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PubMed1995

Comparison of fluticasone propionate and sodium cromoglycate for the treatment of childhood asthma (an open parallel group study).

Inhaled corticosteroids are highly effective in the treatment of asthma at all ages and their use in younger children is increasing. As concerns exist about the long-term systemic side-effects of high dose inhaled corticosteroids, current guidelines continue to recommend sodium cromoglycate (SCG) as first line regular medication for children with frequent symptoms. Few published studies have compared the safety and efficacy of inhaled corticosteroids with SCG in children. This study compares SCG with the new inhaled corticosteroid, fluticasone propionate (FP), which has theoretical advantages over other currently available corticosteroids due to its negligible oral bioavailability. This was a randomized, open, multi-centre, parallel group comparison of 50 micrograms FP twice daily and 20 mg SCG four times daily over 8 weeks, preceded by a 2-week baseline period. Sixty-two general practices and two hospital centres enrolled 225 asthmatic children aged 4-12 years (110 received FP; 115 received SCG). Outcome measures improved in both groups, with a significant difference in favour of FP for the key variables of mean morning and evening % predicted PEFR and % of symptom-free days and nights. No significant difference was observed for FEV1, or relief medication use. Two children taking FP and 10 children taking SCG withdrew because of adverse events. This study showed that low dose FP was effective and superior to SCG in young children with mild-moderate asthma. Safety studies of longer duration are needed before changing the current recommendations for inhaled corticosteroid therapy.

Androstadienes↗
PubMed2003

Selective agonist binding of (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and 2S-(2alpha,3beta,4beta)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) receptors: a molecular modeling study.

Molecular models were constructed, using the published X-ray structure of rat glutamate receptor 2 (GluR2), for the ligand-binding domains of the human (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)- and kainate-selective ionotropic glutamate receptors (iGluRs): GluR1-7 and KA1-2. Based on the analysis of the known X-ray structures of GluR2 in complex with glutamate, kainate, and AMPA, we have constructed binding motifs (relative positioning of a ligand in the binding site and the physico-chemical interactions that take place) for selected agonist ligands and found explanations for ligand-binding selectivity to homomeric receptors among the different iGluRs. Even a single sequence difference can explain significant differences in ligand-binding affinities between two receptors. In total, there are seven residues surrounding the binding cavity that affect agonist selectivity: in GluR2, these residues are Pro478, Thr480, Leu650, Ser654, Thr686, Tyr702, and Met708. Each of these seven positions has been shown, or is predicted, to influence the presence of one or more water molecules that, when present, may form bridging hydrogen bonds between particular ligands and receptors. By using this knowledge it should be possible to design new selective agonist ligands with high affinity for any AMPA/kainate receptor.

Amino Acid Sequence↗
PubMed2006

Regulation of editing and expression of glutamate alpha-amino-propionic-acid (AMPA)/kainate receptors by antidepressant drugs.

BACKGROUND: Several reports have shown that the glutamatergic system is involved in both the pathogenesis of affective and stress-related disorders and in the action of antidepressant drugs. In particular, antidepressant treatment was shown to modulate expression and function of ionotropic glutamate receptors, to inhibit glutamate release and to restore synaptic plasticity impaired by stress. METHODS: We analyzed the mRNA expression and RNA editing of alpha-amino-propionic-acid (AMPA) and kainate (KA) receptor subunits, in the pre-frontal/frontal cortex (P/FC) and hippocampus (HI) of rats chronically treated with three different drugs: the selective serotonin (5-HT) reuptake inhibitor fluoxetine, the selective noradrenaline (NA) reuptake inhibitor reboxetine and the tricyclic antidepressant desipramine. RESULTS: Our data showed that fluoxetine and desipramine exerted moderate but selective effects on glutamate receptor expression and editing, while reboxetine appeared to be the drug that affects glutamate receptors (GluR) most. The most consistent effect, observed with pronoradrenergic drugs (desipramine and reboxetine), was a decrease of GluR3 expression both in P/FC and HI. Interestingly, in HI, the same drugs also decreased the editing levels of either the flip (desipramine) or flop (reboxetine) form of GluR3. CONCLUSIONS: Overall, these results point to specific and regionally discrete changes in the expression and editing level of glutamate receptors and, in particular, to a selective reduction of conductance for GluR3-containing receptors following treatment with antidepressant drugs. These data support the hypothesis that changes in glutamate neurotransmission are involved in the therapeutic effects induced by these drugs.

