Download or read book Characterization of Drug resistant Isolates of Plasmodium Falciparum written by and published by . This book was released on 1997 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Characterization of Drug resistant Isolates of Plasmodium Falciparum written by and published by . This book was released on 1997 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 Characterization of Plasmodium Falciparum Resistance to Novel Drugs written by Sonia Edayé and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Plasmodium falciparum is the deadly protozoan parasite responsible for malaria. Malaria is one of the most important infectious diseases that has been raging for millennia and affecting almost half of the world's population. The treatment regimen that was based on quinoline drugs such as chloroquine (CQ), was efficient for decades. Nowadays, the use of this class of drugs is doomed to failure due to the emergence of quinoline-resistant parasites. Today, artemisinin-based combination therapies (ACTs) are the first-line drugs for uncomplicated falciparum malaria treatment. ACTs improve the cure rate of malaria and thus are seen as efficient treatment against uncomplicated forms of the disease. Despite their efficiency, these drugs are currently facing the development of resistance. PfCRT and PfMDR1, which are membrane transporters, have been shown to be involved in malaria parasites drug resistance. To tackle the inefficiency of existing drugs in regard to the development of resistance, alternative therapies must be discovered. In this thesis, antimalarial activity of novel potential drugs against P. falciparum is assessed and the interaction of these drugs with PfCRT and PfMDR1 is determined. Furthermore, because many ABC transporter genes play a key role in drug resistance, the characterization of an ABC transporter member of the ABCG family in Plasmodium is addressed and its role in drug resistance investigated.In the first part of this thesis, MK571 (a quinoline analogue) activity against P. falciparum parasites is investigated. MK571 is found to be more toxic to most of the CQ-resistant strains than to the CQ-sensitive strains. In addition, we determine that MK571 is not a substrate of PfCRT as are other quinoline drugs, but is instead a substrate of PfMDR1. Therefore, it can be a good complement to existing quinoline drugs in the treatment of uncomplicated malaria. In the second part, novel compound analogues of chloroquine are tested for their antimalarial activity against CQ-sensitive and -resistant parasites. Although chloroquine analogues tested possess the quinoline ring structure of chloroquine, they are less efficient than chloroquine and are not substrates of PfCRT. One of the analogues (3-ICQ) reverses the resistance of CQ-resistant strains to chloroquine and therefore, could be used in combination with chloroquine in cases of CQ-resistant malaria. In the third part of the thesis we conduct the characterization of PfABCG, the sole member of the P. falciparum ABCG family. The characterization study demonstrates that PfABCG is localized on the parasite plasma membrane and is expressed throughout the asexual life cycle of the parasite. In addition, PfABCG is differentially expressed in various Plasmodium strains. This expression does not correlate with the resistance to chloroquine but to the sensitivity of the parasite to an antihistaminic drug named ketotifen. Overall, this thesis sheds light on challenges and understanding of the complex resistance machinery deployed by the P. falciparum parasite from novel drug discovery to characterization of proteins. " --
Download or read book Characterization of Various Effects of Crisis Form Induction on Plasmodium Falciparum in Vitro written by Joseph M. Carlin and published by . This book was released on 1985 with total page 214 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Multi drug Resistance in Malaria written by Pritha Sen and published by . This book was released on 2001 with total page 162 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Artemisinin based Combination Therapy ACTs Drug Resistance Trends in Plasmodium Falciparum Isolates in Southeast Asia written by Jessica L. Schilke and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: ABSTRACT: Plasmodium falciparum, one of the parasites that cause clinical malaria, is a continuous public health concern, especially in Asia and Africa. Unfortunately, the parasite has developed resistance to many drugs created to treat and prevent the disease. Artemisinin and its derivatives are the new gold standard for treatment of malaria, yet treatment failures in clinical studies are starting to be reported. Clearly, artemisinin resistance needs to be characterized and dealt with accordingly. In support of the Gates Foundation Artemisinin Consortium, we conducted a blinded study to elucidate the phenotypic response of artemisinin derivatives of parasites derived from patient blood samples from Cambodia and Thailand. Blood samples containing Plasmodium falciparum were cultured and then assayed using SYBR green as an indicator to obtain drug IC50s. The data suggested that many isolates are not demonstrating resistance to artemisinin. However, a select few are showing some resistant characteristics in the form of elevated IC 50s, especially to some of the drugs already identified in previous studies as drugs having resistant characteristics. Compared to studies conducted within the past ten years, no significant changes in parasite susceptibility to the artemisinin drugs have been observed. Additional analysis of clinical outcomes, therapeutic drug levels, and molecular markers needs to be completed before it can be assumed that artemisinin resistance has emerged.
