Seven-day treatment for Helicobacter pylori infection: ranitidine bismuth citrate plus clarithromycin and tetracycline hydrochloride

1. We have examined a series of novel phosphinic peptides as putative potent and selective inhibitors of endopeptidase 3.4.24.16. 2. The most selective inhibitor, Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 displayed a Ki value of 12 nM towards endopeptidase 3.4.24.16 and was 5540 fold less potent on its related peptidase endopeptidase 3.4.24.15. Furthermore, this inhibitor was 12.5 less potent on angiotensin-converting enzyme and was unable to block endopeptidase 3.4.24.11, aminopeptidases B and M, dipeptidylaminopeptidase IV and proline endopeptidase. 3. The effect of Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2, in vitro and in vivo, on neurotensin metabolism in the central nervous system was examined. 4. Pro-Phe-psi(PO2CHH2)-Leu-Pro-NH2 dose-dependently inhibited the formation of neurotensin 1-10 and concomittantly protected neurotensin from degradation by primary cultured neurones from mouse embryos. 5. Intracerebroventricular administration of Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 significantly potentiated the neurotensin-induced antinociception of mice in the hot plate test. 6. Altogether, our study has established Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 as a fully selective and highly potent inhibitor of endopeptidase 3.4.24.16 and demonstrates, for the first time, the contribution of this enzyme in the central metabolism of neurotensin.     

Helicobacter pylori infection and gastric secretion

We examined whether an immunosuppressant, FK506, inhibits delayed neuronal death in the gerbil hippocampal CA1 sector after 5-min forebrain ischemia. After reperfusion, gerbils were injected intravenously with FK506. Gerbils in the early injection group were injected with FK506 immediately after reperfusion, and gerbils in the delayed injection group were injected with FK506 1 or 2 h postischemia. The body temperature of the FK506-treated gerbils in the normothermic group was maintained at 37.5-38.0 degrees C for 2 h postischemia. In the chronic survival group, neuroprotection was assessed after recovery for 45 days. Seven or 45 days after reperfusion, neuronal density in the CA1 was assessed following perfusion fixation. FK506 ameliorated cell death in the CA1 in a dose-dependent manner in every group, although it showed a hypothermic effect. FK506 is neuroprotective against forebrain ischemia in gerbils.     

High Helicobacter pylori eradication rate with a 1-week regimen containing ranitidine bismuth citrate

HSR-903 is a newly synthesized quinolone antibacterial agent with low toxicity. The biliary and urinary excretion of unchanged HSR-903, its R-isomer, and their glucuronides was determined after iv bolus administration (5 mg/kg) to normal Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic mutant rats (EHBR). The values for the biliary excretion clearance of HSR-903 and its glucuronide in EHBR were decreased to approximately 40 and 2% of those in SDR, respectively, whereas the values for the urinary excretion clearance of HSR-903 and its glucuronide were comparable in SDR and EHBR. The biliary excretion clearance values for the R-isomer and its glucuronide were approximately 3 times greater than those for HSR-903. These results demonstrated that the enantiomers of HSR-903 and their conjugates were excreted into bile in a stereospecific manner. The hepatic uptake of [14C]HSR-903 in vivo was evaluated by means of integration plot analysis. The results indicated that the hepatic uptake of [14C]HSR-903 was very fast and was blood flow-limited. To clarify the mechanism of excretion of HSR-903 into bile, the uptake and efflux of [14C]HSR-903 were studied using isolated hepatocytes from SDR and EHBR. The initial uptake of HSR-903 by hepatocytes was temperature-dependent, saturable, and stereospecific. Unlabeled HSR-903 (S-isomer), the R-isomer, grepafloxacin, and sparfloxacin significantly inhibited the uptake of [14C]HSR-903. The efflux of [14C]HSR-903 from hepatocytes from EHBR was significantly slower than that from hepatocytes from SDR. The addition of sodium azide or bromosulfophthalein reduced the efflux of [14C]HSR-903. These results demonstrate that HSR-903 is actively excreted into bile via the canalicular multispecific organic anion transporter, which is deficient in EHBR.     

