Effects of different omeprazole dosing on gastric pH in non-variceal upper gastrointestinal bleeding: A randomized prospective study.

OBJECTIVE: We aimed to identify the best method of omeprazole (OME) application with respect to intragastric pH, cytochrome P450 2C19 (CYP2C19) genotype and phenotype. METHODS: The patients with non-variceal upper gastrointestinal bleeding (NVUGIB) were prospectively enrolled. After the achievement of endoscopic hemostasis, the patients were randomized to 40-mg intravenous (i.v.) OME bolus injection every 12 h or 8-mg/h continuous i.v. infusion for 72 h after an 80-mg i.v. OME bolus administration. The intragastric pH was recorded for 72 h. The CYP2C19 variant alleles (*2, *3, *17) were analyzed and the serum concentrations of OME and 5-hydroxyomeprazole (5-OH OME) were determined. RESULTS: Altogether 41 Caucasians (18 in the OME infusion [OI] group and 23 in the OME bolus [OB] group) were analyzed. The median percentage of time with an intragastric pH > 4.0 was higher in the infusion group than in the OB group over 48 h (100% vs 96.6%, P = 0.009) and 72 h (100% vs 87.6%, P = 0.006), and that at an intragastric pH >6.0 was higher in the OI group than the OB group over 72 h (97.9% vs 63.5%, P = 0.04). Helicobacter pylori infection was correlated with the fastest increase in intragastric pH, especially in the OI group. In both groups, CYP2C19 genotypes (*1/*1, *1/*17, *17/*17) had no essential effect on intragastric pH. CONCLUSIONS: In patients with NVUGIB, OME i.v. bolus followed by continuous infusion is more effective than OME i.v. bolus every 12 h in maintaining higher intragastric pH, regardless of CYP2C19 genetic polymorphisms. H. pylori infection accelerates the initial elevation of intragastric pH.

[HORMONAL-GENETIC SCREENING IN PATIENTS, SUFFERING GASTRODUODENAL ULCER HEMORRHAGE].

Genetic-hormonal regulation plays a key pathophysiologic role in a blood loss on background of complicated gastroduodenal ulcer disease, but a clinical significance of some genes of compensatory steroidogenesis remains unrevealed. Examination of 63 patients, using a chain reaction with polymerase (CRP); analysis of length of restriction fragments (CRP-RFLP) and immunohistochemical investigation of gastroduodenal mucosa were performed on the base of a Sumsky Rural Clinical Hospital. Trustworthy difference of distribution of polymorphic genes ESR1 and VKORC1 in patients of both gender in presence of the ulcer hemorrhage was not revealed, excluding genotype A/A VKORC1, what trustworthy more frequently was revealed in women (p < 0.05). There was established, that intact zone of gastric fundus owes immunoreactivity towards alpha-receptors of estrogen in nuclei of epitheliocytes and stromocytes. Diagnosis of polymorphic gene VKORC1 and expression of the estrogen receptors may serve the base for pathogenetic therapy in patients with hemorrhage occurrence.

Does COX1 gene polymorphism (A842G/C50T) influence peptic ulcer bleeding in Indian patients?.

This is a pilot study to test the hypothesis that polymorphisms that may be linked to cyclooxygenase production may affect the likelihood and the nature of bleeding in patients with ulcer disease. Of the two polymorphism that have previously been studied for links we chose the A842G polymorphims. Of the 50 patients with ulcer bleeding who were studied, 8 had a heterozygous polymorphisms and 42 had the normal configuration. On comparing these two groups. there were no significant differences in clinical presentation except that there was a tendency to have less gastric ulcers among those with the A842G/C50T polymorphism. Based on these studies we need to undertake a larger studies comparing these groups with those with ulcers without GI bleeding and those without ulcers

Single nucleotide polymorphism markers for low-dose aspirin-associated peptic ulcer and ulcer bleeding.

