Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensis and Its Inhibitory Effect on Topoisomerase 1B

Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current dr...

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Published in:	Antimicrobial agents and chemotherapy Vol. 61; no. 8
Main Authors:	Velásquez, Angela Maria Arenas, Ribeiro, Willian Campos, Venn, Vutey, Castelli, Silvia, Camargo, Mariana Santoro de, de Assis, Renata Pires, de Souza, Rodrigo Alves, Ribeiro, Aline Rimoldi, Passalacqua, Thaís Gaban, da Rosa, João Aristeu, Baviera, Amanda Martins, Mauro, Antonio Eduardo, Desideri, Alessandro, Almeida-Amaral, Elmo Eduardo, Graminha, Marcia A S
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-08-2017
Subjects:	Amphotericin B - therapeutic use Animals Antiprotozoal Agents Antiprotozoal Agents - adverse effects Antiprotozoal Agents - therapeutic use Benzylamines Benzylamines - chemistry Benzylamines - therapeutic use Catalytic Domain - drug effects Cells, Cultured Clinical Therapeutics Disease Models, Animal DNA Topoisomerases, Type I - drug effects Kidney Function Tests Leishmania mexicana Leishmania mexicana - drug effects Leishmania mexicana - growth & development Leishmaniasis, Cutaneous Leishmaniasis, Cutaneous - drug therapy Liver Function Tests Macrophages, Peritoneal - drug effects Male Mice Mice, Inbred BALB C Neglected Diseases - drug therapy Neglected Diseases - parasitology Palladium Palladium - chemistry Palladium - therapeutic use Parasite Load Parasitic Sensitivity Tests Topoisomerase I Inhibitors Topoisomerase I Inhibitors - therapeutic use cyclopalladated complex topoisomerase 1B Leishmania donovani Chagas disease leishmaniasis Leishmania amazonensis Trypanosoma cruzi
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Summary:	Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and , '-dimethylbenzylamine (Hdmba) against The compound [Pd(dmba)(μ-N )] (CP2) inhibits promastigote growth (50% inhibitory concentration [IC ] = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in incubated macrophages (IC = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 μM). In addition, CP2 was also active against intracellular amastigotes (IC = 2.3 ± 0.5 μM, selective index = 225), an indication of its potential for use in Chagas disease therapy. assays using -infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit topoisomerase 1B ( topo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.).
Bibliography:	Citation Velásquez AMA, Ribeiro WC, Venn V, Castelli S, Camargo MS, de Assis RP, de Souza RA, Ribeiro AR, Passalacqua TG, da Rosa JA, Baviera AM, Mauro AE, Desideri A, Almeida-Amaral EE, Graminha MAS. 2017. Efficacy of a binuclear cyclopalladated compound therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis and its inhibitory effect on topoisomerase 1B. Antimicrob Agents Chemother 61:e00688-17. https://doi.org/10.1128/AAC.00688-17.
ISSN:	0066-4804 1098-6596
DOI:	10.1128/AAC.00688-17