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1
Boakye-Agyeman, Felix. "Quantifying the Quality of Antimalarial Drugs in Ghana." ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/4502.
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Malaria is still an epidemic in many parts of the world-about 220 million people are still infected with malaria worldwide and about 700 thousand people die from this disease per year. Most of the drugs used to treat malaria work well if they are used as required and they contain the right amounts of the active ingredient; however, it is estimated that more than 10% of drugs traded worldwide are counterfeits including 38% to 53% of antimalarial tablets produced in China and India. Due to the lack of data covering the extent of counterfeit antimalarial drugs in Ghana, the purpose of this quantitative study was to determine the percentage of counterfeit antimalarial drugs sold in Ghana by assessing the amounts of the 2 most common antimalarial drugs, artemether (ATMT) and lumefantrine (LMFT) in drugs sold in Ghana retail outlets. These drugs were purchased from retail outlets in Ghana and analyses at the Mayo Clinic Pharmacology core lab (Rochester, MN). The quality of the drugs were characterized by comparing the actual amount of ATMT & LMFT in each tablet to the expected amount. Using explanatory theory along with dose response-response occupancy theory, the researcher addressed quantitative solutions to questions related to the percentage and distribution of counterfeit ATMT and LMFT tablets. The results revealed that overall 20% of the drugs are counterfeit; this is not dependent on the location or kind of outlet but rather depends on whether the tablets were imported or locally manufactured and whether the tablets had a pedigree scratch panel. This study provides a better understanding of how much antimalarial medication is counterfeit in Ghana, which will aid interventions to minimize the adverse effects of counterfeit antimalarial medication in Ghana
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Simpson, Julie Ann. "The role of population pharmacokinetic- pharmacodynamic modelling in antimalarial chemotherapy." Thesis, Open University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367218.
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Ochekpe, N. A. "Some applications of HPLC in the biguanide antimalarial drugs." Thesis, Open University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383660.
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Dhaliwal, Balvinder. "Crystallographic studies of NAD⁺-dependent L- and D-2-hydroxyacid dehydrogenases." Thesis, University of Bristol, 2001. http://hdl.handle.net/1983/24fdc816-0f14-457e-98d7-b9e9bdc168af.
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Slater, Lindsay Anne. "Synthesis and evaluation of polyamines as antimalarial agents." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341990.
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Mukhtar, Amira. "Contemporary approaches to malaria chemotherapy : novel quinoline and peroxide-based antimalarial drugs." Thesis, University of Liverpool, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415571.
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Wright, Colin W. "Recent developments in research on terrestrial plants used for the treatment of malaria." Royal Society of Chemistry, 2010. http://hdl.handle.net/10454/4541.
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noNew antimalarial drugs are urgently needed to combat emerging multidrug resistant strains of malaria parasites. This Highlight focuses on plant-derived natural products that are of interest as potential leads towards new antimalarial drugs including synthetic analogues of natural compounds, with the exception of artemisinin derivatives, which are not included due to limited space. Since effective antimalarial treatment is often unavailable or unaffordable to many of those who need it, there is increasing interest in the development of locally produced herbal medicines; recent progress in this area will also be reviewed in this Highlight.
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Adagu, Ipemida Sullayman. "Pharmacological and molecular characterisation of Plasmodium falciparum isolates from Zaria, Nigeria." Thesis, London School of Hygiene and Tropical Medicine (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336559.
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Khan, Tasmiyah. "Development of a novel, quantitative assay for determining the rate of activity of antimalarial drugs." Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1001618.
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Malaria, caused by an intracellular Plasmodium parasite, remains a devastating disease, having claimed approximately 655 000 lives worldwide in 2010. The Medicines for Malaria Venture suggests a "single-dose radical cure" as the ideal malaria treatment since rapid clearance of blood-stage parasites and symptom relief improves patient compliance and limits drug resistance. Thus, novel antimalarials should be rapid-acting and assessing their rate of activity is critical to drug discovery. Traditional evaluation of this rate by morphological assessments is flawed by highly subjective, operator-specific interpretations, mainly due to heterogeneous parasite morphology under routine culture conditions. This study aimed to develop an alternative, quantitative assay. Energy is vital for the growth and maintenance of all living organisms. Commercially available kits allow rapid quantification of the cell's energy currency, ATP. Therefore, quantification of parasite ATP shows potential for diagnosing abnormal parasite metabolism and the kinetics of drug action. In this study, a rapid protocol for detecting ATP in Plasmodium falciparum parasites using a luminescence-based kit was developed and optimised. Furthermore, luciferase-expressing transgenic parasites, in which luciferase activity is detected using a similar kit, were acquired. The utility of both methods for evaluating the rate of drug-induced stress was explored using antimalarials with varying modes of action and, presumably, rates of activity. Results showed that parasite ATP remained unchanged, increased or decreased during drug exposure. Morphological examinations by light microscopy and a Recovery assay, aided interpretation of the drug-induced changes in parasite ATP. These investigations suggested that unchanged parasite ATP levels reflect poor drug action, increased ATP levels indicate a stress response and partially compromised viability, while significantly reduced ATP reflects severely compromised viability. Concerning the Luciferase assay, parasite luciferase activity decreased during drug exposure, even in the presence of proteasome inhibitors. Changes in parasite ATP and luciferase activity occurred at rates which suggested that chloroquine is slow-acting, mefloquine has a moderate rate of activity and artemisinin is rapid-acting. These findings are compatible with the expected rates of activity of these established antimalarials. Hence, measurement of parasite ATP and/or luciferase activity may support assessments of parasite health and the kinetics of antimalarial action during drug discovery
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Kloprogge, Frank Lodewijk. "Pharmacokinetics and pharmacodynamics of antimalarial drugs in pregnant women." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:79ce1a37-3ba2-45e4-9f80-0692a66837f1.
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Malaria is the most important parasitic disease in man and it kills approximately 2,000 people each day. Pregnant women are especially vulnerable to malaria with increased incidence and mortality rates. There are indications that pregnancy alters the pharmacokinetic properties of many antimalarial drugs. This is worrisome as lower drug exposures might result in lowered efficacy and lower drug exposures can also accelerate the development and spread of resistant parasites. The aim of this research was to study the pharmacokinetics and pharmacodynamics of the most commonly used drugs for the treatment of uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy using a pharmacometric approach. This thesis presents a number of important findings that increase the current knowledge of antimalarial drug pharmacology and that may have an impact in terms of drug efficacy and resistance. (1) Lower lumefantrine plasma concentrations at day 7 were evident in pregnant women compared to that in non-pregnant patients. Subsequent in-silico simulations with the final pharmacokinetic-pharmacodynamic lumefantrine/desbutyl-lumefantrine model showed a decreased treatment failure rate after a proposed extended artemether-lumefantrine treatment. (2) Dihydroartemisinin exposure (after intravenous and oral administration of artesunate) was lower during pregnancy compared to that in women 3 months post-partum (same women without malaria). Consecutive in-silico simulations with the final model showed that the underexposure of dihydroartemisinin during pregnancy could be compensated by a 25% dose increase. (3) Artemether/dihydroartemisinin exposure in pregnant women was also lower compared to literature values in non-pregnant patients. This further supports the urgent need for a study in pregnant women with a non-pregnant control group. (4) Quinine pharmacokinetics was not affected by pregnancy trimester within the study population and a study with a non-pregnant control group is needed to evaluate the absolute effects of pregnancy. (5) Finally, a data-dependent power calculation methodology using the log likelihood ratio test was successfully used for sample size calculations of mixed pharmacokinetic study designs (i.e. sparsely and densely sampled patients). Such sample size calculations can contribute to a better design of future pharmacokinetic studies. In conclusion, this thesis showed lower exposures for drugs used to treat uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy. More pharmacokinetic studies in pregnant women with a non-pregnant control group are urgently needed to confirm the current findings and to enable an evidence-based dose optimisation. The data-dependent power calculation methodology using the log likelihood ratio test can contribute to an effective design of these future pharmacokinetic studies.
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Douglas, Nicholas Martin. "Morbidity and mortality due to Plasmodium vivax malaria in Papua, Indonesia and its control using antimalarial drugs." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:3f758304-a3f6-4bfe-aeca-fcb135749267.
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Plasmodium vivax malaria threatens nearly half the world’s population. This relapsing disease may be more severe than previously recognised and is proving refractory to current malaria control measures. This thesis aimed to describe the burden of anaemia and mortality attributable to vivax malaria in Southern Papua, Indonesia, an area endemic for multidrug-resistant P. vivax and P. falciparum, and to determine the potential of currently available antimalarial drugs to reduce transmission of P. vivax in co-endemic regions. Approximately 0.5 million uniquely identified clinical records from patients presenting to Mitra Masyarakat Hospital between April 2004 and May 2009 were matched with corresponding laboratory and pharmacy data in order to determine the burden of anaemia in the hospital setting and the effectiveness of primaquine prescription for preventing P. vivax relapses. Clinical information extracted from patient notes was used to clarify the contribution of P. vivax malaria to a series of deaths detected by an active hospital-based surveillance system. Additional secondary sources of data used in this thesis included a large house-to-house survey and multiple clinical trials of antimalarial therapy from both Southern Papua and Northwestern Thailand. In Southern Papua, P. vivax malaria is an important cause of haematological morbidity both in the hospital and community setting. This morbidity is most significant in the first year of life when P. vivax infection accounts for 23% of all severe anaemia (haemoglobin <5g/dL) in the hospital and approximately 28% of all moderate-to-severe anaemia (haemoglobin <7g/dL) in the community. In this region concomitant P. vivax infection accentuates haematological impairment associated with P. falciparum malaria. Plasmodium vivax in Southern Papua rarely causes death directly but rather indirectly contributes to mortality through exacerbation of comorbid conditions. In Northwestern Thailand, 53.8% of patients with falciparum malaria who were treated with a rapidly eliminated drug between 1991 and 2005 had a recurrence of vivax malaria within two months making P. vivax infection the most common cause of parasitological failure in these individuals. Slowly eliminated artemisinin combination therapies (ACT) provided the greatest protection against recurrent P. vivax parasitaemia during 63 days of follow-up. In three randomised controlled trials from Papua and Thailand, P. vivax gametocytaemia was shown to mirror asexual parasitaemia closely and to have the same characteristics in acute and recurrent infections. This emphasises that the most important chemotherapeutic means of blocking P. vivax transmission is prevention of future relapse. Primaquine is recommended for this purpose but analyses in this thesis suggest that in Southern Papua, unsupervised primaquine at a dose of 0.5mg/kg/day for 14 days, does not reduce the risk of subsequent relapse (Adjusted Hazard Ratio = 1.01 [95% confidence interval 0.95-1.07]). Plasmodium vivax malaria should not be neglected. High priority must be given to new hypnozoitocidal drug discovery. In the interim, optimising the safety and effectiveness of primaquine and adoption of a unified ACT-based blood schizontocidal treatment strategy for malaria of any parasitological cause in co-endemic regions will be crucial for controlling P. vivax malaria.
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Ghavami, Maryam. "Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/96192.
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Worldwide, malaria is one of the deadliest diseases. In 2016 it sickened 216 million people and caused 445,000 deaths. In order to control the spread of this deadly diseases to human, we can either target the mosquito vector (Anopheles gambiae) or the parasite (Plasmodium falciparum). Due to recent emergence of resistance to current insecticides and antimalarial drugs there is a pressing need to discover and develop new agents that engage new targets in these organisms.
