Antipyretic and antioxidant activities of 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles in rats

• Published in: Brazilian journal of medical and biological research Vol. 43; no. 12; pp. 1193 - 1202
• Main Authors: Pasin, J S M, Ferreira, A P O, Saraiva, A L L, Ratzlaff, V, Andrighetto, R, Machado, P, Marchesan, S, Zanette, R A, Bonacorso, H G, Zanatta, N, Martins, M A P, Ferreira, J, Mello, C F
• Format: Journal Article
• Language: English; Portuguese
• Published: Brazil Associação Brasileira de Divulgação Científica 01.12.2010
• Subjects: Animals; Antioxidants - pharmacology; Antipyretics - chemistry; Antipyretics - pharmacology; BIOLOGY; Cyclooxygenase; Cyclooxygenase 1 - pharmacology; Cyclooxygenase 2 - pharmacology; Cytokine levels; Fever; Interleukin-1beta - drug effects; Interleukin-1beta - metabolism; Male; MEDICINE, RESEARCH & EXPERIMENTAL; Oxidative Stress - drug effects; Pyrazole derivatives; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism; Pyrazole derivatives; Cyclooxygenase; Cytokine levels; Fever
• ISSN: 0100-879X; 1414-431X; 1414-431X; 0100-879X
• DOI: 10.1590/S0100-879X2010007500139

The objective of this study was to determine the effect of eight 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-carboxyamidepyrazoles (TFDPs) on rat body temperature and baker's yeast-induced fever. TFDPs or vehicle (5% Tween 80 in 0.9% NaCl, 5 mL/kg) were injected subcutaneously and rectal temperature was measured as a function of time in 28-day-old male Wistar rats (N = 5-12 per group). Antipyretic activity was determined in feverish animals injected with baker's yeast (Saccharomyces cerevisiae suspension, 0.135 mg/kg, 10 mL/kg, ip). 3-Ethyl- and 3-propyl-TFDP (140 and 200 μmol/kg, respectively, 4 h after yeast injection) attenuated baker's yeast-induced fever by 61 and 82%, respectively. These two effective antipyretics were selected for subsequent analysis of putative mechanisms of action. We then determined the effects on cyclooxygenase-1 and -2 (COX-1 and COX-2) activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) oxidation in vitro, on tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels and on leukocyte counts in the washes of peritoneal cavities of rats injected with baker's yeast. While 3-ethyl- and 3-propyl-TFDP did not reduce baker's yeast-induced increases of IL-1β or TNF-α levels, 3-ethyl-TFDP caused a 42% reduction in peritoneal leukocyte count. 3-Ethyl- and 3-propyl-TFDP did not alter COX-1 or COX-2 activities in vitro, but presented antioxidant activity in the DPPH assay with an IC₅₀ of 39 mM (25-62) and 163 mM (136-196), respectively. The data indicate that mechanisms of action of these two novel antipyretic pyrazole derivatives do not involve the classic inhibition of the COX pathway or pyrogenic cytokine release.