Budesonide orodispersible tablets maintain remission in a randomized, placebo-controlled trial of patients with eosinophilic esophagitis

Background & Aims: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder. Swallowed topical-acting corticosteroids are effective in bringing active EoE into remission. However, it is not clear whether these drugs are effective for long-term maintenance of remission. Methods: We performed a double-blind trial to compare the efficacy and safety of 2 dosages of a budesonide orodispersible tablet (BOT) vs placebo in maintaining remission of EoE. Maintenance of remission was defined as absence of clinical and histologic relapse and no premature withdrawal for any reason. Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given BOT 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks. Results: At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo). Median time to relapse in the placebo group was 87 days. The frequency of adverse events was similar in the BOT and placebo groups. Morning serum levels of cortisol were in the normal range at baseline and did not significantly change during treatment. Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment. Conclusions: In a phase 3 trial, up to 48 weeks of treatment with BOT (0.5 mg or 1.0 mg twice daily) was superior to placebo in maintaining remission of EoE. Both dosages were equally effective and well tolerated. EudraCT number; 2014-001485-99; ClinicalTrials.gov number, NCT02434029

Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029

Effect of Omega-3 Fatty Acid Supplementation on Oxylipins in a Routine Clinical Setting

Omega-6 polyunsaturated fatty acid (n-6 PUFA) is the predominant polyunsaturated fatty acid (PUFA), especially in Western diet. A high omega-6/omega-3 ratio in Western diets is implicated in the development of cardiovascular diseases and inflammatory processes. Studies in animal models and in humans have demonstrated beneficial effects of omega-3 PUFA (n-3 PUFA) in a variety of diseases, including cardiac arrhythmias and inflammatory diseases, as well as breast and colon cancer. The molecular mechanisms underlying the effects of n-3 PUFA are still not well understood. Possible mechanisms include competition between n-3 and n-6 PUFAs at the cyclooxygenase (COX) and lipoxygenase (LOX) and cytochrome P450 levels, and subsequent formation of oxylipins with specific anti-inflammatory or anti-arrhythmic effects. In this study, we report the impact of routine long-term treatment with prescription-grade n-3 PUFA (either 840 mg or 1680 mg per day) on blood cell membrane fatty acid composition, as well as plasma oxylipin patterns, in a patient population with severe hyperlipidemia and cardiovascular disease who are on standard lipid-lowering and cardioprotective medications. Lipidomics analyses were performed by LC/ESI-MS/MS. Supplementation led to a dose-dependent increase in n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the blood cell fraction. We also observed a dose-dependent increase in EPA- and DHA-derived epoxy metabolites, whereas the effect of n-3 PUFA supplementation on LOX-dependent EPA- and DHA-derived hydroxy metabolites was less pronounced, with a tendency towards lower metabolites in subjects with higher n-3 PUFA levels. These data thus generally confirm effects of n-3 PUFA supplementation observed previously in healthy individuals. Additionally, they indicate a suppressive effect of high n-3 PUFA supplementation on the formation of LOX metabolites in the context of concomitant aspirin medication

Influence of omega-3 fatty acids on cytokine production in D-galactosamine/lipopolysaccharide induced acute hepatitis in mice

