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Malaria drug resistance

Andrew J Tatem, Peng Jia, Dariya Ordanovich, Michael Falkner, Zhuojie Huang, Rosalind Howes, Simon I Hay, Peter W Gething, David L Smith
BACKGROUND: Malaria remains a problem for many countries classified as malaria free through cases imported from endemic regions. Imported cases to non-endemic countries often result in delays in diagnosis, are expensive to treat, and can sometimes cause secondary local transmission. The movement of malaria in endemic countries has also contributed to the spread of drug resistance and threatens long-term eradication goals. Here we focused on quantifying the international movements of malaria to improve our understanding of these phenomena and facilitate the design of mitigation strategies...
October 21, 2016: Lancet Infectious Diseases
Eric P M Grist, Jennifer A Flegg, Georgina Humphreys, Ignacio Suay Mas, Tim J C Anderson, Elizabeth A Ashley, Nicholas P J Day, Mehul Dhorda, Arjen M Dondorp, M Abul Faiz, Peter W Gething, Tran T Hien, Tin M Hlaing, Mallika Imwong, Jean-Marie Kindermans, Richard J Maude, Mayfong Mayxay, Marina McDew-White, Didier Menard, Shalini Nair, Francois Nosten, Paul N Newton, Ric N Price, Sasithon Pukrittayakamee, Shannon Takala-Harrison, Frank Smithuis, Nhien T Nguyen, Kyaw M Tun, Nicholas J White, Benoit Witkowski, Charles J Woodrow, Rick M Fairhurst, Carol Hopkins Sibley, Philippe J Guerin
BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. METHODS: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling...
October 24, 2016: International Journal of Health Geographics
Ifedayo Victor Ogungbe, William N Setzer
Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp...
October 19, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Tony Fröhlich, Svetlana B Tsogoeva
In order to overcome one of the greatest challenges in malaria treatment, drug resistance, new drug candidates are urgently needed, which should preferably act via novel mechanisms. Successful optimization of a phenotypic screening hit based on a quinoline-4-carboxamide derivative resulted in the highly promising lead structure 4, which according to the Medicines for Malaria Venture (MMV) met the efficacy and drug metabolism and pharmacokinetics (DMPK) requirements for a malaria drug target candidate and consequently was selected for preclinical development...
October 24, 2016: Journal of Medicinal Chemistry
Naren P Tallapragada
In August 2015, Turing Pharmaceuticals acquired the marketing rights to Daraprim (pyrimethamine), a drug used to treat parasitic infections like malaria and toxoplasmosis. Soon after, Turing caused an uproar when it announced that it would raise the price per tablet of Daraprim from [Formula: see text], a 5500% price hike for a drug that has been on the market for over 60 years and off patent since the 1970s. Old, off-patent drugs are becoming increasingly expensive; Daraprim is the archetypal example. Turing had the power to set a high price for Daraprim because the drug's limited patient population, the absence of competing manufacturers, and a lack of therapeutic alternatives all created an effective monopoly...
April 2016: Journal of Law and the Biosciences
Karan Malhotra, Mayavan Subramaniyan, Khushboo Rawat, Md Kalamuddin, M Irfan Qureshi, Pawan Malhotra, Asif Mohmmed, Katrina Cornish, Henry Daniell, Shashi Kumar
Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills >500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (∼0...
October 20, 2016: Molecular Plant
Vasanthanathan Poongavanam, Jacob Kongsted
The high rate of drug resistance as well as the complex biochemical process of the parasite reproduction cycle makes development of new drugs for malaria a very important but challenging task. Falcipain 2 (FL2) and Falcipain 3 (FL3) are the major cysteine protease enzymes that play a central role in providing essential amino acids for the parasite's protein biosynthesis through the hemoglobin hydrolysis process. Selective inhibition of these enzymes is considered as a promising chemotherapeutic target. In the present investigation, the highly efficient linear interaction energy (LIE) method has been parameterized for binding affinity predictions and assessed with a set of 244 compounds for FL2 and FL3 inhibition...
