Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori.

Helicobacter pylori eradication rates by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin at standard doses depend on bacterial susceptibility to clarithromycin and patient CYP2C19 genotypes. We examined the usefulness of a personalized therapy for H. pylori infection based on these factors as determined by genetic testing. First, optimal lansoprazole dosing schedules that would achieve sufficient acid inhibition to allow H. pylori eradication therapy in each of different CYP2C19 genotype groups were determined by a 24-h intragastric pH monitoring. Next, 300 H. pylori-positive patients were randomly assigned to the standard regimen group (lansoprazole 30 mg twice daily (b.i.d.)), clarithromycin 400 mg b.i.d., and amoxicillin 750 mg b.i.d. for 1 week) or the tailored regimen group based on CYP2C19 status and bacterial susceptibility to clarithromycin assessed by genetic testing. Patients with failure of eradication underwent the second-line regimen. The per-patient cost required for successful eradication was calculated for each of the groups. In the first-line therapy, the intention-to-treat eradication rate in the tailored regimen group was 96.0% (95% CI=91.5-98.2%, 144/150), significantly higher than that in the standard regimen group (70.0%: 95% CI=62.2-77.2%, 105/150) (P<0.001). Final costs per successful eradication in the tailored and standard regimen groups were $669 and $657, respectively. In conclusion, the pharmacogenomics-based tailored treatment for H. pylori infection allowed a higher eradication rate by the initial treatment without an increase of the final per-patient cost for successful eradication. However, the precise cost-effectiveness of this strategy remains to be determined.

Role of the vasopressin V(1) receptor in regulating the epithelial functions of the guinea pig distal colon.

Vasopressin has a wide spectrum of biological action. In this study, the role of vasopressin in regulating electrolyte transport in the colon was elucidated by measuring the short-circuit current (I(sc)) as well as the Na(+), K(+), and Cl(-) flux in a chamber-mounted mucosal sheet. The cytosolic Ca(2+) concentration ([Ca(2+)](i)) was also measured in fura 2-loaded cells by fluorescence imaging. Serosal vasopressin decreased I(sc) at 10(-9) M and increased I(sc) at 10(-7)-10(-6) M. The decrease in I(sc) was accompanied by two effects: one was a decrease in the amiloride-sensitive Na(+) absorption, whereas the other was an increase in the bumetanide-sensitive K(+) secretion. The increase in I(sc) was accompanied by an increase in the Cl(-) secretion that can be inhibited by serosal bumetanide or mucosal diphenylamine-2-carboxylate. Vasopressin caused an increase in [Ca(2+)](i) in crypt cells. These responses of I(sc) and the [Ca(2+)](i) increase in crypt cells were all more potently inhibited by the vasopressin V(1) receptor antagonist than by the V(2) receptor antagonist. These results suggest that vasopressin inhibits electrogenic Na(+) absorption and stimulates electrogenic K(+) and Cl(-) secretion. In all of these responses, the V(1) receptor is involved, and the [Ca(2+)](i) increase may play an important role.

Radical intensity and cytotoxic activity of curcumin and gallic acid.

Natural phenolic compounds, curcumin and gallic acid, were compared for their cytotoxic activity in relation to their radical modulating activity. These two compounds induced apoptotic cell death in human promyelocytic leukemic HL-60 cells and human oral squamous carcinoma HSC-4 cells. Curcumin was more cytotoxic than gallic acid. Catalase reduced significantly the cytotoxic activity of gallic acid, but not that of curcumin. ESR spectroscopy demonstrated that curcumin produced radicals under alkaline conditions, scavenged the superoxide anion radical, and enhanced the radical intensity of sodium ascorbate at higher concentrations. As compared with curcumin, gallic acid produced higher amounts of radicals and more efficiently scavenged the superoxide anion radical. Gallic acid reduced the radical intensity of sodium ascorbate, suggesting a possible interaction between these two compounds. These data suggest that curcumin and gallic acid induce apoptosis by different mechanisms.

Role of hydrogen peroxide in cytotoxicity induction by ascorbates and other redox compounds.

Role of hydrogen peroxide (H2O2) in the induction of cytotoxicity by ascorbic acid derivatives was investigated. Ascorbic acid derivatives which produced radicals (sodium 5,6-benzylidene-L-ascorbate (SBA), sodium-L-ascorbate, D-isoascorbic acid) dose-dependently reduced the viable cell number of human squamous carcinoma (HSC-2, HSC-4, NA), human salivary gland tumor (HSG) and human promyelocytic leukemia (HL-60) cell lines. Conversely, L-ascorbic acid-2-phosphate magnesium which did not produce radicals, was inactive. This suggests the possible role of the ascorbate radical in apoptosis induction. The cytotoxic activity of SBA was partially reduced by catalase, and the extent of inhibition by catalase was considerably different, depending upon which target cells were used. On the other hand, the cytotoxic activity of sodium ascorbate, isoascorbic acid, hydrogen peroxide and gallic acid was more effectively inhibited by catalase. These data suggest that mechanisms other than H2O2 might be involved in the induction of cytotoxicity by SBA.

Long-term effects of water-soluble corn bran hemicellulose on glucose tolerance in obese and non-obese patients: improved insulin sensitivity and glucose metabolism in obese subjects.

We examined the effect of soluble corn bran hemicellulose (CBH, 10 g/day) on glucose control and serum insulin in three groups: patients with impaired glucose tolerance (IGT) with (20 subjects) or without (8 subjects) obesity and with healthy non-obese controls (10 subjects). Long-term supplementation (6 months) with CBH decreased the post oGTT curve for patients with impaired mild Type II diabetes, but not that for the controls. Hemoglobin A1c decreased significantly during CBH supplementation in the obese patients, while the fasting glucose level decreased in all three groups, although not significantly. A decreased serum insulin response by oGTT was found in those patients with IGT. The improved oGTT result was associated with improved insulin release and perhaps with peripheral insulin sensitivity. These findings suggest that CBH at a low dose might contribute to glycemic control and would play a useful role in treating Type II diabetes patients.