Akute Leberentzündungen, egal ob viraler, toxischer oder autoimmuner Genese, sind durch eine Aktivierung von Entzündungszellen, wie Monozyten und T- Zellen charakterisiert. Die starke Freisetzung pro-inflammatorischer Mediatoren dieser Zellen führen zu einer Schädigung des Lebergewebes. Eine Schlüsselrolle spielen in diesem Zusammenhang Zytokine wie TNF-alpha und IL-1. Bisher konnte nachgewiesen werden, dass eine erhöhte Zufuhr von Omega-3-Fettsäuren die Entzündungszeichen bei einer Vielzahl chronischer Erkrankungen lindern kann (wie z.B. Koronare Herzkrankheit, rheumatoide Arthritis oder chronisch entzündliche Darmerkrankungen). In weiterführenden Untersuchungen wurde gezeigt, wie Omega-3-Fettsäuren die Produktion der pro-inflammatorischen Zytokine TNF-alpha und IL-1beta in mononuklearen Zellen reduzieren können. In der vorliegenden Studie wurde der Einfluss von Omega-3-Fettsäuren auf die akute D-Galaktosamin/Lipopolysaccharid induzierte akute Hepatitis analysiert. In diesem etablierten Hepatitis-Modell wird die Leberentzündung durch aktivierte monozytäre Zellen der Leber (Kupffer Zellen) und der daraus resultierenden Produktion großer Mengen an Zytokinen hervorgerufen. Um den Einfluss einer erhöhten Konzentration von Omega-3-Fettsäuren im Lebergewebe untersuchen zu können, wurde in dieser Studie das Fat-1-Maus-Modell genutzt. Diese transgenen Mäuse tragen das Fat-1-Gen des Rundwurmes C. elegans. Dadurch ist es Fat-1-Mäusen möglich, eine Desaturase zu exprimieren, mit deren Hilfe sie Omega-6- in Omega-3-Fettsäuren endogen umwandeln können. In der vorliegenden Arbeit konnte gezeigt werden, dass Fat-1-Mäuse mit einem ausgeglichenen AA/EPA-Verhältnis in der Phänotypisierung am Außenohr und erhöhtem n-3-Anteil in der Leber signifikant geringere Leberschäden aufwiesen als Tiere vom Wildtyp. Diese Veränderungen konnten durch eine reduzierte Alaninaminotransferaseaktivität im Serum sowie geringere histopathologische Veränderungen in der Leber nachgewiesen werden. Das beobachtete verminderte Entzündungsgeschehen in der Leber von Fat-1-Mäusen wurde durch signifikant reduzierte Konzentrationen von TNF-alpha im Plasma begleitet. Weitere Messungen mittels Echtzeit RT-PCR zeigten, dass im Lebergewebe der transgenen Fat-1-Tiere die mRNA-Konzentrationen der pro-inflammatorischen Zytokine TNF- alpha, IL-1beta, IL-6 und IFN-gamma deutlich niedriger waren als in den Vergleichstieren vom Wildtyp. Untersuchungen an DAPI-gefärbten Leberschnitten konnten zeigen, dass diese Unterschiede mit deutlich verminderten hepatozellulären Apoptosen in Fat-1-Tieren einhergingen. Die beschriebenen Veränderungen scheinen nur auf den erhöhten Gehalt an Omega-3-Fettsäuren in Tieren der Fat-1-Gruppe zurückzuführen zu sein, da die Konzentrationen der wichtigsten Omega-6-Fettsäure, Arachidonsäure, in beiden Versuchsgruppen ähnlich waren. Die Ergebnisse der vorliegenden Arbeit liefern die ersten Hinweise für anti-inflammatorische Wirkungen von Omega-3-Fettsäuren auf die zytokinabhängigen Signalwege bei der D-GaIN/LPS-induzierten akuten Leberentzündung. Diese Beobachtungen könnten wichtige Hinweise für neue Therapien humaner akuter oder chronischer Hepatitiden liefern.Cytokines such as tumor necrosis factor alpha (TNF-alpha) are key factors in liver inflammation. Supplementation with essential omega-3 polyunsaturated fatty acids (n-3 PUFA) has been demonstrated to lower TNF-alpha and interleukin-1 production in mononuclear cells. Furthermore, an inflammation dampening effect has been observed with increased omega-3 fatty acid suplementation in several inflammatory diseases. In this study we used the transgenic fat-1 mouse, expressing a C. elegans desaturase endogenously forming n-3 PUFA from n-6 PUFA, to analyse the effect of an increased n-3 PUFA tissue status in the macrophage-dependent acute D-GalN/LPS hepatitis model. We show that fat-1 mice were protected from inflammatatory liver injury as evidenced by reduced serum alanine aminotransaminase levels and less severe histological liver damage. This decreased inflammatory response was associated with decreased plasma TNF-alpha levels and with reduced hepatic gene expression of TNF-alpha, IL-1beta, IFN-gamma and IL-6 in fat-1 mice. Notably, protection from inflammation was only dependent on the increased level of n-3 PUFA, as levels of the n-6 arachidonic acid (AA, C20:4 n-6) were similar in fat-1 and wild type animals

Essential Polyunsaturated Fatty Acids in Blood from Patients with and without Catheter-Proven Coronary Artery Disease

