Tablet of Spondias mombin L. Developed from Nebulized Extract Prevents Gastric Ulcers in Mice via Cytoprotective and Antisecretory Effects.

Spondias mombin L. (Anacardiaceae) has a worldwide distribution and is present in all regions of Brazil. Its leaves, flowers and bark are used as teas in folk medicine to treat diseases of the digestive system. This study aimed to evaluate the acute non-clinical toxicity, gastroprotective activity, and the related mechanisms of action of nebulized extract and tablets based on dried Spondias mombin (SmNE). SmNE screening showed the presence of flavonoids (0.65%), polyphenols (25.50%), where the major compound is gallic acid. In the acute oral toxicity assay, a dose of 2000 mg/kg of SmNE administered orally in Swiss mice did not induce any behavioral changes. SmNE (250 or 500 mg/kg p.o) significantly reduced the ulcerative lesion area when compared to the control group in ethanol and non-steroidal anti-inflammatory drug (NSAIDs) models. Results showed that treatment with SmNE (250 mg/kg) reduced acid secretion and gastric content, accompanied with an increase in pH. Previous administration of indomethacin and glibenclamide reversed the protection provided by SmNE, confirming the participation of prostaglandins (PGs) and ATP-sensitive potassium channels (KATP) in its gastroprotective effect. The SmNE tablets met the pharmacopeial quality requirements with gastroprotective activity and similar protection in comparison to the isolated extract administrated. In conclusion, SmNe has a gastroprotective activity related to cytoprotective mechanisms, such as the participation of endogenous prostaglandins and KATP channels, having an anti-secretory effect with systemic action. The formulation obtained presented gastroprotective effects similar to the administration of the extract, the tablets showed favorable compression characteristics by the direct route and met the pharmacopeial quality requirements.

A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.

BACKGROUND & AIMS: p21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/ß-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice. METHODS: IL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT. RESULTS: When compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased ß-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation. CONCLUSIONS: PAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.

Bombax Costatum extract abrogates piroxicam-mediated hepatic and gastric toxicities in rats.

OBJECTIVE: Concurrent administration of orthodox drugs and herbs is common in tropical Africa. This study investigates the effect of co-administration of piroxicam and Bombax costatum on hepatic and gastric toxicities and levels of oxidative stress markers. MATERIALS AND METHODS: Twenty male wistar rats were grouped into four. Rats in group one were administered 1mL/kg distilled water as normal control; group two were treated with 400mg/kg of extract; group three were treated with 20mg/kg of piroxicam; while those in group four were treated with both extract and piroxicam at 400mg/kg and 20mg/kg, respectively. All treatments were given orally for 14 days. At the end of the treatment period, the rats were euthanised; blood samples and stomach were collected for determination of hepatic and gastro-toxicity alongside with oxidative stress markers. RESULTS: Treatment with piroxicam alone shows the presence of oxidative stress with marked hepatic and gastric toxicities. Oxidative stress markers, hepatic and gastric toxicity indices after treatment with extract alone and in combination with piroxicam appear like that of the control group. CONCLUSION: Concurrent administration of piroxicam and Bombax costatum prevents piroxicam-induced hepatic and gastric toxicities with a positive effect on antioxidant levels. This may indicate important health benefits of this drug-herb combination.

Soluble Siglec-9 alleviates intestinal inflammation through inhibition of the NF-κB pathway.

BACKGROUND: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a superfamily of immunoreceptors recognizing sialic acid. Siglec-9 has been shown to mediate inhibitory immune responses. The aim of this study was to evaluate the effect of a soluble form of Siglec-9 (sSiglec-9) on inflamed intestinal epithelial cells (IECs), murine macrophages, and experimental murine colitis models. METHODS: COLO 205 human IECs and RAW 264.7 murine macrophages were pretreated with sSiglec-9 and then stimulated with TNF-α or lipopolysaccharides, respectively. The expression of proinflammatory cytokines such as IL-8 and TNF-α was measured using real-time RT-PCR and ELISA. To demonstrate the inhibitory effects of sSiglec-9 on the NF-κB pathway, IκBα phosphorylation/degradation was determined using western blotting and the DNA binding activity of NF-κB was evaluated using an electrophoretic mobility shift assay. Further, mouse models with dextran sulfate sodium-induced acute colitis and piroxicam-induced IL-10-/- chronic colitis were generated. Intraperitoneal injections of sSiglec-9 were performed, and body weight, colon length, and histopathologic findings were examined. RESULTS: sSiglec-9 suppressed IL-8 and TNF-α gene expression in stimulated COLO 205 and RAW 264.7 cells. sSiglec-9 inhibited IκBα phosphorylation/degradation and the DNA binding activity of NF-κB. sSiglec-9 injections significantly ameliorated weight loss, colon shortening, and the severity of intestinal inflammation in acute and chronic colitis mouse models. CONCLUSION: sSiglec-9 may inhibit NF-κB activation in IECs and macrophages and alleviate experimental colitis in mice, suggesting that sSiglec-9 is a potential therapeutic agent for the treatment of inflammatory bowel disease.

