Septal Rupture During Early Pregnancy and Successful Delivery in Monozygotic Dichorionic Diamniotic Twin After a Single Blastocyst Transfer.

The frequency of twins resulting from a single embryo transfer has been reported to be 1.56%, with the majority being monochorionic. We present a case of septal rupture at 8 weeks of gestation and successful delivery at 36 weeks of gestation of a monozygotic dichorionic diamniotic twin after a single blastocyst transfer. This report could partially clarify the pathogenesis of monozygotic twins and septal disruption. A 37-year-old woman with 9 months of primary infertility was referred to our department. After seven cycles of artificial insemination, she underwent her first in vitro fertilization. Ten cumulous-oocyte complexes were retrieved, of which three were fertilized, and three blastocysts were cryopreserved. The first single blastocyst transfer in a hormone replacement cycle resulted in a dichorionic diamniotic twin pregnancy. Transvaginal ultrasound at 7 weeks and 4 days gestation revealed a size difference in the gestational sacs and a disruption of the inter-amniotic membrane between the two gestational sacs at 8 weeks and 6 days. Both fetuses were seen in the larger gestational sac; however, the umbilical cord of the migrated fetus was from the original gestational sac. Both fetuses developed without discordancy or obvious anomalies. At 36 weeks and 6 days of gestation, the patient underwent cesarean delivery, resulting in the birth of two viable male infants without any congenital anomalies (weighing 2256 g and 2456 g). Two amniotic cavities existed; however, no chorionic villi were present. There have been many reports on septal disruption in monochorionic diamniotic twins; however, only two cases of dichorionic diamniotic twins have been reported. Furthermore, the onsets in both reports were after the second trimester of pregnancy. This report presents the first case of septal disruption in dichorionic diamniotic twins during the first trimester.

Prokinetic actions of luminally acting 5-HT4 receptor agonists.

BACKGROUND: 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS: Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES: These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.

Successful laparoscopic resection of virilizing ovarian steroid cell tumor, not otherwise specified, in a 22-year-old woman: a case report and evaluation of the steroidogenic pathway.

OBJECTIVE: Ovarian steroid cell tumor (SCT) is a rare tumor with steroid-producing ability. We report a 22-year-old woman with secondary amenorrhea and hirsutism caused by an ovarian SCT-not otherwise specified (NOS), who underwent successfully laparoscopic resection of the tumor. CASE REPORT: A 22-year-old null gravida woman presented to a hospital, having amenorrhea for 18 months and increasing facial hair. Physical examination revealed obesity (body mass index, 37.3 kg/m2) with evident facial and trunk hair. Total and free serum testosterone, and dehydroepiandrosterone sulfate levels were found to be elevated. Levels of serum adrenocorticotropic hormone, gonadotropins, cortisol, aldosterone, and ovarian steroids were observed to be within reference intervals. Although polycystic ovaries were not found, a hyperechogenic solid tumor (3 cm) was detected on transvaginal ultrasonography. Laparoscopic resection of the tumor was performed. One month post-surgery, total and free testosterone levels were observed to have decreased, and menstruation resumed two months thereafter. The patient was histologically diagnosed with ovarian SCT-NOS. Expression of ovarian steroidogenic enzymes, which are related to hyperandrogenism, was observed. No disease recurrence has been reported for more than 5 years post-surgery.

[Pharmacological characteristics and clinical efficacies of a novel potassium-competitive acid blocker, vonoprazan fumarate].

