Early effects of Lansoprazole orally disintegrating tablets on intragastric pH in CYP2C19 extensive metabolizers

AIM： To compare rabeprazole （RPZ; 10 mg） with Lansoprazole orally disintegrating tablets （LPZ; 30 mg OD） in terms of antisecretory activity and blood drug concentration after a single dose. METHODS： Eight H pylori-negative cytochrome P450 （CYP） 2C19 extensive metabolizers were assigned to receive a single oral dose of RPZ 10 mg or LPZ 30 mg OD. Twelve hour intragastric pH monitoring was performed on the day of treatment. Blood samples were also collected after the administration of each drug. RESULTS： LPZ 30 mg OD induced a significantly earlier rise in blood drug concentration than RPZ 10 mg; consequently, LPZ 30 mg OD induced a significantly earlier rise in median pH in the third and fourth hours of the study. CONCLUSION： In H pylori-negative CYP2C19 extensive metabolizers, LPZ 30 mg OD induced a significantly faster inhibition of gastric acid secretion than RPZ 10 mg.     

Early effects of oral administration of lafutidine with mosapride compared with lafutidine alone on intragastric pH values

Background

The ideal medication for treatment of acid related diseases should have a rapid onset of action to promote hemostasis and resolution of symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion after a single oral administrations of lafutidine, is a newly synthesized H2-receptor antagonist, with mosapride 5 mg or lafutidine alone.

Methods

Ten Helicobacter pylori negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after a single oral administration of lafutidine 10 mg or lafutidine 10 mg with mosapride 5 mg (the lafutidine being administrated one hour after the mosapride). Each administration was separated by a 7-day washout period.

Results

The average pH during the 4-hour period after administration of lafutidine 10 mg with mosapride 5 mg was higher than after lafutidine 10 mg alone (median: 5.25 versus 4.58, respectively; p = 0.0318). During the 3–4 hour study period, lafutidine 10 mg with mosapride 5 mg provided a higher pH, compared to lafutidine 10 mg alone (median: 7.28 versus 6.42; p = 0.0208).

Conclusion

In H. pylori negative healthy male subjects, an oral dose of lafutidine 10 mg with mosapride 5 mg more rapidly increased intragastric pH than lafutidine 10 mg alone.     

A short-term eradication therapy for Helicobacter pylori acute gastritis

BACKGROUND AND AIMS: Acute gastritis, caused by an initial infection of Helicobacter pylori (H. pylori), may resolve spontaneously, but the infection sometimes becomes chronic. We examined the efficacy of a short-term H. pylori eradication therapy on acute gastritis. METHODS: Among the 15 patients with hemorrhagic acute gastritis who were randomly allocated to group A (eradication therapy) or group B (Lansoprazole, LPZ), 10 of them started to receive treatment within 1 day after the disease onset. The other five patients began the eradication therapy 4-6 days after disease onset (group C). Eradication therapy consisted of a daily oral administration of each of 30 mg lansoprazole (LPZ), once a day; 400 mg clarithromycin, twice a day; 1000 mg amoxicillin, twice a day; and 300 mg rebamipide, three times a day, for one week. If the endoscopy was normal, medication was stopped for the following 4 weeks before gastric endoscopy was performed again in order to assess H. pylori eradication. RESULTS: All group A patients were cured after the 1-week treatment and therefore, they became H. pylori negative. Group B and C patients had erosions or ulcers after the 1-week treatment and so received an additional 3-week administration of LPZ. Four weeks later, their gastritis was cured and except for one group B patient, they became H. pylori-negative. CONCLUSION: In patients with acute gastritis, caused by an initial H. pylori infection, eradication therapy was efficacious in achieving early healing. This therapy should be started as soon as possible after disease onset.     

