Fang Xiao

Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin

Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status.

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non‐enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual’s CYP2C19 status.

Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin.

Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis and H. pylori infection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pylori infection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure of H. pylori infection was achieved in 79 of the 97 patients (81.4%, 95%CI = 71.9-88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6% (95%CI = 42.1-77.3), 91.7% (95%CI = 80.0-97.7), and 93.8% (95%CI = 69.8-99.8), respectively (P = 0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates for H. pylori infection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin.

Effect of high‐dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19

Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid‐inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem.

Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer

Background and Aim:  In Western countries, polymorphism of pro‐inflammatory cytokine genes is associated with the development of gastric cancer and duodenal ulcer. The aim of this study was to clarify the association of polymorphisms of interleukin (IL)‐1β and tumor necrosis factor (TNF)‐α with susceptibility to peptic ulcer diseases and gastric cancer in Japan.

Effect of Helicobacter pylori infection and its eradication on nutrition

To investigate the effects of Helicobacter pylori infection and eradication on nutrition.

Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups

The acid inhibitory effect of lansoprazole depends on the S‐mephenytoin 4′‐hydroxylase (CYP2C19) genotype status. The effect of famotidine is independent of this genotype.

Polymorphism of interleukin-1β affects the eradication rates of Helicobacter pylori by triple therapy ☆

BACKGROUND AND AIMS Polymorphism in interleukin-1beta (IL-1beta) is associated with intragastric pH levels in Helicobacter pylori-positive subjects. Intragastric pH levels affect the activity of antibiotics against H. pylori in the stomach. The aim of this study was to investigate whether IL-1beta polymorphism is associated with eradication rates of H. pylori by triple therapy with a proton pump inhibitor (PPI), amoxicillin, and clarithromycin. METHODS Three hundred thirty-six patients infected with H. pylori completed treatment with omeprazole, 20 mg, or lansoprazole, 30 mg twice daily; clarithromycin, 200 mg 3 times daily; and amoxicillin, 500 mg 3 times daily, for 1 week. IL-1beta-511 and CYP2C19 genotypes of patients and sensitivity of H. pylori to clarithromycin and amoxicillin were determined. RESULTS Logistic regression analysis showed that the IL-1beta-511 polymorphism, as well as CYP2C19 genotype of patients and clarithromycin-resistance of H. pylori, was associated with successful eradication. Eradication rates for H. pylori were 77.3% (75 of 97; 95% confidence interval, 67.5-84.6), 89.6% (147 of 164; 95% confidence interval, 83.9-93.1), and 94.7% (95% confidence interval, 86.9-98.5) in patients with the C/C, C/T, and T/T genotypes of IL-1beta-511, respectively (P = 0.0014). CONCLUSIONS IL-1beta-511 polymorphism is one of the determinants of successful eradication of H. pylori using triple therapy with a PPI, amoxicillin, and clarithromycin, together with CYP2C19 genotype and bacterial resistance to clarithromycin.

Effect of genotypic differences in interleukin-1 beta on gastric acid secretion in Japanese patients infected with helicobacter pylori

Although several studies have demonstrated a close relation between Helicobacter pylori infection and various upper gastrointestinal disorders, including gastric cancer (1–3), the specific pathophysiological explanations for this association are not known. H. pylori infection causes histological gastritis and affects gastric acid secretion (4 – 6). In patients with severe gastritis of the corpus, acid secretion is decreased markedly and the pH of gastric juice is increased (4 – 6). This decrease in acid secretion delays the elimination of bacterial toxins and products of inflammation, such as reactive oxygen radicals and nitrogen oxide (7), thereby increasing the concentration of these well-known mutagens in the stomach. Decreased acid secretion may also result in increased production of carcinogenic N-nitroso compounds because of superinfection by other bacteria or a reduction in vitamin C levels in gastric juice (8,9). An increased rate of cell turnover in inflamed mucosa further increases the opportunity for DNA damage. Moreover, decreased gastric acid secretion permits the reflux of duodenal juice, including bile, into the stomach, which can induce intestinal metaplasia, a precancerous change (10). Therefore, H. pylori–induced gastritis and subsequent acid hyposecretion may be associated with an increased risk of gastric cancer. Several inflammatory cytokines are upregulated in gastric mucosa infected with H. pylori. One of these cytokines, interleukin-1beta (IL-1 ), is important in initiating and amplifying the inflammatory responses to H. pylori infection (11). IL-1 is also a potent inhibitor of gastric acid secretion (12–14), as we have previously observed in patients infected with H. pylori (15). Increased IL-1 gene expression and severe corpus gastritis are related to increased pH of the gastric juice. In an animal model, we have recently reported that acid secretion is decreased by H. pylori infection, which is accompanied by an increase in the expression of IL-1 messenger ribonucleic acid (mRNA) in gastric mucosa as has been observed in humans. Furthermore, the decreased acid secretion in this animal model was restored to normal levels by administration of an antagonist of the IL-1 receptor (16). Therefore, IL-1 may cause the acid hyposecretion that is observed in patients with H. pylori infection and severe gastritis. Polymorphisms in the promoter region of the IL-1 gene have been associated with differences in the production of IL-1 by leukocytes in vitro (17,18). In white patients, polymorphisms in or near the interleukin gene have been associated with enhanced IL-1 production and an increased risk of gastric cancer (7). However, one of the polymorphisms (IL-1RN*2) is rare in Japan (19). Moreover, the polymorphisms in the promoter region of IL-1 (at positions 511 and 31) are closely linked and thus may not convey independent information (7,19). We studied whether gastric pH differed among the different IL-1 ( 511) genotypes in Japanese patients infected with H. pylori.

Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient

A 53‐year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor–based triple therapy, such as lansoprazole‐clarithromycin‐amoxicillin (INN, amoxicilline) and lansoprazole‐minocycline‐cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin‐resistant but amoxicillin‐sensitive strain of H pylori. Moreover, a polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor–based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor–based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.