To circumvent the effect of resistance to pyrethroid insecticides on the efficacy of insecticide treated nets (ITNs), the use of acetylcholinesterase (AChE) inhibitors on ITNs has drawn attention. In the first project, we explored a small library of g- substituted oxoisoxazole- 2(3H)-carboxamides and isoxazol-3-yl carbamates, and nitriles as AChE inhibitors targeting wild- type (G3) and resistant (Akron) An. gambiae mosquito. In total 23 compounds were synthesized and evaluated. Both carbamates and carboximides with a 2-cyclopropylethyl side chain (1-87a and 1-88a) were extremely toxic to Akron mosquitos, yet these compounds did not exhibit appreciable selectivity between human and An. gambiae AChE. Unfortunately, none of the nitriles showed appreciable toxicity to G3 strain of the mosquitoes, nor did they inhibit An. gambiae AChE.
In the second project, conducted in collaboration with Professor Michael Klemba, we focused on the mode of action of an established antimalarial drug, Mefloquine (MQ). Dr. Klemba's recently developed amino acid efflux assay was used to determine the effect of MQ and its open-ring analogs on hemoglobin endocytosis and catabolism in P. falciparum-infected erythrocytes. In total 26 MQ analogs were synthesized and 18 were studied in depth to determine
their potency to inhibit leucine (Leu) efflux and parasite growth (SYBR Green). An excellent correlation (R2 = 0.98) over nearly 4 log units was seen for these 18 compounds in the two assays. These data are consistent with the hypothesis that the antimalarial action of these compounds principally derives from inhibition of hemoglobin endocytosis. After this observation, a number of photo-affinity probes were designed and synthesized in hopes of isolating the molecular target of MQ. These analogs are currently being used by Dr. Klemba in pull-down experiments.
In the third project, conducted in collaboration with Professor Belen Cassera, we sought to optimize a new antimalarial drug lead that would circumvent current resistance mechanisms. In Plasmodium parasites, the methylerythritol phosphate (MEP) pathway is known to be essential for its growth. This pathway is absent in humans, presenting the opportunity to develop potentially safe and effective therapeutic candidates. Previous work in the Cassera and Carlier lab had established that MMV008138 was the only compound in the Malaria Box that targeted the MEP pathway and that it was (1R,3S)-configured. My research expanded previous efforts in the Carlier group and produced synthesis of 73 analogs of MMV008138 (3-21a'1) that were tested for growth inhibition. These analogs featured variation at the A-, B-, C- and D-ring. In the process, a novel Pictet-Spengler ring expansion reaction of ortho-substituted acetphenones was discovered. The ring-expanded products were identified by means of 1D and 2D NMR experiments, HRMS, and X-ray crystallography. Among the 73 analogs prepared, four compounds showed similar growth inhibition potency to the lead 3-21a'1. In particular, the methoxyamide 3-80a, and the fluorinated A-ring analogs 3-124a, 3-124c and 3-124d all showed excellent (500-700 nM) growth IC50 values against P. falciparum. All four showed full rescue upon co-application of IPP (200 μM), confirming that they target the MEP pathway. ADME-Tox evaluation of these new analogs will soon be underway.PHD
13
Matlebjane, Dikeledi M. A. "In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design." Diss., University of Pretoria, 2017. http://hdl.handle.net/2263/63045.
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Malaria is a major public health problem that affects millions of lives globally. The increased
burden of malaria requires new interventions that will address the eradication of the disease.
Current interventions include vector control by using insecticide-treated bed nets and indoor
residual spraying, and antimalarial drugs to control the parasite. Parasite resistance has
been reported for the currently used effective antimalarial drugs. To pre-empt the impact of
parasite resistance a continued development of new antimalarial drugs that have novel
mechanisms of action should be pursued. Antimalarial drug discovery requires that potential
antimalarial drugs should have different drug targets to those already targeted, to lower the
chances of resistance. Potential antimalarial drugs should preferably provide a single radical
cure to prevent reproduction at all life cycle stages.
This study tested the effects of in silico designed compounds targeting plasmodial Ca2+-
dependent protein kinases (CDPK) 1 & 4, FIKK kinases and bromodomain proteins on the
Plasmodium parasite. These enzymes are involved in gene regulation and are important
factors during gene transcription. In P. falciparum the gatekeeper kinases contain small
hydrophobic pockets near the ATP-binding site. These hydrophobic pockets allow for
selective inhibition of these proteins at the ATP-binding site. The compounds were tested in
vitro to determine their antiplasmodial activity. These compounds are shown to be potential
inhibitors of the intra-erythrocytic P. falciparum parasites as three of the compounds showed
selective cytotoxic activity at less than 1 μM against the chloroquine sensitive laboratory
strains (3D7 and NF54). Even though the proteins targeted by these compounds have been
previously indicated to play a role at specific stages during the parasite’s life cycle, the
compounds tested here were not able to target the sexual gametocyte stages of the
Plasmodium parasite. Further optimisation of these compounds should be performed to
improve activity against both the asexual and sexual stages of the parasites.Dissertation (MSc)--University of Pretoria, 2017.
Pharmacology
MSc
Unrestricted
14
Gildenhuys, Johandie. "Interactions of quinoline antimalarial drugs with ferrihaem : structural and kinetic insights into the inhibition of malaria pigment formation." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85621.
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Thesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: The work in this dissertation provides structural and kinetic insight into the mechanism of action of quinoline antimalarial drugs which may aid rational drug design. Quinoline antimalarial drug-ferrihaem (Fe(III)PPIX) complexes were investigated. Single crystal Xray diffraction (SCD) structures of the complexes formed between Fe(III)PPIX and the quinoline methanol antimalarials quinine, quinidine and mefloquine have been determined, and are the first observed structures of complexes formed between free Fe(III)PPIX and quinoline antimalarial compounds. Quinine, quinidine and mefloquine are shown to have a three-point binding mode to Fe(III)PPIX, which comprises direct coordination of the drug to the Fe(III) centre through its benzylic alcohol functionality, π-stacking between the drug and porphyrin aromatic systems, and intramolecular hydrogen bond formation between the porphyrin propionate group and the protonated quinuclidine nitrogen atom of the drug in the case of quinine and quinidine, and formation of an intramolecular hydrogen bonding network in the case of mefloquine. Extended X-ray absorption fine structure spectroscopy (EXAFS) was use to elucidate structural information of Fe(III)PPIX-drug complexes in solution, and indicates that coordination persists in solution. The protocol for lipid-mediated formation of β-haematin, where monopalmitic glycerol was used as a model lipid, was successfully modified to incorporate antimalarial drugs into the aqueous layer in order to investigate drug activity under biologically-relevant conditions. Four compounds were chosen, namely chloroquine and amodiaquine, both 4- aminoquinolines and quinine and quinidine. IC50 values for the inhibition of β-haematin formation show good correlation with biological activities determined against a chloroquine-sensitive Plasmodium falciparum strain. The lipid-water interface system was further used to investigate the effects of quinine, quinidine chloroquine and amodiaquine on the kinetics of β-haematin formation. The results led to the development of a kinetic model based on the Avrami equation and the Langmuir isotherm. The data strongly support a mechanism of antimalarial drug action by adsorption to the growing face of haemozoin, with precipitation of Fe(III)PPIX at high drug concentrations accounting for decreased yields. Adsorptions constants (log Kads) determined for each drug show a strong correlation with biological activity. Finally, the first SCD structure of the μ-propionato dimer of Fe(III)PPIX, the structural unit of haemozoin, has been determined as its DMSO solvate. EXAFS suggests that this species is only formed upon nucleation, with the π-π dimer species being favoured in solution.
AFRIKAANSE OPSOMMING: Die werk in die dissertasie verleen struktuur en kinetiese insig in the meganisme van aktiwiteit vir kinolien antimalariamiddels wat kan bydra tot die ontwikkeling van nuwe medisyne. Kinolien antimalariamiddel-ferriheem (Fe(III)PPIX) komplekse was ondersoek. Navorsing is gedoen op die enkelkristal X-straaldiffraksie strukture van die komplekse gevorm tussen Fe(III)PPIX en die kinolien metanol antimalaria middels kinien, kinidien en mefloquine. Die strukture is die eerste komplekse wat waargeneem is tussen vrye Fe(III)PPIX en kinolien antimalariamiddels. Kinien, kinidien en mefloquine het ʼn driepunt bindingsvorm, direkte koördinasie met die Fe(III) deur die bensielalkohol groep, ʼn π- stapel tussen die middel en die porfirien aromatiese sisteem, ʼn intramolekulêre waterstofbinding tussen the porfirienpropionaat funksie en die geprotoneerde kinuklidien stikstofatoom (kinien en kinidien) en ʼn netwerk van intramolekulêre waterstof bindings (mefloquine) insluit. Uitgebreide X-straal absorpsie fyn struktuur spektroskopie (EXAFS) is gebruik om inligting oor Fe(III)PPIX-middel komplekse in oplossing te verkry en het aangedui dat die koördinasie in oplossing voorkom. Deur gebruik te maak van monopalmitiengliserol as die lipid in the lipid-water interfase sisteem, waar antimalariamiddels suksesvol in die buffer geïnkorporeer was, was die middel se aktiwiteit onder biologiese kondisies geondersoek. Vier middels was gekies naamlik, chloroquine en amodiaquine, albei 4-aminokinoliene en kinien en kinidien om die IC50-waarde vir inhibisie van β-hematien vorming te bepaal. Die IC50 waardes het ʼn goeie korrelasie met biologiese aktiwiteite teen die chloroquine-sensitiewe Plasmodium falciparum stam gewys. Die lipid-water interfase-sisteem was ook gebruik om die effek van kinien, kinidien, chloroquine en amodiaquine op die kineties effek op die vorming van β-hematien te ondersoek. Die resultate het gelei to die ontwikkeling van die kinetiese model gebaseer op die Avrami vergelyking en die Langmuir isoterm. Die data ondersteun ʼn meganisme van middel aksie waar die middel teen die groeiende vlak van hemosoïen kristal adsorbeer. Die neerslag van Fe(III)PPIX wat vorm by hoë konsentrasies, het gelei tot laer opbrengste. Die adsorpsiekonstante (log Kads) bepaal vir elke middel, het goeie korrelasie met biologiese aktiwiteit getoon. Enkelkristal X-straaldiffraksie strukture van μ- propionatodimeer van Fe(III)PPIX, die struktuur eenheid van hemosoïen, was bepaal as ʼn DMSO solvaat. EXAFS het aangedui dat die spesie slegs by kernvorming ontstaan en dat die π-π dimeerspesie in oplossing voorkom.
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Van, Huyssteen Este. "Efficacy enhancement of the antimalarial drugs, mefloquine and artesunate, with PheroidTM technology / E. van Huyssteen." Thesis, North-West University, 2010. http://hdl.handle.net/10394/5050.
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Malaria is currently one of the most imperative parasitic diseases in developing countries. Artesunate has a short half-life, low aqueous solubility and resultant poor and erratic absorption upon oral administration, which translate to low bioavailability. Mefloquine is eliminated slowly with a terminal elimination half-life of approximately 20 days and has neuropsychiatric side effects. Novel drug delivery systems have been utilised to optimise chemotherapy with currently available antimalarial drugs. Pheroid™ technology is a patented drug delivery system which has the ability to capture, transport and deliver pharmaceutical compounds. Pheroid™ technology may play a key role in ensuring effective delivery and enhanced bioavailability of novel antimalarial drugs. The aim of this study was to evaluate the possible efficacy and bioavailability enhancement of the selected antimalarial drugs, artesunate and mefloquine, in combination with Pheroid™ vesicles.
