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International Journal for Parasitology, Drugs and Drug Resistance

Ji Li Zhang, Hong Fei Si, Xiao Fei Shang, Xu Kun Zhang, Bing Li, Xu Zheng Zhou, Ji Yu Zhang
Toxoplasma gondii is the causative agent of toxoplasmosis and causes serious public health problems. However, the current treatment drugs have many limitations, such as serious side effects. Niclosamide is a salicylanilide drug commonly used to treat worm infections. Herein, the effectiveness of niclosamide for the treatment of T. gondii infection was demonstrated. This study was to evaluate the in vitro and in vivo activities of niclosamide against T. gondii and to explore its mechanism of action. The in vitro cytotoxicity of niclosamide on human foreskin fibroblast cells was evaluated by MTT test...
December 21, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Ryan C Henrici, Donelly A van Schalkwyk, Colin J Sutherland
Clinical studies suggest that outcomes for hospitalised malaria patients can be improved by managed hypothermia during treatment. We examined the impact of short pulses of low temperature on ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro. The usually artemisinin-sensitive clone 3D7 exhibited substantially reduced ring-stage susceptibility to a 4-h pulse of 700 nM dihydro-artemisinin administered during a 5-h pulse of low temperature down to 17 °C. Parasite growth through the subsequent asexual cycle was not affected by the temperature pulse...
December 16, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Patrícia Valéria Castelo-Branco, Hugo José Alves, Raissa Lacerda Pontes, Vera Lucia Maciel-Silva, Silma Regina Ferreira Pereira
Leishamaniasis is a neglected disease caused by over 20 Leishmania species, occurring in more than a hundred countries. Miltefosine (hexadecylphosphocholine) is the single oral drug used in treatment for leshmaniases, including cases of infections resistant to pentavalent antimony. Our group has recently demonstrated the ability of miltefosine to cause genomic lesions by DNA oxidation. Acknowledging that antioxidant compounds can potentially modulate Reactive Oxygen Species (ROS), our study verified whether ascorbic acid reduces the genotoxic and mutagenic effects caused by miltefosine, and whether it interferes with drug efficacy...
December 13, 2018: International Journal for Parasitology, Drugs and Drug Resistance
S Hendrickx, D Bulté, M Van den Kerkhof, P Cos, P Delputte, L Maes, G Caljon
Although miltefosine (MIL) has only been approved for the treatment of visceral leishmaniasis (VL) in 2002, its application in monotherapy already led to the development of two confirmed MIL-resistant isolates by 2009. Although liposomal amphotericin B is recommended as first-line treatment in Europe, MIL is still occasionally used in HIV co-infected patients. Since their immune system is incapable of controlling the infection, high parasite burdens and post-treatment relapses are common. Linked to the particular pharmacokinetic profile of MIL, successive treatment of recurrent relapses could in principle facilitate the emergence of drug resistance...
December 11, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Duangkamon Loesbanluechai, Namfon Kotanan, Cristina de Cozar, Theerarat Kochakarn, Megan R Ansbro, Kesinee Chotivanich, Nicholas J White, Prapon Wilairat, Marcus C S Lee, Francisco Javier Gamo, Laura Maria Sanz, Thanat Chookajorn, Krittikorn Kümpornsin
Artemisinin derivatives and their partner drugs in artemisinin combination therapies (ACTs) have played a pivotal role in global malaria mortality reduction during the last two decades. The loss of artemisinin efficacy due to evolving drug-resistant parasites could become a serious global health threat. Dihydroartemisinin-piperaquine is a well tolerated and generally highly effective ACT. The implementation of a partner drug in ACTs is critical in the control of emerging artemisinin resistance. Even though artemisinin is highly effective in parasite clearance, it is labile in the human body...
December 1, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Alan R Wolfe, R Jeffrey Neitz, Mark Burlingame, Brian M Suzuki, K C Lim, Mark Scheideler, David L Nelson, Leslie Z Benet, Conor R Caffrey
Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100 mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by ≥ 90% and ≥46% (mature), and ≥89% and ≥79% (juvenile), respectively...
November 20, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Claude L Charvet, Fabrice Guégnard, Elise Courtot, Jacques Cortet, Cedric Neveu
The control of parasitic nematodes impacting animal health relies on the use of broad spectrum anthelmintics. However, intensive use of these drugs has led to the selection of resistant parasites in livestock industry. In that respect, there is currently an urgent need for novel compounds able to control resistant parasites. Nicotine has also historically been used as a de-wormer but was removed from the market when modern anthelmintics became available. The pharmacological target of nicotine has been identified in nematodes as acetylcholine-gated ion channels...
November 20, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Gilda Padalino, Salvatore Ferla, Andrea Brancale, Iain W Chalmers, Karl F Hoffmann
Schistosomiasis endangers the lives of greater than 200 million people every year and is predominantly controlled by a single class chemotherapy, praziquantel (PZQ). Development of PZQ replacement (to combat the threat of PZQ insensitivity/resistance arising) or combinatorial (to facilitate the killing of PZQ-insensitive juvenile schistosomes) chemotherapies would help sustain this control strategy into the future. Here, we re-categorise two families of druggable epigenetic targets in Schistosoma mansoni, the histone methyltransferases (HMTs) and the histone demethylases (HDMs)...
November 13, 2018: International Journal for Parasitology, Drugs and Drug Resistance
A G Sanford, T T Schulze, L P Potluri, G F Watson, E B Darner, S J Zach, R M Hemsley, A I Wallick, R C Warner, S A Charman, X Wang, J L Vennerstrom, P H Davis
Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype...
