21.01.2008
The Global Fund to Fight AIDS, TB and Malaria Launches Corporate Champions Program [Business Wire via MSN Money] — (English)
The Global Fund to Fight AIDS, TB and malaria today announced the launch of The Global Fund Corporate Champions program, an innovative way for multinational corporations to significantly invest in the fight against the three diseases...
Report to the Executive Board, 122nd session [WHO] — (English)
Dr Margaret Chan: I am concerned, in particular, about the situation in Kenya, where support is urgently needed to ensure the continuity of routine health services and programmes for HIV/AIDS, malaria, tuberculosis, and other diseases...
Indonesia reports more malaria cases in 2007 [Silo Breaker - USA] — (English)
The Indonesian government has reported up to 3 million malaria cases in 2007 while the number of cases stood at 1.8 million the previous year, local press reported Monday...
Malaria vaccine undergoes clinical trials in Tanzania [IPP MEdia] — (English)
Reseachers at the National Institute for Medical Research (NIMR) in Tanga Region are carrying out a clinical trial to evaluate the safety and immunological potential of a candidate malaria vaccine MSP3-LSP...
20.01.2008
Genetic research centre likely to be established in Hyderabad [Nanotechnology Now - USA] — (English)
The proposed centre would focus on convergent technologies like nanotechnology, biotechnology and bio-informatics, apart from promoting basic research on malaria vaccine...
Häufigkeit von Überschwemmungen nimmt zu - Malaria-Gefahr in Europa [KlimaAktiv.com - Germany] — (Deutsch)
Studienleiterin Debrarati Guha-Sapir warnte vor einer Zunahme von Krankheiten, die sich bei Überschwemmungen häufen, wie das Dengue-Fieber und Malaria. «Es ist gut möglich, dass die Malaria in Europa wieder auftaucht», sagte sie...
19.01.2008
63-Jährige stirbt nach Kenia-Urlaub in ihrer Wohnung [ Bild - Germany] — (Deutsch)
Eine Münchnerin ist nach einer Kenia-Reise allein zuhause an Malaria gestorben...
Malaria: la batalla decisiva [El Pais] — (Español)
Mata a un millón de personas al año. Es la enfermedad de los pobres, y los países desarrollados no se la han tomado en serio? Hasta ahora. Las cosas han cambiado gracias al dinero de Bill Gates y los ensayos de vacuna de Pedro Alonso...
Randomized, comparative study of the efficacy and safety of artesunate plus amodiaquine, administered as a single daily intake versus two daily intakes in the treatment of uncomplicated falciparum malaria [Malaria Journal 2008, 7:16 (19 January 2008)] — (English)
This study, conducted in Senegal and in Cameroon in 2005, compared the safety of artesunate plus amodiaquine, given either as a single daily intake versus two daily intakes. At that time, this ACT was only available in a co-blister format and the aim of the intervention was to improve compliance by reducing the number of tablets per intak...
18.01.2008
Monkey Malaria Widespread In Humans And Potentially Fatal [Science Daily - USA] — (English)
A potentially fatal species of malaria is being commonly misdiagnosed as a more benign form of the disease, thereby putting lives at risk, according to research funded by the Wellcome Trust and the University Malaysia Sarawak...
Monkey-Malaria Parasite Poses Deadly Threat to Humans (Update1) [Bloomberg - UK] — (English)
A malaria-causing parasite that usually affects monkeys is capable of killing people, researchers in Malaysia found, identifying a second deadly agent for one of the world's most common tropical diseases...
Going it alone to expose scandal of Africa's malaria drugs racket [Press Gazette - UK] — (English)
Australian-born Elizabeth Tadic won the Sony Impact Award at the 2007 Rory Peck Awards for her film Malaria, Money and Murder. The self-funded investigation exposed how the trade in fake drugs had turned malaria into Africa’s biggest child killer. Tadic travelled and worked alone, working without support from a broadcaster to get the story. The film was picked up by SBS Corporation in Australia...
Dutch-American consortium in €16M project to find malaria vaccine [Science Business - UK] — (English)
Today Top Institute Pharma announces a highly promising research project that is aimed at the development of a malaria vaccine...
