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

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 percent Tween 80 in 0.9 percent 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 percent, 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 percent 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.

Fatores associados com os tipos de heparina usados no tratamento da angina instável em um hospital brasileiro / Factors Associated with the Types of Heparin used in the Treatment of Unstable Angina at a Brazilian Hospital

Unfractionated heparin (UFH) and low-molecularweight heparins (LMWHs) are widely used in curative and preventive treatments of thromboembolic disorders. The aim of the study was to investigate factors associated with the choice of these types of heparin to treat patients with unstable angina under real conditions of hospital use. A cross-sectional study was performed in a private general hospital in Belo Horizonte, Brazil, from January 1st to December 31th, 2001. Data were collected from the hospital electronic database. Inpatients with angina who received enoxaparin or UFH were included in the survey. Data for 555 patients were recorded, including 401 treated with enoxaparin and 154 with UFH. Univariate analysis showed that male and elderly people predominated in both groups, with no statistical difference in the proportions (p>0.05). Multivariate analysis showed 4 factors associated with the use of enoxaparin: cardiac revascularization surgery (OR=0.434), arrhythmias (OR=9.343), risk factors for coronary artery disease (OR=1.333) and private health insurance (OR=0.297). Thus, clinical and organizational factors were associated with the type of heparin used by patients with unstable angina at this hospital. Further drug utilization studies are necessary to expand and improve the data available on the use of heparins in the hospital setting.

A heparina não-fracionada (HNF) e heparinas de baixo peso molecular (HBPM) são amplamente utilizadas em tratamentos curativos e preventivos de tromboembolismo. O objetivo do estudo foi investigar os fatores associados com a escolha desses tipos de heparinas para tratar pacientes com angina instável sob as condições reais de uso hospitalar. Trata-se de um estudo transversal realizado em hospital geral privado, na cidade de Belo Horizonte,MG Brasil, no período de Janeiro a Dezembro de 2001. Para a coleta de dados, utilizou-se o banco de dados informatizado do referido hospital. Pacientes internados com angina que receberam enoxaparina ou HNF foram incluídos no estudo. Registrou-se dados de 555 pacientes, incluindo 401 tratados com enoxaparina e 154 com HNF. Na análise univariada, observouse que o gênero masculino e pacientes idosos foram predominantes em ambos os grupos, sem diferença estatística entre as proporções (p>0,05). A análise multivariada revelou quatro fatores associados ao uso de enoxaparina: cirurgia de revascularização cardíaca (OR=0,434), arritmias (OR=9,343), fatores de risco para doença coronariana (OR=1,333) e atendimento por plano de saúde (OR=0,297). Assim, fatores clínicos e organizacionais estão associados com o tipo de heparina usado por pacientes com angina instável, neste hospital. A realização de mais estudos de utilização de medicamentos é necessária para aprimorar o conhecimento sobre o uso de heparinas, em hospitais.

A pyrazolyl-thiazole derivative causes antinociception in mice

The present study investigates the antinociceptive effect of the pyrazolyl-thiazole derivative 2-(5-trichloromethyl-5-hydroxy-3-phenyl-4,5-dihydro-1 H-pyrazol-1-yl)-4-(4-bromophenyl)-5-methylthiazole (B50) in mice. Male albino Swiss mice (30-40 g) were used in the acetic acid-induced abdominal writhes and tail-immersion tests. B50 caused dose-dependent antinociception (8, 23 and 80 µmol/kg, sc) in the acetic acid writhing assay (number of writhes: vehicle: 27.69 ± 6.15; B50 (8 µmol/kg): 16.92 ± 3.84; B50 (23 µmol/kg): 13.85 ± 3.84; B50 (80 µmol/kg): 9.54 ± 3.08; data are reported as means ± SEM for 9 animals per group). On the other hand, B50 did not cause antinociception in the tail immersion assay. Naloxone (2.75 µmol/kg, sc) prevented B50-induced antinociception (number of writhes: vehicle-saline: 31.11 ± 3.15; vehicle-naloxone: 27.41 ± 3.70; B50 (80 µmol/kg)-saline: 8.70 ± 3.33; B50 (80 µmol/kg)-naloxone: 31.84 ± 4.26; morphine-saline: 2.04 ± 3.52; morphine-naloxone: 21.11 ± 4.26; 8-9 animals per group). The removal of the methyl group of the thiazole ring of B50 or substitution of the bromo substituent with the methyl at position 4 of the phenyl group, which is attached to the thiazole ring of B50, resulted in loss of activity, suggesting that these substituents are important for antinociceptive activity. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the antinociceptive effect of B50 is not related to nonspecific motor effects. The antinociceptive profile of B50 seems to be closer to nonsteroidal anti-inflammatory drugs than to classic opioid agents, since it had no analgesic effect in a thermally motivated test.

Antinociceptive effect of novel pyrazolines in mice

The antinociceptive effect of six novel synthetic pyrazolines (3-ethoxymethyl-5-ethoxycarbonyl-1H-pyrazole (Pz 1) and its corresponding 1-substituted methyl (Pz 2) and phenyl (Pz 3) analogues, and 3-(1-ethoxyethyl)-5-ethoxycarbonyl-1H-pyrazole (Pz 4) and its corresponding 1-substituted methyl (Pz 5) and phenyl (Pz 6) analogues) was evaluated by the tail immersion test in adult male albino mice. The animals (N = 11-12 in each group) received vehicle (5 percent Tween 80, 10 ml/kg, sc) or 1.5 mmol/kg of each of the pyrazolines (Pz 1-Pz 6), sc. Fifteen, thirty and sixty minutes after drug administration, the mice were subjected to the tail immersion test. Thirty minutes after drug administration Pz 2 and Pz 3 increased tail withdrawal latency (vehicle = 3.4 ± 0.2; Pz 2 = 5.2 ± 0.4; Pz 3 = 5.9 ± 0.4 s; mean ± SEM), whereas the other pyrazolines did not present antinociceptive activity. Dose-effect curves (0.15 to 1.5 mmol/kg) were constructed for the bioactive pyrazolines. Pz 2 (1.5 mmol/kg, sc) impaired motor coordination in the rotarod and increased immobility in the open-field test. Pz 3 did not alter rotarod performance and spontaneous locomotion, but increased immobility in the open field at the dose of 1.5 mmol/kg. The involvement of opioid mechanisms in the pyrazoline-induced antinociception was investigated by pretreating the animals with naloxone (2.75 µmol/kg, sc). Naloxone prevented Pz 3- but not Pz 2-induced antinociception. Moreover, naloxone pretreatment did not alter Pz 3-induced immobility. We conclude that Pz 3-induced antinociception involves opioid mechanisms but this is not the case for Pz 2.