Lafutidine, a Newly Developed Antiulcer Drug, Elevates Postprandial Intragastric pH and Increases Plasma Calcitonin Gene-Related Peptide and Somatostatin Concentrations in Humans: Comparisons with Famotidine

Lafutidine, a newly developed histamine H₂-receptor antagonist, inhibits daytime (i.e., postprandial) as well as nighttime gastric acid secretion in clinical studies. It also has gastroprotective activity that particularly affects mucosal blood flow in rats. This study focused on the efficacy of lafutidine on plasma concentrations of gastrointestinal peptides in humans. Six healthy male volunteers aged 23–32 years without Helicobacter pylori infection were orally administered either 10 mg lafutidine, 20 mg famotidine, or water only (control) 30 min after a standard meal (650 kcal). Plasma concentrations of lafutidine and famotidine were highest from 90 to 150 min after administration. Intragastric pH was elevated after both lafutidine and famotidine compared with the control. Plasma concentrations of calcitonin gene-related peptide (CGRP) and somatostatin were significantly increased after lafutidine at 60 and 90 min. We concluded that lafutidine increases plasma concentrations of CGRP and somatostatin in humans, which may result in inhibition of postprandial acid secretion and gastroprotective activity.     

Effect of Helicobacter pylori status on intragastric pH during administration of lafutidine or famotidine

BACKGROUND/AIMS: There has been no study attempting to compare the effects of lafutidine, a novel H2-receptor antagonist and other H2-receptor antagonists in the same subjects and relating them to H. pylori status. The first aim of this study was to investigate the effect of H. pylori status on intragastric pH in healthy volunteers receiving lafutidine or famotidine. The second aim was to compare the effects of the two antisecretory drugs. METHODOLOGY: The study was carried out in 11 healthy asymptomatic male volunteers. H. pylori infection was present in 5 subjects. Subjects were first examined by an ambulatory pH monitoring for 24 hours without medication. The second and third 24-hour pH monitoring study was performed on all subjects. Subjects took 10 mg lafutidine or 20mg famotidine at 9:00 and 21:00. RESULTS: During administration of lafutidine or famotidine, the percentage of period holding intragastric pH >4 was not significantly different between the H. pylori-negative and -positive subjects. Among the H. pylori negative subjects, the percentage of daytime period holding intragastric pH >4 was significantly greater with lafutidine than with famotidine (p < 0.05). CONCLUSIONS: The effect of lafutidine to increase intragastric pH was not affected by the H. pylori status. Among H. pylori-negative subjects, lafutidine was proven to be more effective than famotidine for acid control during the daytime in Japanese healthy volunteers.     

Rapid effect of lansoprazole on intragastric pH: a crossover comparison with omeprazole.

BACKGROUND: The time to onset of acid inhibition is considered an important factor when treating patients with reflux symptoms. This study was therefore designed to investigate the effect of 30 mg lansoprazole and 20 mg omeprazole on gastric pH after single-dose administration. METHODS: The study was of a randomized, open-label, single-dose and two-way crossover design with a washout period of at least 7 days in between. Fifteen healthy adult male and female subjects were included. The subjects were intubated with a pH catheter. Intragastric pH was measured every 4th sec for 10 min before and during 8 h after drug administration. Blood samples, for determination of plasma concentrations of lansoprazole and omeprazole, were obtained on 10 occasions during 6 h after drug administration. The area under the curve (AUC), the elimination halflife (t1/2), and the peak concentration (Cmax) of the two drugs were calculated. RESULTS: All subjects completed the study without major complications. The mean pH (0-8 h) after drug administration was 2.9 for lansoprazole and 2.0 for omeprazole (P = 0.0058). A pH of more than 4 was reached for the first time after 130 min with lansoprazole and after 250 min with omeprazole. AUC was 4919 +/- 2526 nmol/l x h for lansoprazole and 1352 +/- 1120 nmol/l x h for omeprazole. CONCLUSION: Single-dose administration of 30 mg lansoprazole is followed by a rapid absorption of the drug and hence a more efficient acid suppression than after single-dose administration of 20 mg omeprazole in healthy volunteers.     