Animals↗
PubMed2005

The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.

BACKGROUND: A patient-driven, adjustable maintenance dosing (AMD) approach to asthma therapy, in which the dose is adjusted by patients according to the severity of their symptoms, has recently been compared with fixed-dose therapy in open-label studies. OBJECTIVE: This study used a double-blind, double-dummy design to compare the efficacy of 2 treatment approaches: stable dosing of salmeterol/fluticasone propionate (SAL/FP) and AMD of formoterol/budesonide (FOR/BUD). METHODS: This was a 1-year, multicenter, randomized, double-blind, double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid (ICS) plus a long-acting beta2 agonist, or with >500 to 1000 microg/d ICS alone. Patients were randomized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID, both delivered via dry powder inhaler devices. After 4 weeks of stable dosing in both groups, eligible patients continued the study for an additional 48 weeks, receiving either a stable dose of SAL/FP or AMD of FOR/BUD. According to the AMD treatment plan, patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma, frequency of rescue medication use, and changes in morning peak expiratory flow (PEF). The primary end point was the percentage of symptom-free days. Other parameters included daily asthma symptom scores, morning PEF, percentage of days free of rescue medication use, daily rescue medication use, percentage of nighttime awakenings due to asthma, percentage of weeks with well-controlled asthma, and number of exacerbations requiring oral corticosteroids or emergency department (ED) visits/hospitalizations. Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits. RESULTS: The intent-to-treat population comprised 688 patients (344 per treatment arm) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81% of the predicted normal value. After 4 weeks' stable dosing, 581 patients (295 SAL/FP, 286 FOR/BUD) continued beyond visit 3 into the remaining 48-week treatment period. Over weeks 1 through 52, patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD (median, 58.8% vs 52.1%, respectively; P = 0.034). The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47% lower with SAL/FP compared with FOR/BUD (adjusted annual mean rate, 0.18 vs 0.33; P = 0.008). During weeks 5 through 52, patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d (equivalent to BUD 360 microg/d), and 235 (82.2%) patients stepped down to 1 inhalation/d. Mean (SD) daily ICS exposure over 52 weeks was 463 (81) microg FP and 480 (238) microg BUD in the respective treatment arms. CONCLUSIONS: In this adult population with persistent asthma, stable dosing of SAL/FP 50/250 microg BID resulted in significantly greater increases in symptom-free days, days free of rescue medication, and morning PEE, as well as almost halving the exacerbation rate, compared with AMD of FOR/BUD 6/200 microg. The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma.

Adult↗
PubMed2006

Pharmacologic characteristics and adrenal suppression with newer inhaled corticosteroids: A comparison of ciclesonide and fluticasone propionate.

BACKGROUND: Inhaled corticosteroids (ICSs) are the most potent anti-inflammatory choice for patients with asthma. Selecting the most appropriate ICS for a patient requires a thorough understanding of the pharmacologic properties of each drug. OBJECTIVE: This review details the pharmacologic properties of ciclesonide (CIC) and fluticasone propionate (FP) and reviews the available data on suppression of the hypothalamic-pituitary-adrenal axis as a measure of systemic exposure and safety profile. METHODS: Clinical studies and case reports were identified through a MEDLINE and EMBASE search of English-language articles. The databases were searched for the years 1990 to April 2005 using the terms ciclesonide, fluticasone, ICS, and adrenal suppression. All studies were clinical trials of pharmacologic properties of the ICSs in humans. RESULTS: A total of 1082 articles were identified. CIC and FP are 2 of the most potent ICSs. Both have high receptor-binding affinities (12 times and 18 times that of dexamethasone, respectively), and both may provide enhanced respiratory effects through a prolonged pulmonary residence time. The CIC metered dose inhaler dispenses smaller and more highly respirable particles than FP (1.1-2.1 pm vs 2.8-3.2 microm, respectively). Therefore, a greater percentage of administered CIC is topically deposited in the lungs (52% vs 12% to 13% for FP). CIC is delivered as an inactive parent compound, which is converted to its active metabolite, desisobutyryl-CIC (des-CIC), by esterases in the airways. More than 50% of a dose of CIC is deposited and distributed evenly throughout the lungs of healthy adults; lipid conjugation in the lung also may increase lung residence time. On entering the systemic circulation, both corticosteroids are rapidly cleared by the liver (elimination half-life of 3.5 hours for CIC vs 7.8 hours for FP). However, plasma protein binding is greater with CIC/des-CIC (99%/ approximately 99%) than FP (90%), resulting in reduced amounts of des-CIC ( 660 pg/d) may result in adrenal suppression. CIC has not been reported to produce any significant adrenal suppression throughout its studied dose range (up to 1280 micro/d). CONCLUSIONS: A review of the literature suggests that CIC, as compared with FP, achieves greater pulmonary deposition, causes fewer adverse oropharyngeal effects, deposits less biologically active drug in the systemic circulation, and has less potential for adrenal suppression.

