Takuma Kagami

Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype.

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.

High Helicobacter pylori cure rate with sitafloxacin-based triple therapy.

Bacterial resistance of Helicobacter pylori to antibiotics is increasing and it often leads to failure of antibiotic treatment. A new sitafloxacin‐based triple therapy was developed to counter this situation; the fluoroquinolone sitafloxacin has a low minimum inhibitory concentration for H. pylori.

Factors associated with healing of artificial ulcer after endoscopic submucosal dissection with reference to Helicobacter pylori infection, CYP2C19 genotype, and tumor location: Multicenter randomized trial.

Healing speed of peptic ulcer is affected by a number of factors, including Helicobacter pylori (H. pylori) infection and intragastric pH. Acid inhibition exerted by proton pump inhibitors differs by CYP2C19 genotype. Herein, we investigated whether healing speed of artificial ulcers formed after endoscopic submucosal dissection (ESD) was influenced by H. pylori infection, CYP2C19 genotype, or other factors.

Four‐times‐daily Dosing of Rabeprazole with Sitafloxacin, High‐Dose Amoxicillin, or Both for Metronidazole‐Resistant Infection with Helicobacter pylori in Japan

The bacterial resistance of Helicobacter pylori to antimicrobial agents such as clarithromycin and metronidazole has been increasing worldwide, leading to the failure of eradication treatment. Here, we present an eradication regimen consisting of four‐times‐daily dosing (q.i.d.) of rabeprazole with potent acid inhibition.

Improvement of gastroesophageal reflux disease in Japanese patients with spinal kyphotic deformity who underwent surgical spinal correction

Spinal kyphotic deformity occasionally results in gastroesophageal reflux disease (GERD). The effects of acid reflux on the esophagus in kyphotic patients are unclear, however, and it is unknown whether acid reflux, endoscopic GERD, and reflux‐related symptoms improve following surgical spinal correction in these patients. Herein, we investigated the characteristics of GERD in kyphotic patients and the improvement in GERD following surgical correction.

Efficacy of Reduced Dosage of Amoxicillin in an Eradication Therapy for Helicobacter pylori Infection in Patients on Hemodialysis: A Randomized Controlled Trial

Background: An optimum Helicobacter pylori-eradication regimen for hemodialysis patients is yet to be established because of different pharmacokinetics of amoxicillin involved between hemodialysis patients and healthy subjects. We investigated to establish appropriate doses of amoxicillin for H. pylori infection eradication in hemodialysis patients. Methods: Of 409 hemodialysis patients screened for H. pylori infection, 37 H. pylori-positive patients were randomized to different 1-week eradication regimens: esomeprazole 20 mg twice a day (b.i.d.) and clarithromycin 200 mg b.i.d., plus amoxicillin at either 750 mg b.i.d. (group A; conventional) or 250 mg b.i.d. (group B; experimental). Sixty-three patients with normal renal function received the conventional regimen (group C). Successful eradication was confirmed by urea breath testing. Results: Eradication rates of group B (reduced amoxicillin-regimen) were 84.2% in intention-to-treat analysis and 88.9% in per-protocol analysis, which were similar with group A (77.8 and 77.8%) and group C (74.6 and 81.0%). However, the incidence of adverse events in group A was significantly higher than that in group C (22.2 vs. 5.1%, p = 0.027). Conclusions: In H. pylori-positive hemodialysis patients, amoxicillin at 250 mg b.i.d. may be an appropriate scheme for eradication with equivalent effects to the conventional therapy and safety effects for adverse events.

Comparative Study of Effects of Vonoprazan and Esomeprazole on Antiplatelet Function of Clopidogrel or Prasugrel in Relation to CYP2C19 Genotype

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.

Mo1142 Efficacy of Surgical Spinal Correction in Patients With Severe Spinal Kyphotic Deformity for Gastroesophageal Reflux Disease and Bowel Habi

Notes. †Participants were asked to rate symptom improvement on the Global Impression of Change scale ranging from 1 (substantially improved) to 7(substantially worse) at posttreatment. ‡Higher scores on the Tellegen Absorption Scale represent a higher degree of hypnotic ability. §Higher scores are indicative of better perceived health and functioning for the PCS and MCS. ¶QOLRAD, Quality of Life in Reflux and Dysphagia. Lower score indicates more severe impact of symptoms on daily functioning. ††Lower score on the VSI represent greater symptom related anxiety. ‡‡Higher score indicates greater heartburn symptom catastrophizing. *statistically significant. PPI, proton pump inhibitor; Pre, Pretreatment; Post, Post-treatment; PCS, physical component summary; MCS, mental health component summary

