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At least 19 recordsLinked to original sources

PubMed1983

[Effects of nifurtimox, benznidazole, and beta-lapachone on the metabolism of DNA, RNA and proteins in Trypanosoma cruzi].

Nifurtimox and benznidazole have trypanostatic actions in vitro and inhibit the incorporation of [3H] thymidine, [3H] uridine and L-[3H] leucine in T. cruzi macromolecules. The effect of nifurtimox may be explained by (a) direct inhibition of nucleic acid biosynthesis, or (b) generation of the oxygen radicals in T. cruzi and therefore, only mechanism (a) should be valid. In order to obtain more information on the action of these drugs on T. cruzi, in the present study we examined the effect of nifurtimox and benznidazole on DNA, RNA and protein turnover in epimastigote (culture) forms of the parasite. Complementary experiments were performed with beta-lapachone that, like nifurtimox, generates oxygen radicals in T. cruzi. Epimastigotes (Tulahuen strain) at the exponential-phase of growth were cultured with [3H] thymidine, [3H] uridine or L-[3H] leucine to label DNA, RNA and protein, respectively. After incubation, the cells were washed free of radioactive precursor, resuspended in fresh medium and reincubated at 30 degrees C with nifurtimox (10 or 100 microM), benznidazole (38 or 380 microM) or beta-lapachone (1.6 or 7.8 microM), for 1-3 hours. Controls were incubated without drug. At one hour time intervals, sampler were taken, washed free of medium and filtered through 0.45 microns Metricel filters. The filters were washed with 10% trichloroacetic acid to remove the acid soluble material, and after drying, the radioactivity incorporated in DNA, RNA and protein was counted with a scintillation counter. The results show that after elimination of the labelled precursors, 3H activity in DNA, RNA and protein decayed as a function of the time of incubation. Nifurtimox, benznidazole and beta-lapachone, stimulated in all cases they decay of the incorporated radioactivity. Calculation of "half-life" values for DNA, RNA and protein(s) indicated that nifurtimox and beta-lapachone exerted their greatest effects on DNA while benznidazole increased the decay of DNA, RNA and protein to about the same extent. Taking into account the effects of nifurtimox and beta-lapachone on DNA stability, specific lesions (single-strand breaks) were investigated in DNA from control, nifurtimox, benznidazole or beta-lapachone treated epimastigotes. The number of single-strand breaks was (per 10(6)b) 25 with 100 microM nifurtimox, 1.4 with 380 microM benznidazole and 45 with 7.8 microM g-lapachone. Interestingly enough, after reincubation of nifurtimox-damaged epimastigotes in fresh medium for 24 hours, recovery of DNA lesions could be observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

Characterization and trypanocidal activity of nifurtimox-containing and empty nanoparticles of polyethylcyanoacrylates.

The aim of this study was to evaluate the utility of nanoparticles of polyalkylcyanoacrylate as a targeted delivery system for nifurtimox against Trypanosoma cruzi, responsible for Chagas' disease. Ethylcyanoacrylate nanoparticles were prepared by an emulsion polymerization process and formulations containing different concentrations of nifurtimox, polyethylcyanoacrylates and surfactants were investigated and analysed for size and drug content. The nanoparticles obtained were less than 200 nm in size, as measured by electron microscopy and cytometry. The peak percentage of nifurtimox uptake into the nanoparticles was 33.4% for use of 500 microL polyethylcyanoacrylate, 200 microL surfactant (Tween 20) and 10 mg nifurtimox in 50 mL polymerization medium. The highest release of nifurtimox from the nanoparticles was 65.4% after 6-h incubation at pH 7.4. In-vitro studies using cultures of T. cruzi epimastigotes revealed considerably increased trypanocidal activity compared with a standard solution of nifurtimox. Studies of cell cultures previously infected with metacyclic forms of the parasite showed that only 2-h treatment with solutions of 0.001% of the nanoparticle suspension reduced parasitism by 87-94% both when the nanoparticles were loaded with nifurtimox and when unloaded. Electron-microscopic examination revealed processes of degeneration and lysis, suggesting apoptotic processes, in intracellular amastigotes and free amastigotes treated with the nanoparticles. It was demonstrated that unloaded nanoparticles, by mechanisms not completely elucidated, have trypanocide activity similar to that of a standard solution of nifurtimox. It is concluded that the nanoparticles loaded with nifurtimox constitutes a good carrier of the drug against T. cruzi. The loaded-nanoparticles significantly increase trypanocidal activity.