Histological study of the protective role of ginger on piroxicam-induced liver toxicity in mice.

BACKGROUND: Piroxicam is a non-steroidal anti-inflammatory drug widely used in rheumatic diseases. It has analgesic and antipyretic activity, and is one of the drugs being introduced in clinical practice. Piroxicam-hepatotoxicity has been reported as one of its principal side effects. Several natural antioxidants were found to be effective against drug induced toxicity. Ginger is known by its antioxidant activities and hepatoprotective effects. The present study aimed at studying the protective effect of Ginger on Piroxicam-induced histopathological changes in livers of male mice. METHODS: Forty adult mice were randomly divided into 4 groups: Group I served as the control group. Group II received Ginger orally in a dose of 200 mg/kg per day for four weeks. Group III received Piroxicam intraperitoneally in a dose of 0.3 mg/kg per day for four weeks. Group IV received (Piroxicam + Ginger). At the end of the experiment, liver functions were estimated and then the liver was removed, and sampled for histopathological, immunohistochemistry and biochemical studies. RESULTS: Administration of ginger decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and immunoexpression of the proapoptotic protein (Bax), induced by piroxicam. It increased immunoexpression of the antiapoptotic protein (Bcl2). It also ameliorated the morphological changes induced by piroxicam. CONCLUSION: Piroxicam has toxic effects on the liver as indicated by biochemical, histological and immunohistochemical results. Ginger has protective effects against piroxicam-hepatotoxicity by reducing serum marker enzymes, liver fibrosis and apoptosis.

Rosuvastatin attenuates piroxicam-mediated gastric ulceration and hepato-renal toxicity in rats.

Piroxicam (Px) is a non-steroidal anti-inflammatory drug that is widely prescribed in various inflammatory disorders. However, Px is known to induce gastric ulceration and hepato-renal toxicity. Rosuvastatin (ROSV), a member of the statin family, has anti-inflammatory and antioxidant actions independent of its anti-hyperlipidemic action. Therefore, we investigated the protective effects of ROSV against Px-induced gastric, liver, and kidney injury. Five groups of seven rats each were used; control group, ROSV group (20 mg/kg, given orally), Px group (7 mg/kg, given intraperitoneally), Px+ROSV L (7 and 10 mg/kg, respectively), and Px+ROSV H (7 and 20 mg/kg, respectively) group. The results revealed that Px induced severe gastric mucosal damage expressed by high ulcer index along with significant increases in liver and kidney function parameters including AST, ALT, creatinine, and urea. Disrupted lipid metabolism also was observed in Px-treated animals. Moreover, marked an increase in malondialdehyde (MDA) and decreases in glutathione (GSH) and catalase (CAT) levels along with enhanced activated caspase-3 expression in the gastric, hepatic, and renal tissues following Px-insult suggested a possible involvement of lipid peroxidation in Px-induced gastropathy and hepatorenal toxicity. However, in a dose-dependent manner, ROSV was able to mitigate Px-induced lipid peroxidation and apoptosis in gastric, liver, and kidney tissues.

Experimental optimization of Lornoxicam liposomes for sustained topical delivery.

The purpose of the present investigation is to formulate liposomes of Lornoxicam for topical delivery using Central Composite Design, to provide a sustained release of the drug and thereby extend its elimination half-life. Liposomes were prepared by thin film hydration method with pH induced vesiculation. The liposomes were assessed for their particle size, charge, morphology and drug entrapment and characterized using TGA-DSC and FTIR analysis, to assess the interaction between the drug and excipients. The in vitro release study was performed using modified USP dissolution apparatus-I using three different dissolution media and the ex vivo release study was performed using goat skin. The cytotoxicity of Lornoxicam liposomes were studied on NIH 3T3 cells by MTT assay. The optimized formulation with particle size ranging from 100-200nm provided sustained release for 8h. The characterization studies proved very less interactions between the drug and the excipients. The ex vivo studies showed flux value of 23.29µg/cm2/h and Kp 0.011645cm/h. The cytotoxicity study showed increase in toxicity with increase in concentration more than 0.5µg/mL. The in vivo skin toxicity studies and histopathology analysis showed absence of toxic lesions, which confirmed the suitability of the formulation for topical application. Lornoxicam liposomes with good skin permeation and sustained release of drug were finally optimized by the experimental design.

