E-52862-A selective sigma-1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double-blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy. We report the efficacy and safety of E-52862-a selective, sigma-1 receptor antagonist-from phase 2, randomized, proof-of-concept studies in patients with moderate-to-severe, neuropathic, chronic postsurgical pain (CPSP) and painful diabetic neuropathy (PDN). Adult patients (CPSP [N = 116]; PDN [N = 163]) were randomized at a 1:1 ratio to 4 weeks of treatment with E-52862 (CPSP [n = 55]; PDN [n = 85]) or placebo (CPSP [n = 61]; PDN [n = 78]) orally once daily. Pain intensity scores were measured using a numerical pain rating scale from 0 (no pain) to 10 (worst pain imaginable). The primary analysis
The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX
Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity. E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). In this conventional mean change to time-matched placebo analysis, the largest time-matched difference
the completion of chemotherapy that presents as two distinct syndromes: acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309 (previously developed as E-52862) is a novel selective sigma-1 receptor (S1R) antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes
-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analysed. Compared with WT mice, both mechanical and thermal hypersensitivity were attenuated in σR KO mice following SCI. Accordingly, treatment of WT mice with the σR antagonist MR309 (previously developed as E-52862; S1RA) after SCI exerted antinociceptive effects (i.e. reduced mechanical
Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per
regulators of σ1R have been investigated using animal models of ischaemic stroke. As both agonists and antagonists provide some neural protection, the selective involvement of σ1Rs in these effects has been questioned. The availability of S1RA (E-52862/MR309), a highly selective σ1R antagonist, prompted us to explore its therapeutic potential in an animal model of focal cerebral ischaemia. Mice were
Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats. E-52862 (S1RA, 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]-morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E-52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model. Mechanical and thermal response thresholds were tested on 7-, 13-, 14- and 15-week-old ZDF rats treated with saline or with E-52862 acutely administered on week 13, followed by sub-chronic administration (14 days). Axonal peripheral activity (skin-saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15-week-old