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Niemand, Jandeli. "A phage display study of interacting peptide binding partners of malarial S-Adenosylmethionine decarboxylase/Ornithine decarboxylase." Diss., University of Pretoria, 2007. http://hdl.handle.net/2263/24105.
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Due to the increasing resistance against the currently used antimalarial drugs, novel chemotherapeutic agents that target new metabolic pathways for the treatment of malarial infections are urgently needed. One approach to the drug discovery process is to use interaction analysis to find proteins that are involved in a specific metabolic pathway that has been identified as a drug target. Protein-protein interactions in such a pathway can be preferential targets since a) there is often greater structural variability in protein-protein interfaces, which can lead to more effective differentiation between the parasite and host proteins; and b) the important amino acids in a protein-protein interface are often conserved and even one amino acid mutation can lead to the dissociation of the complex, implying that resistance should be slower to appear. Since polyamines and their biosynthetic enzymes occur in increased concentrations in rapidly proliferating cells, the inhibition of polyamine metabolism is a rational approach for the development of antiparasitic drugs. Polyamine synthesis in P. falciparum is uniquely facilitated by a single open reading frame that encodes both rate-limiting enzymes in the pathway, namely ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC). The AdoMetDC/ODC domains are assembled in a heterotetrameric bifunctional protein complex of ~330 kDa. Inhibition of both decarboxylase activities is curative of murine malaria and indicates the viability of such strategies in malaria control. It was hypothesized that protein ligands to this enzyme can be utilized in targeting the polyamine biosynthetic pathway in a novel approach. The bifunctional PfAdoMetDC/ODC was recombinantly expressed with a C-terminal Strep-tag-II to allow affinity purification. Subsequent gel electrophoresis analysis showed the presence of 3 contaminating proteins (~60 kDa, ~70 kDa and ~112 kDa) that co-elute with the ~330 kDa AdoMetDC/ODC. Efforts to purify the bifunctional protein to homogeneity included subcloning into a double-tagged vector for tandem affinity purification as well as size-exclusion HPLC. SDS-PAGE analysis of these indicated that separation of the four proteins was not successful, implicating the presence of strong protein-protein interactions. Western blot analysis showed that the ~112 kDa and ~70 kDa peptides were recombinantly produced with a C-terminal Strep-tag, indicating their heterologous origin. The ~60 kDa fragment was however not recognised by the tag-specific antibodies. This implies that this fragment is of E. coli origin. MS-analysis of the contaminating bands showed that the ~112 kDa peptide is an N-terminally truncated form of the full-length protein, the ~70 kDa peptide is a mixture of N-terminally truncated recombinant protein and E. coli DnaK and the ~60 kDa peptide is E. coli GroEL. A P. falciparum cDNA phage display library was used to identify peptide ligands to PfAdoMetDC/ODC. Of the peptides isolated through the biopanning process, only one was shown to occur in vivo. It could however not be conclusively shown that the isolated peptides bind to PfAdoMetDC/ODC and not to the co-eluting E. coli proteins. It is thought that while it is extremely likely that interacting protein partners to PfAdoMetDC/DOC exist, the available technologies are not sufficient to lead to the identification of such partners.Dissertation (MSc (Biochemistry))--University of Pretoria, 2008.
Biochemistry
unrestricted
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Joanny, Fanny Verfasser], and Peter [Akademischer Betreuer] [Kremsner. "Extending the spectrum of antimalarial treatment : Artemisinin combinations for the treatment of rare Plasmodium species infections and the development of dyes as antimalarials / Fanny Joanny ; Betreuer: Peter G. Kremsner." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1199547360/34.
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Joanny, Fanny [Verfasser], and Peter [Akademischer Betreuer] Kremsner. "Extending the spectrum of antimalarial treatment : Artemisinin combinations for the treatment of rare Plasmodium species infections and the development of dyes as antimalarials / Fanny Joanny ; Betreuer: Peter G. Kremsner." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1199547360/34.
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Svenson, James E. "Compliance with antimalarial chemoprophylaxis and malaria infection : a case-control study." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=69741.
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Objective. To determine if there is a difference in compliance with antimalarial chemoprophylaxis between travellers with and without malaria. Secondarily, to determine if clinical presentation can be used in predicting malaria infection.Design. Case-control study.
Subjects. 157 patients with malaria and recent travel to a malaria-endemic area and 157 matched controls.