Tri/tetra-block co-polymeric nanocarriers as a potential ocular delivery system of lornoxicam: in-vitro characterization, and in-vivo estimation of corneal permeation.

Polymeric micelles that can deliver drug to intended sites of the eye have attracted much scientific attention recently. The aim of this study was to evaluate the aqueous-based formulation of drug-loaded polymeric micelles that hold significant promise for ophthalmic drug delivery. This study investigated the synergistic performance of mixed polymeric micelles made of linear and branched poly(ethylene oxide)-poly(propylene oxide) for the more effective encapsulation of lornoxicam (LX) as a hydrophobic model drug. The co-micellization process of 10% binary systems combining different weight ratios of the highly hydrophilic poloxamers; Synperonic(®) PE/P84, and Synperonic(®) PE/F127 and the hydrophobic poloxamine counterpart (Tetronic(®) T701) was investigated by means of photon correlation spectroscopy and cloud point. The drug-loaded micelles were tested for their solubilizing capacity towards LX. Results showed a sharp solubility increase from 0.0318 mg/mL up to more than 2.34 mg/mL, representing about 73-fold increase. Optimized formulation was selected to achieve maximum drug solubilizing power and clarity with lowest possible particle size, and was characterized by (1)HNMR analysis which revealed complete encapsulation of the drug within the micelles. Further investigations by histopathological and confocal laser studies revealed the non-irritant nature and good corneal penetrating power of the proposed nano-formulation.

Piroxicam treatment augments bone abnormalities in interleukin-10 knockout mice.

BACKGROUND: Osteoporosis and fractures are common complications of inflammatory bowel disease. The pathogenesis is multifactorial and has been partly attributed to intestinal inflammation. The aim of this study was to evaluate bone status and assess the association between bone loss and gut inflammation in an experimental colitis model. METHODS: Colitis was induced in interleukin-10 knockout mice (PAC IL-10 k.o.) by peroral administration of piroxicam for 12 days. The degree of colitis was assessed by clinical, macroscopic, and microscopic evaluation. Trabecular and cortical bone microarchitecture of tibia were determined using micro-computed tomography. Moreover, the serum levels of bone formation and bone resorption biomarkers were measured, and inflammatory protein profiling was performed on colons. RESULTS: PAC IL-10 k.o. mice developed severe colitis, characterized by hyperplasia and focal transmural inflammation, which was consistent with Crohn's disease-like pathology. The gut inflammation was accompanied by a 14% and 12% reduction in trabecular thickness relative to piroxicam-treated wild type and untreated wild type mice, respectively (P < 0.001). The trabecular bone structure was also changed in PAC IL-10 k.o. mice, whereas no differences in cortical bone geometry were observed. The trabecular thickness was inversely correlated with serum levels of CTX (r = -0.93, P = 0.006). Moreover, numerous inflammatory mediators, including RANKL and osteoprotegerin, were significantly increased in the colon of PAC IL-10 k.o. mice. CONCLUSIONS: PAC IL-10 k.o. mice develop bone loss and changed trabecular structure, as a result of increased bone resorption. Thus, the PAC IL-10 k.o. model could be a useful experimental model in preclinical research of inflammatory bowel disease-associated bone loss.

A mononuclear zinc(II) complex with piroxicam: crystal structure, DNA- and BSA-binding studies; in vitro cell cytotoxicity and molecular modeling of oxicam complexes.

A new mononuclear Zn(II) complex, trans-[Zn(Pir)2(DMSO)2], where Pir(-) is 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam), has been synthesized and characterized. The crystal structure of the complex was obtained by the single crystal X-ray diffraction technique. The interaction of the complex with DNA and BSA was investigated. The complex interacts with FS-DNA by two binding modes, viz., electrostatic and groove binding (major and minor). The microenvironment and the secondary structure of BSA are changed in the presence of the complex. The anticancer effects of the seven complexes of oxicam family were also determined on the human K562 cell lines and the results showed reasonable cytotoxicities. The interactions of the oxicam complexes with BSA and DNA were modeled by molecular docking and molecular dynamic simulation methods.

