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Randomised clinical trial: safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of tegoprazan (CJ-12420), a novel potassium-competitive acid blocker, in healthy male subjects.
Han, S, Choi, HY, Kim, YH, Nam, JY, Kim, B, Song, GS, Lim, HS, Bae, KS
Alimentary pharmacology & therapeutics. 2019;(7):751-759
Abstract
BACKGROUND Tegoprazan (CJ-12420) is a potassium-competitive acid blocker (P-CAB) with therapeutic potential for gastro-oesophageal reflux disease (GERD) by reversibly suppressing gastric H+ /K+ -ATPase. AIMS To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of tegoprazan METHODS A phase I, randomised, double-blind and placebo-controlled clinical trial was conducted in 56 healthy male subjects without Helicobacter pylori infection. In the single ascending dose study, 50, 100, 200 and 400 mg tegoprazan were administered to 32 subjects. In the multiple ascending dose study, 100 and 200 mg tegoprazan were administered every 24 hours to each of the eight subjects for 7 days. In the comparative pharmacodynamics study, 40 mg esomeprazole was administered to eight subjects every 24 hours for 7 days. The assessment included safety, tolerability, pharmacodynamics through monitoring of 24-hour gastric pH and pharmacokinetics of tegoprazan in plasma and urine. RESULTS Tegoprazan was generally well tolerated. Most adverse events reported in the study were mild in intensity and resolved without any sequelae. Exposure to tegoprazan increased in a dose-proportional manner. Multiple dosing with tegoprazan showed no accumulation in plasma on day 7. The pharmacodynamic analysis revealed that tegoprazan showed rapid, dose-dependent gastric acid suppression. CONCLUSIONS Tegoprazan was well tolerated and showed rapid and potent gastric acid suppression. This supports the further development of tegoprazan as a treatment for acid-related disorders.
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Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.
Jiao, HW, Sun, LN, Li, YQ, Yu, L, Zhang, HW, Wang, MF, Yu, LY, Yuan, ZQ, Xie, LJ, Chen, J, et al
European journal of clinical pharmacology. 2018;(3):257-265
Abstract
PURPOSE The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. METHODS The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. RESULTS All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. CONCLUSIONS Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.
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Characteristics of the Human Upper Gastrointestinal Contents in the Fasted State Under Hypo- and A-chlorhydric Gastric Conditions Under Conditions of Typical Drug - Drug Interaction Studies.
Litou, C, Vertzoni, M, Goumas, C, Vasdekis, V, Xu, W, Kesisoglou, F, Reppas, C
Pharmaceutical research. 2016;(6):1399-412
Abstract
OBJECTIVE Evaluate the impact of reduced gastric acid secretion after administration of two acid-reducing agents on the physicochemical characteristics of contents of upper gastrointestinal lumen of fasted adults. MATERIALS AND METHODS Eight healthy male adults, fasted from food for 12 h, participated in a three-phase crossover study. Phase 1: No drug treatment prior to aspirations. Phase 2: Oral administration of 40 mg pantoprazole at ~9 am the last 3 days prior to aspirations and at ~7 am on aspiration day. Phase 3: Oral administration of 20 mg famotidine at ~7 pm prior to aspirations and at ~7 am on aspiration day. Samples from the contents of upper gastrointestinal lumen were aspirated for 50 min, after administration of 240 ml table water at ~9 am. RESULTS Reduction of gastric acid secretion was accompanied by reduced buffer capacity, chloride ion concentration, osmolality and surface tension in stomach and by increased pH (up to ~0.7 units) in upper small intestine during the first 50 min post-water administration. The mechanism of reduction of acid secretion seems to be important for the buffer capacity in stomach and for the surface tension in upper gastrointestinal lumen. CONCLUSIONS Apart from gastric pH, reduced acid secretion affects physicochemical characteristics of contents of upper gastrointestinal lumen which may be important for the performance of certain drugs/products in the fasted state.
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A dark brown roast coffee blend is less effective at stimulating gastric acid secretion in healthy volunteers compared to a medium roast market blend.
