Modulation of gastrointestinal function by MuDelta,a mixed μ opioid receptor agonist/ μ opioid receptor antagonist

BACKGROUND & PURPOSE

Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation.

EXPERIMENTAL APPROACH

MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified.

KEY RESULTS

δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model.

CONCLUSIONS AND IMPLICATIONS

MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.     

Development and implementation of a lifestyle intervention to promote physical activity and healthy diet in the Dutch general practice setting: the BeweegKuur programme

Background  

The number of patients with diabetes is increasing. BeweegKuur (Dutch for 'Exercise Therapy') is a Dutch lifestyle intervention which aims to effectively and feasibly promote physical activity and better dietary behaviour in primary health care to prevent diabetes.     

Adolescent Internet use and its relationship to cigarette smoking and alcohol use: A prospective cohort study

The present study aims to investigate the longitudinal impact of situational Internet use on future cigarette smoking and alcohol use among male and female adolescents. A Northern Taiwanese cohort sample of adolescents with no prior use of cigarettes (n = 1445) or alcohol (n = 1468) was surveyed at age 16 and again 4 years later. Information regarding where, why, and length of time spent using the Internet was gathered from the 16-year-old participants. Outcome information regarding cigarette/alcohol use was gathered via a follow-up questionnaire at age 20. Multivariate regressions were used to incorporate peer, individual and family characteristics as measured at age 16 and create models of future cigarette and alcohol use at age 20. The analyses demonstrated that adolescent Internet use, particularly where such use took place, has a significant impact on future cigarette smoking and alcohol use, adjusted for conventional factors, and its relationship differs significantly by gender. Female adolescents with Internet café use appear to be especially likely to develop these two risky behaviors. The why of Internet use is also a predictor of future cigarette smoking. Finally, time spent using the Internet is significantly related to alcohol use; greater use of the Internet is associated with higher levels of drinking. The results revealed that different risky behaviors are differentially influenced by separate components of adolescent Internet use. These findings suggest that programs aimed at promoting adolescent health could potentially benefit Taiwanese adolescents by including components related to situational Internet use and taking gender into consideration.     

Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer

Summary This phase II trial was initiated to assess the efficacy and safety of oral vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Eligible patients must have recurrent and/or metastatic head and neck cancer unresponsive to or intolerant of conventional chemotherapy. Patients must have measurable disease, adequate hematologic, hepatic, and renal function, and be able to swallow capsules. Four or more weeks must have elapsed since prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy, and patients must have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Thirteen patients were enrolled (9 males); 1 withdrew consent prior to starting therapy. Twelve patients received oral vorinostat 400 mg once daily and were evaluable for response. The median age was 54 years (range 40–82). All patients had received prior chemotherapy (including 10 with platinum- or taxane-based combination therapy), and 9 had prior radiation therapy. No confirmed partial or complete responses were observed. One unconfirmed partial response was seen. Three patients had stable disease ranging from 9 to 26 weeks. Nine patients discontinued due to progressive disease, two withdrew consent, and one discontinued therapy for grade 3 anorexia. Grades 3–4 drug-related toxicities included thrombocytopenia (n = 3), anorexia (n = 2), and dehydration (n = 2). Oral vorinostat 400 mg qd was generally well tolerated but did not demonstrate efficacy as defined by tumor response in this small group of heavily pre-treated patients. Presented in part as a poster at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5–8, 2004. This research has not been published elsewhere and has not been submitted simultaneously for publication elsewhere.     

Community Effects on Pregnancy Intention Among Cohabiting Women in The Philippines: Implications for Maternal and Child Health

Unintended pregnancy impacts both maternal and child health. International studies continue to emphasize the importance of reproductive health in the context of community. Only a few researchers have explored the impact of community factors on pregnancy intention using population-based surveys. This issue is of particular importance for women of low socioeconomic status in developing countries, where unintended fertility rates remain relatively high. Using the 1998 (n = 6,849) and 2003 (n = 6,773) Demographic and Health Surveys in the Philippines, we employed multilevel logistic models to explore whether community factors are associated with pregnancy intention among these women. The results showed community social capital, comprised of community-related variables, significantly predicted women's pregnancy intention, even after controlling for women's socioeconomic status, individual background factors, and spousal characteristics. The relationship between pregnancy intention and selected variables associated with community social capital, however, was not consistent across the two surveys. Community context, in general, has a significant influence on women's pregnancy intention. Specific components of the community context vary in their associations with pregnancy intention over time. In addition, differences in pregnancy intention may explain individual-level social disparities between communities. These findings suggest population health policies designed to promote maternal and child health must be context-specific.     

