Angel Cosme

Resveratrol inhibits nonalcoholic fatty liver disease in rats

BackgroundThe prevalence of nonalcoholic fatty liver disease (NAFLD) is high. NAFLD is linked to obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with NAFLD will eventually develop cirrhosis. Our purpose was to investigate whether resveratrol decreased hepatic steatosis in an animal model of steatosis, and whether this therapeutic approach resulted in a decrease in tumor necrosis factor α (TNF-α) production, lipid peroxidation and oxidative stress.MethodsMale Wistar CRL: Wi (Han) (225 g) rats were randomized into three groups. A control group (n = 12) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 12) and resveratrol (n = 12) groups were given free access to feed (a high carbohydrate-fat free modified diet) and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. Rats in the resveratrol group were given resveratrol 10 mg daily by the oral route. All rats were killed at 4 weeks and assessed for fatty infiltration and bacterial translocation. Levels of TNF-α in serum, hepatic malondialdehyde (MDA), oxidative stress (superoxide dismutase, glutathione peroxidase, catalase and nitric oxide synthase) and biochemical parameters were measured.ResultsFat deposition was decreased in the resveratrol group as compared to the steatosis group (Grade 1 vs Grade 3, P < 0.05). TNF-α and MDA levels were significantly increased in the steatosis group (TNF-α; 33.4 ± 5.2 vs 26.24 ± 3.47 pg/ml and MDA; 9.08 ± 0.8 vs 3.17 ± 1.45 μM respectively, P < 0.05). This was accompanied by increased superoxide dismutase, glutathione peroxidase and catalase and decreased nitric oxide synthase in the liver of resveratrol group significantly (P < 0.05 vs steatosis group). Bacterial translocation was not found in any of the groups. Glucose levels were decreased in the group of rats given resveratrol (P < 0.05).ConclusionResveratrol decreased NAFLD severity in rats. This effect was mediated, at least in part, by TNF-α inhibition and antioxidant activities.

Third-Line Rescue Therapy with Levofloxacin After Two H. pylori Treatment Failures

AIM:Eradication therapy with proton pump inhibitor, clarithromycin and amoxicillin fails in a considerable number of cases. A rescue therapy still fails in more than 20% of the cases. Our aim was to evaluate the efficacy and tolerability of a third-line levofloxacin-based regimen in patients with two consecutive Helicobacter pylori eradication failures.METHODS:Design: Prospective multicenter study. Patients: In whom a first treatment with omeprazole-clarithromycin-amoxicillin and a second with omeprazole-bismuth-tetracycline-metronidazole (or ranitidine bismuth citrate with these antibiotics) had failed. Intervention: A third eradication regimen with levofloxacin (500 mg b.i.d.), amoxicillin (1 g b.i.d.), and omeprazole (20 mg b.i.d.) was prescribed for 10 days. Outcome: Eradication was confirmed with 13C-urea breath test 4–8 wk after therapy.RESULTS:One-hundred patients were initially included, and nine were lost for follow-up. All patients but five took all the medications correctly. Per-protocol and intention-to-treat eradication rates were 66% (95% CI = 56–75%) and 60% (50–70%). Adverse effects were reported in 25% of the patients, mainly including metallic taste (8%), nausea (8%), myalgia/arthralgia (5%), and diarrhea (4%); none of them were severe.CONCLUSION:Levofloxacin-based rescue therapy constitutes an encouraging empirical third-line strategy after multiple previous H. pylori eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, and tetracycline.

