Jose G. Ferraz

Antireflux surgery followed by bipolar electrocoagulation in the treatment of Barrett’s esophagus

BACKGROUND Management of Barretts esophagus requires reduction of gastric acid secretion and screening for the development of adenocarcinoma. However, the current therapeutic options are ineffective in reducing the Barretts mucosa. The aim of this study was to evaluate the effectiveness of endoscopic thermal coagulation of Barretts mucosa as an alternative therapeutic approach and the recurrence of the disease in the long term. METHODS Fourteen patients (11 men, 3 women; mean age 45.7 years) with Barretts esophagus participated in the study. They underwent laparoscopic fundoplication and were symptom free with no defective fundoplication wraps before therapeutic endoscopy. Endoscopic thermocoagulation was performed with a flexible videoendoscope and a bipolar probe. Mucosal areas were treated once a month until the Barretts mucosa disappeared. Endoscopy was performed 1 and 7 months after completion of the treatments and once a year thereafter. RESULTS The mean follow-up period was 21.6 months (range 18 to 30 months). The mean length of Barretts esophagus was 4.8 cm. Successful ablation of the columnar epithelium was achieved in 3.7 sessions, as defined by demonstration of normal squamous epithelium at histologic examination of biopsy samples collected after completion of the treatments and at follow-up evaluations. Three patients experienced short-term (10 days) odynophagia or dysphagia. All patients were symptom free with no evidence of Barretts esophagus at the end of the study. CONCLUSIONS Bipolar electrocoagulation after antireflux operations is effective in promoting regression of Barretts esophagus and has few complications. Endoscopic thermal coagulation might reduce risk for adenocarcinoma among these patients.

A pro-resolution mediator, prostaglandin D2, is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Patients with ulcerative colitis (UC) experience unpredictable bouts of active inflammation and ulceration. Relatively little attention has been paid to the role of antiinflammatory mediators in the pathogenesis of UC, although rodent studies suggest an important role of prostaglandin (PG) D2 in the resolution of tissue injury and inflammation. The present study was performed to determine if colonic PGD2 synthesis was altered in patients in remission from UC and if expression of the key enzymes and receptors related to PGD2 was altered. During routine colon-cancer screening, colonic biopsies were obtained from healthy individuals, some of whom had been in remission from UC, without treatment, for >4 y. UC patients with active disease or in medically induced remission were also biopsied. Only patients with active UC exhibited elevated expression of several proinflammatory cytokines (TNFα and IFNγ) and colonic PGE2 synthesis. In contrast, colonic PGD2 synthesis was only elevated (∼3-fold) in the healthy individuals with a prior history of UC. This group also exhibited significantly elevated expression of DP1, the key receptor mediating the antiinflammatory actions of PGD2. Expression of the synthetic enzymes cyclooxygenase-1, cyclooxygenase-2, and hematopoietic PGD synthase was not altered in the healthy individuals with a prior history of UC. These results show a marked up-regulation of synthesis of an antiinflammatory prostanoid and expression of its receptor, specifically in individuals in long-term remission from UC. This is consistent with animal studies showing the importance of PGD2 in the induction and maintenance of remission from colitis.

Increased Primary Resistance to Recommended Antibiotics Negatively Affects Helicobacter pylori Eradication

Objective. To evaluate the efficacy of two commonly employed treatments for Helicobacter pylori infection and the impact of bacterial resistance to antibiotics on eradication rate.

Cyclooxygenase selectivity of non-steroid anti-inflammatory drugs in humans: ex vivo evaluation.

We have recently described a novel assay to assess ex vivo the activity and selectivity on cyclooxygenase-1 and -2 (EC 1.14.99.1) of non-steroid anti-inflammatory drugs (NSAID) administered to rats [Br. J. Pharmacol. 126 (1999) 1824.]. Here, we have extended these studies to humans. Healthy male volunteers were given orally one of the following drugs (mg) for 5 days: etodolac (200 or 400 b.i.d.), meloxicam (7.5 or 15 q.d.), nimesulide (100 or 200 b.i.d.), nabumetone (500 or 1000 b.i.d.) or naproxen (500 b.i.d.). Blood samples were withdrawn from the volunteers before and up to 24 h after the last dose. Plasma obtained from the blood was tested for its ability to inhibit prostanoid formation in interleukin-1beta-treated A549 cells (cyclooxygenase-2 system) and human washed platelets (cyclooxygenase-1 system). Plasma from etodolac-treated subjects demonstrated a slight selectivity towards the inhibition of cyclooxygenase-2. This effect was more prominent in plasma from subjects receiving meloxicam or nimesulide. Plasma from nabumetone-treated subjects showed no or little selectivity towards cyclooxygenase-1 depending on the dose of drug administered, while plasma taken from subjects receiving naproxen was more active at inhibiting cyclooxygenase-1 than cyclooxygenase-2. In conclusion, we have demonstrated that this assay can be used to assess ex vivo the relative activity against cyclooxygenase-1 and cyclooxygenase-2 of NSAIDs consumed by human volunteers. It is to be hoped that data from such systems will aid in our understanding of the relationships between the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by NSAIDs and their reported efficacies and (gastrointestinal) toxicities.

Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1α

During a course of colitis, production of the gaseous mediator hydrogen sulfide (H2S) is markedly up‐regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H2S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H2S in experimental colitis are mediated via stabilization of hypoxia‐inducible factor (HIF)‐1α. The hapten dinitrobenzene sulfonic acid was used to induce colitis in rats and mice. This resulted in an elevated expression of the H2S‐producing enzyme, cystathionine γ‐lyase (CSE), and HIF‐1α at sites of mucosal ulceration, and the expression of these 2 enzymes followed a similar pattern throughout the course of colitis. This represented a functionally important relationship because the loss of CSE‐derived H2S production led to decreased HIF‐1α stabilization and exacerbation of colitis. Furthermore, application of an H2S‐releasing molecule, diallyl disulfide (DADS), stabilized colonic HIF‐1α expression, up‐regulated hypoxia‐responsive genes, and reduced the severity of disease during peak inflammation. Importantly, the ability of DADS to promote the resolution of colitis was abolished when coadministered with an inhibitor of HIF‐1α in vivo (PX‐478). DADS was also able to maintain HIF‐1α expression at a later point in colitis, when HIF‐1α levels would have normally returned to control levels, and to enhance resolution. Finally, we found that HIF‐1α stabilization inhibited colonic H2S production and may represent a negative feedback mechanism to prevent prolonged HIF‐1α stabilization. Our findings demonstrate an important link between H2S and HIF‐1α in the resolution of inflammation and injury during colitis and provide mechanistic insights into the therapeutic value of H2S donors.—Flannigan, K. L., Agbor, T. A., Motta, J. ‐P., Ferraz, J. G. P., Wang, R, Buret, A. G., Wallace, J. L. Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia‐inducible factor‐1α. FASEB J. 29, 1591‐1602 (2015). www.fasebj.org

Comparative study of eosinophil chemotaxis, adhesion, and degranulation in vitro in ulcerative colitis and Crohn's disease

Background Eosinophils have been identified in tissues from patients with Crohns disease (CD) and ulcerative colitis (UC) but whether they contribute to IBD pathogenesis is unknown. This study aimed to investigate the functional activity and morphological aspects of peripheral‐blood eosinophils from IBD patients compared to those from healthy volunteers (HVs). Methods Eosinophils from HVs and CD and UC patients were purified using a Percoll gradient and then a immunomagnetic cell separator. Functional activity in inactivated and previously activated cells was investigated by measuring adhesion to fibronectin and chemotaxis to fMLP, and degranulation was measured by release of eosinophil peroxidase (EPO). Cell morphology was investigated using electron microscopy. Results Eosinophil adhesion to human fibronectin in both inactivated and PAF‐stimulated and PMA‐stimulated eosinophils was markedly higher in patients with CD than in either patients with UC or HVs. Similarly, the chemotactic response was markedly higher in eosinophils isolated from CD patients than in those isolated from UC patients or HVs. Baseline EPO release was higher in eosinophils isolated from UC patients than in those isolated from HVs or CD patients. Stimulation with fMLP or PMA did not further increase EPO release in cells from UC or CD patients. Comparable expression of MAC‐1 and VLA‐4 adhesion molecules was observed on the surfaces of eosinophils from all groups, and an greater number of granules was noted in the eosinophils from UC patients than in those from CD patients. Conclusions Our results indicate that peripheral‐blood eosinophils are potentially primed and activated in IBD patients. Whether the differences in the morphology and functional responses of eosinophil from UC and CD patients reflect differences in disease phenotype remains to be elucidated. (Inflamm Bowel Dis 2007)

Absolute ethanol and 5% ethanolamine oleate are comparable for sclerotherapy of esophageal varices

