Download or read book Mechanisms of Drug Resistance in Plasmodium Falciparum written by and published by . This book was released on 1994 with total page 69 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria continues as a major health threat throughout the tropical world and potential demand for antimalarials is higher than for any other medication yet the world faces a crisis--drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new drugs has all but stopped. This represents a particular threat to the US military. In a short time there may be parts of the world where no effective antimalarial drug is available. The recent emergence of multidrug resistant malaria parasites has intensified this problem. The goal of this work is to use a molecular genetic approach in the investigation of mechanisms of drug resistance and subsequently to use this information in the identification and development of new antimalarial drugs. These studies were initiated based on the observation that one mechanism of drug resistance in P. falciparum may be similar to multidrug resistance in cancer. During this work, we identified and fully characterized two mdr-like genes in P. falciparum, pfmdrl and pfmdr2 and have found an association with the amplification and over expression of one of these genes, pfmdrl with mefloquine resistance and multidrug resistant parasites both in laboratory derived and field isolated strains of Plasmodium falciparum. As a next step in this work, we have initiated the development methods of functional analysis which are critical both to developing and testing new chemotherapeutic interventions. Malaria, Drug resistance, Recombinant DNA, Tropical disease, Infectious disease.

Download or read book Saving Lives Buying Time written by Institute of Medicine and published by National Academies Press. This book was released on 2004-09-09 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: For more than 50 years, low-cost antimalarial drugs silently saved millions of lives and cured billions of debilitating infections. Today, however, these drugs no longer work against the deadliest form of malaria that exists throughout the world. Malaria deaths in sub-Saharan Africaâ€"currently just over one million per yearâ€"are rising because of increased resistance to the old, inexpensive drugs. Although effective new drugs called "artemisinins" are available, they are unaffordable for the majority of the affected population, even at a cost of one dollar per course. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance examines the history of malaria treatments, provides an overview of the current drug crisis, and offers recommendations on maximizing access to and effectiveness of antimalarial drugs. The book finds that most people in endemic countries will not have access to currently effective combination treatments, which should include an artemisinin, without financing from the global community. Without funding for effective treatment, malaria mortality could double over the next 10 to 20 years and transmission will intensify.

Download or read book Investigating Potential Mechanisms of Cytocidal Drug Resistance in Plasmodium Falciparum written by David Alejandro Gaviria and published by . This book was released on 2013 with total page 436 pages. Available in PDF, EPUB and Kindle. Book excerpt: By quantifying antimalarial cytocidal activities (measured as LD50s) and comparing them to cytostatic activities (measured as IC50s), Paguio et al., 2011 showed a clear difference between some drug activities at different drug levels. This work showed that fold-resistance ratios are dramatically different at cytostatic vs. cytocidal drug levels as are multidrug resistance (MDR) patterns and verapamil (VPL) chemoreversal. These observations provide a fertile ground for research in elucidating drug targets and mechanisms at cytocidal levels. Ghosh et al., 2012 elucidated an autophagy pathway involved in mitochondrial degradation in response to starvation in T. gondii, the organism most closely related to human malaria parasites outside of other Plasmodium species. Sequence analyses of the autophagy-related (Atg) proteins found in T. gondii reveal close homologues in P. falciparum. Atg protein homologues involved in every step of the canonical autophagy pathway were found. Vps34 (the catalytic subunit of the kinase complex responsible for phagophore nucleation) is highly homologous within conserved domains, though it is much larger due to repetitive sequences that exist between putative helical regions. Since chloroquine (CQ) is an established inhibitor of autophagy and autophagy appears to be a functional system in malaria parasites, I have investigated the function of this pathway in malaria parasites and any possible connections to CQ resistance (CQR). This work has produced important insights into the poorly understood role of Atg proteins in malaria parasites, their regulation, and signaling pathways. Importantly, the data contained in this work suggest a relationship between autophagy and resistance to CQ. Moreover, differences between CQ sensitive (CQS) and CQR parasites suggest that Ca2+ transients may also play a role in resistance.