Comparative study of the speed of acid-suppressing effects of oral administration of cimetidine and famotidine

BACKGROUND AND AIM: H2 histamine receptor antagonists (H2RAs) are widely used in patients with acid-related diseases, and the onset of antisecretory activity of H2RAs is reported to be faster than that of proton pump inhibitors (PPIs). The aim of this study was to compare the rapidity of onset of antisecretory activity of cimetidine and famotidine when orally administered. METHODS: Fifteen healthy male Japanese volunteers (five H. pylori-positive and 10 H. pylori-negative) participated in a randomized cross-over study. All subjects were examined three times by ambulatory 6-h pH monitoring (from 17:30 to 23:30) with no medication or oral administration of 400 mg of cimetidine or 20 mg of famotidine. Drugs were administered at 19:30 after eating a standard meal, and plasma concentrations were also examined for 4 h periods. RESULTS: The plasma concentration of cimetidine increased rapidly after oral administration, while that of famotidine increased gradually. Intragastric pH was increased and percentage time with pH < 4.0 decreased significantly 2 h after administration of either cimetidine or famotidine. There was no statistically significant difference in acid-suppressing effect between cimetidine and famotidine during the short-term post-administration period. CONCLUSION: Rapidity of antisecretory activity did not differ between oral cimetidine and famotidine administered orally.     

Reversal of the tolerance phenomenon by the intermittent administration of a histamine H2‐receptor antagonist

Background and Aim: The attenuated antisecretory activity of H2‐receptor antagonists (H2RA) during continuous administration is referred to as the tolerance phenomenon. A previous study indicated that Helicobacter pylori (H. pylori) infection prevents the occurrence of tolerance to H2RA. In the present study, we investigated whether intermittent (every other day) administration prevents the tolerance phenomenon in H. pylori‐negative patients. Methods: Ten H. pylori‐negative, healthy volunteers were included in the study. All of the patients underwent two courses of H2RA (lafutidine) administration: 21‐day continuous administration (every day), followed by 21‐day intermittent administration (every other day), with at least a 21‐day lafutidine‐free period between the first and second courses. All of the patients were examined by ambulatory intragastric pH monitoring five times: before medication, and on days 1 and 21 of the first (continuous) and second (intermittent) courses of lafutidine (10 mg b.d.) in a crossover fashion. Results: The continuous administration of lafutidine had a significantly attenuated, acid‐suppressing effect in H. pylori‐negative patients, and showed evidence of the tolerance phenomenon. However, the tolerance phenomenon was not observed through intermittent administration. Conclusions: These results demonstrated that in H. pylori‐negative patients, tolerance to H2RA, induced by continuous lafutidine administration, was reversed by subsequent intermittent administration.     

Effects of a novel histamine H2-receptor antagonist, lafutidine, on the mucus barrier of human gastric mucosa

BACKGROUND AND AIM: Lafutidine is a novel histamine H(2)-receptor antagonist used primarily as an antisecretory agent in Japan. Previous human studies have not assessed its gastroprotective effects. The purpose of the present study was to determine the effects of lafutidine on the human gastric mucus layer using both histological and biochemical methods. METHODS: Of the 14 patients scheduled for gastrectomy who consented to participate, seven were given 14 days of lafutidine 20 mg/day (lafutidine group) and the others received no medication (control group). The surface mucus gel layer in Carnoy-fixed tissue sections was examined immunohistochemically. Both the thickness of the mucus layer and its mucin content were measured in gastric corpus mucosa. RESULTS: There was no detectable difference between the groups in the grade of gastritis or the immunohistochemical staining characteristics. The laminated structure of the surface mucus gel layer was retained after administration of lafutidine and it was thicker than the layer in the control group. The surface layer in the lafutidine group had three-fold more mucin than that in the control group. There was no difference between the two groups in the mucin content of the deep mucosa. CONCLUSION: Lafutidine, given at clinical dosages, not only inhibits acid secretion but also strengthens the mucus barrier of the human gastric mucosa.     

