Mucosal Progranulin expression is induced by H. pylori, but independent of Secretory Leukocyte Protease Inhibitor (SLPI) expression.

BACKGROUND: Mucosal levels of Secretory Leukocyte Protease Inhibitor (SLPI) are specifically reduced in relation to H. pylori-induced gastritis. Progranulin is an epithelial growth factor that is proteolytically degraded into fragments by elastase (the main target of SLPI). Considering the role of SLPI for regulating the activity of elastase, we studied whether the H. pylori-induced reduction of SLPI and the resulting increase of elastase-derived activity would reduce the Progranulin protein levels both ex vivo and in vitro. METHODS: The expression of Progranulin was studied in biopsies of H. pylori-positive, -negative and -eradicated subjects as well as in the gastric tumor cell line AGS by ELISA, immunohistochemistry and real-time RT-PCR. RESULTS: H. pylori-infected subjects had about 2-fold increased antral Progranulin expression compared to H. pylori-negative and -eradicated subjects (P < 0.05). Overall, no correlations between mucosal Progranulin and SLPI levels were identified. Immunohistochemical analysis confirmed the upregulation of Progranulin in relation to H. pylori infection; both epithelial and infiltrating immune cells contributed to the higher Progranulin expression levels. The H. pylori-induced upregulation of Progranulin was verified in AGS cells infected by H. pylori. The down-regulation of endogenous SLPI expression in AGS cells by siRNA methodology did not affect the Progranulin expression independent of the infection by H. pylori. CONCLUSIONS: Taken together, Progranulin was identified as novel molecule that is upregulated in context to H. pylori infection. In contrast to other diseases, SLPI seems not to have a regulatory role for Progranulin in H. pylori-mediated gastritis.

Influence of cyclooxygenase inhibitors on the function of the prostaglandin transporter organic anion-transporting polypeptide 2A1 expressed in human gastroduodenal mucosa.

The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E(2) with IC(50) values of 6.2 +/- 1.2 and 3.1 +/- 1.2 microM. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE(2) transport by 162.7 +/- 13.9, 77.2 +/- 3.6, and 32.3 +/- 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.

Impact of high-resolution transabdominal ultrasound in the diagnosis of complications of Crohn's disease.

OBJECTIVE: Crohn's disease is associated with intestinal complications such as strictures, fistulas and abscesses. As the management of the patients is influenced by the presence or absence of complication, sensitive diagnostic modalities to detect these complications are needed. The aim of this prospective study was to evaluate the diagnostic accuracy of high-resolution transabdominal ultrasound in the diagnosis of complications of Crohn's disease. MATERIAL AND METHODS: From April 2003 to July 2009, 58 patients (31 women, 27 men; mean age 36.3 years, range 13-86 years) with known Crohn's disease were included in the study and investigated with high-resolution transabdominal ultrasound. The diagnosis of Crohn's disease was based on clinical, endoscopic, histological, radiological and operative findings. Patients with other forms of enteritis (e.g. infectious) were excluded from the study. Twenty of the 58 patients were investigated on a second occasion with other symptoms than at the first admission. The time duration between the two ultrasound investigations was at least 3 months. Consequently, a total of 78 ultrasound investigations were done in 58 patients. With respect to their clinical symptoms, all patients were further investigated within 2 weeks after ultrasound with magnetic resonance imaging, and/or computed tomography, and/or enteroclysis, and/or endoscopy with biopsy. Together with clinical data (Crohn's disease activity index) and surgical findings these investigations were used as reference procedure. RESULTS: The sensitivity, specificity, positive predictive and negative predictive values of ultrasound were as follows: 0.86, 0.90, 0.83 and 0.92 for stenoses; 0.78, 0.95, 0.86, and 0.91 for fistulas; 0.90, 0.99, 0.90 and 0.99 for abscesses, respectively. CONCLUSIONS: High-resolution transabdominal ultrasound done by experienced examiners has an excellent diagnostic accuracy in the diagnosis of complications in patients with Crohn's disease. Thus, it can be recommended as one of the primary investigative procedures for evaluation of Crohn's disease.

Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing "concomitant therapy" versus triple therapy for Helicobacter pylori eradication.

