Effects of prolonged oral cimetidine, ranitidine, and famotidine therapy on antipyrine elimination

The effects of three histamine H2-receptor antagonists on the antipyrine metabolizing capacity of the liver were studied in 32 patients with gastrointestinal disorders and in three healthy volunteers. The drugs studied were 800 mg and 400 mg of cimetidine, 300 mg of ranitidine, and 40 mg of famotidine daily. Only cimetidine at 800 mg/day inhibited hepatic antipyrine metabolism, and the inhibitory effects disappeared rapidly with no accumulation.     

Secretory transport of ranitidine and famotidine across Caco-2 cell monolayers

The secretory transport of the H(2)-antagonists, ranitidine and famotidine, across Caco-2 cell monolayers was found to be a saturable process. Both drugs exhibited greater permeability in the basolateral (BL) to apical (AP) direction than in the AP to BL direction, indicating apically directed secretion; BL to AP transport was inhibited by P-glycoprotein (P-gp) inhibitors verapamil and cyclosporin A. The cellular uptake of ranitidine across the BL membrane was saturable and temperature dependent, indicative of carrier-mediated transport. The K(m) and V(max) for the uptake process were estimated to be 66.9 mM and 20.9 nmol/mg of protein/min, respectively. The uptake of [(14)C]ranitidine across the BL membrane was inhibited by unlabeled ranitidine and structurally diverse organic cations. The tetraethylammonium (TEA)-sensitive organic cation transporters are not involved in the uptake of ranitidine and famotidine across the BL membrane of Caco-2. This conclusion was based on the evidence that functionally active TEA-sensitive organic cation transporters did not exist in the BL membranes of the Caco-2 cells, whereas the functionally active TEA-sensitive organic cation transporter(s) in LLC-PK(1) cells did not contribute to the transport of ranitidine or famotidine across the cell monolayers. Thus, we conclude that the secretory transport of ranitidine and famotidine across Caco-2 cell monolayers is mediated by 1) a carrier in the BL membrane that is distinct from the TEA-sensitive organic cation transporter(s) and 2) P-gp in the apical membrane.     

Hepatoprotective,antinociceptive and antioxidant activities of cimetidine,ranitidine and famotidine as histamine H2 receptor antagonists

The antioxidant, antinociceptive and hepatoprotective effects of H₂ receptor blockers were examined with different experimental models. Antioxidant activities were determined by employing various in vitro assay systems such as 1,1‐diphenyl‐2‐picryl hydrazyl (DPPH) radical‐scavenging activity assays, reducing power determination assays, nitric oxide‐scavenging activity assays and hydrogen peroxide‐scavenging activity assays. Antinociceptive effects were determined using the hot plate test in mice. The hepatoprotective effects of cimetidine, ranitidine and famotidine against hepatotoxicity induced by carbon tetrachloride (CCl₄) were determined by measuring the levels of serum enzymes alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities in mice. We found that the IC₅₀ values of cimetidine, ranitidine and famotidine on DPPH radical‐scavenging activity were 671 ± 28, 538 ± 21 and 955 ± 43 μg/mL, respectively. Famotidine showed very strong nitric oxide‐scavenging activity. All three compounds showed very weak hydrogen peroxide‐scavenging activity. Moreover, the compounds did not exhibit any reducing power activity until concentrations of 1.6 mg/mL. All compounds also showed a dose‐dependent and marked analgesic activity in mice relative to controls. Pretreatment of mice with cimetidine, ranitidine or famotidine for three consecutive days reduced CCl₄‐induced hepatotoxicity in mice. Treatment with 200 mg/kg ranitidine reduced AST, AST and ALP serum levels, while 200 and 40 mg/kg of cimetidine and famotidine, respectively, reduced AST and ALP serum levels. H₂ blockers exhibited varying levels of antioxidant activities in various assays. Our results indicate that the antioxidant activities of H₂ blockers have an analgesic activity and protective effect on CCl₄‐induced hepatotoxicity in mice. These effects were greater with ranitidine than with the other compounds.     

Comparison of the effects of pentagastrin and meal-stimulated gastrin on plasma calcitonin in normal man.

