone propionate
Respir Med
(1990)
NewnhamDM et al.
Bronchodilator subsensitivity after chronic dosing with eformorterol in patients with asthma
Am J Med
(1994)
SearsMR et al.
Regular inhaled beta-agonist treatment in bronchial asthma
Lancet
(1990)
Van SchayckCP et al.
Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by desensitization to salbutamol
J Allergy Clin Immunol
(1990)
PaggiaroPL et al.
Salbutamol plus beclomethasone dipropionate but not salbutamol alone, completely prevent early and late asthmatic responses to allergen
Respir Med
(1991)
British Thoracic Society Research Unit of the Royal College of Physicians of London King's Fund Centre. National asthma...
BroddeOE et al.
Terbutalineinduced desensitization of human lymphocyte beta2-adrenoceptors: accelerated restoration of beta-adrenergic responses by prednisolone and ketotifen
J Clin Invest
(1985)
BroddeOE et al.
Effects of prednisolone and ketotifen on beta2-adrenoceptors in asthmatic patients receiving beta2-bronchodilators
Eur J Clin Pharmacol
(1988)
American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease...

PhillipsGH

Structure-activity relationships of topically active steroids: the selection of fluticasone propionate

Respir Med

(1990)

SelroosO et al.

Effect of a Volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroid from a metered-dose inhaler and dry powder inhaler

Thorax

(1991)

Cited by (19)