June 26, 2016: Journal of Molecular Graphics & Modelling
Kristina R Kesely, Antonella Pantaleo, Francesco M Turrini, Peter Olupot-Olupot, Philip S Low
With half of the world's population at risk for malaria infection and with drug resistance on the rise, the search for mutation-resistant therapies has intensified. We report here a therapy for Plasmodium falciparum malaria that acts by inhibiting the phosphorylation of erythrocyte membrane band 3 by an erythrocyte tyrosine kinase. Because tyrosine phosphorylation of band 3 causes a destabilization of the erythrocyte membrane required for parasite egress, inhibition of the erythrocyte tyrosine kinase leads to parasite entrapment and termination of the infection...
2016: PloS One
Alexandre Y Saito, Adriana A Marin Rodriguez, Danielle S Menchaca Vega, Rodrigo A C Sussmann, Emília A Kimura, Alejandro M Katzin
Malaria, an infectious disease that kills more than 438,000 people per year worldwide, is a major public health problem. The emergence of strains resistant to conventional therapeutic agents necessitates the discovery of new drugs. We previously demonstrated that various substances, including terpenes, have antimalarial activity in vitro and in vivo. Nerolidol is a sesquiterpene present as an essential oil in several plants that is used in scented products and has been approved by the US Food and Drug Administration as a food-flavouring agent...
September 30, 2016: International Journal of Antimicrobial Agents
Praveen K Bharti, Man M Shukla, Pascal Ringwald, Sri Krishna, Pushpendra P Singh, Ajay Yadav, Sweta Mishra, Usha Gahlot, Jai P Malaiya, Amit Kumar, Shambhu Prasad, Pradeep Baghel, Mohan Singh, Jaiprakash Vadadi, Mrigendra P Singh, Maria Dorina G Bustos, Leonard I Ortega, Eva-Maria Christophel, Sher S Kashyotia, Gagan S Sonal, Neeru Singh
BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states...
October 13, 2016: Malaria Journal
Thomas E Kraft, Monique R Heitmeier, Marina Putanko, Rachel L Edwards, Ma Xenia G Ilagan, Maria A Payne, Joseph M Autry, David D Thomas, Audrey R Odom, Paul W Hruz
The glucose transporter PfHT is essential to the survival of the malaria parasite Plasmodium falciparum and has been shown to be a druggable target with high potential for pharmacological intervention. Identification of compounds against novel drug targets is crucial to combating resistance against current therapeutics. Here, we describe the development of a cell-based assay system readily adaptable to high-throughput screening that directly measures compound effects on PfHT-mediated glucose transport. Intracellular glucose concentrations are detected using a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose-sensor...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Hannah C Slater, Lucy C Okell, Azra C Ghani
Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development...
October 7, 2016: Trends in Parasitology
Anju Singh, Mudasir Maqbool, Mohammad Mobashir, Nasimul Hoda
Malaria is a critical human disease with extensive exploration yet unestablished due to occurrence of frequent drug resistance. This aspect of malaria pharmacology calls for the introduction of new antimalarial. The drugs reported till date targeted different stages of the parasites in order to stop their growth and proliferation. Beside this, various drugs that could inhibit the imperative enzymes of the parasite have also been reported. Amid them, dihydroorotate dehydrogenase (DHODH) has a key worth. DHODH is involved in the de novo pyrimidine biosynthesis of the malarial parasite which acts as a primary source of energy for its survival...
September 27, 2016: European Journal of Medicinal Chemistry
Saw Thu Wah, Hathairad Hananantachai, Usanee Kerdpin, Chotiros Plabplueng, Virapong Prachayasittikul, Pornlada Nuchnoi
Cerebral malaria is still a deleterious health problem in tropical countries. The wide spread of malarial drug resistance and the lack of an effective vaccine are obstacles for disease management and prevention. Parasite and human genetic factors play important roles in malaria susceptibility and disease severity. The malaria parasite exerted a potent selective signature on the human genome, which is apparent in the genetic polymorphism landscape of genes related to pathogenesis. Currently, much genomic data and a novel body of knowledge, including the identification of microRNAs, are being increasingly accumulated for the development of laboratory testing cassettes for cerebral malaria prevention...
