Randomised clinical trial: efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in the treatment of patients with non-erosive reflux disease - a double-blind, placebo-controlled study.

BACKGROUND: Proton pump inhibitors (PPIs) are less effective in non-erosive reflux disease (NERD) patients than in reflux oesophagitis patients. Whether the addition of prokinetics to PPIs improves NERD patients' symptoms remains unknown. AIM: To evaluate the efficacy of mosapride in NERD patients when used with PPI. METHODS: A total of 200 NERD patients were randomised to one of two arms: omeprazole (10 mg once daily) plus mosapride citrate (5 mg three times a day) (treatment arm) and omeprazole plus placebo (placebo arm). The primary endpoint was the rate of responders [visual analogue scale (VAS) was zero or <1 cm] after 4 weeks of treatment. The secondary endpoints were changes in the VAS score and the safety profile. RESULTS: There was no significant difference between the rates of responders in both arms in intent-to-treat (ITT) and per-protocol (PP) analysis. The change in the VAS score in treatment arm was significantly better than placebo arm in PP analysis (-4.0 ± 0.2 and -3.3 ± 0.2, mean ± S.E.M.) (N.S. in ITT analysis). The rate of adverse events was similar in both groups. CONCLUSION: The addition of mosapride to omeprazole was not more effective than omeprazole alone.

Calcitonin gene-related peptide and somatostatin releases correlated with the area under the lafutidine concentration-time curve in human plasma.

OBJECTIVE: To examine the effects of the histamine H(2)-receptor antagonist, lafutidine, at clinical dosage (10 mg tablet after a standardized meal) on plasma levels of the gastrointestinal peptides, calcitonin gene-related peptide (CGRP), somatostatin and gastrin. METHODS: Six healthy male volunteers ate a standardized meal, and received either lafutidine orally at a dose of 10 mg or water only (control). Blood samples were taken before and up to 4 h after the drug administration. Plasma lafutidine concentrations were determined by high pressure liquid chromatography. Pharmacokinetic analysis of lafutidine was performed using one-compartmental model. The levels of immunoreactive substances of plasma CGRP, somatostatin and gastrin were measured by enzyme immunoassay, and the amount of peptide release was calculated by the trapezoidal method. Lafutidine significantly increased plasma CGRP levels at 1, 1.5, 2.5 and 4 h and the total amount of CGRP release (192 +/- 14.0 pg.h/mL) compared with the control group (128 +/- 21.5 pg.h/mL). RESULTS: Lafutidine significantly increased the plasma somatostatin levels at 1 and 1.5 h, and the total amount of somatostatin released (107 +/- 18.2 pg.h/mL) compared with the control (78.4 +/- 7.70 pg.h/mL). The area under the drug concentration-time curve (AUC) from 0 to 4 h after administration correlated well with the Delta-CGRP and Delta-somatostatin release but not with total amount of gastrin released. However, plasma gastrin levels were significantly elevated at 1.5 h after drug administration. CONCLUSION: Lafutidine at clinical dosage increases plasma CGRP and the somatostatin. The amounts released correlated with the AUC of lafutidine in humans. These results suggest that the increased release of CGRP and somatostatin may contribute to its gastroprotective and anti-acid secretory effect.

Acid-suppressive effects of rabeprazole: comparing 10mg and 20mg twice daily in Japanese Helicobacter pylori-negative and -positive CYP2C19 extensive metabolisers.

BACKGROUND: Rabeprazole 10mg b.i.d. is often administered as therapy for eradication of Helicobacter pylori (H. pylori) and is also proposed as therapy for refractory gastro-oesophageal reflux disease. However, there has not been a comprehensive assessment of its acid-suppressive effects. AIMS: To compare the acid-suppressive effects of rabeprazole 10mg b.i.d. with 20mg b.i.d. considering H. pylori status. SUBJECTS: Thirteen H. pylori-negative and eleven H. pylori-positive Japanese CYP2C19 extensive metabolisers (<35 years). METHODS: Intragastric pH was measured for 24h three times in a randomised manner; on day 7 of the repeated administration of rabeprazole 10mg b.i.d. or 20mg b.i.d., or a placebo. RESULTS: In median intragastric pH value and percent time of pH>3.0, >4.0, >5.0, >6.0, and >7.0 for 24h, no significant differences were observed between the two doses in either H. pylori-negative or H. pylori-positive subjects. At either dose, these parameters were significantly higher in H. pylori-positive subjects than in H. pylori-negative subjects. Nocturnal acid breakthrough occurred in seven and two of the thirteen H. pylori-negative subjects and one and two of the eleven H. pylori-positive subjects at each dose, respectively. CONCLUSIONS: The effects of rabeprazole 10mg b.i.d. were equal to those of 20mg b.i.d. in H. pylori-positive subjects; whereas in H. pylori-negative subjects, 20mg b.i.d. was superior for prevention of nocturnal acid breakthrough.

