Sepsis accounts for >500K hospitalizations in the USA yearly, of which half will progress to a fatal outcome. Because there are no approved pharmaceutical agents that profoundly improve outcome, the mainstay of care is supportive administration of fluids, oxygen, mechanical ventilation, and antibiotics. Sepsis is driven by widespread tissue injury mediated by alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion. The imbalance of these two free radical species produces major changes in the distribution of extracellular water, disrupts epithelial and endothelial tight junctions, impairs endothelial function and vascular smooth muscle tone, chokes off microcirculatory blood flow, triggers pulmonary arterial hypertension, and raises endothelial permeability. Despite aggressive support, sepsis may progress to a state of circulatory collapse, with widespread tissue dysfunction and multiple organ failure prior to death. A successful treatment of sepsis requires the simultaneous replenishment of nitric oxide and removal of superoxide. To address this unmet clinical need, Radikal Therapeutics is developing R-100, a novel agent formed from the covalent linkage of two redox-based moieties: 1) an organic nitrovasodilator that releases nitric oxide, and 2) a pyrrolidine nitroxide that acts as a superoxide dismutase mimetic, a catalase mimic, and a peroxynitrite decomposition catalyst. In combination, these functionalities allow R-100 to remove toxic reactive oxygen species and deliver nitric oxide without the confounding effect of producing peroxynitrite. In a lethal murine model of endotoxinemia, R-100 treatment prevented signs and symptoms of sepsis and produced 100% survival, vs. 0% survival in controls. We now propose to extend these observations and validate the efficacy of R-100 in a gold-standard ovine model of trauma-associated septic shock. Specific Aim: Establish the efficacy of R-100 in an ovine model of trauma-associated sepsis. We will carry out a placebo-controlled ovine study in which respiratory insufficiency and septic shock are induced in anesthetized, mechanically-ventilated Merino sheep via acute smoke inhalation injury and Pseudomonas aeruginosa pneumonia. Treatment with R-100 will be initiated 1 hour after trauma and continued for 24 hours. R-100 is expected to 1) block lung inflammation and injury, by reducing wet/dry ratio, lymphatic drainage, lipid peroxidation, neutrophil infiltration, peroxynitrite production, and poly (ADP-ribose) formation, and 2) improve hemodynamics and airway pressures, by reducing pulmonary vascular resistance, peak inspiratory pressure, and pulmonary shunt. These experimental treatment effects are expected to translate in the clinical setting into shorter duration of mechanical ventilation, accelerated discharge from the intensive care unit, and reduced all-cause 30 day mortality.
Public Health Relevance: Sepsis is a leading cause of mortality in the intensive care unit and a major unmet medical need. The sole approved therapy for septic shock is of limited benefit and rarely prescribed. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant large animal model.
Thesaurus Terms: 5,6,7,8-Tetrahydrobiopterin;Abscission;Accounting;Active Oxygen;Acute;Address;Adenosine 5'-(Trihydrogen Diphosphate), P'-5-Ester With D-Ribose, Homopolymer;Adverse Experience;Adverse Event;After Care;After-Treatment;Aftercare;American;Anabolism;Animal Model;Animal Models And Related Studies;Animals;Antibiotic Agents;Antibiotic Drugs;Antibiotics;Arginine;Arginine, L-Isomer;Au Element;Bh4;Bph4;Biological;Blood Vessels;Blood Flow;Body Tissues;Cnos;Canine Species;Canis Familiaris;Cardiovascular;Cardiovascular Body System;Cardiovascular System;Cardiovascular System (All Sites);Caring;Cessation Of Life;Choking;Circulatory Collapse;Clinical;Clinical Treatment;Common Rat Strains;Constitutive Nos;Consumption;D-Glucose;Death;Dextrose;Diagnostic Findings;Diffusion;Dogs;Dose;Drainage;Drainage Procedure;Drug Delivery;Drug Delivery Systems;Drug Kinetics;Drug Targeting;Drug Targetings;Drugs;Dysfunction;Ec 1.1.3.22;Ecnos;Enos;Endogenous Nitrate Vasodilator;Endothelial Nos;Endothelial Nitric Oxide Synthase;Endothelial Nitric Oxide Synthase 3;Endothelium-Derived Relaxing Factor;Enzymes;Epithelial;Erythrocuprein;Excision;Extirpation;Fatal Outcome;Free Radicals;Functional Disorder;Future;Genetic Toxicology;Germinoblastoma;Glucose;Gold;H2o2;H4b;H4biopterin;Hosp;Hemocuprein;Hepatocyte Nitric Oxide Synthase;Hospitalization;Hour;Hydrogen Oxide;Hydrogen Peroxide;Hydrogen Peroxide (H2o2);Hydrogen-Peroxide[{..}]hydrogen-Peroxide Oxidoreductase;Hydroperoxide;Hypoxanthine Dehydrogenase;Hypoxanthine Oxidase;Hypoxanthine-Xanthine Oxidase;Inos;Inducible Nitric Oxide Synthase;Injury;Intensive Care Units;Ischemia;Isoforms;L-Arginine;Length Of Stay;Lipid Peroxidation;Liquid Substance;Lung;Lung Inflammation;Lymphatic;Lymphoma;Lymphoma (Hodgkin's And Non-Hodgkin's);Lymphoma, Malignant;Mof Syndrome;Macrophage Nitric Oxide Synthase;Mammals, Dogs;Mammals, Mice;Mammals, Rats;Mechanical Ventilation;Mediating;Medical;Medication;Mice;Microcirculation;Micronucleus Assays;Micronucleus Tests;Miscellaneous Antibiotic;Mission;Mitochondria;Modeling;Mononitrogen Monoxide;Mortality;Mortality Vital Statistics;Multiple Organ Failure;Murine;Mus;Muscle Tonus;N Element;N2 Element;Nadph Oxidase;Nih;Nos Type Ii;Nos Type Iii;Nos2;Nos2a;Nos2a Protein, Human;Nos3;Nos3 Protein, Human;Nosiii;National Institutes Of Health;National Institutes Of Health (U.S.);Neutrophil Infiltration;Neutrophil Recruitment;Nitric Oxide;Nitric Oxide Synthase 2a;Nitric Oxide Synthase 3;Nitric Oxide, Endothelium-Derived;Nitrogen;Nitrogen Monoxide;Nitrogen Protoxide;Nitrogen Oxide;Number Of Days In Hospital;O Element;O2 Element;Occluding Junctions;Organ Dysfunction Syndrome, Multiple;Organ System, Cardiovascular;Outcome;Ovis;Oxidation-Reduction;Oxygen;Oxygen Radicals;Oxygen Measurement, Partial Pressure, Arterial;P. 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