Potent and long-lasting action of lafutidine on the human histamine H(2) receptor.

BACKGROUND/AIM: Based on animal models, lafutidine, a novel histamine H(2) receptor (H(2)R) antagonist, is reported to show potent and long-lasting antagonisms of histamine H(2)R-mediated effects. However, no reports have been published concerning its direct interaction with the human H(2)R. This study aims at characterizing its interaction with human H(2)R. METHODS: Chinese hamster ovary cell lines stably expressing human H(2)Rs were obtained. The dose-dependent effects of lafutidine and famotidine on [(3)H]tiotidine binding and histamine-stimulated cAMP production were analyzed. The effects of preincubation with 2.78 x 10(-7) M of lafutidine or famotidine for 30 min on histamine-dependent cAMP production and [(3)H]tiotidine binding were also examined after 0, 1, 2, 4, and 12 h. This concentration is below the C(max) of lafutidine (10 mg p.o.) and above the C(max) of famotidine (20 mg p.o.). RESULTS: Lafutidine inhibited [(3)H]tiotidine binding and histamine-stimulated cAMP production as or more potently than famotidine. At higher concentrations lafutidine was more potent than famotidine. In addition, preincubation with 2.78 x 10(-7) M lafutidine, but not with 10(-5) M famotidine, had marked inhibitory effects which persisted as long as after extensive washing. CONCLUSION: Lafutidine shows a potent and long-lasting antagonism on the human H(2)R.     

Gastro-protective action of lafutidine mediated by capsaicin-sensitive afferent neurons without interaction with TRPV1 and involvement of endogenous prostaglandins

AIM: Lafutidine, a histamine H2 receptor antagonist, exhibits gastro-protective action mediated by capsaicin-sensitive afferent neurons (CSN). We compared the effect between lafutidine and capsaicin, with respect to the interaction with endogenous prostaglandins (PG), nitric oxide (NO) and the afferent neurons, including transient receptor potential vanilloid subtype 1 (TRPV1). METHODS: Male SD rats and C57BL/6 mice, both wild-type and prostacyclin IP receptor knockout animals, were used after 18 h of fasting. Gastric lesions were induced by the po administration of HCI/ethanol (60% in 150 mmol/L HCI) in a volume of 1 mL for rats or 0.3 mL for mice. RESULTS: Both lafutidine and capsaicin (1-10 mg/kg, po) afforded dose-dependent protection against HCI/ ethanol in rats and mice. The effects were attenuated by both the ablation of CSN and pretreatment with NG-nitro-L-arginine methyl ester, yet only the effect of capsaicin was mitigated by prior administration of capsazepine, the TRPV1 antagonist, as well as indomethacin. Lafutidine protected the stomach against HCI/ethanol in IP receptor knockout mice, similar to wild-type animals, while capsaicin failed to afford protection in the animals lacking IP receptors. Neither of these agents affected the mucosal PGE2 or 6-keto PGF1αcontents in rat stomachs. Capsaicin evoked an increase in [Ca2 ]i in rat TRPV1-transfected HEK293 cells while lafutidine did not. CONCLUSION: These results suggest that although both lafutidine and capsaicin exhibit gastro-protective action mediated by CSN, the mode of their effects differs regarding the dependency on endogenous PGs/IP receptors and TRPV1. It is assumed that lafutidine interacts with CSN at yet unidentified sites other than TRPV1.     

Randomized study of lafutidine vs lansoprazole in patients with mild gastroesophageal reflux disease