Helicobacter pylori infection, gastric acid secretion, and infant growth

BACKGROUND: Helicobacter pylori infection is very common in Gambian infants and children, who are also at risk of chronic diarrhoea and undernutrition. Acute H. pylori infection is associated with depressed gastric acid secretion, and loss of the gastric acid barrier may predispose to enteric infections. METHODS: In a prospective study a noninvasive test of gastric acid output (measurement of change in urine acid output before and after a feed) was performed on a population of Gambian infants at high risk of H. pylori infection. The 13C urea breath tests was used to measure the prevalence of H. pylori infection and growth was measured by serial anthropometry. RESULTS: In 101 infants aged 3 to 12 months, there was a significant relation between H. pylori infection and depressed urine acid output in those aged 6 months, during weaning when growth failure and malnutrition begin. Those infants with sustained H. pylori infection grew less well than those without. CONCLUSIONS: We speculate that H. pylori, acquired in infancy, could be a "key that opens the door" to enteric infection in childhood, leading to recurrent diarrhoea, malnutrition, and growth failure.     

Ranitidine bismuth citrate in the treatment of Helicobacter pylori infection and duodenal ulcer

STATEMENT OF PROBLEM: The existence of mandibular lateral translation and the approaches to its measurement and interpretation by using a pantograph are controversial. PURPOSE: This study evaluated the validity of using a pantograph to measure mandibular lateral translation and analyzed human pantographic tracings to determine whether they exhibited mandibular lateral translation. MATERIAL AND METHODS: A pantograph was modified by adding 2 posterior horizontal recording tables and styli at the transverse horizontal axis. Pantographic tracings of 25 human subjects were compared with the corresponding theoretically determined values for tracings that exhibited only rotation with no translation. Differences in the tracings at 2 pantographic recording table locations, relative to the transverse horizontal axis, were also compared. RESULTS: The character of the lateral component of 100 pantographic tracings all differed from the lateral component of theoretically determined values for pure rotation. In 64% of tracings, over 50% of the total mandibular lateral translation occurred by the first 1 mm of forward movement of the nonworking side condyle. In 94% of tracings, more than 50% of the translation had occurred in the first 3 mm of forward movement. For the pantographic system used, the amount of mandibular translation represented in the tracing was not changed by altering the posterior horizontal recording table position in the anterior-posterior direction, relative to the transverse horizontal axis. CONCLUSION: All subjects showed evidence of mandibular lateral translation. New definitions for timing of mandibular lateral translation are proposed. Of the tracings, 64% were classified as exhibiting early translation, 30% as intermediate, and 4% as late mandibular lateral translation.     

A new 1-week therapy for Helicobacter pylori eradication: ranitidine bismuth citrate plus two antibiotics

Glycosyl-trehaloses with an isomaltosyl residue were synthesized by alpha-glucosidase from Aspergillus niger by using maltotetraose as a glucosyl donor and trehalose as the acceptor. The one trisaccharide and two tetrasaccharides formed were isolated by successive column chromatography. The results of an enzymatic digestion, methylation analysis, and 13C-NMR studies indicated that these oligosaccharides were alpha-isomaltosyl alpha-glucoside, alpha-isomaltotriosyl alpha-glucoside and alpha-isomaltoside. These oligosaccharides were not fermented to an acid by Streptococcus mutans, and they effectively inhibited water-insoluble glucan synthesis from sucrose by glucosyltransferase. In an in vitro utilization test with human intestinal bacteria, these oligosaccharides were predominantly utilized by Bifidobacteria.     