Evaluation of toxicities from combined metronomic and maximal-tolerated dose chemotherapy in dogs with osteosarcoma.

OBJECTIVE: To evaluate the tolerability of a piroxicam and cyclophosphamide metronomic treatment protocol combined with carboplatin alone or carboplatin and doxorubicin at maximal-tolerated doses. METHODS: Retrospective study of 30 dogs diagnosed with osteosarcoma. All dogs underwent amputation and chemotherapy treatment with one of the two maximal-tolerated dose protocols. Metronomic chemotherapy was administered in conjunction with these protocols, and continued subsequently. The protocols included 0 · 3 mg/kg piroxicam and 10 to 12 mg/M(2) cyclophosphamide with 300 mg/M(2) carboplatin alone, or 300 mg/M(2) carboplatin alternating with 30 mg/M(2) doxorubicin. RESULTS: Fourteen dogs were treated with the carboplatin and metronomic protocol and 16 were treated with the carboplatin alternating with doxorubicin and metronomic protocol. Grades 3 and 4 toxicities overall were significantly (P = 0 · 018) more common in the former group. The disease-free interval of the carboplatin and metronomic group was 192 days, which was not significantly different (P = 0 · 916) to the 182 days for the carboplatin alternating with doxorubicin and metronomic group. The median survival times of the two groups were 217 and 189 days, respectively. CLINICAL SIGNIFICANCE: Piroxicam and cyclophosphamide metronomic protocols can be safely administered in combination with maximal-tolerated dose chemotherapy protocols. A significantly higher frequency of toxicities was observed in dogs treated with the carboplatin and metronomic protocol.

Enhancement of solubility, dissolution release profile and reduction in ulcerogenicity of piroxicam by inclusion complex with skimmed milk.

CONTEXT: Piroxicam (PXM), a non-steroidal anti-inflammatory drug which is poorly soluble in water and ulcerogenic. Milk has been used against the gastric disturbances caused by non-steroidal anti-inflammatory drugs. In this study, skimmed milk (SKM) is used as the carrier for inclusion complex (IC) due to its surface active agent and amino acid content. PURPOSE: To enhance the solubility, dissolution rate and prevent ulcerogenicity of PXM though IC with SKM. METHODS: IC of PXM were prepared with SKM by solvent evaporation method using rota evaporator and were evaluated for solubility, dissolution, solid state characterization, drug excipient interaction, rat intestinal permeation, ulcerogenicity and histopathological studies. RESULTS: Solubility of PXM was enhanced 2.5 times with IC. The dissolution release and amount of PXM permeated through rat small intestine was enhanced significantly with IC. Decreases in the gastric lesion index values of IC were observed than physical mixture (PM) and free PXM. The histopathological studies revealed significant reduction in ulceration in rat stomach after treatment with IC. CONCLUSION: It is concluded that SKM is a good carrier to prepare IC of PXM for oral administration.

Evaluation of vitreous clearance and potential retinal toxicity of intravitreal lornoxicam (xefo).

PURPOSE: To evaluate the vitreous clearance and toxicological profile of commercially available lornoxicam (Xefo), after a single intravitreal injection in rabbits. METHODS: Twenty-five male albino rabbits (10 rabbits were used for retinal toxicity evaluation, while 15 rabbits were used to evaluate vitreous clearance) were used in this study. Two concentrations of lornoxicam were tested for retinal toxicity: 250 µg/0.1 mL and 1,500 µg/0.1 mL. Each concentration was intravitreally injected randomly in 1 eye of each rabbit (group I received 250 µg/0.1 mL, n=5 and group II received 1,500 µg/0.1 mL, n=5), while in the other eye 0.1 mL of sterile balanced saline solution was injected. Slit-lamp and funduscopic examinations along with intraocular pressure measurements (IOP) were performed prior to injection and at days 1, 15, and 30 after the injection for signs of infection, inflammation, toxicity, and IOP changes. A baseline electroretinogram (ERG) was performed before the experiment and at days 1, 15, and 30 after the intravitreal injection. At the last follow-up day, the animals were sacrificed and the enucleated eyes were prepared for histological evaluation of the retina. Lornoxicam (concentration of intravitreal injection: 250 µg/0.1 mL) clearance from the vitreous was estimated using high-performance liquid chromatography in 30 rabbit eyes. RESULTS: There were no statistical differences between the control and experimental eyes, concerning ERG amplitudes and IOP measurements for both groups (I and II), at all examinations. On the contrary, histological examination of the samples revealed extended retinal damage of group II experimental eyes (morphological alterations at the level of the inner nuclear and outer plexiform layers was evident along with disappearance of normal stratification of outer retina with vacuolization and thinning), whereas the morphology of group I experimental eyes did not differ from that of the control eyes. Lornoxicam is eliminated from the vitreous by a first-order kinetic process with a half-life of 1.7 h. CONCLUSIONS: Intravitreal lornoxicam causes dose-related toxic effect to the retina at a concentration of 1,500 µg. A dose of 250 µg does not seem to cause histological toxic effects at the level of the retina. Lornoxicam could be considered with interest for further research for the development of alternative treatments for ocular inflammatory conditions.

