Dietary Efficacy Evaluation by Applying a Prediction Model Using Clinical Fecal Microbiome Data of Colorectal Disease to a Controlled Animal Model from an Obesity Perspective.

Obesity associated with a Western diet such as a high-fat diet (HFD) is a known risk factor for inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this study, we aimed to develop fecal microbiome data-based deep learning algorithms for the risk assessment of colorectal diseases. The effects of a HFD and a candidate food (Nypa fruticans, NF) on IBD and CRC risk reduction were also evaluated. Fecal microbiome data were obtained from 109 IBD patients, 111 CRC patients, and 395 healthy control (HC) subjects by 16S rDNA amplicon sequencing. IBD and CRC risk assessment prediction models were then constructed by deep learning algorithms. Dietary effects were evaluated based on fecal microbiome data from rats fed on a regular chow diet (RCD), HFD, and HFD plus ethanol extracts or water extracts of NF. There were significant differences in taxa when IBD and CRC were compared with HC. The diagnostic performance (area under curve, AUC) of the deep learning algorithm was 0.84 for IBD and 0.80 for CRC prediction. Based on the rat fecal microbiome data, IBD and CRC risks were increased in HFD-fed rats versus RCD-fed rats. Interestingly, in the HFD-induced obesity model, the IBD and CRC risk scores were significantly lowered by the administration of ethanol extracts of NF, but not by the administration of water extracts of NF. In conclusion, changes in the fecal microbiome of obesity by Western diet could be important risk factors for the development of IBD and CRC. The risk prediction model developed in this study could be used to evaluate dietary efficacy.

Gochujang prepared using rice and wheat koji partially alleviates high-fat diet-induced obesity in rats.

The aim of this study was to compare whether gochujang products prepared using giant embryo rice koji (rice gochujang, RG) and wheat koji (wheat gochujang, WG) have anti-obesity effects on rats fed a high-fat diet (HFD), who served as a model for obesity. The nutritional composition of RG and WG including proximate constituents, amino acid and fatty acid compositions were investigated. Consequently, the secondary fermented metabolites were analyzed in RG and WG by ultrahigh-performance liquid chromatography and mass spectrometry. Rats were fed a HFD containing 10% RG powder (HFD-RG) or 10% WG powder (HFD-WG) for 8 weeks. Body weight gain, weights of liver, epididymal, retroperitoneal, perirenal, and total white fat pads, and levels of serum triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, and leptin were lower in all gochujang groups than in the HFD group. Furthermore, RG and WG treatment decreased the hepatic TG content and lipid accumulation and significantly reduced the size of epididymal adipocytes. These effects are probably mediated through inhibition of hepatic fatty acid synthase, acetyl CoA carboxylase, malic enzyme, and adipose tissue lipoprotein lipase activities. The anti-obesity effect was slightly greater in the HFD-RG group than in the HFD-WG group. This effect may be attributed to secondary metabolites, such as capsaicin, genistein, daidzein, soyasaponin, and lysophosphatidylcholines, contained in gochujang prepared using giant embryo rice or wheat koji.

Effects of Tegoprazan, a Novel Potassium-Competitive Acid Blocker, on Rat Models of Gastric Acid-Related Disease.

