Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) driven through altered immune responses with production of proinflammatory cytokines. Many therapies are used, but side effects and loss of response limit long-term effectiveness. New therapeutic strategies are thus needed for patients who don't respond to current treatments. Recently, there is suggested involvement of the proinflammatory hormone angiotensin II in inflammatory bowel disease. The aim of this study was to investigate the possible role of olmesartan medoximil (OLM-M), an angiotensin II receptor blocker in ameliorating ulcerative colitis. Colitis was induced in male Wistar rats by administration of 5% dextran sodium sulphate (DSS) in drinking water for 5 days. OLM-M (1, 3 and 10 mg/kg) was administered orally during 21 days prior to the induction of colitis, and for 5 days after. Sulfasalazine (500 mg/kg) was used as reference drug. All animals were tested for changes in colon length, disease activity index (DAI) and microscopic damage. Colon tissue concentration/activity of tumor necrosis alpha (TNF-α), myeloperoxidase (MPO), prostaglandin E2 (PGE2), reduced glutathione (GSH) and malondialdhyde (MDA) were assessed. Results showed that the OLM-M dose-dependently ameliorated the colonic histopathological and biochemical injuries, an effect that is comparable or even better than that of the standard sulfasalazine. These results suggest that olmesartan medoximil may be effective in the treatment of UC through its anti-inflammatory and antioxidant effects.
"Rats challenged with TNBS suffered marked weight loss (>10%) as a result of colonic inflammation compared with vehicle-treated control group (Figure 1A). The animals also displayed high DAI scores associated with incidence of diarrhea and rectal bleeding in addition to increased colon weight/length ratio, a reliable marker of colon inflammation , (Figure 1B, C). These data were confirmed by the macroscopic examination of colon that revealed severe colonic injury characterized by mucosal damage, thickening of bowel wall, hyperemia, edema and ulcerations (Figure 1D). "
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.
PLoS ONE 05/2014; 9(5):e97193. DOI:10.1371/journal.pone.0097193 · 3.23 Impact Factor
"During inflammation, proinflammatory cytokines, such as TNFa , are released into the inflamed site, enhancing COX-2 expression and, subsequently, the synthesis of prostaglandin E2 (PGE 2 )  . This prostanoid is a key mediator in IBD  and it appears to have a dual effect . "
[Show abstract][Hide abstract] ABSTRACT: Isatin, an indole alkaloid has been shown to have anti-microbial, anti-tumor and anti-inflammatory effects. Due to its findings, we evaluated whether this alkaloid would have any effect on TNBS-induced colitis. Animals (male Unib:WH rats, aged 8 weeks old) were induced colitis through a rectal administration of 2,4,6- trinitrobenzene sulphonic acid using a catheter inserted 8cm into the rectum of the animals. The rats were divided into two major groups: non-colitic and colitic. The colitic group was sub-divided into 6 groups (10 animals per group): colitic non-treated, Isatin 3; 6; 12,5; 18,75 and 25 mg/Kg. Our main results showed that the oral treatment with Isatin 6 and 25 mg/Kg were capable of avoiding the increase in TNF-α, COX-2 and PGE2 levels when compared to the colitic non-treated group. Interestingly, the same doses (6 and 25 mg/Kg) were also capable of preventing the decrease in IL-10 levels comparing with the colitic non-treated group. The levels of MPO, (an indirect indicator of neutrophil presence), were also maintained lower than those of the colitic non-treated group. Isatin also prevented the decrease of SOD activity and increase of GSH-Px and GSH-Rd activity as well as the depletion of GSH levels. In conclusion, both pre-treatments (6 and 25 mg/Kg) were capable of protecting the gut mucosa against the injury caused by TNBS, through the combination of antioxidant and anti-inflammatory properties, which, together, showed a protective activity of the indole alkaloid isatin.
"In the same time olmesartan (30 mg/kg) produced no significant changed in AST and ALT enzymes when compared to normal animals. In agreement, olmesartan treatment has not been shown to significantly affect liver function testing including AST and ALT enzymes and kidney damage   and this may be attributed to the antioxidant activity of olmesartan as reported in two studies using olmesartan   . "
[Show abstract][Hide abstract] ABSTRACT: Sorafenib was the first multikinase inhibitor to be approved for use in metastatic renal cell carcinoma. Olmesartan me- doxomil used in treatment of hypertension and was reported to inhibit angiogenesis in several models. The present study was designed to assess the safety of a combination of sorafenib plus olmesartan compared to monotherapies in mice bearing Ehrlich’s ascites carcinoma cell line. Mice were divided to seven groups, 1) normal mice, 2) Ehrlich’s ascites carcinoma control, 3 - 5) olmesartan (3, 10, 30 mg/kg/day), respectively, 6) sorafenib (30 mg/kg/day) and 7) the combination group: mice received olmesartan (30 mg/kg/day) plus sorafenib. All drug treatments continued for 21 days. At the end of the experiment, a complete blood count was performed and kidney and liver functions were estimated. The combination therapy produced a non-significant change in most of the measurements of complete blood count and liver enzymes when compared to normal animals. On the other hand, the combined therapy significantly increased blood urea nitrogen when compared to normal group but did not change the serum creatinine level. Concomitant ad- ministration of olmesartan with sorafenib did not significantly augment the toxicity of the later. Therefore; olmesartan might be a safe candidate with sorafenib in treatment of cancer if clinical data proved the benefit of this combination.
Journal of Cancer Therapy 10/2013; 4(8):1355-1361. DOI:10.4236/jct.2013.48160
Sasha Taleban, Fusun Gundogan, Edward K Chien, Silvia Degli-Esposti, Sumona Saha
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