Rubach, M, Lang, R, Bytof, G, Stiebitz, H, Lantz, I, Hofmann, T, Somoza, V
Molecular nutrition & food research. 2014;(6):1370-3
Abstract
Coffee consumption sometimes is associated with symptoms of stomach discomfort. This work aimed to elucidate whether two coffee beverages, containing similar amounts of caffeine, but differing in their concentrations of (β) N-alkanoyl-5-hydroxytryptamides (C5HTs), chlorogenic acids (CGAs), trigonelline, and N-methylpyridinium (N-MP) have different effects on gastric acid secretion in healthy volunteers. The intragastric pH after administration of bicarbonate with/without 200 mL of a coffee beverage prepared from a market blend or dark roast blend was analyzed in nine healthy volunteers. Coffee beverages were analyzed for their contents of C5HT, N-MP, trigonelline, CGAs, and caffeine using HPLC-DAD and HPLC-MS/MS. Chemical analysis revealed higher concentrations of N-MP for the dark brown blend (87 mg/L) compared to the market blend coffee (29 mg/L), whereas concentrations of C5HT (0.012 versus 0.343 mg/L), CGAs (323 versus 1126 mg/L), and trigonelline (119 versus 343 mg/L) were lower, and caffeine concentrations were similar (607 versus 674 mg/mL). Gastric acid secretion was less effectively stimulated after administration of the dark roast blend coffee compared to the market blend. Future studies are warranted to verify whether a high ratio of N-MP to C5HT and CGAs is beneficial for reducing coffee-associated gastric acid secretion.
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The effect of once daily omeprazole and succinic acid (VECAM) vs once daily omeprazole on 24-h intragastric pH.
Chowers, Y, Atarot, T, Pratha, VS, Fass, R
Neurogastroenterology and motility. 2012;(5):426-31, e208-9
Abstract
BACKGROUND Parietal cell H(+)/K(+) ATPase activation is essential for optimal proton pump inhibitor (PPI) activity. Succinic acid (SA) was shown to induce gastric acid secretion. VECAM is a combination of omeprazole (OMP) and SA. To compare the effect of once daily bedtime dosing of VECAM 40 and VECAM 20 without food vs OMP 20 mg administered before breakfast on gastric acidity. METHODS Open label, randomized, crossover study enrolling 36 healthy subjects comparing the study treatments at steady state for 24 h intragastric pH monitoring. KEY RESULTS The median percent time intragastric pH > 4 demonstrated that VECAM 40 was superior to VECAM 20 (65.7%vs 49.1%P < 0.0001) and OMP 20 mg (65.7%vs 47.6%P = 0.005) during 24 h. VECAM 40 was superior to VECAM 20 (52.8%vs 38.8%P = 0.0079) and OMP 20 mg (52.8%vs 27.2%P < 0.0001), and VECAM 20 was superior to OMP 20 mg (38.8 vs 27.2 P = 0.0069) during the nighttime. VECAM 20 and OMP 20 mg were comparable during 24 h. CONCLUSIONS & INFERENCES VECAM 40 and VECAM 20 were significantly better in maintaining intragastric pH > 4 during the nighttime than OMP 20 mg. Succinic acid eliminates the need for a subsequent meal for intragastric pH control by VECAM.
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Oral buffered esomeprazole is superior to i.v. pantoprazole for rapid rise of intragastric pH: a wireless pH metry analysis.
Banerjee, R, Reddy, DN, Guda, NM, Kalpala, R, Mahurkar, S, Darisetty, S, Rao, GV
Journal of gastroenterology and hepatology. 2010;(1):43-7
Abstract
BACKGROUND AND AIMS A pH of more than 6 is required for clot stability and hemostasis. Intravenous proton pump inhibitors have a rapid onset of action compared to oral and have been preferred for management of non-variceal bleeding. Intravenous pantoprazole has been used extensively. Buffered esomeprazole (BE) is an oral preparation consisting of an inner core of non-enteric-coated esomeprazole with a shell of sodium bicarbonate. The buffer protects against acid degradation of esomeprazole in addition to immediate antacid action. The aim of this study was to assess the efficacy of BE for raising and maintaining an intragastric pH of more than 6 in comparison to i.v. pantoprazole in equivalent dosing. METHODS A randomized two-way cross-over study was conducted. Ten healthy volunteers were randomized to twice daily BE 40 mg or pantoprazole 40 mg i.v. bolus. Intragastric pH was measured with a wireless pH radiotelemetry capsule (Bravo, Medtronic). A 2-week washout period was given between doses. RESULTS BE achieved a steady pH of more than 6 in a median time of 2 min (range 1-5 min) after the first dose. The mean % time that intragastric pH was more than 6.0 for BE was 96%, and 90% of the 24-h period compared to pantoprazole (47% and 18%), P = 0.000. A median pH (interquartile range) for the BE group was 6.2 (6.175-6.2) which was higher than i.v. pantoprazole 4.60 (4.5-5.0) (P = 0.005). CONCLUSION BE achieves and maintains a pH of more than 6 within minutes of administration. It was significantly superior to i.v. pantoprazole in equivalent dosing. This finding could have implications in the management of non-variceal bleed where a rapid and sustained pH of more than 6 is desirable.
