Tumor de GIST de intestino delgado como causa de hemorragia digestiva de origen oculto manifiesta diagnosticado por cápsula endoscópica / Overt obscure gastrointestinal bleeding secondary to small bowel gastrointestinal stromal tumor diagnosed by videocapsule endoscopy

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Analysing the role of COX-2 in acute oesophagitis and in melatonin-exerted protection against experimental reflux oesophagitis in rats.

OBJECTIVES: Cyclooxygenase(COX)-2 is implicated in variety of pathophysiological processes, although its role in acute reflux oesophagitis is debatable. This study was designed to evaluate the role of COX-2 during oesophagitis and in melatonin-elicited protection in rats. METHODS: Reflux oesophagitis was induced in rats by ligating the pyloric end and the limiting ridge of the stomach for 5 h. Celecoxib (COX-2 blocker; 10 mg/kg), 16,16-dimethyl prostaglandinE(2) (dmPGE(2); a synthetic analogue of PGE(2) ; 10 µg/kg), melatonin (20 and 40 mg/kg) and omeprazole (10 mg/kg) were given intra-peritoneally 45 min before induction of oesophagitis in rats. Alterations in COX-1 and 2 gene expression and protein levels level were analysed via RT-PCR and Western blotting, respectively. Mucosal PGE(2) level and myeloperoxidase (MPO) activity were measured using an enzyme immunoassay (EIA) kit and spectrophotometrically, respectively. KEY FINDINGS: COX-2 over-expression during reflux oesophagitis promotes inflammation of the oesophagus as celecoxib pretreatment significantly reduced tissue damage and MPO activity in rats with reflux oesophagitis (RE-rats). By contrast, dmPGE(2) pretreatment significantly exacerbated tissue injury and simultaneously increased COX-2 expression, PGE(2) levels and MPO activity in RE-rats. Further, melatonin pretreatment significantly reduced the tissue injury, COX-2 over-expression, PGE(2) level and MPO activity in RE-rats. Melatonin offered more potent suppression of COX-2, PGE(2) and MPO activity than the proton-pump inhibitor omeprazole; however, both reduced the lesion injury to a similar extent. Melatonin at a dose of 20 mg/kg failed to inhibit significantly the dmPGE(2) -induced tissue damage, COX-2 expression, PGE(2) level and MPO activity in RE-rats while at a higher dose of 40 mg/kg it significantly attenuated these changes. CONCLUSION: Our results suggest that COX-2 plays an important pro-inflammatory role during acute reflux oesophagitis in rats and its inhibition contributes significantly to melatonin-exerted protection against reflux oesophagitis.

Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice.

Vasoactive factors that regulate splanchnic hemodynamics include nitric oxide, catecholamines, and possibly extracellular nucleosides/nucleotides (adenosine, ATP). CD39/ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1) is the major vascular ectonucleotidase that hydrolyzes extracellular nucleotides. CD39 activity may be modulated by vascular injury, inflammation, and altered oxygen tension. Altered Cd39 expression by the murine hepatosplanchnic vasculature may impact hemodynamics and portal hypertension (PHT) in vivo. We noted that basal portal pressures (PPs) were comparable in wild-type and Cd39-null mice (n = 9). ATP infusions resulted in increments in PP in wild-type mice, but, in contrast, this significantly decreased in Cd39-null mice (n = 9) post-ATP in a nitric oxide-dependent manner. We then studied Cd39/NTPDase1 deletion in the regulation of portal hemodynamics, vascular integrity, and intestinal permeability in a murine model of PHT. Partial portal vein ligation (PPVL) was performed in Cd39-null (n = 44) and wild-type (n = 23) mice. Sequential measurements obtained after PPVL were indicative of comparable levels of PHT (ranges 14-29 mmHg) in both groups. There was one death in the wild-type group and eight in the Cd39-null group from intestinal bleeding (P = 0.024). Circulatory stasis in the absence of overt portal vein thrombosis, portal congestion, intestinal hemorrhage, and increased permeability were evident in all surviving Cd39-null mice. Deletion of Cd39 results in deleterious outcomes post-PPVL that are associated with significant microcirculatory derangements and major intestinal congestion with hemorrhage mimicking acute mesenteric occlusion. Absent Cd39/NTPDase1 and decreased generation of adenosine in the splanchnic circulation cause heightened vascular permeability and gastrointestinal hemorrhage in PPVL.

Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine?