We compared the effects of exogenous pentagastrin and meal-stimulated gastrin on plasma immunoreactive calcitonin (iCT) in various studies of 13 normal adult men. Bolus intravenous injection of pentagastrin (0.5 microgram/kg) produced increases of iCT in 8 of 9 men. There was a linearly increasing response of iCT concentrations to increasing doses of pentagastrin (0.0625, 0.125, 0.25, and 0.5 microgram/kg) and to achieved serum immunoreactive pentagastrin concentrations (r = 0.72, P less than 0.01). To determine the effects of endogenous gastrin upon peripheral iCT concentrations, we measured serum immunoreactive gastrin (iG) and plasma iCT in four men at frequent intervals for 240 min after ingestion of low- (100 mg) and high- (400 mg) calcium meals. Serum iG increased in all subjects, with a peak at approximately 30 min. However, plasma iCT levels were unchanged from basal throughout the study. The increase of pentagastrin (0.3 pmol/ml) which caused a barely detectable increase of iCT was five- to tenfold greater than the mean maximal increases of gastrin after low- and high-calcium meals (0.04 and 0.06 pmol/ml, respectively). These results suggest that increases of plasma iCT concentrations after administration of pentagastrin in man reflect pharmacologic phenomena and that postprandial gastrin secretion may be insufficient to affect peripheral iCT concentrations.     

Increased tissue concentrations of the gastrin precursor in patients treated with omeprazole

The main form of gastrin in antral mucosa, the amidated heptadecapeptide G17, is generated from an inactive precursor, progastrin, by steps involving endopeptidase cleavage and amidation. Gastrin cells are normally inhibited by gastric acid and in this study we have examined how suppression of acid by treatment with omeprazole for 6-8 weeks influences gastrin production in patients with oesophagitis. Plasma concentrations of total amidated gastrins in the fasting state increased from 18 to 43 pmol l-1; assays specific for G17-immunoreactivity indicated that the plasma concentrations of this form increased from 6 to 12 pmol l-1. In endoscopic biopsies of antral mucosa there was no change with omeprazole treatment in the concentrations of total amidated gastrins, or their immediate precursors, the Gly-extended gastrins. However, assays using an antibody that reacts with progastrin, together with size exclusion chromatography, indicated that tissue progastrin concentration increased 6-fold. The data suggest a modest net increase in gastrin production with omeprazole-treatment; because the ratio of tissue concentrations of total amidated gastrins to Gly-extended gastrins did not change, it would seem that the amidating capacity of the gastrin cell was maintained. However, the increase in progastrin concentrations suggests a relative failure of the initial steps of post-translational processing, and consequently that in certain circumstances endopeptidase cleavage of progastrin may be rate limiting.     

Effects of famotidine on gastric mucus of the rat

The influence of famotidine on the production of gastric mucus was studied at experimental level. We measured the quantity of the intracellular mucus, the surface adherent mucus gel thickness, and the biosynthesis of prostaglandin E2 (PGE2) by the rat gastric mucosa, in pretreated animals. Both the intracellular mucus accumulation and the adherent mucus gel thickness revealed a highly statistically significant increase (P less than 0.0002). PGE2 assay showed that famotidine also led to a statistically significant increase (P = 0.02) of PGE2 in treated versus control animals. These findings raise the question of whether despite its common antisecretory pathway of action this H2-receptor antagonist could play a role in the protection of gastric mucosa. Further research is necessary to determine this.     

奥美拉唑和雷尼替丁对十二指肠溃疡病愈合率和复发率 影响的对比研究

目的 对比奥美担唑和雷尼替丁治疗十二批肠溃疡病近期愈合率和复发率,探索质子泵抑制剂（PPI）与H2受体拮抗剂对防止溃疡病复发的远程疗效。方法 118例经内镜检查证实的性十二指肠溃疡患者,随机分成奥美拉唑组和雷尼替丁组,进行疗效对比。结果 奥美拉唑组和雷尼替丁组4周溃疡愈合率分别为88.3%(68/77)和68.3％（28／41）,雷尼替丁组6周溃疡愈合率为90.2%(37/41)。对溃疡愈合的37例进行长程治疗6－12个月,观察用药时间内的溃疡累计复发率。奥美拉唑组1年内累计复发率为5.2?/19),雷尼替丁组为16.6％（3／16）.结论 奥美拉唑组短程治疗时溃疡愈合率高于雷尼替丁组,而长程治疗时1年累计复发率明显低于雷尼替丁组,由于奥美拉唑对酸抑制程度大而且时间长,因此,临床上可迅速缓解症状,加快溃疡的愈合。     

Coagulation-dependent gene expression and liver injury in rats given lipopolysaccharide with ranitidine but not with famotidine

