Therapeutic Novelties: New Hope?

Hana Nadeem

Five leading experts presented their advances and projects on a variety of topics evolving around pharmacology and critical care on Thursday, May 13 during the Oral Abstract session at the AUA 2021 Annual Meeting. This exciting panel brought new progress and advances in the world of anesthetics. Meghan Lane-Fall, MD, MSHP, FCCM moderated the session, and the following topics were outlined:  lipid modulation of anesthetic receptors, ketamine effect as a long-term antidepressant, the dose and time of effect of isoflurane infusion, chronic kidney disease progression postsurgery and the metformin effect on neurons postinjury.

Wayland Cheng, MD, PhD, from University of Washington and IARS 2021 Frontiers in Anesthesia Research Award Winner, started the panel with a research project, “Structural Mechanisms of Lipid Modulation of a Pentameric Ligand-gated Ion Channel,” focusing on the structural mechanism of lipid modulation of a pentameric ligand-gated ion channel. These channels are involved in fast synaptic signaling in the nervous system and include the GABA_A and nicotinic acetylcholine receptors, which are the primary target of anesthetics. Using a combination of structural and biochemical approaches, it was discovered that these channels are positively modulated by different lipids at two different sites, leading to an increased peak channel activity and decreasing desensitization rate. These binding sites overlap with sites of many anesthetics like propofol, alfaxalone and volatile anesthetics. It makes these findings of lipid modulation fundamental to understand the allosteric modulation of the ion channels and may reveal structural determinants to help with a drug design.

Grace Jang, MPH, from Stanford University School of Medicine, followed Dr. Cheng with a discussion, “Ketamine Produces A Long-Lasting Enhancement of CA1 Neuron Excitability,” focusing on the long-lasting enhancement effect of ketamine on CA1 neuron excitability. Ketamine is an anesthetic identified as a rapid-acting antidepressant. This study used electrophysiology techniques to record the effect of ketamine on synaptic transmission at NDMA-mediated synapses at different concentration, on the CA1 region of mouse hippocampal brain slices. After a period of washout, a long-lasting increase in neuronal excitability highlighted the postsynaptic mechanism of ketamine that may be related to ketamine’s long-lasting antidepressant effect. Compelling evidence suggests that a single subanesthetic dose of ketamine exerts rapid and robust antidepressant effects. However, the cellular mechanism underlying the antidepressant effects still remain unclear.

Christopher A. Fraker, PhD, University of Miami Miller School of Medicine, took a slightly different approach by working on a model for isoflurane release from perfluorocarbon nanoemulsions, predicting the dose rate and time to loss of all reflexes in induction of anesthesia in his presentation on “A Finite Element Model for Isoflurane Release from Perfluorocarbon Nanoemulsions as a Predictor of Bolus Dosing and Time to Effect in a Rodent Model.” As the isoflurane nanoparticles inserted in the bloodstream of rodents accumulated, the decrease in interparticle distance led to an increase in the molar concentration of isoflurane released in the blood. The findings indicated that anesthetic induction with an IV isoflurane nanoemulsion had little side-effect and that dosing can be determined using finite element models correlating well with the effect-time perceived. Based on these efficient and potent advances, this could be a first step towards building a dosing system for automated delivery.

Jamie Privratsky, MD, PhD, from Duke University, presented on the topic of postoperative chronic kidney disease in “Postoperative Acute Kidney Injury is Associated with Progression of Chronic Kidney Disease Independent of Severity.” He implemented a retrospective cohort study and tested the hypothesis of the interaction between preoperative chronic kidney disease (CKD), postoperative acute kidney injury (AKI) and CKD progression within one year of surgery. After comparing preoperative and postoperative creatinine levels and determining the estimated glomerular filtration rate (eGFR) stage postoperatively, patients with any stage of AKI postoperatively and preoperative CKD showed a faster progression of CKD after a surgery. However, no effect of graded severity was noted between worse preoperative kidney function and higher stage AKI. His recommendation at the end of the presentation highlighted the necessity of assessing perioperative risk. Assessing perioperative risk includes measuring both serum creatinine, evaluating the kidney function (eGFR) and adopting perioperative kidney protective practices to prevent the observed CKD progression.

Santiago Miyara, MD, from the Feinstein Institutes for Medical Research, wrapped up the panel with the neuroprotective effects of metformin in his presentation, “The Neuroprotective Effects of Metformin: Insights from Rodent Cardiac Arrest and In Vitro Ischemia-reperfusions of Neurons and Astrocytes.” Adding metformin after an elicited cardiac arrest in vivo or an induced ischemia-hypoperfusion in vitro of neurons and astrocytes showed the following outcomes: increased survival rate of cells, improved neurological function and histological morphology of neurons and dendrocytes, decreased oxidative stress and reactive oxygen species production in the brain. This led to the conclusion that metformin could be a therapeutic tool of intervention for survival, improvement of cell viability after ischemia hypoperfusion injury and prevention of neural death after cardiac death.