Download or read book Studies on the Mechanism of Action and Mechanism of Resistance to Quinoline containing Antimalarial Drugs in Plasmodium Falciparum written by Mathirut Mungthin and published by . This book was released on 1998 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Studies on the Mechanism of Action and Mechanism of Resistance to Quinoline containing Antimalarial Drugs in Plasmodiuum Falciparum written by M. Mungthin and published by . This book was released on 1998 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Studies on the Mechanism of Action and Mechanism of Resistance to Quinoline containing Drugs in Plasmodium Falciparum written by Mathirut Mungthin and published by . This book was released on 1998 with total page 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 Antimalarial Agents written by Graham L. Patrick and published by Elsevier. This book was released on 2020-05-30 with total page 624 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antimalarial Agents: Design and Mechanism of Action seeks to support medicinal chemists in their work toward antimalarial solutions, providing practical guidance on past and current developments and highlighting promising leads for the future. Malaria is a deadly disease which threatens half of the world’s population. Advances over several decades have seen vast improvements in the eff ectiveness of both preventative measures and treatments, but the rapid adaptability of the disease means that the ongoing search for improved and novel antimalarial drugs is essential. Beginning with a historical overview of malaria and antimalarial research, this book goes on to describe the biological aspects of malaria, highlighting the lifecycle of the parasite responsible for malaria, the problem of resistance, genetic mapping of the parasite’s genome, established drug targets, and potential drug targets for the future. This sets the scene for the following chapters which provide a detailed study of the medicinal chemistry of antimalarial agents, with a focus on the design of antimalarial drugs. Drawing on the knowledge of its experienced authors, and coupling historic research with current fi ndings to provide a full picture of both past and current milestones, Antimalarial Agents: Design and Mechanism of Action is a comprehensive yet accessible guide for all those involved in the design, development, and administration of antimalarial drugs, including student academic researchers, medicinal chemists, malaria researchers, and pharmaceutical scientists. Consolidates both past and current developments in the discovery and design of antimalarial drugs Presents content in a style that is both thorough and engaging, providing a supportive and guiding reference to students and researchers from interdisciplinary backgrounds Highlights drug targets currently considered to be the most promising for future therapies, and the classes of compounds that are currently being studied and perfected
Download or read book Antimalarial Chemotherapy written by Philip J. Rosenthal and published by Springer Science & Business Media. This book was released on 2001-04-01 with total page 393 pages. Available in PDF, EPUB and Kindle. Book excerpt: Philip Rosenthal, MD, and a panel of leading malaria experts drawn from academia, the military, and international health organizations survey the latest scientific understanding of antimalarial chemotherapy, emphasizing the molecular mechanisms of resistance and the description of important new targets. Their survey covers the current status of malarial and antimalarial chemotherapy, the relevant biology and biochemistry of malaria parasites, the antimalarial drugs currently available, new chemical approaches to chemotherapy, and possible new targets for chemotherapy. Comprehensive and cutting-edge, Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery clearly delineates all the basic and clinical research now addressing one of the world's major unresolved disease problems, work that is now powerfully driving the rapid pace of antimalarial drug discovery today.