In an animal model of drug idiosyncrasy, rats cotreated with nonhepatotoxic doses of lipopolysaccharide (LPS) and ranitidine (RAN) develop hepatocellular injury, whereas rats treated with LPS and famotidine (FAM) do not. The coagulation system and neutrophils (PMNs) are requisite mediators of LPS/RAN-induced liver injury. We tested the hypothesis that unique gene expression in LPS/RAN-treated rats requires coagulation system activation and that these changes are absent in rats given LPS and FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 x 10(6) endotoxin units/kg i.v.) or its vehicle, and then 1 h later, they were treated with heparin (3000 U/kg) or its vehicle. One hour thereafter, they were given RAN (30 mg/kg), FAM (6 mg/kg, a pharmacologically equiefficacious dose, or 28.8 mg/kg, an equimolar dose), or vehicle (i.v.). They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity, coagulation system activation, and liver gene expression (2 h only). Statistical filtering of gene array results and real-time polymerase chain reaction identified groups of genes expressed in LPS/RAN-treated rats but not LPS/FAM-treated rats that were either changed or unchanged by heparin administration. For example, LPS/RAN-induced mRNA expression of the inflammatory mediators interleukin-6, cyclooxygenase-2, and macrophage inflammatory protein-2 (MIP-2) was reduced by anticoagulation. Enhancement of serum MIP-2 and plasminogen activator inhibitor-1 concentrations in LPS/RAN-treated rats was prevented by anticoagulation. The results suggest cross-talk between hemostasis-induced gene expression and inflammation (e.g., PMN function) in the genesis of hepatocellular injury in LPS/RAN-treated rats. In contrast, neither the expression of such genes nor hepatocellular necrosis occurred in rats treated with LPS/FAM.     

Tenoxicam-induced gastropathy in the rat: a comparison with piroxicam and diclofenac sodium, and the inhibitory effects of ranitidine and sucralfate

The ulcer-inducing potential, indicated by the oral dose that induced gastric ulcers in 50% of rats, was higher for tenoxicam (10.2 mg/kg) than for diclofenac sodium (34 mg/kg, equivalent to 6.8 mg/kg tenoxicam) or piroxicam (6.2 mg/kg). The mean lesion scores, a measure of the intensity of ulceration, using 16 and 32 mg/kg tenoxicam given orally were 3.6 +/- 3.4 and 8.7 +/- 7.3, respectively, compared with 9.6 +/- 6.4 and 24.7 +/- 10.5, respectively, for similar oral doses of piroxicam; the differences were statistically significant (P less than 0.05 and P less than 0.001, respectively). The mean lesion score for 32 mg/kg tenoxicam was also significantly (P less than 0.05) less than that for 160 mg/kg diclofenac sodium: 8.7 +/- 7.3 compared with 14.8 +/- 8.1. Ranitidine (20 40 mg/kg) and 260-520 mg/kg sucralfate but not 4 mg/kg ranitidine strongly inhibited ulceration induced by 32 mg/kg tenoxicam.     

Opposite effects of gastrin on cell proliferation in the antrum and other parts of the upper-gastrointestinal tract in the rat

The effect of gastrin on DNA synthesis and mitotic activity in the mucosa of the upper-gastrointestinal tract was explored in unanesthetized rats with a gastric fistula. Animals were killed at 4-hr intervals, after starting a 3-hr intravenous infusion with the lowest dose of gastrin provoking a maximal acid output. Tritiated thymidine was injected 1 hr before killing. Autoradiography was used, and labeling and mitotic indices were estimated in the fundic, antral, duodenal, and jejunal mucosa. The proliferative activity in the fundic, duodenal, and jejunal glands was significantly increased 16 hr after the administration of gastrin. In the antral glands, however, a significant decrease in both labeling and mitotic indices was observed. Rhythmic variations in proliferative activity were observed in the antral, duodenal, and jejunal mucosa in control animals. They were different from those in the gastrin-treated animals. Our data confirm the trophic action of gastrin in the fundic, duodenal, and jejunal mucosa. They also indicate an inhibitory effect of this hormone on cell proliferation in the antral mucosa.     

Effect of H2-receptor blockade on gastric mucus composition. A comparative study with ranitidine and famotidine

The effects on gastric mucus by two different H2-receptor antagonists, famotidine and ranitidine, have been investigated in 20 patients with duodenal ulcer. Before and after 4 weeks' treatment with either drug the quality of mucus secretion was assessed by means of a 'mucoprotective index'. A significant (P less than 0.01) decrease in the values of this index was observed in famotidine-treated subjects, whereas no changes were detected in those given ranitidine. The findings of this study with famotidine are in keeping with the results previously reported with cimetidine using the same method. It is suggested that blockade of gastric H2-receptors alters the composition of gastric mucus in man. This effect is not shared by ranitidine.     