Tegoprazan, a novel potassium-competitive acid blocker (P-CAB), is a next-generation therapeutics developed for the treatment of acid-related gastrointestinal diseases such as gastroesophageal reflux disease (GERD) and peptic ulcers. In the present study, the in vitro and in vivo pharmacological properties of tegoprazan were compared with those of esomeprazole, a representative proton pump inhibitor. In vitro enzyme assays were performed using ion-leaky vesicles containing gastric H+/K+-ATPases isolated from pigs. The in vivo efficacies of tegoprazan were evaluated in rat models of GERD and peptic ulcer. Tegoprazan inhibited the activity of porcine H+/K+-ATPase with an IC50 value of 0.53 µM in a reversible manner, whereas esomeprazole showed weak and irreversible inhibition with an IC50 value of 42.52 µM. In a GERD model, tegoprazan showed dose-dependent efficacy in inhibiting esophageal injury and gastric acid secretion with an ED50 of 2.0 mg/kg, which was 15-fold more potent than that of esomeprazole. In peptic ulcer models, tegoprazan exhibited superior antiulcer activity compared with esomeprazole. The ED50 of tegoprazan in the naproxen-, ethanol-, and water-immersion restraint stress-induced peptic ulcer models were 0.1, 1.4, and 0.1 mg/kg, respectively. In the acetic acid-induced peptic ulcer model, the curative ratio of tegoprazan at 10 mg/kg was higher than that of esomeprazole at 30 mg/kg (44.2% vs. 32.7%, respectively), after 5 days of repeated oral administration. Thus, tegoprazan is a novel P-CAB that shows potent and reversible inhibition of gastric H+/K+-ATPase and may provide stronger efficacy compared with previous proton pump inhibitors.

Lactobacillus plantarum-derived Extracellular Vesicles Protect Atopic Dermatitis Induced by Staphylococcus aureus-derived Extracellular Vesicles.

PURPOSE: The microbial environment is an important factor that contributes to the pathogenesis of atopic dermatitis (AD). Recently, it was revealed that not only bacteria itself but also extracellular vesicles (EVs) secreted from bacteria affect the allergic inflammation process. However, almost all research carried out so far was related to local microorganisms, not the systemic microbial distribution. We aimed to compare the bacterial EV composition between AD patients and healthy subjects and to experimentally find out the beneficial effect of some bacterial EV composition. METHODS: Twenty-seven AD patients and 6 healthy control subjects were enrolled. After urine and serum were obtained, EVs were prepared from samples. Metagenomic analysis of 16s ribosomal DNA extracted from the EVs was performed, and bacteria showing the greatest difference between controls and patients were identified. In vitro and in vivo therapeutic effects of significant bacterial EV were evaluated with keratinocytes and with Staphylococcus aureus-induced mouse AD models, respectively. RESULTS: The proportions of Lactococcus, Leuconostoc and Lactobacillus EVs were significantly higher and those of Alicyclobacillus and Propionibacterium were lower in the control group than in the AD patient group. Therefore, lactic acid bacteria were considered to be important ones that contribute to the difference between the patient and control groups. In vitro, interleukin (IL)-6 from keratinocytes and macrophages decreased and cell viability was restored with Lactobacillus plantarum-derived EV treatment prior to S. aureus EV treatment. In S. aureus-induced mouse AD models, L. plantarum-derived EV administration reduced epidermal thickening and the IL-4 level. CONCLUSIONS: We suggested the protective role of lactic acid bacteria in AD based on metagenomic analysis. Experimental findings further suggest that L. plantarum-derived EV could help prevent skin inflammation.

Comparison of Antiobesity Effects Between Gochujangs Produced Using Different Koji Products and Tabasco Hot Sauce in Rats Fed a High-Fat Diet.

In this study, we compared the antiobesity effects between gochujangs prepared using different koji products and Tabasco hot sauce in rats fed a high-fat diet (HFD). Male Sprague-Dawley rats were fed HFD containing four different types of 10% gochujang powder or 0.25% commercial Tabasco sauce powder for 8 weeks. The body weight gain, liver and epididymal and mesenteric fat pad weights, serum leptin levels, and lipogenesis-related mRNA levels of HFD-gochujang supplementation groups were significantly decreased compared with those of the HFD group. In addition, gochujang supplement significantly reduced adipocyte size; hepatic triglyceride and total cholesterol levels; the occurrence of fatty liver deposits and steatosis by inhibiting lipogenesis through downregulation of fatty acid synthase, acetly-CoA carboxylase, and glucose-6-phosphate-dehydrogenase. These effects were greater in the gochujang-supplemented groups than the Tabasco hot sauce-supplemented group. The gochujang prepared by nutritious giant embryo rice koji and soybean koji was most effective in terms of antiobesity effects, compared with the other tested gochujangs. In gochujangs, the antiobesity effects are mediated by high levels of secondary metabolites such as isoflavone, soyasaponin, capsaicin, and lysophosphatidylcholine. The current results indicated that the gochujang products have the potential to reduce fat accumulation and obesity.

