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Article ; Online: The translational challenge in Chagas disease drug development.

Kratz, Jadel M / Gonçalves, Karolina R / Romera, Lavínia Md / Moraes, Carolina Borsoi / Bittencourt-Cunha, Paula / Schenkman, Sergio / Chatelain, Eric / Sosa-Estani, Sergio

Memorias do Instituto Oswaldo Cruz

2022 Volume 117, Page(s) e200501

Abstract: Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development ... ...

Abstract	Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development for Chagas disease has historically been hampered by the complexity of the disease, critical knowledge gaps, and lack of coordinated R&D efforts. This review covers some of the translational challenges associated with the progression of new chemical entities from preclinical to clinical phases of development, and discusses how recent technological advances might allow the research community to answer key questions relevant to the disease and to overcome hurdles in R&D for Chagas disease.
MeSH term(s)	Chagas Disease/drug therapy ; Chagas Disease/parasitology ; Drug Development ; Drug Discovery ; Humans ; Neglected Diseases/drug therapy ; Trypanocidal Agents/pharmacology ; Trypanocidal Agents/therapeutic use ; Trypanosoma cruzi
Chemical Substances	Trypanocidal Agents
Language	English
Publishing date	2022-05-23
Publishing country	Brazil
Document type	Journal Article ; Review
ZDB-ID	953293-6
ISSN	1678-8060 ; 0074-0276
ISSN (online)	1678-8060
ISSN	0074-0276
DOI	10.1590/0074-02760200501
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Article: Poly-ε-Caprolactone Implants for Benznidazole Prolonged Release: An Alternative to Chagas Disease Oral Treatment.

Mazzeti, Ana Lia / Gonçalves, Karolina R / Boasquívis, Patrícia Ferreira / Barbosa, Jamile / Pereira, Bruno G / Soeiro, Maria de Nazaré Correia / Mosqueira, Vanessa Carla Furtado / Bahia, Maria Terezinha

Pharmaceutics

2023 Volume 15, Issue 4

Abstract: Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants ...

Abstract	Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-ɛ-caprolactone (PCL) is proposed in this study for a controlled release of BZ and to improve patient compliance. The BZ-PCL implants were characterized by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, which indicated that BZ remains in its crystalline state dispersed in the polymer matrix with no polymorphic transitions. BZ-PCL implants, even at the highest doses, induce no alteration of the levels of hepatic enzymes in treated animals. BZ release from implants to blood was monitored in plasma during and after treatment in healthy and infected animals. Implants at equivalent oral doses increase the body's exposure to BZ in the first days compared with oral therapy, exhibiting a safe profile and allowing sustained BZ concentrations in plasma to induce a cure of all mice in the experimental model of acute infection by the Y strain of
Language	English
Publishing date	2023-04-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15041126
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Article ; Online: Combination therapy using nitro compounds improves the efficacy of experimental Chagas disease treatment.

Mazzeti, Ana Lia / Gonçalves, Karolina R / Mota, Suianne L A / Pereira, Dário Elias / Diniz, Lívia de F / Bahia, Maria Terezinha

Parasitology

2021 Volume 148, Issue 11, Page(s) 1320–1327

Abstract: Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) ...

Abstract	Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day−1 (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.
MeSH term(s)	Animals ; Chagas Disease/drug therapy ; Drug Therapy, Combination ; Female ; Humans ; Inhibitory Concentration 50 ; Mice ; Neglected Diseases/drug therapy ; Nifurtimox/adverse effects ; Nifurtimox/therapeutic use ; Nitro Compounds/adverse effects ; Nitro Compounds/therapeutic use ; Nitroimidazoles/adverse effects ; Nitroimidazoles/metabolism ; Nitroimidazoles/therapeutic use ; Real-Time Polymerase Chain Reaction ; Sulfones/adverse effects ; Sulfones/therapeutic use
Chemical Substances	Nitro Compounds ; Nitroimidazoles ; Sulfones ; fexinidazole (306ERL82IR) ; Nifurtimox (M84I3K7C2O) ; benzonidazole (YC42NRJ1ZD)
Language	English
Publishing date	2021-06-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207627-5
ISSN	1469-8161 ; 0031-1820
ISSN (online)	1469-8161
ISSN	0031-1820
DOI	10.1017/S0031182021001001
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Article: Combination therapy using nitro compounds improves the efficacy of experimental Chagas disease treatment

