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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.To investigate the distribution of radioactivity in the rat stomach after single intravenous administration of [(3)H]-labeled vonoprazan.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.Vonoprazan selectively accumulates in gastric parietal cells in the mucosal layer of the rat stomach after intravenous administration.

Proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases, such as peptic ulcers and gastro-esophageal reflux disease, and for the eradication of Helicobacter pylori. However, the therapeutic efficacy of conventional PPIs is considered limited because: (1) they are unstable under acidic conditions and require an enteric-coated formulation in clinical use; (2) they show high interindividual variability in pharmacokinetics due to genetic polymorphisms of cytochrome P450 (CYP) 2C19 metabolism; (3) they have a relatively slow onset of pharmacological action and may require several doses to achieve optimal acid suppression and symptom relief; and (4) they often do not provide stable suppression of gastric acid secretion over 24 h. Vonoprazan fumarate (TAK-438, hereinafter referred to as “vonoprazan”) is a new potassium-competitive acid blocker (P-CAB) developed to resolve the above limitations of conventional PPIs. Various physicochemical data have shown that vonoprazan has a high solubility and stability over a broad pH range in aqueous conditions. In addition, vonoprazan has a more potent and longer-lasting acid suppression effect than the conventional PPI, lansoprazole. Preclinical pharmacokinetic studies have shown that vonoprazan is accumulated and retained in the stomach for more than 24 h, even after it is eliminated from the plasma. From these findings, we propose that vonoprazan, which possesses a novel mode of action, can improve on the outcomes seen with conventional PPI-based treatments for acid-related diseases. This review project, including the publication of this article, was funded by Takeda Pharmaceutical Company Limited.

Stress-induced colonic functional changes have been investigated mainly under conditions involving physical stress, like in the restraint stress model. In this study, we established a new stress-induced defecation model involving the placement of Mongolian gerbils in a novel environment (novelty stress) and determined the effects of several drugs on novelty stress-induced fecal pellet output. When animals kept in groups were placed individually in small cages, the fecal pellet output markedly increased, although the upper intestinal transit measured by charcoal method was not changed. The concentration of plasma adrenocorticotropic hormone was moderately but significantly increased by the novelty stress. Drugs reportedly effective for stress-induced defecation, like alosetron hydrochloride, atropine sulfate, and trimebutine maleate, inhibited both the novelty stress-induced increase in fecal pellet output and spontaneous defecation. In contrast, TAK-637, a tachykinin NK1-receptor antagonist, and diazepam inhibited the novelty stress induced defecation but did not inhibit spontaneous defecation. The present study indicated that novelty stress increases fecal pellet output without affecting the upper intestinal transit; this model may be useful for evaluating the effects of drugs on stress-stimulated colonic motility. Keywords:: novelty stress, defecation, intestinal transit, fecal pellet, irritable bowel syndrome

The motor-stimulating action of de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (EM574) on the upper gastrointestinal tract was studied in fasted conscious dogs using chronically implanted force transducers and compared with those of porcine motilin and cisapride. EM574 induced gastric phase III-like migrating contractions and increased the plasma motilin levels slightly. The gastric motility induced by low doses of EM574 and motilin was abolished by a 5HT3-receptor antagonist ondansetron and acute vagal blockade, whereas under these conditions, high doses of both agents induced contractions, which were abolished by atropine. Cisapride-induced gastric motility was inhibited by atropine and acute vagal blockade, but not by ondansetron. EM574 did not stimulate gastric secretion in the basal state. These results indicate that EM574- and motilin-induced gastrointestinal motility is attributable mainly to motor-stimulating vagal cholinergic neurons, and 5HT3-receptors are probably involved in the process. At high doses, EM574 and motilin also appear to stimulate cholinergic neurons in a non-vagal pathway, probably the enteric nervous system.

TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK2–receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK2 receptors with a marked species difference and a 10,000-fold selectivity versus NK1 and NK3 receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK2 receptor–selective agonist beta-Ala8-NKA(4-10) (βA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT3–receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid–induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as βA-NKA in an isolated human colon. In conclusion, the novel NK2-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK2 receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients. Keywords:: NK2-receptor antagonist, TAK-480, irritable bowel syndrome, visceral hypersensitivity, stimulated defecation

The effect of EM523 [de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal], an erythromycin derivative, on gastrointestinal motility was investigated using conscious dogs in the fasting state, and it was compared with those of motilin and prostaglandin F2 alpha (PGF2 alpha). EM523 and motilin given as i.v. infusions induced strong contractions in the stomach that migrated along the intestine. On the other hand, PGF2 alpha stimulated intestinal contractions, but its effect on gastric motility was weak. EM523 had 1/50 the potency of motilin and 6 times the potency of PGF2 alpha for stimulation of intestinal motility. Atropine at 0.1 mg/kg, i.v. strongly inhibited gastrointestinal contractions induced by EM52 EM523 or motilin and partly inhibited PGF2 alpha-induced intestinal motility. ICS-205-930, a 5HT3-receptor antagonist, at a dose of 1 mg/kg, i.v. strongly inhibited EM523 or motilin-induced gastric contractions but did not affect the action of PGF2 alpha. Infusion of EM523 at 100 micrograms/kg/hr induced strong migrating contractions even when motility was depressed by dopamine infusion or laparotomy. Infusion of PGF2 alpha at 300 micrograms/kg/hr stimulated intestinal but not gastric motility under these conditions. The results of this study indicate that the cholinergic pathway and 5HT3 receptors are involved in EM523 and motilin-induced migrating gastrointestinal contractions, whereas the cholinergic pathway seems to be only partly involved in PGF2 alpha-induced intestinal contractions.

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 (IC 50 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 2 h followed by washout. Even 8 h 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 [ 14 C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 μM of forskolin. In contrast, high levels of [ 14 C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [ 14 C] 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.

静注用胃酸分泌抑制薬ランソプラゾール（タケプロン®静注用30 mg）は「経口投与不可能な出血を伴う胃潰瘍，十二指腸潰瘍，急性ストレス潰瘍および急性胃粘膜病変」に対する治療薬である．ランソプラゾールは静脈内投与後，胃酸生成細胞である壁細胞に移行して活性体に変換され，酸分泌の最終段階であるH+，K+-ATPaseを強く抑制して胃酸分泌を抑制する．ランソプラゾールはラットにおける基礎酸分泌および各種刺激酸分泌を抑制し，イヌにおける刺激酸分泌も抑制した．ランソプラゾールはラットにおける胃出血モデルに対して強い抑制作用を示し，胃粘膜損傷形成も抑制した．胃出血抑制作用および胃粘膜損傷形成抑制作用はいずれもランソプラゾールの胃酸分泌抑制作用に基づくと考えられ，特に胃出血抑制作用は胃内pHを上昇させることによる血液凝固能および血小板凝集能の改善，並びにペプシン活性を抑制して血液凝固塊の溶解を抑制した結果と考えられた．ランソプラゾール静注剤の臨床試験では，健康成人男子を対象とした臨床薬理試験が実施され，ランソプラゾールを1回30 mg 1日2回投与することで，臨床的に有意な酸分泌抑制効果を示すと考えられた．さらに，経口投与が困難な上部消化管出血患者を対象とした臨床試験も実施され，ランソプラゾール注射剤の止血効果は，ヒスタミンH2受容体拮抗薬である塩酸ロキサチジンアセタート注射剤と比較して臨床的に非劣性が検証された．また，因果関係が否定できなかった有害事象において，自他覚的随伴症状および臨床検査値の異常変動のいずれにおいても特に頻度の高い項目はみられず，塩酸ロキサチジンアセタート注射剤と比較しても発現頻度は同様の値であり，両薬剤群間に差はみられなかった．以上の基礎および臨床試験成績より，ランソプラゾールはH+，K+-ATPase阻害という作用機序に基づいて明確な作用を示し，安全性も高いことから上部消化管出血治療薬として有用な薬剤になると考えられる．

