New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

© 2015, Sociedade Brasileira de Medicina Tropical. All rights reserved. Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB) is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL), its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit ratio.Peer Reviewe

Synthesis, antileishmanial activity and QSAR studies of 2-chloro- N -arylacetamides

We describe herein the synthesis and evaluation of the antileishmanial activity against promastigote forms of Leishmania amazonensis and cytotoxicity to murine macrophages of a series of 2-chloro-N-arylacetamide derivatives. All compounds were active, except one (compound 3). Compound 5 presented the most promising results, showing good antileishmanial activity (CI50=5.39±0.67 µM) and moderate selectivity (SI=6.36), indicating that further development of this class is worthwhile. Preliminary QSAR studies, although not predictive, furnished some insights on the importance of electronic character of aryl substituent to biological activity, as well as an indirect influence of hydrophobicity on activity

Longitudinal Study of a Human Drug-Induced Model of Autoantibody to Cytoplasmic Rods/Rings following HCV Therapy with Ribavirin and Interferon-alpha

Background: A novel pattern in the indirect immunofluorescence antinuclear antibody assay on HEp-2 cells (IIF-HEp-2) characterized by cytoplasmic rods and rings (RR) was reported in HCV patients, but stringent disease specificity studies and longitudinal analysis are lacking. We investigated the clinical significance of anti-RR in an HCV cohort with up to a 12-month treatment follow up.Methodology/Results: 597 patients (342 HCV, 55 HCV/HIV, 200 non-HCV) were screened and titered for anti-RR. Serial samples were available from 78 of 176 treated and 27 of 166 untreated patients. Anti-RR was detected in 14.1% of 342 HCV patients, 9.1% of 55 HCV/HIV, 3.4% of 29 Hepatitis B, and none of 171 non-HCV (p47% tested positive for anti-RR. the anti-RR titer generally increased with sustained treatment and remained high in 53% of patients. After treatment, anti-RR titer was negative in 41%. Non-responders to HCV therapy were 77% in anti-RR-positive versus 64% in anti-RR-negative patients. Response to treatment was not associated with anti-RR titer or the dynamics of anti-RR reactivity during and after treatment.Conclusions: the exquisite association of anti-RR reactivity with combined interferon-a/ribavirin therapy in HCV patients represents a unique model for drug-induced autoantibody generation in humans as demonstrated by the fact that a significant fraction of patients who have anti-RR during therapy becomes anti-RR-negative after completion of therapy.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Brazilian National Council for Research and Technological DevelopmentUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Gastroenterol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Infect Dis, São Paulo, BrazilFleury Med & Hlth Labs, Div Immunol, São Paulo, BrazilUniv Florida, Dept Oral Biol, Gainesville, FL 32610 USAUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Gastroenterol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Infect Dis, São Paulo, BrazilFAPESP: 2010/50710-6Brazilian National Council for Research and Technological Development: 305064/2011-8Web of Scienc

Composição farmacêutica leishmanicida contendo óleo essencial de piper claussenianum

DepositadaA invenção descreve composições farmacêuticas contendo óleo essencial de Piper Claussenianum e excipientes farmaceuticamente aceitáveis para o tratamento das leishmanioses, preferencialmente para o tratamento das infecções causadas pelas espécies Leishmania amazonensis, Leishmania major e Leishmania chegasi. As composições farmacêuticas podem ser apresentadas nas formas sólida, semisólida ou líquida. A presente invenção demostra apresentar uma ação leismanicida igual ou melhor em relação à ação observada para os medicamentos disponíveis no mercado, como a anfotericina B

Computer-aided drug design approaches applied to screen natural product’s structural analogs targeting arginase in Leishmania spp [version 3; peer review: 1 approved, 2 approved with reservations]

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics–generalized Born surface area (MM–GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated

Coadministration of the three antigenic Leishmania infantum poly (A) binding proteins as a DNA vaccine induces protection against Leishmania major infection in BALB/c Mice

