BACKGROUND AND PURPOSE:

Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side-effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile, and to determine whether such molecules would retain anti-inflammatory activity. EXPERIMENTAL APPROACH: The pharmacological properties of GW870086 were compared to fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling. KEY

RESULTS:

GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP, but antagonised the effect of dexamethasone on MMTV driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid regulated genes (such as COX-2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture, but unlike FP was unable to protect the culture from elastase mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation models, GW870086 showed comparable anti-inflammatory efficacy to FP.

CONCLUSIONS

AND

IMPLICATIONS:

GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

Patients with clinical symptoms of esophageal dysfunction and dense eosinophilic infiltration of the esophageal mucosa are suspected to have eosinophilic esophagitis (EoE). Topical steroids are often used as first-line therapy for EoE, although some patients respond clinically to proton pump inhibitors (PPIs). The purpose of this study was to compare the histological and clinical response of patients with esophageal eosinophilia treated with aerosolized swallowed fluticasone propionate vs. esomeprazole.This prospective single-blinded randomized controlled trial enrolled newly diagnosed patients with suspected EoE, defined as having clinical symptoms related to esophageal dysfunction with at least 15 eosinophils/high power field (hpf). Patients underwent 24-h pH/impedance monitoring to establish gastroesophageal reflux disease (GERD). Patients were stratified by the presence of GERD and randomized to receive fluticasone 440 mcg twice daily or esomeprazole 40 mg once daily for 8 weeks followed by repeat endoscopy with biopsies. The primary outcome was histological response of esophageal eosinophilia, defined as <7 eosinophils/hpf. Secondary outcomes included clinical change in symptoms using the validated Mayo dysphagia questionnaire (MDQ) and interval change in endoscopic findings following treatment.Forty-two patients (90% male, 81% white, mean age 38 ± 10 years) were randomized into fluticasone (n = 21) and esomeprazole (n = 21) treatment arms. In all, 19% (8/42) of patients had coexisting GERD and were equally stratified into each arm (n = 4). Overall, there was no significant difference in resolution of esophageal eosinophilia between fluticasone and esomeprazole (19 vs. 33%, P = 0.484). In patients with established GERD, resolution of esophageal eosinophilia was noted in 0% (0/4) of the fluticasone group compared with 100% (4/4) of the esomeprazole group (P = 0.029). In GERD-negative patients, there was no significant difference in resolution of esophageal eosinophilia between treatment arms with fluticasone and esomeprazole (24 vs.18%, P = 1.00). The MDQ score significantly decreased after treatment with esomeprazole (19 ± 21 vs. 1.4 ± 4.5, P<0.001), but not with fluticasone (17 ± 18 vs. 12 ± 16, P = 0.162). Improvement in endoscopic findings and other histological markers were similar between treatment groups.Fluticasone and esomeprazole provide a similar histological response for esophageal eosinophilia. With regard to clinical response, esomeprazole was superior to fluticasone, particularly in patients with established GERD.

Diagnosis of eosinophilic esophagitis (EoE) and determination of response to therapy is based on histological assessment of the esophagus, which requires upper endoscopy. In children, in whom a dietary approach is commonly used, multiple endoscopies are needed, because foods are eliminated and then gradually reintroduced. Ideally, noninvasive methods could supplement or replace upper endoscopy to facilitate management. Fractionated exhaled nitric oxide (FeNO) has been proposed as a useful measure for monitoring disease activity in studies of patients with eosinophil-predominant asthma and in other atopic disorders. Thus, we evaluated whether FeNO levels could be a useful biomarker to assess the response to therapy in EoE patients. This study was designed to determine whether there is a change in FeNO levels during treatment with topical corticosteroids and whether changes correlated with clinical response. This was a prospective, multicenter study that enrolled nonasthmatic patients with established EoE. FeNO levels and symptom scores were measured at baseline, biweekly during 6-week swallowed fluticasone treatment, and 4 weeks posttreatment. Twelve patients completed the trial. We found a statistically significant difference between median pre- and posttreatment FeNO levels [20.3 ppb (16.0-29.0 ppb) vs 17.6 ppb (11.7-27.3 ppb), p=0.009]. However, neither the pretreatment FeNO level, a change of FeNO level after 2 weeks of treatment, nor the FeNO level at the end of treatment confidently predicted a clinical or histological response. Although our findings suggest nitric oxide possibly has a physiological role in EoE, our observations do not support a role of FeNo determination for management of EoE.

An Afro-Caribbean girl showed localized hair depigmentation during treatment with inhaled fluticasone propionate. Although skin depigmentation is common after topical use of corticosteroids, hair depigmentation has never been reported with inhaled corticosteroids. The mechanisms underlying corticosteroid-induced skin depigmentation are not completely understood, but accepted hypotheses suggest a direct cytotoxic effect, changes in ground substance, vasoconstriction, mechanical effects of edema, or a dysregulation of melanogenesis.