Polymorphisms in CYP2C8 and CYP2C9 are common in all the human populations and many CYP2C8 and CYP2C9 gene variations cause decreased enzyme activity towards the NSAIDs aceclofenac, celecoxib, diclofenac, ibuprofen, indomethazine, lornoxicam, meloxicam, naproxen, piroxicam, tenoxicam and valdecoxib. This impairment in drug biodisposition alters drug pharmacokinetics, with carriers of detrimental mutations displaying increased values of AUC and decreased drug clearance. Individuals carrying the gene variants CYP2C8*3 (rs11572080; rs10509681), CYP2C9*2 (rs1799853) or CYP2C9*3 (rs1057910) show increased risk of developing acute gastrointestinal bleeding during the use of NSAID that are CYP2C8 or CYP2C9 substrates. However, it is not known whether parent drugs or products of alternative metabolic pathways are responsible for bleeding. We present an overview of the current knowledge of relevant polymorphisms of CYP2C8 and CYP2C9 genes, their association with NSAID metabolism and pharmacokinetics and a meta-analysis that confirms the clinical significance of these gene variations with regard to gastrointestinal bleeding.

Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding.

OBJECTIVES: To analyze whether gene variants leading to impaired drug metabolism are related with acute gastrointestinal bleeding after nonsteroidal anti-inflammatory drugs (NSAID) use. METHODS: Common CYP2C8 and CYP2C9 polymorphisms were studied in a cross-sectional study, involving 134 NSAID-related bleeding patients and in 177 patients receiving NSAID with no adverse effects. RESULTS: Among patients receiving NSAID that are CYP2C8/9 substrates the frequencies for carriers of variant alleles versus control patients were CYP2C8*3: 0.50 vs. 0.23 [odds ratio (OR); 95% confidence interval (CI)=3.4; 1.5-7.5; P=0.002], CYP2C9*2: 0.48 vs. 0.26 (OR; 95% CI=2.7; 1.2-5.8; P=0.013) and CYP2C9*3: 0.24 vs. 0.20 (OR; 95% CI=1.3; 0.5-3.1; P=0.578). The frequencies for carriers of the CYP2C8*3+CYP2C9*2 genotype were 0.40 vs. 0.15 (OR; 95% CI=3.7; 1.6-8.9; P=0.003). These findings were not influenced by sex, age, smoking or drinking habits. Among bleeding patients receiving NSAID that are not extensively metabolized by CYP2C8/9, no differences in genotypes or allele frequencies were observed as compared with control patients. CONCLUSION: The combined presence of CYP2C8*3 and CYP2C9*2 (CYP2C8*3+CYP2C9*2 genotype), is a relevant determinant in the risk to develop gastrointestinal bleeding in patients receiving NSAID that are CYP2C8/9 substrates.

Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use.

Impaired drug metabolism is a major cause of adverse drug reactions, and it is often caused by mutations at genes coding for drug-metabolising enzymes. Two amino-acid polymorphisms of cytochrome P4502C9 (CYP2C9), an enzyme involved in the metabolism of several nonsteroidal anti-inflammatory drugs (NSAIDs), were studied in 94 individuals with acute bleeding after NSAIDs use and 124 individuals receiving NSAIDs with no adverse effects. The frequency of CYP2C9 variant alleles was increased in overall bleeding patients, with a significant trend to higher risk with increasing number of variant alleles (P=0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n=33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (P<0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.

Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response.

Nonsteroidal anti-inflammatory drugs (NSAID) are well known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and animals too. These effects are related with the inhibition of the enzyme cyclooxygenase, which is the main established mechanism of action for these drugs. Fasted rats were given piroxicam, preferential COX-1 inhibitor (10-20 mg/kg) or meloxicam, preferential COX-2 inhibitor (7.5-15 mg/kg) orally. Six or nine hours (h) later, respectively, the stomach was excised, the severity of the damage assessed and myeloperoxidase (MPO) activity measured, as well as prostaglandin PGE(2) content. Furthermore, in order to assess the effects of these oxicams over previously damaged gastric mucosa, 1 ml of 0.6 N HCl was administered p.o. followed, 1 h after, of the correspondent dose of each NSAID, and the same parameters were determined. Oral administration of both drugs dose-dependently caused acute gastric haemorrhage erosions. Myeloperoxidase activity was significantly increased by piroxicam administration. In addition, PGE(2) content was significantly reduced. The association between the administration of the acid and NSAID caused a worsening of the damage and, while myeloperoxidase activity did not modify by both piroxicam and meloxicam, PGE(2) levels were reduced. These results suggest that the PG derived from both COX-1 and COX-2 pathway plays a beneficial role in the gastroprotection, and thus caution should be exercise in the clinical use of preferential COX-2 inhibitors.

Inhibitory effects of DA-9601 on ethanol-induced gastrohemorrhagic lesions and gastric xanthine oxidase activity in rats.

