An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers

Lönnebo, Anna; Grahnén, A; Jansson, B.; Brundin, R. M.; Ling-Andersson, A.; Eckernäs, S.‐Å.

doi:10.1007/bf00195931

Cited by 71 publications

(17 citation statements)

References 9 publications

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“…is considered not to provoke any clinically important adverse reactions in adults [1], an impaired hypothalamic-pituitary-adrenal (HPA)-axis and/or reduced osteocalcin levels can be demonstrated [1,12,13]. Such biochemical evidence of systemic activity of similar or greater magnitude has been demonstrated also for other glucocorticosteroids including fluticasone propionate and beclomethasone dipropionate [1,12,14].…”

Section: Discussionmentioning

confidence: 96%

Effects of orally inhaled budesonide in seasonal allergic rhinitis

Greiff¹,

Andersson²,

Svensson³

et al. 1998

Eur Respir J

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It has previously been demonstrated that topical nasal treatment with glucocorticosteroids has significant effects on the bronchial airways. Less is known about effects on nasal disease by topical bronchial treatment with these drugs. The present study examined effects on nasal allergic disease of inhaled budesonide (avoiding nasal deposition of the drug). Patients with seasonal allergic rhinitis, but without asthma, were thus given inhalations of budesonide (600 microg b.i.d.) or placebo. The aim of the design was to allow the study of eosinophilic airway disease in a part of the airway other than the directly treated locus. Moderate to high birch pollen levels were recorded during the study season, and nasal symptoms were significantly increased in both treatment groups, although they were milder in patients receiving budesonide than in the placebo group (p<0.05). Nasal brush eosinophils and nasal lavage fluid levels of eosinophil cationic protein as well as blood eosinophils were increased during the season (p<0.05), but these increases were prevented by the inhaled budesonide. Nasal lavage fluid levels of alpha2-macroglobulin were particularly elevated in the placebo group but did not differ between patients receiving placebo and budesonide. Budesonide prevented the seasonal development of increased bronchoconstrictor responses to methacholine challenge (p<0.05). In conclusion, budesonide reduced the seasonal eosinophilia both in the circulation and in the nose along with an attenuation of seasonal nasal symptoms. Hence, at a daily dose of 600 microg b.i.d., known to cause no, or minimal, adverse effects, inhaled budesonide produces clinically significant anti-inflammatory effects in the entire airways, including the nasal mucosa, which is not exposed topically to the drug. We suggest that nasal and systemic anti-eosinophil actions are produced at commonly employed dose levels of orally inhaled budesonide.

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Section: Discussionmentioning

confidence: 96%

Effects of orally inhaled budesonide in seasonal allergic rhinitis

Greiff¹,

Andersson²,

Svensson³

et al. 1998

Eur Respir J

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“…12 This degree of steady state accumulation with fluticasone is in keeping with a 2-fold increase in adrenal suppression between single-and repeated-dose administration. 22,23 In contrast, the much shorter elimination half-life of budesonide results in no significant steady state accumulation, and therefore no significant increase in adrenal suppression between single and repeated dosing. 23 This emphasizes the need to perform comparative studies at the steady state, as effects with single dosing will be less for a drug with a long elimination half-life.…”

Section: Pharmacologic and Pharmacokinetic Determinantsmentioning

confidence: 98%

Systemic Adverse Effects of Inhaled Corticosteroid Therapy

1999

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Objective: To appraise the data on systemic adverse effects of inhaled corticosteroids.Methods: A computerized database search from January 1, 1966, through July 31, 1998, using MEDLINE, EMBASE, and BIDS and using appropriate indexed terms. Reports dealing with the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate. Studies were included that contained evaluable data on systemic effects in healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies.Results: Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1.5 mg/d (0.75 mg/d for fluticasone propionate), although there is a considerable degree of interindividual susceptibility. Metaanalysis showed significantly greater potency for doserelated adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone propionate were approximately equivalent on a 10:1-mg basis. Inhaled corticosteroids in doses above 1.5 mg/d (0.75 mg/d for fluticasone propionate) may be associated with a significant reduction in bone density, although the risk for osteoporosis may be obviated by postmenopausal estrogen replacement therapy. Although medium-term growth studies showed suppressive effects with 400-µg/d beclomethasone dipropionate, there was no evidence to support any significant effects on final adult height. Long-term, high-dose inhaled corticosteroid exposure increases the risk for posterior subcapsular cataracts, and, to a much lesser degree, the risk for ocular hypertension and glaucoma. Skin bruising is most likely to occur with high-dose exposure, which correlates with the degree of adrenal suppression.Conclusions: All inhaled corticosteroids exhibit doserelated systemic adverse effects, although these are less than with a comparable dose of oral corticosteroids. Metaanalysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.8 mg/d. The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life. Med. 1999;159:941-955 Arch Intern

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“…Inhaled¯uticasone has been shown to give a more pronounced plasma cortisol suppression after repeated administration than a single dose, whereas budesonide did not show such a marked difference [7]. This discrepancy between single and repeated dosing for cortisol suppression may be explained by the pharmacokinetic properties of the drugs, since¯uticasone has been found to have a slower systemic elimination than budesonide, leading to accumulation and doubling of plasma concentrations after repeated dosing [3].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Thorsson

Edsbäcker

Källén

et al. 2001

Brit J Clinical Pharma

156

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Aims To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids. Methods Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received uticasone propionate via a chloro¯uorocarbon-propelled pressurized metered-dose inhaler (pMDI) (healthy subjects only) and Diskus 1 and budesonide via Turbuhaler 1 , 1000 mg twice daily for 7 days. Intravenous doses (200 mg) of both compounds were used as references. Plasma concentrations of¯uticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol were determined by LC-MS every second hour for 24 h at baseline, and following each treatment. Results The volume of distribution was found to be larger and the elimination half-life and mean absorption time longer for¯uticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was signi®cantly higher than that of uticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% con®dence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of¯uticasone via pMDI was signi®cantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than that of¯uticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of uticasone Diskus. In addition, the lung deposition of¯uticasone via pMDI was 1.5-fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was signi®cantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for¯uticasone pMDI, which was signi®cantly lower (ratio 0.32 [0.24, 0.42]) than that for¯uticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ signi®cantly between treatments with¯uticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). Conclusions Budesonide and¯uticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for uticasone. Despite a signi®cantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of¯uticasone via pMDI and similar to that of¯uticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of¯uticasone and budesonide.

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An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers

Cited by 71 publications

References 9 publications

Effects of orally inhaled budesonide in seasonal allergic rhinitis

Effects of orally inhaled budesonide in seasonal allergic rhinitis

Systemic Adverse Effects of Inhaled Corticosteroid Therapy

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

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An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers

Cited by 71 publications

References 9 publications

Effects of orally inhaled budesonide in seasonal allergic rhinitis

Effects of orally inhaled budesonide in seasonal allergic rhinitis

Systemic Adverse Effects of Inhaled Corticosteroid Therapy

Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®

Contact Info

Product

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About

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®