Process specific differential metabolomes for industrial gochujang types (pepper paste) manufactured using white rice, brown rice, and wheat.

The metabolic perplexes for gochujang (GCJ) fermentative bioprocess, a traditional Korean pepper paste, has largely remain equivocal for preparative conditions and raw material (RM) additives exacerbating its commercial standardization. Herein, we outlined a differential non-targeted metabolite profiling for three GCJ (white rice-WR; brown rice-BR; wheat-WT) under varying processing steps (P1 - fermentation; P2 - meju addition; P3 - ripening; and P4 - red pepper addition). We correlated the process specific metabolomes with corresponding physicochemical factors, enzymatic phenotypes, and bioactivities for GCJ-types. The P1 was characterized by a uniform increase in the levels of RM-derived lysoPCs. In contrast, P2 was observed with proportionally higher levels of meju-released isoflavones and soyasaponins in WR-GCJ, followed by BR and WT-GCJ. The P3 involved a cumulative increase in primary metabolites in all GCJ samples except lower organic acid contents in WT-GCJ. The pepper derived flavonoids and alkaloids were selectively increased while P4 in all GCJ-types.

Therapeutic effects of orally administered CJLP55 for atopic dermatitis via the regulation of immune response.

Atopic dermatitis (AD) is an inflammatory skin condition accompanied by symptoms such as edema and hemorrhage. Kimchi is a traditional fermented Korean dish consisting of various probiotics. In this study, the therapeutic effect of Lactobacillus plantarum CJLP55 isolated from Kimchi was studied in AD-induced mice. Orally administered Lactobacillus strain, CJLP55, suppressed AD symptoms and high serum IgE levels. CJLP55 administration reduced the thickness of the epidermis, infiltration of mast cells and eosinophils into the skin lesion, enlargement of axillary lymph nodes, and increase in cell population in axillary lymph nodes. CJLP55 treatment decreased the production of type 2 cytokines, such as interleukin (IL)-4, IL-5, IL-10, IL-12, interferon (IFN)-γ, and IL-6,which were stimulated by house dust mite extracts, in the axillary lymph node cells. Orally administered CJLP55 exhibited a therapeutic effect on house dust mite-induced AD in NC/Nga mice after onset of the disease by altering immune cell activation. The Lactobacillus strain, CJLP55, isolated from Kimchi, suppressed AD. Our results suggest its possible use as a potential candidate for management of AD.

Time-resolved comparative metabolomes for Koji fermentation with brown-, white-, and giant embryo-rice.

A time-resolved non-targeted metabolomic study towards evaluating the effects of three rice substrate types viz., white rice (WR), giant embryo rice (GER), and brown rice (BR), on Koji fermentation was performed. Notwithstanding the relatively higher proportions of metabolites in unfermented BR (BR 0>WR 0, GER 0), the relative levels of metabolic repertoire in BR Koji were marginally enhanced during 36h fermentation except those for phenolic acids, fatty acids, and vitamins. The WR Koji showed higher levels of lysophospholipids (LysoPC's) and protease-released amino acids (WR 36>GER 36>BR 36). The higher ß-glucosidase activity in GER Koji effected the increased levels of sugars and flavonoid aglycons complementing its higher antioxidant activity (GER Koji>BR Koji∼WR Koji). The present study holistically underpins the dynamic metabolomes and enzymatic states during rice Koji fermentation with varying substrate types. The present study finds applications in optimization of commercial Koji production.

Effect of fermented soybean products intake on the overall immune safety and function in mice.

