Effects of Trifluralin on Trypanosoma cruzii in vitro and in vivo

Abstract

Trypanosoma cruzi is the aetiologic agent of Chagas disease that affects approximately 24 million people from Southern California to Argentina and Chile (Schofield 1985) and after malaria, is the most prevalent vector-borne illness in Latin America. Current chemotherapy for short-term treatment includes nitrofurans (nifurtimox) and nitroimidazols (benznidazole) which are not recommended for chronic infections because of their limited effectiveness and serious drug-related side effects (Andrade et al. 1989;Maguirre 1990). For this reason new compounds are urgently needed.Trifluralin (a, a, a-2,6-dinitro-N-N-dipropyl-p-toluidine) is a herbicide that affects cell division in plants, altering microtubular organization and arresting cells in metaphase (Parka et al. 1977). Trifluralin also inhibits microtubule polymerization in some parasitic protozoans as different species of leishmanias (L. muyor, L. donovani, L. panamensis) and Trypanosoma brucei (Chan & Fong 1990;Chan et al. 1993;Chan & Fong 1994). The tubulins are conserved among trypanosomatids so, the microtubular system appears to be a target for selective chemotherapy against Trypanosoma cruzi. In this work we investigate the effect of trifluralin on the three main stages of Trypanosoma cruzi (epimastigotes, amastigotes and tripomastigotes) in vitro and its efficacy in an in vivo murine model.In vitro assays. We tested the efficacy of trifluralin (reagent

A Critical Review on Chagas Disease Chemotherapy

“…Trifluralin also inhibited endocytosis in epimastigotes, monitored by complexes of gold with bovine serum albumine (Dantas et al 1998, Dantas 2000. This dinitroaniline presented also in vivo effect in mice model (Zaidenberg et al 1999) and inhibited the differentiation of epimastigotes to trypomastigotes (Bogitsh et al 1999). …”

Treatment of Experimental Chronic Chagas Disease with Trifluralin

“…At day 90 after infection, with 74% survival and at an intermediate phase of chronic Chagas disease (Añez et al 1999), mice were divided into three groups and treated orally for 60 days with trifluralin (Reagent Quality Magan Argentina; 50 mg/kg/day; n=26), benznidazole (reference drug, Roche Labs; 50 mg/kg/day; n=25), and control (0.2 ml peanut oil as vehicle; n=23). The trifluralin and benznidazole dose was chosen by virtue of previously obtained results (Zaidenberg et al 1999). Eletrocardiography, serologic inmunofluorescence and microstrout studies were carried out before the beginning and the end of the treatment.…”

“…We have previously reported the effects of trifluralin on T. cruzi in vitro and in vivo in an acute model in mice, showing the efficacy of the herbicide against epimastigotes and amastigotes in axenic cultures and in vivo (Zaidenberg et al 1999). Trifluralin was effective in the micromolar range, and the effective concentration altering the amastigote proliferation was of the same order as that required to inhibit promastigotes of several Leishmania species (Chan et al 1993).…”

Pharmacokinetics of Trifluralin in Blood and Heart Tissue of Mice

“…While some authors have reported a very low absorption of the drug [9,11,16] , Dow et al [17] found high plasma trifluralin concentrations after oral administration of the drug in rats. At present there is no evidence of trifluralin pharmacokinetics in humans, and all assays performed in vivo by our group have been made using a mouse model [4,7,15,18] . Knowledge about the pharmacokinetics of trifluralin would be important for further use of this drug in the experimental treatment of Chagas disease in this model.…”

“…It is used as a herbicide against most grasses and many broadleaf weeds, and presents antifungal and antiprotozoic activity [4][5][6][7] . Trifluralin acts as an antitrypanosomatid agent, binding to the parasite's tubulins [8] .…”