Results. 152 (48%) of all patients had antimalarial chemoprophylaxis prescribed. Chemoprophylaxis use was correlated with region and purpose of travel. Cases were less likely to have been compliant (53%) than controls (76%) (OR = 0.35 (0.27,0.73)).
Fever pattern, symptom duration, temperature, splenomegaly, and platelet count were correlated with malaria infection. These criteria, either singly, or in combination, had low sensitivity.
Conclusions. Compliance with antimalarial chemoprophylaxis is protective against the subsequent development of malaria. Travel agents and health practitioners should provide travellers with adequate information about chemoprophylaxis.
Because no criterion could accurately predict the presence of malaria, testing for malaria should be done in all symptomatic patients with a history of travel to a malaria-endemic area.
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Hamzah, Juliana. "Characterisation of the antimalarial activity of retinol and assessment of lipid peroxidation in malaria infection." University of Western Australia, 2005. http://theses.library.uwa.edu.au/adt-WU2005.0137.
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Malaria remains a major cause of morbidity and death, especially in developing countries. The effectiveness of conventional antimalarial drugs is waning and there is an urgent need for novel therapeutic approaches. An understanding of malaria parasite biology should facilitate the development of effective therapies that prevent and/or treat malaria. The present studies explore the potential of vitamin A (retinol) as an antimalarial agent. Retinol may act by changing the oxidant milieu within the malaria parasite. Therefore, the nature and consequences of oxidant injury during malaria infection, and its treatment with retinol, have also been explored. The antimalarial potential of retinol was characterised using an established in vitro culture system allowing assessment of efficacy through [3H]-hypoxanthine uptake at different erythrocytic stages of development of Plasmodium falciparum. Retinol losses during culture were significant (>50%). After adjusting for these losses, all parasite stages (early rings to mature trophozoites) showed similar retinol sensitivity, with values of the mean assayed concentration resulting in 50% growth inhibition (IC50) ranging from 10.1 to 21.4 μM. This range was above that in normal human serum (<3 μM) but below that associated with haemolysis in culture (>43 μM). Retinol pre-treatment of uninfected erythrocytes did not inhibit merozoite invasion. Retinol-treated parasites exhibited vacuolisation of the food vacuole and membrane rupture. A P. berghei murine model was used to determine the in vivo preventive and therapeutic efficacy of retinol. Multiple-dose retinol given to healthy Swiss mice before parasite inoculation reduced parasitaemia by 30%, a result comparable to the previously reported reduction in morbidity after vitamin A supplementation in children. A lesser reduction in parasitaemia of 10% was observed when retinol was given after the parasitaemia reached 10-15%. Retinol was ineffective in reducing parasitaemia when given either as single-dose supplementation post-inoculation or at regular intervals before and after infection. Retinol supplementation did not change plasma retinol concentrations during malaria infection whether or not retinol was given, but malaria attenuated the increase in liver retinol content. These data suggest that retinol has most value as prophylaxis. In contrast to published data from humans, previously healthy mice did not develop low plasma retinol concentrations during acute infection
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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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Kheir, Amany. "Factors Influencing Evolution to Antimalarial Drug Resistance in Plasmodium falciparum in Sudan and The Gambia." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-150254.
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Drug resistance is a major obstacle to management and control of malaria and currently progressing at a rapid rate across Africa. This thesis has examined factors influencing evolution of resistant P. falciparum at two sites in Africa, including parasite migration, cross mating and fitness cost of resistance. In Asar village, eastern Sudan, the frequencies of drug sensitive and resistant parasites were monitored throughout the dry season in the absence of anti-malarial drug usage to examine whether persistence of resistant parasites is reduced in the absence of drug pressure. Two cohorts of P. falciparum infected patients were treated with chloroquine in the transmission season (Oct-Dec), and followed monthly in the dry season into the next transmission season. A large proportion of the cohort maintained sub-patent asymptomatic P. falciparum infections throughout the entire study period. Alleles of the chloroquine resistance transporter (Pfcrt) and multi-drug resistance protein (Pfmdr1) were examined. Mutant alleles of Pfcrt reached fixation following CQ treatment and remained high in the transmission season. However, at the start of the dry season, wild type alleles of both genes started to emerge and increased significantly in frequency as the season progressed. The mutant Pfcrt haplotype was invariably CVIET, indicating migration of CQ resistant parasites into an area; otherwise the CVMNK haplotype is normal. In addition, microsatellite haplotypes of dihydrofolate reductase (dhfr) gene and dihydropteroate synthase (dhps) genes, which control the parasite response to pyrimethamine and sulfadoxine respectively, were characterized. One major dhfr haplotype with double dhfr mutations and two major mutant dhps haplotypes were seen in eastern Sudan. These haplotypes are distinct from those prevailing in other African countries, suggesting the likely local origin of dhfr and dhps haplotypes conferring drug resistance. Transmission capacities of different P. falciparum clones within a single infection in The Gambia have a high ability to produce gametocytes and infect Anopheles mosquitoes even when they exist at levels not detectable by microscopy and PCR. These findings emphasize the crucial role of gametocyte complexity and infectivity in generating the remarkable diversity of P. falciparum genotypes seen in infected people. Parasites with different resistant dihydrofolate reductase (dhfr) haplotypes have the ability to infect Anopheles mosquitoes following drug treatment, and cross-mating between parasites with different dhfr haplotypes was detected. Our results showed that the major dhfr haplotype in the Gambia is similar to the common one seen in other African countries, suggesting that parasite migration plays a major role in spread of resistance. Indeed, the dominant resistant haplotype seen in infected patients was readily transmitted to infect mosquitoes.
