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.     

The development of instruments to measure the work disability assessment behaviour of insurance physicians

Background  

Variation in assessments is a universal given, and work disability assessments by insurance physicians are no exception. Little is known about the considerations and views of insurance physicians that may partly explain such variation. On the basis of the Attitude - Social norm - self Efficacy (ASE) model, we have developed measurement instruments for assessment behaviour and its determinants.     

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.     

Early recognition of heart failure in patients with diabetes type 2 in primary care. A prospective diagnostic efficiency study. (UHFO-DM2)

Background  

We hypothesize that the prevalence of unknown heart failure in diabetic patients aged 60 years and over is relatively high (15% or more) and that a cost-effective strategy can be developed to detect heart failure in these patients. The strategy is expected to include some signs and symptoms (such as dyspnoea, orthopnoea, pulmonary crepitations and laterally displaced apical beat), natriuretic peptide measurements (Amino-terminal B-type natriuretic peptide) and possibly electrocardiography. In a subset of patients straightforward echocardiography may show to be cost-effective. With information from our study the detection of previously unknown heart failure in diabetic patients could be improved and enable the physician to initiate beneficial morbidity and mortality reducing heart failure treatment more timely.     

Kr-81m ventilation imaging: clinical utility in suspected pulmonary embolism

The results of Kr-81m/Tc-99m ventilation-perfusion (VP) lung scintigraphy were correlated with the results of pulmonary angiography for 74 patients suspected of having pulmonary embolism (PE). Among patients having a diagnostic scan, the sensitivity and specificity of scintigraphy were 91% and 94%, respectively. Also, 157 consecutive cases of Kr-81m/Tc-99m VP lung scintigraphy were reviewed, and the frequency of an indeterminate scan was found to be 22%. A similar frequency was found for VP scintigraphy with xenon-133. Of eight patients who had indeterminate scans due to the presence of a single VP mismatch, four were demonstrated to have PE by angiography. Kr-81m is an excellent agent for VP scanning in cases of suspected PE, offering accuracy in diagnosis as well as favorable physical properties.     

Trials which randomize practices II: sample size

BACKGROUND: When practices are randomized in a trial and observations are made on the patients to assess the relative effectiveness of the different interventions, sample size calculations need to estimate the number of practices required, not just the total number of patients. OBJECTIVE: Our aims were to introduce the methodology for appropriate sample size calculation and discuss the implications for power. METHOD: A worked example from general practice is used. DISCUSSION: Designs which randomize practices are less powerful than designs which randomize patients to intervention groups, particularly where a large number of patients is recruited from each practice. Studies which randomize few practices should be avoided if possible, as the loss of power is considerable and simple randomization may not ensure comparability of intervention groups.