Search

Background: K+ channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and treat obstructive sleep apnea (OSA). However, these findings have not yet been translated to humans.Research Question: Does a novel, potent, TASK 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans and secondarily, what is the optimal dose and mode of topical application?Study Design and Methods: Pre-clinical study: Pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during placebo, 0.3, 3 and 30μg nasal drops of BAY2586116.Clinical Study: 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 or placebo nasal spray (160μg) prior to sleep via a double-blind, randomized, crossover design. Most participants also returned for three additional overnight visits: 1) nasal drops (160μg), 2) half dose nasal spray (80μg), and 3) direct endoscopic application (160μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit.Results: There were consistent and sustained improvements in pharyngeal collapsibility to negative pressure with 3 and 30μg of BAY2586116 versus placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of ∼2cmH2O versus placebo regardless of topical application mode and dose (mixed model p<0.008) in participants with OSA.Interpretation: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiology findings highlight the therapeutic potential to target K+ channel mechanisms to treat OSA.Clinical Trial Registration: NCT04236440. [ABSTRACT FROM AUTHOR]

A novel one transistor and one diode (1T-1D) dynamic random access memory cell for embedded applications is proposed. This memory cell consists of a floating-gate (FG) MOSFET and a gated diode. The anode of the diode is connected to the FG, so that the threshold voltage of the FG MOSFET can be modulated by the current through the diode. In this paper, basic device operations, speed, retention, and disturb performance are investigated using Silvaco technology computer-aided design simulation tools. The process compatibility is also investigated by integrating the memory array and specific sense amplifier. [ABSTRACT FROM PUBLISHER]

Abstract: S1P1 receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P1 receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P1 receptor agonists. [Copyright &y& Elsevier]

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors.

The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5-HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Gαq-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds.

GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.