The anti-inflammatory profile of fluticasone propionate

Fluticasone propionate is a new corticosteroid based on the androstane nucleus. It is more lipophilic than beclomethasone dipropionate (BDP) and budesonide, and binds more avidly to human lung tissue. It has an absolute affinity (K_D) of 0.5 nM for the glucocorticoid receptor and a relative receptor aflinity 1.5- and 3.0-times greater than that of beclomethasone-17-monopropionate (17-BMP) and budesonide, respectively. The rate of association with the receptor is faster and the rate of dissociation slower than with standard corticosteroids. As a result, the half-life of the corticosteroid-receptor complex is >10 h. Fluticasone propionate is also highly selective for the glucocorticoid receptor, with little or no activity at other steroid receptors. Pretreatment with fluticasone propionate signiflcantly inhibits the increase in mast cell numbers in the nasal mucosa of rats chronically exposed to toluene di-isocyanate (TDI), and suppresses TDI-induced mast cell degranulation. It is more potent in vitro than dexamethasone, BDP and budesonide in inhibiting anti-CD3-induced human T-lymphocyte proliferation, in attenuating tumour necrosis factor-α-induced endothelial cell adhesion molecule expression, and in increasing secretory leucocyte protease inhibitor levels in airway epithelial cells. It is also more potent and longer-acting than other corticosteroids in inhibiting oedema formation, interleukin-5 (IL-5)-induced blood eosinophilia, and IL-5- or platelet activating factor-stimulated eosinophil accumulation in the lung. Fluticasone propionate therefore has increased intrinsic glucocorticoid potency and high topical anti-inflammatory activity.     

Efficacy and onset of action of fluticasone propionate aqueous nasal spray on nasal symptoms, eosinophil count, and mediator release after nasal allergen challenge in patients with seasonal allergic rhinitis

We studied the effect and onset of action of fluticasone propionate aqueous nasal spray (FPANS) on mediator release and eosinophil accumulation in nasal secretions and on nasal symptoms of patients with seasonal allergic rhinitis after nasal allergen challenge (NAC). At the end of the pollen season, 28 patients were randomized in a double-blind and crossover design to receive 7 days' treatment with FPANS (200 μg, once daily) and matching placebo. NACs were performed before and at 6 h and 1. 2. 3. and 7 days during treatment with FPANS or placebo. Nasal secretions were collected for a quantitative determination of mediators and eosinophil count before and 5 min after each challenge. Nasal symptoms were assessed by scales grading the severity of symptoms at the same time. Results showed that for mediator concentrations there was a significant decrease of leukotriene C4 (P<0.001) at 7 days after the first administration of FPANS as compared to placebo. Two days after FPANS. both eosinophil counts and eosinophil cationic protein (ECP) concentrations were lower than those of placebo (eosinophils; f=0.032; ECP; F=0.038). The onset became even more important at day 7 (eosinophils; P=0.001; ECP; P=0.009) during the FPANS treatment period. For the subjective nasal symptoms, a significant reduction of symptom scores for nasal obstruction occurred also at day 3 (F=0.017) and for sneezing at day 7 (f=0.003). There was not yet any significant improvement of the objective nasal airway resistance after the different NACs during the study period. In conclusion, this study demonstrated that topical fluticasone propionate is effective in the treatment of mucosal inflammation induced by NAC. For optimal control of nasal symptoms induced by repeated maximal allergen challenges, a treatment period of more than 1 week is required.     

Effect of intranasal fluticasone proprionate on the immediate and late allergic reaction and nasal hyperreactivity in patients with a house dust mite allergy

