Influence of simethicone and alverine on stress-induced alterations of colonic permeability and sensitivity in rats: beneficial effect of their association.

OBJECTIVES: Alverine, an antispasmodic agent for the treatment of irritable bowel syndrome (IBS), may be combined with simethicone, a protective agent of the mucosa. Stress is a major factor triggering abdominal pain in IBS and causing hypersensitivity to colonic distension in animals through an increased colonic permeability. The antinociceptive effects of alverine and simethicone, separately or in association, were evaluated on stress-induced colonic hypersensitivity to distension in rats. The influence of simethicone on altered permeability was also tested. METHODS: Groups of 8-10 female adult Wistar rats (200-250 g) housed individually were used. Gut paracellular permeability was evaluated after 2 h of partial restraint stress using oral gavage with 5¹Cr-EDTA and 24 h of urine collection. The number of abdominal cramps during colonic distension was evaluated in animals equipped with electrodes on their abdominal striated muscles. KEY FINDINGS: At 200 mg/kg p.o. twice a day, but not at lower doses, simethicone reduced stress-induced increase of colonic permeability and hypersensitivity to distension. Administered alone at 10 mg/kg p.o., alverine also reduced stress-induced hypersensitivity to distension; lower doses were inactive. However, alverine administered at an inactive dose with simethicone suppressed stress-induced hypersensitivity to distension. CONCLUSIONS: We conclude that both simethicone and alverine have visceral antinociceptive effects by two different mechanisms and that simethicone exerts a potentiating effect on the antinociceptive action of alverine.

Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action.

Chronic cholestasis and liver inflammation are the two main pathophysiological components of the two major classes of disease - primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) - leading to bile duct destruction and ultimately to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA), initially introduced as a therapeutic approach to counteract the cholestatic components to PBC and PSC, was subsequently shown to exhibit unexpected anti-inflammatory and immunomodulatoty properties. The use of farnesoid X receptor (FXR) and TGR5 agonists in various animal models have confirmed early observations indicating that bile acids are not only toxicants and inflammagens, but also repressors of innate and adaptive immunity. Obeticholic acid is a bile-acid mimetic, with no toxic or inflammagen behavior, that strongly activates FXR to combat the toxic effects of high concentrations of bile acid. Because UDCA is not an FXR agonist, its combination with obeticholic acid could be a promising tool for the treatment of PBC and PSC. In this overview, the biological properties of UDCA, NorUDCA and FXR agonists are highlighted, as well as their overlapping mechanisms of action in inflammatory biliary disorders.

Clinical application of ghrelin.

Ghrelin as a human natural hormone is involved in fundamental regulatory processes of eating and energy balance. Ghrelin signals the nutrient availability from the gastrointestinal tract to the central nervous system, up-regulates food intake and lowers energy expenditure mainly through hypothalamic mediators acting both centrally and peripherally including the gastrointestinal tract (motility, epithelium), promotes both neuro-endocrine and inflammatory signals to increase skeletal muscle growth and decrease protein breakdown, and increases lipolysis while body fat utilization is reduced. Ghrelin does more to exert its probably sentinel role around "human energy": it influences through mainly extra-hypothalamic actions the hedonic and incentive value of food, mood and anxiety, sleep-wake regulation, learning and memory, and neurogenesis. Recently numerous ghrelin gene-derived peptides were discovered, demonstrating the complexity within the ghrelin/ghrelin receptor axis. For clinical applications, not only the natural ghrelin and its slice variants, but also several modified or artificial molecules acting at ghrelin-associated receptors were and are developed. Current clinical applications are limited to clinical studies, focusing mainly on cachexia in chronic heart failure, COPD, cancer, endstage- renal-disease or cystic fibrosis, but also on frailty in elderly, gastrointestinal motility (e.g., gastroparesis, functional dyspepsia, postoperative ileus), after curative gastrectomy, anorexia nervosa, growth hormone deficient patients, alcohol craving, sleep-wake regulation (e.g. major depression), or sympathetic nervous activity in obesity. The results of completed, preliminary studies support the clinical potential of ghrelin, ghrelin gene-derived peptides, and artificial analogues, suggesting that larger clinical trials are demanded to move ghrelin towards an available and reimbursed pharmaceutical intervention.

Dopamine D2-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration in mice by activating α7 nicotinic acetylcholine receptors.

We have reported that nicotine and the specific α7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating α7 nicotinic acetylcholine receptors (α7nAChR). Dopamine D2-receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the α7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1-10 mg/kg) and metoclopramide (0.03-0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1-3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D2-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by α7nAChR.