The in vitro efficacy of artesunate and mefloquine co-formulated in the oil phase of Pheroid™ vesicles and entrapped in Pheroid™ vesicles 24 hours after manufacturing were investigated against a 3D7 chloroquine-sensitive strain of Plasmodium falciparum. Parasitemia (%) was quantified with flow cytometry after incubation periods of 48 and 72 hours. Drug sensitivity was expressed as 50% inhibitory concentration (IC50) values. An in vivo bioavailability study with artesunate and mefloquine was also conducted in combination with Pheroid™ vesicles, using a mouse model. A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to analyse the drug levels. C57 BL6 mice were used during this study. The selected antimalarial drugs were administered at a dose of 20 mg/kg with an oral gavage tube. Blood samples were collected by means of tail bleeding.
The in vitro drug sensitivity assays revealed that artesunate, co-formulated in the oil phase of Pheroid™ vesicles and evaluated after a 48 hour incubation period, decreased the IC50 concentration significantly by 90%. Extending the incubation period to 72 hours decreased the IC50 concentration of artesunate, also co-formulated in the oil phase of Pheroid ™ vesicles significantly by 72%. No statistically significant differences between the reference and Pheroid™ vesicle groups were achieved when artesunate was entrapped 24 hours after manufacturing of Pheroid™ vesicles. Mefloquine co-formulated in the oil phase of Pheroid™ vesicles and evaluated after a 48 hour incubation period decreased the IC50 concentration by 36%. Extending the incubation period to 72 hours increased the efficacy of the Pheroid™ vesicles and the IC50 concentration was significantly decreased by 51%. In contrast with the results obtained with artesunate, entrapment of mefloquine in Pheroid™ vesicles 24 hours after manufacturing decreased the IC50 concentration significantly by 66%.
The LC-MS/MS method was found to be sensitive, selective and accurate for the determination of artesunate and its active metabolite, dihydroartemisinin (DHA) in mouse plasma and mefloquine in mouse whole blood. Most of the artesunate plasma concentrations were below the limit of quantification in the reference group and relatively high outliers were observed in some of the samples. The mean artesunate levels of the Pheroid™ vesicle group were lower compared to the reference group, but the variation within the Pheroid™ vesicle group lessened significantly. The mean DHA concentrations of the Pheroid™ vesicle group were significantly higher. DHA obtained a higher peak plasma drug concentration with the Pheroid™ vesicle group (173.0 ng/ml) in relation to the reference group (105.0 ng/ml) and at a much faster time (10 minutes in Pheroid™ vesicles in contrast to 30 minutes of the reference group). Pharmacokinetic models could not be constructed due to blood sampling per animal limitation. The incorporation of mefloquine in Pheroid™ vesicles did not seem to have improved results in relation to the reference group. No statistical significant differences were observed in the pharmacokinetic parameters between the two groups. The relative bioavailability (%) of the Pheroid™ vesicle incorporated mefloquine was 7% less bioavailable than the reference group.Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.
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Bassat, Orellana Quique. "Malaria in the paediatric wards of a rural Mozambican hospital and the clinical development of new antimalarial drugs." Doctoral thesis, Universitat de Barcelona, 2009. http://hdl.handle.net/10803/2272.
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Despite a renewed impetus on bringing together efforts to wipe malaria from the globe, the truth is that this ancient disease remains one of the principal threats to child survival in vast areas of the world. The existing control measures are largely insufficient to reduce globally the malaria burden, and as of today, malaria remains endemic in more than 100 countries, where at least half of the world's population live exposed to the risk of being infected. Indeed, the burden of malaria morbidity and mortality continues to be unacceptably high, with more than 250 million clinical episodes and at least one million deaths per year. While morbidity due to malaria affects all age groups and is scattered throughout the world, Sub-Saharan Africa concentrates the brunt of the malaria deaths, which overwhelmingly occur in children under five years of age infected with P. falciparum. The exciting and almost palpable perspective of an effective malaria vaccine, added to the promotion of innovative control strategies such as intermittent preventive treatment for infants or pregnant women, have in the recent years centred the scientific discussions regarding the approach to malaria control. However, in contrast to these innovative perspectives, malaria control has remained in the last two decades essentially dependent on the early identification and prompt treatment of clinical malaria cases and the reduction of man-vector contact. Unless there is a major renewal, optimisation and scale-up of the antimalarial arsenal and strategies, malaria will continue to dictate the health status of the world, and eradication will not be achievable in a realistic timeframe.
As malaria is a life-threatening infection, a fundamental requirement for its adequate control is the availability of effective antimalarial drugs.
The first paper in this thesis describes a large randomised clinical trial (around 1500 children) performed in five different African countries to assess the non-inferiority of a novel combination, dihydroartemisinin-piperaquine, produced under strict good manufacturing practices, when compared to the standard combination therapy AL, for the treatment of uncomplicated malaria in African children under the age of five years.
In the second paper, we describe the results of another large (around 900 patients) randomised clinical trial in which we assessed in 5 different African countries the non-inferiority of a new, paediatric-suited cherry-flavoured, dispersible formulation of AL, when compared to standard crushed AL tablets, for the treatment of uncomplicated malaria in children younger than 12 years of age. The results of these two trials, reflected in paper 1 and paper 2 of this thesis, bring to the malaria community public-health relevant data on alternatives to the currently limited antimalarial drug arsenal.
The third paper in this thesis describes the clinical presentation of severe malaria in a rural Mozambican Hospital, and the associated risk factors for a negative outcome. It also presents minimum community based incidence rates, a useful indicator of the malaria burden in the area.
Finally, the fourth paper addresses the relationship between severe malaria and bacterial invasive disease in children younger than 5 years admitted to a Manhiça's rural hospital, Mozambique.
Malaria is an ancient disease of terrible consequences for mankind. All efforts devised to diminish the burden that malaria imposes in endemic areas need to be embraced and brought together on a coordinated manner to fight this infection from all possible fronts. Understanding the clinical determinants of the infection and its relation with other coexistent infectious diseases will give an insight to the basic pathophysiology of malaria, and thus guide appropriate management strategies. New highly effective drugs, and their paediatric-orientated formulations, need to be developed and made available to those most at need.
A pesar del renovado afán por eliminar la malaria de la faz de la tierra, esta histórica enfermedad se mantiene como uno de los principales peligros para la salud infantil en amplias zonas del mundo. Las medidas de control existentes son claramente insuficientes a la hora de reducir globalmente el impacto de esta enfermedad, y a día de hoy la malaria es endémica en más de 100 países en dónde más de la mitad de la población mundial está expuesta al riesgo de infectarse. De hecho, la carga de esta enfermedad en términos de morbilidad y mortalidad persiste inaceptablemente alta con, anualmente, más de 250 millones de episodios clínicos y cerca de un millón de muertes. Mientras que la enfermedad clínica puede afectar a cualquier grupo de edad, la mortalidad por malaria se ve esencialmente circunscrita a los niños menores de cinco años infectados por P. falciparum.
La apasionante y casi palpable perspectiva de una vacuna efectiva contra la malaria, sumada a la promoción de innovadoras estrategias de control como el tratamiento intermitente en lactantes o mujeres embarazadas han centrado, en los últimos años, el debate científico relacionado con las estrategias de control. En contraste con estas innovadoras estrategias, el control de la malaria se ha visto sin embargo limitado en las últimas décadas a la identificación y tratamiento precoz de los episodios clínicos y a la reducción del contacto entre el reservorio humano y el vector. A menos que se produzca una importante renovación y optimización del arsenal terapéutico y de las estrategias frente a esta infección, acompañado por un despliegue masivo de las intervenciones en aquellas áreas dónde son más necesarias, la malaria continuará dictando el estado de salud global, y su erradicación no dejará de ser una utopía irrealizable a corto plazo.
La malaria es una enfermedad potencialmente mortal, y por lo tanto, un requerimiento fundamental para su control es la disponibilidad de fármacos antimaláricos efectivos para su tratamiento.
El desarrollo de la farmacopea antimalárica, estrechamente relacionada a los diferentes conflictos bélicos del último siglo, ha representado un constante desafío y debido a los repetidos problemas de financiación ha resultado claramente inadecuado, especialmente en comparación con el desarrollo de fármacos para otras enfermedades. Como ejemplo cabe destacar que, entre los años 1975-1999, apenas 4 de los cerca de 1400 fármacos registrados en el mundo, eran antimaláricos. Además, la aparición de resistencias por parte del parásito a los fármacos, un problema creciente y global, resulta un grave peligro para el control de esta infección, y representa una presión añadida para los pocos fármacos efectivos todavía disponibles. Con todo, en los últimos años, la malaria se está desprendiendo del status de enfermedad olvidada que arrastraba, e importantes esfuerzos han surgido para el desarrollo e investigación de nuevos fármacos con actividad antimalárica. Basado en el conocimiento adquirido con otras enfermedades infecciosas como la tuberculosis, la organización mundial de la salud promulga actualmente que el tratamiento frente a P. falciparum, la especie responsable de la mayoría de casos graves y la práctica totalidad de las muertes, debe basarse en la terapia combinada, incluyendo a ser posible un derivado de las artemisininas. La elección de los fármacos a combinar debe basarse en la potencial sinergia entre los perfiles farmacocinéticos y terapéuticos de los diferentes componentes, con el objetivo de conseguir una eliminación de la parasitemia rápida, protegiendo al mismo tiempo a los diferentes componentes frente al desarrollo de resistencias.
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Martí, Coma-Cros Elisabet. "Investigation of branched and linear polymers as oral delivery systems of antimalarial drugs." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667687.
