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Characterisation of the aggregation behaviour in a salmeterol and fluticasone propionate inhalation aerosol system.

Michael Y, Snowden MJ, Chowdhry BZ, Ashurst IC, Davies-Cutting CJ, Riley T.

School of Chemical and Life Sciences, University of Greenwich, Wellington Street, Woolwich, London SE18 6PF, UK.

The nature of the drug-drug aggregation phenomena between salmeterol xinafoate and fluticasone propionate used in a metered-dose inhaler system has been examined. Interactions between the drugs in the solvents 1,1,2-trichlorotrifloroethane (CFC-113) and 1,1,1,2-tetrafluoroethane (HFA-134a) have been characterised using a focused beam reflectance measurement probe by measuring the average floc size of the drug particles individually and in combination as a function of stirrer rate. The floc composition in the CFC-113 system, where the drug particles cream, was determined by high-performance liquid chromatography analysis. The aggregation behaviour of the individual drugs was shown to depend on the physical and chemical properties of both the drug substance and the media. Larger flocs were observed for salmeterol xinafoate compared with fluticasone propionate, while both drugs formed larger aggregates in HFA-134a compared with in CFC-113. The floc composition studies demonstrated that, in the combined formulation in CFC-113, salmeterol xinafoate and fluticasone propionate aggregate together to form hetero-flocs. The interaction between the two drugs was such that they did not separate on creaming, despite having different densities. The average floc size of the combined drug suspension was also found to depend on the dispersion medium.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11397578&dopt=Abstract fluticasone Flonase



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Safety of inhaled corticosteroid therapy in young children with asthma.

Turktas I, Ozkaya O, Bostanci I, Bideci A, Cinaz P.

Department of Pediatric Allergy and Asthma, Gazi University Faculty of Medicine, Ankara, Turkey. ipekt med.gazi.edu.tr

BACKGROUND: Physicians have had some reluctance to use inhaled corticosteroids in very young children with asthma because of the possible risks of adverse systemic effects. OBJECTIVE: The purpose of this study was to evaluate the effects of fluticasone propionate on growth and adrenocortical function in young children with asthma. METHODS: We performed an open, prospective study for 24 weeks of 20 children with asthma, 2.5 to 5.0 years of age, who had received fluticasone by a large volume spacer at dosages ranging from 190.50 to 565.40 microg/m2 daily. Growth was evaluated by height standard deviation scores measured by a stadiometer. Adrenocortical function was evaluated twice in each child, before and after the study, by determining fasting serum cortisol concentrations at 8 AM and also at 30 and 60 minutes after adrenocorticotropic hormone stimulation. Posttreatment values of height standard deviation scores and fasting morning serum cortisol concentrations were compared with those of 18 age-matched children, who constituted the control group. RESULTS: The evaluation of mean +/- SEM (and range) of height standard deviation scores revealed a significant decrease from 0.44 +/- 0.27 (-1.46 to 2.22) to 0.28 +/- 0.26 (-1.51 to 2.07; P = 0.01) at week 18 and to 0.25 +/- 0.24 (-1.90 to 2.13; P = 0.04) at the week 24 in fluticasone-treated children. At the end of the treatment, however, height standard deviation scores of these children did not differ significantly (P = 0.35) from those of the control group. Delayed growth with medium-duration treatment was not associated with alterations in serum cortisol measurements, either at baseline or after stimulation. The mean fasting morning serum cortisol concentrations did not differ significantly between the fluticasone-treated patients and the control group. CONCLUSIONS: Some concern prevails about the safety of medium- or long-term treatment with regularly inhaled corticosteroids in young children with asthma. The prepubertal growth may be delayed, but the effect on ultimate height remains uncertain in such children. Growth should be regularly monitored in children who begin inhaled corticosteroid therapy for mild persistent asthma at an age <5 years old.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11428737&dopt=Abstract fluticasone Flonase



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Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom.

Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D.

