Gastrointestinal safety of triflusal solution in healthy volunteers: a proof of concept endoscopic study.

PURPOSE: Triflusal is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. It was initially marketed as capsules containing 300 mg of active substance. In 2006 a new 600 mg (10 ml) oral solution form of triflusal was authorized in Spain. The primary aim of this study was to compare the gastrointestinal safety of the new triflusal oral solution with triflusal capsules in healthy volunteers. METHODS: Sixty healthy subjects were randomly assigned, in a 2.5:2.5: 1 ratio, into one of three groups, with 25 subjects receiving one bottle of triflusal oral solution (600 mg) daily, 25 subjects receiving two triflusal capsules (600 mg) once daily, and ten subjects receiving two placebo capsules once daily, respectively, during 7 consecutive days. Gastroscopy was performed at baseline before the administration of study drugs and after 4-8 h of the last dose of study drugs. Effects on the esophagus, stomach, and duodenum were measured in accordance with a modified Lanza scale. RESULTS: No differences between groups were detected at baseline. After treatment, median global scores in the placebo, triflusal solution, and triflusal capsules groups were, respectively, 0, 1, and 3 (p = 0.003 for comparison between placebo and triflusal capsules and p = 0.042 for comparison between triflusal solution and triflusal capsules). There were no significant differences between the scores on the triflusal solution and placebo groups. All treatments were well tolerated. CONCLUSION: In healthy subjects, triflusal solution induced less endoscopically apparent gastrointestinal mucosal damage than triflusal capsules and did not induce more damage than the placebo in healthy volunteers.

Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.

BACKGROUND & AIMS: Studies of variceal bleeding have shown that a hemodynamic response to treatment of portal hypertension is appropriate when the hepatic venous pressure gradient (HVPG) decreases below 12 mmHg or by > 20% from baseline. However, in primary prophylaxis, many nonresponders do not bleed and 2 invasive procedures are needed to assess response. We investigated the long-term prognostic value of an acute response to beta-blockers and whether the target reduction in HVPG can be improved in primary prophylaxis. METHODS: An initial hemodynamic study was performed in patients with large varices and without previous bleeding. After baseline measurements were made, propranolol was administered intravenously and measurements were repeated 20 minutes later. Patients were given nadolol daily and a second hemodynamic study was performed. RESULTS: Of 105 patients, 15% had variceal bleeding. Using receiver operating characteristic curve analysis, a decrease of HVPG > or = 10% was the best value to predict bleeding. In the initial study, 75 patients (71%) were responders (HVPG decreased to < or = 12 mmHg or by > or = 10%) and had a lower probability of first bleeding than nonresponders (4% vs 46% at 24 months; P < .001). Acute responders also had a lower risk of developing ascites (P = .001). Chronic responders had a lower probability of bleeding than nonresponders (P < .001). There was a correlation between acute and chronic changes in HVPG (r = 0.62; P = .01). CONCLUSION: The acute hemodynamic response to beta-blockers can be used to predict the long-term risk of first bleeding. An HVPG reduction > 10% from baseline is the best target to define response in primary prophylaxis.

Variceal bleeding : pharmacological treatment and prophylactic strategies.

Oesophageal varices and ascites may develop when the hepatic venous pressure gradient (HVPG) increases above 10 mmHg, and variceal bleeding may occur when the HVPG rises above 12 mmHg. Pharmacological therapy of portal hypertension may prevent bleeding by reducing the HVPG below 12 mmHg. Even if this threshold level is not reached, the risk of bleeding decreases markedly with reductions in HVPG that are >20% from baseline.Endoscopic therapy is a local treatment that prevents bleeding by obliterating the varices, and has no effect on the pathophysiological mechanisms that lead to portal hypertension and variceal rupture. When used together, both pharmacological and endoscopic therapies may have an additive effect, which has been demonstrated in different clinical settings. In acute oesophageal variceal bleeding, vasoactive drugs (either terlipressin or somatostatin) should be started as soon as possible (before diagnostic endoscopy) and maintained for 2-5 days. The efficacy of pharmacotherapy is improved with the addition of emergency endoscopic therapy. Adding endoscopic variceal ligation (EVL) improves the efficacy and safety achieved with the combination of emergency sclerotherapy and vasoactive drugs. Antibacterial prophylaxis should be an integral part of therapy in acute bleeding.To prevent rebleeding, both EVL and the combination of beta-adrenoceptor antagonists (beta-blockers) and isosorbide mononitrate (ISMN) may be a valid first-line choice. Adding beta-blockers improves the efficacy of EVL alone. Haemodynamic responders to beta-blockers with or without ISMN (i.e. those with a decrease in HVPG to <12 mmHg or by >20% of baseline) have a reduction in the risk of haemorrhage to below 10% of patients and, consequently, will not need further treatment, while rescue therapies should be provided to nonresponders. Transjugular intrahepatic portosystemic shunts are the recommended rescue therapy when EVL and/or beta-blockers with or without ISMN fail. beta-Blockers significantly reduce the risk of a first haemorrhage in patients with large varices and improve survival. Compared with beta-blockers, EVL reduces the risk of first bleeding without any differences in mortality and should be offered to patients with large varices who have contraindications or an intolerance to beta-blockers.