Animals↗

PubMed1996

Cellular and molecular biological analyses of nifurtimox resistance in Trypanosoma cruzi.

We induced nifurtimox resistance in both epimastigotes and tissue culture-derived trypomastigotes of several Trypanosoma cruzi strains. The magnitude of nifurtimox resistance was strain-dependent. A variety of karyotype changes occurred in the nifurtimox-resistant (NR) strains. Chromosome-specific DNA probes identified karyotype changes common to the NR strains that were moderately resistant to nifurtimox but not the NR strains that were highly resistant to nifurtimox. A marked increase in nifurtimox resistance in one NR strain was accompanied by a 100% increase in nuclear DNA mass and a 50% increase in kinetoplast DNA mass. These data suggest that nifurtimox resistance can be accompanied by a wide spectrum of DNA changes. Both trypanothione reductase and heat-shock proteins may modulate the effects of exposure of T. cruzi to nifurtimox. However, we did not detect qualitative or quantitative differences in these genes or their transcripts between the NR strains and the sensitive strains from which they were derived. An understanding of the spectrum of diversity in nifurtimox resistance at the cellular and molecular levels demonstrated in this report is critical in the development of drug therapies against Chagas' disease.

Amino Acid Sequence↗

PubMed1998

Nifurtimox plus pyrimethamine for treatment of murine toxoplasmosis.

In the search for novel antitoxoplasmic agents, we evaluated the efficacy of nifurtimox (3-methyl-4[5'-nitrofurfurylidene-amino]-tetrahydroe-4H-1,4- thiazine-1,1-dioxide), an antiprotozoal drug effective against trypanosomiasis, in an experimental model of acute toxoplasmosis in mice. One hundred NIH mice were inoculated intraperitoneally, each with 2,614 RH tachyzoites of Toxoplasma gondii, and randomly allocated into 5 groups (n = 19-21). Animals from each group were orally treated for 10 days either with nifurtimox 25 mg/kg/day (NF1), nifurtimox 50 mg/kg/day (NF2), pyrimethamine 60 mg/kg/day (P), the combination nifurtimox 50 mg/kg/day plus pyrimethamine 60 mg/kg/day (NF2-P), or with corn oil (controls). Survival of mice was recorded daily for 1 mo after the experimental infection. Comparisons of cumulative mortality between groups were made applying the chi2 test. Mean survival time was longer in animals from P and NF2-P groups than those from NF1, NF2, and control groups. Cumulative mortality was less in mice from the NF2-P group (25%), than that in mice from the P (65%), the NF1 (100%), the NF2 (89%), or the control (95%) groups (P < 0.01). The doses of nifurtimox used in the present study were not significantly effective against murine toxoplasmosis. However, when combined with pyrimethamine, a strong anti-toxoplasma effect was obtained in comparison with survival rates associated with pyrimethamine or nifurtimox alone. It seems feasible that nifurtimox inhibits the replication of T. gondii tachyzoites similar to that of other protozoans, e.g., Trypanosoma and Leishmania. It will be important to determine if the reduction of mortality in mice treated with the nifurtimox-pyrimethamine combination results from summation or from synergism. Further studies on the toxic mechanisms exerted by nifurtimox on T. gondii seem warranted.

Administration, Oral↗

PubMedDate not supplied

High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire.

Thirty patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with high-dose nifurtimox (30 mg/kg/d for 30 d). During treatment, the cerebrospinal fluid (CSF) white blood cell (WBC) count decreased in all patients except one (mean CSF WBC count before nifurtimox: 117/mm3; after nifurtimox: 25/mm3), and trypanosomes disappeared from the CSF of all 9 patients in whom parasites had been demonstrated before nifurtimox. Among 25 patients seen at least once after treatment, 9 (36%) have relapsed so far. High-dose nifurtimox was significantly toxic: one patient died during treatment and 8 others developed adverse neurological effects. High-dose nifurtimox seems more effective than the previously used regimen (15 mg/kg/d for 60 d), but at the expense of significant toxicity.