Various functional activities have been reported for the fermented soybean products doenjang (DJ) and cheonggukjang (CGJ), although no systemic investigations of their immune functions have been conducted to date. We examined the effects of an experimental diet of DJ, CGJ, or a mixture of unfermented raw material for 4 weeks on overall immunity and immune safety in mice. No significant alterations were observed in peripheral or splenic immune cells among groups. Enhanced splenic natural killer cell activity was observed in the DJ and CGJ groups compared with the plain diet group. T helper type-1 (Th1)-mediated immune responses were enhanced in the DJ and CGJ groups with an upregulated production ratio of IFN-γ vs. IL-4 and IgG2a vs. IgG1 in stimulated splenic T and B cells, respectively. Resistance to Listeria monocytogenes infection was observed in the DJ and CGJ groups. Overall, the results of this study suggest that DJ and CGJ intake consolidates humoral and cellular immunity to Th1 responses.

Metabolomic Profiles of Aspergillus oryzae and Bacillus amyloliquefaciens During Rice Koji Fermentation.

Rice koji, used early in the manufacturing process for many fermented foods, produces diverse metabolites and enzymes during fermentation. Using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS), ultrahigh-performance liquid chromatography linear trap quadrupole ion trap tandem mass spectrometry (UHPLC-LTQ-IT-MS/MS), and multivariate analysis we generated the metabolite profiles of rice koji produced by fermentation with Aspergillus oryzae (RK_AO) or Bacillus amyloliquefaciens (RK_BA) for different durations. Two principal components of the metabolomic data distinguished the rice koji samples according to their fermenter species and fermentation time. Several enzymes secreted by the fermenter species, including α-amylase, protease, and ß-glucosidase, were assayed to identify differences in expression levels. This approach revealed that carbohydrate metabolism, serine-derived amino acids, and fatty acids were associated with rice koji fermentation by A. oryzae, whereas aromatic and branched chain amino acids, flavonoids, and lysophospholipids were more typical in rice koji fermentation by B. amyloliquefaciens. Antioxidant activity was significantly higher for RK_BA than for RK_AO, as were the abundances of flavonoids, including tricin, tricin glycosides, apigenin glycosides, and chrysoeriol glycosides. In summary, we have used MS-based metabolomics and enzyme activity assays to evaluate the effects of using different microbial species and fermentation times on the nutritional profile of rice koji.

Metabolomics reveal that amino acids are the main contributors to antioxidant activity in wheat and rice gochujangs (Korean fermented red pepper paste).

Metabolite profiling of gochujangs (Korean fermented red pepper paste) produced from different kinds of raw materials (WG, wheat gochujang; RG, rice gochujang) was performed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) and ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Using principal component analysis (PCA), gochujang samples were differentiated based on the differences in starchy source and secondary materials used in their production. The content of amino acids and sugars was higher in WG, whereas the content of flavonoids, soyasaponins, and γ-aminobutyric acid (GABA) was higher in RG. The content of flavonoids and soyasaponins was related to the higher soybean koji content of RG. The level of antioxidant activity in WG was higher than that in RG and showed a strong positive correlation with amino acid content and a negative correlation with flavonoid content. Although the Trolox equivalent antioxidant capacity of flavonoids was only 10-fold higher than that of amino acids in an antioxidant activity assay, the total amino acid content was as much as several hundred fold higher than total flavonoid content in gochujang. This result suggests that the amino acids could be a main contributor to the antioxidant capacity in gochujang.

Milk Collected at Night Induces Sedative and Anxiolytic-Like Effects and Augments Pentobarbital-Induced Sleeping Behavior in Mice.