Antecedentes Las proteínas intracelulares de Leishmania, altamente conservadas, han sido descritas como antígenos en mamíferos infectados natural y experimentalmente. El objetivo del presente estudio es evaluar la antigenicidad y propiedades profilácticas del Leishmania infantum Poly (A) las proteínas (LiPABPs). Metodología/Resultados principales Se han descrito tres diferentes miembros de la familia LiPABP. Se han elaborado herramientas recombinantes basadas en estas proteínas: proteínas recombinantes y vacunas de ADN. Las tres proteínas recombinantes fueron empleadas para recubrir las placas ELISA. Los sueros de pacientes humanos y caninos de leishmaniasis visceral y de pacientes humanos de leishmaniasis mucosa han reconoció los tres LiPABPs. Además, la eficacia protectora de la vacuna de ADN basada en la combinación de los tres Leishmania PABPs ha sido probado en un modelo murino de leishmaniosis progresiva: ratones BALB/c infectados con Leishmania major. La inducción de Th1 como respuesta contra la familia LiPABP por vacunación génica fue capaz de regular a la baja la IL-10 con respuestas predominantes suscitadas por el parásito LiPABPs tras la infección en este modelo murino. Esta modulación se tradujo en una protección parcial contra la infección por L. major. Los ratones vacunados con LiPABP mostraron una reducción de la patología que fue acompañada por una disminución de la carga parasitaria, en títulos de anticuerpos contra antígenos de Leishmania y de la IL-4 y la IL-10 las respuestas mediadas específicas del parásito en comparación con el control de grupos de ratones inmunizados con solución salina o con no-plásmidos recombinantes. Conclusión/significación Los resultados aquí presentados demuestran por primera vez las propiedades profilácticas de una nueva familia de proteínas intracelulares antigénicas de Leishmania, la LiPABPs. La redirección de la respuesta inmune desencadenada frente contra la familia LiPABP (de IL-10 hacia las respuestas mediadas por IFN-γ) por vacunación génica fue capaz de inducir una protección parcial contra el desarrollo de la enfermedad en un modelo murino altamente susceptible de leishmaniasis.Background Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Methodology/Principal Findings Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. Conclusion/Significance The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasis.• Ministerio de Ciencia e Innovación. Proyectos FISPI14/00366 y FISPI11/00095 del Instituto de Salud Carlos III dentro de la Red de Investigación de Enfermedades Tropicales. Proyecto VI P I D I 2008-2011, ISCIII - Subdirección General de Redes y Centros de Investigación Cooperativa (RD12/0018/0009) • CNPq (Ciencia sem Fronteiras), Brasil: PVE 300174/2014-4 • Fundación Ramón Areces: Subvenciones al Centro de Biología Molecular Severo Ochoa (CBMSO).peerReviewe

Vaccination with a CD4+ and CD8+ T-cell epitopes-based recombinant chimeric protein derived from Leishmania infantum proteins confers protective immunity against visceral leishmaniasis.

Vaccination seems to be the best approach to control visceral leishmaniasis (VL). Resistance against infection is based on the development of a Th1 immune response characterized by the production of interferons-? (IFN-?), interleukin-12 (IL-12), granulocyte-macrophage-colony-stimulating factor (GM-CSF), and tumor necrosis factor-? (TNF-?), among others. A number of antigens have been tested as potential targets against the disease; few of them are able to stimulate human immune cells. In the present study, 1 prediction of MHC class I and II molecules-specific epitopes in the amino acid sequences of 3 Leishmania proteins: 1 hypothetical, prohibitin, and small glutamine-rich tetratricopeptide repeat-containing proteins, was performed using bioinformatics tools, and a T-cell epitopes-based recombinant chimeric protein was constructed, synthetized and purified to be evaluated in invitro and in vivo experiments. The purified protein was tested regarding its immunogenicity in peripheral blood mononuclear cells (PBMCs) from healthy subjects and VL patients, as well as to its immunogenicity and protective efficacy in a murine model against Leishmania infantum infection. Results showed a Th1 response based on high IFN-? and low IL-10 levels derived from in chimera-stimulated PBMCs in both healthy subjects and VL patients. In addition, chimera and/or saponin-immunized mice presented significantly lower parasite burden in distinct evaluated organs, when compared to the controls, besides higher levels of IFN-?, IL-2, IL-12, and GM-CSF, and an IgG2a isotype-based humoral response. In addition, the CD4+ and CD8+ T-cell subtypes contributed to IFN-? production in the protected animals. The results showed the immunogenicity in human cells and the protective efficacy against L. infantum in a murine model, and well indicate that this recombinant chimera can be considered as a promising strategy to be used against human disease

Recent updates and perspectives on approaches for the development of vaccines against visceral leishmaniasis

All rights reserved. Visceral leishmaniasis (VL) is one of the most important tropical diseases worldwide. Although chemotherapy has been widely used to treat this disease, problems related to the development of parasite resistance and side effects associated with the compounds used have been noted. Hence, alternative approaches for VL control are desirable. Some methods, such as vector control and culling of infected dogs, are insufficiently effective, with the latter not ethically recommended. The development of vaccines to prevent VL is a feasible and desirable measure for disease control, for example, some vaccines designed to protect dogs against VL have recently been brought to market. These vaccines are based on the combination of parasite fractions or recombinant proteins with adjuvants that are able to induce cellular immune responses, however, their partial efficacy and the absence of a vaccine to protect against human leishmaniasis underline the need for characterization of new vaccine candidates. This review presents recent advances in control measures for VL based on vaccine development, describing extensively studied antigens, as well as new antigenic proteins recently identified using immuno-proteomic techniquesThis work was supported by grants from Instituto Nacional de Ciência e Tecnologia em Nano-Biofarmacêutica, Rede Nanobiotec/Brasil-Universidade Federal de Uberlândia/CAPES, PRONEX-FAPEMIG (APQ-01019-09), FAPEMIG (CBB-APQ-00819-12 and CBB-APQ-01778-2014), and CNPq (APQ-482976/2012-8, APQ-488237/2013-0, and APQ-467640/2014-9). EAFC and LRG are recipients of the grant from CNPq. MACF is the recipient of grants from FAPEMIG/CAPE

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio