Ricardo Sainz

Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding

UNLABELLED BACKGROUND The relation between medications that release nitric oxide, such as nitroglycerin and other nitrovasodilators, and upper gastrointestinal bleeding is uncertain. In animals, these medications reduce the gastric damage induced by nonsteroidal antiinflammatory drugs. Nitric oxide, however, inhibits platelet aggregation and may contribute to bleeding from an ulcer. METHODS We performed a case-control study to determine the risk of bleeding in patients taking nitrovasodilators, low-dose aspirin, or other nonsteroidal antiinflammatory drugs. The case group was made up of 1122 consecutive patients admitted to one of four hospitals with bleeding from a peptic lesion. The 2231 control subjects were 1109 patients hospitalized for other reasons and 1122 outpatients from the same geographic area. RESULTS In the week before admission, 520 (46.3 percent) of the patients with bleeding had taken a nonsteroidal antiinflammatory drug other than low-dose aspirin, 120 (10.7 percent) had taken low-dose aspirin (< or = 300 mg per day), 60 (5.3 percent) a nitrovasodilator, and 135 (12.0 percent) an antisecretory agent such as a histamine H2-receptor antagonist or a proton-pump inhibitor. In multivariate models that adjusted for age, sex, and clinical risk factors, the use of a nonsteroidal antiinflammatory drug other than low-dose aspirin was independently associated with an increased risk of bleeding from a peptic ulcer (odds ratio, 7.4; 95 percent confidence interval, 4.5 to 12.0), as was the use of low-dose aspirin alone (odds ratio, 2.4; 95 percent confidence interval, 1.8 to 3.3). The use of a nitrovasodilator was associated with a decreased risk of bleeding (odds ratio, 0.6; 95 percent confidence interval, 0.4 to 0.9), as was antisecretory therapy (odds ratio, 0.6; 95 percent confidence interval, 0.4 to 0.8). In patients taking any type of nonsteroidai antiinflammatory drug, the use of a nitrovasodilator or antisecretory therapy was independently associated with a decreased risk of bleeding. CONCLUSIONS The use of nitrovasodilator drugs is independently associated with a decreased risk of upper gastrointestinal bleeding.

Effect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer.

The pharmacotherapy of bleeding peptic ulcer is directed at attempting to keep the gastric pH above the proteolytic range for pepsin. In this randomized, prospective, open clinical trial we have compared the effects and outcome of omeprazole versus ranitidine in patients with bleeding peptic ulcer. Of 219 consecutive patients with upper gastrointestinal bleeding, 51 (23.2%) had an ulcer with endoscopic predictors of rebleeding at the time of diagnosis. These 51 patients were selected at random to receive either omeprazole (80 mg bolus and 40 mg/12 h i.v.) or ranitidine (50 mg/4 h i.v.). No endoscopic therapy was performed at the time of diagnosis. Twenty of these patients with duodenal ulcer (n = 10 omeprazole, n = 10 ranitidine) underwent 24-h gastric pH monitoring. Both groups were homogeneous in all clinical and endoscopic parameters. No differences in blood transfusion units, time of hospitalization, the lowest hematocrit measured, and mortality rates were observed between the groups. However, omeprazole reduced the number of rebleeding episodes (p = 0.1) and the need for surgery (3.8% vs. 22.7%; p = 0.05). Omeprazole also reduced the amount of time the gastric pH was < 6 (15.3 +/- 5.9% vs. 61.8 +/- 5.6%, p < 0.0001). We conclude that parenteral omeprazole is much more effective than ranitidine in keeping the gastric pH above the proteolytic range for pepsin in bleeders and that this might explain a better outcome in a subset of patients with bleeding peptic ulcers treated with parenteral omeprazole.

Experimental esophagitis induced by acid and pepsin in rabbits mimicking human reflux esophagitis.