AIM: To compare the clinical efficacy of the second-generation H2RA lafutidine with that of lansoprazole in Japanese patients with mild gastroesophageal reflux disease (GERD).METHODS: Patients with symptoms of GERD and a diagnosis of grade A reflux esophagitis (according to the Los Angeles classification) were randomized to receive lafutidine (10 mg, twice daily) or lansoprazole (30 mg, once daily) for an initial 8 wk, followed by maintenance treatment comprising half-doses of the assigned drug for 24 wk. The primary endpoint was the frequency and severity of heartburn during initial and maintenance treatment. The secondary endpoints were the sum score of questions 2 and 3 in the Gastrointestinal Symptom Rating Scale (GSRS), and the satisfaction score.RESULTS: Between April 2012 and March 2013, a total of 53 patients were enrolled, of whom 24 and 29 received lafutidine and lansoprazole, respectively. After 8 wk, the frequency and severity of heartburn was significantly reduced in both groups. However, lafutidine was significantly inferior to lansoprazole with regard to the severity of heartburn during initial and maintenance treatment (P = 0.016). The sum score of questions 2 and 3 in the GSRS, and satisfaction scores were also significantly worse in the lafutidine group than the lansoprazole group (P = 0.0068 and P = 0.0048, respectively).CONCLUSION: The clinical efficacy of lafutidine was inferior to that of lansoprazole, even in Japanese patients with mild GERD.     

Persistent oxidative stress in the corpus mucosa is evoked by long-term treatment of H. pylori-infected patients with proton pump inhibitors

BACKGROUND/AIMS: To examine the influence of long-term treatment of H. pylori-infected patients with proton pump inhibitors (PPI) on the toxic oxidant production in the stomach. METHODOLOGY: Eight H. pylori-positive patients with gastric ulcer were enrolled, and tissue samples were obtained endoscopically from the antrum and corpus. The tissue contents of neutrophil myeloperoxidase (MPO) and oxygen-derived free radicals were quantified by ELISA and chemiluminescence (ChL) assay. The H. pylori density in the tissue specimens was scored by immunohistochemistry and the mucosal infiltration by neutrophils and monocytes was scored by histopathology. The effects of PPI on these parameters were evaluated by oral administration of lansoprazole (LPZ) at the dose of 30mg od for 8 weeks, followed by 15mg for 24 weeks. RESULTS: Eight-week treatment with LPZ significantly increased the corpus ChL by 400%, which remained unchanged at this level during the subsequent 24 weeks, but the antrum ChL decreased slightly following LPZ-treatment. No significant changes in the mucosal MPO activity or the histologically determined parameters of H. pylori density and neutrophil/monocyte infiltration were observed in either portion of the stomach. CONCLUSIONS: The mucosal oxidative stress level significantly increased in the corpus mucosa after long-term treatment with LPZ, which may be independent of inflammatory cell infiltration.     

Glibenclamide improves postprandial hypertriglyceridaemia in type 2 diabetic patients by reducing chylomicrons but not the very low-density lipoprotein subfraction levels.

AIM: There are scarce data dealing with the degree of postprandial lipaemia after sulphonylurea administration. The aim of this study was to examine the effect of acute glibenclamide administration on postprandial lipaemia in Type 2 diabetic patients. METHODS: Eight randomly selected Type 2 diabetic individuals, aged 43-65 years (mean, 54 years), who had never received any anti-diabetic drug, were included in the study. Each patient was given a 485 kcal mixed meal (45% fat, 40% carbohydrate and 15% protein) twice on separate days after an overnight fast: once with placebo and once with 5 mg glibenclamide, per os, in a random order. The two tests were performed with an interval of 7 days. Venous blood samples were drawn just before and 2 h, 4 h and 6 h after meal consumption. Total triglyceride levels in plasma, in chylomicrons (CM), in CM-deficient plasma, in very low-density lipoprotein (VLDL) subfractions (VLDL-1, VLDL-2) and in intermediate-density lipoprotein (IDL) were determined. Free fatty acid (FFA) and total cholesterol levels in plasma, as well as high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels in CM-deficient plasma, were also measured. Finally, serum glucose, insulin and C-peptide concentrations were measured in each sample. RESULTS: As expected there was a significant decrease in postprandial glycaemia after glibenclamide administration compared to placebo (mean area under the curve values: AUC = 53.3 +/- 18.2 and 69.1 +/- 21.6 mm/h, P = 0.00009). In addition, the mean AUC values of insulin and C-peptide were significantly greater after drug administration. The AUC values of total plasma triglyceride and of CM triglyceride following glibenclamide administration were significantly lower compared to placebo, while the AUC values of postprandial triglyceride in CM-deficient plasma and of postprandial triglyceride in VLDL-1, VLDL-2 and IDL were not different after drug administration compared to placebo. Finally, no significant differences were noted in the AUC values of total cholesterol, LDL cholesterol, HDL cholesterol and plasma FFA levels after glibenclamide administration. CONCLUSIONS: These results demonstrate that glibenclamide administration improves postprandial hypertriglyceridaemia acutely by reducing postprandial triglycerides of intestinal origin.     

