Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new flonase research articles will be listed here shortly after becoming available to us.
Medical research on flonase
Fluticasone Reverses Oxymetazoline Induced Tachyphylaxis of Response and Rebound Congestion.
Am J Respir Crit Care Med. 2010 Mar 4;
Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B
RATIONALE: Chronic use of intranasal decongestants like oxymetazoline leads to tachyphylaxis of response and rebound congestion, due to alpha-adrenoceptor mediated down-regulation and desensitization of response OBJECTIVES: We evaluated if tachyphylaxis can be reversed by intranasal fluticasone propionate, as well as the relative alpha1-/alpha2-adrenoceptor components of tachyphylaxis using the alpha1-antagonist prazosin. METHODS: In a randomized, double-blind, placebo-controlled, crossover design, 19 healthy subjects received intranasal oxymetazoline 200Amicrog tid for 14 days, followed by addition of fluticasone 200Amicrog bid for a further 3 days. At day 1, 14 and 17, participants received a single dose of oral prazosin 1mg or placebo with measurements made before and 2 hours later. MEASUREMENTS AND MAIN RESULTS: Outcomes evaluated were peak nasal inspiratory flow, nasal resistance, blood flow and oxymetazoline dose-response curve (DRC). On day 14 vs. day 1, inspiratory flow decreased (mean difference, 95% CI) (â 47.9 L.min(-1);, â63.9 to â31.9, P
Drug Metab Dispos. 2010 Mar 4;
Foti RS, Rock DA, Wienkers LC, Wahlstrom JL
Understanding the potential for P450-mediated drug-drug interactions (DDI) is a critical step in the drug discovery process. DDI of CYP3A4 is of particular importance, due to the number of marketed drugs which are cleared by this enzyme. In response to studies suggesting the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine/nifedipine and testosterone. However, design of clinical CYP3A4 DDI studies may be confounded for cases such as AMG 458, where testosterone is predicted to exhibit a clinically relevant DDI (AUC(I)/AUC >/= 2), while midazolam and felodipine/nifedipine are not. In order to develop an appropriate path forward for such clinical DDI studies, the inhibition potency of twenty known inhibitors of CYP3A4 were measured in vitro using eight clinically relevant CYP3A4 probe substrates and testosterone. Hierarchical clustering suggested four probe substrate clusters: testosterone; felodipine; midazolam, buspirone, quinidine and sildenafil; and simvastatin, budesonide and fluticasone. The in vivo sensitivities of six clinically relevant CYP3A4 probe substrates (buspirone, cyclosporine, nifedipine, quinidine, sildenafil and simvastatin) were determined in relation to midazolam from literature DDI data. Buspirone, sildenafil and simvastatin exhibited similar or greater sensitivity than midazolam to CYP3A4 inhibition in vivo. Finally, SimCYP was used to predict the in vivo magnitude of CYP3A4 DDI caused by AMG 458 using midazolam, sildenafil, simvastatin and testosterone as probe substrates.
Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids.
N Engl J Med. 2010 Mar 3;
Lemanske RF, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD, Strunk RC, Szefler SJ, Zeiger RS, Bacharier LB, Covar RA, Guilbert TW, Larsen G, Morgan WJ, Moss MH, Spahn JD, Taussig LM,
BACKGROUND: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking. METHODS: We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 mug of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 mug of fluticasone twice daily (ICS step-up), 100 mug of fluticasone plus 50 mug of a long-acting beta-agonist twice daily (LABA step-up), or 100 mug of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%. RESULTS: A differential response occurred in 161 of 165 patients who were evaluated (P
Int J Pediatr Otorhinolaryngol. 2010 Feb 24;
Pudrith C, Martin D, Kim YH, Jahng P, Kim B, Wall M, Jung T
OBJECTIVE: Otitis media with effusion (OME) is a common childhood disease that is characterized by an accumulation of fluid in the middle ear. Chronic OME can also lead to sensorineural hearing loss (SNHL). Nitric oxide (NO), an inflammatory mediator (IM) of OME, is a free radical known to regulate cell proliferation, cell death, and angiogenesis. Previous studies have shown that nitric oxide may cause SNHL through outer hair cell (OHC) cytotoxicity. This experiment was designed to determine whether glucocorticoids, dexamethasone, fluticasone propionate, or rimexolone, can reduce the concentration of NO in middle ear effusion (MEE). METHODS: Fifty-three chinchillas were divided into 7 groups, vehicle vs. each glucocorticoid at 0.1% and 1.0% concentrations. Due to anesthesia complications, N ranged from 6 to 9 per group. Two hundred microlitres of each test article was injected into the bullae of each animal. Two hours later, lipopolysaccharide (LPS) (0.3mg in solution) was added. Test articles were re-administered at 24 and 48h post-LPS induction. After 96h, animals were euthanized and the MEE was collected. RESULTS: All three glucocorticoids numerically reduced NO concentration in the middle ear when administered at 0.1%, but only FP showed a significant reduction. At 1.0% concentrations, all 3 steroids significantly reduced NO concentration. CONCLUSION: This study suggests that glucocorticoid treatment reduces NO concentration in the MEE and may protect the ear from the SNHL caused by NO.
