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.     

Gastric motor effects of endothelins in the lower brainstem of the rat

To characterize the modulatory effect of endothelin on brainstem control of gastric motor function, endothelin-1 (ET-1) and endothelin-3 (ET-3) were applied to the surface of the dorsal medulla oblongata in α-chloralose and xylazine anaesthetized, artificially ventilated Sprague-Dawley rats, while intragastric pressure and contractility of the pyloric circular and greater curvature longitudinal muscles as well as blood pressure were monitored. Endothelin-1 and ET-3 equipotently (at the same range of doses) increased intragastric pressure and stimulated contractility of the gastric circular muscle as well as increasing arterial blood pressure. All the gastric effects of endothelins were abolished by bilateral vagotomy at the midcervical level. These results demonstrate that endothelins have vagally mediated gastrointestinal effects in the lower brainstem of the rat and support a role for endothelins in gastrointestinal regulation. This paper was presented at the Section of IUPHAR GI Pharmacology Symposium on ‘Biochemical pharmacology as an approach to gastrointestinal disorders (basic science to clinical perspectives)’, October 12–14, 1995, Pécs, Hungary.     

A development framework for promoting evidence-based policy action: drawing on experiences in Sri Lanka

Most developing countries have embarked on one form or another of 'health sector reform' as a result of the global trend for health and health care reform that has emerged during the past decade. One consequence is that the issue of health sector performance is moving higher on the agenda of many developing countries, and particularly that of the corporate performance of health sector staff. Along with this movement has come increased attention to strengthening evidence-based management decision-making. To date, studies on measuring health sector performance, have had little impact on developing country health systems and have been limited to explorations primarily at an operational level. However, there is a growing recognition that there is a need to strengthen the policy function of ministries and their ability to monitor policy impact. Sri Lanka is one country that has identified the need to strengthen policy at national level. Many developing countries, like Sri Lanka, are familiar with input, process and output dimensions of operational performance. However, most are not ready to engage in routine performance assessment that can strengthen policy processes at national level. This paper explores (1) the implication and the use of indicators to support evidence based policy decision-making, and (2) the complexity of doing so in Ministries of Health that are undergoing some form of health sector reform. The paper emphasizes that new forms of organizational support are required for performance management at policy level. A conceptual framework for managing the collection and use of performance evidence is developed, including proposals for the introduction of outcome indicators into that process. The paper concludes with recommendations on initiatives required to develop appropriate organizational and technical capacity to engage with performance management at policy level and for further research towards creating ministries of health as 'learning organizations' that can change and adapt with informed decisions.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Localization of immunoreactive tyrosine hydroxylase in the goldfish brain

This report describes the distribution of tyrosine hydroxylase immunoreactive (TH-ir) structures in the brain of the goldfish (Carassius auratus). The localization of TH-ir cell groups revealed by immunocytochemical techniques is largely in accordance with catecholamine distribution previously reported in teleosts by using monoamine fluorescence; however, in the telencephalon and diencephalon, several new cell groups are elucidated. In the telencephalon, TH-ir cell bodies are observed in the olfactory bulb, area ventralis telencephali, and the central zone of the area dorsalis telencephali. TH-ir fibers and terminals are moderately dense throughout the telencephalon except for a sparse innervation of the area dorsalis, pars medialis. Immunostained cells are present in the suprachiasmatic nucleus and magnocellular and parvicellular components of the preoptic nucleus. Immunoreactive fibers from preoptic cells can be traced caudally in two main tracts to the infundibulum. Dense immunoreactivity around cells in the pituitary provides anatomical support for catecholamine involvement in the neuroendocrine axis probably via preopticohypophysial connections. At middiencephalic levels, immunoreactive cells are present in the ventral thalamus, nucleus pretectalis periventricularis, pars ventralis, and paraventricular organ pars anterioris. In the caudal diencephalon, TH-ir cells are seen within the posterior tuberal nuclei and dorsal to posterior recess. No immunostained cells are observed in the midbrain. In the hindbrain, tyrosine hydroxylase containing cells comprise three groups similar to that described using Falck-Hillarp histofluorescence (Parent et al., '78), i.e., isthmal, central medullary, and medullospinal groups. Tyrosine hydroxylase immunoreactivity is interpreted as evidence for the presence of catecholamines and not only provides an anatomical basis for the functional significance of catecholamines in teleosts, but may be useful in elucidating homologous structures in tetrapod vertebrates, although certain sites of immunoreactivity may prove to be unique to teleosts.     

CAPTOPRIL AND HYDROCHLOROTHIAZIDE—A SAFE ANTIHYPERTENSIVE FOR USE IN GENERAL PRACTICE?

The combination of captopril and hydrochlorthiazide was assessed in 15 hypertensive patients in a general practice setting. The first aim was to determine whether the fall in blood pressure, noted after the first dose of an ACE inhibitor given alone, became unacceptable when the drug was given with a diuretic. The second aim was to assess the impact of the ACE inhibitor on the biochemical abnormalities associated with thiazide diuretic therapy. The drug combination markedly reduced blood pressure but not below 110 systolic after the first dose. In the long-term the treatment significantly lowered blood pressure but did not produce any significant or clinically relevant changes in serum chemistry.