Milk has long been known and used to promote sleep. The sleep-promoting effect of milk has been attributed to its psychological associations (i.e., the memory of a mother giving milk at bedtime) and its rich store of sleep-promoting constituents (e.g., tryptophan). Studies have shown that milk harvested at night (Night milk) contains exceptionally high amounts of tryptophan and melatonin. In the present study, we evaluated the psychopharmacological properties of Night milk, particularly its probable sleep-promoting/enhancing, and anxiolytic effects. Night milk was orally administered to ICR mice at various concentrations (100, 200, or 300 mg/kg). An hour after administration, assessment of its sedative (open-field and rotarod tests) and sedative sleep-potentiating effects (pentobarbital-induced sleeping test) was conducted. For comparison, the effects of Day milk (daytime milking) were also assessed. In addition, the effects of Night milk on anxiety behavior (elevated plus maze [EPM] test) and electroencephalographic (EEG) waves were evaluated. Night milk-treated animals exhibited decreased spontaneous locomotion (open-field test) and impaired motor balance and coordination (rotarod test). Furthermore, Night milk shortened the sleep onset and prolonged the sleep duration induced by pentobarbital sodium. These effects were comparable to that of diazepam. In addition, Night milk significantly increased the percentage of time spent and entries into the open arms of the EPM, indicating that it also has anxiolytic effects. No significant changes in EEG waves were observed. Altogether, these findings suggest that Night milk is a promising natural aid for sleep- and anxiety-related disturbances.

Effects of the Combined Extracts of Grape Pomace and Omija Fruit on Hyperglycemia and Adiposity in Type 2 Diabetic Mice.

Grape products have been known to exert greater antioxidant and anti-obesity than anti-hyperglycemic effects in animals and humans. Omija is used as an ingredient in traditional medicine, and it is known to have an anti-hyperglycemic effect. We investigated whether the combined extracts of grape pomace and omija fruit (GE+OE) could reduce fat accumulation in adipose and hepatic tissues and provide beneficial effects against hyperglycemia and insulin resistance in type 2 diabetic mice. C57BL/KsJ-db/db mice were fed either a normal control diet or GE+OE (0.5% grape pomace extract and 0.05% omija fruit extract, w/w) for 7 weeks. GE+OE decreased plasma leptin and resistin levels while increasing adiponectin levels and reducing the total white adipose tissue weight. Furthermore, GE+OE lowered plasma free fatty acid (FFA), triglyceride, and total-cholesterol levels as well as hepatic FFA and cholesterol levels. Hepatic fatty acid synthase and glucose 6-phosphate dehydrogenase activities were decreased in the GE+OE group, whereas hepatic ß-oxidation activity was increased. Furthermore, GE+OE supplementation not only reduced hyperglycemia and pancreatic ß-cell failure but also lowered blood glycosylated hemoglobin and plasma insulin levels. The homeostasis model assessment of insulin resistance levels was also decreased and the decrease seems to be mediated by the lowered activities of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinases. The present data suggest that GE+OE may have the potential to reduce hyperglycemia, insulin resistance, and obesity in patients with type 2 diabetes.

Dual effects of a mixture of grape pomace (Campbell Early) and Omija fruit ethanol extracts on lipid metabolism and the antioxidant defense system in diet-induced obese mice.

BACKGROUND/OBJECTIVES: We investigated the effects of a combination of grape pomace (Vitis labrusca, Campbell Early) and Omija fruit (Schizandra chinensis, Baillon) ethanol extracts on lipid metabolism and antioxidant defense system in diet-induced obese mice. MATERIALS/METHODS: Forty male C57BL/6J mice were divided into four groups and fed high-fat diet (control group, CON) or high-fat diet added 0.5% grape pomace extract (GPE), 0.05% Omija fruit extract (OFE) or 0.5% GPE plus 0.05% OFE (GPE+OFE) for 12 weeks. RESULTS: In contrast to the GPE- or OFE-supplemented groups, the GPE+OFE group showed significantly lower body weight and white adipose tissue weights than the CON group. Moreover, GPE+OFE supplementation significantly decreased plasma total cholesterol and increased the plasma HDL-cholesterol/total-cholesterol ratio (HTR) compared to the control diet. The hepatic triglyceride level was significantly lower in the GPE+OFE and GPE groups by increasing ß-oxidation and decreasing lipogenic enzyme compared to the CON group. Furthermore, GPE+OFE supplementation significantly increased antioxidant enzyme activities with a simultaneous decrease in liver H2O2 content compared to the control diet. CONCLUSIONS: Together our results suggest that supplementation with the GPE+OFE mixture may be more effective in improving adiposity, lipid metabolism and oxidative stress in high-fat diet-fed mice than those with GPE and OFE alone.