Comparison of all-cause and malaria-specific mortality from two West African countries with different malaria transmission patterns [Malaria Journal 2008, 7:15 (18 January 2008)] — (English)
Child mortality in The Gambia and in Burkina Faso declined significantly in the period 1960 to 2004, possibly due to socio-economic development, improved health services and specific intervention projects...
Ministry to ramp up malaria battle in regions 7,8 [Stabroek News - Georgetown,Guyana] — (English)
Minister of Health, Dr Leslie Ramsammy, says Guyana has progressed in the fight against malaria and the battle against the mosquito-borne disease will be ramped up in the vulnerable regions 7 and 8...
17.01.2008
Malaria no More Deutschland e.V. i.G. - T-Shirt Aktion geht in die nächste Runde [AfricaWeb - Germany] — (Deutsch)
Im November 2007 gründete die bekannte Unternehmensberaterin Nina H. Neelsen die gemeinnützige Organisation Malaria no More Deutschland, die eng mit ihren Partnern Malaria no More USA und Malaria no More Holland zusammenarbeitet...
Sénégal: Lutte contre le paludisme en Afrique - 12 pays bénéficieront des nouvelles subventions [Le Soleil (Dakar) via AllAfrica.com] — (Français)
La lutte contre le paludisme en Afrique reçoit une nouvelle fois le concours de Malaria Consortium. Cette structure vient d'allouer trois nouvelles subventions aux projets de plaidoyers dans 12 pays d'Afrique...
Purchase College Lecture On Malaria Prevention
[Westchester.com - Westchester,NY,USA] — (English)
The Purchase College School of Natural and Social Sciences presents “Preventing Malaria in Uganda,” a Sciences in the Modern World lecture, with Dr. Jessie Stone, February 5 at 7 PM in the Purchase College Performing Arts Center...
NGO Holds Malaria Workshop [Modern Ghana - Ghana] — (English)
A ONE-DAY capacity-building workshop on malaria has been organized by Humanitarian Foundation, a local Non-Governmental Organisation (NGO), for residents of Asikuma-Odoben-Brakwa (AOB) district in the Central Region...
Centre issues toll-free number to monitor malaria cases [Zee News - Noida,Uttar Pradesh,India] — (English)
A national level toll-free call centre number 1075 will be operational by January end for monitoring malaria cases by the Union health Ministry...
16.01.2008
Intercell, PATH to develop new malaria vaccine [Reuters - USA] — (English)
Austria's Intercell said on Wednesday it would cooperate with the PATH Malaria Vaccine Initiative to develop a new malaria vaccine...
International Consortium Takes On Malaria Vaccine Development with $23.6M over Four Years [Genetic Engineering - USA] — (English)
Sanaria and two Dutch institutes, Radboud University Nijmegen Medical Centre as well as Leiden University Medical Center, formed a consortium under the auspices of Top Institute Pharma (TI Pharma) to develop a malaria vaccine. The TI Pharma project will have a budget of €16 million, or $23.6 million, over four years...
Youth group joins global campaign against malaria [Danville Register and Bee - Danville,VA,USA] — (English)
The Mount Vernon United Methodist Church Youth have joined with a worldwide campaign to help eradicate malaria in Africa by raising money to buy insecticide-treated mosquito netting...
15.01.2008
YEMEN: Government distributes free mosquito nets in bid to beat malaria [IRINnews.org - New York,NY,USA] — (English)
The National Malaria Control Programme (NMCP) at the Ministry of Health on 15 January launched a national campaign to combat malaria in 15 out of the 21 governorates. The campaign runs for 13 days and aims to get the nation prepared ahead of the summer season when an epidemic is expected...
CAMPUS: Optics used to combat malaria [McGill Tribune - Montreal,Quebec,Canada] — (English)
Here at McGill, a recent breakthrough by a team of researchers led by Professor Paul Wiseman from the departments of physics and chemistry could have a revolutionary impact on the detection methods of malaria-infected bloo...
Much-Needed Malaria Program Launched in Africa [The Heartland Institute - Chicago,IL,USA] — (English)
PMI, initially launched by President George W. Bush in June 2005, increases U.S. funding for anti-malaria campaigns in 15 nations by more than $1.2 billion over the next five years. The program aims to reduce malaria deaths by 50 percent in the targeted nations...