BACKGROUND AND AIM: In our previous study, the SLCO1B1 521TT genotype and the SLCO1B1*1b haplotype were significantly associated with the risk of peptic ulcer in patients taking low-dose aspirin (LDA). The aim of the present study was to investigate pharmacogenomic profile of LDA-induced peptic ulcer and ulcer bleeding. METHODS: Patients taking 100 mg of enteric-coated aspirin for cardiovascular diseases and with a peptic ulcer or ulcer bleeding and patients who also participated in endoscopic surveillance were studied. Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DME Plus Premier Pack. SLCO1B1*1b haplotype and candidate genotypes of genes associated with ulcer bleeding or small bowel bleeding identified by genome-wide analysis were determined using TaqMan SNP Genotyping Assay kits, polymerase chain reaction-restriction fragment length polymorphism, and direct sequencing. RESULTS: Of 593 patients enrolled, 111 patients had a peptic ulcer and 45 had ulcer bleeding. The frequencies of the SLCO1B1*1b haplotype and CHST2 2082 T allele were significantly greater in patients with peptic ulcer and ulcer bleeding compared to the controls. After adjustment for significant factors, the SLCO1B1*1b haplotype was associated with peptic ulcer (OR 2.20, 95% CI 1.24-3.89) and CHST2 2082 T allele with ulcer bleeding (2.57, 1.07-6.17). CONCLUSION: The CHST2 2082 T allele as well as SLCO1B1*1b haplotype may identify patients at increased risk for aspirin-induced peptic ulcer or ulcer bleeding.

Effects of the CYP2C19 genetic polymorphism on gastritis, peptic ulcer disease, peptic ulcer bleeding and gastric cancer.

BACKGROUND: The CYP2C19 genotype has been found to be an important factor for peptic ulcer healing and H. pylori eradication, influencing the efficacy of proton pump inhibitors (PPIs) and the pathogenesis of gastric cancer. The aim of this study was to investigate clinical correlations of the CYP2C19 genotype in patients with gastritis, peptic ulcer disease (PUD), peptic ulcer bleeding (PUB) and gastric cancer in Thailand. MATERIALS AND METHODS: Clinical information, endoscopic findings and H. pylori infection status of patients were assessed between May 2012 and November 2014 in Thammasat University Hospital, Thailand. Upper GI endoscopy was performed for all patients. Five milliliters of blood were collected for H. pylori serological diagnosis and CYP2C19 study. CYP2C19 genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP) and classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). RESULTS: A total of 202 patients were enrolled including 114 with gastritis, 36 with PUD, 50 with PUB and 2 with gastric cancer. Prevalence of CYP2C19 genotype was 82/202 (40.6%) in RM, 99/202 (49%) in IM and 21/202 (10.4%) in PM. Overall H. pylori infection was 138/202 patients (68.3%). H. pylori infection was demonstrated in 72% in RM genotype, 69.7% in IM genotype and 47.6% in PM genotype. Both gastric cancer patients had the IM genotype. In PUB patients, the prevalence of genotype RM (56%) was highest followed by IM (32%) and PM(12%). Furthermore, the prevalence of genotype RM in PUB was significantly greater than gastritis patients (56% vs 36%: p=0.016; OR=2.3, 95%CI=1.1-4.7). CONCLUSIONS: CYP2C19 genotype IM was the most common genotype whereas genotype RM was the most common in PUB patients. All gastric cancer patients had genotype IM. The CYP2C19 genotype RM might be play role in development of PUD and PUB. Further study in different population is necessary to verify clinical usefulness of CYP2C19 genotyping in development of these upper GI diseases.

Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation.

OBJECTIVES: Lysozyme amyloidosis (ALys) is a form of hereditary systemic non-neuropathic amyloidosis, which is inherited in an autosomal dominant fashion. Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages. The aim of this study is to describe the phenotype and outcome of patients with ALys including the role of solid organ transplantation. DESIGN: Retrospective evaluation of patients with ALys. SETTING: UK National Amyloidosis Centre. PATIENTS: All 16 patients with ALys followed at the centre. RESULTS: A family history of amyloidosis was present in every affected individual. Although the phenotype was broadly similar amongst those from the same kindred, there were marked phenotypic differences between kindreds who possessed the same amyloidogenic mutation. Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy. All symptomatic ALys individuals had hepatic amyloid. Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively. All of the liver grafts were functioning at censor 1.7, 5.8, 9.0 and 11.0 years after OLT. Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx). There was no evidence of renal allograft dysfunction at censor 6.6, 1.8 and 0.8 years after RTx. CONCLUSIONS: Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history. There was a clear family history in all cases within this cohort, demonstrating a high clinical penetrance in the presence of an amyloidogenic lysozyme mutation. There is currently no amyloid-specific therapy for the condition which is managed symptomatically. OLT and RTx appear to be successful treatments for patients with liver rupture or end-stage renal disease, respectively, with excellent outcomes in terms of medium-term graft function and patient survival.