Adrenal Cortex Hormones↗
PubMed2006

Synthesis and evaluation of ethylene glycol 3-diethylamino-propionate methacrylate as a polymerizable amine coinitiator for dental application.

OBJECTIVE: The primary objective of this study was to synthesize and characterize ethylene glycol 3-diethylamino-propionate methacrylate (EGDPM) as a polymerizable coinitiator to replace the commercial amine coinitiator. The 2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]-propane (Bis-GMA) and triethylene glycol dimethylacrylate (TEGDMA) resin mixture was polymerized by camphorquinone/EGDPM initiator system under visible light irradiation. The mechanical properties, water sorption and solubility of cured samples were also evaluated. METHODS: EGDPM was synthesized via Michael-Addition reaction and characterized using FTIR and 1H NMR spectroscopy. Photopolymerization kinetics of the dental resin mixtures were monitored by real-time IR (RTIR). The mechanical properties of cured samples were recorded by dynamic mechanical analyzer (DMA). And the water sorption and solubility of cured samples were detected according to ISO 4049. RESULTS: Both the double bond conversion and the rate of polymerization of the resin mixtures increased as increasing the concentration of EGDPM but were lower than that of ethyl-4-dimethylaminobenzoate (EDMAB) and 2-(dimethylamine)ethyl methacrylate (DMEM) as a coinitiator at some concentration. When it served as diluent, the final double bond conversion was comparable to that of EDMAB, and the rate of polymerization was higher than that of DMEM. The modulus and T(g) of the cured samples were very close. Water sorption and solubility of the samples were almost the same except that of EGDPM as diluent. CONCLUSIONS: EGDPM was synthesized by Michael-Addition reaction. It could be used as a potential coinitiator but not suitable as diluent for dental composite.

Aminobenzoates↗
PubMed2006

Edaravone protects the vestibular periphery from free radical-induced toxicity in response to perilymphatic application of (+/-)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid.

Intracochlear infusion of (+/-)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) was performed with a syringe pump in guinea pigs, and peripheral vestibular dysfunction was induced. Animals were administered edaravone systemically or topically. In the systemic application group, animals were administered edaravone once a day for 7 days after AMPA infusion. In the topical application group, edaravone-soaked gelfoam was placed on the round window membrane just after, 12 h after or 24 h after AMPA infusion. Spontaneous nystagmus was observed after AMPA infusion. Immunohistochemistry for 4-hydroxy-2-nonenal (4-HNE), a marker of free radical-induced lipid peroxidation, was performed 24 h after AMPA infusion. In addition, caloric tests were performed to evaluate vestibular function 1 week after AMPA infusion. Animals in both groups showed decreased spontaneous nystagmus, but results were not significant. Animals treated topically with edaravone within 12 h of AMPA infusion showed normal morphology of the ampullar sensory epithelia of the lateral semicircular canals and showed a good response to the caloric tests. 4-HNE immunoreactivity in the sensory epithelia was very low in these animals. In contrast, untreated animals and animals treated with edaravone systemically or topically 24 h after AMPA infusion showed morphologic hair cell damage, reduced caloric response and remarkable 4-HNE immunoreactivity in the sensory epithelia. These results indicate that topical application of edaravone within 12 h after damage protects the vestibular periphery from free radical-induced toxicity in response to intracochlear infusion of AMPA.

Aldehydes↗
PubMed2005

Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons.

