Advances with the discovery and development of novel sigma 1 receptor antagonists for the management of pain.

INTRODUCTION: Interest in sigma-1 receptors (S1Rs) has significantly increased in the last 25 years and more recently for their role in pain modulation. S1Rs are novel chaperone proteins that modulate several cellular processes and can modulate the activity of many ion channels and receptors. They are heavily localized in pain pathways, leading to the development of S1R antagonists for pain modulation. Although the exact mechanism by which S1R antagonists act is unclear, there has been marked advances in the preclinical and clinical development of S1R antagonists. AREAS COVERED: This review covers the brief history of S1Rs and the research leading to the development of S1R antagonists in clinical trials for chronic pain. Focus is given to E-52862 and [18F]FTC-146 (aka CM-304) as their clinical development has broken ground for S1R antagonists- with both being first-in-class ligands for treatment and diagnostic imaging, respectively. EXPERT OPINION: S1R antagonists represent a unique intracellular target for pain modulation, due to the receptor's chaperone activity in modulating various proteins in pain pathways. The research on S1R has grown exponentially in the last 20 years, and as more is understood about the basic science of the receptor, the drug development in this field will also flourish.

Effect of UV irradiation on aflatoxin reduction: a cytotoxicity evaluation study using human hepatoma cell line.

In this proof-of-concept study, the efficacy of a medium-pressure UV (MPUV) lamp source to reduce the concentrations of aflatoxin B1, aflatoxin B2, and aflatoxin G1 (AFB1, AFB2, and AFG1) in pure water is investigated. Irradiation experiments were conducted using a collimated beam system operating between 200 to 360 nm. The optical absorbance of the solution and the irradiance of the lamp are considered in calculating the average fluence rate. Based on these factors, the UV dose was quantified as a product of average fluence rate and treatment time. Known concentrations of aflatoxins were spiked in water and irradiated at UV doses ranging from 0, 1.22, 2.44, 3.66, and 4.88 J cm-2. The concentration of aflatoxins was determined by HPLC with fluorescence detection. LC-MS/MS product ion scans were used to identify and semi-quantify degraded products of AFB1, AFB2, and AFG1. It was observed that UV irradiation significantly reduced aflatoxins in pure water (p < 0.05). Irradiation doses of 4.88 J cm-2 reduced concentrations 67.22% for AFG1, 29.77% for AFB2, and 98.25% for AFB1 (p < 0.05). Using this technique, an overall reduction of total aflatoxin content of ≈95% (p < 0.05) was achieved. We hypothesize that the formation of ˙OH radicals initiated by UV light may have caused photolysis of AFB1, AFB2, and AFG1 molecules. In cell culture studies, our results demonstrated that the increase of UV dosage decreased the aflatoxin-induced cytotoxicity in HepG2 cells. Therefore, our research finding suggests that UV irradiation can be used as an effective technique for the reduction of aflatoxins.