Acid-suppressive effects of generic omeprazole: comparison of three brands of generic omeprazole with original omeprazole.

BACKGROUND: Generic omeprazole contains the same active ingredient as original omeprazole and require verification of the bioequivalence with original omeprazole. However, very few clinical studies have been reported. AIMS: A prospective, randomised, open-label, crossover study to compare acid-suppressive effect of generic omeprazole with that of original omeprazole. SUBJECTS: Seven healthy Helicobacter pylori-negative subjects of CYP2C19 extensive metaboliser. METHODS: Intragastric pH was measured for 24 h without medications (placebo) and on day 7 of repeated administration of 10 mg once daily after breakfast of original omeprazole, Omeprazon, or three brands of generic omeprazole, Omeprazole-Towa, Ovulanze or Omerap. RESULTS: Median values of intragastric pH and percentages of time with pH>4 for 24 h were significantly higher with administration of any omeprazole formulation compared with placebo (P<0.05, Wilcoxon signed-rank test). Whereas, during the night-time period (20:00-08:00 h), percentages of time with pH>4 with Omeprazole-Towa and Omerap were not significantly higher than placebo. Compared with Omeprazon, these two parameters for 24 h showed significantly greater inter-subject variations with Omeprazole-Towa (P<0.05 and P<0.01, F-test) and Ovulanze (P<0.05). CONCLUSIONS: Acid-suppressive effects of some brands of generic omeprazole are not the same as original omeprazole. These differences might be reflected in clinical outcomes.

Effect of CYP2C19 polymorphism on the safety and efficacy of omeprazole in Japanese patients with recurrent reflux oesophagitis.

BACKGROUND: The polymorphic enzyme cytochrome P450 2C19 affects omeprazole metabolism. This influence on metabolism might affect serum gastrin levels, and safety, during long-term treatment of reflux oesophagitis. AIM: To examine the relationship between cytochrome P450 2C19 genotype and the safety profile of long-term omeprazole treatment. METHODS: A total of 119 Japanese patients with recurrent reflux oesophagitis underwent cytochrome P450 2C19 genotyping prior to receiving daily omeprazole 10 mg or 20 mg for 6-12 months, during which adverse event frequency, serum gastrin levels and endoscopic findings were monitored. RESULTS: The incidences of adverse events, serious adverse events and adverse events leading to withdrawal did not differ between homozygous extensive metabolizer (n = 46), heterozygous extensive metabolizer (n = 53) or poor metabolizer (n = 20) groups. In all genotype groups, serum gastrin increased during the first 3 months of dosing but stabilized thereafter. No significant differences were seen either in the rate of reflux oesophagitis healing or symptom improvement among genotype groups. CONCLUSIONS: Long-term treatment with omeprazole was well-tolerated in Japanese patients, irrespective of their cytochrome P450 2C19 metabolic genotype, indicating that dose adjustment depending on metabolic genotype is not required during treatment with omeprazole.

Rabeprazole 10 mg twice daily is superior to 20 mg once daily for night-time gastric acid suppression.

BACKGROUND: Insufficient acid suppression is one of the main causes of proton pump inhibitor-refractory gastro-oesophageal reflux disease. AIM: To achieve more potent and long-lasting acid suppression, different dosage regimens of rabeprazole were compared in relation to the CYP2C19 genotype status. METHODS: In a cross-over study, 18 healthy Helicobacter pylori-negative males (six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers) were given rabeprazole 10 mg once daily, 20 mg once daily or 10 mg twice daily, or water only (baseline data), for 7 days each. On day 7 of each regimen, 24-h intragastric pH-metry was performed. RESULTS: No significant differences were observed in median pH values and pH>4 holding time ratios between rabeprazole 10 mg once daily and 20 mg once daily. However, with rabeprazole 10 mg twice daily, these parameters were significantly higher than those with 20 mg once daily. The potency of acid suppression by rabeprazole was influenced by the CYP2C19 genotype status. The differences were somewhat significant but not large. The incidence of nocturnal acid breakthrough was lowest with rabeprazole 10 mg twice daily. CONCLUSIONS: Rabeprazole 10 mg twice daily, not 20 mg once daily, should be administered to achieve more potent and long-lasting acid suppression.

Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2-receptor antagonist.

BACKGROUND: Omeprazole 10 mg is used as maintenance therapy for gastro-oesophageal reflux disease, but previous reports have not mentioned the potency of its acid suppression. AIM: To evaluate the potency of acid suppression with omeprazole 10 mg, in relation to CYP2C19 genotypes. METHODS: Eighteen healthy subjects without Helicobacter pylori participated. After a 7-day regimen of omeprazole 10 mg, 20 mg, lafutidine 20 mg (a novel H2-receptor antagonist) or water only (baseline data), intragastric pH was measured for 24 h. RESULTS: With omeprazole 10 mg, greater differences were observed than 20 mg in median pH values and pH > 4 holding time ratios between poor metabolizers (PMs, n = 6) and the others [homozygous extensive metabolizers (homo-EMs, n = 6) and heterozygous extensive metabolizers (hetero-EMs, n = 6)]. With lafutidine 20 mg, these parameters were not influenced by the genotype. The potency of acid suppression was: omeprazole 20 mg approximately lafutidine 20 mg > omeprazole 10 mg in homo-EMs, omeprazole 20 mg > omeprazole 10 mg approximately lafutidine 20 mg in hetero-EMs, and omeprazole 20 mg approximately omeprazole 10 mg > lafutidine 20 mg in PMs. CONCLUSIONS: Omeprazole 10 mg strongly suppresses acid secretion, but depending on the CYP2C19 genotypes shows greater interindividual variations in suppression than 20 mg.

Improvement in gastric histology following Helicobacter pylori eradication therapy in Japanese peptic ulcer patients.

We aimed to determine if successful or failed eradication of Helicobacter pylori with triple therapy causes any difference in gastric mucosal histology. Japanese H. pylori-positive patients with a healed peptic ulcer received high (n = 112) or low (n = 113) doses of triple therapy (omeprazole, amoxicillin and clarithromycin) for 1 week. Biopsies from the greater curvature of the central antrum and upper corpus were taken 6 weeks and 30 weeks after treatment completion, and gastric mucosal histology compared between successful (n = 171) and failed (n = 34) eradication groups. Morphological variables of gastritis were graded according to the updated Sydney System. Successful eradication therapy was defined as improvement in inflammation, neutrophil activity and atrophy; failed eradication therapy as improvement in inflammation and neutrophil activity only. Gastric mucosal atrophy gradually improved (in addition to improvements in inflammation and neutrophil activity) with successful eradication of H. pylori infection.

Conversion to docosahexaenoic acid-containing phosphatidylserine from squid skin lecithin by phospholipase D-mediated transphosphatidylation.

Phospholipase D (PLD)-mediated transphosphatidylation of squid skin lecithin with L-serine was examined to prepare docosahexaenoic acid-containing phosphatidylserine (DHA-PS). When a biphasic system with organic solvent and 0.2 M acetate buffer (pH 5.5) was used, PS synthesis was significantly affected by the amount of 3.4 M L-serine-containing acetate buffer. L-Serine concentration in the acetate buffer and choice of organic solvent were also crucial. In a typical reaction with 0.8 unit of PLD (Streptomyces sp.), 2.5 mL of ethyl acetate substrate solution containing 30 mg of squid skin lecithin in combination with 3 mL of 3.4 M L-serine-containing 0.2 M acetate buffer (pH 5.5), PS content in the recovered phospholipid fraction increased to 43.1% after 24 h. DHA composed 37.6% of fatty acids in the converted PS. This was the same DHA level as in the substrate. Phosphatidylcholine (squid skin PC, DHA 44.2%) in the squid skin lecithin was more effectively converted to PS than phosphatidylethanolamine.

Involvement of cholinergic motor neurons in pharmacological regulation of gastrointestinal motility by glucagon in conscious dogs.