Acute dietary effects on plasma lipids, lipoproteins and lipolytic enzymes in healthy normal males

Diurnal plasma lipids and lipoproteins were studied in twelve healthy young males on corn oil and palm oil diets, respectively. The major triglyceridy. Lecithin-cholesterol acyl transferase, lipoprotein lipase and hepatic triglyceride lipase were also measured. diurnal changes of triglycerides and cholesterol were confined to lipoproteins of d less than 1.006 kg/l. There was a diurnal rise of lecithin-cholesterol acyl transferase activity with corn oil but not with palm oil. Fasting and postprandial postheparin lipoprotein lipase and hepatic triglyceride lipase were similar but there was a significant correlation of postprandial hepatic lipase with postprandial plasma triglycerides on palm oil. Marked diurnal changes of triglyceride fatty acids were observed not only in 'very low density lipoprotein' but also in high-density lipoprotein amounting to approximately one third of total high density lipoprotein triglyceride fatty acids.     

Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole

The effect of omeprazole treatment on diazepam plasma levels was studied in four slow and six rapid metabolizers of omeprazole. Single intravenous doses of diazepam (0.1 mg/kg) were administered after 1 week of oral treatment with omeprazole (20 mg) and placebo. This was a double-blind crossover study with randomized placebo and omeprazole treatments. Blood was collected up to 120 hours after diazepam dosing (still during one-daily omeprazole and placebo administration) for measurement of diazepam and its major metabolite desmethyldiazepam. The slow metabolizers of omeprazole also metabolized diazepam slowly, exhibiting only half the diazepam plasma clearance of the others. The mean clearance of diazepam was decreased 26% after omeprazole in the rapid metabolizers, whereas the slow group showed no apparent interaction. The mean plasma concentrations of desmethyldiazepam showed a more rapid formation in the rapid compared with the slow metabolizers, which is a logical consequence of the rate of diazepam metabolism.     

Acute effects of surgery on carbohydrate production and utilization in the fed rat

1. The work utilized a model of uncomplicated abdominal surgery (laparotomy under ether anaesthesia) to delineate the effects of abdominal trauma on glucose homoeostasis in the fed rat. 2. Regulation of glucose production and utilization was investigated by observing the response to the administration of glucose, insulin plus glucose and 5-methylpyrazole 3-carboxylic acid. 3. Glucose administration suppressed hepatic glucose output as assessed by portal-venous concentration differences in control or surgically stressed rats. In contrast, glycaemia was increased and lactaemia decreased in the latter group. Portal-venous concentrations differences for lactate were unaffected. 4. Surgery increased plasma fatty acid concentrations and the antilipolytic response to glucose or glucose plus insulin was diminished. Post-operative increases in fatty acid concentrations were associated with inhibition of hepatic pyruvate dehydrogenase complex which was reversed by insulin, indicating a differential sensitivity of adipose tissue and liver to the hormone. 5. The model of surgical stress utilized, while affecting extrahepatic glucose disposal, did not elicit depletion of liver glycogen or inactivation of L-pyruvate kinase. 6. It is concluded that the initial response to uncomplicated abdominal surgery involves carbohydrate conservation rather than increased glucose production, with effects to decrease extrahepatic glucose uptake and hepatic glucose oxidation.     

Inhibition of acid secretion in guinea pigs by tricyclic antidepressants: comparison with ranitidine and omeprazole

The antisecretory properties of imipramine on gastric secretion in guinea pig in comparison with other antisecretory agents was determined. In awake guinea pigs s.c. infusion of histamine (30 micrograms/kg/hr) increased acid and fluid secretion by 3- to 4-fold. When acid output peaked, a bolus administration of the tricyclic anti-depressant imipramine inhibited acid and fluid secretion. Imipramine and other agents, such as ranitidine and omeprazole, inhibited gastric secretion in a dose-dependent fashion. The most potent was the H2-antagonist ranitidine (IC50, 0.2-0.3 mumol/kg), followed by the gastric H-K-adenosine triphosphatase inhibitor, omeprazole (IC50, 0.5-0.6 mumol/kg). Imipramine (IC50 1-2 mumol/kg) was the least potent of the inhibitors. Both ranitidine and omeprazole could abolish acid secretion, but maximal inhibition with imipramine was 60% of initial. Promethazine (25 mumol/kg), an H1 antagonist, and atropine (12 mumol/kg), a muscarinic antagonist, inhibited gastric secretion by 40 to 50%. Imipramine and atropine also inhibited basal acid secretion. In dispersed gastric cells comparison between imipramine and omeprazole showed that imipramine was about 5-fold more potent than omeprazole in blocking histamine or dibutyryl cyclic AMP stimulation of aminopyrine accumulation. Imipramine probably acts as a protonophore by increasing the rate of proton-gradient dissipation rather than by interfering with the hydrogen-pump system because, in gastric membranes, imipramine was 20-fold less potent than omeprazole in inhibiting the gastric H-K-adenosine triphosphatase activity. These results suggest that imipramine administered s.c. in guinea pigs is a potent antisecretory drug. Its action may be due to a combination of anticholinergic and antihistamine H2 activities.     

