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1.
Maria Terezinha Bahia Isabel Mayer de Andrade Tassiane Ass��ria Fontes Martins ��lvaro Fernando da Silva do Nascimento L��via de Figueiredo Diniz Ivo Santana Caldas Andr�� Talvani Bernadette Bourdin Trunz Els Torreele Isabela Ribeiro 《PLoS neglected tropical diseases》2012,6(11)
Background
New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi.Methods and Findings
We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses.Conclusions
Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD. 相似文献2.
Bessy Gutiérrez Christian Muñoz Luis Osorio Krisztina Fehér Tünde-Zita Illyés Zsuzsa Papp Ambati Ashok Kumar Katalin E. Kövér Hernán Sagua Jorge E. Araya Patricio Morales László Szilágyi Jorge González 《Bioorganic & medicinal chemistry letters》2013,23(12):3576-3579
Aromatic oligovalent glycosyl disulfides and some diglycosyl disulfides were tested against three different Trypanosoma cruzi strains. Di-(β-d-galactopyranosyl-dithiomethylene) benzenes 2b and 4b proved to be the most active derivatives against all three strains of cell culture-derived trypomastigotes with IC50 values ranging from 4 to 11 μM at 37 °C. The inhibitory activities were maintained, although somewhat lowered, at a temperature of 4 °C as well. Three further derivatives displayed similar activities against at least one of the three strains. Low cytotoxicities of the active compounds, tested on confluent HeLa, Vero and peritoneal macrophage cell cultures, resulted in significantly higher selectivity indices (SI) than that of the reference drug benznidazole. Remarkably, several molecules of the tested panel strongly inhibited the parasite release from T. cruzi infected HeLa cell cultures suggesting an effect against the intracellular development of T. cruzi amastigotes as well. 相似文献
3.
Juliana Cogo Juan Cantizani Ignacio Cotillo Diego Pereira Sangi Arlene Gonçalves Corrêa Tânia Ueda-Nakamura Benedito Prado Dias Filho José Julio Martín Celso Vataru Nakamura 《Bioorganic & medicinal chemistry》2018,26(14):4065-4072
Continuous efforts have been made to discover new drugs for the treatment of Chagas’ disease, human African trypanosomiasis, and leishmaniasis. We have previously reported the synthesis and antileishmanial and antitrypanosomal (Y strain) properties of 2,3-disubstituted quinoxalines. Considering their promising antiparasitic potential, the present study was conducted to expand our search and take advantage of high-throughput assays to investigate the effects of quinoxaline derivatives against Leishmania donovani, Trypanosoma brucei, and Trypanosoma cruzi (Tulahuen strain). These compounds were active against the kinetoplastid parasites that were evaluated. The 2-chloro-3-methylsulfoxylsulfonyl and 2-chloro-3-methylsulfinyl quinoxalines were the most potent, and some of these derivatives were even more active than the reference drugs. Although the 2,3-diaryl-substituted quinoxalines were not active against all of the parasites, they were active against T. brucei and intracellular amastigotes of T. cruzi, without interfering with mammalian cell viability. These compounds presented encouraging results that will guide our future studies on in vivo bioassays towards the mode of action. 相似文献
4.