Animals↗

PubMed2005

Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi.

l-Buthionine (S,R)-sulfoximine (BSO) increased the toxicity of nifurtimox and benznidazole toward the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi. BSO at 500 muM decreased total glutathione-derived thiols by 70 to 80% in 48 h. In epimastigotes, 500 muM BSO decreased the concentration of nifurtimox needed to inhibit constant growth of the parasites by 50%, from 14.0 to 9.0 muM, and decreased that of benznidazole from 43.6 to 24.1 muM. The survival of epimastigotes or trypomastigotes treated with nifurtimox or benznidazole, as measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) reduction, was significantly decreased by 500 muM BSO. In Vero cells infected with amastigotes, 25 muM BSO was able to potentiate the effect of nifurtimox and benznidazole as measured by the percentage of infected Vero cells multiplied by the average number of intracellular amastigotes (endocytic index). At 0.5 muM nifurtimox, the proportion of Vero cells infected decreased from 27 to 20% and the endocytic index decreased from 2,500 to 980 when 25 muM BSO was added. Similar results were obtained with benznidazole- and BSO-benznidazole-treated cells. This study indicates that potentiation of nifurtimox or benznidazole by BSO could decrease the clinical dose of both drugs and diminish the side effects or the length of therapy.

Animals↗

PubMed2002

Cytotoxicity and trypanocidal activity of nifurtimox encapsulated in ethylcyanoacrylate nanoparticles.

The aim of the present study was to study the trypanocidal activity of nanoparticles loaded with nifurtimox in comparison with the free drug against Trypanosoma cruzi, responsible for Chagas' disease. Ethylcyanoacrylate nanoparticles acted as the delivery system into cells. As the obligate replicative intracellular form is amastigote, in vitro studies were performed on this form of parasite as well as on cell culture derived trypomastigotes. The fluorescence method used here was very useful as it allowed for the simultaneous study of trypanocide activity and cytotoxicity by determining living or dead parasites within living or dead host cells. According to these results, the greatest trypanocide activity on cell culture-derived trypomastigotes was recorded for nifurtimox-loaded nanoparticles with a 50% inhibitory concentration (IC50) twenty times less than that of the free drug. The cytotoxicity of unloaded nanoparticles at low concentrations was similar to that obtained by free drug when evaluated on Vero cells. Furthermore, nifurtimox-loaded nanoparticles showed increased trypanocide activity on intracellular amastigotes with an IC50 thirteen times less than that of nifurtimox. We also observed that the unloaded nanoparticles possess the previously-described trypanocide activity, similar to the standard solution of nifurtimox, although the mechanism for this has not yet been elucidated. In conclusion, it was possible to establish in vitro conditions using nifurtimox encapsulated nanoparticles in order to decrease the doses of the drug and thus to obtain high trypanocidal activity on both free trypomastigotes and intracellular amastigotes with low cytotoxicity for the host cell.

Animals↗

PubMed1981

Generation of free radicals induced by nifurtimox in mammalian tissues.

Nifurtimox is reduced by rat liver microsomes to a nitro anion-free radical as indicated by ESR spectroscopy. This subcellular fraction gives a steady state radical concentration which is proportional to the square root of the protein concentration, suggesting that the nifurtimox anion radical is a necessary intermediate in the reduction and that the radical decays through a nonenzymatic second order process. The steady state concentration of the anion radical in the microsomal system is not decreased by superoxide dismutase or catalase, thus indicating that neither the superoxide anion nor hydrogen peroxide is an intermediary in the generation of the anion radical. The steady state concentration of the anion radical in the microsomal system is also not altered in the presence of metyrapone or CO and is decreased in the presence of NADP+ and p-chloromercuribenzoate. This observation suggests that the formation of nifurtimox anion radical is mediated through NADPH-cytochrome P-450 (c) reductase and not by the cytochrome P-450 system. In accordance with this interpretation, a model system consisting of NADPH and FMN-reduced nifurtimox to the nitro anion-free radical. Nifurtimox anion radical generation is significantly stimulated by rat brain and testes homogenates. The enhanced free radical formation may be the basic cause of nifurtimox toxicity in mammals.

Animals↗

PubMed1983

Increased biliary secretion and loss of hepatic glutathione in rat liver after nifurtimox treatment.

