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      Benznidazole and Posaconazole in Experimental Chagas Disease: Positive Interaction in Concomitant and Sequential Treatments

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          Abstract

          Background

          Current chemotherapy for Chagas disease is unsatisfactory due to its limited efficacy, particularly in the chronic phase, with frequent side effects that can lead to treatment discontinuation. Combined therapy is envisioned as an ideal approach since it may improve treatment efficacy whilst decreasing toxicity and the likelihood of resistance development. We evaluated the efficacy of posaconazole in combination with benznidazole on Trypanosoma cruzi infection in vivo.

          Methods and Findings

          Benznidazole and posaconazole were administered individually or in combination in an experimental acute murine infection model. Using a rapid treatment protocol for 7 days, the combined treatments were more efficacious in reducing parasitemia levels than the drugs given alone, with the effects most evident in combinations of sub-optimal doses of the drugs. Subsequently, the curative action of these drug combinations was investigated, using the same infection model and 25, 50, 75 or 100 mg/kg/day (mpk) of benznidazole in combination with 5, 10 or 20 mpk of posaconazole, given alone or concomitantly for 20 days. The effects of the combination treatments on parasitological cures were higher than the sum of such effects when the drugs were administered separately at the same doses, indicating synergistic activity. Finally, sequential therapy experiments were carried out with benznidazole or posaconazole over a short interval (10 days), followed by the second drug administered for the same period of time. It was found that the sequence of benznidazole (100 mpk) followed by posaconazole (20 mpk) provided cure rates comparable to those obtained with the full (20 days) treatments with either drug alone, and no cure was observed for the short treatments with drugs given alone.

          Conclusions

          Our data demonstrate the importance of investigating the potential beneficial effects of combination treatments with marketed compounds, and showed that combinations of benznidazole with posaconazole have a positive interaction in murine models of Chagas disease.

          Author Summary

          In this study, we investigated the efficacy of posaconazole in combination with benznidazole against Trypanosoma cruzi acute infections in mice, to support the potential clinical evaluation of such combination therapy for Chagas disease. The curative action of benznidazole/posaconazole combinations was explored in an established acute infection model with the Y strain in which benznidazole and posaconazole treatments induced a 70% and 80% cure rate, respectively, when administered alone at optimal doses. When tested in combination, a 80% to 90% cure rate was detected in mice receiving 25, 50 or 75 mpk of benznidazole, plus 5 or 10 mpk of posaconazole, while treatment with the sub-optimal doses of the drugs given alone induced only 0–43% cures, indicating synergistic effects. Finally, sequential short (10 days) treatments with benznidazole (100 mpk) followed by posaconazole (20 mpk) led to an 80% cure rate, comparable with full-length treatments with either drug given alone, while no cures were observed for short treatments with single drugs. Our results demonstrate that it is possible to achieve the same or better therapeutic effect using lower dosages of posaconazole and benznidazole in combination, decreasing treatment costs and potential toxicity.

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          Most cited references32

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          Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial.

          Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. To compare long-term outcomes of patients with nonacute Chagas disease treated with benznidazole versus outcomes of those who did not receive treatment. Clinical trial with unblinded, nonrandom assignment of patients to intervention or control groups. Chagas disease center in Buenos Aires, Argentina. 566 patients 30 to 50 years of age with 3 positive results on serologic tests and without heart failure. The primary outcome was disease progression, defined as a change to a more advanced Kuschnir group or death. Secondary outcomes included new abnormalities on electrocardiography and serologic reactivity. Oral benznidazole, 5 mg/kg of body weight per day for 30 days (283 patients), or no treatment (283 patients). Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034). Nonrandom, unblinded treatment assignment was used, and follow-up data were missing for 20% of patients. Loss to follow-up was more common among patients who were less sick. Two uncontrolled interim analyses were conducted. Compared with no treatment, benznidazole treatment was associated with reduced progression of Chagas disease and increased negative seroconversion for patients presenting with nonacute disease and no heart failure. These observations indicate that a randomized, controlled trial should now be conducted.
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            Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial

            Summary Background Artemisinin-combination therapy (ACT) is recommended as first-line treatment of falciparum malaria throughout the world, and fixed-dose combinations are preferred by WHO; whether a single gametocytocidal dose of primaquine should be added is unknown. We aimed to compare effectiveness of four fixed-dose ACTs and a loose tablet combination of artesunate and mefloquine, and assess the addition of a single gametocytocidal dose of primaquine. Methods In an open-label randomised trial in clinics in Rakhine state, Kachin state, and Shan state in Myanmar (Burma) between Dec 30, 2008, and March 20, 2009, we compared the effectiveness of all four WHO-recommended fixed-dose ACTs (artesunate–mefloquine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, artemether–lumefantrine) and loose artesunate–mefloquine in Burmese adults and children. Eligible patients were those who presented to the clinics with acute uncomplicated Plasmodium falciparum malaria or mixed infection, who were older than 6 months, and who weighed more than 5 kg. Treatments were randomised in equal numbers within blocks of 50 and allocation was in sealed envelopes. All patients were also randomly assigned to receive either a single dose of primaquine 0·75 mg base/kg or not. Patients were followed up for 63 days. Treatment groups were compared by analysis of variance and multiple logistic regression. The primary outcome was the 63 day recrudescence rate. This study is registered with clinicaltrials.gov, number NCT00902811. Findings 155 patients received artesunate–amodiaquine, 162 artemether–lumefantrine, 169 artesunate–mefloquine, 161 loose artesunate–mefloquine, and 161 dihydroartemisinin–piperaquine. By day 63 of follow-up, 14 patients (9·4%; 95% CI 5·7–15·3%) on artesunate–amodiaquine had recrudescent P falciparum infections, a rate significantly higher than for artemether–lumefantrine (two patients; 1·4%; 0·3–5·3; p=0·0013), fixed-dose artesunate–mefloquine (0 patients; 0–2·3; p<0·0001), loose artesunate–mefloquine (two patients; 1·3%; 0·3–5·3; p=0·0018), and dihydroartemisinin–piperaquine (two patients 1·3%; 0·3–5·2%; p=0·0012). Hazard ratios for re-infection (95% CI) after artesunate–amodiaquine were 3·2 (1·3–8·0) compared with the two artesunate–mefloquine groups (p=0·01), 2·6 (1·0–6–0) compared with artemether–lumefantrine (p=0·04), and 2·3 (0·9–6·0) compared with dihydroartemisinin–piperaquine (p=0·08). Mixed falciparum and vivax infections were common: 129 (16%) had a mixed infection at presentation and 330 (41%) patients had one or more episodes of Plasmodium vivax infection during follow-up. The addition of a single dose of primaquine (0·75 mg/kg) reduced P falciparum gametocyte carriage substantially: rate ratio 11·9 (95% CI 7·4–20·5). All regimens were well tolerated. Adverse events were reported by 599 patients, most commonly vomiting and dizziness. Other side-effects were less common and were not related to a specific treatment. Interpretation Artesunate–amodiaquine should not be used in Myanmar, because the other ACTs are substantially more effective. Artesunate–mefloquine provided the greatest post-treatment suppression of malaria. Adding a single dose of primaquine would substantially reduce transmission potential. Vivax malaria, not recurrent falciparum malaria, is the main complication after treatment of P falciparum infections in this region. Funding Médecins sans Frontières (Holland) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme.
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              A 9,000-year record of Chagas' disease.

              Tissue specimens from 283 principally spontaneously (naturally) desiccated human mummies from coastal and low valley sites in northern Chile and southern Peru were tested with a DNA probe directed at a kinetoplast DNA segment of Trypanosoma cruzi. The time interval spanned by the eleven major cultural groups represented in the sample ranged from approximately 9,000 years B.P. (7050 B.C.) to approximately the time of the Spanish conquest, approximately 450 B.P. ( approximately 1500 A.D.). Forty-one percent of the tissue extracts, amplified by the PCR reacted positively (i.e., hybridized) with the probe. Prevalence patterns demonstrated no statistically significant differences among the individual cultural groups, nor among subgroups compared on the basis of age, sex, or weight of specimen tested. These results suggest that the sylvatic (animal-infected) cycle of Chagas' disease was probably well established at the time that the earliest humans (members of the Chinchorro culture) first peopled this segment of the Andean coast and inadvertently joined the many other mammal species acting as hosts for this parasite.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                August 2013
                15 August 2013
                : 7
                : 8
                : e2367
                Affiliations
                [1 ]Laboratório de Doença de Chagas, Departamento de Ciências Biológicas & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
                [2 ]Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela
                [3 ]Drugs for Neglected Diseases Initiative, Geneva, Switzerland
                Federal University of São Paulo, Brazil
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MTB IR JAU AT LdFD. Performed the experiments: LdFD IMdA ALM TAFM ISC. Analyzed the data: MTB LdFD. Contributed reagents/materials/analysis tools: MTB AT. Wrote the paper: MTB IR JAU LdFD AT.

                Article
                PNTD-D-13-00222
                10.1371/journal.pntd.0002367
                3744424
                23967360
                26c50706-35cc-4fc5-b9ca-9aed32d0d93b
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 February 2013
                : 2 July 2013
                Page count
                Pages: 8
                Funding
                This work received financial support from the Drugs for Neglected Disease Initiative (DNDi; Geneva, Switzerland), UBS Optimus Foundation, Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and research fellowships from CNPq (Bahia MT, Talvani, A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Microbiology
                Protozoology
                Parastic Protozoans
                Trypanosoma
                Medicine
                Drugs and Devices
                Drug Research and Development

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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