Esther Bettiol Marie Samanovic Andrew S. Murkin Jayne Raper Frederick Buckner Ana Rodriguez 《PLoS neglected tropical diseases》2009,3(2)
The development of new drugs against Chagas disease is a priority since the currently available medicines have toxic effects, partial efficacy and are targeted against the acute phase of disease. At present, there is no drug to treat the chronic stage. In this study, we have optimized a whole cell-based assay for high throughput screening of compounds that inhibit infection of mammalian cells by Trypanosoma cruzi trypomastigotes. A 2000-compound chemical library was screened using a recombinant T. cruzi (Tulahuen strain) expressing β-galactosidase. Three hits were selected for their high activity against T. cruzi and low toxicity to host cells in vitro: PCH1, NT1 and CX1 (IC50: 54, 190 and 23 nM, respectively). Each of these three compounds presents a different mechanism of action on intracellular proliferation of T. cruzi amastigotes. CX1 shows strong trypanocidal activity, an essential characteristic for the development of drugs against the chronic stage of Chagas disease where parasites are found intracellular in a quiescent stage. NT1 has a trypanostatic effect, while PCH1 affects parasite division. The three compounds also show high activity against intracellular T. cruzi from the Y strain and against the related kinetoplastid species Leishmania major and L. amazonensis. Characterization of the anti–T. cruzi activity of molecules chemically related to the three library hits allowed the selection of two compounds with IC50 values of 2 nM (PCH6 and CX2). These values are approximately 100 times lower than those of the medicines used in patients against T. cruzi. These results provide new candidate molecules for the development of treatments against Chagas disease and leishmaniasis. 相似文献
5.
Lack of protection against Trypanosoma cruzi by multiple doses of T. lewisi culture forms. A discussion on some strains of "lewisi" 总被引:3,自引:0,他引:3
No protection against Trypanosoma cruzi was afforded to mice by previously inoculating multiple doses of T. lewisi blood stream forms, strain RU or culture forms of the IMT strain.Since these results conflicted with those obtained by other authors, we secured a sample of the strain used by them. This strain, labeled “T. lewisi” and which we called “F”, was verified to be actually T. cruzi. It was characterized by its morphologic features in axenic cultures, its capability to infect HeLa cells where the intracellular cycle was completed, by its infectivity for white mice which had amastigotes in their heart muscle, and in which the strain has been maintained by serial passages, and by the completion of its biologic cycle in triatoma bugs.The necessity for carefully testing doubtful strains, and the criteria to be adopted in these cases are discussed. 相似文献
6.
Endophytic Actinobacteria from the Brazilian Medicinal Plant Lychnophora ericoides Mart. and the Biological Potential of Their Secondary Metabolites
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Andrés Mauricio Caraballo‐Rodriguez Weilan Gomes da Paixão Melo Andréa Mendes do Nascimento Bruno Coêlho Cavalcanti Manoel Odorico de Moraes Cláudia Pessoa Letícia Veras Costa‐Lotufo Renata Krogh Adriano Defini Andricopulo Norberto Peporine Lopes Mônica Tallarico Pupo 《化学与生物多样性》2016,13(6):727-736
Endophytic actinobacteria from the Brazilian medicinal plant Lychnophora ericoides were isolated for the first time, and the biological potential of their secondary metabolites was evaluated. A phylogenic analysis of isolated actinobacteria was accomplished with 16S rRNA gene sequencing, and the predominance of the genus Streptomyces was observed. All strains were cultured on solid rice medium, and ethanol extracts were evaluated with antimicrobial and cytotoxic assays against cancer cell lines. As a result, 92% of the extracts showed a high or moderate activity against at least one pathogenic microbial strain or cancer cell line. Based on the biological and chemical analyses of crude extracts, three endophytic strains were selected for further investigation of their chemical profiles. Sixteen compounds were isolated, and 3‐hydroxy‐4‐methoxybenzamide ( 9 ) and 2,3‐dihydro‐2,2‐dimethyl‐4(1H)‐quinazolinone ( 15 ) are reported as natural products for the first time in this study. The biological activity of the pure compounds was also assessed. Compound 15 displayed potent cytotoxic activity against all four tested cancer cell lines. Nocardamine ( 2 ) was only moderately active against two cancer cell lines but showed strong activity against Trypanosoma cruzi. Our results show that endophytic actinobacteria from L. ericoides are a promising source of bioactive compounds. 相似文献
7.