The presence of cell surface Ca2+ permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels on subsets of central neurons influences both normal physiological function and vulnerability to excitotoxicity. Factors that regulate the formation and membrane insertion of Ca-A/K channels, however, are poorly understood. Recently, the cytokine tumor necrosis factor-alpha (TNF-alpha) was shown to increase the cell surface expression of an AMPA receptor (AMPAR) subunit (GluR1) and to potentiate vulnerability to AMPAR-mediated injury. In this study, we examined the possibility that TNF-alpha might also increase numbers of functional Ca-A/K channels. In acute hippocampal slice preparations, TNF-alpha appeared to increase Ca-A/K channel numbers in pyramidal neurons (HPNs), as assessed using a histochemical stain based on kainate-induced uptake of Co2+ ions (Co2+ labeling). In dissociated hippocampal neuronal cultures, TNF-alpha exposure (6 nM, 15 min) induced a rapid increase in cell surface levels not only of GluR1, but also of the AMPAR subunit GluR2, on most neurons, without evident new protein synthesis. Furthermore, consistent with the slice studies, fluorescence Ca2+ imaging techniques revealed an increase in numbers of Ca-A/K channels on what appeared to be a subset of HPNs. These observations are the first to provide evidence for the rapid upregulation of neuronal Ca-A/K channels in response to a cytokine or any other soluble factor, and provide a novel mechanism through which TNF-alpha may modulate both synaptic function and neuronal vulnerability.

Aniline Compounds↗
PubMed2006

Co-deposition of salmeterol and fluticasone propionate by a combination inhaler.

The combination of the long-acting beta2-agonist, salmeterol xinafoate (salmeterol) and inhaled corticosteroid, fluticasone propionate (FP) (Seretide/Advair) has shown enhanced efficacy compared with concurrent administration of the two drugs from individual inhalers at the same dose. A possible explanation for this increased effect is a higher degree of co-deposition of the two drugs from the combination (Seretide) inhaler compared with the component drugs administered separately. Raman laser spectroscopy, a technique capable of identifying individual drug particles, has been used with novel statistical methodology that we have developed, to determine whether there is any co-association between drug particles and whether this occurs in the Seretide formulation rather than by chance. Samples from a combined Seretide metered dose inhaler (MDI, 25/50 mcg) and salmeterol (25 mcg) with FP (50 mcg) from separate MDI's taken from Plate 4 of an Anderson Cascade Impactor were analysed. Using a statistical test based on the bootstrap technique, it was found that the co-deposition of FP and salmeterol particles from the combination MDI was significantly greater than from the separate inhalers group (p < 0.001). A higher degree of co-deposition on the same cells of the airways may possibly account for the increased efficacy observed in patients prescribed Seretide MDI.

Adrenergic beta-Agonists↗
PubMed2006

The effect of transforming growth factor (TGF)-beta1 and (TGF)-beta2 on nasal polyp fibroblast activities involved upper airway remodeling: modulation by fluticasone propionate.

Transforming growth factor (TGF)-beta may play a significant role in nasal polyposis pathogenesis, possibly through fibroblast activation. We studied the effects of two TGF-beta isoforms (TGF-beta1 and TGF-beta2) on nasal polyposis fibroblasts by evaluating cell proliferation and differentiation into myofibroblasts. In addition, the inhibitory activity of different concentrations of fluticasone propionate (F.P.) was tested in this in vitro system. Primary nasal polyp tissue-derived fibroblasts were stimulated with different concentrations (1, 10 and 20 ng/ml) of TGF-beta1 and TGF-beta2 for different incubation periods (24, 48 and 72 h) and cell proliferation [3H thymidine ([3H]TdR) incorporation] and alpha-smooth muscle actin (alpha-SMA) expression (immunocytochemistry) was evaluated. The lowest concentration of TGF-beta1 (1 ng/ml) induced a significant increase in [3H]TdR incorporation at 48 and 72 h (p<0.05, each comparison), while in the presence of TGF-beta (10 ng/ml) and TGF-beta2 (1 ng/ml) the enhancement in cell proliferation was significant only after 48 h (p<0.05, each comparison with the unstimulated cells). In contrast, a significant increase in alpha-SMA expression was observed in the presence of the two highest concentration of both TGF-beta isoforms, at 48 and 72 h for TGF-beta1 (p<0.05, each comparison), but only at 72 h for TGF-beta2 (<0.05, each comparison). Finally, at all concentrations tested, F.P. significantly inhibited the TGF-beta1 and TGF-beta2-induced 3HTdR incorporation (p<0.01, each comparison) and the alpha-SMA expression (p<0.05, each comparison). Thus, in vitro different concentrations of TGF-beta1 and TGF-beta2 appear to sequentially stimulate primary nasal polyp tissue-derived fibroblast proliferation and myofibroblast differentiation. These activities are effectively inhibited by F.P.

