Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study.

BACKGROUND: Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag-a potent, selective, pan-gastrointestinal 5-hydroxytryptamine type 4 receptor agonist-is under investigation for treatment of GI motility disorders including gastroparesis. AIMS: To assess the efficacy and safety of velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, three-period fixed-sequence crossover phase 2 study, subjects with diabetic or idiopathic gastroparesis received oral velusetrag (5, 15 or 30 mg) or placebo once daily for 7 days each. The primary outcome was proportion of subjects achieving ≥20% reduction in GE half-time (GE t1/2 ) from each treatment period baseline on day 7. Absolute and percent changes from baseline GE t1/2 were also assessed. GE was measured using a [13 C]-octanoate breath test. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: Thirty-four subjects (67.6% female; mean age, 46.3 years; 52.9% with diabetic gastroparesis) were included. Treatment with velusetrag 30 mg significantly increased the proportion of subjects with ≥20% reduction from baseline GE t1/2 compared with placebo (52% vs 5%, P = 0.002), and GE t1/2 was numerically reduced following all three doses of velusetrag relative to placebo treatment. Efficacy was similar between subjects with diabetic and idiopathic gastroparesis. Velusetrag treatment was generally well tolerated; most TEAEs were mild and related to GI transit acceleration. CONCLUSIONS: Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938).

Evaluation of early biomarkers of muscle anabolic response to testosterone.

BACKGROUND: Early biomarkers of skeletal muscle anabolism will facilitate the development of therapies for sarcopenia and frailty. METHODS AND RESULTS: We examined plasma type III collagen N-terminal propeptide (P3NP), skeletal muscle protein fractional synthesis rate, and gene and protein expression profiles to identify testosterone-induced changes in muscle anabolism. Two placebo-controlled studies enrolled community-dwelling men (study 1, 60-75 years; study 2, 18-40 years) with low to normal testosterone levels. Men were randomized to lower dose (study 1, 100 mg; study 2, 200 mg) or higher dose (study 1, 300 mg; study 2, 600 mg) single intramuscular testosterone or saline injection. After 1 week, testosterone acutely increased plasma P3NP levels in a dose-dependent manner and altered the expression of several skeletal muscle transcripts and proteins. Though not statistically significant, mixed muscle protein fractional synthesis rate tended to increase (1.08-fold with 100 mg testosterone, 1.12-fold with 300 mg testosterone). Testosterone exposure also increased skeletal muscle expression of the collagen type III gene that encodes P3NP. CONCLUSION: P3NP is a potentially useful early biomarker for muscle anabolic therapy. Skeletal muscle protein and RNA profiling are useful tools for the discovery of novel muscle anabolic biomarkers.

A network view of disease and compound screening.

The large-scale generation and integration of genomic, proteomic, signalling and metabolomic data are increasingly allowing the construction of complex networks that provide a new framework for understanding the molecular basis of physiological or pathophysiological states. Network-based drug discovery aims to harness this knowledge to investigate and understand the impact of interventions, such as candidate drugs, on the molecular networks that define these states. In this article, we describe how such an approach offers a novel way to understand biology, characterize disease and ultimately develop improved therapies, and discuss the challenges to realizing these goals.

Found in translation.

For those who wish to marry research with clinical applications, finding the right environment can be hard.

Prospective isolation and global gene expression analysis of definitive and visceral endoderm.

In spite of the therapeutic importance of endoderm derivatives such as the pancreas, liver, lung, and intestine, there are few molecular markers specific for early endoderm. In order to identify endoderm-specific genes as well as to define transcriptional differences between definitive and visceral endoderm, we performed microarray analysis on E8.25 definitive and visceral endoderm. We have developed an early endoderm gene expression signature, and clarified the transcriptional similarities and differences between definitive and visceral endoderm. Additionally, we have developed methods for flow cytometric isolation of definitive and visceral endoderm. These results shed light on the mechanism of endoderm formation and should facilitate investigation of endoderm formation from embryonic stem cells.