Background Patients with perennial allergic rhinitis develop nasal symptoms not only after allergen exposure, but generally also after non-specific stimuli. Objective To evaluate the effect of 2 week's treatment with fluticasone propionate aqueous nasal spray (FPANS) on the nasal clinical response, inflammatory mediators and nasal hyperreactivity. Methods Twenty-four rhinitis patients allergic to house dust mite (HDM). participated in a douhle-blind. placebo-controlled crossover study. After 2 week's treatment with placebo or 200 μg FPANS twice daily, patients were challenged with HDM extract. Symptoms were recorded and nasal lavages were collected for up to 9.5 h after challenge. Nasal hyperreaclivity was determined by histamine challenge 24 h later. Results Because of a carry-over effect for the immediate symptom score, for this variable only the data from the first treatment period were used. FPANS treatment resulted in a significant decrease of nasal symptoms with 70%. 69% and 63% after 100. 1000 and 10000 Biological Units (BU)/mL of HDM extract respectively. Active treatment resulted in a 76% decrease of the late-phase symptoms. FPANS treatment significantly reduced albumin influx after HDM 1000 BU/mL with 62% and tended to reduce tryptase release after HDM 1000 BU ml. (P 0.0629). During the late phase FPANS treatment reduced albumin influx with 67% and eosinophil cationic protein (ECP) release with 83%. No effect of FPANS was seen on histamine levels. FPANS significantly decreased histamine-induced symptom score with 34%, secretion with 32%, and sneezes with 41%. Conclusion FPANS significantly inhibits the immediate and late allergic response, and nasal hyperreactivity, probably by suppressing mast cells and eosinophils in the nasal mucosa.     

Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma

BACKGROUND: Studies suggest that nasal treatment might influence lower airway symptoms and function in patients with comorbid rhinitis and asthma. We investigated the effect of intranasal, inhaled corticosteroid or the combination of both in patients with both pollen-induced rhinitis and asthma. METHODS: A total of 262 patients were randomized to 6 weeks' treatment with intranasal fluticasone propionate (INFP) 200 microg o.d., inhaled fluticasone propionate (IHFP) 250 microg b.i.d., their combination, or intranasal or inhaled placebo, in a multicentre, double-blind, parallel-group study. Treatment was started 2 weeks prior to the pollen season and patients recorded their nasal and bronchial symptoms twice daily. Before and after 4 and 6 weeks' treatment, the patients were assessed for lung function, methacholine responsiveness, and induced sputum cell counts. RESULTS: Intranasal fluticasone propionate significantly increased the percentages of patients reporting no nasal blockage, sneezing, or rhinorrhoea during the pollen season, compared with IHFP or intranasal or inhaled placebo. In contrast, only IHFP significantly improved morning peak-flow, forced expiratory volume in 1 second (FEV1) and methacholine PD20, and the seasonal increase in the sputum eosinophils and methacholine responsiveness. CONCLUSIONS: In patients with pollen-induced rhinitis and asthma, the combination of intranasal and IHFP is needed to control the seasonal increase in nasal and asthmatic symptoms.     

Effect of intranasal fluticasone propionate and triamcinolone acetonide on basal and dynamic measures of hypothalamic–pituitary–adrenal-axis activity in healthy volunteers

BACKGROUND : Most published studies show that intranasal corticosteroids have no effect on the hypothalamic-pituitary-adrenal (HPA) axis, but there have been isolated reports to the contrary, contradicting accumulated knowledge on pharmacokinetics. OBJECTIVE : To re-evaluate the effect of fluticasone propionate aqueous nasal spray (FPANS) and triamcinolone acetonide (TAA) aqueous nasal spray on the HPA axis using an improved study design. METHODS : Twenty-three healthy volunteers were randomized in a double-blind, three-way crossover study. The study comprised a 4-day placebo run-in phase followed by three 4-day treatment periods (placebo, FPANS (200 microg once daily) or TAA aqueous nasal spray (220 microg once daily)), separated by 7-14 days washout intervals. Before the first, and on the last day of each treatment period, 12-h overnight urine was collected to assess cortisol excretion and cortisol creatinine ratio. Approximately 26 h after the last administration of study medication, volunteers underwent stimulation with 0.5 microg adrenocorticotropic hormone (ACTH). Serum cortisol concentrations were measured before and 20 and 30 min after injection. Blood and urine samples were analysed for cortisol by liquid chromatography tandem mass spectrometry. RESULTS : Compared with placebo, EP or TAA had no significant effect on mean overnight (12 h) urinary cortisol excretion, and did not significantly suppress the overnight geometric mean urinary cortisol/creatinine excretion ratio. Values for serum cortisol before and after ACTH simulation showed no significant suppression, although there was a slight blunting of the HPA-axis response following TAA treatment. CONCLUSION : This study confirms that there are no detectable effects on the HPA axis following short-term intranasal FP or TAA at their recommended dosages.     