Treatment of rats with nifurtimox, a nitrofuran derivative widely used for the treatment of Chagas' disease, induced a time- and dose-dependent depletion of liver glutathione, maximal effects being obtained with 200 mg nifurtimox/kg body weight. Extra release of both oxidized (GSSG) and reduced (GSH) glutathione into bile contributed to this depletion. Glutathione excretion into bile accounted for only part of liver glutathione loss, thus indicating that, in addition to the GSH-peroxidase reaction (resulting in GSSG generation), other glutathione-related processes were involved in nifurtimox detoxification. Bile flow, bile salt excretion, liver lipid conjugated diene content, liver glutathione reductase and glutathione peroxidase activities, and serum alanine aminotransferase (ALAT) activity were not affected by the nifurtimox treatment, thus ruling out widespread damage of the liver cell by nifurtimox. Nevertheless, the extra GSH release in the nifurtimox-treated rats may indicate an alteration of the hepatocyte membrane.

Alanine Transaminase↗

PubMedDate not supplied

An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire.

Twenty-five patients with arseno-resistant Trypanosoma brucei gambiense sleeping sickness were treated with oral nifurtimox, 12-17 mg/kg/d for 60 d. During treatment, trypanosomes disappeared from the cerebrospinal fluid (CSF) of 7/7 patients; the CSF infections; leucocyte was significantly lower at the end of treatment than before it was begun (pre-nifurtimox: 124.2 (+/- 149.3) per microliter; post-nifurtimox: 11.9 (+/- 12.1) per microliter; P less than 0.001). Nifurtimox was well tolerated, with gastro-intestinal disturbances in 6 patients and a reversible cerebellar syndrome in 2 patients. Among the 19 patients seen at least once at follow-up, 12 (63%) relapsed. The other 7 patients have been followed for 3-18 months, and the CSF remained completely normal in 4 of them. This study confirms that nifurtimox has some activity against T.b. gambiense, but a daily dosage higher than 15 mg/kg/d will be necessary to achieve cure of most patients.

Adolescent↗

PubMed1991

Comparative studies of nifurtimox uptake and metabolism by drug-resistant and susceptible strains of Trypanosoma cruzi.

1. Nifurtimox uptake and metabolism by epimastigote forms of three strains of Trypanosoma cruzi (Basileu, Y, YuYu) with different drug responsiveness in mice experimental infections were compared. 2. Statistical analysis of the results demonstrated no correlation between the ability of the strains to catalyze nifurtimox redox-cycling (Basileu = Y = YuYu) nor nifurtimox multiple electron reduction (Basileu = Y greater than Y) and drug susceptibility (Basileu greater than Y greater than YuYu). 3. A partial correlation however, was observed between drug responsiveness and nifurtimox uptake (Basileu greater than Y = YuYu). 4. The results suggest that drug uptake may be more important than drug metabolism in modulating resistance to nifurtimox in T. cruzi strains.

Animals↗

PubMed2006

Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness.

BACKGROUND: Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection. METHODS: An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment. RESULTS: A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n=48) were observed only with the 3 monotherapy regimens. CONCLUSION: A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.

Administration, Oral↗

PubMed1994

Disposition of nifurtimox and metabolite activity against Trypanosoma cruzi using rat isolated perfused liver.

Nifurtimox disposition was investigated using the rat isolated perfused-liver method after administration of 25 micrograms mL-1 nifurtimox, and its disappearance was monitored by analysing the perfusate sample at various times. Biliary excretion was also measured. The drug concentration profile underwent a biexponential decline over the 2-h study period, with a terminal half-life of 62.76 +/- 17.56 min. Nifurtimox is a high clearance compound (15.23 +/- 5.53 mL min-1). The extraction ratio was 0.621 +/- 0.159. Biliary excretion accounted for 0.05% of the dose, the remainder consisting of highly polar metabolites. By 2 h, a minimal fraction of unchanged nifurtimox was recovered from the perfusate. Nifurtimox activity against Trypanosoma cruzi (clone CA-1) during the perfusion was also determined. Epimastigotes isolated from continuous culture were exposed to the samples of perfusate at different perfusion times in a microtitre plate. After an incubation time of 72 h at 27 degrees C, the parasite number in each well was counted under a microscope. From 0 to 75 min after the perfusion, the anti-trypanosomal activity decreased, but an increase in activity was observed at the later times. These findings show that active metabolites are formed during the perfusion.

Animals↗

PubMed1980

Mutagenicity of nifurtimox in Escherichia coli.

The effects of nifurtimox, a nitrofuran derivative, on killing and mutation induction in 3 Escherichia coli strains having different DNA-repair systems for UV lesion were studied and compared with the effects of furylfuramide. Nifurtimox induces mutations at a high frequency in both Hs3OR (uvrA-) and H/r30R (radiation-resistant), although no significant killing effect is detected with Hs30R. No significantly induced mutation frequency could be detected with NG30 (recA-), which is very sensitive to killing by nifurtimox. The characteristics of lesions of DNA induced by nifurtimox and the mechanism of mutation induction in Hs30R are discussed.

