Ireneusz T. Padol

Peptic ulcer disease today

Over the past few decades, since the introduction of histamine H2-receptor antagonists, proton-pump inhibitors, cyclo-oxygenase-2-selective anti-inflammatory drugs (coxibs), and eradication of Helicobacter pylori infection, the incidence of peptic ulcer disease and ulcer complications has decreased. There has, however, been an increase in ulcer bleeding, especially in elderly patients. At present, there are several management issues that need to be solved: how to manage H. pylori infection when eradication failure rates are high; how best to prevent ulcers developing and recurring in nonsteroidal anti-inflammatory drug (NSAID) and aspirin users; and how to treat non-NSAID, non-H. pylori-associated peptic ulcers. Looking for H. pylori infection, the overt or surreptitious use of NSAIDs and/or aspirin, and the possibility of an acid hypersecretory state are important diagnostic considerations that determine the therapeutic approach. Combined treatment with antisecretory therapy and antibiotics for 1–2 weeks is the first-line choice for H. pylori eradication therapy. For patients at risk of developing an ulcer or ulcer complications, it is important to choose carefully which anti-inflammatory drugs, nonselective NSAIDs or coxibs to use, based on a risk assessment of the patient, especially if the high-risk patient also requires aspirin. Testing for and eradicating H. pylori infection in patients is recommended before starting NSAID therapy, and for those currently taking NSAIDs, when there is a history of ulcers or ulcer complications. Understanding the pathophysiology and best treatment strategies for non-NSAID, non-H. pylori-associated peptic ulcers presents a challenge.

The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis.

PREMISE:It has been suggested that proton pump inhibitor (PPI)-related differences in Helicobacter pylori eradication rates are partly because of CYP2C19 polymorphisms and there have been conflicting data in this area. We conducted a meta-analysis to investigate the evidence relating CYP2C19 to first-line H. pylori eradication rates.METHODS:A search of the literature was conducted up to June 2005 using Medline, EMBase, and Cochrane Register of Controlled Trials (CENTRAL). Twenty-eight arms from 17 papers were extracted for omeprazole, lansoprazole, and rabeprazole, collectively. Review Manager 4.2.8 was used for analysis.RESULTS:When all eradication rates, regardless of PPI used, were combined there was no significant difference between poor metabolizers (PM) and heterozygous extensive metabolizers (HetEMs) (odds ratio [OR] = 1.35, 95% confidence interval [CI] 0.89–2.07, p = 0.15); however, there was a significant difference between HetEM and homozygous extensive metabolizers (HomEMs) (OR = 1.90, 95% CI 1.38–2.60, p < 0.0001). Significant heterogeneity was observed in a HomEM and PM comparison, hence additional subanalysis of individual PPIs revealed that dual and triple omeprazole therapies significantly favored higher H. pylori eradication rates in PM over HomEM (OR = 4.03, 95% CI 1.97–8.28, p = 0.0001), and also over HetEM (OR = 2.24, 95% CI 1.09–4.61, p = 0.03). Dual and triple rabeprazole and triple lansoprazole therapies did not show significantly different H. pylori eradication rates between PM and HomEM (OR = 1.04, 95% CI 0.44–2.46, p = 0.25) and (OR = 1.80, 95% CI 0.67–4.85, p = 0.93), respectively.CONCLUSIONS:The impact of CYP2C19 polymorphisms on H. pylori eradication rates in studied populations appears clinically relevant in patients prescribed omeprazole as a component of their dual- or triple-drug therapy, whereas regimens that include lansoprazole or rabeprazole are unaffected. The choice of PPI and/or dose rather than CYP2C19 genotyping could be a more practical approach to assure the highest H. pylori eradication rates in clinical settings.

Therapeutic effects of the endothelin receptor antagonist Ro 48-5695 in the TNBS/DNBS rat model of colitis.