2016: Tropical Medicine and Health
Anupkumar R Anvikar, Naman Shah, Akshay C Dhariwal, Gagan Singh Sonal, Madan Mohan Pradhan, Susanta K Ghosh, Neena Valecha
Historically, malaria in India was predominantly caused by Plasmodium vivax, accounting for 53% of the estimated cases. After the spread of drug-resistant Plasmodium falciparum in the 1990s, the prevalence of the two species remained equivalent at the national level for a decade. By 2014, the proportion of P. vivax has decreased to 34% nationally, but with high regional variation. In 2014, P. vivax accounted for around 380,000 malaria cases in India; almost a sixth of all P. vivax cases reported globally. Plasmodium vivax has remained resistant to control measures, particularly in urban areas...
October 5, 2016: American Journal of Tropical Medicine and Hygiene
Giovanni Benelli, Claire L Jeffries, Thomas Walker
Mosquitoes represent the major arthropod vectors of human disease worldwide transmitting malaria, lymphatic filariasis, and arboviruses such as dengue virus and Zika virus. Unfortunately, no treatment (in the form of vaccines or drugs) is available for most of these diseases andvectorcontrolisstillthemainformofprevention. Thelimitationsoftraditionalinsecticide-based strategies, particularly the development of insecticide resistance, have resulted in significant efforts to develop alternative eco-friendly methods...
October 3, 2016: Insects
Amélie Le Bihan, Ruben de Kanter, Iñigo Angulo-Barturen, Christoph Binkert, Christoph Boss, Reto Brun, Ralf Brunner, Stephan Buchmann, Jeremy Burrows, Koen J Dechering, Michael Delves, Sonja Ewerling, Santiago Ferrer, Christoph Fischli, Francisco Javier Gamo-Benito, Nina F Gnädig, Bibia Heidmann, María Belén Jiménez-Díaz, Didier Leroy, Maria Santos Martínez, Solange Meyer, Joerg J Moehrle, Caroline L Ng, Rintis Noviyanti, Andrea Ruecker, Laura María Sanz, Robert W Sauerwein, Christian Scheurer, Sarah Schleiferboeck, Robert Sinden, Christopher Snyder, Judith Straimer, Grennady Wirjanata, Jutta Marfurt, Ric N Price, Thomas Weller, Walter Fischli, David A Fidock, Martine Clozel, Sergio Wittlin
BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented...
October 2016: PLoS Medicine
Haythem A Saadeh, Mohammad S Mubarak
Antimicrobial resistance to drugs is a serious threat to public health. Different strategies have been adopted to deal with antimicrobial resistance to known drugs, one such strategy is the use of drug hybrids; this is a promising strategy to address the growing problem of drug resistance. The present review covers the very recent examples of combining (hybrid) of two standard drugs in a single molecule for resistant bacteria and malaria, and to present evidence supporting that drug hybrids are the urgent and practical solution to stop or slow down the spread of drug resistance...
September 27, 2016: Current Topics in Medicinal Chemistry
Michelle de Oliveira Pedrosa, Rayssa Marques Duarte da Cruz, Jéssika Oliveira Viana, Ricardo Olímpio de Moura, Hamilton Mitsugu Ishiki, José Maria Barbosa Filho, Margareth F F M Diniz, Marcus Tullius Scotti, Luciana Scotti, Francisco Jaime Bezerra Mendonça
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost...
September 27, 2016: Current Topics in Medicinal Chemistry
Theresa Tawiah, Kristian Schultz Hansen, Frank Baiden, Jane Bruce, Mathilda Tivura, Rupert Delimini, Seeba Amengo-Etego, Daniel Chandramohan, Seth Owusu-Agyei, Jayne Webster
BACKGROUND: The presumptive approach of confirming malaria in health facilities leads to over-diagnosis of malaria, over use of anti-malaria drugs and the risk of drug resistance development. WHO recommends parasitological confirmation before treatment with artemisinin-based combination therapy (ACT) in all suspected malaria patients. The use of malaria rapid diagnostic tests (mRDTs) would make it possible for prescribers to diagnose malaria at point-of-care and better target the use of antimalarials...
2016: PloS One
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