Full textAbstract:
Malaria is an infectious disease that affects nearly half of the population in 90 countries around the world. In 2017 it was estimated that there were 219 million cases and 435,000 deaths disproportionately distributed worldwide. Indeed, 92 % of malaria cases and 93 % of malaria deaths occur in Africa, while the remaining of the cases are distributed among South East-Asia, Eastern Mediterranean, Western Pacific, and the Americas. Vast global efforts and large economic investments have been made to reduce, control and eliminate malaria, resulting in a great reduction of the incidence in the last two decades. Nevertheless, malaria remains a global public health issue. Actually, malaria in humans is caused by an intracellular protist which has an extremely complicated live cycle that occurs within two hosts, the human and the Anopheles vector. There are five parasite species of the genus Plasmodium capable to infect humans P. ovale, P. malariae, P. knowlesi, P. vivax and P. falciparum, the latter being responsible for the majority of the morbidity and mortality of this disease. Malaria is a treatable disease, however antimalarial drugs must cross at least three sequential membranes (EPM, PVM and PPM) in order to enter the intracellular parasite and reach appropriate therapeutic concentrations; reason why they required drug delivery systems (DDSs). In fact, nano-DDSs have shown to have a positive effect on disease treatment providing solutions to solubility, pharmacokinetics, target selectivity, and/or protection against degradation, resulting in a drug half-life increased. The aim of this thesis was to characterize different polymeric nanocarrier, branched or dendrimeric (DHP-bMPA and HDLDBC-bGMPA) and linear polyamidoamines (PAAs) (AGMA1, ISA1, ISA23 and ARGO7), as oral drug delivery systems. Results obtained performing in vitro experiments demonstrated that PAAs and dendrimers have low unspecific toxicity, no hemolitic activity, specific pRBCs targeting and drug encapsulation capacity. Furthermore, PAAs displayed slow degradation, affinity to parasite proteins, which could explain the preferential binding to pRBCs, and intake by macrophages, indicating PAAs potential to treat other intracellular parasitic disease like Leishmaniasis. Additionally, dendrimers that form spontaneous micellar carrier, and bind to merozoites, showed an intake by HUVEC cells in different location, which could be further investigated to treat as well other disease. On the other hand, encapsulated drugs with the two types of polymers showed optimal in vivo capacity to inhibit Plasmodium growth after i.v or oral administration. Moreover, when PAA-FITC where given to female mosquitoes’ fluorescence was observed in the midgut and in the insect’s tissues. In conclusion, the date showed in this thesis work presented the branched and the linear polymers investigated as a versatile platform for the encapsulation of orally administrated antimalarial drugs, for the direct administration of antimalarial to mosquitoes, and as potential carriers for the treatment of other parasitic diseases.La malària és una malaltia infecciosa que afecta gairebé a la meitat de la població de 90 països d'arreu del món. El 2017 s'estima que va provocar 219 milions de casos i 435.000 morts, el 92% de casos i el 93% de morts es produïren a l'Àfrica. Els darrers anys s'han fet grans esforços globals i inversions econòmiques per reduir, controlar i eliminar la malària, cosa que ha comportat una gran reducció de la incidència en els últims 20 anys. No obstant això, aquesta malaltia continua sent un problema de salut pública global. En humans és causada per un protozou del gènere Plasmodium i concretament se’n coneixen cinc espècies diferents. Però la causant de més morbiditat i mortalitat és P. falciparum. La malaltia en si és tractable, però els fàrmacs antipalúdics han de creuar com a mínim tres barreres seqüencials per tal d'arribar al paràsit a una concentració suficientment elevada. Per això aquests principis actius requereixen sistemes d'administració de fàrmacs que han demostrat tenir efectes positius. L'objectiu d'aquesta tesi ha estat caracteritzar polímers ramificats (DHP-bMPA i HDLDBC-bGMPA) i lineals (AGMA1, ISA1, ISA23 i ARGO7) per l'administració oral d'antipalúdics. Els resultats obtinguts realitzant experiments in vitro i in vivo han demostrat que tots dos tipus de polímers tenen baixa toxicitat inespecífica, no tenen activitat hemolítica, tenen especificitat per pRBCs i bona capacitat d'encapsulació. Els PAAs han demostrat tenir una degradació lenta, afinitat per proteïnes del paràsit, i capacitat per entrar dins de macròfags, una propietat interessant per tractar altres malalties. A més a més els ramificats s'uneixen a merozoites i entren en macròfags. D'altra banda els medicaments encapsulats amb qualsevol dels dos tipus de polímers han mostrat una capacitat òptima in vivo per inhibir el creixement del Plasmodiuim després de l’administració i.v o oral. Per últim, PAAs-FITC administrats a mosquits femelles, s’han pogut observar a l'intestí i altres teixits. Per tant es pot concloure, que les dades recollides en aquesta tesi demostren que tant polímers ramificats com lineals són una plataforma versàtil per a l'encapsulació de medicaments antipalúdics per ser administrat via oral, per a l’administració directa a mosquits, i potencials nanocarriers pel tractament d’altres malalties parasitàries.
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Mwai, Leah Wanjiru. "The activities of various antimalarial drugs on Plasmodium falciparum isolates in Kilifi Kenya and studies on mechanisms of resistance." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:d90f828a-63d4-48aa-9781-3ca2de55e451.
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Drug resistance is a significant challenge in the fight against malaria. Importantly, reduced efficacy has been reported against artemether (ATM)/Lumefantrine (LM) (LM-ATM), amodiaquine (AQ)/artesunate (AS) (AQ-AS), two important combination treatment regimens in Africa, and against piperaquine (PQ), a drug which has been evaluated as a potential alternative in Africa, in combination with dihydroarteminisin (DHA). Chloroquine (CQ) resistance in P.falciparum is associated with two main transporters PfCRT and PfMDR1. I investigated the mechanisms of resistance to PQ, LM and AQ, with the overall goal of identifying molecular markers that can be used to track resistance. I used CQ as a reference. The key antimalarial drugs were highly active against clinical isolates from Kilifi, Kenya with median inhibitory concentrations (IC50s) of <5nM for DHA and <55 nM for CQ, AQ, PQ, LM and DEAQ (desethylamodiaquine, the active metabolite of AQ). pfcrt-76 and pfmdr1-86 mutations were associated with AQ, DEAQ and LM but not DHA or PQ activity. Interestingly, > 20% of analysed isolates had decreased susceptibility to LM (IC50 >100nM); these isolates were the most susceptible to CQ and carried wild type genotypes at pfcrt-76 and pfmdr1-86. I observed that CQ resistance had been declining in Kilifi since 1993 (prior to CQ withdrawal) to 2006 (7 years after its withdrawal), similar to observations in Malawi. My results support the hypothesis that susceptibility to antimalarial drugs returns when drug pressure is removed, and suggest that the use of LM-ATM may hasten the return of CQ susceptibility. Continued monitoring of drug susceptibility is crucial. pfcrt-76 and pfmdr1-86 may be useful molecular markers of LM-ATM efficacy in Kilifi and other African sites. Using a microarray approach, I identified additional genes (including various transporters) that may contribute to LM resistance. I recommend further studies to clarify the exact roles of the identified genes.
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Cederlund, Julia. "Association between maternal level of education and the treatment with antimalarial drugs in children under the age of 5 in Nigeria : A cross-sectional study." Thesis, Uppsala universitet, Internationell mödra- och barnhälsovård (IMCH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-414328.
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Background Malaria is a major threat to global public health, with adverse health effects. Nigeria alone accounts for 25% of the global burden of malaria. Children are especially vulnerable to malaria, and if the disease is not treated it could have fatal consequences. Mothers have an important role in ensuring that adequate and timely treatment is given to the child. Aim The aim of this study was to investigate whether there was an association between maternal level of education and the treatment with antimalarial drugs in malaria positive children under-5 in Nigeria. Methods This study was a cross-sectional study that utilized Demographic and Health Surveys (DHS) data from the 2015 Nigeria Malaria Indicator Survey. Data on 2’622 malaria positive children were used, and a logistic regression analysis was conducted to determine the association with maternal level of education. Results The mothers with a higher level of education had two times higher odds (OR 2.31, CI 1.62- 3.32) of making sure their child received treatment with antimalarial drugs, compared to the mothers with no education. With an increase of 38% (OR 1.38, CI 1.11-1.71) in the odds for the child receiving treatment with antimalarial drugs if the mother has primary education and an increase of 51% (OR 1.51, CI 1.24-1.84) if the mother has secondary education compared to mothers with no education. Conclusion Mothers with a higher level of education waere more likely to make sure that their child received treatment with antimalarial drugs, compared to the mothers with no education.
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De, Villiers Katherine A. "Structural characterisation of ferrihaem in solution : insights into the mechanism of formation of malaria pigment and its inhibition by aryl methanol antimalarial drugs." Doctoral thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/6301.
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Jordão, Fabiana Morandi. "Caracterização da enzima bifuncional farnesil difosfato/geranilgeranil difosfato sintase e efeito do risedronato nos estágios intraeritrocitários de Plasmodium falciparum." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-23042013-093744/.
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O aumento da resistência do parasita da malária a maioria da drogas antimaláricas disponíveis, tornandose necessário pesquisar novos compostos com potencial atividade antimalárica. O objetivo desta tese foi inicialmente caracterizar a atividade do risedronato contra as formas intraeritrocitárias do parasita in vivo, além de identificar seu possível mecanismo de ação. A IC50 do risedronato foi de 20 mM em culturas de Plasmodium falciparum. Risedronato reduziu a biossíntese de FOH e GGOH e a isoprenilação de proteínas, inibindo a transferência do grupo FPP para as proteínas farnesiladas, entretanto, a transferência do GGPP para as proteínas geranilgeraniladas não foi inibida, isto também ocorreu quando proteínas ras e rab foram analisadas, sugerindo que a droga está inibindo a enzima FPPS. A enzima FPPS de P. falciparum foi expressa e obtivemos uma proteína recombinante fusionada a GST (rPfFPPS). Os substratos IPP, DMAPP, GPP e FPP foram utilizados para determinação da atividade catalítica da enzima, demonstrando FPP e GGPP como principais produtos. Os valores de Km para os diferentes substratos foi determinado. Demonstramos também que rPfFPPS é inibida por risedronato, podendo ser explorado como potencial alvo antimalárico.The increased resistance of the malaria parasite most of antimalarial drugs are available, making it necessary to search for new compounds with potential antimalarial activity. The aim of this thesis was initially characterize the activity of risedronate against intraerythrocytic forms of the parasite in vivo, and identify its possible mechanism of action. The IC50 of risedronate was 20 mM in cultures of Plasmodium falciparum. Risedronate reduced biosynthesis and FOH, GGOH and protein isoprenylation, inhibiting the transfer of FPP group for farnesylated proteins, however, the transfer of GGPP to geranygeranylated proteins was not inhibited, this also occurred when ras and rab proteins were analyzed, suggesting that the drug is inhibiting the enzyme FPPS. The FPPS enzyme from P. falciparum was expressed and obtained a recombinant protein fused to GST (rPfFPPS). The substrates IPP, DMAPP, GPP and FPP were used to determine the catalytic activity of the enzyme, demonstrating FPP and GGPP as main products. The Km values for the various substrates were determined. We also demonstrate that rPfFPPS is inhibited by risedronate, which can be exploited as potential antimalarial target.
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Zikusooka, Charlotte Muheki. "Evaluating the cost-effectiveness of artemisinin-based combination antimalarial drugs and malaria rapid diagnostic tests within the context of effective vector control : case study of Southern Africa." Doctoral thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/7439.
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Includes bibliographical references (p. 253-265)This study seeks to use the techniques of cost-effectiveness analysis to evaluate, within the context of effective vector control, the change to artemisinin-based combination therapies (ACTs) as first line malaria treatment and to evaluate the relevance of using definitive diagnosis (as opposed to clinical diagnosis) as the basis for initiating malaria treatment, especially when using ACTs for treatment. The cost-effectiveness of ACTs was evaluated in two study sites (i.e. In Kwazulu Natal which switched from SP monotherapy to AL in 2001 and in Mpumalanga which changed from SP monotherapy to AS+SP in 2003) in South Africa. The economic evaluation of use of routine definitive diagnosis as part of malaria case management, using rapid diagnostic tests (ROTs), was undertaken at two districts (Namaacha and Matutuine), in southern Mozambique, where routine use of ROTs and treating malaria patients with an ACT (using artesunate + SP) were implemented at pilot level in 2003.
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Römsing, Susanne. "Development and Validation of Bioanalytical Methods : Application to Melatonin and Selected Anti-Infective Drugs." Doctoral thesis, Uppsala universitet, Analytisk kemi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-131519.
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This thesis describes bioanalytical methods for measuring melatonin and some anti-infective drugs in biological fluids. Solid-phase extraction (SPE) or protein precipitation was used for enrichment and purification of the analytes and Liquid Chromatography (LC) was used to analyze the samples. Developed methods were validated according to international guidelines. Melatonin is a hormone secreted by the pineal gland with a robust circadian rhythm. Bioanalytical methods for determination of melatonin in plasma and saliva have been developed which were used for monitoring melatonin levels in volunteers and patients suffering from sleep related diseases. Eflornithine (DFMO) is a chiral drug used for the treatment of human African trypanosomiasis. A bioanalytical method for determination of the DFMO enantiomers in plasma, after precolumn derivatization with o-phtalaldehyde and N-acetyl-L-cystein has been developed. The method has been used to study the L- and D-DFMO pharmacokinetics, in order to investigate the possible development of an oral treatment of DFMO. A method for simultaneous determination of three antiretroviral drugs i.e. Lamivudine (3TC), Zidovudine (AZT) and Nevirapine (NVP) in dried blood spots (DBS) was developed. The method was used for drug determination in two subjects after receiving standard antiretroviral treatment. The method seemed well suitable for the determination of 3TC and NVP and in some extent for AZT. Lumefantrine (LF) is one of the active components in a new fixed drug combination recommended by the WHO as a replacement to older drugs that has lost their effect. A method for the determination of LF in DBS was developed. The method is suitable for monitoring of drug treatment in rural settings. Tafenoquine is a new promising antimalarial drug under development. A method for the determination of Tafenoquine in plasma and in DBS is described. The method may be useful in future clinical studies in laboratory environment as well as in rural settings.Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 703
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Maude, Richard James. "Malaria elimination modelling in the context of antimalarial drug resistance." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:3a5321ca-f8fc-45b2-a002-363d982d3cc5.