Objective Endothelins can act as polyfunctional cytokines. It is therefore possible that endothelins could play an active role in gut inflammation. Elevated levels of endothelin‐1 have been reported in ulcerative colitis and Crohns disease. The aim of this study was to establish the therapeutic effect of a ‘new’ endothelin receptor antagonist Ro 48‐5695 in an animal model of inflammatory bowel disease. This study compares the effect of Ro 48‐5695 on colonic damage induced by two haptens: trinitrobenzenesulphonic (TNBS) or dinitrobenzenesulphonic acid (DNBS). Methods Colitis was induced by intra‐rectal administration of TNBS or DNBS. After TNBS/DNBS injury, rats were treated with 10.0, 3.0, 1.0 or 0.3 mg/kg of Ro 48‐5695 orally, daily for 5 days. On day 6 post‐hapten treatment, colonic tissues were removed and examined in a blinded fashion for macroscopic damage (damage score) and myeloperoxidase (MPO) activity. Stool consistency and adhesions were also measured. Results Oral administration of Ro 48‐5695 almost completely prevented TNBS‐induced damage at a dose of 10 mg/kg. The same dose in this model also had a therapeutic effect as measured by MPO and incidence of diarrhoea and adhesions. In DNBS‐induced colonic damage, Ro 48‐5695 was more potent and at 1.0 and 3.0 mg/kg decreased the damage score by 50 and 60% respectively; also the incidence of adhesions and diarrhoea was significantly reduced. However, MPO activity in this model was affected only by the highest dose of Ro 48‐5695 tested (3.0 mg/kg) where it was reduced by 48%. Conclusions These data provide evidence for the involvement of endothelins in the pathophysiology of inflammatory bowel disease and support the possibility of exploring a new therapeutic approach. Eur J Gastroenterol Hepatol 12:257‐265

Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: an evidence-based interpretation

Cyclooxygenase (COX) inhibitors remain a major class of drugs in rheumatology and their widespread use is expected to continue. The view that a prothrombotic effect explains the increase in myocardial infarction (MI) associated with both COX-2 selective and traditional NSAIDs (tNSAIDs) has been increasingly questioned. We review the evidence that prostanoids direct the immune response away from a Th1 response and that consequently inhibition of prostaglandin synthesis results in augmentation of the Th1 response by limiting prostanoid synthesis. Although the role of prostanoids as mediators of inflammation in the periphery is well understood, the systemic immunomodulatory role of prostanoids shifting the immune response away from a Th1 type is less appreciated. Atherosclerosis is an inflammatory arterial disease driven by a Th1 type immune response. Moreover, the vulnerable phenotype of atheroma is associated with the cellular Th1 immune response in contrast to the stable plaque phenotype associated with a Th2 type response. We propose a class effect of COX-2 selective and tNSAIDs, which results in augmentation of Th1-mediated atherogenesis/ production of pro-atherogenic cytokines associated with detrimental plaque remodeling, instability, rupture and embolization resulting in MI. Understanding of the Th1 mediated immunity, which underlies the cardiovascular, and the non-Th1, which underlies gastrointestinal adverse effects associated with the use of COX inhibitors, should lead to better risk assessment and the development of anti-inflammatory treatments with improved safety. Our explanation also emphasizes the pharmacological effects and consequences of immunomodulation in the inflammation associated with atherosclerosis and other Th1- as well as non-Th1-driven diseases.

Immunomodulatory activities of the somatostatin analogue BIM 23014c: effects on murine lymphocyte proliferation and natural killer activity

We have examined the effect of somatostatin and its octapeptide analogue BIM 23014c on concanavalin A-induced lymphocyte proliferation and target-specific natural killer activity both in vitro and in vivo. Using Peyers patches and spleen as a source of lymphocytes, we found that both peptides modulated immunity in a dose-dependent manner. Comparatively, there was no significant difference between the activity of somatostatin or BIM 23014c in the modulation of immunity. Proliferation, both in vitro and in vivo, was significantly inhibited by both peptides in each organ with a higher specificity towards the Peyers patch lymphocytes. Natural killer activity was also inhibited in both organs in vivo and in vitro. Thus, not only did somatostatin and BIM 23014c have similar effects on proliferation and natural killer activity, but their effect was organ specific. Preliminary data suggest that BIM 23014c works via the same receptor as somatostatin, therefore intimating that these two peptides are both clinically and immunologically similar.