Intra-articular lornoxicam loaded PLGA microspheres: enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis.

The aim of this study was to investigate the joint tissue distribution and pharmacodynamics of Lornoxicam (Lnxc) following intra-articular injection of either Lnxc suspensions or sustained release Lnxc-loaded PLGA microspheres (Lnxc-MS), as well as the biocompatibility of PLGA microspheres with or without drugs. In this study, Lnxc suspensions or Lnxc-loaded PLGA microspheres was injected into the knee joint cavity of rats. Blood samples were taken at predetermined times from the jugular vein and the joint tissue (cartilage and synovial membrane) were removed from the rats. Biocompatibility and pharmacodynamics were evaluated by observing the swelling of the joints of the rats and histological analysis following the injection of the microspheres. The plasma drug concentration decreased in rats and retention time increased in rats' joint with intra-articular injections of microspheres, revealing good targeting efficiency and decreased systemic toxicity. After 30 days of intra-articular injection with Lnxc-loaded or blank microspheres, the filtration liquid accumulation, blood vessels and fibrous proliferation were not detected, showing their good compatibility. Furthermore, the articular cartilage damage by papain could also be repaired by the Lnxc-loaded PLGA microspheres. In conclusion, intra-articular Lnxc-MS have considerable potential for creating a sustained release Lnxc delivery system and providing effective healing to Osteoarthritis.

Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(-/-) mice.

BACKGROUND: Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation. AIMS: To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(-/-) mice. METHODS: Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(-/-) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel. RESULTS: Compared to IL-10 (-/-) mice, sEH inhibition or sEH deficiency in IL-10(-/-) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB(4) and 5-HETE. CONCLUSION: These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (-/-) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.

Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam.

Many commonly used non-steroidal anti-inflammatory drugs (NSAIDs) also cause gastrointestinal toxicity, including the development of life-threatening peptic ulcers. We report that mast cell-deficient mice have an extremely high incidence of severe peptic ulceration when exposed to the NSAID piroxicam. This enhanced ulcer susceptibility can be reversed by reconstitution with mast cells. Furthermore, wild type mice treated with diphenhydramine hydrochloride, a commonly used antihistamine that blocks histamine H1 receptors, develop a similarly high incidence of peptic ulcers following piroxicam exposure. The protective effect of mast cells is independent of TNF, blockade of H2 receptors, or acid secretion. These data indicate a critical role for mast cells and the histamine that they produce in prevention and/or repair of piroxicam-induced gastric mucosal injury. Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans.

Colitis and intestinal inflammation in IL10-/- mice results from IL-13Rα2-mediated attenuation of IL-13 activity.