Influence of a nucleotide oligomerization domain 1 (NOD1) polymorphism and NOD2 mutant alleles on Crohn's disease phenotype.

AIM: To examine genetic variation of nucleotide oligomerization domain 1 (NOD1) and NOD2, their respective influences on Crohn's disease phenotype and gene-gene interactions. METHODS: (ND(1)+32656*) NOD1 polymorphism and SNP8, SNP12 and SNP13 of NOD2 were analyzed in 97 patients and 50 controls. NOD2 variants were determined by reaction restriction fragment length polymorphism analysis. NOD1 genotyping and NOD2 variant confirmation were performed by specific amplification and sequencing. RESULTS: The distribution of NOD1 polymorphism in patients was different from controls (P = 0.045) and not altered by existence of NOD2 mutations. In this cohort, 30.92% patients and 6% controls carried at least one NOD2 variant (P < 0.001) with R702W being the most frequent variant. Presence of at least one NOD2 mutation was inversely associated with colon involvement (9.09% with colon vs 36.4% with ileal or ileocolonic involvement, P = 0.04) and indicative of risk of penetrating disease (52.63% with penetrating vs 25.64% with non-penetrating or stricturing behavior, P = 0.02). L1007finsC and double NOD2 mutation conferred the highest risk for severity of disease (26.3% with penetrating disease vs 3.8% with non-penetrating or stricturing behavior presented L1007finsC, P = 0.01 and 21.0% with penetrating disease vs 2.5% with non-penentrating or stricturing behavior carried double NOD2 mutation, P = 0.007). Exclusion of patients with NOD2 mutations from phenotype/NOD1-genotype analysis revealed higher prevalence of *1*1 genotype in groups of younger age at onset and colonic location. CONCLUSION: This study suggests population differences in the inheritance of risk NOD1 polymorphism and NOD2 mutations. Although no interaction between NOD1-NOD2 was noticed, a relationship between disease location and Nod-like receptor molecules was established.

A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding.

BACKGROUND/AIMS: The currently recommended treatment for acute variceal bleeding is the association of vasoactive drugs and endoscopic therapy. However, which emergency endoscopic treatment combines better with drugs has not been clarified. This study compares the efficacy and safety of variceal ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin. METHODS: Patients admitted with acute gastrointestinal bleeding and with suspected cirrhosis received somatostatin infusion (for 5 days). Endoscopy was performed within 6h and those with esophageal variceal bleeding were randomized to receive either sclerotherapy (N=89) or ligation (N=90). RESULTS: Therapeutic failure occurred in 21 patients treated with sclerotherapy (24%) and in nine treated with ligation (10%) (RR=2.4, 95% CI=1.1-4.9). Failure to control bleeding occurred in 15% vs 4%, respectively (P=0.02). Treatment group, shock and HVPG >16 mmHg were independent predictors of failure. Side-effects occurred in 28% of patients receiving sclerotherapy vs 14% with ligation (RR=1.9, 95% CI=1.1-3.5), being serious in 13% vs 4% (P=0.04). Six-week survival probability without therapeutic failure was better with ligation (P=0.01). CONCLUSIONS: The use of variceal ligation instead of sclerotherapy as emergency endoscopic therapy added to somatostatin for the treatment of acute variceal bleeding significantly improves the efficacy and safety.

TNF alpha production to TLR2 ligands in active IBD patients.