Renin-angiotensin system associated with risk of upper GI mucosal injury induced by low dose aspirin: renin angiotensin system genes' polymorphism.

BACKGROUND: We have previously shown that co-treatment of angiotensin type 1 receptor (AT1R) blocker (ARB) or angiotensin converting enzyme (ACE) inhibitor seem to reduce peptic ulcer among patients taking low dose aspirin. It is reported that a series of renin-angiotensin system (RAS) gene polymorphisms significantly influence the rate of the gene transcription. AIM: The aim of this study was to examine the genotypes of RAS genes related to the risk of peptic ulcer and ulcer bleeding among patients taking low dose aspirin. METHODS: Patients taking 100 mg of aspirin who were planning to undergo endoscopy for surveillance or who had history of recent upper GI ulcer bleeding were included. ACE (Ins/Del), angiotensinogen (AGT; G-217A, A-20C, A-6G, T174 M, M235T), and AT1R (T-713G, C-521T, A1166C) genotypes were determined by PCR or PCR-RFLP. RESULTS: Four hundred twenty-five patients were enrolled including 68 patients with peptic ulcer and 20 patients with ulcer bleeding. Co-treatment of ARB was significantly associated with peptic ulcer and ulcer bleeding. AGT-20 CC (adjusted OR 4.94, 95% CI 1.21-20.2) was significantly associated with ulcer bleeding. The CC genotype of AT1R-521 was significantly associated with peptic ulcer only in the subgroup taking neither ACE inhibitor nor ARB. CONCLUSIONS: Co-treatment of ARB reduces peptic ulcer and bleeding among patients taking low dose aspirin. RAS may play an important role in the development of upper GI mucosal injury induced by low dose aspirin.

[Dilemma between gastroprotection and cardiovascular prevention]. / Dilemma zwischen Magenschutz und Kardioprotektion.

Long-term low-dose aspirin intake leads to a 2 - 4-fold risk of risk for upper gastrointestinal bleeding. The additional intake of clopidogrel further increases the risk of upper GI bleeding (OR 7.4). Because of the potential interaction between proton pump inhibitors (PPI) and clopidogrel that compromises the efficacy of clopidogrel on platelet aggregation, there has been a warning in the product information by health authorities in the US and in Europe who discourage the concomitant use of PPI and clopidogrel. In the present study we performed a selected review of the published literature on the indications for gastric protection with PPI in patients on mono- or dual antiplatelet therapy focussing on the possible interaction between clopidogrel and PPI. In ex vivo analyses of platelet function, a reduced efficacy of clopidogrel was observed in patients on comedication with omeprazole. This was not the case with the comedication of other PPIs. To date, clear evidence is missing to state that comedication with PPI reduces the efficacy of clopidogrel IN VIVO. If both Clopidogrel and PPI need to be prescribed, a split dosage regimen of PPI in the morning and clopidogrel in the evening can be recommended. The short half-life of both medications explains the rationale of this recommendation.

Genetic polymorphisms in UDP-glucuronosyltransferase 1A6 are not associated with NSAIDs-related peptic ulcer haemorrhage.

UDP-glucuronosyltransferase 1A6 (UGT1A6) is involved in metabolizing non-steroidal anti-inflammatory drugs (NSAIDs). Genotype variation in UGT1A6 may influence the metabolism of NSAIDs and we studied whether this might modulate the gastrointestinal toxicity of NSAIDs. UGT1A6 genotypes of 114 patients with peptic ulcer haemorrhage were compared with those of two subsets of controls: 158 cardiology patients using similar amounts of NSAIDs and 140 healthy controls, hardly using NSAIDs. Risk factors for peptic ulcer bleeding were male gender (Odds ratio (OR) 2.66, 95% confidence interval (CI) 1.7-4.2), age above 60 years (OR 2.15, 95% CI 1.4-3.4) and use of NSAIDs/aspirin (OR 4.50, 95% CI 2.8-7.3). UGT1A6 genotype frequencies did not differ between patients with peptic ulcer and the two control groups (p=0.76). We conclude that polymorphic UGT1A6 is not implicated in the pathogenesis of NSAIDs-related peptic ulcer disease.

Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms.