Nasogastric Omeprazole: Effects on Gastric pH in Critically Ill Patients

Objective: The efficacy of omeprazole administered by the nasogastric route has not been adequately studied. We sought to determine whether nasogastrically administered omeprazole could effectively maintain an intra-gastric pH greater than 4.0 in patients hospitalized in a medical intensive care unit. Methods: Patients were considered eligible for the study if they had a nasogastric feeding tube in place and had not received omeprazole, antacids, or histamine-2 blockers in the 5 days preceding study enrollment. Exclusionary criteria included active GI bleeding or a mean baseline gastric pH greater than 4.0. Patients served as their own controls during a 24-h lead-in period, during which baseline intragastric pH was measured by gastric aspirate. Omeprazole, 20 or 40 mg, was administered once daily with water through a nasogastric tube. Intragastric pH was measured every 4–8 h for a maximum of 3 days following drug administration. Results: Twenty patients were considered eligible for the study; 10 were excluded because of an elevated baseline gastric pH (n = 8) or because proper gastric aspirates could not be obtained (n = 2). The mean baseline intragastric pH in four patients receiving omeprazole 20 mg q.d. was 2.4 ± 1.1 and increased to 3.7 ± 1.6 after drug administration ( p = 0.013). The mean baseline intragastric pH in six patients receiving omeprazole 40 mg q.d. was 2.8 ± 0.8 and increased to 5.7 ± 1.1 after drug administration ( p < 0.001). The percentage of intragastric pH values greater than 4.0 after drug administration was 34.2% in patients receiving omeprazole 20 mg q.d. and 84.7% in those receiving omeprazole 40 mg q.d. Conclusions: Nasogastric omeprazole 40 mg q.d. is effective in maintaining an intragastric pH greater than 4.0 in critically ill patients. The nasogastric administration of omeprazole offers a costeffective therapeutic option for acid suppression in patients at risk for stress mucosal ulceration.     

Lafutidine increases hepatic blood flow via potentiating the action of central thyrotropin-releasing hormone in rats

BACKGROUND: Lafutidine, (+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2 butenyl]acetamide, is a newly synthesized histamine H2 receptor antagonist and possesses a cytoprotective efficacy, which comprises mucin biosynthesis and stimulation of gastric blood flow mediated through capsaicin-sensitive sensory neurons and endogenous calcitonin gene-related peptide (CGRP). In the present study, an effect of lafutidine on hepatic blood flow was investigated in rats that received an intracisternal injection of a subthreshold dose of thyrotropin-releasing hormone (TRH) analog, RX 77368. METHODS: Change in hepatic blood flow was determined by laser Doppler flowmetry. Male Wistar rats were anesthetized with urethane (1.5 g/kg, i.p.), and positioned on a stereotaxic apparatus. An abdominal incision was made, and a probe of laser Doppler flowmeter was placed on the surface of the liver. After a 60-min stabilization, basal hepatic blood flow was measured for 30 min, and lafutidine (0.5, 1, 3, 5 or 10 mg/kg) or vehicle was injected into the portal vein and a subthreshold dose (1.5 ng) of RX 77368 was injected intracisternally. Hepatic blood flow was monitored for 120 min postinjection. To investigate a role of capsaicin-sensitive sensory neurons and endogenous CGRP, systemic capsaicin treatment (125 mg/kg, s.c., 10-14 days before) and intravenous infusion of a CGRP receptor antagonist, human CGRP-(8-37) (15 micro g/kg as a bolus, followed by infusion at 3 micro g/kg/h) were performed, respectively. RESULTS: Intracisternal injection of RX 77368 (1.5 ng) or intraportal lafutidine (10 mg/kg) by itself did not affect hepatic blood flow, but co-injection of intracisternal RX 77368 (1.5 ng) and intraportal lafutidine (5 mg/kg) increased it with peak response at 30 min postinjection. The effect of lafutidine on hepatic blood flow in rats given RX 77368 was dose-related over the range 1-5 mg/kg. By contrast, intracisternal injection of RX 77368 (1.5 ng) did not change hepatic blood flow in rats injected with another histamine H2 receptor antagonist, famotidine (5 mg/kg), intraportally. The stimulatory effect of co-injection of TRH analog and lafutidine was abolished by systemic capsaicin-treatment and CGRP antagonist. CONCLUSION: These data suggest that lafutidine increases hepatic blood flow by sensitizing the liver to the action of central TRH via both capsaicin-sensitive sensory neurons and endogenous CGRP in urethane-anesthetized rats.     