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 Simplified Reversed Chloroquines to Overcome Malaria Resistance to Quinoline based Drugs written by Bornface Gunsaru and published by . This book was released on 2010 with total page 106 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book A Putative Mechanism of Action of Chloroquine and Other Quinoline containing Antimalarials written by Paul Loria and published by . This book was released on 2000 with total page 406 pages. Available in PDF, EPUB and Kindle. Book excerpt: The malaria parasite spends part of its life cycle in the red blood cell. One of the problems that arise from this is the production of the toxic waste products, which are formed as a result of the parasite's digestion of host haemoglobin. The degradation of haemoglobin in the parasite FV produces free ferriprotoporphyrin IX moieties as a by-product. The ferriprotoporphyrin IX in oxyhaemoglobin is oxidised from the ferrous (Fe II) [on source "II" is superscript] state to the ferric (Fe III) [on source "III" is superscript] state with the consequent production of half a molar equavalent of H2O2 [on source "2" is subscript]. Work presented here on the analysis of the fate of the ferriprotoporphyrin IX molecules in P. falciparum-infected erythrocytes indicates that only one third of the ferriprotoporphyrin IX is converted to haemozoin. The remainder appears to be degraded by a non-enzymatic process, which leads to an accumulation of iron in the parasite. A possible route for degradation of the ferriprotoporphyrin IX is by reaction with H2O2 [in source "2" is subscript] and the work presented here shows that under conditions designed to resemble those of the food vacuole, i.e. at pH 5.2 in the presence of protein, free ferriprotoporphyrin IX undergoes rapid oxidative decomposition. H2O2 [in source "2" is subscript] is also detoxified by non-enzymatic catalse- and peroxidase-like processes. Chloroquine, quinacrine and mefloquine are shown to be efficient inhibitors of the oxidative destruction of ferriprotoporphyrun IX, while epiquinine and primaquine, quinoline compounds with very low schizonticidal activity, have little inhibitory effect. Chloroquine also enhances the association of ferriprotoporphyrin IX with membranes, while epiquinine inhibits this association. Moreover, it is shown that treatment of parasitised erythrocytes with chloroquine leads to a build-up of membrane-associated ferriprotoporphyrin IX in the parasite. The data suggest that chloroquine exerts its antimalarial activity by causing a build-up of toxic membrane-associated ferriprotoporphyrin IX molecules that eventually destroy the integrity of the malaria parasite membranes. It is shown that physiological relevant levels of membrane-associated ferriprotoporphyrin IX, in the presence of H2O2 [in source "2" is subscript], induce lipid oxidation in a model membrane system, as measured by the amount of thiobarbituric acid reactive species accumulated. The oxidation is much greater at pH 5.2 than pH 7 which is consistent with the suggestion that the damage takes place in the parasite food vacuole. Under conditions designed to resemble those of the parasite FV, and at low ferriprotoporphyrin IX concentrations, chloroquine does not greatly affect lipid oxidation, however at high ferriprotopophyrin IX concentrations chloroquine greatly enhances the toxicity of ferriprotoporphyrin IX. Chloroquine resistance can be reversed in vitro and in animal models by co-administration with resistance-modulating drugs such as chlorpromazine. Interestingly it is shown here that chlorpromazine interacts with ferriprotoporphyrin IX and efficiently inhibits its degradation. This may explain the weak antimalarial activities of these compounds. A series of novel bisquinolines were synthsised and evaluated for their antimalarial activity in vitro against strains of Plasmodium falciparum. Four bisquinolines were prepared from 4-epoxyquinoline and diaminoalkanes. These bisquinolines have moderate antimalarial activity with six carbon diaminoalkane linked bisquinolines having the best activity.
Download or read book Assessment of Long Term Health Effects of Antimalarial Drugs When Used for Prophylaxis written by National Academies of Sciences, Engineering, and Medicine and published by National Academies Press. This book was released on 2020-04-24 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.