Download or read book Molecular Characterisation of the Plasmodium Falciparum Pfcrt Gene Involved in Chloroquine Resistance written by and published by . This book was released on 2008 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chloroquine (CQ) resistant P. falciparum was first reported in the 1960s at the Thai-Cambodia border. Gradually CQ resistance has spread and is found in all regions where P. falciparum transmission occurs. The emergence of CQ resistance due to excessive CQ selection pressure on the parasite populations has become an important issue because of the higher mortality and morbidity associated with drug resistance. Currently CQ is no longer recommended to treat falciparum malaria. CQ resistance in P. falciparum has been attributed to a single amino acid substitution on the P. falciparum chloroquine resistant transporter (pfcrt) at position 76 where Iysine is substituted with threonine (K76T). Molecular studies showed that CQ resistance emerged independently at five different geographical locations namely: Southeast Asia, two sites in South America, Papua New Guinea and the Philippines. Further analysis of resistant isolates revealed 22 additional non-silent amino acid substitutions on the pfcrt gene with a new amino acid substitution detected in the study reported here.
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 Molecular Characterization of Mefloquine Resistance in Plasmodium Falciparum written by and published by . This book was released on 1990 with total page 22 pages. Available in PDF, EPUB and Kindle. Book excerpt: The molecular basis for mefloquine resistance in the human malaria parasite, Plasmodium falciparum was investigated using recombinant DNA techniques. The parasites were found to be capable of manifesting extremely high levels of resistance to the drug in vitro. Resistant lines were found to be rapidly growing, impervious to various treatments, and significantly stimulated to grow by low levels of mefloquine. At the molecular levels, it was found that the genes for tubulin, a calmodulin-like protein, and a P-glycoprotein-like protein were all amplified in a quantitative relationship to the degree of resistance. Clones for each of these genes were isolated and characterized. Attempts were made to induce the amplification of tubulin genes in a sensitive parasite to see whether this event would confer resistance. High levels of vinblastine resistance were achieved but without evidence of gene amplification. Hence, the exact relationship between the amplification event and drug resistance remains unresolved. Keywords: Biotechnology; DNA structure; Drugs; Infectious diseases; Malaria; Mefloquine; Plasmodium; Parasitology.
Download or read book Probes for Characterization of Plasmodium Falciparum Isolates written by Temduang Limpaiboon and published by . This book was released on 1990 with total page 364 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 Molecular Analysis of MDR like Genes and RNA Transcripts in Drug resistant and Drug sensitive Strains of Plasmodium Falciparum written by Michael P. Bogenschutz and published by . This book was released on 1990 with total page 75 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Drug Resistance of Plasmodium Falciparum Malaria written by Denise Patricia Mawili-Mboumba and published by . This book was released on 2003 with total page 55 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Antimalarial Drug Resistance in Southern Mozambique written by and published by . This book was released on 2004 with total page 152 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Analysis of the Mismatch Repair System and the Drug Resistance Phenotype of Plasmodium Falciparum written by Susan M. Thomas and published by . This book was released on 2002 with total page 330 pages. Available in PDF, EPUB and Kindle. Book excerpt:
