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Verónica Seguel, Lorena Castro, Chantal Reigada, Leonel Cortes, María V Díaz, Mariana R Miranda, Claudio A Pereira, Michel Lapier, Carolina Campos-Estrada, Antonio Morello, Ulrike Kemmerling, Juan D Maya, Rodrigo López-Muñoz
Benznidazole is the first-line drug used in treating Chagas disease, which is caused by the parasite Trypanosoma cruzi (T. cruzi). However, benznidazole has limited efficacy and several adverse reactions. Pentamidine is an antiprotozoal drug used in the treatment of leishmaniasis and African trypanosomiasis. In T. cruzi, pentamidine blocks the transport of putrescine, a precursor of trypanothione, which constitutes an essential molecule in the resistance of T. cruzi to benznidazole. In the present study, we describe the effect of the combination of benznidazole and pentamidine on isolated parasites, mammalian cells and in mice infected with T...
October 8, 2016: Experimental Parasitology
Meng Yan, Pan Fan, Yanhui Shi, Lifang Feng, Junnan Wang, Ge Zhan, Baoxin Li
Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics...
2016: International Journal of Molecular Sciences
Gyongseon Yang, Gahee Choi, Joo Hwan No
Leishmaniasis is a disease caused by pathogenic Leishmania parasites and the current treatments are toxic and expensive, and drug-resistance has emerged. While pentamidine, a diamidine type of compound, is one of the treatment, its antileishmanial mechanism of action has not been investigated in-depth. Here we tested several diamidines, including pentamidine and its analog DB75, against Leishmania donovani and elucidate their antileishmanial mechanisms. We identified three promising new antileishmanial diamidine compounds with EC50 values of 3...
September 6, 2016: Antimicrobial Agents and Chemotherapy
Johan Maertens, Simone Cesaro, Georg Maschmeyer, Hermann Einsele, J Peter Donnelly, Alexandre Alanio, Philippe M Hauser, Katrien Lagrou, Willem J G Melchers, Jannik Helweg-Larsen, Olga Matos, Stéphane Bretagne, Catherine Cordonnier
The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults ( A-II: ) and children ( A-I: ) and should be given during the entire period at risk...
September 2016: Journal of Antimicrobial Chemotherapy
Carlos A Méndez-Cuesta, Miguel Ángel Herrera-Rueda, Sergio Hidalgo-Figueroa, Hugo Tlahuext, Rosa Moo-Puc, Juan Bautista Chale-Dzul, Manuel Chan-Bacab, Benjamín Otto Ortega-Morales, Emanuel Hernández-Núñez, Oscar Méndez-Lucio, José L Medina-Franco, Gabriel Navarrete-Vazquez
BACKGROUND: Propamidine, an antiseptic aromatic diamidine is a toxic compound with potential use as antiprotozoal drug. On the other hand, benzimidazole derivatives have shown excellent antiparasitic effects. We designed hybrid molecules between propamidine and benzimidazole in order to retain the antiprotozoal action, but decreasing the toxic effect of the molecule. Objetive: Design and prepare 12 hybrids from propamidine and benzimidazole for testing their antiparasitic effect over three protozoa: Giardia intestinalis, Trichomonas vaginalis and Leishmania Mexicana, as well as conduct several in silico simulations such as toxicological profile, molecular docking and molecular dynamics in order to understand their potential mode of action...
August 11, 2016: Medicinal Chemistry
Anthonius A Eze, Matthew K Gould, Jane C Munday, Daniel N A Tagoe, Valters Stelmanis, Achim Schnaufer, Harry P De Koning
BACKGROUND: Isometamidium is the main prophylactic drug used to prevent the infection of livestock with trypanosomes that cause Animal African Trypanosomiasis. As well as the animal infective trypanosome species, livestock can also harbor the closely related human infective subspecies T. b. gambiense and T. b. rhodesiense. Resistance to isometamidium is a growing concern, as is cross-resistance to the diamidine drugs diminazene and pentamidine. METHODOLOGY/PRINCIPAL FINDINGS: Two isometamidium resistant Trypanosoma brucei clones were generated (ISMR1 and ISMR15), being 7270- and 16,000-fold resistant to isometamidium, respectively, which retained their ability to grow in vitro and establish an infection in mice...
August 2016: PLoS Neglected Tropical Diseases
Evelyn Mirella Lopes Pina Diniz, Carlos Henrique Tomich de Paula da Silva, Verónica Gómez Perez, Leonardo Bruno Federico, Joaquín María Campos Rosa
Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes...
August 5, 2016: Journal of Biomolecular Structure & Dynamics
Marc Desquesnes, Sarawut Yangtara, Pawinee Kunphukhieo, Sathaporn Jittapalapong, Stéphane Herder
Beside typical human trypanosomes responsible of sleeping sickness in Africa and Chagas disease in Latin America, there is a growing number of reported atypical human infections due to Trypanosoma evansi, a livestock parasite, or Trypanosoma lewisi, a rat parasite, especially in Asia. Drugs available for the treatment of T. brucei ssp. in humans are obviously of choice for the control of T. evansi because it is derived from T. brucei. However, concerning T. lewisi, there is an urgent need to determine the efficacy of trypanocidal drugs for the treatment in humans...
October 2016: Infection, Genetics and Evolution
Danilo F Rodrigues, David A Maniscalco, Flavia A J Silva, Bruna G Chiari, María V Castelli, Vera L B Isaac, Regina M B Cicarelli, Silvia N López
The trypanocidal potential of the natural chalcone flavokawin B, which was isolated from the hexanic extract of Polygonum ferrugineum Wedd., is reported here. Although flavokawin B is widespread, this is the first report about its trypanocidal properties on both Trypanosoma cruzi (IC50 = 9.5 µM, IC50 = 34.7 µM benznidazol, Y strain) epimastigotes and Trypanosoma brucei (IC50 = 4.8 µM, IC50 = 6.4 µM pentamidine, 29-13 strain) procyclic forms, which was also corroborated on T. brucei strain 427 (IC50 = 6...
July 21, 2016: Planta Medica
Tarcieli Pozzebon Venturini, Luana Rossato, Francieli Chassot, Jéssica Tairine Keller, Fernanda Baldissera Piasentin, Janio Morais Santurio, Sydney Hartz Alves
The genus Fusarium is characterized by hyaline filamentous fungi that cause infections predominantly in immunocompromised patients. The remarkable primary resistance to antifungal agents of this genus requires a search for new therapeutic possibilities. This study assessed the in vitro susceptibility of 25 clinical isolates of Fusarium against antifungal agents (amphotericin B, caspofungin, itraconazole and voriconazole) and antimicrobials (pentamidine, polymyxin B, tigecycline and tobramycin) according to the broth microdilution method (M38-A2)...
August 2016: Journal of Medical Microbiology
Jean-François Faucher, David Morquin, Jacques Reynes, Catherine Chirouze, Bruno Hoen, Vincent Le Moing
Liposomal amphotericin B (LAmb) may fail to heal Leishmania infantum visceral leishmaniasis (VL) in the immunodeficient host. There are currently no guidelines on how to treat such patients and efficacy of miltefosine monotherapy seems limited in this indication. We present 2 cases of patients with VL and AIDS for which LAmb had to be interrupted (one because of toxicity, one because of treatment failure) and who were treated effectively with pentamidine followed by miltefosine.
October 2016: Parasitology International
Ching Chang Cho, Ruey Hwang Chou, Chin Yu
The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia...
August 19, 2016: Biochemical and Biophysical Research Communications
Xiaoyu Zhang, Liang Guo, Haoyu Zeng, Stephen L White, Michael Furniss, Bharathi Balasubramanian, Edward Lis, Armando Lagrutta, Frederick Sannajust, Li Leyna Zhao, Biao Xi, Xiaobo Wang, Myrtle Davis, Yama A Abassi
INTRODUCTION: The ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization screening due to its association with life-threatening "Torsades de Pointes" (TdP) arrhythmia. However, it has become evident that not all hERG channel inhibitors result in TdP and not all compounds that induce QT prolongation and TdP necessarily inhibit hERG. In order to address the limitations of the S7B/E14 guidelines, the FDA through a public/private partnership initiated the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative to examine the possible modification and refinement of the ICH E14/S7B guidelines...