Wildebeest or malaria parasite -- same rules determine number of offspring [EurekAlert - Washington,DC,USA] — (English)
Research has implications for treating many human and animal infections, including malaria and viruses...
Expression Studies of Malaria Parasite Uncover Distinct Forms [Focus - US] — (English)
Researchers have discovered three distinct gene expression patterns in malaria parasites infecting sick children: two of the patterns had never been seen before. The results come from a collaboration stretching from Senegal to San Diego and including researchers at HSPH and the Broad Institute of MIT and Harvard...
Var transcription profiling of Plasmodium falciparum 3D7: assignment of cytoadherent phenotypes to dominant transcripts [Malaria Journal 2008, 7:14 (14 January 2008)] — (English)
Enrichment of phenotypically homogenous parasites by panning on receptor expressing cells is fundamental for the identification of the corresponding var transcript. The paper shows that, at least for 3D7, transfected CHO cell lines are of limited use for the creation of monophenotypic cytoadherent parasite lines...
Implementation of Indoor Residual Spraying of Insecticides for Malaria Control in the WHO African Region Report [WHO/AFROI] — (English)
IRS is expanding into highly endemic perennial transmission areas of the region. With this goes the need for intensive advocacy nationally and globally to ensure sustained political and financial commitment. This is
essential in order to maintain the gains already achieved and to ensure that IRS programs are equipped with the
required overall capacity to be able to deliver the intended impact on malaria as they expand. Inter-country,
national and sub-national trainings should be conducted to provide planners and implementers with the required
technical capacity. Focus on building sub-national technical capacity is of paramount importance due to the fact
that in the majority of the countries IRS programs are decentralized whereby district health management teams are
fully responsible for implementation. Countries should also capitalize on nationally available technical capacity to
strengthen sub-national teams responsible for execution of IRS. Collaboration between NMCPs and local research
institutes needs to be facilitated and supported to ensure evidence-based IRS management. Inter country
collaboration through experience sharing and training should be promoted and supported. Emphasis should be
given also on building logistics, managerial and system capacities at all levels...
Articles requiring subscription
Malaria: Malaria eats out [Nature Reviews Microbiology 6, 94-95 (February 2008) | doi:10.1038/nrmicro1842] — (English)
Although waves of bloodstream-stage parasite (merozoite) replication typify the pathology of Plasmodium falciparum malaria, surprisingly little is known about how parasites exit from infected erythrocytes. A paper published in Cell reveals that the PfSUB1 subtilisin-like serine protease is required for the exit of merozoites from infected erythrocytes. This enzyme is sequestered in exonemes, which are newly discovered parasite organelles...
Malaria: Picking Plasmodium falciparum apart [Nature Reviews Microbiology 6, 95 (February 2008) | doi:10.1038/nrmicro1848] — (English)
Compartmentalization of proteins into subcellular organelles is a widespread process that enables the regulation of many cellular functions. In the malaria parasite Plasmodium falciparum, compartmentalization is well established, but not fully understood. Using imaging techniques, two groups now provide insight into the organelle structures that are present during different stages of the parasite's life cycle. Singh et al. identify a novel invasion-related organelle — the mononeme — that is present during the merozoite stage, and Hanssen et al. take a closer look at the structure of Maurer's cleft organelles, which are present during the intra-erythrocytic stages...
The impact of response to the results of diagnostic tests for malaria: cost-benefit analysis [BMJ, doi:10.1136/bmj.39395.696065.47 (published 16 January 2008)] — (English)
Improving diagnostic methods, including rapid diagnostic tests, can reduce costs and enhance the benefits of effective antimalarial drugs, but only if the consistency of response to test results is also improved. Investing in methods to improve rational response to tests is essential. Economic evaluations of diagnostic tests should take into account whether clinicians’ response is consistent with test results...
Costs of treating malaria according to test results [BMJ, doi:10.1136/bmj.39401.486655.80 (published 16 January 2008)] — (English)
Improving diagnostic tests can reduce costs but only if adherence to test results is also improved ...
Protection against cerebral malaria by the low-molecular-weight thiol pantethine [Proc Natl Acad Sci U S A. 2008 Jan 14] — (English)
We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood–brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation–coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the
intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects...