Mazzeti, Ana Lia / Gonçalves, Karolina R. / Mota, Suianne L. A. / Pereira, Dário Elias / Diniz, Lívia de F. / Bahia, Maria Terezinha

Parasitology. 2021 Sept., v. 148, no. 11

2021

Abstract	Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day⁻¹ (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.
Keywords	Chagas disease ; Trypanosoma cruzi ; benznidazole ; blood serum ; enzymes ; metabolites ; mice ; models ; parasitemia ; parasitology ; toxicity ; weight gain
Language	English
Dates of publication	2021-09
Size	p. 1320-1327.
Publishing place	Cambridge University Press
Document type	Article
ZDB-ID	207627-5
ISSN	1469-8161 ; 0031-1820
ISSN (online)	1469-8161
ISSN	0031-1820
DOI	10.1017/S0031182021001001
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Article ; Online: Benznidazole self-emulsifying delivery system: A novel alternative dosage form for Chagas disease treatment.

Mazzeti, Ana Lia / Oliveira, Liliam Teixeira / Gonçalves, Karolina R / Schaun, Géssica C / Mosqueira, Vanessa Carla Furtado / Bahia, Maria Terezinha

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2020 Volume 145, Page(s) 105234

Abstract: Benznidazole (BZ) tablets are a unique form of treatment available for treating Chagas disease. Development of a liquid formulation containing BZ easy to administer orally for the treatment of paediatric patients, particularly for newborns is urgently ... ...

Abstract	Benznidazole (BZ) tablets are a unique form of treatment available for treating Chagas disease. Development of a liquid formulation containing BZ easy to administer orally for the treatment of paediatric patients, particularly for newborns is urgently required, with the same efficacy, safety and suitable biopharmaceutical properties as BZ tablets. Self-emulsifying drug delivery systems (SEDDS) may improve bioavailability of drugs such as BZ, which have poor water solubility and low permeability. In this context, the aim of this work was to develop a liquid BZ-SEDDS formulation as an alternative to tablets and to evaluate its cytotoxicity in different host cell lines and its efficacy in experimental Trypanosoma cruzi infection in mice. The optimized SEDDS formulation (25 mg/ml of BZ) induced no cytotoxicity in H9c2, HepG2 and Caco2 cells in vitro at 25 μM level. BZ-SEDDS and free-BZ showed similar in vitro trypanocidal activity in H9c2 cells infected by T. cruzi Y strain, with IC
MeSH term(s)	Animals ; Caco-2 Cells ; Cell Survival/drug effects ; Cell Survival/physiology ; Chagas Disease/drug therapy ; Chagas Disease/metabolism ; Dosage Forms ; Dose-Response Relationship, Drug ; Drug Delivery Systems/methods ; Emulsifying Agents/administration & dosage ; Emulsifying Agents/chemistry ; Emulsifying Agents/metabolism ; Female ; Hep G2 Cells ; Humans ; Mice ; Nitroimidazoles/administration & dosage ; Nitroimidazoles/chemistry ; Nitroimidazoles/metabolism ; Rats ; Trypanocidal Agents/administration & dosage ; Trypanocidal Agents/chemistry ; Trypanocidal Agents/metabolism
Chemical Substances	Dosage Forms ; Emulsifying Agents ; Nitroimidazoles ; Trypanocidal Agents ; benzonidazole (YC42NRJ1ZD)
Language	English
Publishing date	2020-01-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2020.105234
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Article ; Online: Synergic Effect of Allopurinol in Combination with Nitroheterocyclic Compounds against Trypanosoma cruzi.