G A A b st ra ct s at least one year of follow-up within THIN who also lacked chronic conditions associated with use of long-term acid suppression. Cases of fracture were defined by the first Read code for incident fracture at any site and the control pool consisted of individuals without a diagnosis of fracture at the time when the corresponding case had his or her first fracture. Using incidence density sampling, cases were matched with up to 5 control subjects by age (within 1 year), sex, THIN practice, and start of follow-up in THIN (within 1 year). PPI exposure was defined as 180 or more cumulative doses of PPIs. We additionally examined the PPI-fracture relationship at varying levels of PPI exposure. As potential confounders, we extracted information related to age, sex, body mass index, and use of other medications. The primary outcome was calculated using conditional logistic regression as the odds of PPI exposure in cases compared to controls. Because the epidemiology of fracture varies by age, we stratified analyses using a cut-off of 18 years old or more. RESULTS: 508,740 children age 4 to 17 years old and 207,181 young adults age 18 to 29 years old within the THIN database were included in the study. We identified 124,799 cases of incident fracture and 605,643 matched controls. In young adults but not children, PPIs were a risk factor for fracture in both unadjusted and adjusted models. The adjusted odds ratio for the risk of fracture associated with PPI exposure was 1.13 (95% CI 0.92 to 1.39) among children and 1.39 (95% CI 1.26 to 1.53) among young adults. In young adults but not children, we observed a dose-response effect with increased total exposure to PPIs (p for trend

The gastroprokinetic effects of de(N-methyl)-N-isopropyl-8, 9-anhydroerythromycin A 6,9-hemiacetal (EM574), a non-peptide motilin receptor agonist, were investigated in conscious dogs in a normal state and with experimentally-induced gastroparesis. Gastric emptying of semi-solid meals was assessed indirectly from acetaminophen absorption with simultaneous recording of gastric antral motility. In the normal state, post-prandial intraduodenal administration of EM574 (0.03 mg/kg) [corrected] stimulated antral motility and significantly enhanced gastric emptying as potently as did intravenous porcine motilin (0.003 mg/kg/h). Intraduodenal cisapride at 1 mg/kg denal cisapride at 1 mg/kg elicited antral contractions and tended to accelerate gastric emptying but at 3 mg/kg, gastric emptying was not enhanced despite a further increase in the motor index. In dogs with gastroparesis induced by intraduodenal oleic acid or intravenous dopamine, EM574 (0.03 mg/kg) increased antral motility and reversed the delayed gastric emptying completely. Cisapride (1 mg/kg) partially ameliorated the impaired emptying under these conditions. In atropinized dogs, no acceleration of gastric emptying by EM574 was observed. These results indicate that EM574 potently accelerates gastric emptying of caloric meals in dogs in a normal state and with experimentally-induced gastroparesis, and also suggest that the effect is mediated through stimulation of a cholinergic neural pathway.

This study was performed to examine whether an erythromycin derivative, de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (EM574) is a motilin receptor agonist in the rabbit gastrointestinal tract. EM574 and porcine motilin induced contractions in segments of isolated rabbit intestine with pEC50 values of 8.26 +/- 0.04 and 8.69 +/- 0.07, respectively, but not in rat or guinea pig preparations. The sensitivity and efficacy of the response to both compounds in rabbits decreased aborally and was insensitive to pretreatment with atropine or tetrodotoxin, but was markedly suppressed under Ca(2+)-free conditions. EM574 and porcine motilin specifically displaced [125I-Tyr23]canine motilin bound to gastric antral smooth muscle homogenates with plC50 values of 8.21 +/- 0.13 and 9.20 +/- 0.11, respectively. The pEC50 value for the contractile response and plC50 value for the receptor binding for motilin, EM574, erythromycin A and three other derivatives correlated well (r = 0.94, P < 0.01). Tissue section autoradiography in the antrum revealed that specific labeled motilin binding sites were localized in the circular muscle layer and myenteric plexus, and could be reduced in the presence of an excess of EM574. These results indicate that EM574 is a potent motilin receptor agonist in the rabbit gastrointestinal tract.