Int Arch Allergy Immunol. 2010 Feb 26; 152(4): 353-361
Futamura K, Orihara K, Hashimoto N, Morita H, Fukuda S, Sagara H, Matsumoto K, Tomita Y, Saito H, Matsuda A
Background: Whilebeta(2)-adrenoceptor agonists (beta(2)-agonists) are widely used as bronchodilators in the treatment of asthma, there has been increasing concern that regular use of beta(2)-agonists may adversely affect the control of asthma. However, the molecular mechanisms of such undesirable effects of beta(2)-agonists are not fully understood. In this study, we examined the effects of beta(2)-agonists on cytokine-induced production of thymic stromal lymphopoietin (TSLP), an indispensable cytokine in the development of allergic diseases, by lung tissue cells. Methods: Normal human bronchial epithelial cells (NHBE), smooth muscle cells (BSMC) and fibroblasts (NHLF) were stimulated with the IL-4 and TNF-alpha cytokines, alone and in combination, and their production of TSLP was examined by ELISA. The effects of beta(2)-agonists (salmeterol, formoterol, salbutamol), intracellular cyclic adenosine monophosphate (cAMP)-elevating agents (8-bromo-cAMP, dibutyryl cAMP, forskolin) and a corticosteroid (fluticasone) on the cytokine-induced TSLP production were examined. Results: The following results were observed in all three types of lung tissue cells tested (that is, NHBE, BSMC and NHLF). Costimulation with IL-4 and TNF-alpha significantly induced TSLP production, and beta(2)-agonists further enhanced it via upregulation of intracellular cAMP. However, addition of a corticosteroid to the cytokines and beta(2)-agonist resulted in a marked decrease in TSLP production. Conclusions: beta(2)-Agonists significantly enhanced the cytokine-induced TSLP production by primary human lung tissue cells. This may be partly responsible for the undesirable clinical effects of continuous beta(2)-agonist monotherapy, and combination therapy with a corticosteroid might effectively inhibit TSLP-mediated allergic inflammation.
Overexpression of glucocorticoid receptor-beta in severe allergic rhinitis.
Auris Nasus Larynx. 2010 Feb 23;
Ishida A, Ohta N, Koike S, Aoyagi M, Yamakawa M
OBJECTIVE: To clarify the role of glucocorticoid receptor-beta in resistance to glucocorticoid therapy for allergic rhinitis, we studied 37 tissue samples from 20 patients with severe allergic rhinitis, and samples from age-matched controls. METHODS: Patients were treated with intranasal fluticasone for 6 months and inferior turbinectomy was performed for patients with poor response to glucocorticoid treatment. The expression of glucocorticoid receptor-alpha (GR-alpha), glucocorticoid receptor-beta (GR-beta), and nuclear factor-kappaB (NF-kappaB) in nasal mucosa was studied immunohistochemically. RESULTS: GR-alpha and NF-kappaB were expressed to a similar extent in patients and controls, but GR-beta was expressed significantly more in patients, resulting in an increased GR-beta/GR-alpha ratio. CONCLUSION: Our findings suggest that GR-beta plays an important role in resistance to glucocorticoid therapy for allergic rhinitis, and its expression might be used as an additional parameter indicating steroid resistance in allergic rhinitis.
Respir Res. 2010 Feb 24; 11(1): 22
Riesenfeld EP, Sullivan MJ, Thompson-Figueroa JA, Haverkamp HC, Lundblad LK, Bates JH, Irvin CG
ABSTRACT: BACKGROUND: The relationship between airway structural changes (remodeling) and airways hyperresponsiveness (AHR) is unclear. Asthma guidelines suggest treating persistent asthma with inhaled corticosteroids and long acting beta-agonists (LABA). We examined the link between physiological function and structural changes following treatment fluticasone and salmeterol separately or in combination in a mouse model of allergic asthma. METHODS: BALB/c mice were sensitized to intraperitoneal ovalbumin (OVA) followed by six daily inhalation exposures. Treatments included 9 daily nebulized administrations of fluticasone alone (6mg/ml), salmeterol (3mg/ml), or the combination fluticasone and salmeterol. Lung impedance was measured following methacholine inhalation challenge. Airway inflammation, epithelial injury, mucus containing cells, and collagen content were assessed 48 hours after OVA challenge. Lungs were imaged using micro-CT. Results and Discussion Treatment of allergic airways disease with fluticasone alone or in combination with salmeterol reduced AHR to approximately naive levels while salmeterol alone increased elastance by 39% compared to control. Fluticasone alone and fluticasone in combination with salmeterol both reduced inflammation to near naive levels. Mucin containing cells were also reduced with fluticasone and fluticasone in combination with salmeterol. CONCLUSIONS: Fluticasone alone and in combination with salmeterol reduces airway inflammation and remodeling, but salmeterol alone worsens AHR: and these functional changes are consistent with the concomitant changes in mucus metaplasia.