Coronary artery disease (CAD) is the leading cause of death worldwide. Statins reduce morbidity and mortality of CAD. Intake of n-3 polyunsaturated fatty acid (n-3 PUFAs), particularly eicosapentaenoic acid (EPA), is associated with reduced morbidity and mortality in patients with CAD. Previous data indicate that a higher conversion of precursor fatty acids (FAs) to arachidonic acid (AA) is associated with increased CAD prevalence. Our study explored the FA composition in blood to assess n-3 PUFA levels from patients with and without CAD. We analyzed blood samples from 273 patients undergoing cardiac catheterization. Patients were stratified according to clinically relevant CAD (n = 192) and those without (n = 81). FA analysis in full blood was performed by gas chromatography. Indicating increased formation of AA from precursors, the ratio of dihomo-gamma-linolenic acid (DGLA) to AA, the delta-5 desaturase index (D5D index) was higher in CAD patients. CAD patients had significantly lower levels of omega-6 polyunsaturated FAs (n-6 PUFA) and n-3 PUFA, particularly EPA, in the blood. Thus, our study supports a role of increased EPA levels for cardioprotection

Effect of Omega-3 Fatty Acid Supplementation on Oxylipins in a Routine Clinical Setting

Omega-6 polyunsaturated fatty acid (n-6 PUFA) is the predominant polyunsaturated fatty acid (PUFA), especially in Western diet. A high omega-6/omega-3 ratio in Western diets is implicated in the development of cardiovascular diseases and inflammatory processes. Studies in animal models and in humans have demonstrated beneficial effects of omega-3 PUFA (n-3 PUFA) in a variety of diseases, including cardiac arrhythmias and inflammatory diseases, as well as breast and colon cancer. The molecular mechanisms underlying the effects of n-3 PUFA are still not well understood. Possible mechanisms include competition between n-3 and n-6 PUFAs at the cyclooxygenase (COX) and lipoxygenase (LOX) and cytochrome P450 levels, and subsequent formation of oxylipins with specific anti-inflammatory or anti-arrhythmic effects. In this study, we report the impact of routine long-term treatment with prescription-grade n-3 PUFA (either 840 mg or 1680 mg per day) on blood cell membrane fatty acid composition, as well as plasma oxylipin patterns, in a patient population with severe hyperlipidemia and cardiovascular disease who are on standard lipid-lowering and cardioprotective medications. Lipidomics analyses were performed by LC/ESI-MS/MS. Supplementation led to a dose-dependent increase in n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the blood cell fraction. We also observed a dose-dependent increase in EPA- and DHA-derived epoxy metabolites, whereas the effect of n-3 PUFA supplementation on LOX-dependent EPA- and DHA-derived hydroxy metabolites was less pronounced, with a tendency towards lower metabolites in subjects with higher n-3 PUFA levels. These data thus generally confirm effects of n-3 PUFA supplementation observed previously in healthy individuals. Additionally, they indicate a suppressive effect of high n-3 PUFA supplementation on the formation of LOX metabolites in the context of concomitant aspirin medication

Activation of Lipid Mediator Formation Due to Lipoprotein Apheresis

Lipoprotein apheresis reliably reduces low-density lipoprotein (LDL) cholesterol in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). Besides lowering lipoproteins and triglycerides, apheresis also decreases levels of essential omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) in blood plasma. In contrast, heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) lipid apheresis might increase the formation of potentially pro-inflammatory and pro-thrombotic lipid mediators derived from n-6 and n-3 PUFAs. The study presented here analyzed lipid mediator profiles in the plasma of patients with hyperlipidemia treated by one of three different apheresis methods, either HELP, direct absorption (DA), or membrane filtration (MDF), in a direct pre- and post-apheresis comparison. Using gas chromatography and liquid chromatography tandem mass spectrometry (LC-MS/MS) we were able to analyze fatty acid composition and the formation of lipid mediators called oxylipins. Our data illustrate&#8212;particularly in HELP-treated patients&#8212;significant decreases of essential omega-6 and omega-3 polyunsaturated fatty acids in blood plasma but significant increases of PUFA-derived lipoxygenase-, as well as cyclooxygenase- and cytochrome P450-derived lipid mediators. Given that n-3 PUFAs in particular are presumed to be cardioprotective and n-3 PUFA-derived lipid mediators might limit inflammatory reactions, these data indicate that n-3 PUFA supplementation in the context of lipid apheresis treatment might have additional benefits through apheresis-triggered protective n-3 PUFA-derived lipid mediators