Appetite stimulation with cannabis-based medicine and methods for assessment of glomerular filtration in older patients with medical illness: A study protocol.

BACKGROUND AND AIM: Malnutrition in older patients is linked to poor appetite. Cannabis-based medicine may have orexigenic properties in older patients, but this has to our knowledge never been investigated. In older patients, uncertainty applies to the accuracy of estimated glomerular filtration rate (eGFR) based on creatinine, which is crucial for medication prescribing. In older patients with poor appetite, the study aims (1) to assess the efficacy of Sativex® (8.1-mg delta-9-tetrahydrocannabinol [THC] and 7.5-mg cannabidiol [CBD]) to stimulate appetite and (2) to compare the performance of various GFR-estimates and measured-GFR (mGFR) for determining gentamicin clearance utilizing population pharmacokinetic (popPK) modelling methods. METHODS AND OBJECTIVES: This study is composed of two substudies. Substudy 1 is an investigator-initiated single-center, double-blinded, randomized, placebo-controlled, superiority, cross-over study. Substudy 1 will recruit 17 older patients with poor appetite, who will also be invited to substudy 2. Substudy 2 is a single-dose pharmacokinetics study and will recruit 55 patients. Participants will receive Sativex® and placebo in substudy 1 and gentamicin with simultaneous measurements of GFR in substudy 2. The primary endpoints are as follows: Substudy 1-the difference in energy intake between Sativex® and placebo conditions; substudy 2- the accuracy of different eGFR equations compared to mGFR. The secondary endpoints include safety parameters, changes in the appetite hormones, total ghrelin and GLP-1 and subjective appetite sensations, and the creation of popPK models of THC, CBD, and gentamicin.

Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake.

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion.

AIM: To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake. METHODS: On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled. RESULTS: In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups. CONCLUSIONS: CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.

Sevelamer in a diabetologist's perspective: a phosphate-binding resin with glucose-lowering potential.

Sevelamer is a calcium-free and metal-free phosphate-binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid-lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These 'novel' effects are most probably derived from the bile acid-binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose-lowering effect of the drug.