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Beneficial effects of the peptidoleukotriene receptor antagonist, SK&F 104353, on the responses to experimental endotoxemia in the conscious rat. 1988

E F Smith, and L B Kinter, and M Jugus, and M A Wasserman, and R D Eckardt, and J F Newton
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, PA 19406.

The purpose of this study was to examine the effects of the peptidoleukotriene receptor antagonist, SK&F 104353, on the responses to endotoxin in conscious male Sprague-Dawley rats. Administration of Salmonella enteritidis endotoxin (30 mg/kg i.v.; LD90) resulted in a decrease in the number of circulating platelets, leukopenia, an increase in hematocrit, and 0% survival at 24 hr. Pretreatment with SK&F 104353 (1 mg/kg, i.v. bolus followed by 3 mg/kg/hr, i.v. infusion for 6 hr) 5 min before injection of endotoxin produced steady state plasma drug levels of 1.6 micrograms/ml in naive animals and levels of approximately 3.4 micrograms/ml in endotoxemic animals (P less than 0.05). SK&F 104353 significantly attenuated the endotoxin-induced thrombocytopenia (P less than 0.05) but had no effect on either the endotoxin-induced early leukopenia or late leukocytosis. Additionally, SK&F 104353 significantly reduced the endotoxin-induced hemoconcentration (P less than 0.05) and improved survival to 30% at 48 hr (P less than 0.05). A higher dose of SK&F 104353 (2 mg/kg, i.v. bolus followed by 10 mg/kg/hr, i.v. infusion for 6 hr) did not produce any further benefit. These data indicate clearly the pathophysiologic role of peptidoleukotrienes in endotoxemia and suggest SK&F 104353 could be useful for ameliorating some of the deleterious sequelae associated with this condition.

UI MeSH Term Description Entries
D008297 Male Males
D009026 Mortality All deaths reported in a given population. CFR Case Fatality Rate,Crude Death Rate,Crude Mortality Rate,Death Rate,Age Specific Death Rate,Age-Specific Death Rate,Case Fatality Rate,Decline, Mortality,Determinants, Mortality,Differential Mortality,Excess Mortality,Mortality Decline,Mortality Determinants,Mortality Rate,Mortality, Differential,Mortality, Excess,Age-Specific Death Rates,Case Fatality Rates,Crude Death Rates,Crude Mortality Rates,Death Rate, Age-Specific,Death Rate, Crude,Death Rates,Determinant, Mortality,Differential Mortalities,Excess Mortalities,Mortalities,Mortality Declines,Mortality Determinant,Mortality Rate, Crude,Mortality Rates,Rate, Age-Specific Death,Rate, Case Fatality,Rate, Crude Death,Rate, Crude Mortality,Rate, Death,Rate, Mortality,Rates, Case Fatality
D009994 Osmolar Concentration The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per liter of solution. Osmolality is expressed in terms of osmoles of solute per kilogram of solvent. Ionic Strength,Osmolality,Osmolarity,Concentration, Osmolar,Concentrations, Osmolar,Ionic Strengths,Osmolalities,Osmolar Concentrations,Osmolarities,Strength, Ionic,Strengths, Ionic
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D001772 Blood Cell Count The number of LEUKOCYTES and ERYTHROCYTES per unit volume in a sample of venous BLOOD. A complete blood count (CBC) also includes measurement of the HEMOGLOBIN; HEMATOCRIT; and ERYTHROCYTE INDICES. Blood Cell Number,Blood Count, Complete,Blood Cell Counts,Blood Cell Numbers,Blood Counts, Complete,Complete Blood Count,Complete Blood Counts,Count, Blood Cell,Count, Complete Blood,Counts, Blood Cell,Counts, Complete Blood,Number, Blood Cell,Numbers, Blood Cell
D003243 Consciousness Sense of awareness of self and of the environment. Consciousnesses
D003998 Dicarboxylic Acids Acyclic acids that contain two carboxyl groups and have the formula HO2C-R-CO2H, where R may be an aromatic or aliphatic group. Acids, Dicarboxylic
D004731 Endotoxins Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. Endotoxin
D006400 Hematocrit The volume of packed RED BLOOD CELLS in a blood specimen. The volume is measured by centrifugation in a tube with graduated markings, or with automated blood cell counters. It is an indicator of erythrocyte status in disease. For example, ANEMIA shows a low value; POLYCYTHEMIA, a high value. Erythrocyte Volume, Packed,Packed Red-Cell Volume,Erythrocyte Volumes, Packed,Hematocrits,Packed Erythrocyte Volume,Packed Erythrocyte Volumes,Packed Red Cell Volume,Packed Red-Cell Volumes,Red-Cell Volume, Packed,Red-Cell Volumes, Packed,Volume, Packed Erythrocyte,Volume, Packed Red-Cell,Volumes, Packed Erythrocyte,Volumes, Packed Red-Cell
D006439 Hemodynamics The movement and the forces involved in the movement of the blood through the CARDIOVASCULAR SYSTEM. Hemodynamic

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