Strong evidence suggests that microbial components are involved in the etiopathology of inflammatory bowel diseases (IBD). Since pathogen-associated molecular patterns are recognized by TLRs, dysregulation of TLR-mediated microbial recognition could be taking place in IBD patients. An in vitro assay with different TLR agonists was used to reproduce the immunostimulation via TLR ligands. Elevated TNFalpha production was found in response to LTA and Zymosan in 48% of active Crohn's disease and ulcerative colitis patients when compared to inactive patients or controls. The expression of CD14 did not differ in active patients, whereas TLR2 was significantly upregulated on monocytes from 71% of those patients with high production of TNFalpha. The marked increase of TNFalpha response to TLR2 ligands correlated with a higher TLR2 expression in a group of IBD patients, suggesting that an abnormal mechanism may provide an excess of inflammatory mediators during the active phase of IBDs.

Pharmacologic treatment of portal hypertension in the prevention of community-acquired spontaneous bacterial peritonitis.

INTRODUCTION: Given that beta-blockers reduce the incidence of bacterial translocation in cirrhotic rats, the aim of this study was to compare the long-term incidence of spontaneous bacterial peritonitis in cirrhotic patients submitted to pharmacologic versus endoscopic treatment to prevent variceal rebleeding. PATIENTS AND METHODS: Two hundred and thirty patients with variceal hemorrhage were included in two previous randomized trials performed to compare the efficacy of medication (nadolol plus isosorbide mononitrate, n=115) versus endoscopic treatment (n=115) with sclerotherapy or ligation for the prevention of rebleeding. RESULTS: The mean follow-up was 23+/-1.4 months. The characteristics of the patients and the number of patients on long-term prophylaxis with norfloxacin were similar in both groups. The incidence of spontaneous bacterial peritonitis was lower in the medication group (9 versus 14.7%, P=NS). The probability of spontaneous bacterial peritonitis was also lower in the medication group (6 versus 12% at 1 year, 22 versus 36% at 5 years; P=0.08), due to a significantly lower probability of community-acquired spontaneous bacterial peritonitis in this group (1 versus 10% at 1 year, 18 versus 32% at 5 years; P=0.02). Patients with no hemodynamic response to therapy had a significantly higher probability to develop community-acquired spontaneous bacterial peritonitis during follow-up than hemodynamic responders (P<0.03). Long-term probability of developing community-acquired spontaneous bacterial peritonitis is lower in patients submitted to pharmacologic treatment for preventing variceal rebleeding than in those submitted to endoscopic treatment. CONCLUSION: Long-term pharmacologic prophylaxis of variceal rebleeding contributes to the prevention of community-acquired spontaneous bacterial peritonitis.

A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use.

BACKGROUND: The worst outcome of gastrointestinal complications is death. Data regarding those associated with nonsteroidal antiinflammatory drug (NSAID) or aspirin use are scarce. AIM: To determine mortality associated with hospital admission due to major gastrointestinal (GI) events and NSAID/aspirin use. METHODS: The study was based on actual count of deaths from two different data sets from 2001. Study 1 was carried out in 26 general hospitals serving 7,901,198 people. Study 2 used a database from 197 general hospitals, representative of the 269 hospitals in the Spanish National Health System. Information regarding gastrointestinal complications and deaths was obtained throughout the Minimum Basic Data Set (CIE-9-MC) provided by participating hospitals. Deaths attributed to NSAID/aspirin use were estimated on the basis of prospectively collected data from hospitals of study 1. RESULTS: The incidence of hospital admission due to major GI events of the entire (upper and lower) gastrointestinal tract was 121.9 events/100,000 persons/year, but those related to the upper GI tract were six times more frequent. Mortality rate was 5.57% (95% CI = 4.9-6.7), and 5.62% (95% CI = 4.8-6.8) in study 1 and study 2, respectively. Death rate attributed to NSAID/aspirin use was between 21.0 and 24.8 cases/million people, respectively, or 15.3 deaths/100,000 NSAID/aspirin users. Up to one-third of all NSAID/aspirin deaths can be attributed to low-dose aspirin use. CONCLUSION: Mortality rates associated with either major upper or lower GI events are similar but upper GI events were more frequent. Deaths attributed to NSAID/ASA use were high but previous reports may have provided an overestimate and one-third of them can be due to low-dose aspirin use.

Hemodynamic effects of terlipressin and high somatostatin dose during acute variceal bleeding in nonresponders to the usual somatostatin dose.

