Eosinophilic esophagitis: treatment with oral viscous budesonide
Abstract
Eosinophilic esophagitis is a clinicopathologic disease isolated to the esophagus. It is caused by immunologic reactions to ingested and inhaled allergans. Symptoms include regurgitation, vomiting, pain, anorexia, and dysphagia. Endoscopy with biopsy is currently the only reliable diagnostic test for eosinophilic esophagitis. The disease should remit with treatments of dietary exclusion, topical corticosteroids, or both. Oral viscous budesonide is one of the promising options of topical corticosteroid to treat eosinophilic esophagitis. Since there are no commercial medicines of oral viscous budesonide, it is solely a compounded medication. This article briefly discusses the properties of the disease and covers a few compounding possibilities to oral viscous budesonide.
... At the end of the article, Casiraghi, A. et al. concluded that the best formulation of oral viscous budesonide was the one already being used in hospitals, based on xanthan gum. In their article, the authors did not emphasize that this specific formula was developed by the compounding pharmacist Eyal Zur from Israel, and was published eight years before [2]. The only difference in the formulas related to one of the two sweeteners that was used. ...
... The formula Casiraghi, A. et al. presented and concluded was the "best" was my formula, and there is no credit given to the formula, nor was there a discussion of the fact that it had been developed and published eight years prior to their publication [2]. ...
In their article, Casiraghi, A. et al. describe a few relevant methods to assess the quality of a pharmaceutical preparation of oral viscous budesonide, intended to be swallowed, and treat the esophagus in eosinophilic esophagitis patients. They choose the following methods for this purpose: rheological properties, syringeability, mucoadhesiveness, and in vitro penetration of budesonide in porcine esophageal tissue. At the end of the article, they concluded that the best formulation of oral viscous budesonide was the one already being used in hospitals, based on xanthan gum. In their article, the authors did not emphasize that this specific formula was developed by the compounding pharmacist Eyal Zur from Israel and was published eight years before, as part of an article in the International Journal of Pharmaceutical Compounding. The purpose of this comment is to give the appropriate credit to the pharmacist who first developed and published this well designed formulation.
... In this paper, the authors concluded that " . . . oral viscous budesonide slurries utilizing xanthan gum may be a superior alternative to a sucralose-based slurry due to its increased mucosal contact time and similar taste tolerance..." This paper does not cite Zur's article [2]. ...
... previous work of Hefner and al. showed that xanthan gum had a longer esophageal mucosal contact time than sucralose. This encouraged the development of a xanthan gum-based formulation..." These authors also proposed the same formulation without quoting Zur's article [2]. ...
The paper entitled “Mucoadhesive Budesonide Formulation for the Treatment of Eosinophilic Esophagitis Pharmaceutics 2020, 12, 211” discusses the physicochemical and technological characterization of a formulation to treat eosinophilic esophagitis [...]
... 2 EoE is a major cause of upper gastrointestinal morbidity in children and adults with an estimated prevalence of 56.7/100,000 persons in the U.S. 3 Despite this fact, there are currently no commercial medicines indicated in EoE, and, therefore, pharmaceutical compounding is the alternative choice to meet this therapeutic need. 4 Due to the nature of EoE, and the intended route of administration, it is beneficial that the compounded medicines dispensed include a mucoadhesive vehicle that adheres to the site of action and prolongs the therapeutic activity of budesonide. There is evidence that suggests oral viscous budesonide suspension or gel as a firstline pharmacologic therapy for the treatment of EoE. 4 According to the clinical guideline by the American College of Gastroenterology (ACG), the initial dosing of budesonide in EoE should be 1 mg/ day for children and 2 mg/day for adults. ...
... There is evidence that suggests oral viscous budesonide suspension or gel as a firstline pharmacologic therapy for the treatment of EoE. 4 According to the clinical guideline by the American College of Gastroenterology (ACG), the initial dosing of budesonide in EoE should be 1 mg/ day for children and 2 mg/day for adults. 5 In this study, two budesonide mucoadhesive oral suspensions (1 mg/10 mL and 2 mg/10 mL) were compounded and tested for the physical and chemical stability, at room temperature and re-Budesonide 1-mg/10-mL and 2-mg/10-mL mucoadhesive oral suspensions were prepared in accordance to the PCCA formula and compounding procedure #12228, as detailed in Table 1. ...