Corticosteroid therapy in asthma: Predictors of responsiveness
2006, Clinics in Chest Medicine
A pilot study examining the relationship between stress and serum cortisol concentrations in women with asthma
2002, Respiratory Medicine
The mechanism (s) by which stress exacerbates asthma is unknown. One explanation could be a reduction in endogenous serum cortisol concentrations as a result of stress. Our objective was to determine if a reduction in morning serum cortisol concentrations is associated with higher levels of stress in women with asthma. In this pilot study, seven women with a history of allergic-asthma were prospectively assigned to either low, moderate, or high stress groups based on a combination of their level of current stress and their resources to cope with the stress. After stress group assignment, women donated a morning blood sample, which was analyzed for serum cortisol concentration by an independent laboratory whose personnel were blinded to the subjects'stress status. Three women were assigned to the low stress group, two to the moderate stress group and two to the high stress group. Serum cortisol concentrations ranged from 8 to 23 μg/dl, averaging 14±6 μg/dl. A Spearman rank correlation indicated that serum cortisol concentrations were significantly inversely related to the stress groupings (r_s = −0.915; P = 0.025). These results suggest that a reduction in morning serum cortisol concentration may be associated with higher levels of stress and lower resources to cope with the stress in women with allergic-asthma.
Reduction of vasopressor requirement by hydrocortisone administration in a patient with cerebral vasospasm
2001, British Journal of Anaesthesia
Citation Excerpt :
Halving the dose of nimodipine did not affect the decrease in SBP, with a concomitant deterioration in the patient's level of consciousness after the administration of each dose of the drug. Corticosteroids prevent homologous down-regulation of β2 receptors14 and up-regulate lymphocyte β receptors.15 16 In addition, Azizet al.17 have reported that inhaled budesonide resensitizes the cardiac β2 receptor response to salbutamol in patients treated with long-acting β2 agonists.
A 67-yr-old female received hypertensive, hypervolaemic treatment for cerebral vasospasm after severe subarachnoid haemorrhage. After 3 days of continuous vasopressor infusion and despite adequate hydration and normal cardiac function, the phenylephrine dose had to be increased to obtain the same systolic blood pressure. This tachyphylaxis to phenylephrine infusion was probably caused by down-regulation of α adrenoceptors, and was reversed by giving i.v. hydrocortisone.
A bolus of inhaled budesonide rapidly reverses airway subsensitivity and β<inf>2</inf>-adrenoceptor down-regulation after regular inhaled formoterol
1999, Chest
Subsensitivity of airwayβ ₂-adrenoceptors develops readily in asthmatics receiving regular long-acting β₂-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid.
Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (± SD) FEV₁ of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV₁ (PC₂₀) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 μg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 μg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyteβ ₂-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol.
There was no significant difference in the geometric mean PC₂₀after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC₂₀ after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte β₂-adrenoceptor density (geometric mean Bmax: fmol/10⁶ cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80).
We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated β₂-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with β₂-agonists during an acute episode of bronchoconstriction.
Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge
1999, Chest
One week of regular treatment with salmeterol can induce tolerance to the protective effect of aβ ₂-agonist on early airway response to allergen (EAR). The objective was to assess whether inhaled corticosteroids revert tolerance to salmeterol.
The study had a randomized, double-blind, placebo-controlled design.
Twelve subjects with mild allergic asthma and positive result of specific bronchial provocation test (sBPT) to allergen underwent three sBPTs, separated by 1 week. sBPT was done in all subjects after a single dose (T₁) and after 1 week of regular treatment with inhaled salmeterol (50 μg bid) (T₂) in order to induce tolerance. Subjects were then randomized to receive either the same dose of salmeterol + beclomethasone dipropionate (BDP, 500 μg bid) (group 1, n = 6) or placebo + BDP (group 2, n = 6) for 1 week before sBPT (T₃).
After a single dose of salmeterol (T₁), all subjects were protected against EAR, whereas after 1 week of regular treatment, the protective effect of salmeterol was totally or partially lost (T₂). Maximum FEV₁ percent fall (MaxΔFEV₁%) after allergen inhalation was significantly higher at T₂ than at T₁. All subjects except one of group 1 were protected against EAR after salmeterol + BDP (T₃), and MaxΔFEV₁% at T₃ (median, 12%; range, 4 to 6%) was significantly lower than T₂ (median, 22%; range, 12 to 43%; p < 0.05 by Wilcoxon test). Subjects of group 2 did not show any significant protection against EAR after placebo + BDP treatment (T₃) MaxΔFEV₁% at T₂(median, 31%; range, 9 to 40%) and T₃ (median, 31%; range, 3 to 42%; not significant).
In conclusion, the addition of inhaled BDP partially restored the bronchoprotective effect of salmeterol on allergen challenge that was lost after 1 week of regular treatment with salmeterol alone. This ability of BDP in reverting tolerance cannot be ascribed to a direct effect of corticosteroids per se on allergen challenge in this group of asthmatics.
Systemic bioavailability and potency of high-dose inhaled corticosteroids: A comparison of four inhaler devices and three drugs in healthy adult volunteers
1999, Chest
To compare the systemic bioavailability (assessed by cortisol suppression) of high-dose 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.
Double-blind, crossover, placebo-controlled trial.
Sixteen healthy, steroid-naive adult volunteers.
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.
Greatest percent suppression (95% confidence interval) of 9:00 amcortisol 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% [+6- to −34]). Nebulized budesonide produced an insignificant rise in 9:00 amcortisol 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%]).
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).

View all citing articles on Scopus

This work was supported by a grant from the National Asthma Campaign (United Kingdom).

revision accepted August 10.

View full text

Chest

Clinical Investigations: AsthmaEffects of Inhaled Fluticasone Propionate and Oral Prednisolone on Lymphocyte β2-Adrenoceptor Function in Asthmatic Patients

Section snippets

Patients

RESULTS

DISCUSSION

Steroids

Respir Med

Am J Med

Lancet

J Allergy Clin Immunol

Respir Med

Terbutalineinduced desensitization of human lymphocyte beta2-adrenoceptors: accelerated restoration of beta-adrenergic responses by prednisolone and ketotifen

J Clin Invest

Effects of prednisolone and ketotifen on beta2-adrenoceptors in asthmatic patients receiving beta2-bronchodilators

Eur J Clin Pharmacol

Structure-activity relationships of topically active steroids: the selection of fluticasone propionate

Respir Med

Effect of a Volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroid from a metered-dose inhaler and dry powder inhaler

Thorax

Clinical Investigations: Asthma
Effects of Inhaled Fluticasone Propionate and Oral Prednisolone on Lymphocyte β₂-Adrenoceptor Function in Asthmatic Patients