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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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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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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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Millet, Pascal. "Développement, en culture cellulaire, de quelques Coccidiomorphes (Isopora, Plasmodium) : mise au point d'un modèle expérimental pour la chimiothérapie du paludisme." Paris 6, 1986. http://www.theses.fr/1986PA066272.
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Adeyemi, Oluwasegun Jerry. "Synthesis characterization and in vitro studies of some transition metal complexes of artesunate and chloroquine diphosphate antimalarial drugs." Diss., 2015. http://hdl.handle.net/11602/798.
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Wright, Colin W., Jonathan A. Addae-Kyereme, Anthony G. Breen, John E. Brown, Marlene F. Cox, S. L. Croft, Yaman Gokcek, H. Kendrick, Roger M. Phillips, and Pamela L. Pollet. "Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents." 2001. http://hdl.handle.net/10454/3946.
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NoThe indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of ß-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg-1 day-1 ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (¿Tm value) or toxicity in the mouse¿malaria model.
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Zimuwandeyi, Memory. "Synthesis of peptidomimetic compounds as potential anti HIV and malaria agents." Thesis, 2015. http://hdl.handle.net/10539/18565.
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A thesis submitted to the Faculty of Science University of the Witwatersrand
Johannesburg in fulfillment for the requirements of the degree of Master of Science.
14 May 2015.Peptidomimetic compounds have been shown to exhibit both anti-HIV and anti-malarial activity. A multicomponent reaction was used to create a library of peptidomimetic compounds with an α-hydroxy-β-amino acid unit. The Passerini reaction between an aldehyde, carboxylic acid and isocyanide was used to prepare compounds containing both ester and amide functionalities. These compounds were then subjected to a deprotection-acyl migration strategy giving rise to the target compounds. This approach, known as the Passerini Amine Deprotection Acyl Migration (PADAM) sequence was successfully used to create a library of novel peptidomimetic compounds. From this library, 22 compounds were tested for activity against HIV and malaria. The Passerini reaction gives rise to a product containing a new stereogenic centre, and as the starting aldehyde used (N-Boc-phenylalaninal) has a stereogenic centre, the products were isolated as a mixture of diastereomers. Our research was also focused on finding ways of influencing the stereoselectivity of the reaction and the separation of the resulting diastereomers. The diastereomeric ratio of the Passerini products was found to be approximately 2:1 for all the reactions performed. This ratio could be modified slightly when using certain carboxylic acids and isocyanides that were either very bulky or had a stereogenic centre. Attempts to enzymatically resolve the diastereomeric products were not successful after trials using a library of 25 lipase enzymes. However, use of preparative HPLC enabled the successful separation of most of the diastereomeric mixtures, affording compounds with high purity. X-ray crystallography enabled us to identify the major diastereomers as having the R,S configuration, whilst the minor diastereomers had the S,S configuration at the two stereogenic centres. A possible explanation for the observed stereoselectivity is based on the Felkin-Anh chelation control model. It suggests that mono-protected amino aldehydes follow a chelation controlled mechanism in nucleophilic addition reactions. Chelation occurs, albeit in the form of hydrogen bonding, between the NH and carbonyl oxygen. The library of compounds was tested for activity against both HIV-1 and malaria. Only three compounds showed moderate activity against the malaria parasite, inhibiting parasitic growth by 37-42% at 5 μM respectively. Significantly, all of the active compounds contained an adamantyl moiety. Unfortunately no anti-HIV activity was seen for any of the compounds tested in the HIV-assay.