Comparative effects of omeprazole, amoxycillin plus metronidazole versus omeprazole, clarithromycin plus metronidazole on the oral, gastric and intestinal microflora in Helicobacter pylori-infected patients.

Fourteen patients with Helicobacter pylori infection were treated with 20 mg omeprazole, 1 g amoxycillin and 400 mg metronidazole bd for 7 days (OAM), and 16 patients were treated with 20 mg omeprazole, 250 mg clarithromycin and 400 mg metronidazole bd for 7 days (OCM). Saliva, gastric biopsies and faecal samples were collected before, during (day 7) and 4 weeks after treatment in order to analyse alterations of the normal microflora and to determine antimicrobial susceptibility. Both treatment regimens resulted in marked quantitative and qualitative alterations. A selection of resistant streptococcal strains were noticed in both treatment groups, most apparent in the OCM group where a shift from susceptible to resistant strains was recorded. In the OAM group, six patients had overgrowth of resistant enterobacteriaceae during treatment compared with none in the OCM group, in the gastric microflora. The MICs for Enterococcus spp. and Enterobacteriaceae in faeces increased significantly during treatment in both groups. Nine patients in the OAM group became intestinally colonized by yeasts during treatment. The total anaerobic microflora was strongly suppressed in both treatment groups, although most pronounced in the OCM group, where the frequency of clarithromycin-resistant bacteroides strains increased from 2 to 76% during treatment, and remained at 59% 4 weeks post-treatment. Even if the treatment outcome was better in the OCM group (100%) than in the OAM group (71%), the amoxycillin-based treatment might be preferable from an ecological point of view, since the qualitative alterations in terms of emergence and persistence of resistant strains seemed to be most pronounced in the clarithromycin-treated group.     

Occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate,ranitidine, and omeprazole

PURPOSE: The purpose of the study was to evaluate the effects of sucralfate, ranitidine, and omeprazole use on incidence of ventilatory-associated pneumonia (VAP) and mortality in ventilated pediatric critical care patients. MATERIALS AND METHODS: This prospective study was conducted at the pediatric intensive care unit (PICU) between August 2000 and February 2002. A total of 160 patients who needed mechanical ventilation were randomized into 4 groups according to the computer-generated random number table: group (S), (n = 38) received sucralfate suspension 60 mg/kg/d in 4 doses via the nasogastric tube that was flushed with 10 mL of sterile water; group (R), (n = 42) received ranitidine 2 mg/kg/d intravenously in 4 doses; group (O), (n = 38) received omeprazole 1 mg/kg/d intravenously in 2 doses; and group (P), (n = 42) did not receive any medication for stress ulcer prophylaxis. Treatment was begun within 6 hours of PICU admission. RESULTS: Seventy patients (44%) developed VAP. VAP rate was 42% (16 of 38) in the sucralfate group, 48% (20 of 42) in the ranitidine group, 45% (17 of 38) in the omeprazole group, and 41% (17 of 42) in the nontreated group. Overall mortality rate was 22% (35 of 160); it was 21% (8 of 38) in the sucralfate group, 23% (10 of 42) in the ranitidine group, 21% (8 of 38) in the omeprazole group, and 21% (9 of 42) in the nontreated group. Our results did not show any difference in the incidence of VAP and mortality in mechanically ventilated PICU patients treated with ranitidine, omeprazole, or sucralfate, or nontreated subjects (P =.963, confidence interval [CI] = 0.958-0.968; P =.988, CI = 0.985-0.991, respectively). Nine patients (5.6%) had macroscopic bleeding. There was no statistically significant difference in macroscopic bleeding between groups. CONCLUSIONS: Our results did not show any difference in the incidence of VAP, macroscopic stress ulcer bleeding, and mortality in the mechanically ventilated PICU patients treated with ranitidine, omeprazole, or sucralfate, or nontreated subjects. None of the treatment regimens increased VAP compared with the nontreated group. Because there is insufficient data about stress ulcer prophylaxis and VAP in the pediatric age group, more studies with larger numbers of patients are needed.