Actins↗
PubMed2006

Two randomized, double-blind, placebo-controlled studies of fluticasone propionate lotion 0.05% for the treatment of atopic dermatitis in subjects from 3 months of age.

A novel lotion formulation of fluticasone propionate 0.05% has recently become available. Two large, randomized, placebo-controlled, double-blind studies involving 438 subjects demonstrated its efficacy and safety when applied once daily in the treatment of atopic dermatitis in subjects from 3 months to 87 years of age. The studies were limited to 4 weeks duration of use of fluticasone lotion and did not assess longer term efficacy or side effects.

Administration, Topical↗
PubMed2004

Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies.

BACKGROUND: Improved adherence to inhaled corticosteroids (ICSs) has also been associated with decreased asthma-associated morbidity and mortality. OBJECTIVE: The purpose of this study was to assess patient medication refill persistence with fluticasone propionate (FP) and salmeterol combination in a single inhaler (FSC), FP and salmeterol in combination from 2 separate inhalers, FP and montelukast in combination, FP as monotherapy, and montelukast as monotherapy. METHODS: We performed a retrospective, observational, 24-month (12-month baseline and 12-month follow-up) database study using medical and pharmacy claims from a large managed care organization. We identified 2511 subjects 12 years of age or older with a claim for asthma (International Classification of Diseases, Ninth Revision: 493.XX): 563 patients receiving FSC, 224 receiving FP plus salmeterol, 75 receiving FP plus montelukast, 798 receiving FP only, and 776 receiving montelukast only. Refill rates of FP, as a measure of adherence, were compared for each FP-containing cohort during the 12-month follow-up period. In addition, refill rates were compared between FSC, an inhaler, and montelukast, an oral medication. RESULTS: Twelve-month baseline asthma medication use and patient demographics were comparable among cohorts. Patients in the FSC cohort obtained significantly more refills compared with the number of FP refills in the other FP-containing cohorts (4.06 for FSC vs 2.35 for FP plus salmeterol, 1.83 for FP plus montelukast, and 2.27 for FP alone) over the 12-month follow-up period. In addition, patients taking FSC had similar refill persistence compared with patients taking the oral leukotriene modifier montelukast (4.51). CONCLUSION: FSC might increase ICS refill persistence compared with FP alone in a single inhaler, FP in combination with salmeterol from 2 separate inhalers, and FP in combination with montelukast. In addition, FSC in a dry powdered inhaler had similar refill rates compared with an oral asthma agent, montelukast. Use of a single inhaler containing both an ICS (FP) and a long-acting bronchodilator (salmeterol) might increase the likelihood that patients are getting more optimal ICS therapy, as well as the benefits from the long-acting bronchodilator, with patient adherence comparable to an oral agent.

Acetates↗
PubMed2004

Fluticasone propionate increases CD4CD25 T regulatory cell suppression of allergen-stimulated CD4CD25 T cells by an IL-10-dependent mechanism.

BACKGROUND: Corticosteroids are the most effective anti-inflammatory therapy for allergic diseases, and these drugs inhibit TH2 T-cell activation. We previously reported that CD4+CD25+ T cells from atopic donors suppressed allergen-stimulated T cells less than those from nonatopic donors. OBJECTIVE: We sought to determine the effect of fluticasone propionate (FP) on allergen-stimulated CD4+CD25- T cells and on the suppressive ability of CD4+CD25+ T cells. METHODS: CD4+CD25+ and CD4+CD25- T cells were separated from peripheral blood of atopic and nonatopic volunteers and cultured alone or mixed in the presence of allergen. Effects of FP were assessed by means of addition to cultures or preincubation with CD4+CD25+ T cells. RESULTS: FP inhibited allergen-stimulated proliferation of CD4+CD25- T cells in a dose-dependent manner. Preincubation of CD4+CD25+ T cells in FP increased subsequent suppressive activity of these cells in allergen-stimulated cultures with CD4+CD25- T cells. This effect was seen when cells were obtained from both nonatopic and atopic donors but was less for cells obtained from atopic individuals. Prior exposure of CD4+CD25+ T cells to FP also increased subsequent IL-10 production by these cells when stimulated with allergen, and addition of anti-IL-10 antibody reversed the steroid-induced enhancement of suppression in mixed cultures. CONCLUSION: Increased suppression by CD4+CD25+ T cells might play a role in anti-inflammatory effects of corticosteroids in asthma and allergic diseases.