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Immediate acid-suppressing effects of ranitidine hydrochloride and rabeprazole sodium following initial administration and reintroduction: A randomized, cross-over study using wireless pH monitoring capsules.
Ono, S, Kato, M, Ono, Y, Imai, A, Yoshida, T, Shimizu, Y, Asaka, M
Journal of gastroenterology and hepatology. 2009;(4):639-45
Abstract
BACKGROUND AND AIM Histamine 2 receptor antagonists and proton-pump inhibitors, drugs that are widely used for the treatment of acid-related diseases, have different clinical characteristics. The objective of this study was to compare the acid-suppressing effects of ranitidine hydrochloride and those of rabeprazole sodium at the first administration and re-administration after withdrawal. METHODS The study was designed as an open-label, randomized, two-way cross-over trial. Seven Helicobacter pylori-negative healthy volunteers were enrolled in this study. Ranitidine hydrochloride (300 mg/day) or rabeprazole sodium (20 mg/day) was administered from days 1 to 7 and from days 11 to 13. The percentage of time with gastric pH < 4 and the median gastric pH were evaluated for 15 consecutive days by a Bravo capsule fixed to the stomach. RESULTS On day 1, there was no significant difference between the acid-suppressing effects of the two drugs (ranitidine vs rabeprazole: not significant). Although rabeprazole sodium maintained a potent and stable effect from days 2 to 7 (ranitidine vs rabeprazole: P < 0.05), the effect of ranitidine hydrochloride was attenuated after day 4. In addition, the effect of ranitidine hydrochloride at re-administration was attenuated (days 11, 12, and 13 vs pre-administration: not significant). CONCLUSION In view of our observations, we expect symptoms associated with gastric acidity to be more adequately controlled with rabeprazole sodium in the short term when compared to ranitidine hydrochloride.
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Effect of intragastric acid stability of fat emulsions on gastric emptying, plasma lipid profile and postprandial satiety.
Marciani, L, Faulks, R, Wickham, MS, Bush, D, Pick, B, Wright, J, Cox, EF, Fillery-Travis, A, Gowland, PA, Spiller, RC
The British journal of nutrition. 2009;(6):919-28
Abstract
Fat is often included in common foods as an emulsion of dispersed oil droplets to enhance the organoleptic quality and stability. The intragastric acid stability of emulsified fat may impact on gastric emptying, satiety and plasma lipid absorption. The aim of the present study was to investigate whether, compared with an acid-unstable emulsion, an acid-stable fat emulsion would empty from the stomach more slowly, cause more rapid plasma lipid absorption and cause greater satiety. Eleven healthy male volunteers received on two separate occasions 500 ml of 15 % (w/w) [13C]palmitate-enriched olive oil-in-water emulsion meals which were either stable or unstable in the acid gastric environment. MRI was used to measure gastric emptying and the intragastric oil fraction of the meals. Blood sampling was used to measure plasma lipids and visual analogue scales were used to assess satiety. The acid-unstable fat emulsion broke and rapidly layered in the stomach. Gastric emptying of meal volume was slower for the acid-stable fat emulsion (P < 0.0001; two-way ANOVA). The rate of energy delivery of fat from the stomach to the duodenum was not different up to t = 110 min. The acid-stable emulsion induced increased fullness (P < 0.05), decreased hunger (P < 0.0002), decreased appetite (P < 0.0001) and increased the concentration of palmitic acid tracer in the chylomicron fraction (P < 0.04). This shows that it is possible to delay gastric emptying and increase satiety by stabilising the intragastric distribution of fat emulsions against the gastric acid environment. This could have implications for the design of novel foods.