Proton pump inhibitors (PPIs) inhibit H+, K+-ATPase, an enzyme which is the final step of gastric acid secretion and is selectively located in the gastric parietal cells. PPIs block the enzyme in a covalent and irreversible binding manner, thus providing better efficacy than previous pharmacological agents such as antacids and histamine H2 receptor antagonists. Although PPIs have been the first-line therapeutic option for acid related diseases (ARDs), there are several limitations to their efficacy, i.e. short half-life in blood, insufficient acid suppression especially at night, necessity of repeated dosages for full action, and large variation in efficacy among patients due to CYP2C19 polymorphism. To overcome these shortcomings, we performed a high-throughput random screening using in-house chemical libraries and further lead optimization to look for the most relevant clinical candidate compounds. As the results of these researches, we discovered vonoprazan fumarate, a novel gastric acid antisecretory agent which inhibits H+, K+-ATPase in a reversible and K+-competitive manner. Vonoprazan exerted a more potent and longer lasting inhibitory effect than lansoprazole on gastric acid secretion in preclinical studies, presumably by its high accumulation profile in the gastric parietal cells. It also exhibited a rapid onset of action and prolonged inhibition of intragastric acidity in humans and showed remarkable effects on multiple ARDs including erosive esophagitis and Helicobacter pylori eradication. Vonoprazan fumarate was approved in 2014 for clinical use in Japan. Vonoprazan is a new therapeutic option which can potentially improve outcomes compared with conventional PPI-based treatments for ARDs.

Combination effects of alogliptin and pioglitazone on steatosis and hepatic fibrosis formation in a mouse model of non-alcoholic steatohepatitis.

This study aimed to evaluate the effects of combination therapy with a dipeptidyl peptidase-4 inhibitor, alogliptin, and a peroxisome proliferator-activated receptor-γ agonist, pioglitazone, in a preclinical model of nonalcoholic steatohepatitis using low-density lipoprotein receptor-knockout mice fed a modified choline-deficient l-amino acid-defined diet. Monotherapy with either alogliptin (10-200 mg/kg) or pioglitazone (6-20 mg/kg) significantly decreased hepatic triglyceride content and fibrosis. The concomitant treatment of alogliptin (30 mg/kg), pioglitazone (20 mg/kg) also decreased hepatic triglyceride and hepatic collagen-I mRNA at greater extent compared to monotherapy. Hepatic expression of CD11b mRNA and monocyte chemoattractant protein-1 were also reduced by the concomitant treatment. These results suggest that via an anti-inflammatory potential in addition to anti-metabolic effects, the combination therapy of alogliptin and pioglitazone may provide therapeutic benefits to type 2 diabetes patients with nonalcoholic steatohepatitis, which will be proven in controlled clinical trials.

Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers.

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.

Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion.

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.

Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action.

With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.

Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APCmin/+ Mouse Models of Experimental Colon Cancer.

Chemopreventative properties of traditional medicines and underlying mechanisms of action are incompletely investigated. This study demonstrates that dietary daikenchuto (TU-100), comprised of ginger, ginseng, and Japanese pepper effectively suppresses intestinal tumor development and progression in the azoxymethane (AOM) and APCmin/+ mouse models. For the AOM model, TU-100 was provided after the first of six biweekly AOM injections. Mice were sacrificed at 30 weeks. APCmin/+ mice were fed diet without or with TU-100 starting at 6 weeks, and sacrificed at 24 weeks. In both models, dietary TU-100 decreased tumor size. In APC min/+ mice, the number of small intestinal tumors was significantly decreased. In the AOM model, both TU-100 and Japanese ginseng decreased colon tumor numbers. Decreased Ki-67 and ß-catenin immunostaining and activation of numerous transduction pathways involved in tumor initiation and progression were observed. EGF receptor expression and stimulation/phosphorylation in vitro were investigated in C2BBe1 cells. TU-100, ginger, and 6-gingerol suppressed EGF receptor induced Akt activation. TU-100 and ginseng and to a lesser extent ginger or 6-gingerol inhibited EGF ERK1/2 activation. TU-100 and some of its components and metabolites of these components inhibit tumor progression in two mouse models of colon cancer by blocking downstream pathways of EGF receptor activation. Copyright © 2016 John Wiley & Sons, Ltd.

Prognostic factors for patients undergoing vitrified-warmed human embryo transfer cycles: a retrospective cohort study.