Second-Line Rescue Therapy With Levofloxacin After H. pylori Treatment Failure: A Spanish Multicenter Study of 300 Patients

AIM:Quadruple therapy is generally recommended as second-line therapy after Helicobacter pylori (H. pylori) eradication failure. However, this regimen requires the administration of four drugs with a complex scheme, is associated with a relatively high incidence of adverse effects, and bismuth salts are not available worldwide anymore. Our aim was to evaluate the efficacy and tolerability of a triple second-line levofloxacin-based regimen in patients with H. pylori eradication failure.METHODS:Design: Prospective multicenter study. Patients: in whom a first treatment with proton pump inhibitor-clarithromycin-amoxicillin had failed. Intervention: A second eradication regimen with levofloxacin (500 mg b.i.d.), amoxicillin (1 g b.i.d.), and omeprazole (20 mg b.i.d.) was prescribed for 10 days. Outcome: Eradication was confirmed with 13C-urea breath test 4–8 wk after therapy. Compliance with therapy was determined from the interview and the recovery of empty envelopes of medications. Incidence of adverse effects was evaluated by means of a specific questionnaire.RESULTS:Three hundred consecutive patients were included. Mean age was 48 yr, 47% were male, 38% had peptic ulcer, and 62% functional dyspepsia. Almost all (97%) patients took all the medications correctly. Per-protocol and intention-to-treat eradication rates were 81% (95% CI 77–86%) and 77% (73–82%). Adverse effects were reported in 22% of the patients, mainly including nausea (8%), metallic taste (5%), abdominal pain (3%), and myalgias (3%); none of them were severe.CONCLUSION:Ten-day levofloxacin-based rescue therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous proton pump inhibitor-clarithromycin-amoxicillin failure, being simple and safe.

The prevalence of peptic ulcer not related to Helicobacter pylori or non-steroidal anti-inflammatory drug use is negligible in southern Europe.

Background and Aim.  Helicobacter pylori is the major cause of peptic ulcer disease, but the proportion of H. pylori‐negative peptic ulcers seems to be increasing in developed countries. We investigated the frequency of H. pylori‐negative peptic ulcer without intake of nonsteroidal anti‐inflammatory drugs (NSAIDs) in a Mediterranean European country.

Clinical patterns and outcomes of ischaemic colitis: results of the Working Group for the Study of Ischaemic Colitis in Spain (CIE study).

Abstract Background. There is a lack of prospective studies evaluating the natural history of colonic ischaemia (CI). We performed such a study to evaluate the clinical presentation, outcome, and mortality as well as clinical variables associated with poor prognosis. Methods. An open, prospective, and multicentre study was conducted in 24 Spanish hospitals serving a population of 3.5 million people. The study included only patients who met criteria for definitive or probable CI. A website (www.colitisisquemica.org) provided logistical support. Results. A total of 364 patients met criteria for inclusion. CI was suspected clinically in only 24.2% of cases. The distribution of clinical patterns was as follows: reversible colopathy (26.1%), transient colitis (43.7%), gangrenous colitis (9.9%), fulminant pancolitis (2.5%), and chronic segmental colitis (17.9%). A total of 47 patients (12.9%) had an unfavorable outcome as defined by mortality and/or the need for surgery. Multivariate analysis identified the following signs as independent risk factors for an unfavorable outcome: abdominal pain without rectal bleeding [odds ratio (OR) 3.9; 95% confidence interval (CI) = 1.6–9.3], non-bloody diarrhoea (OR 10; 95% CI = 3.7–27.4), and peritoneal signs (OR 7.3; 95% CI = 2.7–19.6). Unfavorable outcomes also were more frequent in isolated right colon ischaemia (IRCI) compared with non-IRCI (40.9 vs. 10.3%, respectively; p < 0.0001). The overall mortality rate was 7.7%. Conclusions. The clinical presentation of CI is very heterogeneous, perhaps explaining why clinical suspicion of this disease is so low. The presence of IRCI, and occurrence of peritoneal signs or onset of CI as severe abdominal pain without bleeding, should alert the physician to a potentially unfavorable course.

