Prucalopride induces high-amplitude propagating contractions in the colon of patients with chronic constipation: a randomized study.

BACKGROUND: This study compared prucalopride, a selective, prokinetic, 5-HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high-amplitude propagating contractions (HAPCs) in patients with chronic constipation. METHODS: This randomized, cross-over, reader-blinded study was conducted at a single site in the USA. The study was open to men and women aged 18-75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1 ]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2 ); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3 ). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity. KEY RESULTS: Thirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12-h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2 ) and mean AUC, force, and amplitude (HAPC3 ) compared with PEG3350. Adverse events were mild or moderate. CONCLUSIONS & INFERENCES: Prucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation. ClinicalTrials.gov number NCT01707667.

Helicobacter pylori-antigen-binding fragments expressed on the filamentous M13 phage prevent bacterial growth.

Colonization of the human stomach by Helicobacter pylori is associated with the development of gastritis, duodenal ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. H. pylori-antigen-binding single-chain variable fragments (ScFv) were derived from murine hybridomas producing monoclonal antibodies and expressed as a g3p-fusion protein on a filamentous M13 phage. The recombinant ScFv-phage reacted specifically with a 30-kDa monomeric protein of a H. pylori surface antigen preparation and by means of immunofluorescence microscopy the phage was shown to bind to both the spiral and coccoid forms of the bacterium. In vitro, the recombinant phage exhibited a bacteriocidal effect and inhibited specifically the growth of all the six strains of H. pylori tested. When H. pylori was pretreated with the phage 10 min before oral inoculation of mice, the colonization of the mouse stomachs by the bacterium was significantly reduced (P<0.01). The results suggest that genetic engineering may be used to generate therapy-effective phages.

Structure-activity relationship of 2-[[(2-pyridyl)methyl]thio]-1H- benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy.

A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 microg/mL. The structure-activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]-3-methyl-2-pyridyl)methyl]thio]-1H-be nzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felismodel (125 micromol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to the corresponding methyl sulfinyl derivative, i.e., a proton pump inhibitor, in vivo. Although the antibacterial activity had the potential of decreasing H. felis cell counts in vivo the proton pump inhibitory effect became dominant and actually promoted H. felis cell growth. Hence, we conclude that the antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.

A rat model of chronic Helicobacter pylori infection. Studies of epithelial cell turnover and gastric ulcer healing.

BACKGROUND: Our aim was to infect rats with Helicobacter pylori and to study the effects of the infection on the gastric mucosa in normal and in ulcer-operated rats. METHODS: A mouse-adapted H. pylori (cagA-, VacA-) strain was inoculated into 23 rats. Another 20 uninfected rats served as controls. Two months later a gastric ulcer was induced in some rats. The animals were killed 3, 6, or 15 days after the ulcer operation. Tissues were taken for histology and for culture of H. pylori. Serum antibodies were determined. RESULTS: All inoculated rats were infected by H. pylori after 2 months, mainly in the antrum. In these rats a mild to moderate chronic inflammation and a significantly increased frequency of apoptotic cells were observed in the antrum and in the ulcer margin, the ulcer healing was delayed, and the serum level of H. pylori-specific Ig was increased. CONCLUSIONS: H. pylori infection in rats was successful and was accompanied by a mild to moderate mucosal inflammation. Gastric ulcer healing was delayed in infected rats, probably due to the inflammation and the increased apoptosis in epithelium.

Inoculation of VacA- and CagA- Helicobacter pylori delays gastric ulcer healing in the rat.

BACKGROUND: Helicobacter pylori is associated with peptic ulcer disease. In the present study, the influence of VacA and CagA- H. pylori on gastric ulcer healing was studied in the rat. METHODS: Twenty-four rats with acetic-acid-induced gastric ulcer were divided into two groups and given either vehicle (Brucella broth) or H. pylori suspension by gavage every 12 h for 7 days. The animals were killed 1 and 8 days after the last H. pylori gavage (i.e. 10 and 17 days after the induction of the ulcer). One hour before death, 3H-thymidine was given intraperitoneally. Tissue samples from the stomach (including the ulcer area) and the duodenum were processed for determination of labelling index and apoptotic cells. RESULTS: Compared with the vehicle-treated controls, the ulcer area in H. pylori-inoculated rats was significantly larger, the epithelial apoptotic cells in the ulcer margin and intact corpus were more numerous, while the cell proliferation of gastroduodenal epithelium was slightly, but not significantly, increased by H. pylori gavage. CONCLUSION: Gastric ulcer healing was delayed after the inoculation of VacA- and CagA- H. pylori in the rat, possibly as a result of excess cell loss by apoptosis.

Local acid production and Helicobacter pylori: a unifying hypothesis of gastroduodenal disease.

We aimed to produce a unifying hypothesis to explain the different locations of peptic ulcer and gastritis observed in different populations. The pre-Helicobacter pylori literature on patterns of gastroduodenal disease was reviewed and compared with recent human and animal findings on H. pylori infection. Early observations revealed that duodenal and non-pre-pyloric ulcers tend to be mutually exclusive. In duodenal ulcer patients, gastritis is usually restricted to the antrum, while gastric ulcer patients experience more severe pangastritis. The manipulation of acid output by surgery or acid suppressive therapy alters the distribution of gastritis. Recent experimental evidence in humans and animals has shown that these changes parallel changes in the distribution and cellular responses to H. pylori infection. We propose that the most important factor in the ecology of the H. pylori-infected stomach is local acid production. Local acid production determines the location and severity of inflammation and the clinical outcome of this bacterial infection. Priority research areas should be the investigation of the in vivo behaviour of H. pylori in the acid and the non-acid producing areas of the stomach and the measurement of acid output in populations known to have different patterns of gastroduodenal disease.