Budesonide is a corticosteroid that has been shown effective in the treatment of eosinophilic esophagitis, but there are currently no commercial medicines to treat this chronic allergic/immune condition, despite its prevalence in the U.S. Therefore, pharmaceutical compounding is the alternative choice to meet the therapeutic need of eosinophilic esophagitis patients. Two budesonide mucoadhesive oral suspensions (1 mg/10 mL and 2 mg/10 mL) were developed using the compounding vehicle MucoLox, a proprietary mucoadhesive polymer blend that promotes mucosal adhesion. The physical and chemical stability of the oral suspensions was tested over a period of 182 days, at room temperature and refrigerated conditions, in order to determine the corresponding beyond-use date. The physical characterization consisted in observing all samples for color/appearance and odor, and testing for pH and density, whereas the chemical characterization consisted in ultra-performance liquid chromatography assay testing. Both oral suspensions were proven physically and chemically stable, and the ultra-performance liquid chromatography method was proven stability indicating. As a result, the beyond-use date of the budesonide 1-mg/10-mL and 2-mg/10-mL mucoadhesive oral suspensions (MucoLox), in amber plastic bottles, is six months at both room temperature and refrigerated conditions.
... Frequently, they have been prepared by mixing a commercial sterile suspension of BU to be nebulized, which is indicated in the treatment of bronchial asthma and in infants and children with croup, with a thickening agent (e.g., sucralose) [19][20][21]. Alternatively, cellulose derivatives [22] or gums [23,24] have also been added. Hefner et al. [25] compared the technological performances of different types of thickening agents like sucralose, xanthan gum or honey, demonstrating that the gum permitted a better residence time of the active pharmaceutical ingredients (API) on the esophageal mucosa. ...
Eosinophilic esophagitis (EE) is a chronic immune/antigen-mediated esophageal inflammatory disease for which off-label topical corticosteroids (e.g., budesonide) are widely used in clinic. In general, thickening excipients are mixed with industrial products to improve the residence time of the drug on the esophageal mucosa. The compounding procedures are empirical and the composition is not supported by real physicochemical and technological characterization. The current study aimed to propose a standardized budesonide oral formulation intended to improve the resistance time of the drug on the esophageal mucosa for EE treatment. Different placebo and drug-loaded (0.025% w/w) formulations were prepared by changing the percentage of xanthan gum alone or in ratio 1:1 with guar gum. Both excipients were added in the composition for their mucoadhesive properties. The formulative space was rationalized based on the drug physicochemical stability and the main critical quality attributes of the formulation, e.g., rheological properties, syringeability, mucoadhesiveness and in vitro penetration of budesonide in porcine esophageal tissue. The obtained results demonstrated that gums allowed a prolonged residence time. However, the concentration of the mucoadhesive polymer has to be rationalized appropriately to permit the syringeability of the formulation and, therefore, easy dosing by the patient/caregiver.
... Due to the lack of specific dispenser, multi dose inhalers should be used, and patients have to be instructed to swallow, rather than inhale, the product [57] . A viscous compound of budesonide and sucralose, has also been tested, obtaining excellent results [58] . ...
Eosinophilic esophagitis (EoE) is a chronic immune disease, characterized by a dense eosinophilic infiltrate in the esophagus, leading to bolus impaction and reflux-like symptoms. Traditionally considered a pediatric disease, the number of adult patients with EoE is continuously increasing, with a relatively higher incidence in western countries. Dysphagia and food impaction represent the main symptoms complained by patients, but gastroesophageal reflux-like symptoms may also be present. Esophageal biopsies are mandatory for the diagnosis of EoE, though clinical manifestations and proton pump inhibitors responsiveness must be taken into consideration. The higher prevalence of EoE in patients suffering from atopic diseases suggests a common background with allergy, however both the etiology and pathophysiology are not completely understood. Elimination diets are considered the first-line therapy in children, but this approach appears less effective in adults patients, who often require steroids; despite medical treatments, EoE is complicated in some cases by esophageal stricture and stenosis, that require additional endoscopic treatments. This review summarizes the evidence on EoE pathophysiology and illustrates the safety and efficacy of the most recent medical and endoscopic treatments.
... As an example of aerosolized solutions, fluticasone or budesonide has been used to treat eosinophilic esophagitis (EoE) involving chronic inflammation of the esophageal surface. 53 It has been demonstrated that viscous topical is more effective than nebulized steroid therapy for patients with EoE. 54 An oral viscous slurry of budesonide 1 mg twice daily for 8 weeks was more effective than nebulized or swallowed therapy in reducing numbers of esophageal eosinophils. ...
The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role for ketamine and other alternative treatments in esophageal disorders; the use of linaclotide in the treatment of esophageal pain; the alginate test as a diagnostic criterion in gastroesophageal reflux disease (GERD); the use of baclofen in treatment of GERD; the effects of opioids on the esophagus; the use of antagonists on the receptor level in GERD; the effect of local formulation of drugs on the esophageal mucosa; and the use of electroencephalographic fingerprints to predict the effect of pharmacological treatment.