UNLABELLED: To clarify the exact mechanisms of the pharmacological effects of glucagon on gastrointestinal motility, the following experiments were performed on the conscious and anesthetized dogs. 1) During phase I of interdigestive migrating contractions (IMC), glucagon (5 approximately 50 microg/kg, drip infusion for 5 minutes) induced phasic contractions in the duodenum, jejunum and ileum, but not in the antrum. These excitatory responses were also observed in the truncal vagotomized dogs. These contractions were abolished by atropine or hexamethonium in the conscious dogs, and also by tetrodotoxin in the anesthetized dogs. 2) Glucagon inhibited cisapride-induced contractions only in the antrum in the conscious dogs. After pre treatment with hexamethonium, glucagon inhibited these contractions in the duodenum, jejunum and ileum as well as in the antrum. After pre treatment with tetrodotoxin in the anesthetized dogs, glucagon did not affect acetylcholine induced contractions in any region. 3) Glucagon inhibited spontaneous phase III contractions and erythromycin induced phase III like contractions in the antrum, but did not inhibit either contractions in the other regions in the conscious dogs. These paradoxical effects of glucagon between the antrum and intestine were similar to those involved in the blockade of 5-hydroxytryptamine 3 receptors. After pre-treatment with hexamethonium, glucagon inhibited these contractions in the duodenum, jejunum and ileum as well as in the antrum. IN CONCLUSION: 1) Glucagon latently inhibits cholinergic motor activities in the antrum and intestine not directly, by binding to either receptor on the smooth muscle cells, but through postganglionic cholinergic neurons and possibly through 5-hydroxytryptamine neurons. 2) On the other hand, in the intestine the reverse effects through preganglionic cholinergic neurons involving nicotinic and muscarinic receptors are more potent. 3) As a result, glucagon inhibits antral contractions and does not affect intestinal contractions in a conscious state.

Pharmacological regulation of postprandial gastrointestinal motility by glucagon in conscious dogs.

The physiological or pharmacological role of glucagon in the postprandial regulation of gastrointestinal motility has not yet been clarified. To clarify it, the following experiments were performed on conscious dogs. Antral, duodenal, jejunal and ileal contractile activities were monitored by chronically implanted strain gauge force transducers without restraint. The serum gastrin concentration in response to ingestion was measured by radioimmunoassay. 1) When glucagon (5 approximately 50 microg/kg, drip infusion for 5 minutes) was administered before ingestion of meal or 2 hours after ingestion, it inhibited postprandial motility dose-dependently in the antrum, while enhancing it in the duodenum, jejunum and ileum. 2) At the same time, glucagon inhibited the meal induced elevation of the serum gastrin concentration. 3) On the other hand, glucagon did not inhibit the contractions induced by pentagastrin (4 microg/kg,s.c.) or those induced by acetylcholine chloride (0.5 mg/kg, drip infusion for 10 minutes) in any region. 4) These glucagon-induced inhibitory effects in postprandial antral motility were not affected by phentolamine (0.5 mg/kg, i.v.) or nitro-L-arginine-methyl ester (L-NAME) (3 mg/kg/hr, drip infusion for 30 minutes). These results suggest that: 1) Glucagon inhibits the postprandial elevation of the serum gastrin concentration and thus inhibits postprandial antral motility. 2) On the other hand, in the intestine, glucagon-induced inhibitory responses might be reversed by glucagon-induced excitatory responses through preganglionic cholinergic motor neurons. 3) The mechanism of inhibition of gastrin release was not definite in my experiments, but one of the candidates may be activation of somatostatin release from the D cells by glucagon.

Effect of alpha 2-adrenergic receptor antagonist (midaglizole) on gastrointestinal motility in conscious dogs.

To clarify the physiological role of the mechanism that adrenergic nerve inhibits Ach release from intramural cholinergic nerve endings, the influence of Midaglizole, alpha 2-adrenergic receptor antagonist, to postprandial gastrointestinal motilities in conscious dogs was investigated. Postprandial motilities of gastric antrum, duodenum, ileum, and colon were significantly enhanced by Midaglizole (3.0-5.0 mg/kg body weight, i.v.). These excitatory responses were abolished by atropine (0.05-0.1 mg/kg body weight, i.v.). On the other hand, in most cases (29 cases out of 32), when Midaglizole was administered during quiesent phase of IMC, no change occurred in gastrointestinal motility. However, after subliminal dose of pentagastrin or cisapride, which stimulated Ach release from intramural cholinergic neuron without development of motility, was administered, Midaglizole induced phasic, postprandial motility-like contraction in gastrointestinal tract. Even in the fasted state, when Midaglizole was administered intragastrically, irregular contractions with high amplitude occurred in every regions from gastric antrum to colon. And these excitatory responses were abolished by atropine. Similar reaction was observed also in truncal vagotomized dogs. These results suggest that it is the physiological mechanism that adrenergic nerve presynaptically inhibits Ach release from intramural cholinergic neuron, which is the main mechanism of development of postprandial motility, acting on alpha 2-adrenergic receptor, and has tonic control of postprandial motility.