title: Effects of simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination on the inflammatory process and on the liver metabolic changes of arthritic rats.
abstract: In this study, simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination were administered to arthritic rats, first to determine their effects on the inflammatory response, employing a low-dose adjuvant-induced arthritis model in rats. Arthritis was induced by the subcutaneous injection of a suspension of Mycobacterium tuberculosis (100 μg) in mineral oil [complete Freund's adjuvant used (CFA)] into the plantar surface of the hind paws. Simvastatin(40 mg/kg), atorvastatin(10 mg/kg), ezetimibe(10 mg/kg), ezetimibe(10 mg/kg) + simvastatin(20 mg/kg or 40 mg/kg) were given intragastrically and the treatment began on the day of CFA injection and continued daily up to the 28th day after arthritis induction. The ezetimibe + simvastatin combination was more effective in reducing the inflammatory response in arthritic rats than in atorvastatin, simvastatin, or ezetimibe monotherapy. The observed effect seems to be cholesterol-independent as there were no changes in plasma cholesterol levels. In spite of the benefits on joint lesions, treatment with ezetimibe + simvastatin combination caused a marked increment in liver, kidneys, spleen size, and plasma transaminases activities. Therefore, animals treated with the ezetimibe(10 mg/kg) + simvastatin(40 mg/kg) combination were also submitted to liver perfusion experiments. In this regard, ezetimibe + simvastatin did not improve the liver metabolic alterations seen in control arthritic rats, on the contrary, a worsening was observed in liver production of glucose from alanine, as well as in oxygen uptake. All of these metabolic changes appear to be induced by treatment with ezetimibe + simvastatin combination, as the same metabolic effects were observed in normal and treated arthritic animals.
authors.affiliation: Laboratory of Inflammation, Department of Pharmacy and Pharmacology, University of Maringá, 87.020.900 Maringá, Paraná, Brazil.
authors.forename: Lívia
authors.initials: L
authors.lastname: Bracht
authors.forename: Carmem Patrícia
authors.initials: CP
authors.lastname: Barbosa
authors.forename: Silvana Martins
authors.initials: SM
authors.lastname: Caparroz-Assef
authors.forename: Roberto Kenji Nakamura
authors.initials: RK
authors.lastname: Cuman
authors.forename: Emy Luiza
authors.initials: EL
authors.lastname: Ishii-Iwamoto
authors.forename: Adelar
authors.initials: A
authors.lastname: Bracht
authors.forename: Ciomar Aparecida
authors.initials: CA
authors.lastname: Bersani-Amado
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000069059:Atorvastatin; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008111:Liver Function Tests; D010477:Perfusion; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D001384:Azetidines; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D000069438:Ezetimibe