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International Journal for Parasitology, Drugs and Drug Resistance

Zongze Zhang, Robin B Gasser, Xin Yang, Fangyuan Yin, Guanghui Zhao, Min Bao, Baoliang Pan, Weiyi Huang, Chunren Wang, Fengcai Zou, Yanqin Zhou, Junlong Zhao, Rui Fang, Min Hu
Haemonchus contortus is one of the most important parasitic nematodes of small ruminants around the world, particularly in tropical and subtropical regions. The control of haemonchosis relies mainly on anthelmintics, but the excessive and prolonged use of anthelmintics is causing serious drug resistance issues in many countries. As benzimidazole (BZ) anthelmintics have been broadly used in China, we hypothesized that resistance is widespread. Given the link between three known single nucleotide polymorphisms (SNPs, designated F167Y, E198A and F200Y) in the isotype-1 β-tubulin gene and BZ resistance, our goal here was to explore the presence of these mutations in H...
October 5, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Maeghan O'Neill, Cristina Ballesteros, Lucienne Tritten, Erica Burkman, Weam I Zaky, Jianguo Xia, Andrew Moorhead, Steven A Williams, Timothy G Geary
The use of microfilaricidal drugs for the control of onchocerciasis and lymphatic filariasis (LF) necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by the availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate. FLBZ has demonstrated potent macrofilaricidal effects in a number of experimental rodent models and in one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration campaigns due to its limited oral bioavailability...
October 1, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Miguel Quiliano, Adela Mendoza, Kim Y Fong, Adriana Pabón, Nathan E Goldfarb, Isabelle Fabing, Ariane Vettorazzi, Adela López de Cerain, Ben M Dunn, Giovanny Garavito, David W Wright, Eric Deharo, Silvia Pérez-Silanes, Ignacio Aldana, Silvia Galiano
Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 μM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 μM and C235 IC50 ≤ 0.28 μM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed...
September 28, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Phuong N Tran, Cameron J Tate, Melanie C Ridgway, Kevin J Saliba, Kiaran Kirk, Alexander G Maier
Ketotifen has recently been reported to inhibit the growth of both asexual and sexual malaria parasites. A parasite transporter, PfgABCG2, has been implicated in its mechanism of action. Human dihydrofolate reductase (hDHFR) is the most commonly used selectable marker to create transgenic Plasmodium falciparum cell lines. Growth assays using transgenic P. falciparum parasites with different selectable markers revealed that the presence of hDHFR rather than the absence of PfgABCG2 is responsible for a shift in the parasite's sensitivity to ketotifen...
September 22, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Janis C Weeks, William M Roberts, Kristin J Robinson, Melissa Keaney, Jon J Vermeire, Joseph F Urban, Shawn R Lockery, John M Hawdon
The screening of candidate compounds and natural products for anthelmintic activity is important for discovering new drugs against human and animal parasites. We previously validated in Caenorhabditis elegans a microfluidic device ('chip') that records non-invasively the tiny electrophysiological signals generated by rhythmic contraction (pumping) of the worm's pharynx. These electropharyngeograms (EPGs) are recorded simultaneously from multiple worms per chip, providing a medium-throughput readout of muscular and neural activity that is especially useful for compounds targeting neurotransmitter receptors and ion channels...
September 15, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Marion A David, Stéphane Orlowski, Roger K Prichard, Shaima Hashem, François André, Anne Lespine
Macrocyclic lactones (ML) are important anthelmintics used in animals and humans against parasite nematodes, but their therapeutic success is compromised by the spread of ML resistance. Some ABC transporters, such as p-glycoproteins (Pgps), are selected and overexpressed in ML-resistant nematodes, supporting a role for some drug efflux proteins in ML resistance. However, the role of such proteins in ML transport remains to be clarified at the molecular level. Recently, Caenorhabditis elegans Pgp-1 (Cel-Pgp-1) has been crystallized, and its drug-modulated ATPase function characterized in vitro revealed Cel-Pgp-1 as a multidrug transporter...