Plasmodium berghei merozoite surface protein-9: Immunogenicity and protective efficacy using a homologous challenge model [Vaccine, In Press, Uncorrected Proof, Available online 18 January 2008] — (English)
Merozoite surface protein-9 (MSP-9) from Plasmodium is considered a promising vaccine candidate due to its location and possible role in erythrocyte invasion. We report the identification and characterization of Plasmodium berghei MSP-9 (PbMSP-9) and its properties as an immunogen using a recombinant PbMSP-9 fragment to immunize BALB/c mice. PbMSP-9 was found to harbor RBC binding and serine protease activity. PbMSP-9 formulation in alum was highly immunogenic in BALB/c mice. To evaluate the protective efficacy, immunized mice were submitted to homologous challenge with P. berghei NK65 blood-stage parasites. Protection against the parasite challenge was observed in BALB/c mice immunized with the PbMSP-9 formulation. These results suggest for the first time that MSP-9 based immunogens may constitute part of an effective malaria vaccine...
Import of malaria in a Romanian Western County [Trends in Parasitology, In Press, Corrected Proof, Available online 15 January 2008] — (English)
Findings of our study have shown that P. falciparum is the main malaria species in Timis County, outlining the difficulties in the diagnosis and management of the imported cases...
Is chemical genetics the new frontier for malaria biology [Trends in Pharmacological Sciences, In Press, Corrected Proof, Available online 15 January 2008] — (English)
Malaria is a global disease, causing at least 500 million clinical cases and more than one million deaths each year. Moreover, drug-resistant Plasmodium falciparum, the organism that causes most malaria-associated deaths, has become a major problem. Therefore, discovery and investigation of novel targets for anti-malarial drug design is essential to combat this disease. The malarial genome has been sequenced, revealing 5500 genes. The current post-genomic challenge is functionally to evaluate the essential genes and validate them for therapeutic design. Unfortunately, standard genetics techniques are limited in scope because of low transfection efficiency and a lack of knockdown techniques, thereby rendering the analysis of essential genes difficult...
Immunological evidence of Plasmodium falciparum infection in an Egyptian child mummy from the Early Dynastic Period [Journal of Archaeological Science, In Press, Corrected Proof, Available online 14 January 2008] — (English)
A 15–18 months old child mummy, presently housed in Turin's Museum of Anthropology, was discovered in Gebelein (Upper Egypt) during excavations carried out by the Missione Archeologica Italiana, most likely in 1914. Atomic Mass Spectrometry radiocarbon dating indicated that the mummy belongs to the end of the Early Dynastic Period – beginning of the Old Kingdom. Whole body spiral CT scan and 3D reconstructions did not show evidence of congenital malformations or fractures. Immunochromatographic and immunohistochemical analyses on skin and muscle samples were positive for Plasmodium falciparum malaria and for Plasmodium spp. malaria. Our data provide clear evidence for the presence of P. falciparum infection in the sample we examined and show the usefulness of the immunological investigations for the detection of malaria in ancient human remains...
Effect of protease inhibitors on exflagellation in Plasmodium falciparum [Molecular and Biochemical Parasitology, In Press, Uncorrected Proof, Available online 14 January 2008] — (English)
Enzymes involved in sexual differentiation and fertilization of the human malaria parasite Plasmodium falciparum represent potential targets for transmission blocking strategies. Parasite proteases are putatively involved in several steps during fertilization, but the types of proteases, their targets and modes of action remain hitherto unknown. We investigated the involvement of proteases in gametogenesis via exflagellation and immunofluorescence assays, using a variety of commercially available as well as newly designed protease inhibitors. The assays revealed a blockade of microgamete formation by the cysteine/serine protease inhibitors TLCK and TPCK. The serine protease inhibitor PMSF, the falcipain-targeting inhibitor RV112D, and the aspartic protease inhibitor EPNP also significantly decreased formation of microgametes. The metalloprotease inhibitor 1,10-phenanthroline, on the other hand, inhibited exflagellation by interfering with microgamete motility. Furthermore, EPNP reduced the activation of male and female gametocytes. Our data point to a major involvement of serine proteases and a non-thermolysin-like zinc metalloprotease in microgametocyte exflagellation...