BACKGROUND: Low success rates with triple therapy for Helicobacter pylori infections have prompted search for alternatives. In one, a proton-pump inhibitor (PPI) and amoxicillin was followed by the PPI plus clarithromycin and a nitroimidazole (sequential therapy); in another, these four drugs were given concomitantly (concomitant therapy). AIM: To compare concomitant therapy with standard triple therapy for H. pylori infection. METHODS: By searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and abstracts of major gastrointestinal meeting, two independent reviewers systemically identified randomized controlled trials (RCT) comparing concomitant quadruple to standard triple therapies as well as studies reporting eradication rates of concomitant quadruple therapy in treatment of H. pylori. Pooled eradication rates and odds ratios (OR) with 95% confidence intervals (CI) were calculated, and univariable metaregression analysis for all extracted variables was conducted. RESULTS: We identified nine studies (10 treatment arms) including five qualifying RCTs (576 subjects) comparing concomitant (293 subjects, duration 3 to 5 days) and triple therapy (283 subjects, duration 5 to 10 days) and four other studies evaluating concomitant therapy (478 subjects, duration 3 to 7 days). Pooled estimates of the five RCTs showed superiority of concomitant therapy over triple therapy; with intention-to-treat) pooled OR of 2.86 (95% CI: 1.73-4.73) and per-protocol (PP) pooled OR of 3.52 (95% CI: 1.95-6.38). Considering all 10 treatment arms, the ITT eradication rate was 89.7% (95% CI: 86.8-92.1%) and PP was 92.9% (95% CI: 90.2-94.8%). CONCLUSION: Concomitant therapy appears to be an effective alternative to triple therapy and is less complex than sequential therapy.

Helicobacter pylori infection and short-term intake of low-dose aspirin have different effects on alpha-1 antitrypsin/alpha-1 peptidase inhibitor (alpha1-PI) levels in antral mucosa and peripheral blood.

OBJECTIVE: Alpha-1 protease inhibitor (alpha1-PI) is the major circulating serine protease inhibitor. The purpose of the study was to investigate alpha1-PI expression in gastroduodenal mucosa and blood with respect to two major etiological risk factors for gastroduodenal diseases, Helicobacter pylori infection and intake of low-dose aspirin. MATERIAL AND METHODS: Twenty volunteers (H. pylori-positive and -negative: n=10) received 2 x 50 mg aspirin/day for 7 days. H. pylori-positive subjects underwent eradication therapy and repeated the protocol. Blood and tissue samples were obtained on days 0, 1, 3 and 7; alpha1-PI levels were determined by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and analyzed for histopathological findings. RESULTS: Mucosal alpha1-PI expression was between 30 and 75 pg/10 microg total protein in H. pylori-negative subjects, and found to be similar in antral, corpus and duodenal mucosa. In H. pylori-infected subjects, alpha1-PI levels were significantly increased in the antrum (mean: 111 versus 37.4 pg/10 microg protein; p=0.019), whereas corresponding levels in the corpus, duodenum and sera were unchanged. Alpha-1-PI transcript levels were similarly induced in H. pylori-infected subjects (0.13+/-0.15 versus 0.027+/-0.043 a.u. (arbitrary units), p=0.018). Immunohistochemistry demonstrated that infiltrating immune cells and antral surface epithelium contributed to elevated alpha1-PI expression in H. pylori-infected subjects. The concomitant use of low-dose aspirin did not change mucosal alpha1-PI levels, but led to a 2-fold increase in alpha1-PI levels in sera independently of the H. pylori status (p<0.009). CONCLUSIONS: Antral alpha1-PI expression is specifically induced by H. pylori infection, suggesting a pathophysiological role of this protease inhibitor in the upper gastrointestinal tract, whereas low-dose aspirin led to an increase in systemic alpha1-PI levels.

Short-term/low-dose aspirin-induced duodenal erosions are not dependent on Helicobacter pylori infection, cyclooxygenase expression and prostaglandin E2 levels.