Eosinophilic esophagitis (EE) is a recent pathology defined by abnormal immune response of the esophageal mucosa to exogenous allergens, leading to chronic mucosa infiltration by 15 eosinophils per High-Power-Field (Eos/HPF). The present retrospective study was designed to assess the hospital care for children suffering from EE in several hospitals in western France in order to highlight discrepancies and improve future care. Twenty-eight children ranging from 1.5 months to 17 years old were included in the study. Episodes of food blockage were the most frequently reported symptoms (46 %). A ratio of 29 % of EE patients reported macroscopically normal endoscopy; diagnosis was then established upon histological anomalies found in biopsies. The mean eosinophil count was 72.4 Eos/HPF. Centralized immunohistochemical staining revealed the presence of IgG4-responding plasma cells in 76.5 % of patients, as well as IgG4 intraepithelial degranulation in 14 % of them. The evaluation of the treatment plan showed important inter-center discrepancies with only 43 % of patients receiving endoscopic reevaluation. This study objectively highlights heterogeneities in diagnosis and care provided to children suffering from EE. Therefore, improving the consistency of practices seems to be crucial to optimize the patients' outcome. The role of IgG4 as a new diagnosis marker remains to be clarified.
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Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.
Sucralose is a non-nutritive sweetener used in a broad range of foods and beverages and is the non-nutritive sweetener in retail SPLENDA® Sweetening Products, composed of sucralose and common food ingredients. A review of the extensive body of evidence that supports the safety of sucralose is provided. The results of an independent review of a new study investigating the safety of a sucralose-mixture retail product, Granulated SPLENDA® No Calorie Sweetener, are also discussed. The collective evidence supports the conclusion that the ingredient, sucralose, is safe for use in food and that the sucralose-mixture product, Granulated SPLENDA® No Calorie Sweetener, is also safe for its intended use.
Eosinophilic esophagitis (EE) is a clinicopathologic syndrome comprising isolated eosinophilic inflammation of the esophagus, with symptoms of dysphagia, and possibly, reflux. It was initially described in children, and in recent years, there is a heightened awareness in adults. The etiology is not completely understood. The treatments include dietary manipulation, topical corticosteroids, systemic corticosteroids, Montelukast, and endoscopic dilation. In adults, there are no randomized trials demonstrating the efficacy of any particular treatment, and no prospective studies describing the natural history of the disease following treatment.
We performed an interval follow-up of patients treated with a swallowed corticosteroid inhaler. We contacted 51 adult patients who were diagnosed with EE and treated with a swallowed corticosteroid inhaler between September 1, 1999, and May 31, 2003. All patients had received 6 wk of treatment with fluticasone 220 mEq/puff, four puffs swallowed twice daily for 6 wk.
Thirty-two patients replied (63%) with a mean follow-up duration of 3.3 yr. Ninety-one percent of patients reported recurrent symptoms; a mean of 8.8 months after treatment was completed. Sixty-nine percent of patients repeated treatment with the steroid inhaler at least once.
It appears that EE is a chronic remitting disorder that requires more than one topical steroid treatment course.
Although eosinophilic esophagitis has been increasingly diagnosed over recent years, little is known about this disease. In this study, symptoms, accompanying allergic disorders, and endoscopic findings in 117 patients with eosinophilic esophagitis were analyzed retrospectively.
The physicians who had treated the 117 patients (mean age 42.2 years; 9 children, 108 adults; male patients 71.8%) with the histological diagnosis of eosinophilic esophagitis were asked to provide data on symptoms, accompanying allergic disorders, and endoscopic findings.
In 82.2% of the patients symptoms appeared in adulthood, predominantly between the ages of 21 and 30 years. The average duration of symptoms until final diagnosis of eosinophilic esophagitis was 4.2 years (range 0-44 years). The most frequent symptom was dysphagia (70.1%), followed by heartburn (47%), chest pain (29%), epigastric pain (29%), and a combination of dysphagia and heartburn (29%). Allergic disorders were seen in 48.7% of our patients. The most frequent endoscopic findings were stipple-like exudates (25.6%), linear fissures (25.6%), and reddening (25.6%), followed by rings (18.8%) and strictures (16.2%) of the esophagus. The esophageal mucosa was regarded as "normal" in 24.8% of the patients.
Dysphagia in the second or third decade of life may suggest eosinophilic esophagitis. Symptoms of eosinophilic esophagitis may be indistinguishable from those of gastroesophageal reflux disease. The endoscopic appearance is not specific. Biopsies taken from multiple locations in the esophageal mucosa are essential for diagnosis of eosinophilic esophagitis.
The histologic appearance of esophageal eosinophils has been correlated with esophagitis and gastroesophageal reflux disease in children. Esophageal eosinophilia that persists despite traditional antireflux therapy may not represent treatment failure, but instead may portray early eosinophilic gastroenteritis or allergic esophagitis. In this study, a series of pediatric patients with severe esophageal eosinophilia who were unresponsive to aggressive antireflux therapy were examined and their clinical and histologic response to oral corticosteroid therapy assessed.