Vaccine Adjuvant Systems containing monophosphoryl lipid A and QS21 induce strong and persistent humoral and T cell responses against hepatitis B surface antigen in healthy adult volunteers [Vaccine, In Press, Uncorrected Proof, Available online 14 January 2008] — (English)
The Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be fundamental to develop effective prophylactic vaccines against complex pathogens, e.g. malaria, HIV infection and tuberculosis, and for special target populations such as subjects with an impaired immune response, due to age or medical conditions
...
Direct effect of Plasmodium vivax recombinant vaccine candidates AMA-1 and MSP-119 on the innate immune response [Vaccine, In Press, Uncorrected Proof, Available online 14 January 2008] — (English)
The recombinant apical membrane antigen 1 (AMA-1) and 19-kDa fragment of merozoite surface protein (MSP-119) are the lead candidates for inclusion in a vaccine against blood stages of malaria due to encouraging protective studies in humans and animals. Despite the importance of an efficacious malaria vaccine, vaccine-related research has focused on identifying antigens that result in protective immunity rather than determining the nature of anti-malarial immune effector mechanisms. Moreover, emphasis has been placed on adaptive rather than innate immune responses. In this study, we investigated the effect of Plasmodium vivax vaccine candidates Pv-AMA-1 and Pv-MSP-119 on the immune response of malaria-naïve donors. Maturation of dendritic cells is altered by Pv-AMA-1 but not Pv-MSP-119, as observed by differential expression of cell surface markers. In addition, Pv-AMA-1 induced an increased production of MIP-1α/CCL3 and decreased production of TARC/CCL17 levels in both dendritic cells (DCs) and peripheral blood mononuclear cells (PBMCs). Finally, a significant pro-inflammatory response was elicited by Pv-AMA-1-stimulated PBMCs. These results suggest that the recombinant vaccine candidate Pv-AMA-1 may play a direct role on innate immune response and might be involved in parasite destruction...
Positive selection on the Plasmodium falciparum sporozoite threonine-asparagine-rich protein: Analysis of isolates mainly from low endemic areas [Gene. 2008 Jan 15] — (English)
The sporozoite threonine–asparagine-rich protein (STARP) of Plasmodium falciparum is an attractive target for a pre-erythrocytic stage malaria vaccine because both naturally acquired and experimentally induced anti-STARP antibodies can block sporozoite invasion of hepatocytes. To explore the extent of sequence variation, we surveyed nucleotide polymorphism across the entire gene, encompassing 2 exons and an intron, of 124 P. falciparum-infected blood samples from Thailand and 10 from 4 other endemic areas. In total 24 haplotypes were identified despite low-level nucleotide diversity at this locus. The mean number of nonsynonymous substitutions per nonsynonymous site (dN) significantly exceeded that of synonymous substitutions per synonymous site (dS), suggesting that the STARP gene has evolved under positive selection, probably from host immune pressure. The preponderance of conservative amino acid exchanges and a strongly biased T-nucleotide toward the third position of codons in repeat arrays have reflected simultaneous constraints on this molecule, probably from its respective unknown function and nucleotide composition. Sequence conservation in the STARP locus among clinical isolates from different disease endemic areas would not compromise vaccine incorporation...
Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection [Genes and Immunity advance online publication 17 January 2008] — (English)
We describe the haplotypic structure of the interferon regulatory factor-1 (IRF-1) locus in two West African ethnic groups, Fulani and Mossi, that differ in their susceptibility and immune response to Plasmodium falciparum malaria. Both populations showed significant associations between IRF-1 polymorphisms and carriage of P. falciparum infection, with different patterns of association that may reflect their different haplotypic architecture. Genetic variation at this locus does not therefore account for the Fulani-specific resistance to malaria while it could contribute to parasite clearance's ability in populations living in endemic areas. We then conducted a case–control study of three haplotype-tagging single nucleotide polymorphisms (htSNPs) in 370 hospitalised malaria patients (160 severe and 210 uncomplicated) and 410 healthy population controls, all from the Mossi ethnic group. All three htSNPs showed correlation with blood infection levels in malaria patients, and the rs10065633 polymorphism was associated with severe disease (P=0.02). These findings provide the first evidence of the involvement in malaria susceptibility of a specific locus within the 5q31 region, previously shown to be linked with P. falciparum infection levels...