Albuterol↗
PubMed2004

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma.

BACKGROUND: In asthma T cells are characterized by an increased activation state and by reduced apoptosis. OBJECTIVE: Because the clinical efficacy of inhaled corticosteroids combined with long-acting beta 2 -agonists has been widely demonstrated in asthma, we studied, in vitro, the effect of fluticasone propionate (FP) and salmeterol alone and in combination on the activation and apoptosis of peripheral blood T cells (PBTs), on the expression of phosphorylated nuclear factor kappaB inhibitor (IkappaBalpha), and on the nuclear translocation of glucocorticoid receptor (GR) in PBTs from asthmatic subjects. METHODS: Apoptosis was evaluated on the basis of annexin V binding, whereas the expression of caspases 8 and 3 and phosphorylated IkappaBalpha, as well as the nuclear translocation of the GR, were evaluated by means of Western blot analysis. RESULTS: FP alone increases and salmeterol alone does not affect T-cell apoptosis. The combination of FP and salmeterol significantly increases PBT apoptosis in comparison with FP alone. FP at the lower concentration, when combined with salmeterol, is equivalent to FP at the higher concentration in inducing PBT apoptosis. The synergy in the induction of cell apoptosis is associated with more efficient activation of caspases 8 and 3. FP plus salmeterol is also able to synergistically reduce the expression of phosphorylated IkappaBalpha, thus limiting nuclear factor kappaB activation. The synergy was related to an increased nuclear translocation of the GR. CONCLUSION: This study shows that the combination of FP and salmeterol is able to control PBT activation in asthmatic patients more efficiently than FP alone and with a lower concentration of steroids.

Active Transport, Cell Nucleus↗
PubMed2005

Treatment of nasal polyposis and chronic rhinosinusitis with fluticasone propionate nasal drops reduces need for sinus surgery.

BACKGROUND: Steroid treatment is the mainstay of therapy for nasal polyps and rhinosinusitis. Oral steroids have considerable systemic side effects, and nasal sprays do not sufficiently reach the middle meatus, where polyps originate. Nasal drops might be a more useful formula to deliver steroids into the middle meatus. OBJECTIVE: We sought to investigate whether treatment with fluticasone propionate nasal drops (FPNDs) can reduce the need for surgery, as measured by signs and symptoms of nasal polyposis and chronic rhinosinusitis, in patients who are on the waiting list for functional endoscopic sinus surgery (FESS). METHODS: Fifty-four patients (28 male) with severe nasal polyposis, chronic rhinosinusitis, or both indicated for FESS were included in a 12-week, double-blind, placebo-controlled study. Use of intranasal steroid spray was stopped at least 4 weeks before randomization. Signs and symptoms were recorded before, during, and at the end of the study period. At the end of the study, a computed tomographic scan was performed, and the need for operation was reassessed by using a standardized scoring method. RESULTS: FESS was no longer required in 13 of 27 patients treated with FPNDs versus 6 of 27 in the placebo group (P < .05). Six patients from the placebo group dropped out versus 1 from the FPND group. Symptoms of nasal obstruction, rhinorrhea, postnasal drip, and loss of smell were reduced in the FPND group (P < .05). Peak nasal inspiratory flow scores increased significantly (P < .01). Polyp volume decreased in the FPND group (P < .05), and computed tomographic scores improved in both groups (P < .05). CONCLUSION: Treatment with FPNDs in patients indicated for FESS can reduce the need for surgery.

Administration, Intranasal↗
PubMed2005

Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features.

