Anti-inflammatory effects of budesonide in intestinal epithelial cells (original) (raw)
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The glucocorticoid budesonide has protective and deleterious effects in experimental colitis in mice
Biochemical Pharmacology, 2016
Glucocorticoids are widely used for the management of inflammatory bowel disease, albeit with known limitations for long-term use and relevant adverse effects. In turn, they have harmful effects in experimental colitis. We aimed to explore the mechanism and possible implications of this phenomenon. Regular and microbiota depleted C57BL/6 mice were exposed to dextran sulfate sodium (DSS) to induce colitis and treated with budesonide. Colonic inflammation and animal status were compared. In vitro epithelial models of wound healing were used to confirm the effects of glucocorticoids. Budesonide was also tested in lymphocyte transfer colitis. Budesonide (1-60 lg/day) exerted substantial colonic antiinflammatory effects in DSS colitis. At the same time, it aggravated body weight loss, increased rectal bleeding, and induced general deterioration of animal status, bacterial translocation and endotoxemia. As a result, there was an associated increase in parameters of sepsis, such as plasma NO x , IL-1b, IL-6, lung myeloperoxidase and iNOS, as well as significant hypothermia. Budesonide also enhanced DSS induced colonic damage in microbiota depleted mice. These effects were correlated with antiproliferative effects at the epithelial level, which are expected to impair wound healing. In contrast, budesonide had significant but greatly diminished deleterious effects in noncolitic mice or in mice with lymphocyte transfer colitis. We conclude that budesonide weakens mucosal barrier function by interfering with epithelial dynamics and dampening the immune response in the context of significant mucosal injury, causing sepsis. This may be a contributing factor, at least in part, limiting clinical usefulness of corticoids in inflammatory bowel disease.
Effects of budesonide on P-glycoprotein expression in intestinal cell lines
British Journal of Pharmacology, 2007
Background and purpose: P-glycoprotein (P-gp) is an important efflux transporter that supports the barrier function of the gut against invading antigens and against administered drugs. Since glucocorticoids, such as budesonide, are frequently used during inflammatory bowel disease we investigated how budesonide influences P-gp expression in different intestinal cell lines. Experimental approach: LS180 and Caco-2 cells were incubated with budesonide and changes in P-gp expression were determined on mRNA, protein and functional level. The mRNA expression levels of glucocorticoid receptor (GR) and pregnane X receptor (PXR) were determined in these cell lines. PXR receptor was transiently transfected into Caco-2 cells. Key results: Budesonide showed an induction of P-gp in LS180 cells and a down-regulation in Caco-2 cells. Expression levels of nuclear receptors revealed high expression of PXR only in LS180 cells and exclusive expression of GR in Caco-2 cells. Mifepristone, an anti-glucocorticoid, could not reverse the down-regulation of P-gp by budesonide in Caco-2 cells. In PXRtransfected Caco-2 cells the budesonide-mediated down-regulation of P-gp was abolished. Furthermore the expression of cytochrome P450 3A4 (CYP3A4), another PXR target gene, was induced in PXR-transfected Caco-2 cells after budesonide treatment. Conclusions and Implications: Budesonide has the potential to influence MDR1 expression in vitro. In LS180 cells, the induction of MDR1 by budesonide probably is mediated via PXR. The mechanism of the down-regulation in Caco-2 cells still remains unclear, but GR does not seem to be involved. Further studies are required to evaluate how budesonide alters P-gp expression in vivo.
Budesonide for ulcerative colitis
Falk Symposium
In this review, we examined studies published on oral and topical formulations of budesonide (Entocort ® and Budenofalk ® , in Spain: Entocord ® and Intestifalk ®) for the treatment of ulcerative colitis. This glycocorticosteroid has a potent local action and an important first-pass liver metabolism. It has proven successful over the last years as a controlled-release formulation. It obtained results similar to prednisolone, without the latter's significant suppression of plasma cortisol. Many publications exist on the effects of oral budesonide for the treatment of Crohn's disease (CD). These have led to the registration of this drug for the treatment of CD. Studies on oral formulations of budesonide for the treatment of ulcerative colitis (UC) are scarce. After reviewing published evidence, we suggest the conduction of controlled trials for the treatment of UC to obtain evidence-based efficacy and safety results in order to benefit patients with this form of inflammatory bowel disease (IBD).
Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis
Clinical and Experimental Gastroenterology, 2014
Ulcerative colitis (UC) is a chronic, relapsing, and remitting inflammatory disease involving the large intestine (colon). Treatment seeks to break recurrent inflammation episodes by inducing and maintaining remission. Historically, oral systemic corticosteroids played an important role in inducing remission of this chronic disease; however, their long-term use is limited and can lead to adverse events. Budesonide is a synthetic steroid with potent local antiinflammatory effects and low systemic bioavailability due to high first-pass hepatic metabolism. Several studies have demonstrated oral budesonide's usefulness in treating active mild to moderate ileocecal Crohn's disease and microscopic colitis and in an enema formulation for left sided UC. However, there is limited information regarding oral budesonide's efficacy in UC. A novel oral budesonide formulation using a multimatrix system (budesonide-MMX) to extend drug release throughout the colon has been developed recently and seems to be an effective treatment in active left sided UC patients. This article summarizes budesonide's long-term safety and efficacy in treating UC.
