Summary
Background
Acid inhibitory effects of proton pump inhibitors (PPIs) are influenced by CYP2C19 genotype. In contrast, the potent acid inhibition of vonoprazan is not influenced by CYP2C19 ...genotype.
Aim
To compare the acid inhibitory effects of vonoprazan and esomeprazole in relation to CYP2C19 genotype.
Methods
Twenty‐eight healthy Japanese volunteers 7 CYP2C19 poor metabolisers (PMs), 11 intermediate metabolisers (IMs) and 10 rapid metabolisers (RMs) received four different regimens in a randomised crossover manner: (i) vonoprazan 20 mg twice daily (b.d.), (ii) vonoprazan 20 mg daily, (iii) esomeprazole 20 mg b.d. and (iv) esomeprazole 20 mg daily. The timing of each dosing was 1 h before a meal. Twenty‐four‐hour intragastric pH monitoring was performed on day 7 on each regimen.
Results
In the overall genotype group, pH ≥4 holding time ratios (pH 4 HTRs) with vonoprazan b.d., vonoprazan daily, esomeprazole b.d. and esomeprazole daily were 100%, 95%, 91%, and 68% respectively. pH 5 HTRs were 99%, 91%, 84% and 54% respectively. Vonoprazan b.d. potently suppressed acid for 24 h, and was significantly superior to other regimens irrespective of CYP2C19 genotype. Vonoprazan daily was equivalent to esomeprazole b.d. in IMs and PMs, but superior in RMs. CYP2C19 genotype‐dependent differences were observed in esomeprazole daily but not in vonoprazan b.d. or daily.
Conclusion
Vonoprazan 20 mg b.d. inhibits acid irrespective of CYP2C19 genotype, more potently than esomeprazole 20 mg b.d., pH 4 and 5 holding time ratios reached 100% and 99%, respectively.
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.
Clinical Pharmacology & Therapeutics (2007) 81, 521–528. doi:10.1038/sj.clpt.6100043; published online 10 January 2007
Summary
Background
Although autoimmune gastritis (AIG) is generally considered relatively rare, we frequently encounter AIG among patients at to our hospital who have experienced at least two ...episodes of Helicobacter pylori eradication failure.
Aims
We investigated the incidence of AIG in consecutive patients who consulted our department for H. pylori eradication with reference to eradication history.
Methods
A total of 404 consecutive patients who visited the H. pylori‐specific out‐patient unit of our hospital from June 2015 to June 2017 were enrolled. Of these, 137 were treatment‐naive, 47 had failed treatment once (single failure), and 220 had failed treatment twice or more (multiple failures) by 13C‐UBT. Gastroscopy was performed in all patients. Culture tests of gastric mucosal samples were performed for H. pylori and other bacteria positive for urease activity. Anti‐parietal cell antibody (APCA) was measured. Patients with severe atrophy in the gastric corpus and positivity for APCA were diagnosed as having AIG.
Results
A total of 43 patients were diagnosed as having AIG, of whom two were treatment‐naive (1.5%, 2/137), 1 failed eradication once (2.1% 1/47), and 40 failed treatment at least twice (18.2%, 40/220). The incidence of AIG was significantly higher in the multiple failure group than in the single failure or treatment‐naive groups. Urease‐positive bacteria, such as Klebsiella pneumoniae and alpha‐streptococcus, were identified in 33 of the 35 AIG patients who underwent culture testing.
Conclusion
AIG patients were often misdiagnosed as refractory to eradication therapy, probably because achlorhydria in AIG might allow urease‐positive bacteria other than H. pylori to colonise the stomach, causing positive 13C‐UBT results.
Summary
Background
Twice‐daily dosing of proton pump inhibitors (PPIs) is used to treat Helicobacter pylori or acid‐related diseases, such as gastro‐oesophageal reflux disease (GERD) refractory to ...standard dose of a PPI. Genetic polymorphisms of CYP2C19 are involved to different extents in the metabolism of four kinds of PPIs (omeprazole, lansoprazole, rabeprazole and esomeprazole) available in Japan.
Aim
To compare acid‐inhibitory effects of the four PPIs dosed twice daily in relation to CYP2C19 genotype.
Methods
We performed 24‐h pH monitoring studies on Day 7 of PPI treatment for 40 Japanese H. pylori‐negative volunteers 15 CYP2C19 rapid metabolisers (RMs), 15 intermediate metabolisers (IMs) and 10 poor metabolisers (PMs) using a randomised four‐way crossover design: omeprazole 20 mg, esomeprazole 20 mg, lansoprazole 30 mg and rabeprazole 10 mg twice daily.
Results
Although median pH values with esomeprazole, omeprazole, lansoprazole and rabeprazole were 5.7 (3.5–7.2), 5.5 (2.4–7.2), 5.5 (3.7–7.3) and 5.2 (2.5–7.3), respectively (no statistically significant differences), CYP2C19 genotype‐dependent differences were smaller for esomeprazole and rabeprazole compared with values for omeprazole and lansoprazole. In CYP2C19 RMs, the median pH with esomeprazole 5.4 (3.5–6.8) was significantly higher than those with omeprazole 5.0 (2.4–5.9), P = 0.018, lansoprazole 4.7 (3.7‐5.5), P = 0.017 or rabeprazole 4.8 (2.5–6.4), P = 0.002. In IMs and PMs, the median pH was >5.0 independent of the PPI.
Conclusions
In intermediate and rapid metabolisers of CYP2C19, PPIs dosed twice daily could attain sufficient acid suppression, while in CYP2C19 RMs, esomeprazole 20 mg twice daily caused the strongest inhibition of the four PPIs. Therefore, esomeprazole may be effective in Japanese population when dosed twice daily.
Chromosomal instability (CIN) is recognised as a hallmark of cancer and is caused by a spindle assembly checkpoint disorder or chromosome mis-segregation during mitosis. Although the recent ...identification of human shugoshin (hSgo1), an important player in proper chromosome segregation, has suggested the involvement of hSgo1 in colorectal tumourigenesis, little is known about how it is involved. The aim of this study was to obtain information about the status of hSgo1 in human colorectal cancer.
Among the 46 colorectal cancer cases, hSgo1 mRNA expression was decreased in the tumour tissue in comparison with the corresponding normal tissue (p = 0.032). Human Sgo1-downregulated tumours (tumour to normal mucosa ratio<0.5) had preferential location on the left side large bowel rather than on the right side (p = 0.012), and a higher variation of centromere numbers revealed by fluorescence in situ hybridisation (FISH). To assess the effects of hSgo1 downregulation, hSgo1 knockdown was performed by transfecting the diploid HCT116 cell line with a short hairpin RNA expression vector. hSgo1 knockdown cells proliferated slowly because of both G(2)/M arrest and apoptosis (p<0.001), and markers of CIN in the form of aneuploidy (p<0.001) and micronuclei (p<0.005) were later observed in hSgo1 knockdown cells. Increased centrosome amplification (p<0.05), the presence of binucleated cells and mitotic catastrophes were also noted in hSgo1 knockdown cells.
These findings suggest that hSgo1-downregulated colorectal cancers have a clinicopathological character of CIN, and hSgo1 downregulation leads to CIN in colorectal cancer cells.
Mitosis is the most conspicuous cell cycle phase, because it is the phase in which the dynamic physical distributions of cellular components into the two daughter cells occur. The separation of ...sister chromatids is especially important during mitosis, because of the extreme accuracy required for distribution to the next generation of cells. Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation. We have reported finding that chromosome instability is more likely in SGOL1-downregulated colorectal cancers, but it is still unknown whether there is an association between cancer and SGOL1 transcript variation. Here, we identified a novel SGOL1 variant, SGOL1-P1, in human colon cancer. The SGOL1-P1 transcript contains an exon-skip of exon 3 that results in a stop codon occurring within exon 4. Overexpression of SGOL1-P1 in HCT116 cells resulted in an increased number of cells with aberrant chromosome alignment, precociously separated chromatids and delayed mitotic progression, occasionally followed by inaccurate distribution of the chromosomes. These phenotypes, observed when SGOL1-P1 was present, were also observed very frequently in SGOL1-knockdown cells. Furthermore, the overexpression of SGOL1-P1 inhibited the localization of endogenous SGOL1 and cohesin subunit RAD21/SCC1 to the centromere. These results suggest that SGOL1-P1 may function as a negative factor to native SGOL1, and that abundant expression of SGOL1-P1 may be responsible for chromosomal instability.
When considering the genetic implications of immigrant gene flow, it is important to evaluate both the proportions of immigrant gametes and their genetic composition. We simultaneously investigated ...paternal and maternal gene flow in dispersed seeds in a natural population of Pinus densiflora located along a ridge. The paternity and maternity of a total of 454 dispersed seeds (in 2004 and 2005) were accurately and separately assigned to 454 candidate adult trees, by analyzing the nuclear DNA of both diploid biparentally derived embryos and haploid maternally derived megagametophytes of the seeds. The relative genetic diversities and differences between within-population and immigrant groups of both paternally and maternally derived gametes (4 groups) that formed the genotypes of the seeds were evaluated. Using 8 microsatellite markers, we found that 64.0-72.6% of paternally derived gametes, and 17.8-20.2% of maternally derived gametes, were from other populations. Principal coordinate analysis showed that the 4 gamete groups tended to be plotted at different locations on the scattergram, indicating that they each have different genetic compositions. Substantial paternal and maternal immigrant gene flow occurred in this population, and therefore, the overall genetic variation of dispersed seeds is enhanced by both paternally and maternally derived immigrant gametes.
We developed 32 microsatellite markers from an enriched genomic DNA library of hinoki (
), one of the most important Japanese forestry conifer species. From a total of 1,056 cloned plasmids, 96 ...sequence-specific primer pairs were designed from 110 candidate clones. We selected 32 primers that showed successful amplification and marked polymorphism and evaluated their characteristics using DNA from 38
elite trees planted in the Forest Tree Breeding Center. The markers were highly polymorphic, with the number of alleles ranging from 8 to 32 (mean: 20.09), and expected heterozygosity ranging from 0.811 to 0.958 (mean: 0.901). Progress in breeding projects and studies of the ecological genetics of this species can be expected through the use of this enlarged marker pool.
Drug–drug interaction between antiacid and antiplatelet agents has not been fully elucidated. Vonoprazan, a new potassium competitive acid blocker, has been available in Japan. CYP2C19 and CYP3A4 are ...involved in the metabolism of clopidogrel, prasugrel, esomeprazole, and vonoprazan. Using a P2Y12 assay, we compared the effects of vonoprazan and esomeprazole on the antiplatelet functions of clopidogrel or prasugrel in 31 healthy Japanese volunteers (14 CYP2C19 homo‐extensive (homo‐EMs), nine hetero‐extensive (hetero‐EMs), and eight poor metabolizers (PMs)). Vonoprazan decreased the median inhibition of platelet aggregation (IPA) values of clopidogrel and prasugrel more potently than esomeprazole (P < 0.001 for clopidogrel and P = 0.011 for prasugrel). The same tendencies were observed when stratified by CYP2C19 genotype groups (P = 0.004 in homo‐EMs, 0.033 in hetero‐EMs, and 0.043 in PMs). Vonoprazan attenuated the antiplatelet function of clopidogrel more potently than esomeprazole. Esomeprazole did not affect that of prasugrel irrespective of CYP2C19 genotype.
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