Disease relevance of Lampit

• The enhanced free radical formation may be the basic cause of nifurtimox toxicity in mammals [1].
• Nifurtimox-treated chagasic animals injected with 2,500 trypomastigotes developed higher parasitemia and increased mortality compared with nontreated chagasic mice [2].
• Cell-mediated immunity in Chagas' disease: Alterations induced by treatment with a trypanocidal drug (nifurtimox) [3].
• Role of classical nitroreductase and O-acetyltransferase on the mutagenicity of nifurtimox and eight derivatives in Salmonella typhimurium [4].
• These data indicate a non-random distribution of chromosomal aberrations induced by nifurtimox therapeutic treatment [5].

High impact information on Lampit

• In Trypanosoma cruzi, an organism that is highly susceptible to oxidative stress, LipDH participates in the redox cycling of nifurtimox, one of the most effective anti-Chagas agents [6].
• Reduction of nifurtimox and nitrofurantoin to free radical metabolites by rat liver mitochondria. Evidence of an outer membrane-located nitroreductase [7].
• Nifurtimox is reduced by rat liver microsomes to a nitro anion-free radical as indicated by ESR spectroscopy [1].
• Nifurtimox anion radical generation is significantly stimulated by rat brain and testes homogenates [1].
• 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 [1].

Chemical compound and disease context of Lampit

• l-Buthionine (S,R)-sulfoximine (BSO) increased the toxicity of nifurtimox and benznidazole toward the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi [8].
• Study on the mutagenicity of nifurtimox and eight derivatives with the L-arabinose resistance test of Salmonella typhimurium [9].
• Since MK-436 showed better efficacy in chronic rodent infections than either nifurtimox or benznidazole, such compounds should be evaluated for efficacy in human Chagas' disease [10].
• Primaquine effects upon Trypanosoma cruzi extracts are compared with those obtained with nifurtimox, a compound effective in the treatment of Chagas' disease [11].
• 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 [12].

Biological context of Lampit

• 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 [2].
• Nifurtimox inhibition affected polyenoic fatty acids and cytochrome P-450 degradation that follows lipid peroxidation [13].
• A group of 66 children was treated with nifurtimox, and followed up every 3 months during the first year and every 6 months during the second and third year post-therapy, by PCR, xenodiagnosis and serology [14].
• Labeling of RNA with [3H]uridine in the presence of nifurtimox followed atypical kinetics since, depending on incubation time and concentration, RNA degradation prevailed over RNA synthesis [15].
• Isolated from axenic cultures of the parental cells (IC50 1.5 microM), R-Dm28 epimastigotes exhibited 13-fold (IC50) 20 microM) higher resistance to this inhibitor and did not display cross-resistance to unrelated trypanocidal drugs, such as benznidazol and nifurtimox [16].

Anatomical context of Lampit

• 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 [8].
• Antibodies reacting against endothelial cells, vascular structures, and heart and skeletal muscle cells (EVI antibodies) were studied in 10 patients (one to 14 years of age) treated with Nifurtimox [17].
• Nevertheless, the extra GSH release in the nifurtimox-treated rats may indicate an alteration of the hepatocyte membrane [18].
• Furthermore, the cell-free supernatant from PPD-stimulated lymphocytes from FCA-immunized nifurtimox-treated guinea-pigs did not inhibit the migration of normal cells [19].
• Results with nifurtimox, ketoconazole, and formycin B, compounds known to have in vivo activity against T. cruzi, revealed that the ELISA technique was capable of detecting small dose-response variations in the rate of phagocytosis of different life cycle stages of T. cruzi by normal and activated mouse macrophages [20].

Associations of Lampit with other chemical compounds

• Deletion of the Trypanosoma brucei Superoxide Dismutase Gene sodb1 Increases Sensitivity to Nifurtimox and Benznidazole [21].
• Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection.Methods [22].
• In vitro studies on a mammalian LipDH revealed the ability of the flavoenzyme to catalyze the redoxcycling and superoxide anion production of nitrofuran derivatives including the antitrypanosomal drug Nifurtimox [23].
• The effect of length of treatment of Trypanosoma cruzi with Bayer 2502 (Bay 2502, Lampit, Nifurtimox) on resistance to challenge and parasite isolation was studied in two experiments [24].
• Verapamil alone was not active against either parasite, but in combination with nifurtimox it reversed the drug resistance of T. cruzi and in combination with sodium stibogluconate reversed the drug resistance of L. donovani [25].

Gene context of Lampit

• No significantly induced mutation frequency could be detected with NG30 (recA-), which is very sensitive to killing by nifurtimox [12].
• 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 [18].
• 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 [12].
• Both trypanothione reductase and heat-shock proteins may modulate the effects of exposure of T. cruzi to nifurtimox [26].
• Nifurtimox, the drug used in the treatment of Chagas' disease, is a stronger inhibitor of glutathione reductase (Ki = 40 microM) than of trypanothione reductase (IC50 = 200 microM) [27].

Analytical, diagnostic and therapeutic context of Lampit

• Reinfection of chronic chagasic mice after treatment with nifurtimox resulted in different outcomes according to the number of parasites used for inoculation [2].
• Treatment of Trypanosoma cruzi-infected children with nifurtimox: a 3 year follow-up by PCR [14].
• Early diagnosis and treatment with benznidazole or nifurtimox probably improve the survival rate [28].
• Continuous perfusion with 10(-6) M Lampit resulted in a linear increase in intracellular parasite reproduction time [29].
• 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 [26].

References