Helicobacter pylori infection and chronic gastric acid hyposecretion

PURPOSE: To evaluate the effects of preirradiation chemotherapy on patterns of failure in children with medulloblastoma. METHODS AND MATERIALS: Fifty-three patients (pts) with medulloblastoma were given preirradiation chemotherapy as initial postoperative treatment at St. Jude Children's Research Hospital from November 1984 to September 1993. Patients < or = 3 years of age (n = 23) received chemotherapy (CH) with delayed craniospinal irradiation (CSI). Children > or = 3 years with more advanced disease (T3b-T4, M+ or measurable residual after resection) were given CH followed by CSI (30 patients). Chemotherapy regimen depended on protocol, but usually included cis- or carboplatin and etoposide, +/- cyclophosphamide and vincristine. RESULTS: Actuarial overall survival and event-free survival rates are 60% (95% confidence interval [41,79]) and 37% [19,55] at 5 years. Children < or = 3 at diagnosis: six of 23 pts completed CH without progression and received consolidative CSI; all six are alive with no evidence of disease (NED) at 2.4-9.1 years. Seventeen patients progressed during CH and were then given CSI. Sites of progression during CH were posterior fossa (PF) in 11 patients, neuraxis (NEUR) in 4, and PF+NEUR in 2. Following CSI, 7 patients are alive NED at 2.0-8.6 years; 10 patients died of progressive disease. Eleven patients had M0 disease at diagnosis; 8 (73%) progressed during CH, 3 in the neuraxis. Children > or = 3 at diagnosis: 20 of 30 patients completed pre-CSI CH without progression; 15 are alive NED at 1.3-9.2 years, and 5 showed post-CSI progression in the PF (n = 3), in the NEUR (n = 1) and in bone marrow (n = 1). Ten of the 30 (33%) patients progressed on CH (6 in NEUR, 4 in PF); 5 are alive and NED or with stable disease. Seventeen patients had M0 disease at diagnosis; 3 out of 17 (18%) progressed during CH, 2 in NEUR and 1 in an extraneural site. In the total group of 30 patients, 11 have had disease recurrence after completion of XRT. The actuarial rate of failure was 23 +/- 9% for the patients < or = 3 years of age and 21 +/- 8% for the older children when evaluated at 4 months after diagnosis (at the completion of chemotherapy in the older children but during the ongoing chemotherapy in the younger children). CONCLUSIONS: In patients presenting with M0 disease and receiving pre-CSI chemotherapy, the risk of neuraxis progression seems to increase with duration of chemotherapy. The sites of progression during preirradiation chemotherapy are nearly equally divided between posterior fossa and other neuraxis sites. CSI salvage of patients progressing on chemotherapy is possible in approximately 50% of patients. Following CSI, neuraxis progression is more frequent than posterior fossa relapse.     

Effects of cytokines, without and with Helicobacter pylori components, on mucus secretion by cultured gastric epithelial cells

Cytokines are suspected to play a crucial role in the pathogenesis of Helicobacter pylori-associated gastric diseases. Hence, considerable attention has been paid to the actions of cytokines on gastric cells. We examined the effects of cytokines on mucus secretion by gastric epithelial cells, without or with H. pylori components. Mucus secretion by cultured gastric epithelial cells was assessed as secretion of [3H]glucosamine-prelabeled high-molecular-weight glycoproteins. Interleukin (IL)-1beta and IL-6 significantly stimulated mucus secretion, but other cytokines such as IL-7, IL-8, IL-10, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha had no effect. H. pylori lysate caused a decrease in both basal and stimulated secretion of mucus. In addition, IFN-gamma significantly potentiated the lysate-induced reduction of basal and stimulated secretion. Cell viability was not affected by any of treatments. These results indicate that IL-1beta and IL-6 stimulate mucus secretion, while IFN-gamma potentiates H. pylori-decreased secretion by gastric epithelial cells.     

Duodenal ulcer, Helicobacter pylori, and gastric secretion

Patients with chronic dyspepsia were categorised by macroscopic appearance at oesophagogastroduodenoscopy as having duodenal ulceration (DU), other diagnosed lesions such as reflux oesophagitis, carcinoma of stomach, etc, or no organic lesion (non-ulcer dyspepsia, NUD). Material was collected to identify gastric infection with Helicobacter pylori (H pylori) by CP urease test, culture, and histological examination and to make the microscopic diagnosis of active chronic gastritis. Each patient in the DU and NUD categories was then invited to volunteer for a gastric secretion study in which maximal gastric secretion in response to histamine was measured. Sixty two gastric secretion tests were performed (31 DU, 31 NUD). The presence of H pylori was associated with active chronic gastritis (100%). DU patients secreted more acid than the NUD patients. H pylori positivity was associated with decreased maximal gastric secretion in both groups. There was a positive correlation between smoking and maximal acid output shown only in H pylori negative but not in H pylori positive patients. These findings were clear cut when all corrections of maximal gastric secretion were made for pyloric loss, duodenogastric reflux, and stature. This study failed to show any aetiological link between H pylori and DU by increased maximal gastric secretion.     

The effect of atropine on insulin stimulated gastric secretion and gastrin release

A 28-years-old patient with a palpable mass of two fist's size in the upper abdomen rapidly developed an obstructive jaundice. A pancreatic tumor was suspected and therefore ERCP was carried out. Unusual alterations caused by metastatic lesions of a post mortem diagnosed testicular teratoma narrowing and invading the common bile duct and displacing the main pancreatic duct were visualized.     