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Introduction: Antimalarial resistance, particularly artemisinin resistance, is a major threat to P. falciparum malaria elimination efforts worldwide. Urgent intervention is required to tackle artemisinin resistance but field data on which to base planning of strategies are limited. The aims were to collect available field data and develop population level mathematical models of P. falciparum malaria treatment and artemisinin resistance in order to determine the optimal strategies for elimination of artemisinin resistant malaria in Cambodia and treatment of pre-hospital and severe malaria in Cambodia and Bangladesh. Methods: Malaria incidence and parasite clearance data from Cambodia and Bangladesh were collected and analysed and modelling parameters derived. Population dynamic mathematical models of P. falciparum malaria were produced. Results: The modelling demonstrated that elimination of artemisinin resistant P. falciparum malaria would be achievable in Cambodia in the context of artemisinin resistance using high coverages with ACT treatment, ideally combined with LLITNs and adjunctive single dose primaquine. Sustained efforts would be necessary to achieve elimination and effective surveillance is essential, both to identify the baseline malaria burden and to monitor parasite prevalence as interventions are implemented. A modelled policy change to rectal and intravenous artesunate in the context of pre-existing artemisinin resistance would not compromise the efficacy of ACT for malaria elimination. Conclusions: By being developed rapidly in response to specific questions the models presented here are helping to inform planning efforts to combat artemisinin resistance. As further field data become available, their planned on-going development will produce increasingly realistic and informative models which can be expected to play a central role in planning efforts for years to come.
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Jones, Karen. "The basis for naphthoquinone and biguanide synergy." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368631.
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Ho, Wing Yan. "Studies on molecular mechanism of action and synthesis of new derivatives of the antimalarial drug artemisinin /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?CHEM%202004%20HOW.
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Low, Chee Kin Andrew. "Characterisation and evaluation of novel potential target (tubulin) for antimalarial chemotherapy /." Access via Murdoch University Digital Theses Project, 2004. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20050930.125714.
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Blake, Lynn Dong. "Antimalarial Exoerythrocytic Stage Drug Discovery and Resistance Studies." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6182.
Full textAbstract:
Malaria is a devastating global health issue that affects approximately 200 million people yearly and over half a million deaths are caused by this parasitic protozoan disease. Most commercially available drugs only target the blood stage form of the parasite, but the only way to ensure proper elimination is to treat the exoerythrocytic stages of the parasite development cycle. There is a demand for the discovery of new liver stage antimalarial compounds as there are only two current FDA approved drugs for the treatment of liver stage parasites, one of which fails to eliminate dormant forms and the other inducing hemolytic anemia in patients with G6PD deficiency. In efforts to address the dire need for liver stage drugs, we developed a high-throughput liver stage drug-screening assay to identify liver stage active compounds from a wide variety of chemical libraries with known blood stage activity. The liver stage screen led us to further investigate an old, abandoned compound known as menoctone. Menoctone was developed as a liver stage active antimalarial, however, the development of more potent compounds led to the abandonment of further menoctone research. Our research demonstrated that resistant parasites can transmit mutations through mosquitoes, which was previously believed to not be possible. Furthermore, we studied a novel genetic marker that may indicate potential resistance against malaria parasite infection and the cytotoxic effects associated with the disease. Future experiments aim to identify and advance our methods for the elimination of Plasmodium exoerythrocytic parasites.
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Laing, Lizahn. "The characterization of pharmacokinetic properties and evaluation of in vitro drug combination efficacies of novel antimalarial compounds." Doctoral thesis, Faculty of Health Sciences, 2020. http://hdl.handle.net/11427/32717.
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Relief of the global malaria burden relies on the management and application of effective therapies. Unfortunately, the continuous development of resistance to therapies by the deadliest parasite strain, Plasmodium falciparum, has made the treatment and control of malaria much more difficult. Derivatives of the Chinese peroxidic antimalarial drug artemisinin primarily used in first-line combination therapy for treatment of P. falciparum malaria have proved to be highly effective. However, their use also is now compromised by the development of resistance by the parasite to the artemisinin derivative in the drug combination. This event emphasizes the need for ongoing development of new and effective drug combinations. This research aimed to identify efficacious combinations selected from a group of compounds known to induce oxidative stress by redox cycling combined with an artemisinin, which as an oxidant drug also induces oxidative stress but is unable to undergo redox cycling. Combination of the artemisinin with a redox-active compound is expected to both enhance and maintain oxidative stress within the parasite's proliferative environment. These combinations should be used together with a third drug with a completely different mode of action, such as a quinolone. Selected amino artemisinins and redox active phenothiazines, phenoxazines, thiosemicarbazones, and quinolone derivatives were screened for antimalarial activity and mammalian toxicity. These were found to be potently active (11 μM) to Chinese Hamster ovarian (CHO) cells. The compounds are thus highly selective for P. falciparum, as revealed by the selectivity indices (SI) of >270. The in vitro absorption, distribution, metabolism, and elimination (ADME) properties of the compounds were also determined through the application of specific assays. In vivo pharmacokinetic (PK) profiling was also carried out by intravenous and oral administration of the individual compounds to healthy C57BL/6 mice. Biological samples were analysed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical methods, which were validated according to the fit-for purpose recommendations by the FDA. Evaluation of the in vitro and in vivo profiles thereby facilitated the identification of suitable combination candidates. The phenoxazine and phenothiazine derivatives were identified as the best potential redox partners and were each investigated in combination with the amino-artemisinin artemisone through fixed ratio isobole analysis. A substantial synergistic interaction was observed. Overall, the investigation enabled the identification of drug combinations that are potently active in vitro. This synergistic interaction strongly supports the redox cycling rationale for identifying new antimalarial therapies and further suggests that such combinations in chemotherapy may delay the onset of resistance to the new agents. The results strongly encourage further investigation of the in vivo pharmacokinetic and pharmacodynamic (PK/PD) relationships of these combinations in the humanized murine model of P. falciparum
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au, low@wehi edu, and CK Andrew Low. "Characterisation and Evaluation of Novel Potential Target (Tubulin) for Antimalarial Chemotherapy." Murdoch University, 2004. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20050930.125714.
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Malaria has long affected the world both socially and economically. Annually, there
are 1.5-2.7 million deaths and 300-500 million clinical infections (WHO, 1998).
Several antimalarial agents (such as chloroquine, quinine, pyrimethamine,
cycloguanil, sulphadoxine and others) have lost their effectiveness against this
disease through drug resistance being developed by the malarial parasites (The-
Wellcome-Trust, 1999). Although there is no hard-core evidence of drug resistance
shown on the new antimalarial compounds (artemisinin and artesunate), induced
resistant studies in animal models have demonstrated that the malarial parasites have
capabilities to develop resistance to these compounds (Ittarat et al., 2003; Meshnick,
1998; Meshnick, 2002; Walker et al., 2000). Furthermore, a useful vaccine has yet
to be developed due to the complicated life cycle of the malarial parasites (The-
Wellcome-Trust, 1999). As such, the re-emergence of this deadly infectious disease
has caused an urgent awareness to constantly look for novel targets and compounds.
In this present study, Plasmodium falciparum (clone 3D7) was cultured in vitro in
human red blood cells for extraction of total RNA which was later reverse
transcribed into cDNA. The áI-, áII- and â-tubulin genes of the parasite were then
successfully amplified and cloned into a bacterial protein expression vector, pGEX-
6P-1. The tubulin genes were then sequenced and analysed by comparison with
previously published homologues. It was found that the sequenced gene of áItubulin
was different at twelve bases, of which only six of these had resulted in
changes in amino acid residues. áII- and â-tubulin genes demonstrated 100%
sequence similarity with the published sequences of clone 3D7, but differences were
observed between this clone and other strains (strains NF54 & 7G8) of â-tubulin.
Nevertheless, the differences were minor in áI- and â-tubulins and there was greater
than 99% homology. Subsequently, all three Plasmodium recombinant tubulin
proteins were separately expressed and purified. Insoluble aggregates (inclusion
bodies) of these recombinant tubulins were also refolded and have been tested
positive for their structural characteristics in Western blot analysis.
Both soluble and refolded recombinant tubulins of malaria were examined in a drugtubulin
interaction study using sulfhydryl reactivity and fluorescence quenching
techniques. Known tubulin inhibitors (colchicine, tubulozole-c and vinblastine) and
novel synthetic compounds (CCWA-110, 239 and 443) were used as the drug
compounds to determine the dynamics and kinetics of the interactions. In addition,
mammalian tubulin was also used to determine the potential toxicity effects of these
compounds. Similarities were observed with other published reports in the binding
of colchicine with the recombinant tubulins, hence confirming proposed binding sites
of this compound on the Plasmodium recombinant tubulins. Two synthetic
compounds (CCWA-239 and 443) that have previously tested positive against P.
falciparum in vitro were found to bind effectively with all three tubulin monomers,
while displaying low binding interactions with the mammalian tubulin, thus
indicating that these compounds have potential antimalarial activity. Therefore, this
study has satisfied and fulfilled all the aims and hypotheses that have previously
been stated.
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Adendorff, Matthew Ralph. "Marine anti-malarial isonitriles : a synthetic and computational study." Thesis, Rhodes University, 2010. http://hdl.handle.net/10962/d1006674.
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The development of Plasmodium falciparum malarial resistance to the current armoury of anti-malarial drugs requires the development of new treatments to help combat this disease. The marine environment is a well established source of potential pharmaceuticals. Of interest to us are isonitrile, isocyanate and isothiocyanate compounds isolated from marine sponges and molluscs which have exhibited nano-molar anti-plasmodial activities. Through quantitative structure-activity relation studies (QSAR), a literature precedent exists for a pseudoreceptor model from which a pharmacophore for the design of novel anti-malarial agents was proposed. The current theory suggests that these marine compounds exert their inhibitory action through interfering with the heme detoxification pathway in P. falciparum. We propose that the computational methods used to draw detailed conclusions about the mode of action of these marine compounds were inadequate. This thesis addresses this problem using contemporary computational methodologies and seeks to propose a more robust method for the rational design of new anti-malarial drug compounds that inhibit heme polymerization to hemozoin. In order to investigate the interactions of the marine compounds with their heme targets, a series of modern computational procedures were formulated, validated and then applied to theoretical systems. The validations of these algorithms, before their application to the marine compound-heme systems, were achieved through two case studies. The first was used to investigate the applicability of the statistical docking algorithm AutoDock to be used for the exploration of conformational space around the heme target. A theoretical P. falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) enzyme model, constructed by the Biochemistry Department at Rhodes University, provided the ideal model to validate the AutoDock program. The protein model was accordingly subjected to rigorous docking simulations with over 30 different ligand molecules using the AutoDock algorithm which allowed for the docking algorithm’s limitations to be ascertained and improved upon. This investigation facilitated the successful validation of the protein model, which can now be used for the rational design of new PfDXR-inhibiting anti-plasmodial compounds, as well as enabling us to propose an improvement of the docking algorithm for application to the heme systems. The second case study was used to investigate the applicability of an ab initio molecular dynamics algorithm for simulation of bond breaking/forming events between the marine compounds and their heme target. This validation involved the exploration of intermolecular interactions in a naturally occurring nonoligomeric zipper using the Car-Parrinello Molecular Dynamics (CPMD) method. This study allowed us to propose a model for the intermolecular forces responsible for zipper self-assembly and showcased the CPMD method’s abilities to simulate and predict bond forming/breaking events. Data from the computational analyses suggested that the interactions between marine isonitriles, isocyanates and isothiocyanates occur through bond-less electrostatic attractions rather than through formal intermolecular bonds as had been previously suggested. Accordingly, a simple bicyclic tertiary isonitrile (5.14) was synthesized using Kitano et al’s relatively underutilized isonitrile synthetic method for the conversion of tertiary alcohols to their corresponding isonitriles. This compound’s potential for heme detoxification inhibition was then explored in vitro via the pyridine-hemochrome assay. The assay data suggested that the synthesized isonitrile was capable of inhibiting heme polymerization in a similar fashion to the known inhibitor chloroquine. Attempts to synthesize tricyclic analogues of 5.14 were unsuccessful and highlighted the limitation of Kitano et al’s isonitrile synthetic methodology.
