Adrenal function as assessed by low-dose adrenocorticotropin hormone test before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate.

Low-dose adrenocorticotropin hormone (ACTH) tests (0.5 microg/L 73 m2) were done before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate in 12 patients 33-77 years old who had mild-to-severe asthma to compare the effects of these drugs on adrenal function. Low-dose ACTH tests were performed after the subjects had received inhaled beclomethasone dipropionate (200-900 microg/day) for at least 12 wk. Treatment was then switched to inhaled fluticasone propionate (200-600 microg/day) for at least 12 wk, and a second low-dose ACTH test was done. Pulmonary function was assessed on the basis of peak expiratory flow rate (PEFR, % of predicted value). After switching treatment, the daily dose of inhaled corticosteroid decreased by about 40%. Basal serum cortisol and ACTH levels were similar with both treatments. The adrenal response, as assessed by incremental rise in the serum cortisol level (peak minus basal) after ACTH challenge, improved significantly (5.6-7.9 microg/dL, p < 0.01) after switching to fluticasone. All three patients who had lower serum cortisol levels during beclomethasone treatment than during fluticasone treatment showed improvement in both the peak cortisol level and the incremental rise in cortisol. Mean morning and evening PEFRs significantly increased after switching from beclomethasone to fluticasone (morning: 71.2 to 76.0%, p < 0.01; evening: 67.3 to 72.1%, both p < 0.05). The diurnal variation of PEFR significantly decreased from 10.9% to 8.3% after switching treatment (p < 0.01). We conclude that switching from beclomethasone to fluticasone reduces the risk of adrenal dysfunction associated with inhaled steroids and improves pulmonary function.

Expression of c-fos, rather than c-jun or glucocorticoid-receptor mRNA, correlates with decreased glucocorticoid response of peripheral blood mononuclear cells in asthma.

Resolution of the molecular mechanism(s) underlying glucocorticoid (GC) resistance is an important clinical problem when performing individualized GC therapy according to the GC response of peripheral cells in asthma. In order to investigate the mechanism(s) underlying the individual differences of lymphocyte GC response, we examined the relationship between lymphocyte sensitivity to GC in vitro and the expression of mRNAs for GC receptor (GR) alpha, GRbeta, c-fos and c-jun, which are reported to be implicated in the regulation of the pharmacological effects of GCs in asthma patients. Twenty-seven patients with bronchial asthma and 14 healthy subjects were included in the study. IC50s of prednisolone and methylprednisolone on blastogenesis of peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A in vitro were estimated. Transcripts for GRalpha, c-fos, c-jun and beta-actin genes in PBMCs were quantitatively determined by reverse transcription-competitive polymerase chain reaction (RT-cPCR) procedures. GRbeta mRNA expression was examined with an RT-PCR technique. A statistically significant positive correlation was observed between the IC50s for prednisolone (p <0.002) or methylprednisolone (p <0.001) and expression of c-fos mRNA in PBMCs of asthma patients (n = 27). Thus, the increased expression of c-fos mRNA correlated with the decreased responses of PBMCs to prednisolone and methylprednisolone in vitro. In contrast, the expression of GRalpha and c-jun mRNAs did not correlate with the IC50 for prednisolone and methylprednisolone in asthma patients. In addition, no statistically significant difference in IC50s of GCs between asthma patients with PBMCs exhibiting GRbeta mRNA and those without GRbeta mRNA expression was observed. The increased expression of c-fos mRNA suggests to attenuate PBMC response to GCs, which may contribute to progression of GC resistance in asthma. On the other hand, c-jun and GC receptor mRNA expression appears to have less influence on poor GC-response establishment.