Analysis of antimicrobial susceptibility and virulence factors in Helicobacter pylori clinical isolates

BACKGROUND: In this study, we evaluated the prevalence of primary resistance of Brazilian H. pylori isolates to metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone. In addition, the vacA, iceA, cagA and cagE genotypes of strains isolated from Brazilian patients were determined and associated with clinical data in an effort to correlate these four virulence markers and antibiotic resistance. METHODS: H. pylori was cultured in 155 H. pylori-positive patients and MICs for metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone were determined by the agar dilution method. Genomic DNA was extracted, and allelic variants of vacA, iceA, cagA and cagE were identified by the polymerase chain reaction. RESULTS: There was a strong association between the vacA s1/cagA -positive genotype and peptic ulcer disease (OR = 5.42, 95% CI 2.6–11.3, p = 0.0006). Additionally, infection by more virulent strains may protect against GERD, since logistic regression showed a negative association between the more virulent strain, vacA s1/cagA-positive genotype and GERD (OR = 0.26, 95% CI 0.08–0.8, p = 0.03). Resistance to metronidazole was detected in 75 patients (55%), to amoxicillin in 54 individuals (38%), to clarithromycin in 23 patients (16%), to tetracycline in 13 patients (9%), and to furazolidone in 19 individuals (13%). No significant correlation between pathogenicity and resistance or susceptibility was detected when MIC values for each antibiotic were compared with different vacA, iceA, cagA and cagE genotypes. CONCLUSION: The analysis of virulence genes revealed a specific association between H. pylori strains and clinical outcome, furthermore, no significant association was detected among pathogenicity and resistance or susceptibility

Comparative Effects of Metamizole (Dipyrone) and Naproxen on Renal Function and Prostacyclin Synthesis in Salt-Depleted Healthy Subjects - A Randomized Controlled Parallel Group Study.

Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α. Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing. Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC50 0.69 ± 0.27 µM) compared with naproxen (EC50 0.034 ± 0.033 µM). Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis

Hematological safety of metamizole: retrospective analysis of WHO and Swiss spontaneous safety reports

Since the 1970s, the use of metamizole is controversial due to the risk of agranulocytosis. The aim of this study was to analyze individual case safety reports (ICSRs) of metamizole-associated hematological adverse drug reactions (ADRs).; International and Swiss metamizole-associated ICSR concerning selected hematological ADR were retrieved from VigiBase™, the World Health Organization Global Database of ICSR, and the Swiss Pharmacovigilance Database. We evaluated demographic data, co-medication, drug administration information, dose and duration of metamizole treatment, as well as the latency time of ADR, their course, and severity. The subgroup analysis of Swiss reports allowed us to analyze cases with fatal outcome more in depth and to estimate a rough minimal incidence rate.; A total of 1417 international and 77 Swiss reports were analyzed. Around 52 % of the international and 33 % of the Swiss metamizole-associated hematological ADR occurred within a latency time of ≤7 days. More women were affected. The annual number of hematological reports and those with fatal outcome increased over the last years parallel to metamizole sales figures. In Switzerland, the minimal incidence rate of agranulocytosis was 0.46-1.63 cases per million person-days of use (2006-2012). Female sex, old age, pancytopenia, and co-medication with methotrexate were striking characteristics of the seven Swiss fatal cases.; Metamizole-associated hematological ADR remain frequently reported. This is underscored by increasing annual reporting rates, which mainly reflect growing metamizole use. Early detection of myelotoxicity and avoidance of other myelotoxic substances such as methotrexate are important measures for preventing fatalities

Glucose-Induced Glucagon-Like Peptide 1 Secretion Is Deficient in Patients with Non-Alcoholic Fatty Liver Disease

BACKGROUND & AIMS: The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients. METHODS: N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH) patients) and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration. RESULTS: Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH. CONCLUSIONS: Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.status: publishe

Glucose-Induced Glucagon-Like Peptide 1 Secretion Is Deficient in Patients with Non-Alcoholic Fatty Liver Disease

<div><p>Background & Aims</p><p>The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.</p><p>Methods</p><p>N = 52 patients (n = 16 NAFLD and n = 36 Non-alcoholic steatohepatitis (NASH) patients) and n = 50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.</p><p>Results</p><p>Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.</p><p>Conclusions</p><p>Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.</p></div

Glucose, insulin and glucagon concentrations in response to oGTT.

<p>Plasma glucose <b>(A, B)</b>, insulin <b>(C, D)</b> and glucagon <b>(E, F)</b> concentration curves are shown for patients vs. controls <b>(A, C, E)</b> and NAFLD and NASH vs. controls <b>(B, D, F)</b>. Patients n = 52 (NAFLD n = 16; NASH n = 36); controls n = 50. Glucose (mmol/l), insulin (µU/ml) and glucagon (pg/ml) are expressed as mean±SEM.</p

Glucagon-like peptide 1 (GLP-1) secretion in response to oral glucose tolerance test (oGTT).

<p><b>(A)</b> GLP-1 secretion in response to oGTT is significantly decreased in patients vs. controls (p<0.001). Patients n = 52; controls n = 50. <b>(B)</b> GLP-1 secretion in NAFLD and NASH vs. controls. NAFLD n = 16; NASH n = 36; controls n = 50. GLP-1 (pmol/ml) is expressed as mean±SEM.</p

Secretion of Glucagon-like peptide-1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon and glucose disposal in NAFLD and NASH subgroups vs. controls in response to oral glucose tolerance test.

<p>NAFLD n = 16; NASH n = 36; controls n = 50. Data are expressed as mean±SEM. AUC, area under the curve; c_max, maximum plasma concentration. Multiple Mann-Whitney tests with Bonferroni-Holm adjustment of p-values for multiplicity of testing. P≤0.05, statistically significant difference; ns, not significant.</p

Glucose-dependent insulinotropic polypeptide (GIP) secretion in response to oGTT.

<p><b>(A)</b> GIP secretion in response to oGTT is not different in patients vs. controls. Patients n = 52; controls n = 28. <b>(B)</b> GIP secretion in NAFLD and NASH vs. controls. NAFLD n = 16; NASH n = 36; controls n = 28. GIP (pg/ml) is expressed as mean±SEM.</p

Baseline characteristics of Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) patients and controls.

<p>Data are expressed as mean±SEM. n = 52 patients (NAFLD n = 16 (30.8%), NASH n = 36 (69.2%)); n = 50 controls. Differences in baseline characteristics of patients vs. controls and NAFLD vs. NASH are expressed as p-values (Mann-Whitney U test). P≤0.05, statistically significant difference; ns, not significant.</p