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Reynolds, Jonathan James. "Structure-based drug discovery against a novel antimalarial drug target, S-adenosylmethionine decarboxylase/ornithine decarboxylase." Diss., University of Pretoria, 2012. http://hdl.handle.net/2263/27172.
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Malaria is one of the most life-threatening diseases affecting mankind, with over 3 billion people being at risk of infection, with most of these people living in Africa, South America and Asia. As the malaria parasite is rapidly becoming resistant to many of the possible treatments on the market, it is of upmost importance to identify new possible drug targets and describe drugs against these that are inexpensive, easy to manufacture and have a long shelf-life in order to combat malaria. One such target is the polyamine pathway. The polyamines putrescine, spermidine, and spermine are crucial for cell differentiation and proliferation. Interference with polyamine biosynthesis by inhibition of the rate-limiting enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) has been discussed as a potential chemotherapy of cancer and parasitic infections. Usually, both enzymes are individually transcribed and highly regulated as monofunctional proteins. However, ODC and AdoMetDC from P. falciparum (PfODC and PfAdoMetDC, respectively) are found as a unique bifunctional protein (PfAdoMetDC/ODC) in the malaria parasite, making it an enticing target for new, selective antimalarial chemotherapies. In order to apply structure-based drug discovery strategies to design inhibitors for PfAdoMetDC/ODC, the atomic resolution structures of these proteins are needed. Each individual domain has had its structure proposed through homology modelling; however atomic resolution structures of these domains are not yet available. The homology model of PfAdoMetDC/ODC has not yet been elucidated due to the interactions between the domains of the bifunctional protein not being fully understood. High levels of recombinant expression of the bifunctional protein have been either unsuccessful or resulted in the formation of insoluble proteins being produced. The purpose of this project is to optimise the recombinant expression of PfAdoMetDC/ODC, and the PfODC domain, to produce high yields of pure, soluble protein for subsequent atomic resolution structure determination. Ultimately, this will enable the utilisation of PfAdoMetDC/ODC in structure-based drug discovery strategies. Overexpression of P. falciparum proteins in E. coli is notoriously difficult, mainly due to the codon bias between the two species. Comparative studies were performed on four constructs of the PfAdoMetDC/ODC gene, containing either the wild-type, fully codon harmonised, or partially codon harmonised gene sequences to analyse the effect codon harmonisation had on protein expression and activity of both domains of PfAdoMetDC/ODC as well as on the monofunctional PfODC domain. Codon harmonisation did not improve the expression levels or the purity of recombinantly expressed PfAdoMetDC/ODC or the monofunctional PfODC domain. Truncated versions of both proteins, and contamination by the E. coli chaperone proteins DnaK and GroEL, were present in the protein samples even after purification by affinity chromatography. However, codon harmonisation improved the activity levels of the PfAdoMetDC domain, while decreasing the activity of the PfODC domain of PfAdoMetDC/ODC. Harmonisation of the monofunctional PfODC domain resulted in a decrease in the activity of the protein. In order to identify possible inhibitors of the PfODC domain of the bifunctional protein, a structure-based drug discovery study was initiated based on a homology model for PfODC. Four hundred compounds with known antimalarial activity were virtually screened against the PfODC homology model and the top two scoring compounds were selected for enzyme inhibition assays based on their predictive binding affinity against the enzyme, and two medium scoring compounds were selected as controls. Enzyme inhibition studies were performed on the bifunctional PfAdoMetDC/ODC to determine the effect the compounds had on both domains of the protein. Of the compounds assayed one of the compounds significantly reduced the activity levels of both domains of PfAdoMetDC/ODC. Additionally, one compound significantly reduced the activity level of the PfAdoMetDC domain of PfAdoMetDC/ODC. This work therefore contributes towards characterisation of the unique PfAdoMetDC/ODC in malaria parasites as a novel drug target.Dissertation (MSc)--University of Pretoria, 2012.
Biochemistry
unrestricted
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Eriksen, Jaran. "Managing childhood malaria in rural Tanzania : focusing on drug use and resistance /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-678-6/.
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Park, Daniel John. "Evolutionary Adaptation and Antimalarial Resistance in Plasmodium falciparum." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11088.
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The malaria parasite, Plasmodium falciparum, has a demonstrated history of adaptation to antimalarials and host immune pressure. This ability unraveled global eradication programs fifty years ago and seriously threatens renewed efforts today. Despite the magnitude of the global health problem, little is known about the genetic mechanisms by which the parasite evades control efforts. Population genomic methods provide a new way to identify the mutations and genes responsible for drug resistance and other clinically important traits.
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Obua, Celestino. "Fixed-dose chloroquine and sulfadoxine/pyrimethamine treatment of malaria : outcome and pharmacokinetic aspects /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-144-9/.
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Dlamini, Sabelo Vusi. "Malaria in Swaziland : disease incidence and prevalence of molecular markers of antimalarial drug resistance." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536875.
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Kanzi, Aquillah Mumo. "Falcipains as malarial drug targets." Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1003842.
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Malaria is an infectious disease caused by parasites of the Plasmodium genus with mortality rates of more than a million annually, hence a major global public health concern. Plasmodium falciparum (P. falciparum) accounts for over 90% of malaria incidence. Increased resistance to antimalarial drugs by the Plasmodium parasite, coupled with the lack of an effective malaria vaccine necessitates the urgent need for new research avenues to develop novel and more potent antimalarial drugs. This study focused on falcipains, a group of P. falciparum cysteine proteases that belong to the clan CA and papain family C1, that have emerged as potential drug targets due to their involvement in a range of crucial functions in the P. falciparum life cycle. Recently, falcipain-2 has been validated as a drug target but little is known of its Plasmodium orthologs. Currently, there are several falcipain inhibitors that have been identified, most of which are peptide based but none has proceeded to drug development due to associated poor pharmacological profiles and susceptibility to degradation by host cysteine proteases. Non-peptides inhibitors have been shown to be more stable in vivo but limited information exists. In vivo studies on falcipain-2 and falcipain-3 inhibitors have also been complicated by varying outcomes, thus a good understanding of the structural variations of falcipain Plasmodium orthologs at the active site could go a long way to ease in vivo results interpretation and effective inhibitor design. In this study, we use bioinformatics approaches to perform comparative sequence and structural analysis and molecular docking to characterize protein-inhibitor interactions of falcipain homologs at the active site. Known FP-2 and FP-3 small molecule nonpeptide inhibitors were used to identify residue variations and their effect on inhibitor binding. This was done with the aim of screening a collection of selected non-peptide compounds of South African natural origin to identify possible new inhibitor leads. Natural compounds with high binding affinities across all Plasmodium orthologs were identified. These compounds were then used to search the ZINC database for similar compounds which could have better binding affinities across all selected falcipain homologs. Compounds with high binding affinities across all Plasmodium orthologs were found.
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Tacoli, Costanza. "Molecular and functional aspects of antimalarial drug resistance in isolates from Africa and Asia." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/22036.
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Malariakontrolle ist von Resistenzen gegen Malariamedikamente wie Chloroquin (CQ) und Artemisininderivaten (ART) bedroht. Hier untersuchten wir das Ausmaß dieser Resistenzen in Fünf Feldstudien in Nigeria, Ruanda und Südwestindien unter Beurteilung der Prävalenzen Arzneimittelresistenz-assoziierter Mutation der Plasmodium-Parasiten (P. falciparum: K13, dhps, dhfr, mdr1 und P. vivax: mdr1) z.T. in Korrelation mit klinischen Patientendaten und ex-vivo Überlebensraten (ÜLR) unter Zugabe von ART.
K13 wurde in 360 zwischen 2010-2018 gesammelte ruandischen P. falciparum Isolaten genotypisiert. Erstmals fanden wir dort niedrige Frequenzen der mit ART-Resistenz assoziierten K13-Mutation. Jedoch lassen Mutation mit niedrigen ÜLR, sowie ein Isolat mit hohen ÜLR aber ohne K13-Mutation eines Patienten der die Infektion unter Therapie nicht eliminieren konnte, Fragen offen.
Ca.100 indische P. falciparum und P. vivax Isolaten aus 2015 wurden auf Mutationen in P. falciparum Markern für die Resistenz gegen Sulfadoxin-Pyrimethamin (SP) (d.h. pfdhps/pfdhfr), Artesunat (AS) (d.h. K13) und Lumefantrin (d.h. pfmdr1) sowie P. vivax Marker für CQ-Resistenz (pvmdr1) untersucht. Der Großteil der Isolate zeigt Mutationen die SP-Resistenz hervorrufen, daher könnte die Effizienz der AS+SP-Therapie begrenzen sein. Außerdem eignet sich Lumefantrin nicht als alternatives Medikament auf Grund der beobachteten Dominanz des pfmdr1-Haplotyps „NFD“. Die Abwesenheit der pvmdr1-Mutation Y976F und erfolgreiche Behandlungen zeigen, die Wirksamkeit von CQ gegen vivax Malaria im Studiengebiet.
Auch Isolate von nigerianischen Schwangeren mit asymptomatischer P. falciparum Infektion zeigten hohe Prävalenzen von pfdhfr/pfdhps Vier- und Fünffachmutanten darum ist die Wirksamkeit der präventiver Therapie Schwangerer mit SP in Nigeria ernsthaft gefährdet.