November 10, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Adrian J Wolstenholme, Richard J Martin
The third scientific meeting in the series "Anthelmintics: From Discovery to Resistance" was held in Indian Rocks Beach, Florida, at the end of January 2018. The meeting focused on a variety of topics related to the title, including the identification of novel targets and new leads, the mechanism of action of existing drugs and the genetic basis of resistance against them. Throughout there was an emphasis on the exploitation of new technologies and methods to further these aims. The presentations, oral and poster, covered basic, veterinary and medical science with strong participation by both academic and commercial researchers...
November 5, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Reto Rufener, Luca Dick, Laura D'Ascoli, Dominic Ritler, Amani Hizem, Timothy N C Wells, Andrew Hemphill, Britta Lundström-Stadelmann
The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite...
October 31, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Janis C Weeks, Kristin J Robinson, Shawn R Lockery, William M Roberts
Many anthelmintic drugs used to treat parasitic nematode infections target proteins that regulate electrical activity of neurons and muscles: ion channels (ICs) and neurotransmitter receptors (NTRs). Perturbation of IC/NTR function disrupts worm behavior and can lead to paralysis, starvation, immune attack and expulsion. Limitations of current anthelmintics include a limited spectrum of activity across species and the threat of drug resistance, highlighting the need for new drugs for human and veterinary medicine...
October 30, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Micah K Callanan, Sarah A Habibi, Wen Jing Law, Kristen Nazareth, Richard L Komuniecki, Sean G Forrester
The cys-loop superfamily of ligand-gated ion channels are well recognized as important drug targets for many invertebrate specific compounds. With the rise in resistance seen worldwide to existing anthelmintics, novel drug targets must be identified so new treatments can be developed. The acetylcholine-gated chloride channel (ACC) family is a unique family of cholinergic receptors that have been shown, using Caenorhabditis elegans as a model, to have potential as anti-parasitic drug targets. However, there is little known about the function of these receptors in parasitic nematodes...
October 27, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Helen L Whiteland, Anand Chakroborty, Josephine E Forde-Thomas, Alessandra Crusco, Alan Cookson, Jackie Hollinshead, Caroline A Fenn, Barbara Bartholomew, Peter A Holdsworth, Maggie Fisher, Robert J Nash, Karl F Hoffmann
Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities...
October 26, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Astra S Bryant, Elissa A Hallem
Infection with gastrointestinal parasitic nematodes is a major cause of chronic morbidity and economic burden around the world, particularly in low-resource settings. Some parasitic nematode species, including the human-parasitic threadworm Strongyloides stercoralis and human-parasitic hookworms in the genera Ancylostoma and Necator, feature a soil-dwelling infective larval stage that seeks out hosts for infection using a variety of host-emitted sensory cues. Here, we review our current understanding of the behavioral responses of soil-dwelling infective larvae to host-emitted sensory cues, and the molecular and cellular mechanisms that mediate these responses...
October 26, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Cristiana T Trinconi, Danilo C Miguel, Ariel M Silber, Christopher Brown, John G M Mina, Paul W Denny, Norton Heise, Silvia R B Uliana
Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmaniasis. Using a combination of metabolic labeling with [3 H]-sphingosine and myo-[3 H]-inositol, alkaline hydrolysis, HPTLC fractionations and mass spectrometry analyses, we observed a perturbation in the metabolism of inositolphosphorylceramides (IPCs) and phosphatidylinositols (PIs) after treatment of L...
October 24, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Medard Ernest, Carol Hunja, Yuka Arakura, Yohei Haraga, Hussein M Abkallo, Weiguang Zeng, David C Jackson, Brendon Chua, Richard Culleton
Both vaccine and therapeutic approaches to malaria are based on conventional paradigms; whole organism or single antigen epitope-based vaccines administered with or without an adjuvant, and chemotherapeutics (anti-malaria drugs) that are toxic to the parasite. Two major problems that limit the effectiveness of these approaches are i) high levels of antigenic variation within parasite populations rendering vaccination efficacy against all variants difficult, and ii) the capacity of the parasite to quickly evolve resistance to drugs...
October 23, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Anna C C Aguiar, Erika Murce, Wilian A Cortopassi, Andre S Pimentel, Maria M F S Almeida, Daniele C S Barros, Jéssica S Guedes, Mario R Meneghetti, Antoniana U Krettli
In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P...
October 13, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Josh Foster, Everett Cochrane, Mohammad Hassan Khatami, Sarah A Habibi, Hendrick de Haan, Sean G Forrester
The UNC-49 receptor is a unique nematode γ-aminobutyric acid (GABA)-gated chloride channel that may prove to be a novel target for the development of nematocides. Here we have characterized various charged amino acid residues in and near the agonist binding site of the UNC-49 receptor from the parasitic nematode Haemonchus contorts. Utilizing the Caenorhabditis elegans GluCl crystal structure as a template, a model was generated and various charged residues [D83 (loop D), E131 (loop A), H137 (pre-loop E), R159 (Loop E), E185 (Loop B) and R241 (Loop C)] were investigated based on their location and conservation...
October 6, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Jonathan S Marchant, Wayne W Harding, John D Chan
Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscular function to sexual maturation and egg laying. In the parasitic blood fluke Schistosoma mansoni, 5-HT targets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement. This receptor, Sm.5HTRL , has been successfully co-expressed in mammalian cells alongside a luminescent cAMP-biosensor, enabling pharmacological profiling for candidate anti-schistosomal drugs...
September 28, 2018: International Journal for Parasitology, Drugs and Drug Resistance
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