BACKGROUND & AIMS The lack of appropriate animal models might explain the paucity of information on the mechanisms of mucosal damage and defense in reflux esophagitis. The aim of this study was to develop a model of esophagitis in rabbits mimicking human reflux esophagitis. METHODS New Zealand white rabbits underwent surgery for placement of a plastic tube into the cervical esophagus. Acidified pepsin (AP) was intermittently perfused for different periods. Esophageal injury was assessed by macroscopic and microscopic examination, including the cell proliferation immunohistochemical parameter mib1. RESULTS Rabbit losses (20%) were attributable mostly to postsurgical mortality and tube displacement. Perfusion of AP for 60 min/12 h or 45 min/12 h induced high-grade esophagitis by days 3 and 5, respectively, characterized by diffuse erosion/ulceration, inflammation, bleeding, and reactive epithelial changes. Perfusion of acidified pepsin for 60 min/day, especially at 30 min/12 h, induced low-grade esophagitis characterized by superficial epithelial loss, mild/absent inflammation, and epithelial reactive changes including increased cell proliferation, basal hyperplasia, and papillomatosis, which reached maximal expression by day 7. This perfusion regimen induced mucosal adaptation to damage. CONCLUSIONS Different and highly reproducible esophageal mucosal lesions mimicking human reflux esophagitis can be induced in rabbits with repetitive acid and pepsin exposure.

Risk factors associated with refractory peptic ulcers

BACKGROUND & AIMS The risk factors associated with refractory peptic ulcers are still undefined. The purpose of this study was to identify these factors in a multivariate context. METHODS Clinical and endoscopic findings as well as Helicobacter pylori status, gastric secretion analysis, serum gastrin levels, nonsteroidal anti-inflammatory drug (NSAID) use, and objective testing of aspirin use by platelet cyclooxygenase activity were studied in 60 consecutive refractory patients with peptic ulcer and 54 matched nonrefractory controls. RESULTS Refractory patients had a longer history of symptomatic ulcer, had an earlier onset, had more frequent relapses, and smoked more during the episode of refractoriness. H. pylori status was similar in both groups, but H. pylori eradication in a subset of refractory patients (23 of 26) was highly effective in healing these ulcers (14 of 23). Globally, NSAID-analgesic abuse (including > 1500 mg/day paracetamol) was present in 40% of refractory patients (P < 0.006). Objective testing showed that 43.7% of NSAID use was surreptitious. Multivariate logistic regression analysis identified only NSAID and analgesic abuse and the number of relapses as individually affecting refractoriness. CONCLUSIONS NSAID and analgesic abuse is the single most important exogenous factor associated with refractoriness. H. pylori infection emerges as an important intrinsic factor, but almost a quarter of refractory patients cannot be linked to either NSAID use or H. pylori infection.

Adaptation of Esophageal Mucosa to Acid- and Pepsin-Induced Damage (Role of Nitric Oxide and Epidermal Growth Factor)

To study whether the esophageal mucosa was ableto elicit mucosal adaptation, we induced esophagealdamage by perfusing acidified pepsin in rabbits. Mucosaladaptation was induced by preexposing the esophageal mucosa to a mild irritant (acidified saline)for 60 min prior to acidified pepsin (strong irritant).Macroscopic and microscopic esophageal injury, cellproliferation, and mucosal barrier function(H+, K+, hemoglobin flux rates)were studied. Preexposure of the esophageal mucosa toacidified saline significantly decreased both themucosal damage and the mucosal barrier dysfunctioninduced by acidified pepsin. The development of this phenomenon wasnondependent on cell proliferation. Concomitanttreatment with either the nitric oxide synthaseinhibitor, NG-nitro-L-arginine, or theperfusion of immunospecific EGF-receptor antibodies or tyrphostin-25, aninhibitor of the tyrosine kinase activities ligated tothe intracytoplasmatic domain of the EGF receptor,during the preexposure period completely reversed the protection induced by acid. We conclude thatthe rabbit esophageal mucosa shows mucosal adaptation toacid and pepsin. The development of this phenomenon isfast, not dependent on cell proliferation, and dependent, at least in part, on nitric oxideand EGF-receptor-mediated mechanisms.

