title: Antipyretic and antioxidant activities of 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles in rats.
abstract: 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.
authors.affiliation: Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
authors.forename: J S M
authors.initials: JS
authors.lastname: Pasin
authors.forename: A P O
authors.initials: AP
authors.lastname: Ferreira
authors.forename: A L L
authors.initials: AL
authors.lastname: Saraiva
authors.forename: V
authors.initials: V
authors.lastname: Ratzlaff
authors.forename: R
authors.initials: R
authors.lastname: Andrighetto
authors.forename: P
authors.initials: P
authors.lastname: Machado
authors.forename: S
authors.initials: S
authors.lastname: Marchesan
authors.forename: R A
authors.initials: RA
authors.lastname: Zanette
authors.forename: H G
authors.initials: HG
authors.lastname: Bonacorso
authors.forename: N
authors.initials: N
authors.lastname: Zanatta
authors.forename: M A P
authors.initials: MA
authors.lastname: Martins
authors.forename: J
authors.initials: J
authors.lastname: Ferreira
authors.forename: C F
authors.initials: CF
authors.lastname: Mello
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D058633:Antipyretics / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D058633:Antipyretics; D053583:Interleukin-1beta; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2