Topical corticosteroids used in various dermatological diseases are available in different potencies and different formulations. The reservoir effect of different potency corticosteroids in the stratum corneum will help the clinicians to choose an appropriate topical steroid to maximize their efficacy and safety as therapeutic agents.This study was designed to compare the duration of reservoir of different potency topical corticosteroids experimentally in rabbits using histamine-induced wheal suppression test.The study was carried out in albino rabbits (as their skin is similar to humans) using four different concentrations of topical steroids, namely mometasone furoate ointment (0.1%), fluticasone propionate ointment (0.005%), betamethasone valerate cream (0.1%), and hydrocortisone butyrate cream (0.1%). These were applied on the back of rabbit on one side and the vehicle was applied on the other. One hour later, histamine-induced wheal suppression test was performed on both sides and wheal area was measured at 10 min for 7 days. Statistical analysis was done by ANOVA followed by post hoc test.Maximum wheal suppression was seen on day 1 (P<0.001) in all four groups, both at test and at control sites. Interday comparison of mean wheal size by topical steroids showed that the reservoir of mometasone furoate ointment (0.1%) persisted till day 4 in the stratum corneum of the skin. In case of fluticasone propionate ointment (0.005%) and betamethasone valerate cream (0.1%), the reservoir persisted till day 2 and for hydrocortisone butyrate cream (0.1%), the reservoir was present only on day 1.It is concluded that the duration of reservoir depends on the potency of topical steroids. Higher the potency more is the duration of reservoir in stratum corneum and vice versa.

Although Interleukin (IL)-17A has been suggested to play a role in corticosteroid hyporesponsiveness, whether IL-17A is able to affect the sensitivity of MUC5AC to intranasal corticosteroid treatment in patients with allergic rhinitis (AR) is unclear.Twenty patients with moderate to severe AR were enrolled in this study and the expression of MUC5AC, IL-17A, and glucocorticoid receptor beta (GR beta) was detected using immunochemical staining and quantitative reverse transcription polymerase chain reaction (RT-PCR) before and after treatment with fluticasone propionate (FP) nasal spray for 4 weeks, respectively. In addition, the effects of FP on IL-13- and IL-17A-induced MUC5AC and GR beta were also evaluated in the primarily cultured human nasal epithelial cells (HNECs) in vitro.The increased MUC5AC expression was associated with IL-17A levels in AR, and IL-17A was found to affect the inhibition of MUC5AC by corticosteroid treatment. Both IL-13 and IL-17A significantly promoted MUC5AC mRNA expression in HNECs, and FP treatment was able to significantly inhibit MUC5AC mRNA expression in HNECs induced by IL-13 but not for that induced by IL-17A. Also, IL-17A but not IL-13 promoted GR beta mRNA expression in HNECs, which was not affected by administration of corticosteroid.Our results suggest that the sensitivity of MUC5AC to topical corticosteroid is negatively associated with IL-17A in AR patients. This might help us to gain more insight into the pathophysiology and the pharmacotherapeutic mechanisms on AR treatment.

Eosinophilic esophagitis (EoE) is a chronic esophageal disease increasingly recognized in adults for its gastrointestinal manifestations. This paper discusses a young woman with EoE who presented with persistent hiccups and intermittent dyspepsia. The patient was initially treated with trials of both H(2) blocker and proton pump inhibitor. However, her hiccups resolved only after treatment with topical fluticasone. A repeat upper endoscopy while on steroid treatment demonstrated both histologic remission of EoE and resolution of esophageal trachealization. Our patient's clinical course supports an association between hiccups and EoE, suggesting that EoE be considered in the differential diagnosis of patients with refractory hiccups.

Fluticasone propionate (FP) is an anti-inflammatory agent with topical and inhaled applications commonly used in the treatment of asthma in steroid-dependent individuals. The drug is used in racehorses to treat Inflammatory Airway Disease; this work was performed in order to advise on its use and detect potential misuse close to racing. Methods were developed for the extraction and analysis of FP from horse plasma and a carboxylic acid metabolite (FP-17βCOOH) from horse urine. The methods utilize ultra high performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) in order to detect the extremely low concentrations of analyte present in both matrices. The developed methods were used to analyse plasma and urine samples collected following inhaled administration of FP to six thoroughbred horses. FP was detected in plasma for a minimum of 72 h post-administration and FP-17βCOOH was detected in urine for approximately 18 h post-administration. The results show that it is possible to detect FP in the horse following inhaled administration. Copyright © 2012 John Wiley & Sons, Ltd.

Eosinophilic oesophagitis is a clinicopathological disease characterized by oesophageal eosinophilia and gastrointestinal symptoms. Currently, the optimal treatment regimens remain unclear. The pathogenesis of eosinophilic oesophagitis appears to involve immune dysregulation, while acid reflux may have a secondary role; the mainstays in treatment are aimed principally at these dual processes. While a trial of a PPI is worthwhile it is likely that PPI therapy is treating concurrent acid reflux rather than true eosinophilic oesophagitis. Dietary elimination with elemental feed is safe but poorly tolerated. Swallowed topical steroids are the mainstay of commercially available therapies. Both fluticasone and budesonide have been proven to be beneficial both symptomatically and in reducing oesophageal eosinophil counts in the short and medium term. Basic studies have determined a role for IL-5 in oesophageal remodelling in eosinophilic esophagitis. Initial clinical studies have shown single or multiple infusions of monoclonal antibody to IL-5 to be well tolerated and to cause a long-term decrease in both peripheral and sputum eosinophil count in these eosinophil driven conditions. At present, swallowed corticosteroids are the mainstay of treatment for patients with eosinophilic oesophagitis in patients failing PPI therapy. Studies have been heterogenous in their diagnostic criteria for eosinophilic oesophagitis and in the definition of response to therapy, making comparison of results difficult.