Aspirin related gastrointestinal bleeders have an exaggerated bleeding time response due to aspirin use.

BACKGROUND: Gastrointestinal bleeding is related to non-steroidal anti-inflammatory drug (NSAID) use, especially aspirin, but only a small subset of users bleed. AIM: To look for risk factors or mechanisms whereby aspirin may promote gastrointestinal bleeding. PATIENTS: Sixty one patients with previous aspirin related upper gastrointestinal bleeding and 61 matched controls. METHODS: Patients and controls were given 375 mg of aspirin and sequential skin bleeding time and blood aspirin levels were measured. Additional studies included platelet lumiaggregation, von Willebrand factor, Factor VIII, and coagulation studies. RESULTS: Baseline skin bleeding time was similar in bleeders and controls, but bleeders had a more prolonged skin bleeding time after aspirin use. Hyper-response was more frequent in bleeders (30% v 9.3%; p < 0.01) and was associated with more than one previous separate bleeding event and a lower packed cell volume during the preceding bleeding episode. No differences were found in other factors studied. Logistic regression analysis identified prolonged skin bleeding time after aspirin use as an independent factor contributing to aspirin related gastrointestinal bleeding (RR = 5.4; 95% CI: 1.8 to 17.1). CONCLUSIONS: 30% of patients with a history of aspirin related gastrointestinal bleeding have an exaggerated prolongation of skin bleeding time in response to aspirin, which may be a risk factor for bleeding. This intrinsic defect or to subclinical von Willebrand disease or different aspirin metabolism.

CagA-positive Helicobacter pylori infection is not associated with decreased risk of Barrett's esophagus in a population with high H. pylori infection rate

Background & aimThe role that H. pylori infection plays in the development of and Barretts esophagus (BE) is uncertain. We tested the hypothesis that infection with cagA+ Helicobacter pylori strains protects against the development of BE.MethodsWe studied 104 consecutive patients, residents in an area with a high prevalence of H. pylori infection, with BE and 213 sex- and age-matched controls. H. pylori infection and CagA antibody status were determined by western blot serology.ResultsH. pylori prevalence was higher in patients with BE than in controls (87.5% vs. 74.6%; OR. 2.3; 95% CI: 1.23–4.59). Increasing age was associated with a higher prevalence of H. pylori (p < 0.05). The prevalence of CagA+ H. pylori serology was similar in patients with BE and controls (64.4% vs. 54.5%; NS). Type I H. pylori infection (CagA+ and VacA+) was similar in patients with BE and controls (44.2% vs. 41.3%; NS). Logistic regression analysis identified alcohol (O.R. 7.09; 95% CI 2.23–22.51), and H. pylori infection (OR: 2.41; 95%CI: 1.20–4.84) but not CagA+ serology as independent factors.ConclusionNeither H. pylori infection nor H. pylori infection by CagA+ strains reduce the risk of BE in a population with high prevalence of H. pylori infection.

Cytokine effects on pepsinogen secretion from human peptic cells.