British Journal of Pharmacology, 1999
The combination of interleukin-2 (IL-2) and IL-4 reduces the inhibitory eects of glucocorticoids on granulocyte-macrophage colony-stimulating factor (GM-CSF) production, in agreement with the hypothesis that this combination causes glucocorticoid resistance. Whether a general cytokine resistance to glucocorticoids is induced by IL-2 and IL-4 has not been reported. 2 Mononuclear blood cells from healthy individuals were pre-treated with IL-2, IL-4, or IL-2+ IL-4 (31.3 ± 500 U ml 71) for 48 h, prior to lipopolysaccharide (LPS; 10 ng ml 71 ; 20 h) and budesonide addition. Cytokine levels in the supernatants were analysed using speci®c immunoassays. DNA content was analysed to estimate cell numbers. 3 GM-CSF production was totally inhibited by budesonide at 10 78 M in vehicle treated cultures, while IL-10 was inhibited to 33.4+4.3% of control. IL-2, IL-4, or IL-2+IL-4 reduced the inhibitory eects of budesonide on GM-CSF to similar levels (23.7+6.7, 31.6+8.5 and 35.1+4.3% of control, respectively). IL-2, IL-4, or IL-2+IL-4 also reduced the inhibitory eects of budesonide on IL-10 production (46.5+6.6, 55.9+7.3%, and 68.3+9.9% of control, respectively). In contrast, IL-8, IL-12 and TNF-a production did not become resistant to budesonide. 4 Thus, glucocorticoid resistance induced by IL-2 and IL-4 is not general at the cytokine production level. While the glucocorticoid sensitivity of GM-CSF and IL-10 production decreased, the sensitivity of IL-8, IL-12 or TNF-a production was unchanged. Also, the mixture of IL-2 and IL-4 is not crucial for induction of glucocorticoid resistance of GM-CSF production.
Plasma concentrations and therapeutic effects of budesonide in dogs with inflammatory bowel disease
American Journal of Veterinary Research, 2013
Objective-To evaluate the pharmacokinetics and clinical efficacy of budesonide in dogs with inflammatory bowel disease (IBD). Animals-11 dogs (mean ± SD age, 5.7 ± 3.9 years; various breeds and body weights) with moderate or severe IBD. Procedures-Each dog received a controlled-release formulation of budesonide (3 mg/ m 2 , PO, q 24 h) for 30 days (first day of administration was day 1). The concentration of budesonide and its metabolite (16-α-hydroxyprednisolone) was measured via liquid chromatography-tandem mass spectrometry in plasma and urine samples obtained on days 1 and 8 of treatment. On those days, plasma samples were obtained before the daily budesonide administration and 0.5, 1, 2, 4, and 7 hours after drug administration, whereas urine samples were obtained after collection of the last blood sample. A clinical evaluation was performed on the dogs before onset of drug administration and on days 20 and 30 after start of drug administration. Results-The highest plasma concentration of budesonide and 16-α-hydroxyprednisolone on day 1 was detected at 1 hour and at 2 hours after drug administration, respectively. After standardization on the basis of specific gravity, the ratio between urinary concentrations of budesonide and 16-α-hydroxyprednisolone was 0.006 and 0.012 on days 1 and 8, respectively. The clinical response was adequate in 8 of 11 dogs. Conclusions and Clinical Relevance-Budesonide was rapidly absorbed and metabolized in dogs with IBD. The drug gradually accumulated, and there was an adequate therapeutic response and no adverse effects. (Am J Vet Res 2013;74:78-83)
Evaluation of oral budesonide in the treatment of active distal ulcerative colitis
Drugs of today (Barcelona, Spain : 1998), 2004
Budesonide, a topical corticosteroid, has proven useful for the management of Crohn's disease. Its efficacy is similar to prednisone but it has fewer side effects. A new pH-modified release capsule (Budenofalk) is probably efficacious in distal ulcerative colitis. The aim of the present study was to establish the pharmacokinetics, pharmacodynamics, and safety of two dosage regimens of budesonide capsules and to obtain efficacy information. Budenofalk 9 mg daily was administered as a single dose 9 mg in 8 patients and as three 3 mg doses in 7 patients with active distal ulcerative colitis for 8 weeks. Symptoms were assessed at three timepoints during the study: baseline, 4 and 8 weeks after start of treatment. Endoscopic evaluation and budesonide concentration in mucosal biopsy specimens was performed at 0 and 8 weeks. A pharmacokinetic profile and pharmacodynamic profile (cortisol, lymphocytes and neutrophils) was performed at day 5. In the 9 mg o.d. group, higher peak concentra...