Cases J. 2009; 2: 7770
ABSTRACT : We report a case study of a 55-year-old white male with severe persistent refractory corticosteroid-dependent asthma receiving inhaled combination therapy with fluticasone propionate 500 mug and salmeterol 50 mug twice-daily in addition to 6-week cycles of oral corticosteroid treatment for the previous 7 months. The patient was switched to high-dose mometasone furoate delivered via a dry powder inhaler (660 mug twice-daily) for 6 weeks.Considerable improvement from baseline in peak expiratory flow, use of rescue medication, and asthma symptoms of coughing and wheezing was observed. The patient discontinued the oral corticosteroid after 1 week of high-dose mometasone furoate treatment. Plasma cortisol value at 8 a.m. was 8.4 mug/dL (normal range, 4.3-22.6 mug/dL) at week 6.
Can low-dose combination products for inhalation be formulated in single crystalline particles?
Eur J Pharm Sci. 2010 Feb 19;
Kumon M, Kwok PC, Adi H, Heng D, Chan HK
This study aims to produce and test the performance of novel crystalline respirable particles containing two low-dose active ingredients and mannitol. This technique overcomes the usual requirement of blending with lactose carriers in formulating combination inhalation products. Ternary powders were produced by co-spray drying solutions containing an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and mannitol as a crystalline excipient. Two formulations comprising widely used ICS and LABA were studied: budesonide/formoterol fumarate dihydrate/mannitol (B/F/M-SD) and fluticasone propionate/salmeterol xinafoate/mannitol (F/S/M-SD). Various physicochemical properties of the powders were analyzed. Aerosol performance was evaluated by dispersing each powder from an Aerolizer((R)) at 60 and 100L/min into a Next Generation Impactor. We obtained partially hollow spherical particles (volume median diameters of 2mum) with drug-enriched surfaces. Both formulations contained alpha-mannitol, and the ICSs were crystalline. The content of each drug component in the powder was found to conform to the theoretical dose. The ternary powders generated high fine particle fractions (>50% of the loaded dose), with concomitant drug deposition on the impactor stages. The aerosol performance of B/F/M-SD was maintained after storage over silica gel at 22 degrees C for 11 weeks. In conclusion, co-spray dried particles of ICS/LABA/M-SD were largely crystalline, stable and showed excellent aerosol performance. They may provide an attractive alternative strategy to develop combination products without lactose blends.
J Asthma. 2010 Mar; 47(2): 217-23
O'Connor RD, Patrick DL, Parasuraman B, Martin P, Goldman M
OBJECTIVE: Assessment of patient-reported outcomes is important in evaluating the impact of asthma treatment. This study was conducted to compare effects of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler with fixed-dose fluticasone propionate/salmeterol dry powder inhaler regimens on patient-reported outcomes in patients aged > or =18 years with moderate to severe asthma. METHODS: In this phase III, randomized, open-label study, 1225 patients were randomized 2:1 to fixed-dose budesonide/formoterol 160/4.5 microg x 2 inhalations (320/9 mug) twice daily or fixed-dose fluticasone propionate/salmeterol 250/50 microg twice daily for 1 month. In the subsequent 6 months, patients receiving fixed-dose fluticasone propionate/salmeterol continued therapy, whereas those receiving fixed-dose budesonide/formoterol were randomized 1:1 to fixed-dose or adjustable-dose budesonide/formoterol (adjustable from 320/9 microg twice daily to 320/9 microg once daily or 640/18 microg twice daily). RESULTS: Mean improvements from baseline to end of treatment in the Asthma Quality of Life Questionnaire (standardized) overall and individual domain scores and the Asthma Control Questionnaire score were clinically important (> or =0.5 points) for all treatments. Patients in both budesonide/formoterol groups reported greater treatment satisfaction on the Asthma Treatment Satisfaction Measure questionnaire than patients in the fluticasone propionate/salmeterol dry powder inhaler group for the attributes of timely relief of symptoms (p < or = .037) and feel medication working (p < or = .020). Onset of Effect Questionnaire scores showed a greater percentage of patients perceiving onset of effect with budesonide/formoterol regimens versus fixed-dose fluticasone propionate/salmeterol (p < or = .002). CONCLUSIONS: Treatment regimens did not differ regarding improvements in asthma-specific quality of life and asthma control. Questions related to perceived rate of onset and feeling medication working in the Asthma Treatment Satisfaction Measure and Onset of Effect Questionnaire generally elicited somewhat more favorable responses with budesonide/formoterol pressurized metered-dose inhaler regimens versus fixed-dose fluticasone propionate/salmeterol dry powder inhaler.