The beneficial effects of combined grape pomace and omija fruit extracts on hyperglycemia, adiposity and hepatic steatosis in db/db mice: a comparison with major index compounds.

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic ß-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice.

The ameliorating effect of Rosa roxburghii against ethanol-induced psychomotor alterations in rats.

BACKGROUND: Ethanol (EtOH) is one of the oldest recreational substances known to man, primarily taken because it induces a sense of well-being (euphoric effects) and relaxation (anxiolytic effects). EtOH use entails various negative consequences. Of particular interest are EtOH-induced psychomotor alterations, because of its immediate manifestation and adverse consequences. Rosa roxburghii (RR), a wild plant of Southwest China, has gained attention on account of its numerous beneficial effects on the immune, nervous, and cardiovascular systems. OBJECTIVE: In the present study we assessed the effects of Rosa roxburghii (RR) on EtOH-induced psychomotor alterations in rats. METHODS: Sprague Dawley rats were orally administered distilled water (control group) or ethanol (4 g/kg BW) (EtOH-group) to induce psychomotor alterations. RR extract (25, 50, and 100 mg/kg, p.o.) was administered 30 min before EtOH treatment (RR-group). EtOH-induced psychomotor alterations were evaluated in the open-field, accelerating rotarod, hanging wire, and cold swimming tests. Behavioral evaluation and hematological analysis (EtOH and acetaldehyde concentration) were done at 1, 2, 4 and 8 hours after EtOH administration. RESULTS: The EtOH group showed psychomotor alterations as compared with the control group. These EtOH-induced psychomotor alterations were directly related to the rise in blood ethanol and acetaldehyde concentrations. Pre-treatment of RR significantly improved EtOH-induced psychomotor alterations on open-field, accelerating rotarod, hanging wire, and cold swimming tests. These improvements in psychomotor performance coincided with the decreased blood ethanol and acetaldehyde levels observed in the RR-treated group. CONCLUSION: These results suggest that RR has ameliorating effects against EtOH-induced psychomotor alterations.

New phytopharmaceutical agent CJ-20001 modulates stress-induced inflammatory infiltration into gastric mucosa.

BACKGROUND/AIMS: CJ-20001 is a phytopharmaceutical agent and currently being investigated in a Phase II trial for the treatment of acute and chronic gastritis patients in Korea. In this study we addressed the protective effects of CJ-20001 against water immersion restraint stress (WIRS)-induced gastric injury in rats and studied the underlying mechanisms. METHODOLOGY: To evaluate the protective effect of CJ-20001 on stress-induced gastric lesions, rats were exposed to water immersion restraint stress. Inflammatory infiltration into gastric mucosa was examined by immunohistochemistry and in vitro invasion assay. Expression of proinflammatory cytokines was detected with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Pretreatment with CJ-20001 dose-dependently attenuated the WIRS-induced gastric lesions as demonstrated by gross pathology and histology. WIRS increased infiltration of mast cells and macrophages into the gastric mucosa and submucosal layer, whereas the inflammatory infiltration was markedly inhibited by CJ-20001 administration. An in vitro cell invasion assay showed that treatment with CJ-20001 decreased the migration of macrophages. CJ-20001 suppressed the expression of proinflammatory cytokines, IL-18, IP-10 and GRO/KC, in lipopolysaccharides (LPS)-treated macrophages. CONCLUSIONS: These data suggest that novel phytopharmaceutical agent CJ-20001 has the potent anti-inflammatory properties through inhibition of inflammatory infiltration in psycho-physiological stress-induced gastric injury.

Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers.

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH>4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.