title: Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion.
abstract: Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States; Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Fettiplace
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States; Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States.
authors.forename: Kinga
authors.initials: K
authors.lastname: Lis
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States; Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Ripper
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States; Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kowal
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States; Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States.
authors.forename: Adrian
authors.initials: A
authors.lastname: Pichurko
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States.
authors.forename: Dominic
authors.initials: D
authors.lastname: Vitello
authors.affiliation: Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States; Section of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Medicine, University of Illinois College of Medicine, 840 South Wood Street (MC 719), Room 920-N CSB, Chicago, IL 60612, United States.
authors.forename: Israel
authors.initials: I
authors.lastname: Rubinstein
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States.
authors.forename: David
authors.initials: D
authors.lastname: Schwartz
authors.affiliation: Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton Street, Chicago, IL 60607, United States. Electronic address: akpa@uic.edu.
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Akpa
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, 1740 West Taylor Street, Suite 3200 W, MC515, Chicago, IL 60612, United States; Research & Development Service, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Avenue, 60612, United States. Electronic address: guyw@uic.edu.
authors.forename: Guy
authors.initials: G
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D002045:Bupivacaine / Q000493:pharmacokinetics / Q000633:toxicity*; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D066126:Cardiotoxicity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D054715:Cardiotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D004655:Emulsions / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010743:Phospholipids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013024:Soybean Oil / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014280:Triglycerides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D054715:Cardiotoxins; D004655:Emulsions; D010743:Phospholipids; D014280:Triglycerides; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D002045:Bupivacaine
keywords: Antidote; Biodetoxification; Bupivacaine; Lipid emulsion; Local anesthetic; Triglyceride