Download or read book The Effect of Antimalarial Drugs on Intracellular PH in Plasmodium Falciparum written by Juliane Wunderlich and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Malaria is one of the most severe public health problems worldwide and a leading cause of death and disease in developing countries. The alarming spread of resistance to antimalarials accentuates the need for the better biochemical and physiological understanding of the interaction of malaria parasites with these drugs in order to develop novel therapeutic strategies that either inhibit or circumvent resistance mechanisms. The digestive vacuole (DV) of Plasmodium falciparum is the site of action of many antimalarials and plays a pivotal role in drug resistance. Its membrane is thought to contain pumps and transporters that are implicated in the maintenance of an acidic pH in the DV lumen (pHDV) and the transport of antimalarials. The low pHDV is important for the functions of this compartment, including hemoglobin degradation and heme detoxification. pH alterations in response to quinoline-containing antimalarials (QCAs) have not yet been quantitatively determined and the mechanisms of action of these drugs are still unclear.The QCAs chloroquine (CQ), quinine (QN) and mefloquine (MQ) are weak bases, increase pHDV in drug-sensitive parasites and may thus negatively affect heme detoxification pathways, causing the accumulation of toxic byproducts and ultimately the death of the parasite. In contrast, drug-resistant parasites are thought to avoid changes in pHDV via an increased efflux of the antimalarial from this organelle. The P. falciparum chloroquine resistance transporter (PfCRT) has been suggested to mediate proton-coupled efflux of CQ and QN from the DV into the cytosol of the parasite, reducing the accumulation of these drugs at their site of action. Furthermore, specific inhibition of the vacuolar-type H+-ATPase (V-ATPase) that acidifies the DV lumen may lead to an increase in pHDV. To test these hypotheses, single live parasites expressing pHluorin, a ratiometric pH-sensitive green fluorescent protein, were imaged under physiological conditions at 37°C using confocal fluorescence microscopy. At concentrations of 500 nM, CQ, QN and MQ significantly decreased the cytosolic pH by 0.2 - 0.3 units and increased pHDV by 0.5 - 0.6 units within seconds in both sensitive (3D7) and resistant parasites (Dd2). In Dd2, the PfCRT inhibitor verapamil (VP) circumvented the decrease in cytosolic pH caused by CQ and QN, while it did not modify the pH response to CQ or QN in 3D7 nor to MQ in either of the two strains. Interestingly, VP is known to sensitize Dd2 to both CQ and QN. Inhibiting the V-ATPase in P. falciparum caused a profound disruption of intracellular pH regulation: ConA almost completely abolished and BafA1 reduced the transvacuolar pH gradient. The pH effects were reversible within 15 min and parasite morphology was affected after 6 h but not within 2 h of exposure to the inhibitors.Our quantitative data indicate that vacuolar alkalinization is probably not a determinant of QCA resistance and are consistent with the hypothesis that proton-coupled efflux of CQ and QN from the DV is mediated by PfCRTCQR and sensitive to VP in drug-resistant parasites. In contrast, MQ is probably not transported by PfCRT. Our results suggest that BafA1 and ConA1 do not bind covalently to the V-ATPase and that a disruption of the transvacuolar pH gradient can by tolerated by P. falciparum for at least 2 hours, whereas the viability of the parasite is affected after 6 h." --
Download or read book Chemotherapy and Drug Resistance in Malaria written by Wallace Peters and published by . This book was released on 1987 with total page 822 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 Handbook of Antimicrobial Resistance written by Matthias Gotte and published by Springer. This book was released on 2018-02-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: While many volumes have been written about various aspects of antimicrobial resistance, this book is a comprehensive reference work. All manifestations of resistance are addressed: viral; bacterial, parasitical and fungal are given dedicated sections. The underlining molecular mechanisms, which depend not only on the microbe but on the specific drug (target), are highly diverse. This work discusses and compares the biological, biochemical and structural aspects of resistance and its evolution.