OBJECTIVES: High dose of somatostatin infusion achieves a greater reduction of hepatic venous pressure gradient (HVPG) than the usual dose, and terlipressin decreases HVPG through mechanisms other than somatostatin. Our aim was to assess the hemodynamic effects of terlipressin and high somatostatin dose during acute variceal bleeding in nonresponders to the usual somatostatin dose. METHODS: Hemodynamic studies were performed in 80 patients with cirrhosis and variceal bleeding during the first 3 days of admission. After baseline measurements, somatostatin was administered (250 microg/h with an initial bolus of 250 microg). Patients were considered responders when the HVPG decreased by >10% from baseline (n = 31). Nonresponders were randomized under double-blind conditions to a control group (n = 7), or to receive terlipressin (2 mg IV bolus, n = 22), or high dose of somatostatin (500 microg/h, n = 20). Final measurements were obtained 30 min later. RESULTS: Terlipressin caused a decrease in HVPG (from 22.2 +/- 5 to 19.1 +/- 5.2, p < 0.01) and heart rate (p < 0.01), while mean arterial pressure increased (p < 0.01). High somatostatin dose also reduced HVPG (from 21.8 +/- 3.4 to 19.6 +/- 3.1, p < 0.01), although this decrease was more pronounced with terlipressin (15%+/- 9%vs 10%+/- 6% from baseline, p= 0.05). Both terlipressin and high somatostatin dose achieved a significantly higher rate of response than that in the control group. A decrease in HVPG >20% was observed in 36% of cases with terlipressin versus 5% with high somatostatin dose (p= 0.02). CONCLUSIONS: In nonresponders to usual somatostatin dose, both terlipressin and high-dose of somatostatin infusion significantly decreased HVPG and increased the rate of hemodynamic responders. Such effects were greater with terlipressin. Both treatments may be an alternative when standard somatostatin fails.

Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis.

BACKGROUND/AIMS: Following treatment with beta blockers in patients with cirrhosis and portal hypertension, reduction of hepatic venous pressure gradient (HVPG) to <12 mmHg or by >20% of baseline induces an extremely low risk of variceal bleeding. However, several factors such as compliance to therapy or alcohol abstinence may change the initial response after a long follow-up, and the effect of response on other complications of cirrhosis is less clear. The aim of this study was to assess the long-term maintenance of hemodynamic response and its influence on complications of cirrhosis. METHODS: One hundred and thirty two cirrhotic patients received nadolol and isosorbide mononitrate to prevent variceal rebleeding. HVPG was measured at baseline, after 1 to 3 months under treatment and again 12 to 18 months later. RESULTS: Sixty four patients were responders. After a longer follow-up, earlier response did not change in 81% of cases. Changes of response were mainly related to modifications in medication dose or in alcohol intake. As compared with poor-responders, responders had a lower probability of developing ascites (P<0.001) and related conditions, a greater improvement of Child-Pugh score (P=0.03), and a lower likelihood of developing encephalopathy (P=0.001) and of requiring liver transplantation (P=0.002). Eleven responders and 22 poor-responders died (P=0.029). CONCLUSIONS: Hemodynamic response to treatment of portal hypertension is usually sustained after a long-term follow-up. Response decreases the probability of developing complications of cirrhosis and the need for liver transplantation, and significantly improves survival.

Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis.

BACKGROUND/AIMS: Probiotics and antioxidants could be alternatives to antibiotics in the prevention of bacterial infections in cirrhosis. The aim of the present study was to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats. METHODS: Twenty-nine Sprague-Dawley rats with cirrhosis induced by CCl(4) and ascites received Lactobacillus johnsonii La1 10(9)cfu/day in vehicle (antioxidants: vitamin C+glutamate) (n=10), vehicle alone (n=11), or water (n=8) by gavage. Another eight non-cirrhotic rats formed the control group. After 10 days of treatment, a laparotomy was performed to determine microbiological study of ileal and cecal feces, bacterial translocation, endotoxemia, and intestinal malondialdehyde (MDA) levels as index of intestinal oxidative damage. RESULTS: Intestinal enterobacteria and enterococci, bacterial translocation (0/11 and 0/10 vs. 5/8, P<0.01), and ileal MDA levels (P<0.01) were lower in cirrhotic rats treated with antioxidants alone or in combination with Lactobacillus johnsonii La1 compared to cirrhotic rats receiving water. Only rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05). CONCLUSIONS: Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis.