RESUMEN
Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for treatment of arthritis. However, their long-term use has been associated with considerable morbidity, limiting their application. Thus, there remains a need to develop new drugs for the effective and safe relief of chronic inflammatory pain. In this context, the present study was designed to evaluate the antinociceptive and antiedematogenic effects of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazole derivatives EPFCA3 and MPFCA4 after acute (1-1000 micromol/kg) and chronic (100 micromol/kg for 15 days) administration in rats submitted to a model of adjuvant-induced arthritis. We also analyzed some biochemical indicators of toxicity (alanine aminotransferase, aspartate aminotransferase, urea and creatinine levels) after prolonged administration of these compounds. We found that acute and chronic subcutaneuous administration of EPFCA3 and MPFCA4 produces an antinociceptive, but not antiedematogenic, effect on the arthritis animal model induced by complete Freund's adjuvant (CFA). No signs of toxicity were observed in the animals chronically treated with EPFCA3 or MPFCA4. Dipyrone (1-1000 micromol/kg) was used as the positive control and its effect was similar to that of the novel pyrazoles. The activity of tissue myeloperoxidase, the tissue TNF-alpha level and the serum haptoglobin level was increased by intraplantar CFA injection. However, chronic administration of EPFCA3, MPFCA4 or dipyrone was not able to alter the relation between these parameters and inflammation. Our results suggest that EPFCA3 and MPFCA4 are good candidates for the development of new drugs for pain treatment.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Dolor/tratamiento farmacológico , Pirazoles/farmacología , Analgésicos/administración & dosificación , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/enzimología , Artritis Experimental/metabolismo , Artritis Experimental/patología , Peso Corporal/efectos de los fármacos , Enfermedad Crónica/tratamiento farmacológico , Creatinina/sangre , Dipirona/administración & dosificación , Dipirona/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/sangre , Edema/tratamiento farmacológico , Edema/enzimología , Edema/patología , Haptoglobinas/metabolismo , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Inflamación/patología , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Tamaño de los Órganos/efectos de los fármacos , Dolor/sangre , Dolor/enzimología , Dolor/patología , Pirazoles/administración & dosificación , Pirazoles/química , Pirazoles/uso terapéutico , Ratas , Ratas Wistar , Estándares de Referencia , Estómago/efectos de los fármacos , Estómago/patología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Urea/sangreRESUMEN
A series of sixteen 2-substituted-2-imidazolines (where the substituent R=Ph, Me-4-Ph; MeO-4-Ph; (MeO)(2)-3,4-Ph; (MeO)(3)-3,4,5-Ph; Ph-4-O-C(O)-Ph; Cl-4-Ph; Cl-2-Ph; Cl(2)-2,4-Ph; NO(2)-4-Ph; NO(2)-3-Ph; Naphth-2-yl; Fur-2-yl; Benzofur-2-yl; Pyridin-2-yl; Quinolin-2-yl) has been synthesized from the reaction of the substituted-aldehydes and ethylenediamine by ultrasound irradiation with NBS in an aqueous medium in high yields (80-99%). The 2-imidazoline ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO) was investigated and some of them showed potent and selective MAO inhibitory activity especially for the MAO-B isoform and could become promising candidates for future development.