McHardy N. and Elphick J. P. 1978. Immunization of mice against infection with Trypanosoma cruzi. Cross-immunization between five strains of the parasite using freeze-thawed vaccines containing epimastigotes of up to five strains. International Journal for Parasitology8: 25–31. Groups of male CD-1 mice were immunized with two doses of vaccines containing 108 freeze-thawed cultured epimastigotes of Trypanosoma cruzi of five strains—Y, M, BG, Peru and Tulahuen, with saponin as adjuvant. Each vaccine contained 1, 2, 3 or 5 strains of the parasite. The mice were challenged with each of the five strains. All the single-strain vaccines gave good protection against both homologous and heterologous challenges, with the exception of the strain Y vaccine, which gave poor protection against homologous challenge, but good protection against all four heterologous challenges. The inclusion of more than one strain of epimastigote in the vaccine failed to increase protection, and in some instances appeared to reduce it, in comparison with vaccines containing only one of the component strains. It is suggested that this is due to antigenic competition. 相似文献
8.
Sarah Higginbotham Weng Ruh Wong Roger G. Linington Carmenza Spadafora Liliana Iturrado A. Elizabeth Arnold 《PloS one》2014,9(1)
The extraordinary biological diversity of tropical forests harbors a rich chemical diversity with enormous potential as a source of novel bioactive compounds. Of particular interest are new environments for microbial discovery. Sloths – arboreal mammals commonly found in the lowland forests of Panama – carry a wide variety of micro- and macro-organisms on their coarse outer hair. Here we report for the first time the isolation of diverse and bioactive strains of fungi from sloth hair, and their taxonomic placement. Eighty-four isolates of fungi were obtained in culture from the surface of hair that was collected from living three-toed sloths (Bradypus variegatus, Bradypodidae) in Soberanía National Park, Republic of Panama. Phylogenetic analyses revealed a diverse group of Ascomycota belonging to 28 distinct operational taxonomic units (OTUs), several of which are divergent from previously known taxa. Seventy-four isolates were cultivated in liquid broth and crude extracts were tested for bioactivity in vitro. We found a broad range of activities against strains of the parasites that cause malaria (Plasmodium falciparum) and Chagas disease (Trypanosoma cruzi), and against the human breast cancer cell line MCF-7. Fifty fungal extracts were tested for antibacterial activity in a new antibiotic profile screen called BioMAP; of these, 20 were active against at least one bacterial strain, and one had an unusual pattern of bioactivity against Gram-negative bacteria that suggests a potentially new mode of action. Together our results reveal the importance of exploring novel environments for bioactive fungi, and demonstrate for the first time the taxonomic composition and bioactivity of fungi from sloth hair. 相似文献
9.
10.
Valeria P. Sülsen Silvia I. Cazorla Fernanda M. Frank Laura C. Laurella Liliana V. Muschietti Cesar A. Catalán Virginia S. Martino Emilio L. Malchiodi 《PLoS neglected tropical diseases》2013,7(10)
Among the natural compounds, terpenoids play an important role in the drug discovery process for tropical diseases. The aim of the present work was to isolate antiprotozoal compounds from Ambrosia elatior and A. scabra. The sesquiterpene lactone (STL) cumanin was isolated from A. elatior whereas two other STLs, psilostachyin and cordilin, and one sterol glycoside, daucosterol, were isolated from A. scabra. Cumanin and cordilin were active against Trypanosoma cruzi epimastigotes showing 50% inhibition concentrations (IC50) values of 12 µM and 26 µM, respectively. Moreover, these compounds are active against bloodstrean trypomastigotes, regardless of the T. cruzi strain tested. Psilostachyin and cumanin were also active against amastigote forms with IC50 values of 21 µM and 8 µM, respectively. By contrast, daucosterol showed moderate activity on epimastigotes and trypomastigotes and was inactive against amastigote forms. We also found that cumanin and psilostachyin exhibited an additive effect in their trypanocidal activity when these two drugs were tested together. Cumanin has leishmanicidal activity with growth inhibition values greater than 80% at a concentration of 5 µg/ml (19 µM), against both L. braziliensis and L. amazonensis promastigotes. In an in vivo model of T. cruzi infection, cumanin was more active than benznidazole, producing an 8-fold reduction in parasitemia levels during the acute phase of the infection compared with the control group, and more importantly, a reduction in mortality with 66% of the animals surviving, in comparison with 100% mortality in the control group. Cumanin also showed nontoxic effects at the doses assayed in vivo, as determined using markers of hepatic damage. 相似文献
11.