Low adherence to colonoscopy in the screening of first- degree relatives of patients with colorectal cancer

Background: Colonoscopy is one of the methods of choice for screening relatives of patients with colorectal cancer. Objective: To evaluate the rate of adherence to colonoscopy in first-degree relatives of patients with colorectal cancer and describe the lesions found. Methods: A prospective, cross-sectional, multicentre, nationwide study was conducted. The study population was composed of first-degree relatives of patients with colorectal cancer selected randomly from the EPICOLON study. Seventy-four index patients were included. These had 342 living first-degree relatives (parents, siblings and children), of whom 281 were interviewed. Results: The adherence rate was 38% (107/281). Adherence was greater in families with a higher degree of familial aggregation for colorectal cancer (88.9% for Amsterdam vs 33.3% for Bethesda and sporadic cancer; p<0.05), an index patient aged under 65 years (60% for patients <65 years vs 32.9% for patients ⩾65 years; p<0.05) and an index patient who was female (46.2% for women vs 31% for men; p = 0.28). Adherence was also greater in relatives under 65 years (54% in patients <65 years vs 18% in patients ⩾65 years; p = 0.05), in female relatives (49% in female relatives vs 27.3% in male relatives; p<0.05) and in siblings and children (40% in siblings and children vs 13% in parents; p<0.05). Lesions were found in 26% (28/107) of the study population. Nine (8.4%) individuals had a total of 18 advanced lesions. Conclusions: These results indicate that adherence to colonoscopy in our population of first-degree relatives was low. The adherence was more frequently associated with a higher degree of familial aggregation, a relative age of under 65 years, a sibling or offspring relationship, and female sex.

Mouse models of pancreatic cancer.

Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States, and potent therapeutic options are lacking. Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer, currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed. In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes. In the last few years, several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer. Genetic alterations such as activating mutations in KRas, or TGFb and/or inactivation of tumoral suppressors such as p53, INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice. These mouse models have a spectrum of pathologic changes, from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system. These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches, chemopreventive and/or anticancer treatments. Here, we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

Long-Term Follow-Up of 1,000 Patients Cured of Helicobacter pylori Infection Following an Episode of Peptic Ulcer Bleeding

OBJECTIVES:To evaluate the effect of Helicobacter pylori (H. pylori) eradication on ulcer bleeding recurrence in a prospective, long-term study including 1,000 patients.METHODS:Patients with peptic ulcer bleeding were prospectively included. Prior non-steroidal anti-inflammatory drug (NSAID) use was not considered exclusion criteria. H. pylori infection was confirmed by rapid urease test, histology, or 13C-urea breath test. Several eradication therapies were used. Subsequently, ranitidine 150 mg o.d. was administered until eradication was confirmed by 13C-urea breath test 8 weeks after completing therapy. Patients with therapy failure received a second, third, or fourth course of eradication therapy. Patients with eradication success did not receive maintenance anti-ulcer therapy and were controlled yearly with a repeat breath test. NSAID use was not permitted during follow-up.RESULTS:Thousand patients were followed up for at least 12 months, with a total of 3,253 patient-years of follow-up. Mean age 56 years, 75% males, 41% previous NSAID users. In all, 69% had duodenal ulcer, 27% gastric ulcer, and 4% pyloric ulcer. Recurrence of bleeding was demonstrated in three patients at 1 year (which occurred after NSAID use in two cases, and after H. pylori reinfection in another one), and in two more patients at 2 years (one after NSAID use and another after H. pylori reinfection). The cumulative incidence of rebleeding was 0.5% (95% confidence interval, 0.16–1.16%), and the incidence rate of rebleeding was 0.15% (0.05–0.36%) per patient-year of follow up.CONCLUSION:Peptic ulcer rebleeding virtually does not occur in patients with complicated ulcers after H. pylori eradication. Maintenance anti-ulcer (antisecretory) therapy is not necessary if eradication is achieved. However, NSAID intake or H. pylori reinfection may exceptionally cause rebleeding in H. pylori-eradicated patients.

