Pharmacology and physiology of gastrointestinal enteroendocrine cells.

Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.

Microvascular free tissue transfer in the management of squamous cell carcinoma of the tongue during pregnancy.

We describe a 36-year-old patient with a stage III carcinoma (pT2N1M0) of the tongue that presented in the second trimester of pregnancy. It was treated by primary excision and reconstruction with a free flap. To our knowledge this is the first reported case of successful microvascular free tissue transfer for oral cancer during pregnancy.

Molecular field analysis of clozapine analogs in the development of a pharmacophore model of antipsychotic drug action.

In an attempt to elucidate some aspects of clozapine's favorable receptor binding profile, we modeled a series of 30 clozapine analogs using a pharmacophore based on the ligands octoclothepin and tefludazine. Molecular field analysis using CoMFA combined with HINT was carried out on published D2 receptor binding affinities. Several alternative alignments of the analogs gave r2 values in the range of 0.8-0.95. The final model had good predictive abilities with q2 > 0.6 and r2 > 0.9. This provides an excellent framework to aid in the design of novel antipsychotics with diminished propensity to produce clinically limiting side effects.

The SMART needle. A new Doppler ultrasound-guided vascular access needle.

Central venous access is an essential part of patient management in many clinical settings. Traditionally this has been achieved by a blind, external landmark guided technique which may not correlate exactly with the location of the vessel. We have prospectively evaluated the SMART needle, a new Doppler ultrasound guided vascular access device, in 40 patients, to evaluate whether it can improve on the standard technique. The SMART needle was easy to use and reliably distinguished between arterial and venous signals. No advantage was demonstrated in 'easy' internal jugular vein cannulations. Although ease of cannulation in difficult cases was subjectively improved, the differences in time to cannulation and number of passes between the groups failed to reach statistical significance and the complication rates were similar. However, the use of the SMART needle on two occasions enabled avoidance of carotid artery puncture by correctly distinguishing the artery from the vein, so that it may have a rôle in patients in whom difficult internal jugular venous cannulation is anticipated.

Hyperthermia associated with 3,4-methylenedioxyethamphetamine ('Eve').

A patient was admitted with hyperthermia, muscle rigidity, rhabdomyolysis and disseminated intravascular coagulation. He was initially thought to have taken 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), but subsequent toxicology revealed the presence of 3,4-methylenedioxyethamphetamine (MDEA, 'Eve'), its sister drug, in his blood. Subsequent in vitro testing for malignant hyperthermia proved to be negative.

Abolition of the extradural sieve by addition of fentanyl to extradural bupivacaine.

A patient is described in whom breakthrough of pain occurred from uterine rupture during effective extradural analgesia, demonstrating the hypothesis of the "extradural sieve". Subsequent abolition of this pain by addition of fentanyl to bupivacaine 0.25% raises the question whether or not this combination should be avoided in women with a scarred uterus undergoing "trial of labour".