Galina Stoyancheva Marta Marzotto Franco Dellaglio Sandra Torriani 《Archives of microbiology》2014,196(9):645-653
The human vagina is a complex and dynamic ecosystem containing an abundance of microorganisms. In women of childbearing age, this system is dominated by Lactobacillus spp. In the present work, seventeen newly isolated vaginal strains were identified by 16S rDNA sequencing and were investigated for their antimicrobial properties. Twelve of the isolated Lactobacillus strains showed activity against one or more microorganisms. Six and five of them produced substances that inhibited the growth of two different Klebsiella strains and Staphylococcus aureus, respectively. Two lactobacilli strains were active against an Escherichia coli strain, one isolate was active against an Enterococus faecalis strain and another lactobacilli strain showed antimicrobial activity against a Candida parapsilosis strain. The nature of the active compounds was additionally studied, and the presence of bacteriocin-like substances was proved. The genes related to the bacteriocin production in three of the newly isolated strains were identified and sequenced. The presence of gassericin A operon in the genome of the species Lactobacillus crispatus was described for the first time. The presence of antimicrobial activity contributes to their possible use as potential probiotic strains after further research. 相似文献
12.
《Phytomedicine》2015,22(4):469-476
Six compounds (1–6), isolated from the methanol extract of the roots of the African medicinal plant Zanthoxylum capense Thunb. (Rutaceae), and seven ester derivatives (7–13) were evaluated for their antibacterial activities and modulatory effects on the MIC of antibiotics (erythromycin, oxacillin, and tetracycline) and ethidium bromide (EtBr) against a Staphylococcus aureus reference strain (ATCC 6538). Using the same model, compounds 1–13 were also assessed for their potential as efflux pump inhibitors by a fluorometric assay that measures the accumulation of the broad range efflux pump substrate EtBr. Compounds 8 and 11 were further evaluated for their antibacterial, modulatory and EtBr accumulation effects against four additional S. aureus strains, which included two clinical methicillin-resistant S. aureus (MRSA) strains. Compounds (1–13) have not shown antibacterial activity at the concentration ranges tested. When evaluated against S. aureus ATCC 6538, oxychelerythrine (1) a benzophenanthridine alkaloid, showed the highest modulatory activity enhancing the susceptibility of this strain to all the tested antibiotics from two to four-fold. Ailanthoidiol diacetate (8) and ailanthoidiol di-2-ethylbutanoate (11) were also good modulators when combined with EtBr, increasing the bacteria susceptibility by four and two-fold, respectively. In the EtBr accumulation assay, using ATCC 6538 strain, the phenylpropanoid (+)-ailanthoidiol (6) and most of its ester derivatives (8−11) exhibited higher activity than the positive control verapamil. The highest effects were found for compounds 8 and 11 that also increased the accumulation of EtBr, using S. aureus ATCC 25923 as model. Furthermore, both compounds (8, 11) were able to enhance the ciprofloxacin activity against the MRSA clinical strains tested, causing a reduction of the antibiotic MIC values from two to four-fold. The EtBr accumulation assay revealed that this modulation activity was not due to an inhibition of efflux pumps mechanism.These results suggested that Z. capense constituents may be valuable as leads for restoring antibiotic activity against MRSA strains. 相似文献
13.