BACKGROUND Endoscopic sclerotherapy is widely accepted as an effective treatment for the eradication of esophageal varices in patients with portal hypertension and a history of upper gastrointestinal bleeding. The objective of this study was to assess the effectiveness and safety of absolute ethanol as an alternative sclerosing agent to the commonly used 5% ethanolamine oleate. METHODS One hundred fifty-seven patients with portal hypertension and a history of variceal bleeding were randomly assigned to sclerotherapy with absolute ethanol (n = 66) or 5% ethanolamine oleate (n = 91) between January 1992 and July 1994. Once eradication was achieved, these patients were prospectively followed until September 1998. RESULTS Sclerotherapy with both sclerosants resulted in similar eradication rates (approximately 90%), with comparable numbers of sessions required for eradication (5.4 and 5.9 sessions for absolute ethanol and 5% ethanolamine oleate, respectively). Similar complication and recurrent bleeding rates were observed among both groups. CONCLUSION Sclerotherapy with absolute ethanol is as effective as with 5% ethanolamine oleate in preventing further bleeding in patients with portal hypertension.

Transfer of Clarithromycin to Gastric Juice is Enhanced by Omeprazole in Helicobacter pylori -Infected Individuals

Background: The effects of proton-pump inhibitors and Helicobacter pylori infection on the distribution of drugs employed for the eradication of H. pylori are poorly understood. The aim of this study was to investigate the effects of a 7-day oral administration of 20 mg omeprazole on the distribution of clarithromycin in the gastric juice of individuals with H. pylori infection. Methods: Eighteen H. pylori infected dyspeptic male volunteers without endoscopic lesions were enrolled in a study with an open, randomized, two-period crossover design and a 21-day washout period between phases. Plasma and gastric juice concentrations of clarithromycin in subjects with and without omeprazole pretreatment were measured by means of liquid chromatography coupled to tandem mass spectrometry. Results: The maximum concentration of clarithromycin (C max ) and the area under the time-concentration curve from 0 to 2 h (AUC 0-2h ) were significantly higher in gastric juice than in plasma. Omeprazole treatment further augmented clarithromycin C max and AUC 0-2h in gastric juice approximately 2-fold ( P < 0.05). Conclusions: Short-term treatment with omeprazole in H. pylori -positive volunteers increases the amount of clarithromycin transferred to the gastric juice, confirming a synergism between these drugs. Our results suggest the presence of an active transport mechanism for clarithromycin from plasma to the gastric lumen, which is influenced by omeprazole.Background: The effects of proton-pump inhibitors and Helicobacter pylori infection on the distribution of drugs employed for the eradication of H. pylori are poorly understood. The aim of this study was to investigate the effects of a 7-day oral administration of 20 mg omeprazole on the distribution of clarithromycin in the gastric juice of individuals with H. pylori infection. Methods: Eighteen H. pylori infected dyspeptic male volunteers without endoscopic lesions were enrolled in a study with an open, randomized, two-period crossover design and a 21-day washout period between phases. Plasma and gastric juice concentrations of clarithromycin in subjects with and without omeprazole pretreatment were measured by means of liquid chromatography coupled to tandem mass spectrometry. Results: The maximum concentration of clarithromycin (C max ) and the area under the time-concentration curve from 0 to 2 h (AUC 0-2h ) were significantly higher in gastric juice than in plasma. Omeprazole treatment further augme...

Bleeding Duodenal Varices Successfully Treated with TIPS

Upper gastrointestinal hemorrhage is a life-threatening complication of liver cirrhosis and portal hypertension. It is well recognized that, despite adequate pharmacologic and endoscopic therapy, there is a 20–35% mortality ratio in the first occurrence of gastrointestinal bleeding [1, 2]. Ruptured esophageal varices, peptic ulcer disease, portal hypertensive gastropathy, and ruptured gastric varices are most commonly associated with bleeding events, and the severity seems to be associated with the degree of liver dysfunction. The most common site of variceal bleeding is the lower esophagus, followed by gastric varices. These can be detected in up to 25% of portal hypertensive, cirrhotic patients [3–5]. Duodenal varices are uncommon among cirrhotic patients [6], and bleeding duodenal varices represent a major challenge for management, as both pharmacological and endoscopic therapy may not fully control hemorrhage. We report a case of a patient diagnosed with liver cirrhosis and portal hypertension on a waiting list for liver transplantation who developed upper gastrointestinal bleeding secondary to duodenal varices, managed with transjugular intrahepatic portosystemic shunt (TIPS). Endoscopic features preand post-TIPS are reviewed.

Amoxicillin and ampicillin are not transferred to gastric juice irrespective of Helicobacter pylori status or acid blockade by omeprazole

The effects of proton pump inhibitors and Helicobacter pylori infection on the distribution of drugs used for the eradication of the bacteria are poorly understood.