The exposure of gastric mucosa to ethanol produces pathological changes such as inflammatory process, hemorrhagic erosions, even acute ulcers. The gastric mucosal lesions accompanied by a significant decrease of gastric blood flow and increase of reactive oxygen species (ROS) implicate a role of xanthine oxidase in ethanol-induced gastric hemorrhagic erosions. DA-9601, a novel antipeptic formulation of extracts of Artemisia asiatica Nakai, was studied for its inhibitory effect on gastric xanthine oxidase activity and type conversion of the enzyme that has a profound role in free radical generation. Intubation of absolute ethanol (4 g/kg) significantly induced gastrohemorrhagic lesions and lipid peroxidation in the rat stomach. Oral administration of DA-9601 at 40 mg/kg body weight significantly reduced ethanol-induced gastric mucosal hemorrhagic lesions and lipid peroxidation, which was proportional to the inhibitory effect of DA-9601 on alcohol-induced xanthine oxidase-type conversion and enzyme activity. The results suggest that alcohol-induced gastric mucosal damage may be, in part, due to the increased activity of xanthine oxidase and type conversion rate of the enzyme and that the preventive effect of DA-9601 on gastrohemorrhagic lesions would result from its inhibitory action against xanthine oxidase and oxidative stress in alcohol-treated rats.

Gastric damage induced by subchronic administration of preferential cyclooxygenase-1 and cyclooxygenase-2 inhibitors in rats.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to induce gastrointestinal damage including bleeding, ulceration and perforation in humans and animals. The aim of this study was to compare the effects of two oxicams, preferential cyclooxygenase (COX)-1 or COX-2 inhibitors, on both gastric mucosa and some biological parameters (hematological, hepatic and renal) after subchronic administration (14 and 28 days) in rats. Neutrophil infiltration was also assessed. Equipotent doses of meloxicam (3.75 and 7.5 mg/kg) and piroxicam (5 and 10 mg/kg) were administered. Both drugs dose-dependently caused multiple gastric erosions and hemorrhage in rats after 14 and 28 days of administration. Treatment with meloxicam led to a higher gastric damage than with piroxicam on day 14 although these results were not significant. The levels of myeloperoxidase activity (as an index of neutrophil infiltration) were not changed compared with control after drug treatment. All the hematological parameters obtained after drugs administration for 14 and 28 days were in the range of normal values, and a significant increase in platelet levels could be observed in the group treated with 5 mg/kg of piroxicam for 14 days. Aspartate aminotransferase (AST or GOT) increased significantly after 14 days, but after 28 days the values returned to normality. Creatinine and urea did not undergo significant changes except for the piroxicam 14-day 5 mg/kg group, in which uremia increased significantly over normal values. In conclusion, our results show that meloxicam, a preferential COX-2 inhibitor, causes rates of gastric lesion comparable to those seen with traditional NSAIDs, without inducing important changes in biological parameters.

Gastropathy and defense mechanisms in common bile duct ligated portal hypertensive rats.

Portal hypertensive gastropathy is associated with a broad spectrum of gastric mucosal damage inspite of decreased gastric acid secretion, suggestive of compromised endogenous protective mechanisms. To determine the mechanisms of damage in portal hypertensive gastropathy we measured lipid peroxidation, glutathione, antioxidant and lysosomal enzymes in gastric mucosal homogenates from male Wistar rats with elevated intrasplenic pulp pressure, eighteen days after common bile duct ligation. Thiobarbituric acid-reactive substances and lysosomal enzymes (beta-glucuronidase and acid phosphatase) were increased in the common bile duct ligated group as compared to the sham-operated group. The levels of antioxidant defense enzymes, superoxide dismutase, glutathione peroxidase, catalase and glutathione were decreased as compared to the sham-operated controls. Pre-operative vitamin E administration decreased mucosal lipid peroxidation increased the levels of antioxidant defense enzymes and lowered the lysosomal enzymes. The plasma vitamin E levels in this group were lower when compared to animals receiving it post-operatively. In conclusion, free radical and lysosomal enzyme mediated damage may play a role in portal hypertensive gastropathy.

Towards the safer use of non-steroidal anti-inflammatory drugs.

Musculoskeletal conditions afflict most of us at some time in our lives, and we all have relatives and friends who suffer the pain and disability sometimes associated with conditions such as back or neck pain, fibrositis and osteoarthritis. The goal of those of us who try to help individuals with these conditions is to achieve effective, but also safe, management of their musculoskeletal disorders, the commonest symptom of which is pain. This goal can be achieved by better diagnosis and problem formulation (allowing better selection of treatment options); informed selection of non-drug and drug therapeutic options, based on relative cost-benefit considerations; and the judicious, appropriate and safe use of drugs, particularly non-steroidal anti-inflammatory drugs (NSAID). Setting realistic goals and maintaining regular surveillance of patients are also important considerations. Finally, the active involvement of the patient in their own management is associated with better and safer outcomes.

On the genesis of gastric haemorrhage.