Intragastric pH monitoring during antisecretory therapy in patient with gastrointestinal bleeding

This study was undertaken to evaluate the effect of various cimetidine and ranitidine administration schedules on intragastric pH in patients with recent episodes of hematemesis. The investigation was performed on 10 subjects whose hemorrhage had ceased either spontaneously or after pharmacological treatment for at least 24-36 h. The following therapeutic regimens were randomly evaluated: bolus infusions of ranitidine (100 mg/6 h and 50 mg/4 h) and cimetidine (400 mg/6 h and 200 mg/4 h) and continuous infusions of ranitidine (0.2 and 0.4 mg/kg/h) and cimetidine (100 mg/h). Each study evaluated at least two consecutive boli or an 8-h continuous infusion. All treatments produced significant elevations in the basal intragastric pH (p less than 0.001). With bolus administrations, however, the pH displayed consistent oscillations. The pH fell below 4 approximately 6 h after the administration in all the patients treated with 400 mg of cimetidine and in three treated with 50 mg of ranitidine. The administration of histamine H2-receptor antagonists every 4 h allowed better control of intragastric acidity. The pH dropped below 4 in seven of the 10 patients in the 4-h period after the administration of 200 mg cimetidine, and in one of the 10 patients treated with 50 mg of ranitidine/4 h. Increasing bolus dose did not reduce the time lapse or increase the inhibition of intragastric acidity. Continuous infusions were efficacious in maintaining pH values constantly above 6. Ranitidine (0.2 mg/kg/h) achieved the same inhibitory efficiency as cimetidine (100 mg/h). These data indicate that continuous venous infusion of both ranitidine and cimetidine is significantly more efficacious than repeated single bolus administrations.     

Pantoprazole versus omeprazole: influence on meal-stimulated gastric acid secretion

AIMS: To determine the influence of recommended therapeutic doses of pantoprazole and omeprazole on meal-stimulated acid secretion. METHODS: In this double-blind, placebo-controlled, three-period crossover study, 12 healthy male volunteers received 40 mg pantoprazole od, 20 mg omeprazole od or placebo at 08:00 h for 5 days in a randomized order. Meal-stimulated acid secretion was determined by means of a homogenized test meal, and intragastric titration on day 1, 4-6 h, 8-10 h, 16-18 h, and 24-26 h, and on days 3 and 5, 4-6 h after oral drug administration. RESULTS: On day 1 (4-6 h after oral drug administration), meal-stimulated acid secretion was decreased by 36% and 24% after administration of 40 mg pantoprazole or 20 mg omeprazole, respectively. After 3 and 5 days of dosing, the decreases were 88% and 85% with 40 mg pantoprazole, and 70% and 74% with 20 mg omeprazole. At all measuring points during the 5-day dosing periods, 40 mg pantoprazole proved superior to 20 mg omeprazole in inhibiting meal-stimulated gastric acid secretion. The differences were statistically significant for pantoprazole on day 1, 24-26 h after oral drug administration and on day 3 (P = 0.0425 and P = 0.0244, respectively). On day 1, only pantoprazole was significantly better than placebo (P = 0.0210, 4-6 h after dosing; P = 0.0093, 8-10 h after dosing and P = 0.0068, 16-18 h after dosing). CONCLUSION: Pantoprazole 40 mg is significantly more effective than omeprazole 20 mg in inhibiting meal-stimulated acid secretion. In addition, pantoprazole exhibits a more rapid onset of action.     

