A TRP channel contributes to insulin secretion by pancreatic β-cells

The release of insulin by pancreatic β-cells involves a complex interplay of conductances that generate oscillations and drive secretion. A recent report identifies a new player in this process, the ion channel TRPM 5. TRPM 5 was originally identified in taste cells, where it forms a Ca2+-activated cation channel that is required for sensory responses to bitter and sweet tastes. New research now shows that TRPM 5 is expressed within the pancreatic islets of Langerhans, where it regulates the frequency of Ca2+ oscillations and contributes to insulin release by β-cell

APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the µ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy

Eugene R Viscusi,1 Franck Skobieranda,2 David G Soergel,2 Emily Cook,2 David A Burt,2 Neil Singla3 1Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA; 2Trevena Inc., Chesterbrook, PA, USA; 3Lotus Clinical Research, LLC, Pasadena, CA, USA Purpose: Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide intravenous (IV) analgesia with a lower risk of opioid-related adverse events (ORAEs) than conventional opioids. Patients and methods: APOLLO-1 (NCT02815709) was a phase III, double-blind, randomized trial in patients with moderate-to-severe pain following bunionectomy. Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine, 1 mg morphine, or placebo). The primary endpoint compared the proportion of treatment responders through 48 hours for oliceridine regimens and placebo. Secondary outcomes included a composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs morphine. Results: Effective analgesia was observed for all oliceridine regimens, with responder rates of 50%, 62%, and 65.8% in the 0.1 mg, 0.35 mg, and 0.5 mg regimens, respectively (all P<0.0001 vs placebo [15.2%]; 0.35 mg and 0.5 mg non-inferior to morphine). RSB showed a ose-dependent increase across oliceridine regimens (mean hours [SD]: 0.1 mg: 0.04 [0.33]; 0.35 mg: 0.28 [1.11]; 0.5 mg: 0.8 [3.33]; placebo: 0 [0]), but none were statistically different from morphine (1.1 [3.03]). Gastrointestinal adverse events also increased in a dose-dependent manner in oliceridine regimens (0.1 mg: 40.8%; 0.35 mg: 59.5%; 0.5 mg: 70.9%; placebo: 24.1%; morphine: 72.4%). The odds ratio for rescue antiemetic use was significantly lower for oliceridine regimens compared to morphine (P<0.05). Conclusion: Oliceridine is a novel and effective IV analgesic providing rapid analgesia for the relief of moderate-to-severe acute postoperative pain compared to placebo. Additionally, it has a favorable safety and tolerability profile with regard to respiratory and gastrointestinal adverse effects compared to morphine, and may provide a new treatment option for patients with moderate-to-severe postoperative pain where an IV opioid is required. Keywords: postoperative, analgesia, patient controlled, clinical trial, orthopedic surger

A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (µ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty

Neil Singla,1 Harold S Minkowitz,2 David G Soergel,3 David A Burt,3 Ruth Ann Subach,3 Monica Y Salamea,3 Michael J Fossler,3 Franck Skobieranda3 1Lotus Clinical Research, Pasadena, CA, 2Memorial Hermann Memorial City Medical Center, Houston, TX, 3Trevena, Inc, King of Prussia, PA, USA Background: Oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (µ-GPS) modulator, was designed to improve the therapeutic window of conventional opioids by activating G-protein signaling while causing low β-arrestin recruitment to the µ receptor. This randomized, double-blind, patient-controlled analgesia Phase IIb study was conducted to investigate the efficacy, safety, and tolerability of oliceridine compared with morphine and placebo in patients with moderate to severe pain following abdominoplasty (NCT02335294; oliceridine is an investigational agent not yet approved by the US Food and Drug Administration). Methods: Patients were randomized to receive postoperative regimens of intravenous oliceridine (loading/patient-controlled demand doses [mg/mg]: 1.5/0.10 [regimen A]; 1.5/0.35 [regimen B]), morphine (4.0/1.0), or placebo with treatment initiated within 4 hours of surgery and continued as needed for 24 hours. Results: Two hundred patients were treated (n=39, n=39, n=83, and n=39 in the oliceridine regimen A, oliceridine regimen B, morphine, and placebo groups, respectively). Patients were predominantly female (n=198 [99%]) and had a mean age of 38.2 years, weight of 71.2 kg, and baseline pain score of 7.7 (on 11-point numeric pain rating scale). Patients receiving the oliceridine regimens had reductions in average pain scores (model-based change in time-weighted average versus placebo over 24 hours) of 2.3 and 2.1 points, respectively (P=0.0001 and P=0.0005 versus placebo); patients receiving morphine had a similar reduction (2.1 points; P<0.0001 versus placebo). A lower prevalence of adverse events (AEs) related to nausea, vomiting, and respiratory function was observed with the oliceridine regimens than with morphine (P<0.05). Other AEs with oliceridine were generally dose-related and similar in nature to those observed with conventional opioids; no serious AEs were reported with oliceridine. Conclusion: These results suggest that oliceridine may provide effective, rapid analgesia in patients with moderate to severe postoperative pain, with an acceptable safety/tolerability profile and potentially wider therapeutic window than morphine. Keywords: TRV130, acute pain, analgesic, opioid, biased ligan

Maitotoxin converts the plasmalemmal Ca2+ pump into a Ca2+-permeable nonselective cation channel

Maitotoxin (MTX) activates Ca2+-permeable nonselective cation channels and causes a dramatic increase in cytosolic free Ca2+ concentration ([Ca2+]i) in every cell examined to date, but the molecular identity of the channels involved remains unknown. A clue came from studies of a structurally related marine toxin called palytoxin (PTX). PTX binds to the plasmalemmal Na+-K+-ATPase (NKA) and converts the Na+ pump into a nonselective cation channel. Given the high permeability of the MTX channel for Ca2+, we considered the possibility that MTX may bind to the plasmalemmal Ca2+-ATPase (PMCA) pump, and like PTX, convert the pump into a channel. To test this hypothesis, the PMCA was overexpressed in Spodoptera frugiperda (Sf9) insect cells and in human embryonic kidneys (HEK) 293 cells. In both cell types, enhanced expression of the PMCA was associated with a significant increase in MTX-induced whole cell membrane currents. The effect of MTX on whole cell currents in both wild-type and PMCA overexpressing HEK cells was sensitive to pump ligands including Ca2+ and ATP. MTX-induced currents were significantly reduced by knockdown of PMCA1 in HEK cells using small interfering RNA or in mouse embryonic fibroblasts from genetically modified mice with the PMCA1(+/−) PMCA4(−/−) genotype. Finally, PMCA catalytic activity (i.e., Ca2+-ATPase) in isolated membranes, or in purified PMCA preparations, was inhibited by MTX. Together, these results suggest that MTX binds to and converts the PMCA pump into a Ca2+-permeable nonselective cation channel