September 15, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Rasika Kumarasingha, Avinash V Karpe, Sarah Preston, Tiong-Chia Yeo, Diana S L Lim, Chu-Lee Tu, Jennii Luu, Kaylene J Simpson, Jillian M Shaw, Robin B Gasser, David J Beale, Paul D Morrison, Enzo A Palombo, Peter R Boag
Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus...
August 26, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Monica Cal, Jean-Robert Ioset, Matthia A Fügi, Pascal Mäser, Marcel Kaiser
Total clearance of the T. cruzi infection - referred to herein as "sterile cure" - seems to be a critical prerequisite for new drug candidates for Chagas disease, ensuring long-term beneficial effects for patients in the chronic indeterminate stage. This requirement is notably supported by the recent findings of clinical studies involving posaconazole and fosravuconazole, where the majority of patients treated eventually relapsed after an apparent clearance of parasitaemia at the end of treatment. We have adapted an in vitro system to predict the ability of a compound to deliver sterile cure...
August 26, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Sarah Preston, Yaqing Jiao, Abdul Jabbar, Sean L McGee, Benoît Laleu, Paul Willis, Timothy N C Wells, Robin B Gasser
There is a substantial need to develop new medicines against parasitic diseases via public-private partnerships. Based on high throughput phenotypic screens of largely protozoal pathogens and bacteria, the Medicines for Malaria Venture (MMV) has recently assembled an open-access 'Pathogen Box' containing 400 well-curated chemical compounds. In the present study, we tested these compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility, growth and development of H...
July 28, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Swarna Bais, Robert M Greenberg
Praziquantel (PZQ) is effectively the only drug currently available for treatment and control of schistosomiasis, a disease affecting hundreds of millions of people worldwide. Many anthelmintics, likely including PZQ, target ion channels, membrane protein complexes essential for normal functioning of the neuromusculature and other tissues. Despite this fact, only a few classes of parasitic helminth ion channels have been assessed for their pharmacological properties or for their roles in parasite physiology...
July 27, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Verónica Gómez Pérez, Raquel García-Hernandez, Victoriano Corpas-López, Ana M Tomás, Joaquina Martín-Sanchez, Santiago Castanys, Francisco Gamarro
Visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania infantum, is one of the most important zoonotic diseases affecting dogs and humans in the Mediterranean area. The presence of infected dogs as the main reservoir host of L. infantum is regarded as the most significant risk for potential human infection. We have studied the susceptibility profile to antimony and other anti-leishmania drugs (amphotericin B, miltefosine, paromomycin) in Leishmania infantum isolates extracted from a dog before and after two therapeutic interventions with meglumine antimoniate (subcutaneous Glucantime(®), 100 mg/kg/day for 28 days)...
August 2016: International Journal for Parasitology, Drugs and Drug Resistance
Sanketkumar Pandya, Rahul Kumar Verma, Prashant Khare, Brajendra Tiwari, Dadi A Srinivasarao, Anuradha Dube, Neena Goyal, Amit Misra
We investigated efficacy of nitric oxide (NO) against Leishmania donovani. NO is a mediator of host response to infection, with direct parasiticidal activity in addition to its role in signalling to evoke innate macrophage responses. However, it is short-lived and volatile, and is therefore difficult to introduce into infected cells and maintain inracellular concentrations for meaningful periods of time. We incorporated diethylenetriamine NO adduct (DETA/NO), a prodrug, into poly(lactide-co-glycolide) particles of ∼200 nm, with or without amphotericin B (AMB)...