Effect of esomeprazole and rabeprazole on intragastric pH in healthy Chinese: an open, randomized crossover trial

BACKGROUND AND AIM: Esomeprazole is the S-isomer of omeprazole, with a stronger acid suppressive effect than omeprazole. This open, randomized crossover study was designed to evaluate the effect of esomeprazole and another proton-pump inhibitor, rabeprazole, on intragastric pH in healthy Chinese. METHODS: Thirty-six healthy volunteers (26 men and 10 women, aged between 20 and 31 years) were enrolled. Subjects were given either esomeprazole 40 mg (n = 18) or rabeprazole 10 mg (n = 18) orally once daily for 5 days during the first dosing period, then the other medicine at the set dosage for the second dosing period. The two periods were separated by a 14-day washout phase. The doses were chosen according to the State Food and Drug Administration of China for the treatment of acid-related diseases. Intragastric pH was continuously monitored for 24 h on days 1 and 5 of each dosing period. CYP2C19 genotypes were analyzed to identify the extensive metabolizers (EM) and poor metabolizers (PM). RESULTS: The percentage of time with intragastric pH >4 was significantly higher (P < 0.001) in subjects receiving esomeprazole than in those receiving rabeprazole in the first 4 h after administration of the first dose (70.65% vs 44.87%), at 24 h on day 1 (73.7% vs 54.8%) and at 24 h on day 5 (84.2% vs 76.2%). The median intragastric pH was also higher in subjects receiving esomeprazole than in those receiving rabeprazole in the first 6 h, day 1 and day 5 (P 4 for at least 16 h on day 1 (63.9% vs 33.3%) and on day 5 (88.9% vs 61.1%) was higher after administration of esomeprazole than after rabeprazole (both P < 0.05). On genotype analysis, 28 of the subjects were EM and eight were PM. Those who were PM tended to have a higher, albeit not statistically significant, percentage of time with intragastric pH >4 and the median 24-h intragastric pH than those who were EM. Both drugs were well tolerated. CONCLUSIONS: Esomeprazole 40 mg orally once daily is more effective and faster in increasing intragastric pH than rabeprazole 10 mg orally once daily, and thus offers a potential for improved efficacy in acid-related diseases.     

Effect of a proton pump inhibitor AG-1749 (lansoprazole) on intragastric pH: 24-hour intragastric pH monitoring]

Proton pump inhibitors, as agents for use against peptic ulcers, potently suppress gastric acid secretion, as is the case with H2 receptor antagonists. To evaluate this antisecretory action as objectively as possible, intragastric pH was continuously monitored during 24 hours. Eight subjects were enrolled and divided into 2 treatment groups: a group receiving a daily dose of 30 mg of AG-1749 (lansoprazole) and the other group receiving 60 mg. Intragastric pH recording was made in each subject before and after the consecutive administration of the drug, and the corresponding pH holding time was calculated to evaluate the effect obtained in each group. The result indicated that the proportion of time in 24 hours after medication during which the pH was maintained above each level was significantly larger than that after placebo administration, and the duration of action was superior to that of H2-receptor antagonists. From the above, it was concluded that the consecutive administration of ag-1749, at doses of 60 mg as well as 30 mg, exhibits excellent antisecretory action in terms of intragastric pH control.