One-week use of ranitidine bismuth citrate, amoxycillin and clarithromycin for the treatment of Helicobacter pylori-related duodenal ulcer

BACKGROUND: Proton pump inhibitors have been widely used in combination with amoxycillin, clarithromycin or metronidazole for the treatment of Helicobacter pylori infection. AIM: To study the effects of 1-week ranitidine bismuth citrate (RBC)-based triple therapy in the treatment of H. pylori-related duodenal ulcers. METHOD: Patients with duodenal ulcers and H. pylori infection were prospectively randomized to receive either RBC with amoxycillin and clarithromycin for 1 week (RAC), or omeprazole with amoxycillin and clarithromycin for 1 week (OAC). No additional ulcer healing drug was used after the 1-week medication. Patients were assessed for H. pylori eradication, ulcer healing and side-effects after receiving the therapies. RESULTS: One hundred consecutive patients were recruited to this study, with 50 patients randomized to each treatment group. In the intention-to-treat analysis, duodenal ulcers were completely healed in 45 (90%) patients in the RAC group and 43 (89.6%) in the OAC group (P = 1.0). H. pylori eradication was confirmed in 47 (94%) in the RAC group and 42 (87.5%) in the OAC group (P = 0.31). There was no significant difference in the severity of side-effects experienced by the two treatment groups. CONCLUSION: One-week RBC-based triple therapy is an effective treatment for H. pylori-related duodenal ulcers. The therapeutic effects are comparable to a 1-week course of proton pump inhibitor-based triple therapy.     

Helicobacter pylori infection induces gastric cancer in mongolian gerbils

BACKGROUND & AIMS: Although epidemiological studies have indicated that Helicobacter pylori infection plays a crucial role in gastric carcinogenesis in humans, there is no direct proof that H. pylori is actually associated with gastric carcinogenesis. The purpose of this study was to elucidate the relationship between H. pylori infection and gastric carcinogenesis using an animal model of long-term H. pylori infection. METHODS: Mongolian gerbils were orally inoculated with H. pylori, and the sequential morphological changes in the stomach were examined for up to 62 weeks. RESULTS: H. pylori was constantly detected in all infected animals throughout the study. At the 26th week, severe active chronic gastritis, ulcers, and intestinal metaplasia could be observed in infected animals. By the end of the study, adenocarcinoma had developed in the pyloric region of 37% of the infected animals. All tumors consisted of well-differentiated intestinal-type epithelium, and their development seemed to be closely related to intestinal metaplasia. CONCLUSIONS: We have successfully demonstrated that long-term infection with H. pylori induces adenocarcinoma in Mongolian gerbils. The observations are thus highly suggestive of the involvement of H. pylori infection in gastric carcinogenesis in humans.     

Helicobacter pylori infection and gastric mucosa-associated lymphoid tissue hyperplasia

The association of Helicobacter pylori (Hp) infection with mucosa-associated lymphoid tissue (MALT) hyperplasia in gastric mucosa was investigated. The results showed that the incidence of Hp infection increased as the degree of the mucosal injury was aggravated, but the prevalence of lymphoid follicles in the mucosa with atrophic antritis was much more than in the mucosa without the atrophic and the frequency of detecting Hp and intestinal metaplasia in the mucosa with lymphoid follicles significantly increased, as compared with the mucosa without it. These findings suggest that gastric MALT hyperplasia induced by Hp infection may lead to destruction of gastric glands through hypersensitivity.     

High concentrations of ammonia, but not volatile amines, in gastric juice of subjects with Helicobacter pylori infection

A variety of external stimuli are accepted as important in modifying the severity of psoriasis. We sought to determine whether there is any difference in the influence of external factors on psoriasis in relation to extent of involvement or clinical type. A total of 870 psoriasis patients seen between 1982 and 1995 were categorized as mild, moderate, or severe on the basis of extent of the disease, and as guttate, nummular/plaque, or exfoliative/generalized pustular according to clinical type. We then performed a questionnaire survey concerning the influence of external factors such as seasonal changes, sunlight, stress, and pregnancy. These data sets were combined and analysed. The majority of patients stated favorable effects of summer, sunlight, and pregnancy and adverse effects of winter and stress. A statistically significant correlation was noted between the extent of psoriasis and the proportion of patients stating that their disease worsened at times of psychological stress (p < 0.01). We confirmed that psoriasis patients with more extensive involvement experience greater fluctuations in their condition, notice these changes, and therefore relate them to psychological stress.     