Antrim Area Hospital, Antrim, UK. drgeoffreytodd hotmail.com

BACKGROUND: Until recently, only two cases of acute adrenal crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency of this side effect in the United Kingdom. METHODS: Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in a UK medical directory, asking whether they had encountered asthmatic patients with acute adrenal crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs and abnormal hypothalamic-pituitary-adrenal axis function test results. RESULTS: From an initial 2912 questionnaires, 33 patients met the diagnostic criteria (28 children, five adults). Twenty-three children had acute hypoglycaemia (13 with decreased levels of consciousness or coma; nine with coma and convulsions; one with coma, convulsions and death); five had insidious onset of symptoms. Four adults had insidious onset of symptoms; one had hypoglycaemia and convulsions. Of the 33 patients treated with 500-2000 micro g/day ICS, 30 (91%) had received fluticasone, one (3%) fluticasone and budesonide, and two (6%) beclomethasone. CONCLUSIONS: The frequency of acute adrenal crisis was greater than expected as the majority of these patients were treated with ICS doses supported by British Guidelines on Asthma Management. Despite being the least prescribed and most recently introduced ICS, fluticasone was associated with 94% of the cases. We therefore advise that the licensed dosage of fluticasone for children, 400 micro g/day, should not be exceeded unless the patient is being supervised by a physician with experience in problematic asthma. We would also emphasise that until adrenal function has been assessed patients receiving high dose ICS should not have this therapy abruptly terminated as this could precipitate adrenal crisis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12456538&dopt=Abstract fluticasone Flonase



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Fluticasone and salmeterol downregulate in vitro, fibroblast proliferation and ICAM-1 or H-CAM expression.

Silvestri M, Fregonese L, Sabatini F, Dasic G, Rossi GA.

Pulmonary Division, G. Gaslini Institute, Genoa, Italy.

Beta2-adrenoreceptor agonists have pharmacological properties that may suggest an inhibitory effect on various aspects of the inflammatory and repair processes that characterize asthma. Since fibroblasts express beta2-adrenoreceptors, the effects of different concentrations (0.1-100 nM) of fluticasone propionate (FP), salmeterol (S) and their combination (FP+S) on lung fibroblast proliferation and adhesion molecule expression were evaluated. Stimulation of human foetal lung fibroblasts with a fibrogenic cytokine, basic fibroblast growth factor (bFGF), resulted in a [methyl-3H] thymidine ([3H]TdR) uptake, four-fold higher than that of control cultures (p=0.0001) and was significantly inhibited by S, at all the concentrations tested (0.1-100 nM; p<0.05). No changes in bFGF-induced cell proliferation were observed in the presence of FP (0.1-100 nM; p>0.05, all comparisons). In addition, the association FP+S did not improve the inhibitory activity of S alone (p>0.05, each comparison). An upregulation of intercellular adhesion molecule-1 (ICAM-1) expression was induced by tumour necrosis factor-alpha (TNF-alpha) (p=0.0004), but not by interleukin-4 (IL-4) (p>0.05), while none of the two cytokines were able to increase hyaluronic-cellular adhesion molecule (H-CAM) expression by lung fibroblasts (p>0.05). A significant downregulation of ICAM-1 or H-CAM expression was demonstrated in the presence of FP or S, at all concentrations tested (0.1-100 nM; p<0.01, each comparison). Interestingly, S (10 nM and 100 nM) was able to enhance the inhibitory activity of FP on ICAM-1 expression (p<0.01), but not on H-CAM expression (p>0.1). These results show that in human foetal lung fibroblasts, fluticasone propionate and salmeterol are effective in modulating in vitro, different lung fibroblast biological functions that are likely to be involved in airway remodelling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11510784&dopt=Abstract fluticasone Flonase



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The penetration of 0.005% fluticasone propionate ointment in eyelid skin.

Tan MH, Lebwohl M, Esser AC, Wei H.

Department of Dermatology, The Mount Sinai School of Medicine of New York University, 5 E 98th St., New York, NY 10029, USA.

BACKGROUND: The use of corticosteroids to treat periorbital dermatoses carries significant risk of serious side effects such as glaucoma, cataracts, and blindness. Studies to assess levels of corticosteroid penetration in the eyelid are lacking. OBJECTIVE: We assessed corticosteroid penetration in eyelid skin in vitro to obtain information leading to the establishment of safer dosing regimens. METHODS: Fluticasone propionate ointment, 0.005%, was applied (approximately 2-5 mg/cm(2)) to samples of human eyelid skin, and penetration was assessed by using modified Franz diffusion cells. Drug concentration was determined at 12, 24, 36, and 48 hours after application by liquid chromatography tandem mass spectrometry. RESULTS: Only very small amounts of fluticasone propionate penetrated the skin (range, 0.618% +/- 0.339% to 1.467% +/- 0.695%). CONCLUSION: Further studies are warranted to examine the safety and efficacy of 0.005% fluticasone propionate ointment for the treatment of eyelid dermatoses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11511836&dopt=Abstract fluticasone Flonase