Download or read book Global Technical Strategy for Malaria 2016 2030 written by World Health Organization and published by World Health Organization. This book was released on 2015-11-04 with total page 35 pages. Available in PDF, EPUB and Kindle. Book excerpt: The World Health Organization's Global Technical Strategy for Malaria 2016- 2030 has been developed with the aim to help countries to reduce the human suffering caused by the world's deadliest mosquito-borne disease. Adopted by the World Health Assembly in May 2015 it provides comprehensive technical guidance to countries and development partners for the next 15 years emphasizing the importance of scaling up malaria responses and moving towards elimination. It also highlights the urgent need to increase investments across all interventions - including preventive measures diagnostic testing treatment and disease surveillance- as well as in harnessing innovation and expanding research. By adopting this strategy WHO Member States have endorsed the bold vision of a world free of malaria and set the ambitious new target of reducing the global malaria burden by 90% by 2030. They also agreed to strengthen health systems address emerging multi-drug and insecticide resistance and intensify national cross-border and regional efforts to scale up malaria responses to protect everyone at risk.

Download or read book Resistance of Malaria Parasites to Drugs written by World Health Organization. Scientific Group on Resistance of Malaria Parasites to Drugs and published by . This book was released on 1965 with total page 76 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Analysis of Drug Resistance Mechanisms in Intact Plasmodium Falciparum infected Red Blood Cells written by Sarah Reiling and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Malaria is a major global health concern, with half of the world's population being at risk of infection. Among the Plasmodium species that infect humans, P. falciparum causes most fatalities. Chloroquine (CQ) was the drug of choice for decades and considered safe, affordable and easy-to-use until resistance emerged. However, the exact mechanism of CQ resistance is not known. CQ is suggested to accumulate in the parasite's digestive vacuole due to its weak base properties, where it exerts its antimalarial action. Several transporters are involved in intracellular distribution of antimalarial drugs. Among them are the P. falciparum chloroquine resistance transporter (PfCRT) and the P. falciparum multidrug resistance 1 transporter (PfMDR1). Both are located in the digestive vacuolar membrane but transport substrates in opposing directions. While PfCRT transports substrates out of the digestive vacuole (DV), PfMDR1 transports substrates into the DV. PfMDR1 contains five polymorphisms that are suggested to be involved in altered drug transport, although the exact role of each amino acid mutation remains unknown. To gain more insight into the transport functions of PfMDR1, variants with different mutation patterns were analyzed using the fluorescent substrate Fluo-4. We found a crucial role for asparagine (N) at residue 1042 in Fluo-4 transport, while substitution with aspartic acid (D) abolished all transport. In addition, we showed an association of the PfMDR1 N1042D mutation with increased mefloquine but decreased quinine sensitivity. Furthermore, competition studies of Fluo-4 with the antimalarial drugs chloroquine, mefloquine and quinine showed distinct transport inhibition patterns for parasites of different genetic background. This can be used as a tool to evaluate parasite susceptibility to antimalarial drugs.Next, we investigated the mechanism of resistance to CQ in more detail. We showed that parasite survival is higher in CQ-resistant strains compared to CQ-sensitive strains in the initial 10 hours after exposure to equally lethal CQ concentrations. Moreover, dark cytosolic structures appeared in CQ-sensitive strains that were later confirmed as hemozoin-containing compartments surrounded by a membrane bilayer. Leakage of hemozoin crystals out of the DV was ruled out since lysis of the digestive vacuolar membrane did not occur during that time frame. These data suggest that CQ resistance is not linked to reduced drug concentrations in the DV alone, and additional regulatory mechanisms in the parasite must play a crucial role during CQ exposure.To pursue these findings, a commercially available fluorescent tagged CQ analogue, LynxTagTM-CQ-GREEN (CQ-GREEN), was examined for its suitability in studying CQ transport and intracellular drug accumulation. While CQ-GREEN was half as effective in parasite killing of CQ-sensitive strains compared to unmodified CQ, no significant changes in parasite killing were observed in CQ-resistant strains. However, live cell imaging showed that CQ-GREEN accumulated in the parasite cytosol and not the DV. These results show for the first time a potential target for a CQ analogue outside the digestive vacuole. Moreover, intracellular CQGREEN uptake rates were reduced in CQ-resistant strains compared to CQ-sensitive strains. This, too, suggests that CQ-resistant strains must have evolved a regulatory mechanism to decrease intracellular CQ accumulation.The results presented in this thesis expand our understanding of substrate transport by PfMDR1. Furthermore, a novel phenotype was described for CQ-sensitive strains upon drug exposure that was not seen in CQ-resistant strains. These data suggest that altered regulatory mechanisms play a role in CQ resistance and are likely located in the parasite cytosol." --

Download or read book Malaria written by Institute of Medicine and published by National Academies Press. This book was released on 1991-02-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death. This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities. The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the: Nature, clinical manifestations, diagnosis, and epidemiology of malaria. Biology of the malaria parasite and its vector. Prospects for developing malaria vaccines and improved treatments. Economic, social, and behavioral factors in malaria control.

