Trypanothione reductase inhibitors: Overview of the action of thioridazine in different stages of Chagas disease

Presti, María Silvina Lo; Bazán, Paola Carolina; Strauss, Mariana; Báez, Alejandra L.; Rivarola, Héctor Walter; Paglini-Oliva, Patrícia

doi:10.1016/j.actatropica.2015.02.012

Cited by 42 publications

(28 citation statements)

References 89 publications

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“…As a consequence, chemotherapy with trypanocidal agents remains unsatisfactory, due to the significant limitations of the currently available drugs and the multiple side effects associated with therapy, which frequently result in noncompliance with long-term treatment, particularly in the treatment of chronic patients (8,9).…”

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confidence: 99%

“…The infection then enters the chronic phase and, without successful treatment, becomes permanent. Several years or even decades after the initial infection, approximately 30% to 40% of all infected individuals develop a chronic inflammatory disease that primarily affects the heart tissue (6,8,9). Chagasic myocarditis is the most common form of nonischemic cardiomyopathy worldwide and the most expressive manifestation of the disease because of its frequency and severity (8).…”

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confidence: 99%

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Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

García

Ponce

Sanmarco

et al. 2016

Antimicrob Agents Chemother

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bChagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.

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confidence: 99%

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confidence: 99%

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

García

Ponce

Sanmarco

et al. 2016

Antimicrob Agents Chemother

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“…Although some studies have shown that the decrease of parasites influences the reduction of cardiac damage and the increase of animals’ survival, our results showed that although the 25(+) group presented lower parasitemia in the acute phase, the reduction of the inflammatory process in histopathological studies was observed in the 50(+) group ( Table 3 ). These differences may be related to the levels of active compounds present in the different dosages administered, since they may inhibit oxidation processes in certain systems, but this does not mean that they can protect cells and tissues from all types of oxidative damages, since they may present pro-oxidant activity under certain conditions 38 , 39 .…”

Section: Discussionmentioning

confidence: 99%

Antioxidant effect of Morus nigra on Chagas disease progression

Montenote

Wajsman

Konno

et al. 2017

Rev. Inst. Med. trop. S. Paulo

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Considering the widespread popular use of Morus nigra and the amount of scientific information on its antioxidant and anti-inflammatory activity, the effectiveness of this phytotherapeutic compound in the parasitemia progression during the acute phase of Chagas disease and its role in the development of the inflammatory process as well as its effects on the oxidative damage in the chronic phase of infection were evaluated. Thus, 96 male Swiss mice were randomly divided into eight groups, four groups were uninfected controls, and four groups were intraperitoneally infected with 5.0 x 104 blood trypomastigotes forms of T. cruzi QM2 strain. Four batches composed of one uninfected and one infected group were respectively treated with 70% alcohol solution and 25 μL, 50 μL and 75 μL of the phytotherapeutic compound. Levels of antioxidant elements (TBARS, FRAP, GSH and Sulfhydryl groups) were measured in plasma samples. The phytotherapeutic compound’s antioxidant activity was measured by polyphenol and total flavonoid quantification, DPPH, NO, and FRAP method. Our results showed that the vehicle influenced some of the results that may have physiological relevance in Chagas disease. However, an important action of M. nigra tincture was observed in the progression of Chagas disease, since our results demonstrated a reduction in parasitemia of treated groups when compared to controls, especially in the group receiving 25 µL. However, in the chronic phase, the 50-µL dosage presented a better activity on some antioxidant defenses and minimized the tissue inflammatory process. Results indicated an important action of M. nigra tincture on the Chagas disease progression.

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“…Some phenothiazines demonstrated inhibitory activity against TryR [85]. Within them, thioridazine (44) is one of the most potent TryR inhibitors as investigations have suggested [86]. Clomipramine (45) [87] is another psychiatric drug with inhibiting action towards TryR.…”

Section: Chagas Disease -Basic Investigations and Challenges 162mentioning

confidence: 99%

New Approaches for Chagas’ Disease Chemotherapy

Liñares¹

2018

Chagas Disease - Basic Investigations and Challenges

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The latest advances concerning drug design and chemotherapy development to combat the Chagas' disease are discussed. This chapter is based on the metabolic differences between the pathogenic parasite and mammal hosts that led to the progress in the search for novel metabolic pathways in parasites that may be essential for parasite's survival but with no counterpart in the host. There is a considerable amount of work in the search of more promising molecular targets for drug design. However, the chemotherapy for this disease remains unsolved. It is based on old and fairly not specific drugs associated with long-term treatments, severe side effects, drug resistance, and different strains' susceptibility. Herein, a thorough analysis of selected molecular targets is described in terms of their potential usefulness for drug design. Therefore, rational approaches to the chemotherapeutic control of American trypanosomiasis describing some useful metabolic pathways are covered. Enzymes involved in ergosterol biosynthesis (squalene synthase, HMG-CoA reductase, farnesyl diphosphate synthase (FPPS), sterol 24-methyltransferase, and sterol 14α-demethylase), trypanothione system (glutathionyl-spermidine synthetase, trypanothione synthetase, and trypanothione reductase), cysteine proteases, transsialidase, and so on are discussed. The design of specific inhibitors of these metabolic activities as possible means of controlling the parasites without damaging the hosts is presented. Different compounds can behave as TryR inhibitors when turning into reactive radical speciesthrough the reduction single-electron step [83,91]. Within these structures, 1, 4 naphthoquinones and nitrofurans have been largely studied [92,93]. The most potent derivative of 1,4 naphthoquinone was a quinone-coumarin hybrid [51] despite showing toxicity against rat skeletal myoblasts [94].Between nitrofurans compounds, several 5-nitrofuroic acid derivatives have been synthesized and evaluated against T. cruzi. The best compound was 5-nitro-furan-2-carboxylic acid dibenzyl amide [52], which it significantly increased the trypanocidal nifurtimox activity being TryTR your molecular target [95]. ConclusionsCurrently, the chemotherapy of American trypanosomiasis remains a serious problem in the field of neglected tropical diseases. There are no vaccines, and chemotherapy is limited to old drugs, which present important drawbacks. Taking into account that this disease is associated with poor populations and bad housing conditions, pharmaceutical companies have no economic motivations. Therefore, all efforts to the development of new drugs must be made by academic and/or governmental institutions and new chemotherapies are needed urgently. In order to search new, safer and efficient drugs for the Chagas' treatment, an overview of possible molecular targets based on specific features of the biochemistry of Trypanosoma cruzi was given. Although there are numerous potentially valid targets, only the more representative ones were discussed here. Furthermore, some of t...

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Trypanothione reductase inhibitors: Overview of the action of thioridazine in different stages of Chagas disease

Cited by 42 publications

References 89 publications

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

Antioxidant effect of Morus nigra on Chagas disease progression

New Approaches for Chagas’ Disease Chemotherapy

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