An hypothesis involving a three step mechanism to account for the initiation of gastric lesions is described. The mechanism necessitates: (a) A drop in the internal energy (ATP) of the mucosal cells of the stomach upon being subjected to stress; either pathological or psychological. (b) Membranes of mucosal "suicidal sacs" containing potent lysosomal acid-hydrolases are rendered fragile and burst, thus releasing hydrolytic acid-hydrolases into the cytoplasm of the mucosal cells as the latter develop an energy deficit under stress. (c) Gastric mucosal cell necrosis, via the degradation of cytoplasmic and mucinous gastric glycoproteins by these lysosomal acid- hydrolases and subjection of the submucosal tissue to the corrosive effects of the luminal fluid containing hydrochloric acid and pepsin, i.e., initiation of gastric haemorrhage. The above mechanism is a general one that describes events associated with the development of gastric lesions regardless of the factor(s) or the agent(s) initiating gastric mucosal haemorrhage.

An analysis of creatine phosphokinase in the mucosa and the muscularis of the gastrointestinal tract.

Previous work has shown that mesenteric infarction causes elevation of total serum creatine phosphokinase (CPK) and each of its three isoenzymes. The exact origin of the CPK has not been determined. Little is known about the actual tissue distribution of CPK in bowel. Experiments were performed to confirm the expectation that CPK was present in the bowel wall and to determine its concentration and the distribution of CPK isoenzymes in the muscularis and mucosa, respectively. Multiple segments were resected from the esophagus, stomach, duodenum, jejunum, ileum, and the proximal and distal colon of normal dogs. The mucosa (MUC) was separated from the seromuscular (MSL) tissue in each of the segments and 1-g samples were analyzed individually for total CPK activity by spectrophotometric analysis and for isoenzyme distribution by agarose gel electrophoresis. The results show that all three isoenzymes of CPK are present throughout the GI tract and that the majority of CPK found is in the MSL. Hence, elevations in serum CPK associated with injuries to the GI tract suggest seromuscular injury. While no isoenzyme is located specifically in the bowel, certain associations were seen. CPK-MM, presumably from striated muscles, was most prevalent in the esophagus. In other portions of the bowel all three isoenzymes were present almost equally. In the mucosa the levels of CPK-MM and CPK-BB always exceeded the level of CPK-MB. Knowledge of the distribution of CPK and its isoenzymes in bowel provides a framework for studying and interpreting serum levels of CPK during bowel injury.

Studies on porcine pancreatic elastase activity. II. Immunoreactive elastase level during acute hemorrhagic pancreatitis in pigs.

Acute hemorrhagic pancreatitis was produced in pig to study serum concentration of elastase and its physiological role. Pancreatitis was induced in two groups of young pigs by the injection of autologous bile. One group was injected with autologous bile (0.5 ml/kg) at high pressure, and the second group was injected as low pressure (100 cm H2O). Then femoral blood, portal blood and thoracic lymph were sampled at scheduled time intervals. The control level of immunoreactive elastase was around 90 ng/ml in each site, which significantly increased beginning 15 min after bile injection; the level of immunoreactive elastase was higher in the thoracic lymph duct than in the femoral and portal vein. The total and free elastase of both groups in pancreatic tissue were significantly decreased in pancreatitis, and an abundance of immunoreactive elastase was found in the ascites. The increasing pattern of immunoreactive elastase and amylase after bile injection was very similar. Therefore, the level of immunoreactive elastase was considered to be inadequate to determine the grade of severity of pancreatitis as well as the level of amylase which is already known.

Relationship between site of peptic ulceration and gastric acid-peptic activity: new evaluation of gastric analysis in patients with acute gastric bleeding and chronic peptic ulcer.

In an attempt to elucidate the etiology of acute gastric bleeding and/or erosion and chronic peptic ulcer, a measurement of gastric juice and mucosal pepsin was carried out in surgically-treated patients. Patients with massive gastric mucosal bleeding in the fundic gland area showed high levels of fundic mucosal pepsin without acid-pepsin appearance in the gastric contents. In these patients, a significantly high value of the peptic activity ratio of gastric mucosa to gastric juice (MJPR, 36.4 +/- 6.7) was observed. It can be suggested that transient blockage of pepsin output from peptic cells with occur in the course of the acute mucosal bleeding, while acid-peptic digestion could be carried out within the fundic gland mucosa. On the other hand, a close correlation between relatively high acid-and-pepsin concentration of the gastric contents and a low level of MJPR (5.6 +/- 1.2) was observed in patients with chronic gastric ulcer. Patients who had a gastric ulcer within the pyloric gland mucosa had a highest acid-peptic activity among three groups with ulcers in fundic gland area, border zone and pyloric gland area. There is a rule that acid-peptic activity becomes low when the site of gastric ulcer moves from pylorus to fundus. A marked increase in acid-and-pepsin secretion into the gastric cavity was observed in patients suffering from chronic duodenal ulcer showing the lowest level of MJPR (3.40 +/- 0.50).