Die Daten spiegeln die Häufigkeit der Resistenzen gegen Malariamittel in diesen Gebieten wieder mit großen Unterschieden zwischen Regionen und Medikamenten.The spread of resistance to antimalarial drugs such as chloroquine (CQ) and artemisinins (ART) is a great threat to malaria control. Here, we investigated the extent of such resistance in Nigeria, Rwanda and south-western India. We assessed the prevalence of mutations in few Plasmodium parasites’ markers of resistance, namely P. falciparum genes K13 (ART), pfdhps/pfdhfr (sulfadoxine-pyrimethamine, SP) and pfmdr1 (lumefantrine) as well as P. vivax gene pvmdr1 (CQ) in 5 field studies conducted in 2010-2018, and partially correlated the results to patients’ clinical outcome. Few isolates from Rwanda, were also evaluated for their parasite ex vivo survival rates (SR) upon exposure to ART. We tracked ART resistance in Rwanda by genotyping K13 in 360 P. falciparum isolates from 2010-2018. We showed for the first time that K13 mutations associated with ART resistance are present here, thus in Africa, at a low frequency. However, mutations occurred in patients who recovered and/or had low SR. Of note, one patient with high SR but no K13 mutation was still parasitemic after ART treatment. Moreover, we assessed the presence of mutations in K13, pfdhps/pfdhfr, pfmdr1 and pvmdr1 in ca 100 P. falciparum and 100 P. vivax isolates from south-western India. Most of P. falciparum isolates carried pfdhfr/pfdhps mutations conferring SP resistance, menacing the efficacy of SP-ART treatment. Also, the high prevalence of pfmdr1 haplotype “NFD” advised against the introduction of lumefantrine. The low rates of P. vivax pvmdr1 Y976F and patients’ successful parasite clearance, indicated that CQ remains effective in the area. Finally, a high rate of pfdhfr/pfdhps quadruple and quintuple mutant was observed in Nigerian pregnant women with asymptomatic P. falciparum infection, hence the effectiveness of preventive treatment with SP in pregnancy might be threatened. The data reflected the abundance of antimalarials resistance in these areas with important differences between regions and drugs.
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Abrahams, Meryl Arlene. "Bioassay-guided fractionation of Artemisia afra for in vitro antimalarial activity against Plasmodium falciparum." Master's thesis, University of Cape Town, 1997. http://hdl.handle.net/11427/26263.
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With the increase in recent years in the prevalence of malaria, and in drug resistance of Plasmodium falciparum, there has been much interest in natural plant products for new antimalarials with novel modes of action against Plasmodium. Artemisinin or Qinghaosu is one such antimalarial isolated from a Chinese herb, Anemisia annua (Asteraceae) and it is currently undergoing phase I and II clinical trials. The Southern African species, Artemisia afra (African wormwood, wildeals, lengana) is commonly used by local traditional healers for symptoms of malaria, in particular fever. Thus it seemed appropriate to investigate this species for antimalarial activity. Crude petroleum ether soxhlet extracts of Anemisia afra had demonstrated antimalarial activity against Plasmodium falciparum, FCR-3, cultured in vitro. The IC₅₀ values ranged from 5-13μg/ml. The extract from leaves and flowers was then screened against D10 (chloroquine-sensitive) and FAC8 (chloroquineresistant) P. falciparum, in vitro, with IC₅₀ values of 1.03μg/ml and l.5μg/ml respectively. This extract was fractionated by column chromatography using silica gel-60 and the fractions obtained were screened for antimalarial activity. The most active fraction had an IC₅₀ of 0.5μg/ml against D10 and FAC8. Using TLC and HPLC-UV analysis with pure artemisinin as a standard, no artemisinin could be detected in this fraction. This result was confirmed by thermospray LC-MS analyses. Purification of this fraction yielded ultimately a single pure compound; a clear colourless oil identified by MS and NMR analyses as hydroxydavanone. The compound was screened against a variety of P. falciparum strains with varying degrees of sensitivity and resistance to both chloroquine and mefloquine. Their sensitivity against artemisinin was also established. IC₅₀ values obtained for the isolated pure compound against P. falciparum ranged from 0.87 to 2.54μg/ml. The IC₅₀ values obtained for general cytotoxicity of the crude extract and isolated pure compound against RAT-I fibroblast cells were 34.78 ± 8.23 and 6.29 ± 0.95 μg/ml (n=4) respectively. Thus the crude extract and isolated pure compound exhibited a greater antimalarial than cytotoxic effect. Hence, there are implications for A. afra to be used as a phytomedicine for the treatment of malaria. In vivo studies are recommended for hydroxydavanone in order to fully assess its potential for clinical use.
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Mokoena, Fortunate. "Malarial drug targets cysteine proteases as hemoglobinases." Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1004065.
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Malaria has consistently been rated as the worst parasitic disease in the world. This disease affects an estimated 5 billion households annually. Malaria has a high mortality rate leading to distorted socio-economic development of the world at large. The major challenge pertaining to malaria is its continuous and rapid spread together with the emergence of drug resistance in Plasmodium species (vector agent of the disease). For this reason, researchers throughout the world are following new leads for possible drug targets and therefore, investigating ways of curbing the spread of the disease. Cysteine proteases have emerged as potential antimalarial chemotherapeutic targets. These particular proteases are found in all living organisms, Plasmodium cysteine proteases are known to degrade host hemoglobin during the life cycle of the parasite within the human host. The main objective of this study was to use various in silico methods to analyze the hemoglobinase function of cysteine proteases in P. falciparum and P. vivax. Falcipain-2 (FP2) of P. falciparum is the best characterized of these enzymes, it is a validated drug target. Both the three-dimensional structures of FP2 and its close homologue falcipain-3 (FP3) have been solved by the experimental technique X-ray crystallography. However, the homologue falcipain-2 (FP2’)’ and orthologues from P.vivax vivapain-2 (VP2) and vivapain-3 (VP3) have yet to be elucidated by experimental techniques. In an effort to achieve the principal goal of the study, homology models of the protein structures not already elucidated by experimental methods (FP2’, VP2 and VP3) were calculated using the well known spatial restraint program MODELLER. The derived models, FP2 and FP3 were docked to hemoglobin (their natural substrate). The protein-protein docking was done using the unbound docking program ZDOCK. The substrate-enzyme interactions were analyzed and amino acids involved in binding were observed. It is anticipated that the results obtained from the study will help focus inhibitor design for potential drugs against malaria. The residues found in both the P. falciparum and P. vivax cysteine proteases involved in hemoglobin binding have been identified and some of these are proposed to be the main focus for the design of a peptidomimetric inhibitor.
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Yepuri, Nageshwar Rao. "The design and synthesis of novel anti-malarial agents." Access electronically, 2004. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20050330.085201/index.html.
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Tanner, Delia Caroline. "Over-expression, purification and biochemical characterization of DOXP reductoisomerase and the rational design of novel anti-malarial drugs." Thesis, Rhodes University, 2004. http://hdl.handle.net/10962/d1003990.
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Malaria poses the greatest threat of all parasites to human life. Current vaccines and efficacious drugs are available however their use is limited due to toxicity, emergence of drug resistance, and cost. The discovery of an alternative pathway of isoprenoid biosynthesis, the non-mevalonate pathway, within the malarial parasite has resulted in development of novel anti-malarial drugs. 1-Deoxy-D-xylulose-5-phosphate (DOXP) reductoisomerase, the second enzyme in this pathway, is responsible for the synthesis of 2-C-methyl-D-erythritol 4-phosphate (MEP) in an intramolecular rearrangement step followed by a reduction process involving NADPH as a hydrogen donor and divalent cations as co-factors. Fosmidomycin and FR900098 have been identified as inhibitors of DOXP reductoisomerase. However, they lack clinical efficacy. In this investigation recombinant DOXP reductoisomerase from Escherichia coli (EcDXR) and Plasmodium falciparum (pfDXR) were biochemically characterized as potential targets for inhibition. (His)6-EcDXR was successfully purified using nickel-chelate affinity chromatography with a specific activity of 1.77 μmoles/min/mg and Km value 282 μM. Utilizing multiple sequence alignment, previous structural data predictions and homology modeling approaches, critical active site amino acid residues were identified and their role in the catalytic activity investigated utilizing site-directed mutagenesis techniques. We have shown evidence that suggests that Trp212 and Met214 interact to maintain the active site architecture and hydrophobic interactions necessary for substrate binding, cofactor binding and enzyme activity. Replacement of Trp212 with Tyr, Phe, and Leu reduced specific activity relative to EcDXR. EcDXR(W212F) and EcDXR(W212Y) had an increased Km relative to EcDXR indicative of loss in affinity toward DOXP, whereas EcDXR(W212L) had a lower Km of ~8 μM indicative of increased affinity for DOXP. The W212L substitution possibly removed contacts necessary for full catalytic activity, but could be considered a non-disruptive substitution in that it maintained active site architecture sufficient for DOXP reductoisomerase activity. EcDXR(M214I) had 36-fold reduced enzyme activity relative to EcDXR, while its Km (~8 μM) was found to be lower than that of EcDXR. This suggested that the M214I substitution had maintained (perhaps improved) substrate and active site architecture, but may have perturbed interactions with NADPH. Rational drug design strategies and docking methods have been utilized in the development of furan derivatives as DOXP reductoisomerase inhibitors, and the synthesis of phosphorylated derivatives (5) and (6) has been achieved. Future inhibitor studies using these novel potential DOXP reductoisomerase inhibitors may lead to the development of effective anti-malarial drug candidates.
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Elsherbiny, Doaa. "Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8426.
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Gupta, Seema. "Experimental pharmacodynamic and kinetic studies related to new combination therapies against falciparum malaria /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-066-4/.
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Laming, Dustin. "Development of a high-throughput bioassay to determine the rate of antimalarial drug action using fluorescent vitality probes." Thesis, Rhodes University, 2016. http://hdl.handle.net/10962/64434.
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Malaria is one of the most prevalent diseases in Africa and the Plasmodium falciparum species is widely accepted as the most virulent, with a fatality rate of 15 – 20 % of reported cases of infection. While various treatments have been accepted into early stage clinical trials there has been little progress towards a proven vaccine. Pending a long term solution, endemic countries rely heavily on the development of innovative drugs with acute efficacy coupled with rapids mode of action. Until recently the rate of drug action has been measured by light microscopic examination of parasite morphology using blood slides of drug treated parasite cultures at regular time intervals. This technique is tedious and, most importantly, subject to interpretation with regards to distinguishing between viable and comprised parasite cells, thus making it impossible to objectively quantitate the rate of drug action. This study aimed to develop a series of bioassays using the calcein-acetoxymethyl and propidium iodide vitality probes which would allow the rate of drug action on Plasmodium falciparum malaria parasites to be assessed and ranked in relation to each other. A novel bioassay using these fluorescent vitality probes coupled with fluorescence microscopy was developed and optimized and allowed the rate of drug action on malaria parasites to be assessed i) rapidly (in relation to current assay techniques) and ii) in a semi-quantitative manner. Extrapolation to flow cytometry for improved quantification provided favourable rankings of drug killing rates in the pilot study, however, requires further development to increase throughput and approach the ultimate goal of producing a medium-throughput assay for rapidly assessing the rate of action of antimalarial drugs. Attempts to adapt the assay for use in a multiwell plate reader, as well as using ATP measurements as an indication of parasite vitality after drug treatment, was met with erratic results. The viability probes assay as it stands represents an improvement on other assay formats in terms of rapidity and quantification of live/compromised parasites in cultures.
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Taleli, Lebusetsa. "Synthesis of triazole-linked chloroquinoline derivatives as novel antimalarial agents." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79827.
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Thesis (MSc)--Stellenbosch University, 2013.Aminoquinolines are important class of drugs that have been used for malaria chemotherapy for centuries. However, long-term exposure to these drugs leads to extensive spread of drug resistance. As such, modified chloroquinoline derivatives are being studied as alternative antimalarial agents with the possibility to overcome drug resistance associated with chloroquine analogues. In this study, 15 aminoquinoline derivatives that are linked by a 1,4-disubstituted 1,2,3-triazole ring to an ethyl and propyl carbon spacer with a distal amine motif were designed and synthesized as novel antimalarial agents using the Cu(I)-promoted Huisgen reaction. The compounds have been synthesized from the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine alkyne precursor and the azides of ethyl and propyl amino moieties using a 1,3-dipolar cycloadditioncoupling in the presence of CuI catalyst to obtain moderate to good yields (53 – 85%). These compounds have been characterized by the combination of NMR, ESI+ HRMS and IR spectroscopic methods. The antiplasmodial activity of the compounds was investigated in vitro against P. falciparum strain NF54 using chloroquine as a reference drug together with a standard antimalarial drug artesunate. Of the 15 novel chloroquinoline derivatives, 11 have demonstrated to possess promising potency by way of the inhibition concentrations less than 250 nM with the lowest being 28 nM. The observed activities have been ascribed to the overall modifications such as the introduction of a triazole linker and changing of carbon chain length as these were the variables. The compounds are accordingly under further biological investigations and only the chloroquine sensitive results are reported in this work.