We examined the prognostic factors for pregnancy in 210 vitrified-warmed embryo transfer (ET) cycles in 121 patients. The univariate analysis showed that age, gravida, the number of cycles associated with infertility caused by endometriosis, the number of previous assisted reproductive technology (ART) treatment cycles, and the number of ICSI procedures were significantly lower in pregnant cycles compared with non-pregnant cycles. The percentages of ET using at least one intact embryo and of ET using at least one embryo that had developed further after warming were significantly higher in pregnant cycles compared with non-pregnant cycles. Multivariate logistic regression analysis showed that previous ART treatment cycles, ET with at least one intact embryo, and ET using at least one embryo that had developed further were independent prognostic factors for pregnancy in vitrified-warmed ET cycles. We conclude that fewer previous ART treatment cycles, ET using at least one intact embryo, and ET with embryos that have developed further after warming might be favourable prognostic factors for pregnancy in vitrified-warmed ET cycles.

Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases.

Acid-related diseases (ARDs), such as peptic ulcers and gastroesophageal reflux disease, represent a major health-care concern. Some major milestones in our understanding of gastric acid secretion and ARD treatment reached during the last 50years include 1) discovery of histamine H2-receptors and development of H2-receptor antagonists, 2) identification of H+,K+-ATPase as the parietal cell proton pump and development of proton pump inhibitors (PPIs), and 3) identification of Helicobacter pylori (H. pylori) as the major cause of peptic ulcers and development of effective eradication regimens. Although PPI treatments have been effective and successful, there are limitations to their efficacy and usage, i.e. short half-life, insufficient acid suppression, slow onset of action, and large variation in efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers (P-CABs) inhibit H+,K+-ATPase in a reversible and K+-competitive manner, and exhibit almost complete inhibition of gastric acid secretion from the first dose. Many pharmaceutical companies have tried to develop P-CABs, but most of their clinical development has been discontinued due to safety concerns or a similar efficacy to PPIs. Revaprazan was developed in Korea and was the first P-CAB approved for sale. Vonoprazan, approved in 2014 in Japan, has a completely different chemical structure and higher pKa value compared to other P-CABs, and exhibits rapid onset of action and prolonged control of intragastric acidity. Vonoprazan is an effective treatment for ARDs that is especially effective in healing reflux esophagitis and for H. pylori eradication. P-CABs, such as vonoprazan, promise to further improve the management of ARDs.

Radiographic Localization Study of a Novel Potassium-Competitive Acid Blocker, Vonoprazan, in the Rat Gastric Mucosa.

BACKGROUND: Vonoprazan fumarate (TAK-438) is a novel potassium-competitive acid blocker that appears to exert a longer/more potent antisecretory effect than lansoprazole due to high accumulation/slow clearance from the gastric glands. However, there is no direct evidence that vonoprazan selectively accumulates in gastric parietal cells of gastric glands. AIM: To investigate the distribution of radioactivity in the rat stomach after single intravenous administration of [(3)H]-labeled vonoprazan. METHODS/RESULTS: Autoradioluminography of the stomach revealed that at 5 h after administration, radioactivity levels in the corpus mucosal layer was higher than radioactivity levels in the muscular layer, pylorus, and forestomach. At 24 h, although overall radioactivity was significantly decreased, the highest radioactivity was still observed in the mucosal layer. Accumulation of radioactivity in gastric parietal cells was quantitatively analyzed using microautoradiography. The number of silver granules in parietal cells from vonoprazan-injected rats was higher than in cells from a saline-injected rat. At 24 h, the number of granules was approximately at 20 % of the number of granules at 5 h. There was no clear deposition of granules in other components. At 5 h, radioactivity was measured at 1.799 µg Eq/g in the stomach and 0.172 µg Eq/mL in plasma. After 24 h, radioactivity had decreased to 0.584 µg Eq/g in the stomach and 0.078 µg Eq/mL in plasma. CONCLUSIONS: Vonoprazan selectively accumulates in gastric parietal cells in the mucosal layer of the rat stomach after intravenous administration.