Download or read book The Travel and Tropical Medicine Manual E Book written by Christopher A. Sanford and published by Elsevier Health Sciences. This book was released on 2016-08-07 with total page 682 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prevent, evaluate, and manage diseases that can be acquired in tropical environments and foreign countries with The Travel and Tropical Medicine Manual. This pragmatic resource equips medical providers with the knowledge they need to offer effective aid, covering key topics in pre- and post-travel medicine, caring for immigrants and refugees, and working in low-resource settings. It's also the perfect source for travelers seeking quick, easy access to the latest travel medicine information. Dynamic images illustrate key concepts for an enhanced visual understanding. Evidence-based treatment recommendations enable you to manage diseases confidently. This eBook allows you to search all of the text, figures, images, and references from the book on a variety of devices. Highlights new evidence and content surrounding mental health and traveling. Covers emerging hot topics such as Ebola virus disease, viral hemorrhagic fevers, the role of point-of-care testing in travel medicine, and antibiotic-resistant bacteria in returning travelers and students traveling abroad. Includes an enhanced drug appendix in the back of the book.

Download or read book Global Report on Antimalarial Drug Efficacy and Drug Resistance written by and published by . This book was released on 2010 with total page 115 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report provides a comprehensive, global overview of antimalarial drug efficacy and the resistance of malaria parasites to the antimalarial medicines used between 2000 and June 2010. Policy-makers in national ministries of health will benefit from this document, as it provides both a global and a regional picture of the efficacy of the antimalarial medicines currently used in national treatment programmes. In addition, the report will be a reference for scientists, enhancing their understanding of the complexity of antimalarial drug resistance.

Download or read book Mechanism of Action of Artemisinin Antimalarials and Implications for Drug Resistance in Plasmodium Falciparum written by Stanley Cheng Xie and published by . This book was released on 2015 with total page 206 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Investigating the Cytostatic and Cytocidal Mechanisms of Quinoline Drug Resistance in Plasmodium Falciparum written by Alexander Patrick Gorka and published by . This book was released on 2013 with total page 626 pages. Available in PDF, EPUB and Kindle. Book excerpt: Collectively, this work provides additional insight into cytostatic and cytocidal quinoline drug pharmacology and assists development of new, efficacious drugs in the fight against resistance.

Download or read book Investigation of the Molecular Mechanism of Drug Resistance with Specific Reference to the Pfcrt Gene in Plasmodium Falciparum written by Yik-to Chung and published by . This book was released on 2011 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book World Malaria Report 2008 written by World Health Organization and published by World Health Organization. This book was released on 2008 with total page 212 pages. Available in PDF, EPUB and Kindle. Book excerpt: Curious kids will delight in the joy of scientific discovery through the fifty fun activities in The Budding Scientist! This book is filled with great ways for you and your child to learn about how our world works. Create memories together as you make invisible ink, explore ice crystals, and investigate magnets. Perfect for children ages three to six, this fun-filled introduction to science features easy-to-follow instructions and easy-to-find materials that will help you satisfy your child’s natural curiosity.