BACKGROUND: Several topical corticosteroids are available as anti-inflammatory treatment for asthma. Their comparative effects on allergic inflammation and airway remodeling are unclear. OBJECTIVE: We compared the effects of ciclesonide with those of fluticasone propionate in a Brown Norway rat model of chronic allergic asthma. METHODS: Rats sensitized and exposed to ovalbumin (OVA) were treated with dry powder vehicle, ciclesonide, or fluticasone (0.01, 0.03, and 0.1 mg/kg administered intratracheally) 24 hours and 1 hour before each of 6 OVA exposures. In a second protocol we administered 0.1 mg/kg ciclesonide or fluticasone only after the third OVA exposure. RESULTS: Ciclesonide at all doses inhibited the allergen-induced increase in airway eosinophils and T cells, reduced goblet cell hyperplasia, and decreased 5-bromo-2'-deoxyuridine-immunoreactive airway smooth muscle (ASM) and epithelial cells. At 0.03 and 0.1 mg/kg ciclesonide, bronchial hyperresponsiveness (BHR) was also inhibited. Fluticasone did not attenuate allergen-induced BHR, despite inhibiting airway eosinophils and T cells, goblet cell hyperplasia, and 5-bromo-2'-deoxyuridine-immunoreactive ASM and epithelial cells. Fluticasone (0.1 mg/kg) caused a significant reduction in body weight (9%) compared with ciclesonide (0.1 mg/kg). Ciclesonide did not change plasma corticosterone levels, whereas fluticasone (0.1 mg/kg) reduced them. In the second protocol both fluticasone and ciclesonide inhibited BHR, bronchial inflammation, goblet cell hyperplasia, and ASM proliferation. CONCLUSION: Ciclesonide potently inhibited chronic allergic inflammation, remodeling, and BHR without having an effect on body weight and the hypothalamic-pituitary-adrenal axis. Fluticasone prevented airway inflammation but not BHR, but both fluticasone and ciclesonide are effective at reversal of BHR, inflammation, and remodeling features.

Administration, Inhalation↗
PubMed2005

Fluticasone propionate plasma concentration and systemic effect: effect of delivery device and duration of administration.

BACKGROUND: Inhaled corticosteroids are the preferred therapy in persistent asthma. Dry powder inhalers (DPIs) generate a larger particle size compared with metered-dose inhalers (MDIs), which affects pulmonary deposition, bioavailability, and subsequent systemic effects of fluticasone propionate (fluticasone). OBJECTIVE: To examine the relationship of fluticasone pharmacokinetics and cortisol suppression for 2 fluticasone formulations (DPI and MDI) administered in adults over 1-week and 6-week treatment periods. METHODS: Two previous studies conducted in adults by the Asthma Clinical Research Network examined relative efficacy and systemic effect of fluticasone from MDI and DPI. Sample sets (n=33) were analyzed for fluticasone after administration of 352 microg from the MDI, and 400 microg from the DPI formulation, twice daily, after a 1-week treatment period. The second study's sample sets (n=9) were analyzed for fluticasone after 6 weeks therapy at 352 microg twice daily from the MDI formulation, allowing achievement of steady state. RESULTS: ANOVA revealed a significant trend of increasing fluticasone area under the curve from 0 to time t (AUC(0-->t)) when comparing DPI with MDI for 1 week with MDI for 6 weeks (P<.0001). Similarly, ANOVA revealed increasing cortisol suppression between these groups (P=.007). Linear regression demonstrated that increasing fluticasone AUC(0-->t) was significantly correlated with cortisol suppression (P<.0001; r(2)=0.41). MDI for 6 weeks showed increasing fluticasone AUC (P=.0008, t test) compared with MDI for 1 week, suggesting accumulation. CONCLUSION: Fluticasone plasma concentrations are significantly greater after MDI compared with DPI, and cortisol suppression is associated with fluticasone plasma concentrations. Accumulation of fluticasone concentrations suggests that time to steady state exceeds 1 week of treatment with MDI.

Administration, Inhalation↗
PubMed2006

Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate.

BACKGROUND: Inhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved. OBJECTIVE: We investigated whether or not bronchial responsiveness to leukotriene (LT) D(4) is reduced by fluticasone propionate in subjects with asthma. METHODS: In 13 subjects with mild asthma, inhalation challenges with methacholine and LTD(4) were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 mug, twice daily, in a double-blind, randomized, placebo-controlled study with crossover design and 3 weeks of washout between periods. Exhaled nitric oxide was measured as a marker of corticosteroid responsiveness, and baseline urinary LTE(4) concentrations as an index of cysteinyl-leukotriene biosynthesis. RESULTS: Fluticasone produced a significant decrease in methacholine responsiveness, corresponding to 2.6-fold shift in the PD(20) FEV(1), and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD(4) in the same subjects was unaffected by fluticasone, as were urinary LTE(4) concentrations. CONCLUSION: These new data indicate that neither the biosynthesis nor the actions of leukotrienes appear to be sensitive to inhaled corticosteroids. CLINICAL IMPLICATIONS: The study provides mechanistic support for the additive therapeutic efficacy of antileukotrienes and inhaled corticosteroids in asthma.

Administration, Inhalation↗