High expression level of CD44v8-10 in cancer stem-like cells is associated with poor prognosis in esophageal squamous cell carcinoma patients treated with chemoradiotherapy

Background Strong reactive oxygen species (ROS) suppression in cancer stem-like cell components in various solid tumors is associated with therapeutic resistance. In this study, we investigated the influence of CD44v8-10 expression on the overall survival of esophageal squamous cell carcinoma (E-SCC) patients after definitive chemoradiotherapy (dCRT) and on radio-sensitivities of E-SCC cell lines treated with or without sulfasalazine, a CD44v8-10-xCT-GSH axis inhibitor. Methods Seventy-three patients with E-SCC who received dCRT were examined retrospectively. CD44v8-10 expression was analyzed immunohistochemically using paraffin-blocked pre-dCRT biopsy specimens obtained by esophagoscopy and was expressed as a histo-score (H-score). The relationship between the H-score and overall survival was analyzed. From human E-SCC cell lines (T.T, T.Tn, or Kyse-3650), we collected CD44v8-10High and CD44v8-10Low subpopulations using a cell sorter. Water-soluble tetrazolium salt-8 (WST), glutathione-SH (GSH) and ROS assays were performed to compare the effect of sulfasalazine on the radio-sensitivities of these subpopulations in T.Tn and Kyse-3650. Results High CD44v8-10 expression was independently associated with poor prognosis in E-SCC patients treated with dCRT (hazard ratio = 2.906, 95% CI = 1.277–6.611, p = 0.011). In CD44v8-10High cells of each cell line, sulfasalazine decreased cellular GSH levels, resulting in increased radiation-induced ROS and reduced cell viability. In contrast, sulfasalazine had no significant effects in CD44v8-10Low cells. Conclusion High CD44v8-10 expression was an independent prognostic factor in E-SCC patients treated with dCRT. CD44v8-10-xCT-GSH axis inhibition sensitized CD44v8-10High E-SCC cells to ROS-inducing treatments such as radiotherapy. Targeting CD44v8-10-xCT-GSH axis may improve the prognosis of post-dCRT E-SCC patients.

Response to “CYP‐Mediated Drug–Drug Interaction Is Not a Major Determinant of Attenuation of Antiplatelet Function of Clopidogrel by Vonoprazan”

Active metabolization of clopidogrel and prasugrel consists of two steps. For both the second step is mediated by cytochromes P450 (CYPs), such as CYP2C19, CYP3A4, CYP2B6, and CYP2C9. However, while the first step of clopidogrel is also mediated by CYPs, such as CYP2C19, CYP1A2, and CYP2B6, that of prasugrel is mediated by esterase, not CYPs. Clopidogrel is therefore more dependent for its activation on CYPs than prasugrel. In our study, vonoprazan more strongly inhibited clopidogrel than prasugrel, clearly indicating that vonoprazan inhibits the activity of CYPs and that the different dependence of clopidogrel and prasugrel on CYPs reflects the different influence of vonoprazan on them. We found that vonoprazan attenuated antiplatelet functions of clopidogrel and prasugrel more potently than esomeprazole. Published data demonstrated that vonoprazan has a stronger inhibitory effect on CYP3A4 than esomeprazole and a much longer plasma half-life (Table 1). Drs. Nishimura and Czerniak performed an in vitro study of vonoprazan on the metabolism of C-clopidogrel and concluded that vonoprazan had no significant effect or time-dependent inhibition (TDI) on the metabolization of clopidogrel. Unfortunately, they did not use a positive control, such as clarithromycin or a proton pump inhibitor (PPI), and the accuracy of their assay system in measuring the effects of vonoprazan is therefore unclear. Moreover, the incubation time was only 30 minutes, vs. a plasma half-life of vonoprazan in humans of around 8 hours. Our in vivo study results were obtained from 1-week treatment in 31 subjects, while it is unclear how many times they repeated the in vitro experiment. We consider that extrapolation of the results of a single, small, short-term in vitro study without either a positive or negative control to clinical settings is unsuitable. In particular, due consideration should be given to concerns that this interaction has been associated with cardiovascular death. Drs. Nishimura and Czerniak speculated on the involvement of gastric pH changes. However, the median 24-hour intragastric pH attained by vonoprazan 10mg was 5.2, while that by esomeprazole 20mg was 4.8. This small difference cannot account for the different effects of vonoprazan and esomeprazole on antiplatelet functions of clopidogrel and prasugrel. We therefore consider it absolutely clear that vonoprazan attenuates the antiplatelet function of clopidogrel and prasugrel more potently than esomeprazole, and that this interaction involves a drug–drug interaction (DDI) with CYPs. Clinicians must give due attention to this DDI.