September 2016: Journal of Pharmacological and Toxicological Methods
Sabrin R M Ibrahim, Hossam M Abdallah, Gamal A Mohamed, Samir A Ross
Three new tetracyclic triterpenoids namely, integracides H (1), I (4), and J (5), along with integracides B (3) and F (2) have been isolated from the endophytic fungus Fusarium sp. isolated from the roots of Mentha longifolia L. (Labiatae) growing in Saudi Arabia. The structure elucidation of the isolated compounds was achieved by spectroscopic analysis including UV, IR, 1D ((1)H and (13)C) and 2D ((1)H(1)H COSY, TOCSY, HSQC, HMBC, and NOESY) NMR as well as HRESIMS and comparison with literature data. Integracides H (1) and J (5) showed significant anti-leishmanial activity towards Leishmania donovani with IC50 values of 4...
July 2016: Fitoterapia
D A Curi, R E Duerst, C Badke, J Bell, S Chaudhury, M Kletzel, J Schneiderman, W T Tse, W J Muller, N Hijiya
No abstract text is available yet for this article.
May 23, 2016: Bone Marrow Transplantation
Graham T Dempsey, Khuram W Chaudhary, Nicholas Atwater, Cuong Nguyen, Barry S Brown, John D McNeish, Adam E Cohen, Joel M Kralj
INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative seeks an in vitro test to accurately predict clinical Torsades de Pointes (TdP). We developed a cardiotoxicity assay incorporating simultaneous measurement of the action potential (AP) waveform and Ca(2+) transient (CT) in human iPSC-derived cardiomyocytes (CMs). Concurrent optogenetic pacing provided a well-controlled electrophysiological background. METHODS: We used the Optopatch platform for all-optical electrophysiology (Hochbaum et al...
September 2016: Journal of Pharmacological and Toxicological Methods
Loriel J Solodokin, Liana M Klejmont, Marco R Scipione, Yanina Dubrovskaya, Jennifer Lighter-Fisher, John Papadopoulos
BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection that can lead to significant morbidity and mortality in immunocompromised pediatric hematology/oncology patients. Trimethoprim/sulfamethoxazole is the gold standard for prophylaxis. Intravenous (IV) pentamidine is the preferred second-line agent for PCP prophylaxis at our institution and is used first-line under certain circumstances. The purpose of this study is to evaluate the effectiveness and safety of IV pentamidine for PCP prophylaxis in pediatric hematology/oncology patients...
August 2016: Journal of Pediatric Hematology/oncology
Élodie Gazanion, Christopher Fernández-Prada, Barbara Papadopoulou, Philippe Leprohon, Marc Ouellette
Innovative strategies are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. Here we develop a sensitive method, which we term Cosmid Sequencing (or "Cos-Seq"), based on functional cloning coupled to next-generation sequencing. Cos-Seq identified >60 loci in the Leishmania genome that were enriched via drug selection with methotrexate and five major antileishmanials (antimony, miltefosine, paromomycin, amphotericin B, and pentamidine). Functional validation highlighted both known and previously unidentified drug targets and resistance genes, including novel roles for phosphatases in resistance to methotrexate and antimony, for ergosterol and phospholipid metabolism genes in resistance to miltefosine, and for hypothetical proteins in resistance to paromomycin, amphothericin B, and pentamidine...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Rajan Kumar Pandey, Bajarang Vasant Kumbhar, Shyam Sundar, Ambarish Kunwar, Vijay Kumar Prajapati
Visceral leishmaniasis (VL) is the most fatal form of leishmaniasis and it affects 70 countries worldwide. Increasing drug resistant for antileishmanial drugs such as miltefosine, sodium stibogluconate and pentamidine has been reported in the VL endemic region. Amphotericin B has shown potential antileishmanial activity in different formulations but its cost of treatment and associated nephrotoxicity have limited its use by affected people living in the endemic zone. To control the VL infection in the affected countries, it is necessary to develop new antileishmanial compounds with high efficacy and negligible toxicity...
May 5, 2016: Journal of Receptor and Signal Transduction Research
Sohyoung Her, Lei Cui, Robert G Bristow, Christine Allen
Triple negative breast cancer (TNBC) is an aggressive disease with a high risk of recurrence and death. Here, we present a novel strategy to enhance the radiotherapy of TNBC by combining gold nanoparticles (AuNPs) with pentamidine, a clinically approved anti-parasitic agent with anti-cancer properties. The radiosensitization effects of PEG-stabilized AuNPs (PEG-AuNPs) in combination with pentamidine were evaluated in two human TNBC cell lines (MDA-MB-231 and MDA-MB-436). Our results showed that PEG-AuNPs alone sensitized both cell lines to radiation, achieving dose enhancement factors of 1...
May 2016: Radiation Research
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