OBJECTIVE: The mechanisms of interaction between Helicobacter pylori infection and low-dose aspirin in the induction of duodenal erosions are not fully understood. The aim of this study was to investigate the effects of low-dose aspirin on the induction of duodenal erosions, the expression of cyclooxygenases and prostaglandin (PG)-E(2) levels in healthy subjects according to their H. pylori status. MATERIAL AND METHODS: Twenty healthy volunteers (H. pylori-negative n=10, H. pylori-positive n=10) received 100 mg aspirin/day for 1 week. During esophagogastroduodenoscopy, duodenal biopsies were taken before and at days 1, 3, and 7 of medication. COX-1 and -2 expressions were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), and immunohistochemistry; mucosal PGE(2) levels were determined by ELISA. Three months after successful eradication of infection, nine H. pylori-positive subjects repeated the protocol. RESULTS: Aspirin-induced duodenal erosions occurred independently of whether H. pylori infection was present or not. There was no difference in duodenal COX-1 and COX-2 expression among the groups and expression was not affected by aspirin. Basal duodenal PGE(2) levels were similar among the different groups (H. pylori-negative 4.3+/-4.2, H. pylori-positive 5.2+/-1.3, following H. pylori eradication 5.2+/-1.4 ng/microg protein) and were not affected by low-dose aspirin. CONCLUSIONS: In healthy subjects, low-dose aspirin-induced duodenal erosions are not influenced by H. pylori status. Low-dose aspirin medication for one week does not affect either cyclooxygenase expression or duodenal PGE(2) levels and therefore is likely to induce duodenal damage mainly through topical toxicity.

Budesonide induces complete remission in autoimmune hepatitis.

AIM: Prednisone and azathioprine represent the standard treatment for autoimmune hepatitis (AIH). However, only 65% of the patients enter complete histological remission. Recently, budesonide (BUD) was reported to be a promising alternative. In this study we assessed the efficacy and safety of BUD in AIH. METHODS: Eighteen patients (12 women, 6 men; mean age 45.4+/-21 years)with AIH were treated with BUD (Budenofalk) 3 mg thrice daily and followed up for at least 24 wk. Seven patients also had features of primary biliary cirrhosis (n=5) or primary sclerosing cholangitis (n=2). Advanced liver fibrosis or cirrhosis was present in 6 patients. RESULTS: Fifteen (83%) patients had a complete clinical and biochemical remission. Ten patients, including five with acute hepatitis,were given BUD as first-line therapy, of which seven enter remission. Three patients, two with liver cirrhosis, did not improve.All patients with second-line therapy experienced long-term remission. A histological remission was also seen in three patients. Clinically relevant BUD-induced side effects were recorded only in patients with liver cirrhosis (n=4). CONCLUSION: BUD is effective in remission induction in the majority of our patients with AIH. Side effects and treatment failure was mainly observed in patients with liver cirrhosis.

Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data.

BACKGROUND: The clinical outcome of acid-related disorders treated by proton pump inhibitors (PPIs) might be dependent on the polymorphically expressed cytochrome P450 (CYP) 2C19, which is involved in PPI metabolism. We tested whether esomeprazole-induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype. METHODS: Two hundred five patients with GERD (Los Angeles classification grade A or B) were included in a case-control study according to endoscopic outcome (healed versus unhealed group, matched for confounders) after treatment with 40 mg esomeprazole daily for 4 weeks. The frequency of CYP2C19 genotypes was determined as the primary outcome measure for both groups. In a second trial plasma levels of esomeprazole and corresponding CYP2C19 and CYP3A4 metabolites (5-hydroxyomeprazole and omeprazole sulfone) were monitored in 10 CYP2C19 wild-type patients with GERD after the first and last doses (day 7) of 40 mg esomeprazole daily to calculate metabolic ratios. RESULTS: CYP2C19 wild-type (n = 148) and heterozygous (n = 51) or homozygous variant (n = 6) patients did not differ with respect to baseline characteristics. The frequency distribution of CYP2C19 genotypes was not different between patients with complete (75/100) and incomplete (73/105) healing (P = .65). When a single esomeprazole dose and multiple dosing were compared, the low contribution of CYP2C19 to the elimination of esomeprazole decreased further by 50%. In contrast, the CYP3A4-dependent formation of omeprazole sulfone increased by 40%, and consequently, the metabolic ratio of omeprazole sulfone to 5-hydroxyomeprazole was elevated from 7.9 to 19.3 (P = .0004). CONCLUSION: In contrast to other PPIs, esomeprazole-induced healing of GERD is unrelated to the CYP2C19 genotype, which can be explained by the metabolic shift toward the CYP3A4-mediated pathway.

Acute exacerbation of autoimmune hepatitis induced by Twinrix.

We report on a 26-year-old man who presented with severe jaundice and elevated serum liver enzyme activities after having received a dose of Twinrix. In his past medical history, jaundice or abnormal liver function tests were never recorded. Following admission, an elevated immunoglobulin G level and antinuclear antibodies at a titer of 320 with a homogenous pattern were found. Histology of a liver biopsy showed marked bridging liver fibrosis and a chronic inflammation, compatible with autoimmune hepatitis. Treatment was started with budesonide and ursodeoxycholic acid, and led to complete normalization of the pathological liver function tests. We believe that Twinrix led to an acute exacerbation of an unrecognized autoimmune hepatitis in our patient. The pathogenesis remains to be clarified. It is tempting to speculate that inactivated hepatitis A virus and/or recombinant surface antigen of the hepatitis B virus -as seen in patients with chronic hepatitis C and unrecognized autoimmune hepatitis who were treated with interferon alpha-might have been responsible for disease exacerbation.

Breath and string test: a diagnostic package for the identification of treatment failure and antibiotic resistance of Helicobacter pylori without the necessity of upper gastrointestinal endoscopy.

AIM: Helicobacter pylori (H pylori) resistance after failed eradication has a major impact on the outcome of a further treatment regimen. The aim of this study was to assess the validity of a non-invasive strategy using the 13C-urea breath test (UBT) and the gastric string test in identifying post-treatment resistance of H pylori. METHODS: The UBT was routinely performed 4 to 6 wk after H pylori eradication therapy. Forty-two patients (24 females, 18 males, mean age 48 years) with a positive UBT were included in the study. A gastric string test using a capsule containing a 90 cm-long nylon fiber was performed. Before the capsule was swallowed, the free end of the string was taped to the cheek. After one hour in the stomach, the string was withdrawn. The distal 20 cm of the string was inoculated onto an agar plate and processed under micro-aerophilic conditions. Following the string test, upper gastrointestinal endoscopy was performed to obtain gastric biopsies for conventional culture. RESULTS: H pylori was successfully cultured from the gastric string in 34 patients (81%), but not in 5 patients due to contamination with oropharyngeal flora. H pylori was cultured from the gastric biopsies obtained at endoscopy in 39 patients (93%). CONCLUSION: The UBT followed by the gastric string test in the case of treatment failure is a valid diagnostic strategy with the aim of determining the post-therapeutic antibiotic resistance of H pylori with little inconvenience to the patient. Upper GI-endoscopy can be avoided in several cases by applying consequently this diagnostic package.

Clinical outcome and influencing factors of a new short-term quadruple therapy for Helicobacter pylori eradication: a randomized controlled trial (MACLOR study).

BACKGROUND: Short-term therapies for eradicating Helicobacter pylori in selected patients might offer advantages in terms of costs, compliance, and adverse effects in contrast to standard 1-week triple therapy. METHODS: To determine eradication success and influencing factors in a new short-term quadruple therapy, a total of 243 patients positive for H pylori were randomly assigned to 1 of 3 regimens according to age, smoking status, and diagnosis: a 5-day treatment with 3 antibiotics (amoxicillin, 1 g twice daily [bid]; clarithromycin, 250 mg bid; and metronidazole, 400 mg bid) and lansoprazole (30 mg bid [L5; reference treatment]) or ranitidine hydrochloride (300 mg bid [R5]), or the same 3-day antibiotic-lansoprazole combination (L3) with a 2-day pretreatment with lansoprazole. RESULTS: A total of 234 patients completed the study. On an intention-to-treat basis, overall eradication of H pylori was confirmed in 86.4%: 89.2% in the L5 group vs 81.2% in the L3 group vs 88.8% in the R5 group; differences were not significant. Multiple logistic regression analysis showed that younger age (<55 years; P =.03), history of peptic ulcer disease (P =.04), smoking (P =.03), metronidazole resistance (P =.003), low ranitidine trough serum concentrations (P =.005), cytotoxin-associated gene A-negative strains in peptic ulcer disease (P =.04), and outer inflammatory protein A-positive strains (P =.02) were associated with eradication failure. CONCLUSIONS: This new quadruple H pylori eradication regimen is efficacious, safe, well tolerated, and cost saving, and may be a treatment option for patients older than 55 years with no history of peptic ulcer disease. Furthermore, strains that are sensitive to all antibiotics, cytotoxin-associated gene A-positive, and outer inflammatory protein A-negative could be suitable for short-term quadruple therapy. Patients with an unfavorable combination of characteristics should be treated for a minimum of 7 days.

CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori.

OBJECTIVE: Proton pump inhibitors, metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2C19, are essential drugs for Helicobacter pylori eradication. It was reported that patients with CYP2C19 wild type in Asia had lower eradication rates. This study tests the hypothesis that CYP2C19 wild type ( wt/wt ) in white patients is also associated with a higher probability of treatment failure. METHODS: This was a cohort study involving 131 H pylori -positive white (German) patients treated by quadruple therapy including lansoprazole (30 mg twice daily for 5 days). Eradication success, as well as lansoprazole trough steady-state serum concentrations, was determined according to different CYP2C19 genotypes. RESULTS: We found 3 homozygous variant patients (2.3%) ( mt/mt, CYP2C19*2/*2 ), 42 heterozygous patients (32.1%) ( wt/mt, CYP2C19*1/*2 ), and 86 wild-type individuals (65.6%). Significant differences in eradication success could be found between wt/wt patients (80.2%) versus combined mt/mt (100%) and wt/mt patients (97.8%) ( P <.01; odds ratio, 10.8 [confidence interval, 1.4-84]), which were associated with corresponding changes in the serum levels of lansoprazole (median, 753 ng/mL for mt/mt, 59 ng/mL for wt/mt, and 21 ng/mL for wt/wt; P <.001). Apart from antibiotic resistance, CYP2C19 polymorphism was the most important influencing factor for eradication success on multivariate analysis ( P <.0001). CONCLUSION: Eradication rates of H pylori highly depend on CYP2C19 in white patients if standard doses of lansoprazole (30 mg twice daily) are administered within a quadruple regimen. Because wt/wt individuals have lower eradication rates and lower serum concentrations of lansoprazole, these patients might benefit from a higher proton pump inhibitor dosage.

CYP2C19 polymorphism and proton pump inhibitors.

Proton pump inhibitors such as omeprazole (esomeprazole), lansoprazole, pantoprazole and rabeprazole are eliminated by the hepatic route and the polymorphic CYP2C19 is mainly involved in their metabolism. In different populations three phenotypes have been identified: extensive metabolizers, poor metabolizers and individuals carrying one wild type and one mutant allele (het extensive metabolizers). Systemic exposure to the proton pump inhibitors as expressed by the AUC (area under the plasma level time profiles) is 5-12-times higher in poor metabolizers than in extensive metabolizers. As the pharmacodynamic response (elevation of intragastric pH) to the proton pump inhibitors is related directly to their AUC, a much higher pH can be monitored over 24 hr in poor metabolizers than in extensive metabolizers. Furthermore, clinical efficacy of all proton pump inhibitors depend on maintaining intragastric pH above certain threshold levels and significantly higher eradication rates of Helicobacter pylori have been observed in patients of the poor metabolizers and het extensive metabolizers phenotype if compared to extensive metabolizers. Likewise, limited data suggest that proton pump inhibitors-induced healing rates in gastro-oesophageal reflux disease are apparently higher in poor metabolizers/het extensive metabolizers than in extensive metabolizers of CYP2C19. Therefore initial genotyping for this enzyme and higher dosage in extensive metabolizers is likely to improve the clinical efficacy of proton pump inhibitors.

Impact of endoscopy-based research on quality of life in healthy volunteers.