Corky Root of Lettuce Caused by Strains of a Gram-Negative Bacterium from Muck Soils of Florida, New York, and Wisconsin
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Ariena H. C. van Bruggen Philip R. Brown Kenneth N. Jochimsen 《Applied microbiology》1989,55(10):2635-2640
Slow-growing bacteria similar to the bacterium causing lettuce corky root (CR) in California (strain CA1) were isolated from muck soils of Florida, New York, and Wisconsin, using lettuce seedlings as bait. All strains were tested for reaction with polyclonal antibodies produced against strain CA1 and for pathogenicity on CR-susceptible (Salinas) and CR-resistant (Green Lake) lettuce cultivars in a greenhouse. Five strains from Florida, three from New York, and three from Wisconsin induced severe CR symptoms on Salinas and mild symptoms on Green Lake. All strains were gram-negative, aerobic, oxidase positive, and catalase positive and reduced nitrate to ammonia. Whole-cell fatty acid compositions were similar for all strains and resembled that of Pseudomonas paucimobilis. Since this fatty acid pattern is unique, it is suggested that CR of lettuce is caused by strains of the same bacterium in Florida, New York, Wisconsin, and California. 相似文献
14.
Maria V. Papadopoulou William D. Bloomer Howard S. Rosenzweig Marcel Kaiser Eric Chatelain Jean-Robert Ioset 《Bioorganic & medicinal chemistry》2013,21(21):6600-6607
We have previously shown that 3-nitro-1H-1,2,4-triazole-based amines demonstrate significant trypanocidal activity, in particular against Trypanosoma cruzi, the causative parasite of Chagas disease. In the present work we further expanded our research by evaluating in vitro the trypanocidal activity of nitrotriazole-based piperazines and nitrotriazole-based 2-amino-1,3-benzothiazoles to establish additional SARs. All nitrotriazole-based derivatives were active or moderately active against T. cruzi; however two of them did not fulfill the selectivity criteria. Five derivatives were active or moderately active against Trypanosoma brucei rhodesiense while one derivative was moderately active against Leishmania donovani. Active compounds against T. cruzi demonstrated selectivity indexes (toxicity to host cells/toxicity to T. cruzi amastigotes) from 117 to 1725 and 12 of 13 compounds were up to 39-fold more potent than the reference compound benznidazole. Detailed SARs are discussed. 相似文献
15.
Leonid Heifets Julie Simon Van Pham 《Annals of clinical microbiology and antimicrobials》2005,4(1):1-7
Background
Eradication of Helicobacter pylori is an important objective in overcoming gastric diseases. Many regimens are currently available but none of them could achieve 100% success in eradication. Eugenol and cinnamaldehyde that are commonly used in various food preparations are known to possess antimicrobial activity against a wide spectrum of bacteria.Aim
The present study was performed to assess the in vitro effects of eugenol and cinnamaldehyde against indigenous and standard H. pylori strains, their minimum inhibitory concentrations (MICs) and time course lethal effects at various pH.Methods
A total of 31 strains (29 indigenous and one standard strain of H. pylori ATCC 26695, one strain of E. coli NCIM 2089) were screened. Agar dilution method was used for the determination of drug sensitivity patterns of isolates to the commonly used antibiotics and broth dilution method for the test compounds.Results
Eugenol and cinnamaldehyde inhibited the growth of all the 30 H. pylori strains tested, at a concentration of 2 μg/ml, in the 9th and 12th hours of incubation respectively. At acidic pH, increased activity was observed for both the compounds. Furthermore, the organism did not develop any resistance towards these compounds even after 10 passages grown at sub-inhibitory concentrations.Conclusion
These results indicate that the two bioactive compounds we tested may prevent H. pylori growth in vitro, without acquiring any resistance. 相似文献16.