DNA Repair↗

PubMed1985

Studies on pentane evolution by rats treated with nifurtimox or benznidazole.

Sprague-Dawley male rats were treated with either 100 mg/kg Nifurtimox or Benznidazole p.o. and pentane evolution was measured at different periods of time. No significant increase in pentane evolution was observed in animals treated with Benznidazole during periods of time up to 10 h. In animals treated with Nifurtimox, a significant increase in pentane evolution was observed at 10 h but not at 3 or 6 h. The pentane evolution effect of Nifurtimox was compared to that of carbon tetrachloride. The latter was very intense up to 1 h and ceased thereafter. The possible participation of lipid peroxidation in the unwanted toxic side effects of Nifurtimox and Benznidazole is discussed.

Animals↗

PubMed1988

Differences in resistance to reinfection with low and high inocula of Trypanosoma cruzi in chagasic mice treated with nifurtimox and relation to immune response.

Reinfection of chronic chagasic mice after treatment with nifurtimox resulted in different outcomes according to the number of parasites used for inoculation. Nifurtimox-treated chagasic animals injected with 2,500 trypomastigotes developed higher parasitemia and increased mortality compared with nontreated chagasic mice. When reinfection was done with 25 trypomastigotes, treated and nontreated animals showed similar parasitemias and mortalities, which were significantly higher in nonchagasic controls infected for the first time. Immunological studies showed that treatment with nifurtimox led to a decrease in anti-Trypanosoma cruzi antibodies engaged in parasite destruction, inducing either complement-dependent lysis or antibody-dependent cytotoxicity, but no difference in anti-T. cruzi cell-mediated immunity was found between treated and nontreated chagasic animals. It is concluded that treatment with nifurtimox leads to a loss of resistance to reinfection with a large number of trypanosomes, which is maintained with challenge with a few parasites, and that these two thresholds of premunition are probably associated with humoral and cell-mediated anti-T. cruzi immune responses, respectively.

Animals↗

PubMedDate not supplied

[Comparative controlled study on the use of benznidazole, nifurtimox and placebo, in the chronic form of Chagas' disease, in a field area with interrupted transmission. I. Preliminary evaluation].

A controlled clinical trial was carried out to evaluate the therapeutic efficacy and tolerance of nifurtimox and benznidazole in patients with chronic Chagas' disease. All patients had immunofluorescence and complement fixation reactions positives for T. cruzi antibodies and at least two xenodiagnoses positives in three performed before treatment, and they were submitted to clinical examinations, ECG and X-ray of the heart and esophagus. Of 77 patients studied, 27 were treated with nifurtimox and 26 with benznidazole in the dosage of 5 m/kg/day for 30 consecutive days, and 24 received a placebo in tablets similar to benznidazole. From the 77 patients, 64 (83.1%) accomplished the treatment: 23 (88.4%) with benznidazole, 19 (70.3%) with nifurtimox and 22 (91.6%) with placebo. The patients were evaluated, clinically, serologically and parasitologically (six xenodiagnoses within one year after treatment). The benznidazole group showed only 1.8% of positive xenodiagnoses post-treatment, the nifurtimox 9.6% and the placebo 34.3%. All serologic reactions continued positive and there were no clinical, ECG or X-ray changes one year after treatment.

Chagas Disease↗

PubMed1986

Mutagenicity of nifurtimox and benznidazole in the Salmonella/microsome assay.

The genetic activities of two widely used anti-Trypanosoma cruzi drugs, nifurtimox and benznidazole, were investigated. The Salmonella mutagenicity (Ames) test was used to evaluate the mutagenic activity of both drugs. Nifurtimox and benznidazole preferentially induced backward mutations in the base substitution mutagen indicator strain TA100. The observed mutation rates for both drugs were linear over a wide concentration range. Maximum mutagenic activity was obtained at 35 and 100 micrograms per plate for nifurtimox and benznidazole, respectively. No increase in the mutagenic activity of either drug was observed in the presence of rat liver microsomal extracts. Survival experiments revealed that nifurtimox was at least four times more toxic than benznidazole for the Salmonella indicator strain.

Mutagenicity Tests↗