The impact of HIV infection in pregnant women on variant specific immunity to malaria [Clin Vaccine Immunol. 2008 Jan 16] — (English)
HIV increases susceptibility to malaria infection, and this has been most clearly demonstrated in pregnant women. Variant surface antigens on the surface of erythrocytes infected with Plasmodium falciparum are major targets of protective immunity. We studied the impact of HIV infection on pregnant women's humoral immunity to variant surface antigens expressed by placental and pediatric isolates of P. falciparum. By flow cytometry, sera from HIV-infected women more frequently lacked antibodies to these antigens than did sera from HIV-uninfected women. This difference was similar in magnitude for pediatric (unadjusted OR = 6.36; 95% CI = 1.14, 35.32, p<0.05) and placental isolates (unadjusted OR = 6.47; 95% CI = 0.75, 55.64 p<0.10). We divided women into high and low responders, based on antibody levels. After adjusting for CD4 count, maternal age and gravidity, we found that HIV infected women more frequently had low responses to both pediatric (OR = 5.34; 95% CI: 1.23, 23.16; p=0.025) and placental isolates (OR = 4.14; 95% CI: 1.71, 10.02; p=0.002). Relative quantity of antibodies to both pediatric (p=0.035) and placental isolates (p=0.005) was lower in HIV infected women than uninfected women. HIV infection has a broad impact on variant specific immunity, which may explain the susceptibility of infected individuals to clinical malaria episodes...
Quantification of artemisinin in Artemisia annua extracts by H-NMR [Phytochem Anal. 2008 Jan 15] — (English)
Artemisinin is a polycyclic sesquiterpene lactone that is highly effective against multidrug-resistant strains of Plasmodium falciparum, the etiological agent of the most severe form of malaria. Determination of artemisinin in the source plant, Artemisia annua, is a challenging problem since the compound is present in very low concentrations, is thermolabile and unstable, and lacks chromophoric or fluorophoric groups. The ain of this study was to develop a simple protocol for the quantification of artemisinin in a plant extract using an 1H-NMR method. Samples were prepared by extraction of leaf material with acetone, treatment with activated charcoal to remove chlorophylls and removal of solvent. 1H-NMR spectra were measured on samples dissolved in deuterochloroform with tert-butanol as internal standard. Quantification was carried out using the 5.864 signal of artemisinin and the 1.276 signal of tert-butanol. The method was optimised and fully validated against a reference standard of artemisinin. The results were compared with those obtained from the same samples quantified using an HPLC-refractive index (RI) method. The 1H-NMR method gave a linear response for artemisinin within the range 9.85-97.99 mm (r2 = 0.9968). Using the described method, yields of artemisinin in the range 0.77-1.06% were obtained from leaves of the A. annua hybrid CPQBA × POP, and these values were in agreement with those obtained using an HPLC-RI...
Drug-regulated gene expression of Plasmodium falciparum P-glycoprotein homologue 1: a putative role for nuclear receptors [Antimicrob Agents Chemother. 2008 Jan 14] — (English)
Acquired resistance to therapeutic agents is a major clinical concern in the prevention/treatment of malaria. The parasite has developed resistance to specific drugs through two mechanisms: mutations in target proteins such as dihydrofolate reductase and bc1 complex for antifolates and nathoquinones respectively and alterations in parasite predicted transporter molecules such as p-glycoprotein homologue 1 (Pgh1) and PfCRT. Alterations in the expression of Pgh1 have been associated with modified susceptibility to a range of unrelated drugs. The molecular mechanism(s) that are responsible for this phenotype are unknown. We have shown previously (21) that the anticonvulsant phenobarbitone (PB) can induce reduced susceptibility to chloroquine (CQ) in Plasmodium falciparum, and in the current study we provide the first evidence for a molecular mechanism underlying this phenomenon. We demonstrate that pre-treatment with PB can elicit decreased susceptibility to CQ in both CQ-resistant and CQ-sensitive parasite lines, and that this is associated with increased expression of the drug transporter Pgh1, but not PfCRT. Furthermore we have investigated the proximal promoter regions from both pfmdr1 and pfcrt, and identified a number of putative binding sites for nuclear receptors with sequence similarities to regions known to be activated by phenobarbitone in mammals. Whole genome analysis has revealed a putative nuclear receptor gene, providing the first evidence that nuclear-receptor mediated responses to drug exposure may be a mechanism of gene regulation in Plasmodium falciparum...