Of 1809 patients evaluated prospectively over 2.5 years for symptoms of gastroesophageal reflux, 20 had persistent symptoms and esophageal eosinophilia, despite aggressive therapy with omeprazole and cisapride. These patients were treated with 1.5 mg/kg oral methylprednisolone per day, divided into twice-daily doses for 4 weeks. All patients underwent clinical, laboratory, and histologic evaluation before and after treatment.
Histologic findings in examination of specimens obtained in pretreatment esophageal biopsies in children with primary eosinophilic esophagitis indicated significantly greater eosinophilia (34.2+/-9.6 eosinophils/high-power field [HPF]) compared with that in children with gastroesophageal reflux disease who responded to medical therapy (2.26+/-1.16 eosinophils/HPF; p < 0.001). After corticosteroid therapy, all but one patient with primary eosinophilic esophagitis had dramatic clinical improvement, supported by histologic examination (1.5 +/-0.9 eosinophils/HPF, p < 0.0001).
Pediatric patients in a series with marked esophageal eosinophilia and chronic symptoms of gastroesophageal reflux disease unresponsive to aggressive medical antire-flux therapy had both clinical and histologic improvement after oral corticosteroid therapy.
Eosinophilic esophagitis (EE) involves marked accumulation of eosinophils in the esophageal mucosa that responds to swallowed fluticasone propionate (FP) in a subset of patients.
We aimed to uncover the mechanism of action of swallowed FP in patients with EE by providing evidence for a topical effect in the esophagus by identifying a molecular signature for FP exposure in vivo.
Global microarray expression profiles, immunofluorescence microscopy, and cell signaling in esophageal tissue and cell lines were analyzed.
Thirty-two transcripts exhibited altered expression in patients who responded to swallowed FP treatment. Esophageal FK506-binding protein 5 (FKBP51) mRNA levels were increased (P < .05) in FP responders compared with those seen in control subjects and patients with untreated active EE. After FP treatment of esophageal epithelial cells, FKBP51 mRNA and protein levels were increased in a dose- and time-dependent manner by FP treatment in vitro. FP-induced FKBP51 was steroid receptor dependent because RU486 completely inhibited gene and protein induction. The half-life of FKBP51 mRNA was 16 to 18 hours independent of FP treatment. FKBP51 overexpression reduced FP action as assessed by FP inhibition of IL-13-induced eotaxin-3 promoter activity.
Our results suggest that swallowed glucocorticoid treatment directly affects esophageal gene expression in patients with EE. In particular, increased FKBP51 transcript levels identify glucocorticoid exposure in vivo and distinguish FP responders from untreated patients with active EE and patients without EE. In addition, FKBP51 reduces glucocorticoid-mediated inhibition of IL-13 signaling in epithelial cells in vitro, suggesting that FKBP51 might influence FP responsiveness. We propose that esophageal FKBP51 levels have diagnostic and prognostic significance in patients with EE.
Eosinophilic esophagitis (EoE) is characterized by eosinophilic infiltration of the esophagus. The purpose of this prospective study was to determine the prevalence and clinical predictors of EoE in patients undergoing elective upper endoscopy.
We enrolled 400 consecutive adults (median age, 50 years; range, 19-92 years) who underwent routine upper endoscopy from March to September 2007 at a tertiary care military hospital. All patients completed a symptom questionnaire. All endoscopic findings were noted. Eight biopsies were obtained from proximal and distal esophagus and were reviewed by a blinded gastrointestinal pathologist. Patients had EoE if > or =20 eosinophils/high-power field were present.
The prevalence of EoE in this cohort was 6.5% (25/385; 95% confidence interval, 4.3%-9.4%). Compared with EoE negative patients, EoE positive patients were more likely to be male (80.0% vs 48.1%, P = .003), younger than 50 years (72.0% vs 48.9%, P = .037), and have asthma (32.0% vs 10.8%, P = .006), a food impaction (32.0% vs 8.9%, P = .002), dysphagia (64.0% vs 38.1%, P = .018), and classic endoscopic findings (rings, furrows, plaques, or strictures) of EoE (all P < .01). Logistic regression identified asthma (odds ratio [OR], 4.48), male gender (OR, 4.23), and esophageal rings (OR, 13.1) as independent predictors of EoE. The presence of classic endoscopic findings of EoE had a sensitivity of 72% (54%-88%), specificity of 89% (87%-90%), and negative predictive value of 98% (95.6%-99.1%).
The prevalence of EoE in an outpatient population undergoing upper endoscopy was 6.5%. The characteristic findings of EoE patients included male gender, history of asthma, and the presence of classic findings of EoE on endoscopy, which is the strongest predictor of this disease process.