BACKGROUND AND AIMS: Several nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 2C9 (CYP2C9). Two common variants of the CYP2C9 gene (CYP2C9*2 and *3) were reported to significantly affect the activity of the CYP2C9 enzyme. The aim of this study was to evaluate the impact of CYP2C9 polymorphisms on the risk of gastroduodenal bleeding in acute NSAID users. METHODS: This case-control study included 26 patients with endoscopically documented NSAID-related gastroduodenal bleeding lesions and 52 age-, sex- and NSAID use-matched controls with no lesions at endoscopy. Both cases and controls were Helicobacter pylori negative and acute users of an NSAID or cycloxygenase-2 inhibitor that undergoes CYP2C9 metabolism (ie, celecoxib, diclofenac, ibuprofen, naproxen, or piroxicam). Two marker single nucleotide polymorphisms in the CYP2C9 gene, identifying the CYP2C9 *2 and *3 allele, were evaluated in all subjects. RESULTS: Setting the CYP2C9*1/*1 wild type as reference, significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P < .001; odds ratio [OR], 12.9; 95% confidence interval [CI], 2.917-57.922) and CYP2C9*1/*2 (26.9% vs 15.4%; P = .036; OR, 3.8; 95% CI, 1.090-13.190) were identified in bleeding versus control patients, whereas no differences between bleeding and controls were observed in the distribution of CYP2C9*2/*3 heterozygotes. Considering allele carriers, the presence of CYP2C9*3 allele was associated with a significant high risk of bleeding (adjusted OR, 7.3; 95% CI, 2.058-26.004). CONCLUSIONS: CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Further studies that evaluate the effectiveness of a strategy using CYP2C9 genotyping in NSAID users are needed before genotyping is introduced into clinical practice.

Effect of a specific cyclooxygenase-gene polymorphism (A-842G/C50T) on the occurrence of peptic ulcer hemorrhage.

Cyclooxygenases (COX) catalyze the conversion of arachidonic acid to prostaglandins (PGs). COX-inhibiting drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), increase the risk for peptic ulcer disease. As a corollary, COX gene polymorphisms could be important in the pathogenesis of peptic ulcer disease because these affect prostaglandin formation and impair its protective effect at the level of the gastric mucosa. This study was designed to investigate the association between the functional single-nucleotide polymorphism, A-842G/C50T, in the COX-1 gene and peptic ulcer bleeding. We obtained DNA samples from 106 patients who underwent upper gastrointestinal endoscopy because of bleeding peptic ulcer disease and from 88 healthy control subjects. Genetic polymorphism in A-842G/C50T was determined by PCR followed by restriction-fragment-length-polymorphism analysis. Adjusted logistic regression analysis was performed to evaluate the associations. Risk factors associated with peptic ulcer bleeding were male gender (odds ratio, 4.78; 95% confidence interval, 2.6-8.8) and NSAID/aspirin-use (odds ratio, 38.39; 95% confidence interval, 14.2-103.6). The A-842G/C50T heterozygote was less frequent in peptic ulcer bleeding (n = 7) compared with healthy control subjects (n = 11). The adjusted risk for peptic ulcer bleeding among individuals who were heterozygote for the A-842G/C50T polymorphism was 0.75 (range, 0.19-3.01) compared with wild type. The COX-1 A-842G/C50T SNP does not influence the risk for developing peptic ulcer bleeding.

Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) may be involved in the pathogenesis of peptic ulcers through suppression of fibrinolysis. This study was designed to investigate associations of t-PA and PAI-1 genes with clinical features of the patients with bleeding gastric ulcers. Eighty-four patients with peptic ulcers and 100 controls were studied between January 1998 and April 2000. We used polymerase chain reaction and endonuclease digestion to genotype for 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alurepeat insertion/deletion (I/D) polymorphism in intron h of the t-PA gene. Various clinical features, including lesion site, bleeding event, recurrence of ulcer, and rebleeding, were assessed using a multiple logistic regression model. The genotype distributions of both the t-PA and PAI-1 genes did not differ between the patient and control groups. The occurrence of the I/D or D/D genotype of t-PA was significantly higher in cases of duodenal ulcer (adjusted OR=4.39, 95% CI=1.12-17.21). When a dominant effect (i.e., 4G/4G or 4G/5G versus 5G/5G) of the 4G allele was assumed, the PAI-1 4G/4G genotype was independently associated with rebleeding after hemostasis (adjusted OR=5.07, 95% CI=1.03-24.87). Our data suggest that t-PA gene polymorphism is associated with duodenal ulcers, and that the PAI-1 gene may be a risk factor leading to recurrent bleeding after initial hemostasis.