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Gbedema, Stephen Y., M. T. Bayor, K. Annan, and Colin W. Wright. "Clerodane diterpenes from Polyalthia longifolia (Sonn) Thw. var. pendula: Potential antimalarial agents for drug resistant Plasmodium falciparum infection." 2015. http://hdl.handle.net/10454/7497.
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noBackground Plasmodium falciparum drug resistance is a major public health challenge in sub-Sahara Africa. Many people are now resorting to the use of herbs in managing malaria due to the increasing treatment failures with the conventional drugs. In this study the ethanolic extract of Polyalthia longifolia (Sonn) Thw. var. pendula, a variety fondly used in folklore medicine in Ghana was investigated for potential antimalarial drug development. Method The ethanolic extract of P. longifolia (Sonn) Thw. var. pendula stem bark was screened against the multidrug resistant, K1 strain of P. falciparum by the parasite lactate dehydrogenase (pLDH) assay and a good antiplasmodial activity (IC50 22.04 ± 4.23 µg/ml) was observed which led to further chromatographic analysis in search for actives. Results Bioassay guided fractionation of the extract yielded; three clerodane diterpenes [16-hydroxycleroda-3,13-dien-16,15-olide (1), 16-oxocleroda-3,13E-dien-15-oic acid (2) and 3,16-dihydroxycleroda-4(18),13(14)Z-dien-15,16-olide (3)], a steroid [beta-stigmasterol (4)] and two alkaloids [darienine (5) and stepholidine (6)]. While compounds 4, 5 and 6 exhibited weak antiplasmodial activity (IC50 22–105 µg/ml), the clerodane diterpenes exhibited significantly potent (p<0.005) blood schizonticidal activity (IC50: 3–6 µg/ml). This is the first report of the antiplasmodial activity of compounds 2 and 3. In combination assay with chloroquine, compounds 1, 2, 3 and 5 antagonized the antiplasmodial activity of chloroquine while 4 and 6 demonstrated a synergistic action. Conclusion The potent antiplasmodial activity of the extract of P. longifolia (Sonn) Thw. var. pendula and compounds therein strongly suggests its usefulness as an antimalarial agent and supports its inclusion or exploitation in formulations of herbal remedies for malaria in Ghana.
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Lin, Che-Ming, and 林哲民. "Case Management of Plasmodium falciparum Infection among Children Aged 5 Years or less and Survey of Antimalarial Resistance of Plasmodium falciparum in the Democratic Republic of Sao Tome and Principe." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/38799217848489402874.
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碩士國立臺灣大學
微生物學研究所
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We aimed to assess the efficacy of an antimalarial combination therapy with artesunate (A) and sulfadoxine/pyrimethamine (SP) for children aged less than 5 years (258 persons, 124 males and 134 females; median age, 37 months) who were inhabitants of selected farm villages and diagnosed with falciparum malaria; and to analyze the prevalence of SP resistant gene of P. falciparum and its incidence after treatment with SP in the Democratic Republic of San Tome and Principe. Treatment regimens were administered on a directly-observed-therapy basis. In the study, blood specimens were collected from children infected with malaria on day 0 (before the initiation of A/SP), day 1, day 2, day 3, day 7, day 14, day 21, and day 28 for microscopic examinations. The rate of parasitemia on day 3, day 7, day 14, day 21, and day 28 of antimalarial therapy was 7.87%, 5.51%, 2.81%, 6.1%, and 7.26%, respectively, on an as-treat analysis. The regimen was well tolerated. In addition, we designed primers specific to the DHFR and DHPS genes of P. falciparum for nested PCR；then, we purified the PCR products and sequence them. At baseline, we found that 61% of P. falciparum demonstrated intermediate-level resistance to pyrimethamine, 35% of P. falciparum low-level resistance to pyrimethanine, 12% of P. falciparum intermediate-level resistance to sufadoxine and 80% of P. falciparum low-level resistance to sulfadoxine. Furthermore, we used PCR-RFLP genotyping method to distinguish recrudescence from reinfection. We found that 35 of 59 children had reinfection；among the other 24 children we were not able to distinguish the two by this method. We concluded that A plus SP was effective as a antimalarial combination treatment for children aged less than 5 years who developed falciparum malaria in the Democratic Republic of San Tome and Principe. Prevalence of P. falciparum resistant to SP was high, other antimalarial combination regimens should be investigated.