Download or read book DNA Mismatch Repair in Plasmodium Falciparum written by Meryl A. Castellini and published by . This book was released on 2010 with total page 268 pages. Available in PDF, EPUB and Kindle. Book excerpt: Plasmodium falciparum, the causative agent of the most lethal strain of human malaria, presents an enormous public health threat due to its ability to rapidly develop resistance to current antimalarial treatment. This accelerated resistance to multiple drugs, or ARMD phenotype, is widely documented, however the molecular mechanisms that govern it are poorly understood. There is much precedence, both in human cancers and in bacterial systems, to implicate the DNA mismatch repair pathway in the parasite's dramatic ability to quickly develop resistance to a multitude of antimalarials. DNA mismatch repair (MMR) is responsible for repairing mismatched bases that arise from replication, recombination, or DNA damaging agents and facilitates genomic fidelity by a thousand fold. Mutations in MMR genes have been linked to cancer, microsatellite instability, and chemotherapeutic drug resistance. Loss of mismatch repair is most commonly associated with drug resistance due to the rapid development of advantageous point mutations. In fact, there are several examples of P. falciparum drug resistance that can be traced directly back to one point mutation in a single gene. Among these examples are resistance to chloroquine and pyrimethamine, which can be traced to point mutations in the Pfcrt and Pfdhfr genes, respectively. While P. falciparum contains most key gene homologs required for mismatch repair, the actual repair efficiency of the parasite and how it correlates with drug resistance remain unexplored. We propose that drug resistanc parasited have defective mismatch repair and that this defect has lent P. falciparum a mechanism for the development of advantageous point mutations. These parasites would then be selected for when placed under drug pressure. Using a versatile genetic assay, we established that drug sensitive HB3 parasites possess proficient, bi-directional mismatch repair. We also determined that the multiple drug resistanc, ARMD parasites W2 and Dd2 have defective DNA mismatch repair activity. Dd2 was deficient in both 3' and 5' nick directed mismatch repair. The W2 strain demonstrated the absence of 3' nick directed MMR, but was proficient on 5' nicked substrates. This repair bias is attributable to the loss of a key mismatch repair protein, MLH1, which is known to be critical for 3' nick directed MMR. To our knowledge, these studies represent the first quantification of mismatch repair activity in P. falciparum and we now hope to begin to gain new insight on the mechanisms by which the malaria parasite quickly develops resistance to current antimalarial drugs.

Download or read book The Effect of Drug Resistance on Plasmodium Falciparum Transmission and Gametocyte Development written by Samantha Olivia Aylor and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Identification and Characterization of Novel Drug Resistance Loci in Plasmodium Falciparum written by Daria Natalie Van Tyne and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria has plagued mankind for millennia. Antimalarial drug use over the last century has generated highly drug-resistant parasites, which amplify the burden of this disease and pose a serious obstacle to control efforts. This dissertation is motivated by the simple fact that malaria parasites have become resistant to nearly every antimalarial drug that has ever been used, yet the precise genetic mechanisms of parasite drug resistance remain largely unknown. Our work pairs genomics-age technologies with molecular biology, genetics and molecular epidemiology in order to identify and characterize novel genes that contribute to drug resistance in P. falciparum.

Download or read book Genomics and Transcriptomics Approaches to Understanding Drug Resistance Mechanisms in the Malaria Parasite Plasmodium Falciparum written by Justin Allan Gibbons and published by . This book was released on 2019 with total page 184 pages. Available in PDF, EPUB and Kindle. Book excerpt: The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the gene with the strongest association with artemisinin resistance, and the potential genetic mechanisms associated with resistance to atovaquone, another widely used antimalarial. To precisely study the transcriptome characteristics of an isogenic k13 dysregulation mutant and wild type strain, I developed a new computational algorithm called Dephasing Identifier (DI) that is capable of identifying the genes dysregulated in cell cycle shifts. DI is designed to solve the problem of pinpointing important patterns in complex genomics data with temporal sequences that cannot be resolved by standard pair-wise comparison methods, by using an innovative method that leverages external reference data for systematic comparisons. In the k13 study, I demonstrated that the algorithm identifies co- regulated gene sets that have consistent annotated functions. The DI algorithm successfully identified aberrantly early DNA replication as the driving process of transcriptome changes in the mutant. To understand genome-wide changes that occurred in a set of atovaquone resistance stains, I analyzed whole genome sequencing data previously generated for a P. falciparum strain that underwent in vitro atovaquone selection to create atovaquone resistant strains. I systematically analyzed the genomes of these strains to search for significant genetic changes associated with atovaquone resistance; and used stringent criteria to identify genes involved in regulating transcription and protein modifications as acquiring non- synonymous mutations. Additionally, copy number variations in plasmepsin genes, a family known to be involved in resistance, were found in the resistant strains. In summary, genomics and transcriptomics technologies can be used to rapidly identify resistance mechanisms allowing for faster adjustment of current containment strategies. Future research on the critical targets identified in this study can aid new drug discovery efforts and novel control strategies.