[Immunogenetic features of patients with ulcer disease of the stomach and duodenum and the significance of genetic markers in prognosis of complications of stomach and duodenal ulcers in Azerbaijan]. / Immunogeneticheskie osobennosti u bol'nykh s iazvennoi bolezn'iu zheludka i dvenadtsatiperstnoi kishki i znachenie geneticheskikh markerov v prognozirovanii vozniknoveniia oslozhnenii iazvennoi bolezni zheludka i dvenadtsatiperstnoi kishki v Azerbaidzhane.

The work has shown that patients with ulcer disease of the stomach and duodenum have immunogenetic features. In particular, genetic markers were detected for ulcer disease of the stomach and duodenum whose presence allows to predict with certain probability the development of ulcer disease of the stomach and duodenum. The presence of antigen HA-At and haploids--AxB18 and HLA--A10B27 is prognostically unfavorable factors for the development of complications of this disease.

Tissue Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 Gene Polymorphism in Patients with Gastric Ulcer Complicated with Bleeding

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) may be involved in the pathogenesis of peptic ulcers through suppression of fibrinolysis. This study was designed to investigate associations of t-PA and PAI-1 genes with clinical features of the patients with bleeding gastric ulcers. Eighty-four patients with peptic ulcers and 100 controls were studied between January 1998 and April 2000. We used polymerase chain reaction and endonuclease digestion to genotype for 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alurepeat insertion/deletion (I/D) polymorphism in intron h of the t-PA gene. Various clinical features, including lesion site, bleeding event, recurrence of ulcer, and rebleeding, were assessed using a multiple logistic regression model. The genotype distributions of both the t-PA and PAI-1 genes did not differ between the patient and control groups. The occurrence of the I/D or D/D genotype of t-PA was significantly higher in cases of duodenal ulcer (adjusted OR=4.39, 95% CI=1.12-17.21). When a dominant effect (i.e., 4G/4G or 4G/5G versus 5G/5G) of the 4G allele was assumed, the PAI-1 4G/4G genotype was independently associated with rebleeding after hemostasis (adjusted OR=5.07, 95% CI=1.03-24.87). Our data suggest that t-PA gene polymorphism is associated with duodenal ulcers, and that the PAI-1 gene may be a risk factor leading to recurrent bleeding after initial hemostasis.

Bleeding duodenal ulcer and association with polymorphism of endothelial constitutive nitric oxide synthase gene.

Nitric oxide (NO) exerts both protective and proinflammatory actions in the gastrointestinal tract. Enhanced gastric NO synthase (NOS) activity has been shown in duodenal ulcer patients. Recently, intron-4 polymorphism of the endothelial constitutive (ec) NOS gene has been associated with some pathological conditions. Our aim was to determine the genotype and allele frequencies of the ecNOS4 polymorphism in peptic ulcer patients. The distribution of the polymorphism ecNOS4a/b was studied in 188 ulcer patients and 120 healthy controls, from genomic DNA. Genotypes ab, bb, and aa and allele frequency were similar in both peptic ulcer patients and controls, and no differences were found when patients and controls were analyzed according to the presence of several etiological factors. However, alelle "a" carrier status was associated with decreased risk of bleeding in duodenal ulcer patients (OR = 0.49; 95% CI = 0.25-0.95; P = 0.03). In conclusion, this ecNOS4 polymorphism gene could be related to susceptibility of duodenal ulcer patients to bleeding.

[Prognosis of bleeding from duodenal ulcers]. / Prognozirovanie razvitiia krovotechenii iz iazv dvenadtsatipestnoi kishki.

Clinical and pathogenetic findings on 147 patients with duodenal ulcer (DU) and 29 patients with DU complicated by ulcerogenic bleeding were compared. This allowed to single out significant criteria for prediction of development of bleeding in such patients: male sex freguent seasonal exacerbations, hereditary load, location of the ulcer at the back wall of the duodenal bulb, negative atropine test, HLA-phenotype B35, A2 A3, A2 AX. High acidity and large sixe of DU were hot prognostically independent. The importance of complex approach in solution of prognostic problems is emphasized.