August 2016: International Journal for Parasitology, Drugs and Drug Resistance
Catherine Bourguinat, Hua Che, Thangadurai Mani, Kathy Keller, Roger K Prichard
Dirofilaria immitis is a filarial nematode causing infection and heartworm disease in dogs and other canids, cats, and occasionally in humans. Prevention with macrocyclic lactones (ML) is recommended during the mosquito transmission season. Recently, ML resistance has been reported. ABC-B transporter genes are thought to be involved in the mechanism of ML resistance in other nematodes. This study aimed to identify all the ABC-B transporter genes in D. immitis using as a reference the nDi.2.2 D. immitis whole genome, which is not completely annotated...
August 2016: International Journal for Parasitology, Drugs and Drug Resistance
Ali Raza, Steven R Kopp, Neil H Bagnall, Abdul Jabbar, Andrew C Kotze
This study investigated the interaction of ATP binding cassette (ABC) transport proteins with ivermectin (IVM) and levamisole (LEV) in larvae of susceptible and resistant isolates of Haemonchus contortus in vitro by measuring transcription patterns following exposure to these anthelmintics. Furthermore, we studied the consequences of drug exposure by measuring the sensitivity of L3 to subsequent exposure to higher drug concentrations using larval migration assays. The most highly transcribed transporter genes in both susceptible and resistant L3 were pgp-9...
August 2016: International Journal for Parasitology, Drugs and Drug Resistance
David Leitsch, Joachim Müller, Norbert Müller
The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs...
July 22, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Guilherme Curty Lechuga, Júlio Cesar Borges, Claudia Magalhães Calvet, Humberto Pinheiro de Araújo, Aline Araujo Zuma, Samara Braga do Nascimento, Maria Cristina Machado Motta, Alice Maria Rolim Bernardino, Mirian Claudia de Souza Pereira, Saulo Cabral Bourguignon
Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4-arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro...
July 14, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Thangadurai Mani, Catherine Bourguinat, Kathy Keller, Elena Carreton, Andrew Peregrine, Roger K Prichard
Dirofilaria immitis, a filarial parasite, causes cardiopulmonary dirofilariasis in dogs, cats and wild canids. The macrocyclic lactone (ML) class of drugs has been used to prevent heartworm infection. There is confirmed ML resistance in D. immitis and thus there is an urgent need to find new anthelmintics that could prevent and/or control the disease. Targeting ion channels of D. immitis for drug design has obvious advantages. These channels, present in the nematode nervous system, control movement, feeding, mating and respond to environmental cues which are necessary for survival of the parasite...
July 1, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Adam Novobilský, Natalia Amaya Solis, Moa Skarin, Johan Höglund
Anthelmintic resistance (AR) to Fasciola hepatica is emerging worldwide. Recently, AR to the adulticide compound albendazole (ABZ) was shown in Argentina and Spain. In Sweden, ABZ treatment failure against F. hepatica was first reported in sheep in 2012. The present study tested the efficacy of ABZ and triclabendazole (TCBZ) in sheep naturally infected with F. hepatica using a combination of three different diagnostic methods: faecal egg counts (FEC), coproantigen ELISA (cELISA) and Fasciola egg hatch test (FEHT)...
June 26, 2016: International Journal for Parasitology, Drugs and Drug Resistance
John D Chan, Thomas Grab, Jonathan S Marchant
The diversity and uniqueness of flatworm G protein coupled receptors (GPCRs) provides impetus for identifying ligands useful as tools for studying flatworm biology, or as therapeutics for treating diseases caused by parasitic flatworm infections. To catalyse this discovery process, technologies optimized for mammalian GPCR high throughput screening need be transposed for screening flatworm GPCRs. Here, we demonstrate the utility of a genetically encoded cAMP biosensor for resolving the properties of an abundantly expressed planarian serotonergic GPCR (S7...
June 23, 2016: International Journal for Parasitology, Drugs and Drug Resistance
John D Chan, Sreemoyee Acharya, Timothy A Day, Jonathan S Marchant
5-hydroxytryptamine (5-HT) is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL), prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products - nuciferine, D-glaucine, boldine and bulbocapnine - were demonstrated to block Sm...
June 23, 2016: International Journal for Parasitology, Drugs and Drug Resistance
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