Predictive factors for oocyte retrieval failure in controlled ovarian hyperstimulation protocols: a retrospective observational cohort study.

BACKGROUND: Oocyte retrieval failure following an ovarian hyperstimulation protocol is uncommon in assisted reproductive technology (ART) programs. We analyzed the predictive factors for oocyte retrieval failure following controlled ovarian hyperstimulation (COH) with gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist protocols in ART programs. METHODS: This study was a retrospective cohort observational study. In total, 744 cycles from 361 patients who underwent controlled ovarian hyperstimulation with GnRH agonist long protocol or antagonist protocol were analyzed. Treatment cycles with oocyte retrieval failure and with one or more oocytes retrieved were compared to determine predictive factors for oocyte retrieval failure using univariate and multilevel multivariate logistic regression analyses. RESULTS: Oocyte retrieval failure occurred in 38 cycles (5.1%). The oocyte retrieval failure rate of the GnRH antagonist protocol (8.1%) was significantly higher than that of the GnRH agonist long protocol (3.7%). On multilevel multivariate logistic analysis, cycles with GnRH antagonist protocol (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.05-8.96), estradiol level on the day of human chorionic gonadotropin (hCG) injection (OR 0.997, 95% CI 0.996-0.998), and luteinizing hormone (LH) level on the day of hCG injection (OR 1.19, 95% CI 1.06-1.33) were independent predictive factors for oocyte retrieval failure. The efficacy of estradiol and LH levels on the day of hCG injection for predicting oocyte retrieval failure was evaluated using receiver operating characteristic curves. In all cycles, the areas under the curve (AUCs) for estradiol and LH were 0.84 and 0.63, respectively, for all cycles; 0.84 and 0.52, respectively, for cycles with GnRH agonist long protocol; and 0.81 and 0.82, respectively, for cycles with GnRH antagonist protocol. CONCLUSIONS: Our results suggest that in cycles with GnRH antagonist protocol, the levels of estradiol and LH on the day of hCG injection might be predictive factors for oocyte retrieval failure. This relationship may provide useful information to both patients and physicians for developing better COH protocols in ART programs.

Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB).

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.

A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands.

TAK-438 is a novel potassium-competitive acid blocker (P-CAB) type antisecretory agent that reversibly inhibits gastric H+, K+-ATPase. Previously, we showed that TAK-438 has superior efficacy compared to lansoprazole, a proton pump inhibitor, in the inhibition of acid secretion in vivo. In this study, we investigated the differences in the mode of actions of the two drugs using primary cultured rabbit gastric glands. TAK-438 and lansoprazole inhibited gastric acid formation in acutely isolated gastric glands (IC50) values, 0.30 and 0.76 µM, respectively). In cultured gastric glands that were preincubated with TAK-438, the inhibitory effect on forskolin-stimulated acid formation was augmented over the incubation period, whereas the inhibitory effect of lansoprazole was not affected by time of incubation. Next, we evaluated the durations of the actions of TAK-438 and lansoprazole after gastric glands were incubated with either drug for 2h followed by washout. Even 8h after the drug washout, TAK-438 at higher concentrations inhibited acid formation, but the inhibitory effect of lansoprazole disappeared immediately after washout. Additionally, only a small amount of [¹4C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 µM of forskolin. In contrast, high levels of [¹4C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [¹4C] TAK-438 from the glands. These findings suggest that TAK-438 exerts a longer and more potent antisecretory effect than lansoprazole as a result of its high accumulation and slow clearance from the gastric glands.

A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals.

Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases.

Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H(+),K(+)-ATPase activity in porcine gastric microsomes with IC(50) values of 0.019, 0.14, and 7.6 µM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K(+)-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-d-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.