Ranitidine bismuth citrate plus clarithromycin 7-day regimen is effective in eradicating Helicobacter pylori in patients with duodenal ulcer

AIMS: Application of single methods to assess liver blood flow (LBF) yielded conflicting results on the magnitude and duration of effect on LBF of oral nifedipine and captopril. The aim of this study was to investigate the influence of these drugs on LBF by simultaneous use of ICG infusion and echo-Doppler. METHODS: The study was performed according to a double-blind, placebo-controlled, randomized, cross-over design in nine healthy male volunteers. After an overnight fast and an equilibration period, subjects received a continuous i.v. indocyanine green (ICG) infusion for 4 h. At presumed ICG steady state (t=45 min), subjects were dosed with oral nifedipine (20 mg), captopril (50 mg) or placebo. During the experiment, blood sampling for ICG assay and measurement of portal venous blood flow (echo-Doppler) took place regularly. Treatments were compared using analysis of variance. Differences are reported with 95% confidence intervals (CI). RESULTS: The area under the curves (AUC) for ICG over 1 h and over 3 h after nifedipine were 15% (difference in AUC: + 0.6, + 7.0 mg l(-1) min) and 22% (+ 7.0, + 28.4 mg l(-1) min) lower compared with placebo. After captopril, the AUC values were 8-10% lower compared with placebo but the 95% CIs included zero. Portal venous flow was 15% (+ 5, + 86 ml min(-1)) higher compared to placebo after nifedipine but not after captopril (-3%; -49, +33 ml min(-1)). The duration of effect on liver blood flow lasted approximately 2 h but was variable (range: 40-160 min). The time to maximal blood flow increase and the duration of effect after nifedipine were very similar for both measures of LBF. Changes in ICG concentrations could be reasonably well predicted from the changes in portal blood flow. CONCLUSIONS: Nifedipine increases LBF for a substantial period of time but the effect is variable between subjects. This effect could be detected by both the ICG method and echo-Doppler and the findings of both methods were in agreement. In this respect it is likely that captopril does not influence LBF in healthy volunteers as no effect was detected with either method.     

Circadian gastric acidity in Helicobacter pylori positive ulcer patients with and without gastric metaplasia in the duodenum

BACKGROUND: The presence of gastric metaplasia allows helicobacter pylori to colonise the duodenum and this condition is thought to be acquired as a response to acid hypersecretion. This functional disorder, however, is present only in a subgroup of duodenal ulcer patients and, in addition, surface gastric metaplasia has been frequently found in the proximal duodenum of normal subjects and patients with non-ulcer dyspepsia, who cannot be certainly considered as acid hypersecretors. AIMS: To clarify the role of acid in inducing gastric type epithelium in the duodenum. This study aimed at assessing whether the pattern of circadian gastric acidity differs between H pylori positive duodenal ulcer patients with and without duodenal gastric metaplasia. PATIENTS: Seventy one patients with duodenal ulcer confirmed by endoscopy and who were found to be positive for H pylori infection by histology on antrum biopsy specimens were enrolled into this study. METHODS: Gastric type epithelium in the duodenum was found in 49 of 71 ulcer patients (69%). Continuous 24 hour gastric pH metry was performed in 50 healthy subjects and in the two subgroups of duodenal ulcer patients with and without gastric metaplasia in the duodenum. Gastric acidity was calculated for 24 hours (1700-1659), night (2000-0759) and day-time (0800-1959). RESULTS: Ulcer patients without gastric metaplasia showed a significantly higher gastric acidity (p < 0.001) than controls for every time interval considered, while the ulcer subgroup with gastric metaplasia was more acid than healthy subjects (p < 0.001) during the whole 24 hour period and the daytime. There was no difference between the two subgroups of duodenal ulcer patients with and without gastric metaplasia during the various time segments analysed. CONCLUSION: The findings confirm that the circadian gastric acidity of duodenal ulcer patients is higher than that of controls. As there is no difference in gastric pH between duodenal ulcer patients with and without gastric metaplasia, gastric hyperacidity is not specific to patients with duodenal gastric metaplasia. It is probable that this histological change is a non-specific response to mucosal injury resulting from various factors and not exclusively to acid.