Distribution of oral nutritional supplements with medication: Is there a benefit? A systematic review.

OBJECTIVES: Disease-related malnutrition remains a major burden for patients and health care systems. The Medication Pass Nutritional Supplement Program (MEDPass) involves providing patients with oral nutritional supplements (ONS) in unusually small amounts three to four times per day during medication rounds. This systematic review aims to evaluate the impact of MEDPass ONS administration on compliance, total energy and protein intake, food intake, body weight and handgrip strength in hospitalized adults and nursing-home residents. METHODS: We conducted a systematic literature search in the databases MEDLINE, Embase, ScienceDirect, and the Cochrane Library and included randomized controlled trials (RCTs), non-RCTs, and before-after studies. Validated tools specific to the study design were used to assess the included studies. RESULTS: Ten studies were identified, including two RCTs, three non-RCTs, and five before-after trials. Compliance increased by 23.4% to 66% with MEDPass administration, resulting in compliance rates of 72.7% to 96%. With MEDPass administration, body weight increased by 1% to 6.8% or remained stable. The assessed evidence on total energy intake is ambiguous for protein, with a trend toward an increased intake. Trials on energy intake from food show mixed results as well. One study suggested a slight increase in handgrip strength. The included studies predominantly raise concerns for bias. CONCLUSIONS: We conclude that MEDPass ONS administration increases compliance in hospitalized adults and nursing-home residents. For all other outcomes, robust and well-powered trials are necessary.

Ligand-Specific Restriction of Extracellular Conformational Dynamics Constrains Signaling of the M2 Muscarinic Receptor.

G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and ß-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands. Using the muscarinic M2 receptor as a model system, we have analyzed the relationship between ligand-dependent conformational changes as revealed in all-atom MD simulations and the activation of specific G proteins. We find that the extent of closure of the extracellular, allosteric binding site interferes with the activation of certain G proteins. Our data allow the rational design of Gi-biased agonists at the M2 receptor and delineate a simple principle which may be translated to other GPRCs.

Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.

Dynamic ligand binding dictates partial agonism at a G protein-coupled receptor.

We present a new concept of partial agonism at G protein-coupled receptors. We demonstrate the coexistence of two functionally distinct populations of the muscarinic M2 receptor stabilized by one dynamic ligand, which binds in two opposite orientations. The ratio of orientations determines the cellular response. Our concept allows predicting and virtually titrating ligand efficacy, which opens unprecedented opportunities for the design of drugs with graded activation of the biological system.