Malaria and oral health [Oral Diseases, doi:10.1111/j.1601-0825.2007.01389.x] — (English)
Half of the world population resides in malaria-prone areas, and the disease is responsible for more than a million deaths annually. This is apart from the economic impact of the disease through resources expended towards treatment and prevention and the loss of manpower. In addition to the overt clinical signs and symptoms, the association of malaria with other diseases such as tuberculosis and HIV infection has been described. However few studies have attempted to investigate its relationship to oral diseases. This review provides an overview of the relevance of malaria to the mouth and adjacent structures. The need for further research is also emphasized...
Dissecting the components of quinine accumulation in Plasmodium falciparum [Molecular Microbiology, doi:10.1111/j.1365-2958.2008.06108.x] — (English)
Although quinine, the active ingredient of chinchona bark, has been used in the treatment of malaria for several centuries, there is little information regarding the interactions of this drug with the human malaria parasite Plasmodium falciparum. To better understand quinine's mode of action and the mechanism underpinning reduced responsiveness, we have investigated the factors that contribute to quinine accumulation by parasites that differ in their susceptibility to quinine. Interestingly, passive distribution, in accordance with the intracellular pH gradients, and intracellular binding could account for only a small fraction of the high amount of quinine accumulated by the parasites investigated. The results of trans-stimulation kinetics suggest that high accumulation of quinine is brought about by a carrier-mediated import system. This import system seems to be weakened in parasites with reduced quinine susceptibility. Other data show that polymorphisms within PfCRT are causatively linked with an increased verapamil-sensitive quinine efflux that, depending on the genetic background, resulted in reduced quinine accumulation. The polymorphisms within PfMDR1 investigated did not affect quinine accumulation. Our data are consistent with the model that several factors, including acidotropic trapping, binding to intracellular sites and carrier-mediated import and export transport systems, contribute to steady-state intracellular quinine accumulation...
Probing the Role of Parasite-Specific, Distant Structural Regions on Communication and Catalysis in the Bifunctional Thymidylate Synthase-Dihydrofolate Reductase from Plasmodium falciparum [Biochemistry, ASAP Article 10.1021/bi701624u S0006-2960(70)01624-0, Web Release Date: January 12, 2008] — (English)
Plasmodium falciparum thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in nucleotide biosynthesis and a validated molecular drug target in malaria. Because P. falciparum TS and DHFR are highly homologous to their human counterparts, existing active-site antifolate drugs can have dose-limiting toxicities. In humans, TS and DHFR are two separate proteins. In P. falciparum, however, TS-DHFR is bifunctional, with both TS and DHFR active sites on a single polypeptide chain of the enzyme. Consequently, P. falciparum TS-DHFR contains unique distant or nonactive regions that might modulate catalysis: (1) an N-terminal tail and (2) a linker region tethering DHFR to TS, and encoding a crossover helix that forms critical electrostatic interactions with the DHFR active site. The role of these nonactive sites in the bifunctional P. falciparum TS-DHFR is unknown. We report the first in-depth, pre-steady-state kinetic characterization of the full-length, wild-type (WT) P. falciparum TS-DHFR enzyme and probe the role of distant, nonactive regions through mutational analysis. We show that the overall rate-limiting step in the WT P. falciparum TS-DHFR enzyme is TS catalysis. We further show that if TS is in an activated (liganded) conformation, the DHFR rate is 2-fold activated, from 60 s-1 to 130 s-1 in the WT enzyme. The TS rate is also reciprocally activated by ~1.5-fold if DHFR is in an activated, ligand-bound conformation. Mutations to the linker region affect neither catalytic rate nor domain-domain communication. Deletion of the N-terminal tail, although in a location remote from the active site, decreases the DHFR single rate and the bifunctional TS-DHFR rate by a factor of 2. The 2-fold activation of the DHFR rate by TS ligands remains intact, although even the activated N-terminal mutant has just half the DHFR activity of the WT enzyme. However, the reciprocal communication between TS active site and DHFR ligands is impaired in N-terminal mutants. Surprisingly, deletion of the analogous N-terminal tail in Leishmania major TS-DHFR causes a 3-fold enhancement of the DHFR rate from ~14 s-1 to ~40 s-1. In summary, our results demonstrate a complex interplay of domain-domain communication and nonactive-site modulation of catalysis in P. falciparum TS-DHFR. Furthermore, each parasitic TS-DHFR is activated by unique mechanisms, modulated by their nonactive site regions. Finally, our studies suggest the N-terminal tail of P. falciparum TS-DHFR is a highly selective, novel target for potential antifolate development in malaria...
Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase [J. Med. Chem., 10.1021/jm7010673, Web Release Date: January 12, 2008] — (English)
Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5′-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5′-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure–activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6-N-methylamino, and 6-N,N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5′-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6-N-Methylamino and 6-N,N-dimethylamino uridine derivatives exhibited moderate antimalarial activities...
2-Oxotetrahydroquinoline-Based Antimalarials with High Potency and Metabolic Stability [J Med Chem. 2008 Jan 17] — (English)
We report a series of novel inhibitors of protein farnesyltransferase based on the 2-oxotetrahydroquinoline scaffold. We developed an efficient synthesis of these compounds. These compounds show selective inhibtion of the malaria versus human farnesyltransferase and inhibit the growth of the malaria parasite in the low nanomolar range. Some of the compounds are at least an order of magnitude more stable to metabolic degradation than the corresponding tetrahydroquinolines...
Comparative study of interactions between chloroquine and chlorpheniramine or promethazine in healthy volunteers [Annals of Tropical Medicine and Parasitology, Volume 102, Number 1, January 2008 , pp. 3-9(7)] — (English)
Although, in in-vitro and limited in-vivo studies, chlorpheniramine (CP) and promethazine (PR) have each been shown to reverse chloroquine (CQ) resistance, the pharmacokinetic basis of this reversal has not been fully elucidated. In the present study, 15 healthy volunteers were randomly allotted to receive standard doses of CQ alone or in combination with CP or PR. Blood samples were collected from each volunteer at 21 time-points, from immediately before to 168 h after the initial dose. These samples were used to follow the changes in the plasma and erythrocytic concentrations of CQ. The ratio between the mean maximum CQ concentration in the erythrocytes and that in the plasma was 4.2 for the volunteers given CQ alone, 7.3 in those given CQ-CP, and 3.2 in those given CQ-PR. CP significantly enhanced the erythrocytic accumulation of CQ, increasing the maximum CQ concentration observed in the erythrocytes by 24% (P = 0.02). The bio-availability of CQ was also significantly increased in the presence of CP, with the mean value for the area under the curve, of erythrocytic concentration v. time, increasing from 99,921 to 214,516 ng/ml.h (P=0.001). The mean half-life of CQ in the erythrocytes also increased when CP was used, from 51 to 100 h, but this change was not statistically significant (P=0.83). In contrast to CP, PR had no statistically significant effect on the disposition of CQ...
The antischistosomal efficacies of artesunate-sulfamethoxypyrazine-pyrimethamine and artemether-lumefantrine administered as treatment for uncomplicated, Plasmodium falciparum malaria [Annals of Tropical Medicine and Parasitology, Volume 102, Number 1, January 2008 , pp. 39-44(6)] — (English)
Although artemisinin and its derivatives are widely used for the treatment of malaria, they also have antischistosomal activity. In a small study in eastern Sudan, the effects of the treatment of uncomplicated, Plasmodium falciparum malaria with artesunate-sulfamethoxypyrazine-pyrimethamine (AS-SMP) and artemether-lumefantrine (AT-LU) on co-infections with Schistosoma mansoni were therefore investigated. Faecal samples from 14 of the 306 patients screened on presentation, at the start of a clinical trial of antimalarial treatment, were found to contain Schistosoma mansoni eggs. For the treatment of their malaria, the 14 egg-positive cases, who were aged 6-40 years (mean = 13.7 years), were each subsequently treated with three tablets of a fixed combination of AS-SMP, with a 12-h (six patients) or 24-h interval (five patients) between each tablet, or with six doses of AT-LU given over 3 days. When checked 28 and 29 days after the initiation of treatment, all 14 patients were found stool-negative for schistosome eggs. These results indicate that AS-SMP and AT-LU are currently very effective treatments not only for uncomplicated, P. falciparum malaria but also for S. mansoni infections...
Prepared in cooperation with WHO ANGOLA INFO.
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