Effect of Purified Lipopolysaccharides from Strains of Helicobacter pylori and Helicobacter felis on Acid Secretion in Mouse Gastric Glands In Vitro

ABSTRACT As a bacterial product, Helicobacter pylorilipopolysaccharide (LPS) can originate in close proximity to parietal cells, but the role of this uniquely structured endotoxin on acid secretion has not been fully investigated and remains unclear. The purpose of this study was to test the direct effect of purified LPS (tested range, 0.1 to 100 μg/ml) from various strains of H. pylori and from one Helicobacter felis strain on histamine- and carbachol-stimulated acid secretion in vitro using mouse gastric glands and the accumulation of [14C]aminopyrine. In addition, we investigated whether H. pylori LPS can interfere with two native antisecretory substances, prostaglandin E2 (PGE2) and somatostatin, which may contribute to bacterial pathogenicity. Except for the LPS from H. pylori SS1 (Sydney strain), which gave a statistically significant increase in both histamine- and carbachol-stimulated acid output (38 and 24%, respectively; P < 0.05), no effect of the tested LPS was observed on acid secretion. H. pylori LPS purified from a patient isolate did not affect the potency or the efficacy of the inhibitory dose response curve to PGE2 or somatostatin. Bacterial interstrain variation in the direct stimulatory effect of Helicobacter-derived LPS on acid secretion was observed, which probably reflects the molecular structure of LPS and the potential to contribute to virulence. Importantly, the data showed that H. pylori LPS did not have any direct antisecretory properties. It can be speculated that the acid stimulatory properties of LPS from H. pylori SS1 may contribute to the gastric damage observed in the mouse model ofH. pylori infection.

Altered physiology of acid secretion in depression-prone Flinders rats results in exacerbated NSAID and stress-induced gastric damage.

Background  Flinders Sensitive Line (FSL) rats are characterized by hypersensitivity to cholinergic stimuli and have been extensively used for studying depressive disorders. A link between depression and peptic ulcers has long been established; however, there is a lack of data from animal models.

Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice.

SAMP1/YitFcs mice serve as a model of Crohns disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD4(+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract.

W1720 Gastric Hypersecretion Related to Cholinergic Hypersensitivity in the Flinders Rat Model of Depression Contributes to Stress Induced Ulceration of the Stomach

G A A b st ra ct s that such gradient expression of Shh was disappeared by H. pylori colonization (J. Pathol. 206:186-197, 2005) or by hypochlorhydria due to immature parietal cells (J. Pathol. 213:161-169, 2007). The present study was designed to investigate the expression of AQP4 in the mouse stomach after acid suppression with a histamine type 2 receptor antagonist (H2RA) or proton pump inhibitor (PPI). Methods. Male 5-week-old C57B/6 mice were prepared for this study, and an H2RA (Famotidine: FAM, 15mg/kg, 2x/day, s.c.) or PPI (Lansoprasole: LPZ 30mg/kg, 1x/day, s.c.) was administered to the animals. A saline was administered as control. One, 4 or 8 weeks after the administration, the stomachs of the mice were removed and examined. The mRNA expression of AQP4 was evaluated by quantitative RT-PCR. The protein levels of AQP4 were examined by Western blotting and its localization was assessed by immunohistochemistry. Results. The LPZ group exhibited higher expression levels of the gastric AQP4 mRNA than the control or FAM group (AQP4/ β-actin: 1 week: cont. 0.77±0.05, FAM 0.75±0.05, LPZ 1.42±0.12; p<0.05; 4 weeks: cont. 0.72±0.06, FAM 0.72±0.05, LPZ 1.12±0.11; p<0.05; 8 weeks: cont. 0.73±0.05, FAM 0.65±0.03, LPZ 1.22±0.11; p<0.05). The protein level of AQP4 and Shh also exhibited higher level in LPZ group than the control or FAM group (AQP4/β-actin:% expression of control, 1 week: FAM 63.1±10.6, LPZ 203.1±22.5; p<0.01; 4 weeks: FAM 90.1±12.1, LPZ 148.9±7.9; p<0.01; 8 weeks: FAM 87.8±22.9, LPZ 134.3±18.8; p<0.01). AQP4 was specifically expressed in the basolateral membrane of the gastric parietal cells. A significant increase in the number of AQP4-positive parietal cells even in the neck of fundic glands was observed after acid suppression by LPZ. On the other hand, Shh expression was extensively reduced in LPZ group. Conclusion. Increase in the number of AQP4-positive parietal cells in the fundic glands was observed in the Shh faded area under the condition of potent acid suppression by PPI, not by H2RA. This observation suggests that the reduced proton pump activity paralleled with a faded Shh expression in basal parietal cells might determine the expression of its water channel, AQP4.