Background & Aims EM523, a motilin agonist, is intended to be used as a gastroprokinetic during the postprandial period, but the mechanism(s) by which EM523 stimulates postprandial contractions in the stomach has not been studied before. The aim of this study was to examine the mechanism of contraction-stimulating activity by EM523 in fed dogs. Methods Contractile activity in the gastric antrum of 5 dogs was monitored using a long-term implanted force transducer and measured by integrating the area under the curve. Test materials were continuously infused or injected intravenously. Results EM523 (1–30 μg/kg) induced a dose-dependent increase in fed-type contractions. EM523-induced contractile activity was partially inhibited by atropine, hexamethonium, dopamine, 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist, and substance P antagonist. Atropine-resistant and EM523-induced contractions were further inhibited by 5-HT 3 receptor antagonist and substance P antagonist, and the combined use of the two antagonists completely eliminated the atropine-resistant and EM523-induced contractions. Conclusions EM523-induced contractions in the fed stomach are quite different from phase III contractions in the fasted state and are mediated partially through the cholinergic pathway. The noncholinergic pathway involves 5-HT 3 and neurokinin 1 receptors.

The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED 50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25–200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E 2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H + and Na + caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E 2 , exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E 2 . The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.

The intracellular level of cyclic AMP in the taenia from the guinea pig caecum was significantly increased by isoprenaline in a dose-dependent manner. Papaverine also increased the intracellular cyclic AMP level, but a synthetic antispasmodic agent, Aspaminol (1,1-diphenyl-3-piperidinobutanol hydrochloride) did not modify it. The results suggest that there are two mechanisms for the so-called papaverine-like actions. The increase in the intracellular cyclic AMP concentration produced by isoprenaline was prevented by propranolol. In taenia depolarized by KCl, papaverine caused relaxation but isoprenaline did not. This difference can be explained by the observation that the intracellular cyclic AMP level in the KCl-depolarized taenia is increased by papaverine but not by isoprenaline.

The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog proximal duodenal mucosa mounted in an Ussing chamber. Spizofurone (10−4-10−3 M) as well as prostaglandin E2 (PGE2, 10−8-10−5 M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.

Mitochondrial, microsomal and soluble fractions separated from the guinea pig taenia and from the dog longitudinal smooth muscle were used as phosphodiesterase preparation. Each preparation had low and high Km values, indicating the existence of at least two kinds of phosphodiesterase. Papaverine and Aspaminol (1, 1-diphenyl-3-piperidinobutanol hydrochloride), hydralazine, caffeine Na benzoate and aminophylline were used at test drugs. Aspaminol had little inhibitory effect on phosphodiesterase. Ki value of papaverine almost equalled the concentration (M) which was necessary to produce 50% relaxation. Relaxation of the guinea pig taenia by papaverine was preceded by an increase of intracellular cyclic AMP,. Therefore, the action of papaverine is likely to be mediated by an increase in cyclic AMP, which is caused by inhibition of the phosphodiesterase-catalyzed breakdown of cyclic AMP. There was little correlation between relaxing activities of the drugs used and their antiphosphodiesterase activities. Relaxation of the smooth muscle induced by the smooth muscle relaxants excepting papaverine is not due to inhibition of phosphodiesterase.

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.

The mechanism of stress-induced acute gastric mucosal lesions (AGML) has been investigated for some time. We have reported that in hemorrhagic shock, the decrease of gastric mucosal blood flow, volume, and its oxygenation precedes the gastric ulceration which appears usually after infusion of blood or at the recovery stage in rats and humans. It is believed that the microcirculatory disturbance resulting in hypoxia in the gastric mucosa produced an incipient mucosal state for ulcerogenesis and that in this hydrochloric acid and histamine played an aggressive role. The precise mechanism leading to cell death after ischemia is, however, obscure. In this symposium, we presented a movie film which showed the process of gastric mucosal microcirculatory disturbance and bleeding caused by indomethacin, leukotriene C4 (LTC4), platelet-activating factor (PAF) and HCI and also reported the role of chemical and ionic factors in the repefusion state in the etiology of gastric ulceration.