Diosgenin induces hypoxia-inducible factor-1 activation and angiogenesis through estrogen receptor-related phosphatidylinositol 3-kinase/Akt and p38 mitogen-activated protein kinase pathways in osteoblasts

Diosgenin, extracted from the root of wild yam (Dioscorea villosa), has been reported to demonstrate an opportunity for medical application. Vascular endothelial growth factor-A (VEGF-A) plays an important role in bone-related angiogenesis, a critical process occurring during bone formation and fracture healing. In this study, we examine whether diosgenin is able to induce VEGF-A expression and to promote angiogenesis in osteoblasts. For murine MC3T3-E1 preosteoblast-like cells, VEGF-A mRNA and protein expression seemed to be significantly elevated in response to diosgenin in a concentration-dependent fashion. Conditioned media prepared from cells treated with diosgenin induced strong angiogenic activity in either in vitro or ex vivo angiogenesis assay. Furthermore, diosgenin treatment increased the stability and activity of HIF-1alpha protein. Inhibition of HIF-1alpha activity by transfection with DN-HIF-1alpha significantly diminished diosgenin-mediated VEGF-A up-regulation. The use of pharmacological inhibitors or genetic inhibition revealed that both the phosphatidylinositol 3-kinase (PI3K)/Akt and p38 signaling pathways were potentially required for diosgenin-induced HIF-1 activation and subsequent VEGF-A up-regulation. It is noteworthy that an estrogen receptor binding assay revealed that diosgenin has the strong ability to replace [(3)H]estradiol bound to estrogen receptor (IC(50), 10 nM). In addition, the specific estrogen receptor antagonists ICI 182,780 (faslodex) and tamoxifen were noted to be able to strongly inhibit diosgenin-induced, src kinase-dependent Akt and p38 MAPK activation. Taken together, such results provide evidence that diosgenin up-regulates VEGF-A and promotes angiogenesis in preosteoblast-like cells by a hypoxia-inducible factor-1alpha-dependent mechanism involving the activation of src kinase, p38 MAPK, and Akt signaling pathways via estrogen receptor.     

To what extent does IQ 'explain' socio-economic variations in function?

Background  

The aims of this study were to examine the extent to which higher intellectual abilities protect higher socio-economic groups from functional decline and to examine whether the contribution of intellectual abilities is independent of childhood deprivation and low birth weight and other socio-economic and developmental factors in early life.     

Efficacy and tolerability of pantoprazole 40 mg versus 80 mg in patients with reflux oesophagitis.

BACKGROUND: Pantoprazole is a substituted benzimidazole which is a potent inhibitor of gastric acid secretion by its action upon H+, K+- ATPase. METHODS: Pantoprazole 40 mg and 80 mg were compared in a randomized double-blind study in 192 out-patients with stage II or III (Savary-Miller classification) reflux oesophagitis. Patients received either pantoprazole 40 mg (n = 97) or pantoprazole 80 mg (n = 95), once daily before breakfast for 4 weeks. Treatment was extended for a further 4 weeks if the oesophagitis had not healed. RESULTS: After 4 weeks complete healing of the reflux oesophagitis was seen in 78% of protocol-correct patients given pantoprazole 40 mg daily (n = 86), and in 72% in the 80 mg (n = 87) group. The cumulative healing rates after 8 weeks were 95 and 94%, respectively (P > 0.05, Cochran-Mantel- Haenszel), and time until healing of oesophagitis comparable in both groups. Differences between doses were also not significant in an intention-to-treat analysis. Both dosing schedules were well tolerated and the patients experienced remarkable symptom relief. No adverse event or changes in laboratory values of clinical significance could definitely be ascribed to the trial medication. CONCLUSION: The 40 mg pantoprazole dosage is comparable to 80 mg in reflux oesophagitis, both in efficacy and tolerability.     

Radiological assessment of dysphagia with endoscopic correlation

Four hundred fifty consecutive patients with dysphagia were evaluated radiologically over a 14-month period; 127 of these (28.2%) were also examined endoscopically. The most common abnormality seen was dysmotility (34%), followed by hiatal hernia, benign stricture, and esophagitis. Correlation with endoscopy was generally good. Radiologic study demonstrated all cases of esophageal malignancy; radiologic/endoscopic correlation was also strong in patients with moderate or severe esophagitis, though the radiologist had some difficulty detecting mild inflammation. Endoscopy failed to demonstrate some benign strictures. Radiologic study was relatively accurate in detecting significant organic disease; most motility disorders were not detected by endoscopy. For these reasons, as well as lower cost, increased convenience, and patient comfort, radiologic assessment is recommended as the primary method of evaluating patients with dysphagia.