BACKGROUND & AIMS: The cytokine interleukin (IL)-10 is required to maintain immune homeostasis in the gastrointestinal tract. IL-10 null mice spontaneously develop colitis or are more susceptible to induction of colitis by infections, drugs, and autoimmune reactions. IL-13 regulates inflammatory conditions; its activity might be compromised by the IL-13 decoy receptor (IL-13Rα2). METHODS: We examined the roles of IL-13 and IL-13Rα2 in intestinal inflammation in mice. To study the function of IL-13Rα2, il10(-/-) mice were crossed with il13rα2(-/-) to generate il10(-/-)il13rα2(-/-) double knockout (dKO) mice. Colitis was induced with the gastrointestinal toxin piroxicam or Trichuris muris infection. RESULTS: Induction of colitis by interferon (IFN)-γ or IL-17 in IL-10 null mice requires IL-13Rα2. Following exposure of il10(-/-) mice to piroxicam or infection with T muris, production of IL-13Rα2 increased, resulting in decreased IL-13 bioactivity and increased inflammation in response to IFN-γ or IL-17A. In contrast to il10(-/-) mice, dKO mice were resistant to piroxicam-induced colitis; they also developed less severe colitis during chronic infection with T muris infection. In both models, resistance to IFN-γ and IL-17-mediated intestinal inflammation was associated with increased IL-13 activity. Susceptibility to colitis was restored when the dKO mice were injected with monoclonal antibodies against IL-13, confirming its protective role. CONCLUSIONS: Colitis and intestinal inflammation in IL10(-/-) mice results from IL-13Rα2-mediated attenuation of IL-13 activity. In the absence of IL-13Rα2, IL-13 suppresses proinflammatory Th1 and Th17 responses. Reagents that block the IL-13 decoy receptor IL-13Rα2 might be developed for inflammatory bowel disease associated with increased levels of IFN-γ and IL-17.

Effect of tenoxicam on rat liver tissue.

BACKGROUND/AIMS: Tenoxicam is a non-steroidal antiinflammatory drug, which has antipyretic and antiinflammatory effects. Though it is known that the major side effect of non-steroidal antiinflammatory drugs is on the gastrointestinal tract and liver, there have been few studies regarding the effects of tenoxicam. In this study, we aimed to investigate whether tenoxicam has a deleterious effect on liver tissue using immunohistochemical staining and biochemical analysis. METHODS: A total of 30 male Wistar albino rats were included in this study. Animals were equally and randomly divided into three groups as follows: Group I (Controls), Group II (Injection with 10 mg/kg/day of tenoxicam) and Group III (Injection with 20 mg/kg/day of tenoxicam). At the end of the study, some liver tissue samples were taken and kept in neutral formalin for histological and immunohistochemical evaluation. Liver tissue samples were embedded in paraffin blocks after routine tissue preparation procedures, and were stained with hematoxylin-eosin and immunohistochemical stain. Liver samples taken for biochemical analysis were washed with physiological saline. Thiobarbituric acid reactive substances and superoxide dismutase activity were measured in the obtained supernatants. RESULTS: There were significant structural changes in liver tissues of the tenoxicam-administered groups when compared with the controls. We observed that hepatic (inducible nitric oxide synthase) receptors were increased in the study groups. Furthermore, hepatic superoxide dismutase and malondialdehyde levels were prominently higher in the tenoxicam-administered groups when compared to levels of the control group. CONCLUSIONS: Nitric oxide may exert an antioxidative effect against lipid peroxidation to one point at low levels; however, it may also have the opposite effect at higher levels in tenoxicam induced liver injury.

Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.

BACKGROUND: P-glycoprotein (P-gp), the product of the multidrug resistance gene (MDR), is an ATP-dependent transmembrane pump, which is expressed in multiple cell lineages including epithelial and hematopoetic cells. The human MDR gene is located on chromosome 7 (7q21.1), a susceptibility loci for inflammatory bowel disease (IBD). A significant number of IBD patients carry mutations in this gene and P-gp-deficient FVB/N mice develop a severe spontaneous colitis, characterized by impaired intestinal barrier function and immune reactivity to intestinal bacterial antigens. METHODS: In this work we explored the role of mouse strain, as well as environmental insults, on the development of colonic inflammation in the absence of P-gp. Among the induction methods utilized, dextran sodium sulfate (DSS) disrupts the intestinal epithelium, while piroxicam is a nonsteroidal antiinflammatory (NSAID) drug that inhibits prostaglandin production and initiates colitis in IL10-deficient animals. Helicobacter bilis is a known mediator of bacterial-induced colitis. RESULTS: We demonstrate that crossing this mutation onto the C57BL/6 strain confers protection from spontaneous colitis. C57BL/6.mdr1a-deficient animals demonstrated increased histological inflammation, colonic shortening, fecal blood, and reduced body weight after 7 days of treatment with 2.25% DSS. C57BL/6.mdr1a-deficient mice treated with piroxicam or infected with H. bilis showed no weight loss, or alterations in colonic histology. CONCLUSIONS: These data indicate that the effects of P-gp deficiency are significantly modulated by background strain influences, but that the epithelium continues to have increased susceptibility to chemical injury in the C57BL/6 model.

Exantema fijo medicamentoso por piroxicam / Fixed drug eruption due to piroxicam

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