Esther del Olmo Gloria María Molina-Salinas Ricardo Escarcena Mario Alves José L. López-Pérez Rogelio Hernandez-Pando Salvador Said-Fernández Arturo San Feliciano 《Bioorganic & medicinal chemistry letters》2009,19(19):5764-5768
Fifteen dihydrosphingosine analogues have been synthesized and tested in vitro against Mycobacterium tuberculosis (MTB). Two ether (3 and 4b) and one diamine (8b) derivatives have displayed high mycobactericidal potency, with similar MIC values of 1.25 μg/mL, against the virulent strain H37Rv, as well as against a clinical isolate resistant to the five first-line anti-TB drugs. The three compounds, tested on other eleven cultured MTB strains with different multi-drug-resistance (MDR) patterns, retained their MIC values for most strains, or even lowered it, as in the case of compound 4b, which, assayed on strain No. 332, also resistant to all first-line anti-TB drugs, attained the MIC value of 0.78 μg/mL. 相似文献
17.
An operation friendly protocol for the synthesis of novel di(indolyl)indolin-2-ones via Cu(OTf)2 catalyzed bis-addition of N-allyl and N-propargyl indole with isatin was developed. This methodology allowed us to achieve the products in excellent yields without requiring purification technique like column chromatography. All the synthesized compounds were evaluated for their in vivo anticonvulsant activity against maximal electroshock test. Six compounds showed maximum activity compared to the standard drug phenytoin. The scope of the new molecules as antimicrobial agents were tested against two bacterial strains (Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans). 相似文献
18.
Gianni Balliano Henrietta Dehmlow Simonetta Oliaro-Bosso Matilde Scaldaferri Silvia Taramino Franca Viola Giulia Caron Johannes Aebi Jean Ackermann 《Bioorganic & medicinal chemistry letters》2009,19(3):718-723
A series of 25 compounds, some of which previously were described as inhibitors of human liver microsomal oxidosqualene cyclase (OSC), were tested as inhibitors of Saccharomyces cerevisiae, Trypanosoma cruzi, Pneumocystis carinii and Arabidopsis thaliana OSCs expressed in an OSC-defective strain of S. cerevisiae. The screening identified three derivatives particularly promising for the development of novel anti-Trypanosoma agents and eight derivatives for the development of novel anti-Pneumocystis agents. 相似文献
19.
Chiung-Kuang Chen Patricia S. Doyle Liudmila V. Yermalitskaya Zachary B. Mackey Kenny K. H. Ang James H. McKerrow Larissa M. Podust 《PLoS neglected tropical diseases》2009,3(2)
Background
The two front-line drugs for chronic Trypanosoma cruzi infections are limited by adverse side-effects and declining efficacy. One potential new target for Chagas'' disease chemotherapy is sterol 14α-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols.Methodology/Principal Finding
In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51Mt), we previously identified the N-[4-pyridyl]-formamide moiety as a building block capable of delivering a variety of chemotypes into the CYP51 active site. In that work, the binding modes of several second generation compounds carrying this scaffold were determined by high-resolution co-crystal structures with CYP51Mt. Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51Tc, demonstrated that two of the compounds tested in the earlier effort bound tightly to this enzyme. Both were tested in vitro for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. One of the compounds had potent, selective anti–T. cruzi activity in infected mouse macrophages. Cure of treated host cells was confirmed by prolonged incubation in the absence of the inhibiting compound. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability (phenylalanine versus isoleucine) of a single residue at a critical position in the active site.Conclusions/Significance
CYP51Mt-based crystal structure analysis revealed that the functional groups of the two tightly bound compounds are likely to occupy different spaces in the CYP51 active site, suggesting the possibility of combining the beneficial features of both inhibitors in a third generation of compounds to achieve more potent and selective inhibition of CYP51Tc. 相似文献20.
Tiago Ant?nio de Oliveira Mendes Jo?o Luís Reis Cunha Rodrigo de Almeida Lourdes Gabriela Flávia Rodrigues Luiz Lucas Dhom Lemos Ana Rita Rocha dos Santos Ant?nia Cláudia Jácome da Camara Lúcia Maria da Cunha Galv?o Caryn Bern Robert H. Gilman Ricardo Toshio Fujiwara Ricardo Tostes Gazzinelli Daniella Castanheira Bartholomeu 《PLoS neglected tropical diseases》2013,7(10)