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[Mechanism of action of Nizhne-Ivkinskaya 2K sulfate-calcium mineral water in combined treatment of acid-dependent gastrointestinal diseases].
Guliaev, PV, Pomaskina, TV, Kunshin, AA, Chervotkina, LA, Guliaeva, SF, Tsirkin, VI
Terapevticheskii arkhiv. 2008;(1):23-8
Abstract
AIM: To study efficacy of drinking mineral water (MW) nizhne-ivkinskaya 2K in combined sanatorium treatment of gastrointestinal acid-dependent diseases (ADD) and the role of endogenic modulators of M-cholinoreactivity in pathogenesis of ADD. MATERIAL AND METHODS General condition of the patients, gastric pH and peristalsis (computer system Gastrolog-M), gastric and gall bladder motility (Aloka SSD 1100), hepatic function (by bilirubin and AST and ALT activity), lipid spectrum (including LDLP and HDLP) and M-cholinomodulating activity of the blood serum (by biomethod) were examined in 134 subjects: 20 healthy subjects and 114 patients with ADD. RESULTS In ADD, gastric juice acidity is high, gastric and gall bladder motility is low, total cholesterol and LDLP cholesterol are elevated, M-cholinoblocking activity of the blood serum is reduced 10-fold. Intake of nizhne-ivkinskaya 2K mineral water for 21 days improved the patients' health, normalized gastric pH, motility of the stomach and gall bladder, reduced content of LDLP and restored M-cholinoblocking serum activity. CONCLUSION ADD development is thought to result from excessive vagus effect due to elevated blood level of lysophosphatidylcholine (LPC). In certain concentrations it can enhance efficacy of M-cholinergic impacts on gastric cells. Reduction of LDLP content due to intake of the mineral water leads to normalization of M-cholinergic impacts on gastric cells.
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Comparison of gastric pH with omeprazole magnesium 20.6 mg (Prilosec OTC) o.m. famotidine 10 mg (Pepcid AC) b.d. and famotidine 20 mg b.d. over 14 days of treatment.
Miner, PB, Allgood, LD, Grender, JM
Alimentary pharmacology & therapeutics. 2007;(1):103-9
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Abstract
BACKGROUND The onset of acid inhibition for proton pump inhibitors is slower than with H2RAs and generally considered to be at a steady-state after 5 days. Thus, little direct comparison data exists between H2RAs and proton pump inhibitors for gastric acid suppression on day 1 of therapy. Furthermore, the durability of their acid suppression has not been systematically compared. AIM: To compare the effects of 20.6 mg omeprazole magnesium o.m. (Ome-Mg 20), famotidine 10 mg b.d. (Fam 10) and famotidine 20 mg b.d. (Fam 20) on intragastric pH on day 1 and throughout 14 days of dosing. METHODS The study was a randomized, double-blind, three-dosing regimens, three-period crossover. Healthy adults with frequent heartburn (> or =2 days/week) underwent 24-h gastric pH monitoring on days 0 (baseline), 1, 3, 7 and 14. RESULTS Thirty-one subjects were included in the per-protocol analyses. On day 1, the mean percentage time pH > 4 (pH4%) was higher for Ome-Mg 20, 44.6%, than for Fam 10, 36.7% (P = 0.032), and not different from Fam 20, 46.9% (P = 0.541). The pH4% was higher for Ome-Mg 20 than either famotidine regimen on all subsequent monitoring days (P < 0.001). The 24-h area under the mean intragastric pH curve showed a similar pattern. Furthermore, after day 1, Ome-Mg 20 demonstrated an increasing and sustained effect in contrast to a decreasing effect for famotidine, consistent with H2RA tolerance. CONCLUSION Gastric acid suppression on Ome-Mg 20 mg o.m. over 14 days was comparable with Fam 10 mg b.d. or Fam 20 mg b.d. on day 1, and superior thereafter.