Hirulog effect in rat endotoxin shock |
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| Affiliation: | 1. Department of Experimental Pharmacology, via Domenico Montesano 49, 80131 Naples, Italy;1. Biogen Inc. 14 Cambridge Center, Cambridge, Massachusetts 02142 USA;1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation (BHF) Centre of Research Excellence, University of Oxford, Oxford, OX3 7BN, United Kingdom;2. Department of Materials and London Centre for Nanotechnology, Imperial College London, London, SW7 2AZ, United Kingdom;3. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), The Botnar Research Centre, University of Oxford, Oxford, OX3 7LD, United Kingdom;4. Department of Chemistry, Khalifa University of Science and Technology, P.O. Box, 127788, Abu Dhabi, United Arab Emirates;5. Centre for Advanced Electron Spin Resonance (CAESR), Inorganic Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, OX1 3QR, United Kingdom;6. Department of Materials, University of Oxford, Parks Road, Oxford, OX1 3PH, United Kingdom;7. Department of Biochemical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, GU2 7XH, United Kingdom;8. Institute of Biomedical Engineering (IBME), Department of Engineering Science, University of Oxford, Oxford, OX3 7LD, United Kingdom;1. Cardiovascular Research Center of the General Medical Services and the Departments of Anesthesia, Critical Care and Pain Medicine, Pediatrics, and Medicine, Massachusetts General Hospital - East, 149 13th St, Boston, MA, USA;2. Harvard Medical School, Harvard University, Cambridge, MA, USA;1. Texas A&M University College of Medicine, Department of Medical Physiology, 8447 Riverside Parkway, Medical Research and Education Building Rm 1341, Bryan, TX, 77807, USA;2. Texas A&M University School of Veterinary Medicine & Biomedical Sciences, Department of Veterinary Physiology & Pharmacology, 4466 TAMU, College Station, TX, 77843-4466, USA;3. Texas A&M University, Department of Animal Science, Kleberg Center Rm 133, 2471 TAMU, College Station, TX, 77843-2471, USA;4. Lerner Research Institute, Department of Biomedical Engineering, 9500 Euclid Avenue, Mail Code ND20, Cleveland, OH, 44196, USA |
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| Abstract: | HirulogTM is a thrombin catalytic site inhibitor which exhibits specificity for the anionic binding exosite of alpha thrombin. Here, we have evaluated the effect of HirulogTM (1, 5 and 10 mg/kg, 30 min pretreatment) in a rat model of endotoxemia. Intravenous injection of lipopolysaccharide from E. coli (25 mg/kg; serotype 0127:B8) caused decreases in blood pressure which were significantly reduced (about 60%) in animals pretreated with HirulogTM. Rat survival to endotoxin was significantly increased in HirulogTM pretreated group (5 and 10 mg/kg) up to 24 hours. HirulogTMat the dose of 10 mg/kg inhibited both endotoxin-induced leukopenia at 30 and 60 minute points and thrombocytopenia at 30 minute point but not at 90 and 120 minute points. Fibrinogen levels were significantly reduced after 2 hours following endotoxin administration. Pretreatment with HirulogTM (5–10 mg/kg i.v.) 30 min prior to administration of endotoxin prevented changes in fibrinogen plasma levels. These results demonstrate that HirulogTM-induced inhibition of thrombin is effective in reducing toxic and lethal effects of endotoxin. |
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