Mazzeti, Ana Lia / Diniz, Lívia de F / Gonçalves, Karolina R / WonDollinger, Ruan Schott / Assíria, Tassiane / Ribeiro, Isabela / Bahia, Maria T

Antimicrobial agents and chemotherapy

2019 Volume 63, Issue 6

Abstract: Combination therapy has gained attention as a possible strategy for overcoming the limitations of the present therapeutic arsenal for Chagas disease. The aim of this study was to evaluate the effect of allopurinol in association with nitroheterocyclic ... ...

Abstract	Combination therapy has gained attention as a possible strategy for overcoming the limitations of the present therapeutic arsenal for Chagas disease. The aim of this study was to evaluate the effect of allopurinol in association with nitroheterocyclic compounds on infection with the Y strain of
MeSH term(s)	Allopurinol/therapeutic use ; Animals ; Cell Line ; Chagas Disease/parasitology ; Humans ; Mice ; Mortality ; Nifurtimox/therapeutic use ; Nitroimidazoles/therapeutic use ; Real-Time Polymerase Chain Reaction ; Trypanosoma cruzi/drug effects ; Trypanosoma cruzi/pathogenicity
Chemical Substances	Nitroimidazoles ; Allopurinol (63CZ7GJN5I) ; Nifurtimox (M84I3K7C2O) ; benzonidazole (YC42NRJ1ZD)
Language	English
Publishing date	2019-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.02264-18
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Article ; Online: The role of fat on cardiomyopathy outcome in mouse models of chronic Trypanosoma cruzi infection.

Zaki, Paul / Domingues, Elisa Lbc / Amjad, Farhad M / Narde, Maiara B / Gonçalves, Karolina R / Viana, Mirelle L / de Paula, Heberth / de Lima, Wanderson G / Huang, Huan / Bahia, Maria T / Sherer, Philipp E / Dos Santos, Fabiane M / Weiss, Louis M / Tanowitz, Herbert B

Parasitology research

2020 Volume 119, Issue 6, Page(s) 1829–1843

Abstract: The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi ... ...

Abstract	The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2-RIDα/β transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1
MeSH term(s)	Animals ; Chagas Cardiomyopathy/parasitology ; Chagas Cardiomyopathy/pathology ; Chagas Disease/complications ; Chagas Disease/parasitology ; Chagas Disease/pathology ; Diet, High-Fat ; Disease Models, Animal ; Female ; Heart/parasitology ; Inflammation/parasitology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Myocardium/pathology ; Parasite Load ; Trypanosoma cruzi/physiology ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Tumor Necrosis Factor-alpha
Language	English
Publishing date	2020-03-24
Publishing country	Germany
Document type	Journal Article
ZDB-ID	284966-5
ISSN	1432-1955 ; 0932-0113 ; 0044-3255
ISSN (online)	1432-1955
ISSN	0932-0113 ; 0044-3255
DOI	10.1007/s00436-020-06645-z
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Article ; Online: Correction to: The role of fat on cardiomyopathy outcome in mouse models of chronic Trypanosoma cruzi infection.

Zaki, Paul / Domingues, Elisa L B C / Amjad, Farhad M / Narde, Maiara B / Gonçalves, Karolina R / Viana, Mirelle L / de Paula, Heberth / de Lima, Wanderson G / Huang, Huan / Bahia, Maria T / Scherer, Philipp E / Dos Santos, Fabiane M / Weiss, Louis M / Tanowitz, Herbert B

Parasitology research

2020 Volume 119, Issue 6, Page(s) 1845

Abstract: The authors regret that Philipp E Scherer's name was spelt incorrectly in the author list. The name of the author is now corrected above. ...

Abstract	The authors regret that Philipp E Scherer's name was spelt incorrectly in the author list. The name of the author is now corrected above.
Language	English
Publishing date	2020-04-16
Publishing country	Germany
Document type	Journal Article ; Published Erratum
ZDB-ID	284966-5
ISSN	1432-1955 ; 0932-0113 ; 0044-3255
ISSN (online)	1432-1955
ISSN	0932-0113 ; 0044-3255
DOI	10.1007/s00436-020-06685-5
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Article ; Online: Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi.