Helicobacter pylori first-line treatment and rescue option containing levofloxacin in patients allergic to penicillin

AIM To assess the efficacy and tolerability of Helicobacter pylori first-line treatment (omeprazole-clarithromycin-metronidazole) and second-line rescue option (omeprazole-clarithromycin-levofloxacin) in patients allergic to penicillin. METHODS PATIENTS Prospective multicenter study including consecutive patients allergic to penicillin. Therapy regimens: First-line treatment (50 patients): Omeprazole (20mg b.i.d.), clarithromycin (500 mg b.i.d.) and metronidazole (500 mg b.i.d.) for 7 days. Second-line treatment (15 therapy failures out of the aforementioned 50 patients): Omeprazole (20mg b.i.d.), clarithromycin (500 mg b.i.d.) and levofloxacin (500 mg b.i.d.) for 10 days. OUTCOME VARIABLE Negative (13)C-urea breath test 8 weeks after completion of treatment. RESULTS (1) First-line treatment (omeprazole-clarithromycin-metronidazole): Per-protocol and intention-to-treat eradication rates were 55% (27/49; 95%CI=40-70%) and 54% (27/50; 95%CI=39-69%). Compliance with treatment and follow-up was complete in 98% of cases (one patient was not compliant due to nausea). Adverse events were reported in 5 patients (10%): 4 nausea, 1 diarrhoea. (2) Second-line treatment (omeprazole-clarithromycin-levofloxacin): Per-protocol and intention-to-treat eradication rates were both 73% (11/15; 95%CI=45-92%). Compliance with treatment and follow-up was complete in all the cases. Adverse events were reported in 4 patients (20%), which did not prevent the completion of treatment: Mild nausea (2 patients), and vomiting and myalgias/arthralgias (1 patient). CONCLUSION In H. pylori infected patients allergic to penicillin, the generally recommended first-line treatment with omeprazole, clarithromycin and metronidazole has low efficacy for curing the infection. On the other hand, a levofloxacin-containing regimen (together with omeprazole and clarithromycin) represents an encouraging second-line alternative in the presence of penicillin allergy.

Second-line therapy with levofloxacin after failure of treatment to eradicate helicobacter pylori infection: time trends in a Spanish Multicenter Study of 1000 patients.

Background: Second-line bismuth-containing quadruple therapy is complex and frequently induces adverse effects. A triple rescue regimen containing levofloxacin is a potential alternative; however, resistance to quinolones is rapidly increasing. Aim: To evaluate the efficacy and tolerability of a second-line triple-regimen–containing levofloxacin in patients whose Helicobacter pylori eradication treatment failed and to assess whether the efficacy of the regimen decreases with time. Methods: Design: Prospective multicenter study. Patients: In whom treatment with a regimen comprising a proton-pump inhibitor, clarithromycin, and amoxicillin had failed. Intervention: Levofloxacin (500 mg bid), amoxicillin (1 g bid), and omeprazole (20 mg bid) for 10 days. Outcome: Eradication was confirmed using the 13C-urea breath test 4 to 8 weeks after therapy. Compliance/tolerance: Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by means of a questionnaire. Results: The study sample comprised 1000 consecutive patients (mean age, 49±15 y, 42% men, 33% peptic ulcer) of whom 97% took all medications correctly. Per-protocol and intention-to-treat eradication rates were 75.1% (95% confidence interval, 72%-78%) and 73.8% (95% confidence interval, 71%-77%). Efficacy (intention-to-treat) was 76% in the year 2006, 68% in 2007, 70% in 2008, 76% in 2009, 74% in 2010, and 81% in 2011. In the multivariate analysis, none of the studied variables (including diagnosis and year of treatment) were associated with success of eradication. Adverse effects were reported in 20% of patients, most commonly nausea (7.9%), metallic taste (3.9%), myalgia (3.1%), and abdominal pain (2.9%). Conclusions: Ten-day levofloxacin-containing therapy is an encouraging second-line strategy, providing a safe and simple alternative to quadruple therapy in patients whose previous standard triple therapy has failed. The efficacy of this regimen remains stable with time.