药品行政保护品种介绍:甾体药物(二)(续一)

氟替卡松干粉吸入剂通用名:氟替卡松(fluticasone)干粉吸入剂.商品名:辅舒酮(Flixotide)干粉吸入剂.化学名与结构式同上期介绍.申请日:1999年3月11日.申请人:德国葛兰素威康有限公司.申请号:A-DE990 3 1104.授权号:B-DE00071008.授权日:2000年7月10日.法定行政保护期:因本国专利到期而提前终止,即到2005年3月8日.专利介绍:德国专利第3105307号.剂型及规格:干粉吸入剂 , 每支50,100,250 μg.药理作用:本品是一种作用于局部的皮质激素,具有较高的治疗指数和强效的抗炎活性.在肺部产生强效糖皮质激素的抗炎作用,从而减轻哮喘的症状和阻止哮喘恶化.Product brief of administrative protection of pharmaceuticals: steroidal agent s (2) (continuation 1)     

沙美特罗替卡松粉吸入剂治疗50例中、重度儿童哮喘的疗效

目的 :观察沙美特罗替卡松粉吸入剂在儿童中、重度哮喘治疗中的疗效、安全性。方法 :将 80例中、重度哮喘病儿分成沙美特罗替卡松粉吸入剂治疗组 (治疗组 )和氟替卡松治疗组 (对照组 )。治疗组 5 0例 ,5～ 11a给予沙美特罗替卡松粉吸入剂 5 0μg / 10 0 μg·次 - 1(沙美特罗 5 0 μg,氟替卡松10 0 μg) ,bid。 12～ 14a给予沙美特罗替卡松粉吸入剂 5 0 μg/ 2 5 0 μg·次 - 1,bid。氟替卡松治疗组(对照组 ) 30例 ,5～ 11a给予氟替卡松 12 5 μg·次 - 1,bid。 12～ 14a给予氟替卡松 2 5 0 μg·次 1,tid。2组均连用 6mo ,按需使用沙丁胺醇。结果 :2组平均早、晚最大呼气峰流速值 (PEFam ,PEFpm ) ,需使用沙丁胺醇的日数在 8wk内有显著差异 ,自我评价在 4wk内有显著差异 ,症状评分在 3mo内有显著差异。 2组各有 1例咽部不适 ,经处理后缓解。结论 :沙美特罗替卡松粉吸入剂在儿童中、重度哮喘治疗中具良好的有效性、安全性。     

Advances in pharmacotherapy for the treatment of allergic rhinitis; MP29-02 (a novel formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) fills the gaps

Introduction: Effective pharmacologic treatment exists for most patients suffering from allergic rhinitis (AR). However, both in clinical trials and in real-life studies, many patients are dissatisfied with treatment. Physicians often use multiple therapies, in an attempt to improve symptom control, often with limited evidence of success. Novel treatment options are needed and must consider unmet medical needs.

Areas covered: This article reviews the clinical data for a new AR treatment. MP29-02 (Dymista®, Meda, Solna, Sweden) contains azelastine hydrochloride (AZE) and fluticasone propionate (FP), in a novel formulation and delivered in an improved device as a single nasal spray. It has shown superior efficacy in AR patients than either commercially available AZE or FP monotherapy for both nasal and ocular symptom relief, regardless of disease severity. MP29-02 also provided more effective and rapid symptom relief than either AZE or FP monotherapy delivered in the MP29-02 formulation and device. However, the effect was less than that observed versus commercial comparators, suggesting the impact of formulation and device on clinical efficacy.

Expert opinion: MP29-02 simplifies AR management, surpassing the efficacy of gold standard treatment, intranasal corticosteroids (INS), for the first time. It is indicated for the treatment of moderate-to-severe seasonal allergic rhinitis and perennial allergic rhinitis when monotherapy with either intranasal antihistamine or INS is NOT considered sufficient. Most patients present with moderate/severe disease, with evidence of current or previous treatment insufficiency. MP29-02 should be the treatment of choice for these patients.