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Abshire, James R. (James Robbins). "Development of novel chemical biology tools to probe malaria parasite physiology and aid in antimalarial drug discovery." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98921.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2015.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Malaria remains a major burden to global public health. Antimalarial drugs are a mainstay in efforts to control and eventually eradicate this disease. However, increasing drug resistance threatens to reverse recent gains in malaria control, making the discovery of new antimalarials critical. Antimalarial discovery is especially challenging due to the unique biology of malaria parasites, the scarcity of tools for identifying new drug targets, and the poorly understood mechanisms of action of existing antimalarials. Therefore, this work describes the development of two chemical biology tools to address unmet needs in antimalarial drug discovery. A particular challenge in antimalarial development is a shortage of validated parasite drug targets. Potent antimalarials with demonstrated clinical efficacy, like the aminoquinolines and artemisinins, represent a promising basis for rational drug development. Unfortunately, the molecular targets of these drugs have not been identified. While both are thought to interact with parasite heme, linking in vitro heme binding with drug potency remains challenging because labile heme is difficult to quantify in live cells. This work presents a novel genetically-encoded heme biosensor and describes its application to quantify labile heme in live malaria parasites and test mechanisms of antimalarial action. Another challenge is posed by the widespread malaria parasite Plasmodium vivax, which, unlike P. falciparum, cannot be propagated in vitro, hindering research into parasite biology and drug target identification. P. vivax preferentially invades reticulocytes, which are impractical to obtain in continuous supply. The basis for this invasion tropism remains incompletely understood, mainly because current tools cannot directly link molecular binding events to invasion outcomes. This work presents novel methods for immobilizing synthetic receptors on the red blood cell surface. These receptors are used in proof-of-concept experiments to investigate requirements for efficient invasion via a well-characterized P. falciparum invasion pathway, suggesting this method can be used to elucidate molecular mechanisms underlying parasite invasion tropisms. Future receptor designs could promote the invasion of P. vivax into mature red blood cells and potentially facilitate practical in vitro culture. Taken together, these tools present new opportunities for drug discovery to aid efforts in malaria control and eventual eradication.
by James R. Abshire.
Ph. D.
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Cenni, Bruno. "Pharmacological aspects of malaria chemotherapy : interactions of the antimalarial drug halofantrine with human blood cells, serum proteins and Plasmodium falciparum parasitised red blood cells /." [S.l. : s.n.], 1994. http://www.gbv.de/dms/bs/toc/159397723.pdf.
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Mira, Martínez Sofía. "A new mechanism of antimalarial drug resistance regulated at the epigenetic level." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/523484.
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Malaria is responsible of almost half a million deaths every year. Currently, campaigns for the control and elimination of malaria are implemented in malaria endemic areas. However, drug resistance is one of the major impediments to achieve malaria elimination. In this thesis we have investigated how
P. falciparum parasites develop resistance to some toxic compounds by functional variation linked to epigenetic regulation of clag3 genes. These genes present clonally variant expression and determine the formation of the main channel for the transport of solutes at the membrane of the infected RBC: Plasmodium Surface Anion Channel (PSAC). Hence, we hypothesized that P. falciparum parasites can modify the permeability of the membrane to specific solutes by epigenetic regulation of clag3 genes expression; this way, parasites could develop resistance to antimalarial drugs. To test this hypothesis, we have investigated the role of switches in clag3 expression in the acquisition of resistance to the antibiotic BS, the dynamics of clag3 genes expression in human infections and we have tested drugs susceptible to failure by this drug resistance mechanism.
First, we show that BS pressure at low concentrations selected for parasites expressing clag3.1, whereas parasites exposed to higher concentrations of BS had repressed the expression of both clag3 genes. We did not find any mutation in the genome of these parasites that could explain the change in their phenotype. Thus, we concluded that parasites can develop resistance to toxic compounds through epigenetic regulation of clag3 genes. Then, we found that parasites collected from patients with uncomplicated malaria predominantly express one of the two paralogues, consistent with the property of mutually exclusive expression, previously described in lab-adapted parasite lines. Adaptation to culture conditions or selection with toxic compound results in isolate-dependent changes in clag3 expression, implying functional differences between the proteins encoded. We also observed that samples collected at day 9 post-infection in human experimental infections (when parasites had been in the peripheral blood for approximately one erythrocytic cycle) showed a mix of parasites expressing either clag3.1 or clag3.2, suggesting that the epigenetic memory of clag3 genes is reset during transmission stages. Finally, we tested whether other drugs, that are suspected to require facilitated transport to reach the cell, could be susceptible of failure by this drug resistance mechanism. We found that the antimalarial compounds T3 and T16 (bis-thiazolium salts) require the product of clag3 genes to enter the infected erythrocyte and that P. falciparum populations can develop resistance to these compounds by selection of parasites with dramatically reduced expression of both genes. The rest of the drugs that we tested might use alternative routes in which clag3 genes are not involved.
We have described for the first time an antimalarial drug resistance mechanism regulated at the epigenetic level in P. falciparum parasites. This phenomenon may be of relevance for parasite adaptation to the presence of toxic compounds in human blood, selecting rapidly those parasites that present the less permeable phenotype and developing drug resistance in a single infection.Actualmente, la resistencia a los medicamentos antimaláricos es uno de los principales impedimentos para lograr la eliminación de la malaria. En esta tesis hemos investigado cómo los parásitos de P. falciparum desarrollan resistencia a algunos compuestos tóxicos por variación funcional relacionada con la regulación epigenética de los genes clag3 (clag3.1 y clag3.2), los cuales presentan expresión clonal variante y mutuamente exclusiva (en condiciones normales sólo uno de los dos genes está en estado activo). clag3 determinan la formación del canal principal para el transporte de solutos a través de la membrana del eritrocito infectado: PSAC. En este trabajo, primero observamos que la aplicación de bajas concentraciones del antibiótico blasticidina en cultivos de P. falciparum resultó en la selección de parásitos que expresan clag3.1, mostrando una IC50 a este compuesto más elevada que aquellas líneas que expresan clag3.2. Por otro lado, parásitos expuestos a concentraciones más altas de blasticidina reprimieron la expresión de ambos clag3 y mostraron altos niveles de resistencia al fármaco. No encontramos ninguna mutación en el genoma de estos parásitos que explicase el cambio de fenotipo, sugiriendo que se trata de un mecanismo regulado a nivel epigenético. El estudio de clag3 en parásitos recolectados de pacientes con malaria no complicada mostró que P. falciparum en infecciones naturales expresa predominantemente uno de los dos parálogos: clag3.2, indicando que este patrón de expresión confiere una ventaja fenotípica en sangre humana. Por otro lado, el análisis de muestras recogidas de infecciones humanas experimentales determinó que la memoria epigenética de los genes clag3 se restablece durante las etapas de transmisión, seleccionándose en pocos ciclos aquellos parásitos que presentan el patrón de expresión más favorable en sangre humana: clag3.2. Finalmente, probamos si otros fármacos que requieren transporte facilitado para llegar a la célula podrían ser susceptibles de fracaso terapéutico a través de este mecanismo de resistencia. Hayamos que los compuestos antipalúdicos T3 y T16 (sales de bis-tiazolio) requieren el producto de los genes clag3 para ingresar en el eritrocito infectado y que poblaciones de P. falciparum puedan desarrollar resistencia a estos compuestos mediante la selección de parásitos con expresión reducida de ambos genes.
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Urbán, Patricia. "Development of nanovectors for the targeted drug delivery of antimalarials." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/104509.
Full textAbstract:
Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease, and the complexity of the life cycle of its causative agent, the protozoan Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day.
At present, administration methods of antimalarial drugs release the free compound in the blood stream, from where it can be significantly removed by many tissues and organs, thus reducing its availability for Plasmodium-infected erythrocytes. Due to this lack of specificity regarding the target cells, current oral or intravenous delivery approaches for most antimalarial drugs require high doses. However, unspecificity of toxic drugs demands low concentrations to minimize undesirable side-effects, thus incurring the risk of sublethal doses favouring the appearance of resistant pathogen strains. Targeted nanovector systems can fulfill the objective of achieving the intake of total doses sufficiently low to be innocuous for the patient but that locally are high enough to be lethal for the malaria parasite.
With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells.
We work on the development of antimalarial drug-carrying nanovectors specifically targeted to Plasmodium-infected red blood cells (pRBCs). Our first immunoliposomal prototype delivers its contents exclusively to pRBCs containing the P. falciparum late forms trophozoites and schizonts, and improves on average tenfold the efficacy of the antimalarial drugs chloroquine and fosmidomycin. Using chloroquine concentrations well below its IC50, and by modifying parameters such as liposome size, density of targeting antibodies on the liposome surface, targeted antigen, and intraliposomal drug concentration, we approach 100% of parasitemia reduction both in vitro and in vivo using a murine model for P. falciparum malaria. We are working in the improvement of the nanovector through modification of (i) the targeting element: better antibodies, non-protein molecules such as DNA aptamers and polysaccharides, (ii) the encapsulated drug(s), and (iii) the type of nanocapsule, making special emphasis on polymeric structures. Our objective in the short term is the design of a nanostructure adequate to enter the preclinical pipeline as an economically affordable new antimalarial therapy.Desarrollo de nanovectores para la liberación dirigida de antimaláricos Los métodos actuales de administración oral o intravenosa requieren dosis elevadas que a menudo desencadenan efectos secundarios perniciosos. Por el contrario, el riesgo de suministrar dosis subletales a causa de dichas concentraciones terapéuticas críticas o por razones de inestabilidad del compuesto, favorece la aparición de cepas resistentes de Plasmodium. La liberación dirigida de antimaláricos es una aproximación prometedora para evitar ese riesgo. El trabajo presentado en esta tesis doctoral tiene como objetivo principal el desarrollo de un nanovector para la mejora de la eficacia de los antimaláricos existentes y la comprensión de los parámetros fundamentales de su diseño que determinan la eficacia de dicho nanovector. Liposomas con quantum dots en su interior y que han sido funcionalizados con hemi-anticuerpos contra formas tardías del parásito se unen en menos de 90 minutos a eritrocitos infectados por Plasmodium y liberan su contenido en el interior de las células diana. Cuando se encapsulan fármacos antimaláricos en el modelo inmunoliposomal, se incrementa hasta diez veces la eficacia de los fármacos. La formulación para administración oral de anticuerpos y liposomas es complicada, nanovectores adecuados para esta vía de administración serían una contribución valiosa para el tratamiento de la malaria en zonas endémicas, alejadas de centros de salud. Durante la última parte de esta tesis, nos hemos centrado en el desarrollo de nuevos nanovectores poliméricos que liberen de forma específica los fármacos a pRBCs, ya que las nanopartículas poliméricas pueden ser formuladas para administración oral más fácilmente que los liposomas. Las diferentes partes de futuros nanovectores (moléculas direccionalizadoras, formulación liposomal, recubrimiento exterior, fármaco encapsulado) están diseñadas de tal manera que puedan ser sustituidas por nuevos elementos para su utilización contra diferentes especies del parásito o para reconocer diferentes dianas intracelulares.