AIM: To study the impact of an endoscopy-based long-term study on the quality of life in healthy volunteers (HV). METHODS: Ten HV were included into a long-term prospective endoscopy-based placebo-controlled trial with 15 endoscopic examinations per person in 5 different drug phases. Participants completed short form-36 (SF-36) and visual analog scale-based questionnaires (VAS) for different abdominal symptoms at days 0, 7 and 14 of each drug phase. Analyses were performed according to short- and long-term changes and compared to the control group. RESULTS: All HV completed the study with duration of more than 6 mo. Initial quality of life score was comparable to a general population. Analyses of the SF-36 questionnaires showed no significant changes in physical, mental and total scores, either in a short-term perspective due to different medications, or to potentially endoscopic procedure-associated long-term cumulative changes. Analogous to SF-36, VAS revealed no significant changes in total scores for pathological abdominal symptoms and remained unchanged over the time course and when compared to the control population. CONCLUSION: This study demonstrates that quality of life in HV is not significantly affected by a long-term endoscopy-based study with multiple endoscopic procedures.

mTOR inhibitors for hepatocellular cancer: a forward-moving target.

mTOR is a central regulator of cell growth and angiogenesis. The mTOR pathway is activated in 40-50% of patients with hepatocellular cancer (HCC). In different models (i.e., hepatoma cell lines and implanted HCC tumors in rats), mTOR inhibitors (mTORIs) were effective in reducing cell growth and tumor vascularity. Synergistic effects were observed for mTORIs and chemotherapeutic agents in these studies, while other combinations involving mTORIs and inhibitors of growth hormones and angiogenesis are awaiting further clinical testing. A number of mTORIs are already clinically available (e.g., sirolimus, temsirolimus and everolimus), sharing similiar pharmacokinetic parameters (except for absorption) and side effects. Clinical data are, as yet, only preliminary and are mainly derived from retrospective studies in patients who underwent liver transplantation for HCC. Those patients had received sirolimus thereafter for immunosuppression, and a much lower rate of tumor recurrence than with calcineurin inhibitors alone was noted. Current prospective trials for treatment of advanced HCC include mTORIs alone or in combination with either transarterial chemoembolization or other systemic drugs, and will be discussed in detail in this review.

Low-dose aspirin has no impact on systemic level of serine protease inhibitors in healthy volunteers.

Low-dose aspirin (100 mg/day) was recently found to increase serum levels of alpha-1 protease inhibitor (A1-PI). Here, we studied the serum levels of 2 major serine protease inhibitors, A1-PI and serine leukocyte protease inhibitor (SLPI), in 10 Helicobacter pylorinegative healthy volunteers (HVs) treated with low-dose aspirin alone and in combination with other drugs.(1) Neither the treatment with low-dose aspirin alone or in combination altered serum levels of both serine protease inhibitors. The previously described increase of A1-PI levels by low-dose aspirin was most likely caused by multiple endoscopies within a few days, which caused a systemic stress response.

The long-term effect of Helicobacter pylori eradication on COX-1/2, 5-LOX and leukotriene receptors in patients with a risk gastritis phenotype--a link to gastric carcinogenesis.

To identify the role of eicosanoid-mediated pathways for gastric carcinogenesis, the expression of enzymes (COX-1, COX-2, 5-LOX) and receptors (BLT-1, CysLTR(1)) were immunohistochemically studied in H. pylori positive patients with a risk gastritis phenotype and either successful or unsuccessful eradication (n=12, each; followed up for a median of 5 years). Gastric cancer risk index improved significantly after successful eradication (p<0.001). Semiquantitative immunohistochemistry revealed distinct significant changes in the expression patterns for COX-2, CysLTR1, COX-1 and BLT-1 depending on the eradication outcome, whereas 5-LOX expression was not altered. These results suggest an involvement of the COX-LOX pathway in gastric carcinogenesis.

Treatment and dosing of Helicobacter pylori infection: when pharmacology meets clinic.

Helicobacter pylori infection is a major cause of diseases located in the upper gastrointestinal tract. Successful eradication of the bacteria may improve H. pylori-related symptomatic complaints in functional dyspepsia, cure peptic ulcer disease and prevent gastric cancer. As vaccines are not available, the search for the optimal drug regimen has dominated the last decade. Today, most countries prefer a 7- to 10-day regimen containing a proton pump inhibitor, clarithromycin and amoxicillin as first-line treatment. An alternative (or second-line) treatment contains a proton pump inhibitor, bismuth, tetracycline and metronidazole. This review also highlights the impact of new drugs, new drug combinations, and their optimal dosing required to maximise clinical outcome.