Santos, Fabiane M / Mazzeti, Ana L / Caldas, Sérgio / Gonçalves, Karolina R / Lima, Wanderson G / Torres, Rosália M / Bahia, Maria Terezinha

Acta tropica

2016 Volume 161, Page(s) 44–54

Abstract: Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and the relevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the present study, we used a canine model infected with ... ...

Abstract	Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and the relevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the present study, we used a canine model infected with the benznidazole-sensitive Berenice-78 Trypanosoma cruzi strain to verify the efficacy of an etiologic treatment in reducing the parasite load and ameliorating cardiac muscle tissue damage and left ventricular diastolic dysfunction in the chronic phase of the infection. The effect of the treatment on reducing the parasite load was monitored by blood PCR and blood culture assays, and the effect of the treatment on the outcome of heart tissue damage and on diastolic function was evaluated by histopathology and echo Doppler cardiogram. The benefit of the benznidazole-treatment in reducing the parasite burden was demonstrated by a marked decrease in positive blood culture and PCR assay results until 30days post-treatment. At this time, the PCR and blood culture assays yielded negative results for 82% of the treated animals, compared with only 36% of the untreated dogs. However, a progressive increase in the parasite load could be detected in the peripheral blood for one year post-treatment, as evidenced by a progressive increase in positive results for both the PCR and the blood culture assays at follow-up. The parasite load reduction induced by treatment was compatible with the lower degree of tissue damage among animals euthanized in the first month after treatment and with the increased cardiac damage after this period, reaching levels similar to those in untreated animals at the one-year follow-up. The two infected groups also presented similar, significantly smaller values for early tissue septal velocity (E' SIV) than the non-infected dogs did at this later time. Moreover, in the treated animals, an increase in the E/E' septal tissue filling pressure ratio was observed when compared with basal values as well as with values in non-infected dogs. These findings strongly suggest that the temporary reduction in the parasite load that was induced by benznidazole treatment was not able to prevent myocardial lesions and diastolic dysfunction for long after treatment.
MeSH term(s)	Animals ; Chagas Cardiomyopathy/drug therapy ; Chagas Cardiomyopathy/parasitology ; Dogs ; Female ; Heart/parasitology ; Humans ; Male ; Models, Animal ; Myocardium/pathology ; Nitroimidazoles/pharmacology ; Nitroimidazoles/therapeutic use ; Parasite Load ; Polymerase Chain Reaction ; Trypanocidal Agents/pharmacology ; Trypanocidal Agents/therapeutic use ; Trypanosoma cruzi/drug effects
Chemical Substances	Nitroimidazoles ; Trypanocidal Agents ; benzonidazole (YC42NRJ1ZD)
Language	English
Publishing date	2016-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	210415-5
ISSN	1873-6254 ; 0001-706X
ISSN (online)	1873-6254
ISSN	0001-706X
DOI	10.1016/j.actatropica.2016.05.007
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Article ; Online: Time and dose-dependence evaluation of nitroheterocyclic drugs for improving efficacy following Trypanosoma cruzi infection: A pre-clinical study.

Mazzeti, Ana Lia / Diniz, Lívia de F / Gonçalves, Karolina R / Nascimento, Alvaro F S / Spósito, Pollyanna A F / Mosqueira, Vanessa C F / Machado-Coelho, George L L / Ribeiro, Isabela / Bahia, Maria T

Biochemical pharmacology

2018 Volume 148, Page(s) 213–221

Abstract: Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use ... ...

Abstract	Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3-10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease.
MeSH term(s)	Animals ; Chagas Disease/drug therapy ; Chagas Disease/parasitology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Resistance ; Mice ; Nifurtimox ; Parasitemia ; Trypanocidal Agents/administration & dosage ; Trypanocidal Agents/pharmacology ; Trypanosoma cruzi/drug effects
Chemical Substances	Trypanocidal Agents ; Nifurtimox (M84I3K7C2O)
Language	English
Publishing date	2018-01-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2018.01.005
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