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 Dissecting Mechanisms of Antimalarials Using CRISPR Cas9 Editing in Plasmodium Falciparum written by SooNee Tan and published by . This book was released on 2019 with total page 123 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria, caused by Plasmodium infections, continues to be a global disease of public health importance with 300 million annual cases and about 500,000 deaths. Continual emergence of resistance to commonly used antimalarials underscores the importance of finding new drug targets and new antimalarial drugs. Previously, the Rathod lab has established systematic approaches to study targets of antimalarials and resistance mechanisms with the use of in vitro selection methods and deep sequencing of selected mutants. There are some limitations with these approaches as deep sequencing data does not reveal the stepwise mechanism of mutagenesis and mutations observed from the sequencing result might not associate with the resistance phenotype. This thesis has multiple projects aimed to expand the molecular toolbox with genome manipulation using CRISPR/Cas9 technique. It will complement the current tools that we have in performing target identification/validation as well as understanding the mechanism of mutagenesis in malaria parasites. Ciprofloxacin is an antibacterial known to target bacterial DNA Gyrase. In some instances, ciprofloxacin has been used for malaria prophylaxis but little is known about the mode-of-action of ciprofloxacin in malaria parasites. In the first project, we aim to understand the essentiality of Plasmodium falciparum DNA gyrase A subunit (PfGyrA) and its relationship with ciprofloxacin. Based on bioinformatics analyses, PfGyr A and B subunits are known to contain apicoplast-targeting signals. To test the predicted localization of this enzyme in the apicoplast and the function of this enzyme at the subcellular level, a CRISPR/Cas9 gene-editing tool was used to disrupt PfGyrA. It is known that isopentenyl pyrophosphate (IPP) rescues malaria parasites from apicoplast-targeting inhibitors and indeed successful growth of Pf[delta]GyrA required chemical rescue with IPP. PfGyrA disruption was accompanied by loss of the plastid acyl-carrier protein (ACP) immunouorescnce and the plastid genome. Drug sensitivity assays revealed that a Pf[delta]GyrA clone, supplemented with IPP was less sensitive to antibacterial compounds (doxycycline and ciprofloxacin) but not the nuclear topoisomerase inhibitor (etoposide). In addition, at high concentrations, ciprofloxacin continued to inhibit IPP-rescued Pf[delta]GyrA suggesting that this drug has an additional target in P. falciparum. We concluded that PfGyrA is an apicoplast enzyme in malaria parasite and it is essential for blood-stage parasites. In the future, untangling the two possible inhibitory functions of ciprofloxacin in malaria parasites may reveal a new and important drug target. The second project aim involves target validation of a tetrahydroquinolone compound, BMS-388891. Previous publications from the lab showed that resistance to BMS-388891 arises from a single point mutation in either the protein farnesyl transferase (PFT) alpha or beta subunit. Although results indicated that a single point mutation on the PfPFT enzyme led to BMS-3888891 resistant parasites, whole genome sequencing on those mutants have yet to be done. To test that a single mutation is sufficient for parasite acquisition of resistance to BMS-388891, gene alteration with CRISPR/Cas9 tool was utilized to introduce a point mutation (Y837N, Y837S, or Y837C) on the PFT-[Beta]-subunit. The CRISPR-modified mutant parasites have shown an increase of 10-20 fold resistance to BMS-388891. This data is the first to formally demonstrate that a single point mutation on the Pfpft-[Beta]-subunit is sufficient for parasites to confer resistance to BMS-388891 compound. There are very few validated compound to target relationships and CRISPR/Cas9 technique will be a valuable tool in the malaria field. The third project aim involves the understanding of the mechanism of mutagenesis in malaria parasites. While it is known that amplification and point mutation are the possible outcomes of resistance selection, the order of the processes is less understood. Recent work by Guler et. al. points to a novel step-wise amplification mechanism in the malarial parasite response to DSM1 selection pressure. In these selected parasites, 25-30 kb regions surrounding the Pfdhodh locus were amplified. Taking advantage of the highly amplified Pfdhodh locus, we were able to introduce Pfpft-[alpha]-subunit into this region. This sets up future studies for us to dissect the step-wise resistance mechanism in malaria parasites. Overall, the utilization of CRISPR/Cas9 tool has allowed us to efficiently perform gene knockout, gene alteration and gene translocation. These applications not only enable us to prove for the first time the importance of the PfGyrA enzyme but also to directly confirm the causality of specific point mutations in BMS-388891 resistant parasites. The addition of CRISPR/Cas9 gene-editing to our systematic approach toolbox will ultimately aid in our understanding of how mutagenesis occurs in malaria parasites and allow us to expand our knowledge in the mode-of-action of different antimalarials in P. falciparum.
Download or read book A Study of the Mechanism of Action and Resistance of Artemisinin Antimalarials in Plasmodium Falciparum written by M. Phanchana and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