BACKGROUND: Different cytokines, including epidermal growth factor (EGF) and interleukin 1 beta (IL 1 beta), participate in the pathogenesis of gastric mucosal damage and repair by means of different mechanisms that are either paracrine or autocrine in nature. AIMS: To study whether EGF and IL 1 beta affect pepsinogen secretion in vitro. METHODS: Dispersed human peptic cells were prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and density gradient centrifugation. RESULTS: EGF dose dependently increased basal pepsinogen secretion and mitogenic concentrations (0.1 nM) of EGF induced submaximal stimulation. Similar effects were observed with transforming growth factor alpha. EGF effects on pepsinogen secretion were in addition to that induced by CCK-OP and db-cAMP stimulated pepsinogen secretion. EGF stimulated pepsinogen secretion was completely inhibited by a human immunospecific EGF receptor antibody and reduced by both genistein and tyrphostin-25, two different tyrosine kinase inhibitors. IL 1 beta does not affect basal, CCK-OP or acetylcholine stimulated pepsinogen secretion. However, IL 1 beta dose dependently inhibited db-cAMP and histamine stimulated pepsinogen secretion. CONCLUSIONS: These results show that both EGF and IL 1 beta modulate human pepsinogen secretion in vitro and suggest that the paracrine effects of these cytokines on pepsinogen secretion might be involved in some pathological conditions of damage and inflammation of the gastric mucosa.

Aspirin renders the oesophageal mucosa more permeable to acid and pepsin

Objective: To examine the effects of aspirin on the oesophageal mucosa and on acid- and pepsin-induced oesophagitis Design and methods: The effects both of intraluminal (18 mg/ml) and of parenteral (100 mg/kg per h) aspirin on an in-vivo rabbit model of oesophagitis induced by acidified pepsin (pH 2) were studied. Oesophageal injury was assessed by macroscopic and microscopic scoring including the cell proliferation immunohistochemical parameter mib 1. The mucosal barrier function was determined by hydrogen, potassium and haemoglobin flux rates. Results: Acidified saline alone caused no damage, but the addition of aspirin induced mucosal barrier damage (P<0.05). The exposure of the oesophageal mucosa to acidified aspirin and then acidified pepsin significantly increased mucosal injury and mucosal barrier dysfunction compared with control experiments (exposure to acidified saline and acidified pepsin). This damage was significantly (P<0.05) reduced (>40%) by prostaglandin cotherapy (prostaglandin E2) administered before acidified aspirin exposure. Mucosal damage was less severe (P<0.05) when the oesophageal mucosa was exposed to a pH 6 aspirin solution. Parenterally administered aspirin also increased the oesophageal damage induced by acidified pepsin compared with control experiments, but the damage was 23% lower than that obtained with intraluminal aspirin. Cell proliferation studies showed a significant increase in the number of positive cells in those experiments with a higher degree of damage and in those treated with prostaglandins. Conclusion: Aspirin renders the oesophageal mucosa more permeable to acid and pepsin. These effects are in part part pH-dependent and might be partially reversed by prostaglandin E2 cotherapy.

Platelet-Derived Growth Factor and Epidermal Growth Factor Play a Major Role in Human Colonic Fibroblast Repair Activities

Background and Aims: Ulceration is a common feature of inflammatory bowel diseases, where subepithelial cell growth is frequently necessary for resolution. In order to further understand the role of colonic fibroblasts in this process, we have used an in vitro model of wound repair to study the response of human colonic fibroblasts to several growth factors expressed in colonic tissues. Methods: Proliferation was determined by [3H]thymidine incorporation into DNA in subconfluent fibroblast cultures. In vitro wound repair was determined in confluent fibroblast monolayers after mechanical denudation. The presence of growth factors secreted by fibroblasts was studied in conditioned medium by heparin affinity chromatography and immunodetection with specific antibodies. Results: Serum and platelet-derived growth factor (PDGF-BB) induced a dramatic increase in both colonic fibroblast proliferation and closure of wounded cell monolayers. Epidermal growth factor (EGF) stimulated both fibroblast activities, but the effect was less potent. However, colonic fibroblasts did not respond to transforming growth factor-β1. Conditioned medium stimulated fibroblast proliferation and wound repair activity, which was reverted by the addition of suramin. Furthermore, a PDGF-like factor was isolated from colonic fibroblast-conditioned medium. Conclusions: EGF and PDGF-BB promote human colonic fibroblast-dependent wound repair activities. Human colonic fibroblasts may exert an autocrine regulation via the production of growth factors.